Clinical trial NCT02765854
Conditions: Recurrent Plasma Cell Myeloma Refractory Plasma Cell Myeloma
Sponsor: Emory University
Start date: 2016-09-01; Completion date: 2023-05-23
Enrollment: 70 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase II trial studies how well ixazomib and dexamethasone or ixazomib, dexamethasone, and lenalidomide work based on the presence of the rearrangement of a gene called nuclear factor of kappa light polypeptide gene enhancer in B-cells 2 (NFKB2) in treating patients with multiple myeloma that has returned after a period of improvement or does not respond to treatment. Ixazomib may stop the growth of cancer cells by blocking enzymes called proteasomes needed for cell growth. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Lenalidomide may stimulate the immune system against cancer cells and may also prevent the growth of new blood vessels that tumors need to grow. It is not yet known whether ixazomib and dexamethasone, or ixazomib, dexamethasone, and lenalidomide are more effective in treating multiple myeloma.

Detailed description:
PRIMARY OBJECTIVES:

To test whether the NFKB2 rearrangement can guide the selection of treatment (ixazomib \[ixazomib citrate\] plus dexamethasone \[Id\] or ixazomib plus lenalidomide and dexamethasone \[IRd\]) by conducting the following comparisons:

I. To compare the response rate at 4 cycles between patients treated with Id and patients treated with IRd and confirm the lack of significant difference in overall response.

II. To compare the response rate at 4 cycles between non-rearranged and rearranged NFKB2 treated with Id and confirm that NFKB2 rearrangement is associated with reduce response rate.

III. To compare the responses rate at 4 cycles of patients with rearranged NFKB2 treated with Id or IRd and confirm that adding lenalidomide increases the response rate in this population.

SECONDARY OBJECTIVES:

I. To determine time to treatment failure (TTF).

II. To determine the frequency and severity of adverse events (AE) in IRd treated cohort.

III. To identify novel transcribed mutations associated with Id and IRd resistance in patients with multiple myeloma (MM).

IV. To determine the prevalence of NFKB2 rearrangement in relapsed/refractory MM patients screened in the study.

V. To determine the prevalence of NFKB2 rearrangement according to the type of previous therapies received in all patients screened in the study.

VI. To determine the toxicity profile of the study drugs according to the presence of NFKB2 rearrangement.

VII. Delineate transcribed mutations associated with relapse or refractoriness to Id or IRd treatment by ribonucleic acid (RNA)-sequencing.

OUTLINE:

ARM A (UNMUTATED NFKB2 REARRANGEMENT): Patients receive ixazomib orally (PO) on days 1, 8, and 15 and dexamethasone PO on days 1, 8, 15, and 22.

Patients with mutated NFKB2 rearrangement are randomized in to 1 of 2 treatment arms.

ARM B (MUTATED NFKB2 REARRANGEMENT): Patients receive ixazomib and dexamethasone as in arm A.

ARM C (MUTATED NFKB2 REARRANGEMENT): Patients receive ixazomib and dexamethasone as in arm A and lenalidomide PO daily on days 1-21.

In all arms, cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients may proceed to autologous stem cell transplant after 4 cycles of treatment.

After completion of study, patients are followed up monthly.

Arms: arm 1: MUTATED NFKB2 REARRANGEMENT: Patients receive ixazomib and dexamethasone as in arm A. arm 2: MUTATED NFKB2 REARRANGEMENT: Patients receive ixazomib and dexamethasone as in arm A and lenalidomide PO daily on days 1-21. arm 3: UNMUTATED NFKB2 REARRANGEMENT: Patients receive ixazomib and dexamethasone.
Interventions: intervention 1: Dexamethasone intervention 2: Ixazomib intervention 3: Lenalidomide
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Given PO

Protocol documents:
Prot_SAP_001.pdf: 
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CLINICAL STUDY PROTOCOL
Phase II trial of IXAZOMIB and Dexamethasone versus IXAZOMIB, Dexamethasone and
Lenalidomide, Randomized with NFKB2 rearrangement.
(Proteasome Inhibitor NFKB2 Rearrangement Driven Trial, PINR)
Indication:
Relapsed/Refractory Multiple Myeloma
Phase:
II
Protocol History
Original DRAFT
6October.2014
Amendment v1.1
12 October 2015
Amendment v1.2
10 June 2016
Amendment v1.3
09 September 2016
Amendment v1.4
28 December 2016
Amendment v 1.5
15 November 2017
Amendment v 1.6
12 March 2020
Amendment v 1.7
09 December 2022
MMRC Lead Investigator and Study Center:
Leon Bernal-Mizrachi, MD (PI)
Sagar Lonial, MD (SubI)
Jonathan Kaufman, MD (SubI)
Ajay Nooka, MD (SubI)
Winship Cancer Institute of Emory University 1365 Clifton Road
NE, Bldg. C
Atlanta, Georgia 30322
Telephone: (404) 778-1900
E mail: lbernal@emory.edu
MMRC Participating Academic Investigators and Institutions:
Ravi Vij, MD
Siteman Cancer Center, Washington University in St. Louis
Erica Leigh Campagnaro, MD
University of Michigan
Multi-Site Coordinators for Participating Academic Investigators and Institutions:
Monica Goings, MA
Emory University, Winship Cancer Institute


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Phone 404-778-5747
Email: monica.s.goings@emory.edu
Latrisha Moore
Emory University, Winship Cancer Institute
Phone 404-712-0425
E-mail: Latrisha.moore@emory.edu
This is an investigator-initiated study.


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PROTOCOL SUMMARY
Study Title: Phase II trial of ixazomib and Dexamethasone versus ixazomib, dexamethasone and
lenalidomide, randomized with NFKB2 rearrangement. (Proteasome Inhibitor NFKB2
rearrangement Driven Trial, PINR)
Phase: II
Number of Patients: 90
Study Objectives
Primary

The primary objective of the study is to test whether the NFKB2 rearrangement can guide
the selection of treatment (ixazomib plus dexamethasone (Id) or ixazomib plus
lenalidomide and dexamethasone (IRd)) by conducting the 3 following comparison

To compare the response rate at 4 cycles between non-rearranged NFKB2- patients
treated with Id and patients treated with IRd and confirm the lack of significant difference
in overall response.

To compare the response rate at 4 cycles between non-rearranged and rearranged
NFKB2 treated with Id and confirm that NFKB2 rearrangement is associated with reduce
response rate

To compare the responses rate at 4 cycles of patients with rearranged NFKB2 treated with
Id or IRd and confirm that adding lenalidomide increases the response rate in this
population
We assume that adding lenalidomide in the treatment among non-rearranged patients
will not further improve the response rate, because our preliminary data allow us to expect
that that the response rate of non-rearranged patients with Id will reach 95% and has little
room to improve. Therefore, the arm non-rearranged NFKB2 gene treated with IRd has been
omitted in order to save resources. Our preliminary data has shown that adding lenalidomide
to bortezomib in rearranged NF-kB2 patients, another inhibitor of the proteasome,
resulted in response rates of 95% and published phase 1/2 data has shown that oral
ixazomib in combination with lenalidomide and dexamethasone in newly diagnosed
multiple myeloma achieved a 92% ORR; hence, has little room for improvement either.
(Kumar SK et al Lancet Oncology 2014) .
Secondary

To compare response rates between arms at 8 cycles of treatment

To determine time to treatment failure (TTF)

To determine the frequency and severity AE in IRd treated cohort

To identify novel transcribed mutations associated with Id and IRd resistance
in patients with MM.


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
To determine the prevalence of NFKB2 rearrangement in Relapsed/Refractory
MM patients screened in the study.

To determine the prevalence of NFKB2 rearrangement according to the type of
previous therapies received in all patients screened in the study.

To determine the toxicity profile of the study drugs according to the presence
of NFKB2 rearrangement.

Delineate transcribed mutations associated with relapse or refractoriness to Id or
IRd treatment by RNA-sequencing.
Overview of Study Design:
This is a multicenter open-label, 3-arm, phase II clinical trial to study the differential effect in
the treatment efficacy in term of response rate between treatment (Id vs IRd) and plasma cells
NFKB2 rearrangement status in relapsed patients with multiple myeloma.
Eligible patients with relapsed MM will be randomized in a 1:1 fashion according to their
NFKB2 rearrangement status. Patients without NFKB2 rearrangement will receive ixazomib
and dexamethasone. On the other hand, patients with NFKB2 rearrangement will be
subsequently randomized in a 2:2 fashion to receive ixazomib and dexamethasone or ixazomib,
dexamethasone and lenalidomide. Patients will be administered ixazomib orally at a dose of
4 mg on Days 1, 8, and 15 during a 28-day treatment cycle. Dexamethasone will be
administered orally at a dose of 40mg daily on Days, 1, 8, 15 and 22 of a 28 day treatment
cycle. In the IRd arm, lenalidomide will be administered orally at a dose of 25 mg daily on
Days 1-21. (Lenalidomide starting dose to be adjusted according to baseline renal function
according to Package Insert guideline). Patient without unacceptable toxicity and with at least
minimal response should continue treatment until completion of 8 cycles.
Study overview diagram
Patients without NFKB2 rearrangement in their plasma cells will be treated with Id. Patients
carrying NFKB2 rearrangement in their plasma cells will be randomized on a 2:2 ratio to
either Id or IRd using a randomization table. The study is unblinded and both patient and
investigator will know the identity of each patient’s study treatment.


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Study Population:
Inclusion Criteria:
Each patient must meet all of the following inclusion criteria to be enrolled in the
study:
1. Male or female patients 18 years or older.
2. 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.
3. Females of childbearing potential (FCBP)* must have a negative serum or urine
pregnancy test with a sensitivity of at least 50 mIU/mL within 10 – 14 days prior
to and again within 24 hours of starting Id (ixazomib and dexamethasone) or IRd
(ixazomib, lenalidomide and dexamethasone) and must either commit to
continued abstinence from heterosexual intercourse or begin TWO acceptable
methods of birth control, one highly effective method and one additional effective
method AT THE SAME TIME, at least 28 days before she starts taking
lenalidomide through 90 days after the last dose of study drug. FCBP must also
agree to ongoing pregnancy testing. Men must agree to use a latex condom during
sexual contact with a FCBP even if they have had a vasectomy from the time of
signing the informed consent form through 90 days after the last dose of study
drug. In the event that the male patients choose to agree to practice true
abstinence, this must follow the timelines detailed above. All patients assigned
to the lenalidomide treatment group must be registered in and must comply with
all requirements of the Revlimid REMS™program.
4. Multiple myeloma diagnosed according to standard criteria either currently or at
the time of initial diagnosis.
5. The patient has confirmed relapsed or refractory MM.
6. For patients that relapse following a response to prior treatment with bortezomib
or carfilzomib, six months must have elapsed since the last dose of treatment.
7. The patient has received 1 to 3 prior treatment regimens.
8. Patients must have measurable disease defined by at least 1 of the following


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measurements:
Serum M-protein ≥1.0 g/dL (≥10 g/L) for an IgG myeloma, ≥0.1 g/dL
for an IgD myeloma or 0.5 g/dL (≥5g/L) for an IgA myeloma
Urine light chain ≥200 mg/24 hours
Serum free light chain ≥10 mg/dL provided the FLC ratio is abnormal.
Patients with oligo- or non-secretory disease must have bone marrow
involvementwith at least 30% plasmacytosis on aspiration.
9. Eastern Cooperative Oncology Group (ECOG) performance status and/or other
performance status 0, 1, or 2.
10. Patients must meet the following clinical laboratory criteria:

Absolute neutrophil count (ANC) 1,000/mm3 and platelet count
75,000/mm3. In the case that platelets are between 50,000 -75,000, the
patient can be enrolled if the plasma cell count in the bone marrow is
superior to ≥50%. To meet this hematological eligibility transfusion
support are not allowed within 7 days before study enrollment.

Total bilirubin 1.5 the upper limit of the normal range (ULN).

Alanine aminotransferase (ALT) and aspartate aminotransferase
(AST) 2.5 ULN.

Serum creatinine ≤2.5 mg/dL or a calculated creatinine clearance 50
mL/min.
* A female of childbearing potential is a sexually mature woman who: 1) has not undergone
a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for
at least 24 consecutive months.
Exclusion Criteria
1. The patient is refractory to carfilzomib or bortezomib. (Refractory is defined as
patients who never achieved a response and progressed while on carfilzomib or
bortezomib or within 60 days of completing treatment).
2. Prior treatment with any investigational proteasome inhibitor within 6 months of
study entry.


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3. Female patients who are breast feeding or have a positive serum pregnancy test during
the screening period.
4. Failure to have fully recovered (ie, > Grade 1 toxicity) from the reversible effects of
prior chemotherapy.
5. Diarrhea > Grade 1 according to NCI CTCAE v4.03
6. Prior chemotherapy and/or immunotherapy within 14 days before enrollment. Major
surgery within 14 days before enrollment and minor surgery within 7 days prior to
Cycle 1 Day 1
7. Radiotherapy within 14 days before enrollment. If the involved field covered ≤5% of
the bone marrow reserve, the patient may be enrolled irrespective of the end date of
radiotherapy.
8. Central nervous system involvement.
9. Infection requiring systemic antibiotic therapy or other serious infection within 14
days before study enrollment.
10. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled
hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure,
unstable angina, or myocardial infarction within the past 6 months.
11. Systemic treatment, within 14 days before the first dose of ixazomib, with strong
CYP3A
inducers
(rifampin,
rifapentine,
rifabutin,
carbamazepine,
phenytoin,
phenobarbital), or use of Ginkgo biloba or St. John’s wort.
12. Active hepatitis B or C virus infection, or known human immunodeficiency virus
(HIV) positive.
13. Any serious medical or psychiatric illness that could, in the investigator’s opinion,
potentially compromise the patient’s ability to understand the patient information, to
give informed consent, to comply with the treatment according to this protocol or
complete the study.
14. Diagnosed or treated for another malignancy within 2 years before study enrollment
or previously diagnosed with another malignancy and have any evidence of residual


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disease. Patients with non-melanoma skin cancer or carcinoma in situ of any type are
not excluded if they have undergone complete resection.
15. Patient has ≥Grade 2 peripheral neuropathy or neuropathy with pain, regardless of
grade that is seen on clinical examination during the screening period.
16. Known intolerance to IMiDs.
17. History of allergic reaction/hypersensitivity to any of the study medications, their
analogues or excipients in the various formulations.
18. Known GI disease or GI procedure that could interfere with the oral absorption or
tolerance of ixazomib or lenalidomide, including difficulty swallowing.
19. Participation in other clinical trials, including those with other investigational agents
not included in this trial, such as monoclonal antibodies, within 30 days of the start
of this trial and throughout the duration of this trial.
20. Corticosteroid doses > 10 mg/day of prednisone or equivalent within 14 days prior
to Cycle 1 Day 1.
21. Autologous or allogeneic stem cell or bone marrow transplant within 3 months prior
to Cycle 1 Day 1.
22. Cytotoxic therapy within 21 days prior to Cycle 1 D1
23. Patients that have previously been treated with ixazomib, or participated in a study
with ixazomib whether treated with ixazomib or not.
Duration of Study: The study duration for an individual patient will include a screening
period for inclusion of up to 21 days, the treatment period may continue until disease
progression, unacceptable adverse reaction or other reason for discontinuation. After study
treatment discontinuation an end of treatment (EOT) visit will be done at 30 days to assess
safety. Patients who discontinue treatment for reasons other than progression of disease will
be followed monthly until progression or initiation of subsequent therapy.


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STUDY OVERVIEW DIAGRAM


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SCHEDULE OF EVENTS
Screen
Cycle 1
Each cycle is 28 days
Cycle 2-8
Each cycle is 28 days
Cycle 9+
Each cycle
is 28 days
End of
Treatme
nt
Post
Study
Follow
Up
PROCEDURES
-21d to
-1d
Day
1
Day
8
Day
15
Day
22
Day
1
Day
8
Day
15
Day
22
Day1
Window
± 1
± 1
± 1
± 1
± 1
± 1
± 1
± 1
Informed Consent
X
Medical History, Demographics
X
Concomitant Medications
X
X
X
X
X
X
PE, Height1, Weight, ECOG
X
X
X
X
X
Toxicity Evaluation
X
X
X
X
Vital Signs (HR, Temp, BP)
X
X
X
X
X
12-lead ECG3
X
CBC with differential4
X
X
X
X
X
X
Serum Chemistry5
X
X
X
X
X
X
Microscopic Urinalysis
X
Neurological exam (FACT/GOG
Ntx)6
X
X
X
X
PT/PTT
X
TSH
X
Pregnancy test [FCBP] 2 (serum or
urine)
X
X
X
X
X
X
X2
X
Extramedullary disease7
X
X
Skeletal Survey 8
X
X8
X
Bone Marrow Aspiration/Biopsy9
X
X9
X
Myeloma-specific lab tests10
X
X
X
X
X
Blood for correlative labs11
X
X
X


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Screen
Cycle 1
Each cycle is 28 days
Cycle 2-8
Each cycle is 28 days
Cycle 9+
Each cycle
is 28 days
End of
Treatme
nt
Post
Study
Follow
Up
PROCEDURES
-21d to
-1d
Day
1
Day
8
Day
15
Day
22
Day
1
Day
8
Day
15
Day
22
Day1
ixazomib Administration
X
X
X
X
X
X
Days 1, 8, 15
Dexamethasone
X
X
X
X
X
X
X
X
Days 1, 8,
15, 22
Lenalidomide Administration (IRd
arm only)
Days 1 – 21
IRd Arm only
Days 1 – 21
IRd Arm only
Days 1 – 21
IRd Arm only
Follow for PD and survival
X12
1.
Measured at screening only.
2.
ARM A and B: FCBP on this arm will not be taking lenalidomide. Females of reproductive potential in these arms must have 2 negative
pregnancy tests before initiating therapy. The first test should be performed within 10-14 days, and the second test within 24 hours prior to the
first dose of ixazomib. A pregnancy test will be performed at day one on all future cycles or every 14 days if she has irregular menstruation.
ARM C: This arm will be taking lenalidomide. FCBP must have 2 negative pregnancy tests before initiating therapy. The first test should be
performed within 10-14 days, and the second test within 24 hours prior to prescribing lenalidomide and ixazomib. Repeat pregnancy test every
week for the first 4 weeks and then every 28 days while on therapy and during interruptions in therapy and 28 days following discontinuation
of lenalidomide. Women with irregular menstruation must have pregnancy testing every 14 days while on therapy and during interruptions and
14 and 28 days after discontinuation of lenalidomide. * FCBP - A female of childbearing potential is a sexually mature woman who: 1) has not
undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months.
3.
ECG (12-Lead) should be performed at screening and read locally.
4.
CBC to be performed and reviewed by clinician within 24 hours of day of dosing (first day of each cycle), on Day 15 of Cycle 1 and more
frequently if clinically indicated. Alternately, a STAT CBC may be drawn on day of dosing however should be reviewed prior to administration
of investigational product(s).
5.
Serum Chemistry to be performed and reviewed by the investigator within 24 hours of day of dosing (first day of each cycle). Alternately,
a STAT CMP may be drawn on day of dosing however should be reviewed by the investigator prior to administration of investigational
product(s). Chemistry includes: glucose, calcium, albumin, total protein, sodium, potassium, CO2, chloride, BUN, creatinine, ALP, ALT, AST,
bilirubin, uric acid, magnesium, phosphorus, LDH. Weight and serum creatinine will be used to calculate creatinine clearance by Cockroft-Gault
equation (see appendix 16.2).


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6. FACT GOG NTx: Neurological assessment required at screening and Day 1 of Cycle 2+. Results should be compared with prior
assessment for the presence of peripheral neuropathy or other neurotoxicity.
7. Extramedullary Disease: Assess by physical exam and/or radiologic evaluation as clinically indicated. Disease that can be
assessed by physical exam should be evaluated on Day 1 of each cycle. Disease that can be assessed by radiologic evaluation should
be assessed according the IMWG criteria for evaluation of response. This may include computerized tomography (CT) scan,
ultrasound, positron emission tomography [PET]/CT or MRI. The same method of assessment should be used at each evaluation
8. Skeletal survey (including skull, all long bones, pelvis and chest) with tumor measurements if plasmacytomas present. Also
required if previous survey >28 days from study entry and at any time when clinically indicated to confirm progression according
to IMWG criteria. Subjects should repeat the skeletal survey at minimum every 12 months as SOC, or as clinically indicated.
9. A bone marrow biopsy and aspiration is required at screening for cytogenetic analysis by fluorescence in situ hybridization
(FISH), standard karyotyping, % plasma cells, morphology, NFKB2 rearrangements and correlative studies. Repeat bone marrow
aspirate if CR (at any time during study participation), at relapsed, or at progression, stringent complete response (sCR) is suspected
to confirm achievement of response according to IMWG criteria and End of therapy.
10. Myeloma lab tests: β2 Microglobulin at baseline, serum and 24 hours urine immunoelectrophoresis, serum immunoglobulin
assay, Serum/urine immunofixation and serum free light chain with kappa/lambda ratio to be performed at baseline, every cycle
prior to study treatment administration thereafter and at end of treatment (if last tests were > 4 weeks) and for patients who
discontinue therapy for reasons other than progression, MM labs will be repeated every month until progression or initiation of
subsequent therapy. Response assessment will be done at the beginning of every cycle.
11. One 5-mL blood sample will be collected during screening or on Cycle 1, Day 1 before the first dose of Id or IRd is administered
to assess potential biomarkers that predict response to Id vs IRd. One 5-mL blood sample will be collected on Cycle 4 Day 1 and
One 5-mL blood sample will be collected at progression. If progression/relapse occurs before Cycle 4, then only the progression
sample is needed. Details regarding the preparation, handling, and shipping of samples are provided in the Study Manual.
12. After study treatment discontinuation an end of treatment (EOT) visit will be done at 30 days to assess safety. Patients who
discontinue treatment for reasons other than progression of disease will be followed monthly until progression or initiation of
subsequent therapy.
*Additional tests to be performed at the beginning of each cycle and at any reasonable time point during treatment if indicated for
monitoring of drug profile/safety or, for disease/health status at the discretion of the clinical investigator.


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TABLE OF CONTENTS
CLINICAL STUDY PROTOCOL ...................................................................................................1
Phase II trial of IXAZOMIB and Dexamethasone versus IXAZOMIB, Dexamethasone and
Lenalidomide, Randomized with NFKB2 rearrangement......................................................1
PROTOCOL SUMMARY ...............................................................................................................3
Exclusion Criteria.........................................................................................................................6
SCHEDULE OF EVENTS.............................................................................................................10
TABLE OF CONTENTS ...............................................................................................................13
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ................................................19
1. BACKGROUND AND STUDY RATIONALE..................................................................21
1.1 Scientific Background ..........................................................................................................21
1.1.1
Multiple Myeloma .......................................................................................................21
1.1.2
Risk stratification in Multiple Myeloma. ....................................................................21
1.2 Clinical Experience With Lenalidomide and Dexamethasone in Newly Diagnosed Multiple
Myeloma...............................................................................................................................22
1.3 Multiple Myeloma and Response to Proteasome Inhibitor. .................................................23
1.4 Clinical Experience of BORTEZOMIB [Bortezomib] Plus Lenalidomide and
Dexamethasone.....................................................................................................................24
Table 1-1. Best confirmed response ...........................................................................................26
Table 1-2. Selected Adverse Events...........................................................................................27
1.5 Ixazomib...............................................................................................................................28
1.5.1
Preclinical Experience .................................................................................................28
1.5.2
Clinical Experience......................................................................................................28
1.5.3
Pharmacokinetics and Drug Metabolism.....................................................................30
1.5.4
Clinical Trial Experience Using the Oral Formulation of ixazomib ...........................31
Table 1-1
Clinical Studies of Oral ixazomib...........................................................................32
1.5.5
Overview of the Oral Formulation of ixazomib..........................................................33
1.5.6
Relapsed and/or Refractory Multiple Myeloma ..........................................................36
1.5.7
Newly Diagnosed Multiple Myeloma (NDMM).........................................................37
1.5.8
Clinical Trial Experience Using the Intravenous Formulation of
ixazomib.............39
1.6 NFKB2 Biomarker ...............................................................................................................39
1.6.1
Somatic Rate of NFKB2 rearrangement......................................................................40
1.6.2
Origin of NFKB2 break point......................................................................................40
1.6.3
Somatic NFKB2 rearrangement and response to Bortezomib and dexamethasone
treatment...............................................................................................................................40


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1.6.4
In vitro data..................................................................................................................42
1.6.4.2
NFKB2 is important in bortezomib mediated apoptosis. ............................................44
1.6.4.2.1 NFKB2 promotes the complex formation of p62/FADD and .....................................44
caspase-8 to facilitate caspase 8 processing. ..............................................................................44
1.7 Study Rationale ....................................................................................................................46
2. STUDY OBJECTIVES ........................................................................................................46
2.1 Primary Objectives...............................................................................................................46
2.2 Secondary Objectives...........................................................................................................47
2.3 Hypothesis:...........................................................................................................................47
3. STUDY ENDPOINTS..........................................................................................................48
3.1 Primary Endpoints................................................................................................................48
3.2 Secondary Endpoints............................................................................................................48
4. STUDY DESIGN.................................................................................................................48
4.1 Overview of Study Design ...................................................................................................48
4.2 Treatment Assignment..........................................................................................................49
4.3 Number of Patients...............................................................................................................50
4.4 Duration of Study .................................................................................................................50
5. STUDY POPULATION.......................................................................................................52
5.1 Inclusion Criteria..................................................................................................................52
5.2 Exclusion Criteria.................................................................................................................53
6. STUDY DRUG ....................................................................................................................55
6.1 Description of Investigational Agents..................................................................................55
6.1.1
Ixazomib Capsules.......................................................................................................55
6.2 Study Drug Administration ..................................................................................................56
6.2.1
Ixazomib Administration.............................................................................................56
6.2.2
Ixazomib Destruction ..................................................................................................56
6.3 Lenalidomide........................................................................................................................56
6.3.1
Lenalidomide Administration......................................................................................57
6.4 Dexamethasone.....................................................................................................................57
7. DOSE-MODIFICATION.....................................................................................................57
7.1 Dose Reduction Steps...........................................................................................................58
7.1.1
Ixazomib Dose Reduction Steps..................................................................................58
7.1.2
Lenalidomide Dose Reduction Steps...........................................................................58
7.1.3
Dexamethasone Dose Reduction Steps .......................................................................58
7.2 Dose Modification Guidelines during A Cycle Of Therapy ................................................59
7.2.1
Ixazomib and Lenalidomide dose modification Guidelines During a cycle of therapy


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7.3 Dexamethasone dose modification Guidelines ....................................................................62
7.4 Criteria for Initiation of A New Cycle of Therapy...............................................................63
7.5 Concomitant Medications.....................................................................................................64
7.5.1
Excluded Concomitant Medications and Procedures ..................................................64
7.6 Permitted Concomitant Medications and Procedures...........................................................64
7.7 Required/Recommended Concomitant Therapy ..................................................................65
7.8 Precautions and Restrictions.................................................................................................65
7.9 Pregnancy .............................................................................................................................66
7.9.1
Females........................................................................................................................66
7.9.2
Males ...........................................................................................................................67
7.10
Management of Clinical Events ..................................................................................67
7.10.1
Thromboembolism Prophylaxis ..................................................................................67
7.10.2
Prophylaxis against Risk of Reactivation of Herpes Infection....................................68
7.10.3
Nausea and/or Vomiting..............................................................................................68
7.10.4
Diarrhea .......................................................................................................................68
7.10.5
Erythematous Rash With or Without Pruritus.............................................................68
7.10.6
Thrombocytopenia.......................................................................................................69
7.10.7
Neutropenia .................................................................................................................69
7.10.8
Fluid Deficit.................................................................................................................69
7.10.9
Hypotension.................................................................................................................70
7.10.10
Posterior Reversible Encephalopathy Syndrome ...................................................70
7.10.11
Transverse Myelitis ................................................................................................70
7.11
Preparation, Reconstitution, and Dispensing...............................................................70
7.12
Packaging and Labeling...............................................................................................70
7.12.1
Ixazomib ......................................................................................................................70
7.12.2
Lenalidomide...............................................................................................................71
7.12.3
Dexamethasone............................................................................................................71
7.13
Storage, Handling, and Accountability........................................................................71
7.13.1
Ixazomib ......................................................................................................................71
7.13.2
Lenalidomide...............................................................................................................72
7.13.2.1 Storage........................................................................................................................72
Only enough lenalidomide capsules for 1 cycle of therapy may be provided to the patient
each cycle. ............................................................................................................................72
7.14
Disposition of used supplies........................................................................................72
7.15
Other Safety Issues ......................................................................................................73


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7.15.1
Overdose......................................................................................................................73
8. STUDY CONDUCT ............................................................................................................73
8.1 Arrangements for Recruitment of Patients...........................................................................73
8.2 Enrollment............................................................................................................................73
8.3 Treatment Group Assignments.............................................................................................73
9. STUDY PROCEDURES......................................................................................................73
9.1 Informed Consent.................................................................................................................74
9.2 Inclusion and Exclusion Criteria ..........................................................................................74
9.3 Patient Demographics...........................................................................................................75
9.4 Medical History and Physical Examination .........................................................................75
9.5 Eastern Cooperative Oncology Group Performance Status .................................................75
9.6 Vital Signs, Body Weight and Height..................................................................................75
9.7 Pregnancy Test .....................................................................................................................76
9.8 Clinical Laboratory Evaluations...........................................................................................76
9.8.1
Hematology .................................................................................................................76
9.8.2
Serum Chemistry .........................................................................................................77
9.8.3
2-Microglobulin.........................................................................................................77
9.8.4
Serum Kappa/ Lambda measurement..........................................................................77
9.8.5
Urinalysis.....................................................................................................................77
9.9 Computed Tomography/Magnetic Resonance Imaging.......................................................77
9.10
Skeletal Survey............................................................................................................78
9.11
Quantification of M-Protein ........................................................................................78
9.12
Serum Free Light Chain Assay....................................................................................78
9.13
Immunofixation of Serum and Urine...........................................................................78
9.14
Bone Marrow Biopsy/Aspiration.................................................................................78
9.14.1
Morphology .................................................................................................................78
9.14.2
Cytogenetics ................................................................................................................79
9.14.3
Biomarkers...................................................................................................................79
9.15
Quantification of Immunoglobulins ............................................................................79
9.15.1
Blood Sample for Genotyping- Germline DNA and RNA..........................................79
9.16
Pretreatment Events and Adverse Events....................................................................80
9.17
Stem Cell Collection and Autologous Stem Cell Transplantation ..............................80
9.18
Premedications and Concomitant Medications and Procedures..................................80
10. STATISTICAL AND QUANTITATIVE ANALYSES ......................................................80
10.1
Statistical Methods ......................................................................................................80
10.1.1
Study design and Power Consideration.......................................................................81


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10.1.2
Populations for Analysis..............................................................................................83
10.1.3
Response Assessment..................................................................................................84
10.1.4
Demographic and Baseline Characteristics .................................................................85
10.1.5
Efficacy Analysis.........................................................................................................85
10.1.5.1
Primary Efficacy.....................................................................................................85
10.1.5.2
Secondary Efficacy.................................................................................................85
10.1.5.3
ORR in the Subset of High-Risk Patients...............................................................86
10.1.5.4
Autologous Stem Cell Transplant Evaluation ........................................................86
10.1.6.
Exploratory Biomarker Analysis.................................................................................86
10.1.7
Safety Analysis............................................................................................................88
10.1.8
Interim Analysis...........................................................................................................88
10.1.9
Early Stopping Rule.....................................................................................................88
11. ADVERSE EVENTS ...........................................................................................................90
11.1
Definitions ...................................................................................................................90
11.1.1
Adverse Event Definition ............................................................................................90
11.1.2
Serious Adverse Event Definition ...............................................................................90

Is a congenital anomaly/birth defect.....................................................................................90
11.2
Reporting Serious Adverse Events..............................................................................91

Event term(s) ........................................................................................................................92
11.3
Procedures for AE and SAE Recording and Reporting...............................................93
11.4
Reporting Requirements..............................................................................................93
11.5
Reporting to the MMRC Lead Investigator.................................................................94
11.5.1
Serious Adverse Event Reporting................................................................................94
11.6
Non-Serious Adverse Event Reporting .......................................................................96
11.7
Reporting to the Institutional Review Board (IRB).....................................................96
11.8
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events..........96
12. ADMINISTRATIVE REQUIREMENTS............................................................................97
12.1
Good Clinical Practice.................................................................................................97
12.2
Data Quality Assurance...............................................................................................97
12.3
Ethical Considerations.................................................................................................98
12.4
Patient Information and Informed Consent .................................................................98
12.5
Patient Confidentiality.................................................................................................99
12.6
Investigator Compliance..............................................................................................99
12.7
Study Documentation and Archives..........................................................................100
12.7.1
Source Documents.....................................................................................................100
12.7.2
Case Report Form Completion ..................................................................................100


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12.7.3
Archival of Records...................................................................................................100
12.8
Data and Safety Monitoring Plan ............................................................................100
12.9
Study Monitoring and Data Collection for Participating sites ..................................101
12.10
Investigator and Site Responsibility for Drug Accountability ..................................102
12.11
Ixazomib Product Complaints ...................................................................................103
12.12
Study Termination .....................................................................................................103
13. INVESTIGATOR AGREEMENT.....................................................................................104
14. REFERENCES...................................................................................................................105
15. APPENDICES....................................................................................................................107
15.1
Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status.........107
15.2
Cockcroft-Gault Equation..........................................................................................108
FACT/GOG-Neurotoxicity Questionnaire, Version 4.0...........................................................109
Participant Signature: ...............................................................................................................109
15.3
International Myeloma Working Group Response Criteria27 ..................................110


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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS
Abbreviation
Term
5-HT3
5-hydroxytryptamine 3 serotonin receptor
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the plasma concentration versus timecurve
BCRP
breast cancer resistance protein
BSA
body surface area
BUN
blood urea nitrogen
CBC
complete blood count
CFR
Code of Federal Regulations
CO2
carbon dioxide
CR
complete response
CT
computed tomography
CV
cardiovascular
CYP
cytochrome P450
DDI
drug-drug interaction
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
EBMT
European Group for Bone and Bone Marrow Transplant
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EOS
End of Study (visit)
EOT
End of Treatment (visit)
EU
European Union
FDA
United States Food and Drug Administration
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
GM-CSF
granulocyte macrophage-colony stimulating factor
HIV
human immunodeficiency virus
IB
Investigator’s Brochure


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Abbreviation
Term
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IRB
institutional review board
IV
intravenous; intravenously
MedDRA
Medical Dictionary for Regulatory Activities
Millennium
Millennium Pharmaceuticals, Inc., and its affiliates
MRI
magnetic resonance imaging
MSC
multi-site coordinator
MTD
maximum tolerated dose
NCI
National Cancer Institute
NCI CTCAE
National Cancer Institute Common Terminology Criteria for AdverseEvents
PCR
polymerase chain reaction
PD
progressive disease (disease progression)
Pgp
P-glycoprotein
PK
pharmacokinetic(s)
PO
per os; by mouth (orally)
PR
partial response
RBC
red blood cell
sCR
stringent complete response
SAE
serious adverse event
t1/2
terminal disposition half-life
TGI
tumor growth inhibition
Tmax
single-dose time to reach maximum (peak)concentration
ULN
upper limit of the normal range
US
VD
United States
Bortezomib dexamethasone
VGPR
very good partial response


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1.
BACKGROUND AND STUDY RATIONALE
1.1
Scientific Background
1.1.1
Multiple Myeloma
Multiple myeloma is a heterogeneous malignancy characterized by the accumulation of terminally
differentiated antibody secreting B cells that result in bone marrow failure, bone destruction,
hypercalcemia, and renal failure. In the United States (US), multiple myeloma represents the
second most common hematological malignancy with approximately 5 to 7 new cases diagnosed
per 100,000 people each year. Approximately 20,000 cases of multiple myeloma are diagnosed
each year and 11,000 deaths per year are due to the disease (approximately 2% of all cancer
deaths) and these rates are similar to those seen in Europe. [1]
Although multiple myeloma is uniformly fatal, treatment has dramatically improved over the last
several decades because of the use of cytotoxic drugs, the introduction of high dose therapy and
autologous transplant, and the development of novel agents. Five-year survival has improved
from 25% in 1975 to 34% in the period from 1999 to 2005 because of the development of more
effective treatment. [2,3] Most patients receive multiple therapies over the course of their disease;
however, responses are transient despite the marked improvement in treatment options. Multiple
myeloma is sensitive to a number of cytotoxic drugs such as alkylating agents, anthracyclines,
and corticosteroids for initial treatment and for relapsed disease. With the introduction of several
effective agents such as proteasome inhibitors (bortezomib), thalidomide, and lenalidomide, the
treatment response and the 5-year survival of multiple myeloma has improved.
1.1.2
Risk stratification in Multiple Myeloma.
The completion of the sequencing of the MM human genome and many genomic studies
confirmed multiple molecular entities that differ in clinical outcome.[4] The completion of
these studies have been accompanied with the approval of many new drugs, but in contrast to
other tumors, these technologies have been unable to identify a companion diagnostic test that
predict the subset of patients that would benefit from specific therapies. As a result much effort
has been dedicated to define relevant MM molecular categories that will predict a successful
outcome. As such, the use of genetic approaches (like t(4-14), t(14-16) or chromosome 13 deletion
or inactivation of p53, etc), clinical risk categories (International Staging System Grade III),
biological markers (high proliferation rate), and gene expression analyses (FGFR3/MMSET,
MAF, cyclin D, hyperdiploid) have been developed to identify patients with high risk disease.
However, none of these technologies affect the selection of initial therapeutic combinations,


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making it difficult to justify for some of them their constant clinical application. Therefore,
standard regimens are applied to all patients without scrutinizing for biological characteristics that
could determine the intensity of the therapy required to achieve an optimal response.
1.2
Clinical Experience With Lenalidomide and Dexamethasone in Newly
Diagnosed Multiple Myeloma.
Revlimid (lenalidomide) is a thalidomide analogue that has significant clinical activity in multiple
myeloma. Lenalidomide in combination with dexamethasone is approved by the US Food and
Drug Administration (FDA) for the treatment of multiple myeloma patients who have received at
least 1 prior therapy. [5, 6] Based on the activity of this combination in the relapse/refractory
setting, clinical trials are ongoing or have been completed in patients with NDMM. [7]
The Eastern Cooperative Oncology Group (ECOG) conducted a randomized phase 3, multicenter,
open-label study (E4A03) in patients with NDMM. The primary outcome of the trial was to
determine whether low-dose dexamethasone plus lenalidomide was noninferior to high-dose
dexamethasone plus lenalidomide. After 4 cycles of therapy, patients could either discontinue the
planned protocol therapy to undergo a stem-cell transplant or continue on protocol therapy until
disease progression. [7] Results suggest that that lenalidomide plus low-dose dexamethasone is
associated with better OS and a lower toxicity profile compared to lenalidomide plus high-dose
dexamethasone. [7] In this study, 445 patients were randomly assigned to a high-dose (n = 223)
or low-dose (n = 222) dexamethasone/lenalidomide regimen. Patients randomized to the high-
dose regimen were administered lenalidomide 25 mg on Days 1 through 21, plus dexamethasone
40 mg on Days 1 through 4, 9 through 12, and 17 through 20 of a 28-day cycle. Patients assigned
to the low-dose regimen received the same schedule of lenalidomide with dexamethasone 40 mg
on Days 1, 8, 15, and 22 of a 28-day cycle.
One hundred and sixty-nine (79%) of 214 patients receiving high-dose treatment and 142 (68%)
of 205 patients on low-dose treatment had complete response (CR) or partial response (PR) within
4 cycles. At the 1-year, second interim analysis, however, OS was 96% (95% confidence interval
94–99) in the low-dose dexamethasone group compared with 87% (82–92) in the high-dose group
(p = 0.0002). The most common Grade 3 toxicities were deep vein thrombosis (26% vs 12%; p =
0.0003), infections including pneumonia (16% vs 9%; p = 0.04), and fatigue (15% vs 9%, p =
0.08)
for
the
high-dose
vs
low-dose
dexamethasone
containing
groups
respectively.
Consequently, the trial was stopped and patients on high-dose therapy were crossed over to low-
dose therapy. [7]


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The Southwest Oncology Group (SWOG) conducted a randomized, phase 3, double-blind,
crossover, placebo-controlled, multicenter study in patients with NDMM. [8] The primary
endpoint was to compare the progression-free survival (PFS) of patients treated with
dexamethasone plus lenalidomide or placebo. The target accrual was 500 patients; however the
study closed early with an accrual of 198 after results of the ECOG trial E4A03 reported improved
survival using low-dose dexamethasone versus high-dose dexamethasone plus lenalidomide. [8]
These results affected the acceptability of the high-dose dexamethasone control group.
In a blinded manner, patients participating in the SWOG trial were randomized to lenalidomide
25 mg on Days 1 through 28 of a 35-day cycle for 3 induction cycles, then 21 of 28 days as
maintenance, plus dexamethasone 40 mg on Days 1 through 4, 9 through 12, and 17 through 20
in induction, and then on Days 1 through 4, and Days 15 through 18 during maintenance; the
comparator arm included dexamethasone plus placebo administered according to the same
induction and maintenance schedules. Therapy was unblinded at disease progression and patients
in the control arm could cross over to the lenalidomide-dexamethasone regimen. The estimated
1-year PFS was 77% in the 100 patients treated with lenalidomide-dexamethasone and 55% in the
98 with dexamethasone plus placebo; however, 1-year OS was similar in both groups (93% vs
91%).[8] The response rate was 85.3% (22.1% CR) versus 51.3% (3.8% CR) in the groups
respectively. Grade ¾ neutropenia, infections, and thrombosis were more common in patients
treated with lenalidomide-dexamethasone.
1.3
Multiple Myeloma and Response to Proteasome Inhibitor.
Protein homeostasis that occurs through regulation of protein production and destruction is one
of the critical biological processes that play a role in cell survival. The ubiquitin-proteasome
system is the major regulatory system through which this occurs and represents the primary
mechanism by which cells degrade proteins, including those involved in growth control, cell cycle
regulation, and apoptosis.
The completion of these biological studies has allowed the development of several new potent
drugs in MM1. One such medication, the proteasome inhibitor, has become the backbone of
current therapeutic approaches for MM. These drugs inhibit the catalytic proteolytic core (20S)
subunit of the 26S proteasome. As a consequence proteasome inhibitors reduced protein
degradation and disrupt several distinct cell regulatory mechanisms leading to inhibition of cell
growth and survival pathways, dysregulation of the cell cycle, and induction of apoptosis. Clinical
studies with the only FDA approved proteasome inhibitor, bortezomib, have validated the
proteasome as a therapeutic target for the treatment of malignancies. Bortezomib is approved for


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the treatment of patients with multiple myeloma and previously treated mantle cell lymphoma.
(Bortezomib product label)
Bortezomib has proven effective in the frontline setting, has shown marked response in the
relapsed setting, and is an effective agent in the pretransplant setting. However, 38% of the
patients treated with the first generations of bortezomib combination (dexamethasone) achieved
optimal response (defined as complete or very good response), 60%-87% of patients fail toreach
this goal 2. Hence, second generation of bortezomib combinations including other novel agents
have been develop and are achieving significant improvements in its therapeutic response (OR:70-
90% with complete responses in 40-50% of the cases) and overall survival (of 29-35% at 5 years)
3. But, despite the marked increase in the number of therapeutic options, the disease remains
incurable and there remains a need for new and better agents. Hence new efforts to target the 20S
proteasome has allowed the dosing of second-generation proteasome inhibitor (Ixazomib) forthe
treatment of both hematologic and non-hematologic malignancies.
1.4 Clinical Experience of BORTEZOMIB [Bortezomib] Plus Lenalidomide and
Dexamethasone.
Evidence to support combining bortezomib with immunomodulatory analogues, includes
preclinical data demonstrating synergistic effects on apoptosis, clinical efficacy seen with the
combination of bortezomib, lenalidomide, and dexamethasone in relapsed/ refractory disease, and
the clinical activity of these agents in NDMM patients. [11-16].
Richardson and colleagues conducted a phase 1/2 study combining lenalidomide, bortezomib, and
dexamethasone in NDMM patients. [11] The primary endpoints were to determine themaximum
tolerated dose (MTD) of this combination (phase 1) and to evaluate response rate (PR) to the
combination (phase 2). Response assessments were done after 4 and 8 cycles of therapy.
Responses were assessed by modified European Group for Bone and Bone Marrow Transplant
(EBMT) and Uniform criteria [17] to include near complete response (nCR) and very good partial
response (VGPR). Patients received lenalidomide on Days 1 through 14, bortezomib on Days 1,
4, 8, and 11, and dexamethasone on Days 1, 2, 4, 5, 8, 9, 11, and 12, for eight 21-day cycles.
Patients with a CR or nCR/PR after Cycle 4 could proceed at any point to stem cell mobilization
and transplantation. Patients with stable or responding disease without unacceptable toxicity at
the completion of Cycle 8, were allowed to continue onto the maintenance phase of the study
which comprised 3-week cycles of bortezomib on Days 1 and 8, lenalidomide on Days 1 through
14 at the doses tolerated at the completion of Cycle 8, and dexamethasone 10 mg the day before
and after bortezomib (Days 1, 2, 8, and 9). [11]


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In the phase 1 portion of the study, dose-escalation proceeded (3 patient cohorts) depending on
dose-limiting toxicities (DLTs) initially with 4 planned dose levels (lenalidomide/bortezomib:
15/1.0, 15/1.3, 20/1.3, 25/1.3 plus dexamethasone at fixed doses of 40 mg cycles 1-4 /20mg cycles
5-8). Based on safety data, an additional dose level (ie, 4M [lenalidomide 25mg/bortezomib1.3
mg/m2]) with reduced dexamethasone (20/10 mg), was added; this was determined to be the MTD
of the combination and the recommended phase 2 dose (RP2D). Overall 66 patients were enrolled
to this study (phase 1 n = 31; phase 2 n = 35). [11]
Results indicated that the combination of lenalidomide, bortezomib, and dexamethasone was
highly active in patients with NDMM, with all patients (100%) achieving at least a pre-ASCT
response of PR and high rates of VGPR or better (CR+ nCR+VGPR). Consistent with reports
from other studies, response rates were unaffected by adverse cytogenetic abnormalities. In both
the phase 2 population and overall, 74% and 67% respectively achieved a VGPR or better.
Overall, 49 patients achieved at least a PR after 4 cycles of treatment (6% CR/nCR; 5% VGPR,
and 64% PR). Improvement in response by at least one response category was noted in 75% of
the 56 patients that continued on therapy from Cycle 4 through Cycle 8, with further improvement
in response noted in 20 of 37 patients who continued beyond cycle 8 with maintenance therapy.
With a median follow-up of 21 months, neither the median duration of response (DOR) nor
median OS has been reached. With 68% of patients still responding after more than 18 months,
the estimated 18-month PFS and survival with/without ASCT is 75% and 97% respectively. The
3-drug combination was well tolerated with generally manageable toxicities. Neuropathy was
noted but often low grade and reversible with dose modification. There was no Grade 4
neuropathy and limited rates of Grade 3 neuropathy (2% peripheral sensory neuropathy [any grade
80%], 2% peripheral motor neuropathy [any grade 18%], and 3% neuropathic pain [any grade
32%]). Other Grade 3 or 4 toxicities reported in at least 5% of patients included lymphopenia
(14%), neutropenia (9%), thrombocytopenia (6%), thrombosis (6%), hypokalemia (5%), and
hypophosphatemia
(5%).
[11]
The
authors
concluded
the
bortezomib,
lenalidomide,
dexamethasone (VRD) combination was a highly effective regimen for patients with NDMM
supporting the ongoing phase 3 clinical trials designed to assess the benefit of this 3-drug approach
compared with a 2-drug approach (dexamethasone plus either bortezomib or lenalidomide,
depending on the specific trial). [11]
Kumar and colleagues reported results of a randomized, phase 1/2 study of 3- and 4-drug
combination regimens containing bortezomib (BORTEZOMIB; V), dexamethasone
(D),
lenalidomide (Revlimid, R), with or without cyclophosphamide (C) in subjects with NDMM


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(EVOLUTION Study). [12] Previously untreated patients with measurable disease were
randomized to 1 of 4 treatment groups receiving up to eight 21-day cycles of induction therapy
followed by four 42-day maintenance cycles of V 1.3 mg/m2 (Days 1, 8, 15, 22) (all treatment
arms). Patients eligible for autologous stem cell transplant could undergo stem cell mobilization
any time after cycle 2 and stem cell transplant (SCT) any time after Cycle 4. Response categories
were based on the IMWG Criteria (See section 15.3) with the addition of nCR, and adverse events
(AEs) were graded using the National Cancer Institute Common Terminology Criteria for
Adverse Events (NCI CTCAE) version 3.0. The phase 1 part of the study evaluated increasing
doses of cyclophosphamide with fixed doses of bortezomib, dexamethasone, and lenalidomide in
order to determine the MTD of the combination. [12] The primary endpoint of the Phase 2 portion
of the study was the combined CR + VGPR rate. All combinations administered bortezomib 1.3
mg/m2IV (Days 1, 4, 8, 11) and dexamethasone 40 mg orally (Day 1, 8, 15) every 21 days repeated
for 8 cycles followed by bortezomib 1.3 mg/m2 alone (Days 1, 8, 15, 22) in a 6-week cycle for 4
cycles. Revlimid was given at 25 mg orally (Days 1-14) in the VDR arm and at 15 mg in the VDCR
arm. In the VDCR arm, patients were treated with escalating doses of cyclophosphamide (100,
200, 300, 400, or 500 mg/m2) orally Days 1, 8, and every 21 days. As previously reported, the
recommended phase 2 dose of cyclophosphamide in the VDCR regimen was the highest
planned dose of 500 mg/m2. [13] In the phase 2 part of the study, the VDC arm was modified to
add a Day 15 dose of cyclophosphamide given the lower than previously reported efficacy rate of
the VDC combination.
One-hundred forty patients were enrolled with 132 patients being response evaluable (42 VDCR,
42 VDR, 32 VDC, and 17 VDC-modified) at the data cut-off. Responses and estimated long-term
outcomes are noted below in Table 1-1. The median number of VDR, VDCR, VDC, and VDC-
modified cycles received is 5 (range 1-12), 6 (range 1-12), 6 (range 3-12), and 6 (range 3-12),
respectively. The median DOR had not been reached in any arm as of the data cut-off. Forty-six
patients had samples assessed for minimal residual disease with 46% of those who achieved CR
(including stringent CR [sCR]) or nCR being minimal residual disease-negative. [13]
Table 1-1. Best confirmed response
Response %
VDCR
VDR
VCD
VCD-mod
ORR (> PR) (%)
88
83
78
100
CR
24
24
22
47


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sCR
10
14
3
29
CR + nCR
34
38
31
47
VGPR
59
50
41
59
nCR pts with MRD negative
% (# MRD negative/# assessed).
48
(10/21)
75
(9/12)
0
(0/7)
33
(2/6)
1 Year PFS, %
82
68
97
100
Survival at 1 yr/ 2 yrs, %
92/76
100/96
100/100
100/NE
Source: Kumar S, Flinn I, Richardson P, Hari P, Callander N, Noga S, et al. [13] Novel Three- and Four-Drug
Combination Regimens of Bortezomib, Dexamethasone, Cyclophosphamide, and Lenalidomide, for Previously
Untreated Multiple Myeloma: Results From the Multi-Center, Randomized, Phase 2 EVOLUTION Study. Blood
(ASH Annual Meeting Abstracts) 2010;116(21):abstr 621. [13] Abbreviations: C = cyclophosphamide; CR =
complete response; D = dexamethasone; MRD = minimal residual disease; N = number; nCR = near CR; PFS =
progression-free survival; PR = partial response; R = Revlimid (lenalidomide); sCR = stringent CR; V = Velcade
(bortezomib). a Censoring at transplant.
All treatment regimens were generally well tolerated. The five most common all-grade AEs across
all treatment groups were fatigue (range 47%–67%), nausea (36%–67%), constipation (40%–
62%), diarrhea not otherwise specified (42%–65%), and neutropenia (19%–52%). The incidence
of Grade >2 neuropathy was similar across each arm with no reports of Grade 4 peripheral
neuropathy (Table 1-2).
Table 1-2. Selected Adverse Events
AE %
VDCR
(n=41)
VDR
(n=42)
VCD
(n=32)
VCD-mod
(n=17)
> G3 AE
81
76
79
88
SAE
42
40
21
41
AE resulting in study discontinuation
19
17
12
6
Peripheral Neuropathy
34
38
31
47
>G2 (>G3)
40(13)
45 (14)
48 (9)
41 (18)
Neutropenia (>G3)
42
7
36
65
Thrombocytopenia > G3
82
68
97
100
Survival at 1 yr/ 2 yrs, %
10
7
12
18
Source: Kumar S, Flinn I, Richardson P, Hari P, Callander N, Noga S, et al. [13] Novel Three- and Four-Drug
Combination Regimens of Bortezomib, Dexamethasone, Cyclophosphamide, and Lenalidomide, for Previously
Untreated Multiple Myeloma: Results From the Multi-Center, Randomized, Phase 2 EVOLUTION Study. Blood
(ASH Annual Meeting Abstracts) 2010;116(21):abstr 621. [13] Abbreviations: AE = adverse event; C =
cyclophosphamide; D = dexamethasone; Gr = grade; N = number; R = Revlimid (lenalidomide); SAE = serious AE;
sCR = stringent CR; V = VELCADE(bortezomib).


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The authors concluded that VDR, VDCR, and VDC (initial and modified) are highly active in
patients with NDMM. The regimens are well tolerated with modest increase in hematologic
toxicity (ie, Grade 3/4 neutropenia) in the cyclophosphamide-containing regimens. The VDC-
mod regimen was associated with high and rapid responses comparable to VDR and VDCR.
Long-term follow-up continues to assess the durability of response as well as the depth of the
response. [13]
SWOG is currently conducting a randomized, phase 3 trial of lenalidomide with low-dose
dexamethasone (LLD) versus bortezomib plus LLD for induction in patients with NDMM without
intent for immediate autologous stem cell transplant (S0777). The primary outcome of the trialis
to compare PFS with LLD with or without bortezomib. A secondary objective is to assess OS and
long-term outcomes stratified by intent to undergo transplantation at progression. Patients are
randomized to lenalidomide 25 mg on Days 1 through 21 plus dexamethasone 40 mg on Days 1,
8, 15, 22, and every 28 days for 6 cycles or to bortezomib 1.3 mg/m2 on Days 1, 4, 8, and 11 plus
dexamethasone 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 with lenalidomide 25 mg on Days 1
through 14 every 21 days for 8 cycles. Patients whose disease progresses or who experience
unacceptable toxicity are removed from the study at that time. After 6 months of therapy, patients
without progressive disease (PD) or unacceptable toxicity receive maintenance therapy consisting
of dexamethasone 40 mg on Days 1, 8, 15, and 22 with lenalidomide 25 mg on Days 1 through
21 every 28 days. Maintenance continues until disease progression or unacceptable toxicity. In
both arms, patients who intend to undergo SCT may undergo collection of stem cells after 2 cycles
of therapy with the ASCT at relapse. The trial began accrual in April 2008 with a target of 440
patients.
1.5
Ixazomib
1.5.1
Preclinical Experience
Please refer to the current ixazomib Investigator’s Brochure (IB) and Safety Management
Attachment (SMA).
1.5.2
Clinical Experience
Ixazomib has been evaluated as an oral single agent in Phase 1 studies that have included patients
with advanced solid tumors, lymphoma, relapse/refractory MM (RRMM), and relapsed or
refractory light-chain (AL) amyloidosis and demonstrated early signs of activity. Ongoing studies
continue to investigate both single-agent ixazomib and ixazomib in combination with standard
treatments. Based on encouraging preliminary data observed in patients with MM
requiring


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systemic treatment, 2 Phase 3 trials in newly diagnosed MM (NDMM) (C16014) and RRMM
(C16010) patient populations are currently evaluating ixazomib in combination with Revlimid
and Dexamethasone (RevDex) versus placebo/RevDex. Both trials are combining ixazomib at a
weekly dose of 4.0 mg on Days 1, 8, and 15 in a 28-day cycle to a standard dose of lenalidomide
with a weekly dexamethasone dose of 40 mg. In addition, ongoing clinical pharmacologystudies
include evaluation of drug-drug interactions (DDI) with ketoconazole and rifampin, effect of food,
and oral bioavailability. Studies evaluating the safety and pharmacokinetic (PK) of ixazomib
alone (in Japanese patients) and in combination with lenalidomide and dexamethasone in Asian
adult patients (including Japanese patients) with a diagnosis of NDMM are ongoing.
As of 27 March 2013, preliminary clinical data is available for a total of 653 patients across 13
studies. The emerging safety profile indicates that ixazomib is generally well tolerated. The
adverse events (AEs) are consistent with the class-based effects of proteasome inhibition and are
similar to what has been previously reported with VELCADE though the severity of some, for
example peripheral neuropathy, is less. While some of these potential toxicities may be severe,
they can be managed by clinical monitoring and standard medical intervention, or, as needed,
dose modification or discontinuation.
Fatigue was the most common AE reported among 384 patients treated in the oral (PO) studies
(47%). Other common AEs reported in the pooled intravenous (IV) and PO safety populations
include nausea, thrombocytopenia, diarrhea, and vomiting. Rash is also a commonly reported
treatment-emergent event; however, there is some variety in its characterization and causality
resulting in different preferred terms to describe it. A high-level term outline of rash events
includes rashes, eruptions and exanthemas NEC; pruritus NEC; erythemas; papulosquamous
conditions; and exfoliative conditions. The dose escalation phases of most trials reported in the
IB have now completed enrollment, and gastrointestinal (GI) symptoms were the common dose-
limiting toxicities (DLTs) when the use of prophylactic anti-emetics was not permitted per
protocol. In the expansion cohorts or phase 2 cohorts (as per each study), the incidence and
severity of GI symptoms was mitigated by the use of the lower maximum tolerated dose
(MTD)/recommended phase 2 dose (RP2D) (as per each study) and standard clinical usage of
anti-emetics and/or antidiarrheal medications as deemed appropriate. Prophylactic use of anti-
emetics has not been required as with other agents but (as outlined in Section 6.7) has been used
according to standard practice and are effective.
The most frequent (at least 20%) treatment-emergent adverse events (TEAEs) reported with the
PO formulation pooled from single-agent studies (n = 201) irrespective of causality to ixazomib,
include nausea (53%), fatigue (51%), diarrhea (44%), thrombocytopenia (34%), vomiting (38%),


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decreased appetite (32%), fever (21%), and anemia (21%). The most frequent (at least 20%)
TEAEs reported with the PO formulation pooled from combination trials (irrespective of the
combination) (n = 173), irrespective of causality to ixazomib, include diarrhea (47%), fatigue
(44%), nausea (38%), peripheral edema (35%), constipation (33%), insomnia
(29%),
thrombocytopenia (28%), anemia (26%), vomiting (26%), neutropenia (25%), back pain (24%),
pyrexia (23%), peripheral edema (21%, each), fever (20%), cough (20%), hypokalemia (20%),
neutropenia (20%), and upper respiratory tract infection (20%). Overall rash of all grades is
reported in approximately 50% of patients and is more common when ixazomib is given in
combination with lenalidomide where rash is an overlapping toxicity.
Additional detailed information regarding the clinical experience of ixazomib may be found in
the IB, including information on the IV formulation.
1.5.3 Pharmacokinetics and Drug Metabolism
Clinical IV and PO PK data show that ixazomib citrate (measured as the biologically active
boronic acid form of ixazomib [MLN2238]) has multi-exponential disposition with a rapid initial
phase that is largely over by 4 hours. Oral ixazomib citrate is rapidly absorbed with a median
single-dose first time of occurrence of maximum (peak) concentration (Tmax) of
approximately
0.5 to 2.0 hours and a terminal disposition half-life (t1/2) after multiple dosing of approximately 5
to 7 days [6]. Results of a population PK analysis (n = 137) show that there is no relationship
between body surface area (BSA) or body weight and clearance (CL). Also, based on stochastic
simulations for fixed dose, exposures are independent of the individual patient’s BSA [7]. Based
on these data, a recommendation was made for fixed dosing in clinical trials. An absolute
bioavailability of 67% was determined for ixazomib using the population PK analysis. Please
refer to the current ixazomib IB and Safety Management Attachment (SMA) for information on
the PK for IV doses of ixazomib.
Metabolism appears to be the major route of elimination for ixazomib, and urinary excretion of
the parent drug is negligible (< 5% of dose). In vitro studies indicate that ixazomib is metabolized
by multiple cytochrome P450s (CYPs) and non-CYP enzymes/proteins. The rank order of relative
biotransformation activity of the 5 major human CYP isozymes was 3A4 (34.2%) > 1A2 (30.7%)
> 2D6 (14.7%) > 2C9 (12.1%) > 2C19 (< 1%). ixazomib is not an inhibitor of CYPs 1A2, 2C9,
2C19, 2D6, or 3A4 nor a time-dependent inhibitor of CYP3A4/5. The potential for ixazomib
treatment to produce drug-drug interactions (DDIs) via CYP inhibition is inferred to be low.
However, there may be a potential for DDIs with a concomitant strong CYP3A4 or CYP1A2
inhibitor or inducer because of the potential for first-pass metabolism when ixazomib
is


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administered via the PO route and because of the moderate contribution of CYP3A4-and CYP1A2-
mediated metabolism of ixazomib in human liver microsomes. ixazomib may be a weak substrate
of P-glycoprotein (Pgp), breast cancer resistance protein (BCRP), and multidrug resistance
associated protein (MRP2) efflux pump transporters. ixazomib is not an inhibitor of Pgp, BCRP,
and MRP2. The potential for DDIs with substrates or inhibitors of Pgp, BCRP, and MRP2 is,
therefore, inferred to be low. Clinical Study C16009 (Arm 1) with ketoconazole, a strong
CYP3A4 inhibitor, showed a 2-fold increase in area under the plasma concentration versus time
curve (AUC) in the presence of ketoconazole. This resulted in the continued exclusion of strong
CYP3A4 inhibitors in ongoing/planned clinical studies.
Further details on these studies are provided in the IB.
1.5.4
Clinical Trial Experience Using the Oral Formulation of ixazomib
As of 27 March 2013, a total of 507 patients with differing malignancies (multiple myeloma, AL
amyloidosis, nonhematologic cancers, and lymphoma) have been treated in studies evaluating the
oral ixazomib formulation. These patients have been treated with different doses of ixazomib
either as a single-agent treatment (in 201 patients) or in combination with currently clinically
available treatments (in 306 patients). Information regarding the ongoing studies, patient
populations, and doses investigated is included in Table 1-1.
Table 1-1
Clinical Studies of Oral ixazomib
Trial/
Population
Description
Doses Investigated
C16003
RRMM
N = 60
PO, TW, single agent
0.24-2.23 mg/m2 TW
MTD: 2.0 mg/m2
DLT: rash, thrombocytopenia
Closed to enrollment
C16004
RRMM
N = 60
PO, W, single agent
0.24-3.95 mg/m2 W
MTD: 2.97 mg/m2
DLT: rash, nausea, vomiting, diarrhea
Closed to enrollment
C16005
NDMM
N = 65
PO, W, combination with LenDex
28-day cycle
1.68-3.95 mg/m2 W
MTD: 2.97 mg/m2
DLT: nausea, vomiting, diarrhea, syncope
RP2Da: 4.0 mg fixed (switched to fixed dosing in
phase 2, equivalent to 2.23mg/m2)
Closed to enrollment


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C16006
NDMM
N = 20
PO, TW (Arm A- 42 day cycle) and
W (Arm B- 28 day cycle),
combination with Melphalan and
Prednisone
Arm Aa: 3-3.7-mg fixed dose TW
DLT: rash, thrombocytopenia, subileus
Arm Ba: 3-5.5-mg fixed dose, W
DLT: Esophageal ulcer nausea, vomiting,
hematemesis, thrombocytopenia, ileus,
neurogenic bladder
MTD = 3.0 mg
C16007
RRAL
N = 27
PO, W, single agent
4-5.5-mg fixed dosea W
DLT: thrombocytopenia, diarrhea, dyspnea, acute
rise in creatinine, cardiac arrest
MTD: 4.0 mg W
C16008
NDMM
N = 64
PO, TW, combination with LenDex
21-day cycle
3.0-3.7-mg fixed dosea W
MTD: 3.0 mg
Closed to enrollment
C16009
Solid tumors,
Lymphomas
N = 54
PO, W, single agent
5.5-mg fixed dosea W
C16010
RRMM
N = 200
PO, W, with LenDex versus placebo-
LenDex
4.0 mg W
C16011
RRAL
N = 4
PO, W, with Dex versus physician’s
choice of a Dex-based regimen
4.0 mg W
C16013
RRMM
N = 9
PO, W, with LenDex
4.0 mg W
Table 1-1
Clinical Studies of Oral ixazomib
Trial/
Population
Description
Doses Investigated
C16014
Symptomatic
MM
N=701
PO, combination with LenDex
Ixazomib 4.0 mg or matching placebo on Days 1,
8, and 15, plus Len 25 mg on Days 1-21 (10 mg if
low creatinine clearance, with escalation to 15 mg
if tolerated) and Dex 40 mg (or 20 mg if >75
years old) on Days 1, 8, 15, and 22
C16015
Symptomatic
MM with
normal renal
function or
severe renal
impairment
N=28
PO, combination with Dex
Part A: Ixazomib 3.0 mg on Day 1
Part B: Ixazomib 4.0 mg on Days 1, 8, and 15,
plus Dex 40 mg (or 20 mg if >75 years old) on
Days 1, 8, 15 and 22 of a 28-day cycle


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C16017
RR follicular
lymphoma
N=58
PO, W
4.0, 5.3, and 7.0 mg, W
Treatment at RP2D once determined.
C16018
Advanced
solid tumors
or
hematologic
malignancies
with varying
degrees of
liver
dysfunction
N=45
Part A: PO, Day 1 of 15-day cycle
Part B: PO, W
1.5 mg (severe hepatic impairment), 2.3 mg
(moderate hepatic impairment), or 4.0 mg (normal
hepatic function)
TB-
MC010034
RRMM
N = 10
PO, W
4.0 mg, W
Single agent: 4.0 mg
Combination with Rd
Abbreviations: RRAL = Relapsed and/or refractory Primary systemic light chain (AL) amyloidosis; BSA=
body surface area; Dex=dexamethasone; DLT = dose-limiting toxicity; IV = intravenously; LenDex=
lenalidomide plus dexamethasone; MTD = maximum tolerated dose; NDMM = newly diagnosed multiple
myeloma; PO = orally; RR= relapsed and/or refractory; RRAL= relapsed and/or refractory systemiclight
chain amyloidosis RRMM = relapsed and/or refractory multiple myeloma; TBD = to be determined;TW
= twice weekly; W = weekly; RP2D= recommended phase 2 dose.
Note that blinded data from pivotal Studies C16010 and C16011 are not included.
a Approximate BSA and fixed dosing equivalence: 3 mg~ equivalent to 1.68 mg/m2 BSA dosing; 4.0 mg ~
equivalent to 2.23 mg/m2 BSA dosing; and 5.5 mg~ equivalent to 2.97 mg/m2 BSA dosing.
1.5.5
Overview of the Oral Formulation of ixazomib
The emerging safety profile indicates that ixazomib is generally well tolerated. The adverse
events (AEs) are consistent with the class-based effects of proteasome inhibition and are similar
to what has been previously reported with VELCADE though the severity of some, for example
peripheral neuropathy, is less. While some of these potential toxicities may be severe, they can be
managed by clinical monitoring and standard medical intervention, or, as needed, dose
modification or discontinuation.
In the 4 ongoing studies (C16003, C16004, C16007, and C16009) investigating single-agent oral
ixazomib in patients with differing malignancies (multiple myeloma, AL
amyloidosis,
nonhematologic cancers, and lymphoma), a total of 201 patients have been treated as of 27 March
2013. These patients have been treated with different doses of ixazomib as they are all Phase 1
trials. An overview of the most frequent (at least 10%) AEs occurring in the pooled safety
population from single-agent oral ixazomib Studies (C16003, C16004, C16007, and C16009) is
shown in Table 1-2.


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Table 1-2
Most Common (At Least 10% of Total) Treatment-Emergent Adverse
Events in Oral Single-Agent Studies
Primary System Organ Class
Preferred Term
Oral Single Agent
Total
n = 201
n (%)
Subjects with at Least One Adverse Event
197 (98)
Gastrointestinal disorders
160 (80)
Nausea
106 (53)
Diarrhea
88 (44)
Vomiting
77 (38)
Constipation
46 (23)
Abdominal pain
33 (16)
General disorders and administration site
conditions
151 (75)
Fatigue
103 (51)
Pyrexia
51 (25)
Oedema peripheral
27 (13)
Asthenia
31 (15)
Nervous system disorders
92 (46)
Headache
29 (14)
Dizziness
26 (13)
Neuropathy peripheral
21 (10)
Metabolism and nutrition disorders
107 (53)
Decreased appetite
64 (32)
Dehydration
37 (18)
Blood and lymphatic system disorders
98 (49)
Thrombocytopenia
68 (34)
Anaemia
42 (21)
Neutropenia
29 (14)
Lymphopenia
20 (10)
Skin and subcutaneous tissue disorders
90 (45)
Rash maculara
23 (11)
Musculoskeletal and connective tissue disorders
93 (46)
Back pain
24 (12)
Arthralgia
28 (14)
Respiratory, thoracic and mediastinal disorders
78 (39)
Cough
28 (14)
Dyspnea
30 (15)
Infections and infestations
89 (44)
Upper respiratory tract infection
31 (15)


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Source: ixazomib Investigator’s Brochure Edition7
Abbreviations: MedDRA = Medical Dictionary for Regulatory Activities, version 15.0.
Subject Incidence: A subject counts once for each preferred term. Percentages use the number of treated
subjects as the denominator.
a Note that rash maculopapular and rash macular represent the 2 most common terms used to describe rash.
As of 27 March 2013, there are 5 studies actively enrolling patients with multiple myeloma to
investigate oral ixazomib in combination with standard combination regimens.
The most frequent (at least 10%) AEs occurring in the pooled safety population from Studies
C16005, C16006, C16008, and C16013 are shown for all grades (Table 1-3). Note that in
combination trials, related is defined as related to any study drug in the combination regimen.
Table 1-3
Most Common (At Least 10% of Total) Treatment-Emergent Adverse
Events in Oral Combination Studies
Primary System Organ Class
Preferred Term
Total Oral Combo Agent
(5/6/8/13)
n = 173
n (%)
Subjects with at Least One Adverse Event
163 (94)
Gastrointestinal disorders
139 (80)
Nausea
65 (38)
Diarrhea
81 (47)
Vomiting
51 (29)
Constipation
57 (33)
General disorders and administration site
conditions
132 (76)
Fatigue
76 (44)
Pyrexia
39 (23)
Edema peripheral
61 (35)
Asthenia
20 (12)
Nervous system disorders
115 (66)
Headache
28 (16)
Dizziness
34 (20)
Neuropathy peripheral
45 (26)
Metabolism and nutrition disorders
91 (53)
Decreased appetite
25 (14)
Hypokalemia
34 (20)
Blood and lymphatic system disorders
88 (51)
Thrombocytopenia
49 (28)
Anemia
45 (26)
Neutropenia
43 (25)
Lymphopenia
20 (12)


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Table 1-3
Most Common (At Least 10% of Total) Treatment-Emergent Adverse
Events in Oral Combination Studies
Primary System Organ Class
Preferred Term
Total Oral Combo Agent
(5/6/8/13)
n = 173
n (%)
Skin and subcutaneous tissue disorders
102 (59)
Rash maculopapulara
29 (17)
Rash maculara
22 (13)
Musculoskeletal and connective tissue
disorders
99 (57)
Back pain
42 (24)
Pain in extremity
31 (18)
Arthralgia
22 (13)
Respiratory, thoracic and mediastinal
disorders
80 (46)
Cough
36 (21)
Infections and infestations
92 (53)
Upper respiratory tract infection
35 (20)
Psychiatric disorders
73 (42)
Insomnia
50 (29)
Source: Ixazomib Investigator’s Brochure Edition7
Abbreviations: MedDRA = Medical Dictionary for Regulatory Activities, version 15.0.
Subject Incidence: A subject counts once for each preferred term. Percentages use the number of treated
subjects as the denominator.
Data from ongoing blinded pivotal trials (C16010) are notincluded.
a Note that rash maculopapular and rash macular represent the 2 most common terms used to describerash..
The clinical experience with ixazomib also shows early signs of antitumor activity as evidenced
by at least a 50% reduction in disease burden in some patients and prolonged disease stabilization
in others across all ongoing trials. The antitumor activity has been seen with single-agent
ixazomib, when combined with established therapies, and across the malignancies studied
(advanced solid tumors [7], non-Hodgkin’s disease, Hodgkin’s disease [8], relapsed and/or
refractory multiple myeloma [RRMM; 9-17], relapsed or refractory systemic light chain
amyloidosis [RRAL; 12], and newly diagnosed multiple myeloma [NDMM; 13-15]) to date.
Though additional data are needed to characterize the clinical benefit of this drug, the emerging
data supports the ongoing development of ixazomib.
1.5.6
Relapsed and/or Refractory Multiple Myeloma
The early development of ixazomib in patients with RRMM involves 2 studies (C16003 and


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C16004) with similar objectives, but each investigated 1 of the 2 dosing schedules commonly
used with the first-in-class proteasome inhibitor, VELCADE.
Study C16003 is an open-label, dose escalation, Phase 1 study of ixazomib dosing on a twice-
weekly schedule on Days 1, 4, 8, and 11 of a 21-day cycle in adult patients with RRMM.(15, 16)
Study C16004 is an open-label, dose escalation, Phase 1 study of ixazomib dosing on a weekly
schedule on Days 1, 8, and 15 of a 28-day cycle in adults patients with RRMM.(17, 18, 19) Both
studies have now completed enrollment. The DLTs in Study C16003 were rash macular and
thrombocytopenia and the DLTs in C16004 were nausea, diarrhea, vomiting, and erythema
multiforme.
In the dose escalation component of both studies, patients had multiple myeloma that had relapsed
following at least 2 lines of therapy that must have included bortezomib, thalidomide (or
lenalidomide), and corticosteroids. In both studies, when the MTD was established, cohorts of
patients representing the heterogeneous patient population currently seen in clinical practice were
to be enrolled into 1 of 4 expansion cohorts, including a relapsed and refractory cohort, a
carfilzomib cohort, a proteasome inhibitor-naïve cohort, and a VELCADE-relapsed cohort.
Ixazomib trial C16003 a Phase 1 study of twice-weekly dosing of investigational oral proteasome
inhibitor ixazomib in patients with relapsed and/or refractory multiple myeloma(21). Among 55
response-evaluable patients, 15% achieved partial response or better (with 76% stable disease or
better). These findings have informed the subsequent clinical development of ixazomib in multiple
myeloma.
In trial C16004, weekly dosing of ixazomib in relapsed/refractory multiple myeloma (22), the
MTD was determined to be 2.97 mg/m . Dose-limiting toxicities were grade 3 nausea, vomiting,
and diarrhea in 2 patients, and grade 3 skin rash in 1 patient. Common drug-related adverse events
were thrombocytopenia (43%), diarrhea (38%), nausea (38%), fatigue (37%), and vomiting
(35%). The observed rate of peripheral neuropathy was 20%, with only one grade 3 event reported.
Nine (18%) patients achieved a partial response or better, including 8 of 30 (27%) evaluable
patients treated at the MTD. Pharmacokinetic studies suggested a long terminal half- life of 3.6-
11.3 days, supporting once-weekly dosing.
1.5.7
Newly Diagnosed Multiple Myeloma (NDMM)
Multiple research paths are being explored in patients with NDMM with a focus on evaluating
ixazomib in combination with agents commonly used across treatment settings. The development
of ixazomib in combination with lenalidomide with dexamethasone (LenDex) in patients with
NDMM who are transplant eligible or ineligible involves 2 studies (C16005 and C16008) with


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similar study designs except for a few key differences, namely the schedules of ixazomib and
dexamethasone. Ixazomib is also being evaluated in combination with melphalan and prednisone
(MP) for patients who are not transplant eligible due to age or coexisting morbidity (in Study
C16006).
The C16005 trial evaluated the combination of weekly MNL9708 and lenalidomide in a phase
1/2 trial. Of 19 response-evaluable pts (Ph 1 + Ph 2), all achieved ≥PR, including 5 CR (1 sCR),
4 VGPR, and 10 PR; all remain in response with duration of confirmed response of up to 9.5
months. Of 4 response-evaluable Ph 2 pts, 1 has achieved VGPR and 3 PR to date. Oral ixazomib
plus lenalidomide and dexamethasone appears well tolerated with manageable toxicity. These
data show antitumor activity at the RP2D in pts with previously untreated MM, with ≥PR in all
patients at the time of reporting (ref).
Twice-weekly oral ixazomib in combination with lenalidomide (len) and dexamethasone (dex) in
patients with newly diagnosed multiple myeloma was also reported.(23) In 58 response-evaluable
pts, ≥PR rate to date was 93%, including 67% ≥VGPR (24% CR, including 14% sCR). 54% of
pts had 100% decreases in M-protein or serum free light chain from baseline. Analysis of minimal
residual disease is ongoing; data will be presented. Depth of response increased over the course
of treatment; median time to first response (≥PR) was 0.69 mos and to best response to date was
2.07 mos. Median DOR to date was 5.9+ mos, ranging up to 18+ mos. Most common AEs were
rash (61%; pooled high-level terms), fatigue, peripheral edema (each 50%), diarrhea (41%), and
neuropathy peripheral (36%). Drug-related (to any drug in the regimen) grade 3 AEs were seen in
56% of pts, including rash (16%), hyperglycemia (8%), pneumonia (6%), and PN (5%; high- level
term). No drug-related grade 4 AEs were seen; 58% of pts required dose reductions of at least
one drug due to AEs including rash (16%), anxiety (11%), and PN (8%). AEs resulting in
discontinuation were seen in 11%, with the majority reported as not related to therapy. There was
1 on-study death due to cardio-respiratory arrest, likely a pulmonary embolism, considered by the
investigator to be unrelated to ixazomib or dex, but probably len. Based on phase 1 preliminary
PK data, MLN2238 was absorbed quickly with a Tmaxof 0.5–4 hours. Terminal half-life was 2–
8 days. PK data were similar to single-agent twice-weekly dosing studies, suggesting no MLN2238
PK interaction with len or dex.
These data suggest that twice-weekly oral ixazomib plus len-dex is feasible and active in pts with
newly diagnosed MM. However, rates of rash, PN, and dose reductions appear higher than in the
parallel study using weekly ixazomib, with similar response rates and better convenience,
supporting use of weekly dosing in ongoing phase 3 trials and future combination trials such as
this one.


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All 3 studies are Phase 1/2, with Phase 1 focusing on safety and Phase 2 on efficacy (and further
characterization of safety). Please refer to the ixazomib IB and SMA for further information.
1.5.8
Clinical Trial Experience Using the Intravenous Formulation of
ixazomib
See the IB for descriptions of the 2 studies that investigated IV ixazomib in advanced solid tumors
and advanced lymphoma (Studies C16001 and C16002, respectively).
1.6
NFKB2 Biomarker
A prospective study between May 2007 to June 2012 was performed to analyze the loss of NFKB2
3’end in patients treated with Bortezomib and Dexamethasone (VD). The outcome of the study
was to determine if the loss of NFKB2 was associated with suboptimal (defined as stable or
progressive disease) response at 4 cycles. In this study 83 patients were recruited. Twenty seven
ineligible patients were excluded from the study because they had a treatment variation (n=15),
misdiagnosis (n=2), poor quality of bone marrow sample (n=3), low quality sorting (n=5) or extra
medullary disease only (n=2). Thus, clinical information, plasma cells and match germ line DNA
derived from blood granulocytes was obtained from 56 patients. Patient characteristics at
inclusion are shown in Table 1 (appendix 1). Twelve patients (21%) with impaired renal function
(serum creatinine more than 1.5 mg/dL) were included.
In this population, 40 patients (70%) had available results from FISH or G banding karyotyping.
chromosomal abnormalities were detected in 15 patients (37%) of which 8 patients (20%) had
deletion chromosome 13, 3 patients (7.5%) had complex cytogenetics, 2 patients (5%) had cyclin
D1 amplification, 2 patients (5%) with t(11-14) and 2 patients (5%) with t(4-14).
Figure
1.
Structural
abnormalities in NF-kB2. A.
Whole genome sequencing
analysis
of
NF-kB2.
Illustration
demonstrated
the distribution of the reads
that have a partner out sided
of NF-kB2. B. Diagram of
3/17 primer combinations
used to evaluate for break
points. C. PCR reaction of
multiple
primer
combinations (A,B and C)
using
different
annealing
temperatures.
Two
no
responder and 1 responder
were
used
for
this
experiments. D. Example of
a break a part NF-kB2 FISH
in a bortezomib responder
and a no responder.


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1.6.1
Somatic Rate of NFKB2 rearrangement
We measured the 3’ end of NFKB2 of CD38(+) plasma cells and match germ line DNA derived
from blood granulocytes of 56 patients included in the study. Our preliminary data showed that
that 25 out of 56 had lower NFKB2 3’ end mRNA expression levels. To identify whether the loss
of NFKB2 3’end resulted from a rearrangement, we performed a NFKB2 break a part FISH in 31
patient of this cohort. Our results demonstrated that 9 (29%) patients with a positive structural
defect in this region. In addition, when we expanded the screening with the NFKB2 break a part
FISH in 20 MM patients identified outside of our original study, we detected a structural defect
in 7/20 patients (35%).
1.6.2
Origin of NFKB2 break point.
To identify potential sites of break and partners rearranged with NFKB2, we performed analysis
of the WGS data obtained from Genotypes and Phenotypes (dbGAP) database. We first selected
paired end reads in which one read was mapped to NFKB2 and the mate outside of NFKB2. This
analysis delineated three potential sites of break clustered in the promoter region, intron 1, and
the exon-intron junction of exon 12 (Figure 1A). These results were expanded by performing
RNA sequencing in 3 samples from our clinical database (2 non responder and 1 responder patient
as control) and found in addition to the break point between exon 12 and 13 another potential site
of break near exon 20, both of which had the presence of a repetitive element. To further validate
the site of NFKB2 break in our population, we performed long range PCR in 3 cases treated with
VD (2 non responders and 1 responder). As shown in figure 2B-C, a break point was located
between exons 12 and 14. In addition, these results were confirmed by break a part fluorescent
in situ hybridization methods (Figure 2D). Our findings demonstrated that 9 patients out of 31
patients studied had NFKB2 break (29%) and 4 out of 8 patients with low NFKB2 3’end also had
NFKB2 breaks.
1.6.3
Somatic NFKB2 rearrangement and response to Bortezomib and
dexamethasone treatment
We assessed the influence of the loss of NF-kB 3’end and the presence of NFKB2 rearrangement
on the clinical response of patients with multiple myeloma after 4 cycles of treatment with
bortezomib and dexamethasone. Figure 2A-B, illustrate the response status and the depth of
response with the level of NFKB2 3’ end, as displayed by a ratio generated from comparing
NFKB2 3’ end from CD138 (+) cells and peripheral blood leukocytes. Our univariate analysis
demonstrated that patients with low NFKB2 3’end ratio and abnormal FISH experience a lower
response rate than those with >1 ratio and a normal break a part FISH (odds ratio [OR] of
10.8;


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95% CI 1.99 to 58.16, p<0.01). In addition, history of monoclonal gammopathy of undetermined
significance also predicted for a better response to treatment with proteasome inhibitors (OR: 7.6;
95% CI of 1.2 to 47.6, p<0.05). However, after adjusting for potential predictors of patient
outcome in our multivariate Cox model analysis we found that only loss of NFKB2 3’end was
associated with a significant decrease in bortezomib and dexamethasone response ( HR:21.47,
95% CI: 2.99 to 154.399, p <0.01).
We further examined the sensitivity and specificity of the NFKB2 3’ end ratio after performing
an ROC curve. Using a cut off of 0.83 will allow to predict that patients with a higher value have
a 73% chance of achieving an optimal response. In contrast, those with levels lower than 0.83
have a 93.3% chance of not reaching an optimal response. To further evaluate the possible use of
NFKB2 break-apart FISH signal as a predictor of response, we performed FISH on whole bone
marrow of 31 patients in which QPCR data was available. Using a cut off detected by AUC curve,
we identified NFKB2 structural rearrangement in 9 patients (30%) patients of which 6/10 were
present in VD-non responders and 3/21 of VD-responders. To validate these findings we
performed FISH on CD38+ sorted cell from 23 new patients treated with bortezomib and
dexamethasone or carfilzomib, an irreversible inhibitor of the proteasome, and found consistency
with our previous results, in which 7 patients demonstrated a NFKB2 positive break signal. Five
out of 7 samples of non-responders patients demonstrated a positive break signal while 1/16 were
positive in the responders, indicating a chromosome translocation or inversion had disrupted the
NFKB2 locus and that this disruption predispose tumors to respond poorly to proteasome
inhibitors.
Subsequently, we tested multiple cell lines for NFKB2 rearrangement and identified by target
sequencing that HUT88 presents a balance translocation between chromosomes 10 and 3. Taking
advantage of this finding we compared the sensitivity of detection between 3’end NFKB2 qPCR
3’ end NFKB2 ratio and the break-apart FISH. To this end, we mixed cell line with normal
NFKB2, as it is in MM1S, with titrating doses of HUT88. Quantitative PCR was able to detect a
minimum of 3% HUT88 cells in the mix, while NFKB2 break-apart FISH was able to detect when
the percent of HUT88 reach 10%. The correlation between both tests was r2:0.98, P<0.02.
The association between pretreatment NFKB2 levels and bortezomib response was further
validated in 3 published gene expression and clinically annotated dataset originated from 3
independent clinical trials of MM patients treated with bortezomib. To best distinguish the
predictive power of the NFKB2 levels, we compare the affimetrix signal detected by 3 different
probes on patients that responded (CR + PR) or progressed to bortezomib treatment from trials
25 and 40. Logistic regression analysis fitting the model outcome response (CR and PR) vs.
no


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response (PD) to bortezomibtreatment
determine that NFKB2 mRNA levels
were
significantly
associated
with
bortezomib
response
(probe
_207535_s_at : OR: 2.42, 95% CI:
1.12-5.22,
OR
P-value:
0.025;
probe_209636_at: OR: 1.72, 95%CI:
1.16-2.55, OR p-value: 0.007
and
probe _211524_at: OR:2.27, 95% CI:
1.17-4.38, OR p-value: 0.015, Figure
2C).
We
next
build
a
receiver
operating
curve
analysis
using
bortezomib responders and
patients
with progression and showed thateach
probe
predicted
the
response
to
bortezomib with an overall accuracy
that
ranged
between
64%
and
74%(probe _207535_s_at:
accuracy
74%,
p-value
<0.002,
probe_209636_at: accuracy 72%, p-
value <0.001 and probe _211524_at:
accuracy 64%, p-value <0.03). Only
probe_209636_at kept its significant overall accuracy when patients that achieve stable disease
were included (overall accuracy of 66%, p-value =0.004, Figure 2). This analysis lacked of
significance when samples from trial 039 as independent set were used, which could be explained
by the notably higher response rates seen in this trial, as well as heterogeneity of the disease.
1.6.4
In vitro data
1.6.4.1Presence of NFKB2 3’end predict bortezomib sensitivity
The capacity to identify that loss of the NFKB2 3’end, by qPCR or FISH analysis, gave us the
ability to identify patterns of noncanonical NF-kB pathway dysregulation within MM samples.
Since loss of NFKB2 3’end was associated with poor response to bortezomib treatment, we
Figure 2. (A) Ratio of NF-kB2 3’end mRNA levels of
CD38(+) and peripheral blood granulocytes in bortezomib
and dexamethasone responder and nonresponder patients.
(B) NF-kB2 3’ end ratio according to Bortezomib
and
dexamethasone response. (C) Binary classification test
generate from one of the affymetrix NF-kB2 probes used
in patients treated with bortezomib treatment in 2 different
clinical trials. Affimetrix units were obtained after RMA
normalization of the full dataset.


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investigated the role of NFKB2 in bortezomib mediated apoptosis. We screened NFKB2protein
levels in a panel of HMCLs. Among them RPMI, L363, JJN3, EJM, KMS18 and JK6L
demonstrated the lowest protein levels of NFKB2 (Figure 3A). These results confirmed
previously described alterations in NFKB2 regulatory proteins such as NIK truncations (JJN3,
L363 and EJM), NFKB2 frameshift mutation disrupting the C-terminal ankyrin repeat (JK6L) and
homozygous deletions of BIRC2/BIRC3 chromosomal locus (KMS18). To determine whether
the NFKB2 levels correlated with bortezomib response, we selected cells with low (JJN3, RPMI,
Figure 3. (A) Western Blot
analysis of p100(NF-kB2) and
p52 in a panel of MM cell lines.
(B)
Treatment
curves
of
titrating doses of bortezomib.
Cells with high or low p100
protein levels were treated for
24 hours. Percent of live cells
was
measured
using
an
ImageXpress
5000A
Automated
Acquisition
and
Analysis
System
(Molecular
Devices), quantitating for Yo-
pro-1 or PI -negative cells. (C)
Western
blot
analysis
measuring
NF-kB2
protein
levels in cells stably expressing
V5 3’ tagged NF-kB2, (D)
Reduction
of
bortezomib
sensitivity in NF-kB2 silenced
cells. Cell survival measured in
a OPM1 and OPM2 cells after
stably
silencing
NF-kB2
expression. (E) Cell survival
in
NF-kB2
OPM1coexpressing
3’end
(Ankyrin
silenced
the
domain,
Ank)
or
the
5’end
rel
homology
domain.
(F)
Western blot illustrating the
expression of the NF-kB2
ankyrin domain, NF-kB2-death
domain
and
LacZ
(control)
protein. (G) Treatment curves
of titrating doses of bortezomib
treated cells expressing NF-
kB2 or its mutants (DD= death
domain).


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L363, EJM and JK6L) or high (OPM1, MM1S and KMS11) to evaluate cell survival to titrating
doses of bortezomib. Cells with low levels of NFKB2 show more resistance to bortezomib
treatment than cells with high NFKB2 levels, suggesting that NFKB2 might be important for
bortezomib mediated apoptosis (Figure 3B).
1.6.4.2
NFKB2 is important in bortezomib mediated apoptosis.
To determine whether the NFKB2 is involved in bortezomib sensitivity, we silenced NFKB2 in
2 bortezomib sensitive cell lines (OPM1 and OPM2) and tested for their response to bortezomib.
Our results demonstrated that silencing of NFKB2 in OPM1 and OPM2 cell lines decrease
bortezomib apoptotic effect significantly (Figure 3E-F, P<0.01). However, when we restore the
expression of the domains contained in the 3’ end of NFKB2 (ankyrin domain) in NFKB2 silenced
cells, we observed an improvement in bortezomib sensitivity. Furthermore, overexpression of
NFKB2 or any of the 3’end domains (Ankyrin or death domain) increased bortezomib apoptotic
effect independent of their original sensitivity to bortezomib (Figure 3F-G).
1.6.4.2.1 NFKB2 promotes the complex formation of p62/FADD and
caspase-8 to facilitate caspase 8 processing.
Since previous work has established that autophagy and caspase 8 are apical events for
mitochondrial activation and cell death during bortezomib treatment, we performed a time course
in 2 bortezomib-sensitive cells (MM1S and OPM1) to measure the sequence of events that leads
to caspase 3 activation. Caspase 8 was processed to their 43/41 subunits at 2 hours, and to p20 at
times correlating with caspase 9 cleavage (6 hours, Figure 4A-B). Supported by these results,we
investigated the consequence that silencing NFKB2 has on caspase 8 activation. NFKB2 reduced
caspase 8 activation early on followed by 9 and 3 activation (Figure 4B.1 and B.2).
The domains contained in the NFKB2 3’end participate in the formation of a death-inducing
signaling complex that links death receptor signals with caspase 8 activation upon irradiation or
TNFtreatment. Furthermore, in T cells FADD dependent binding to Atg5-Atg12
in
autophagosomes is essential for caspase 8 processing. We therefore investigated whether NFKB2
is linked with several of the autophagy members required for caspase 8 processing during
proteasome inhibition. NFKB2-v5 tagged protein was immunoprecipitated after treatment with
bortezomib, TNF or control OPM1 cells expressing a 3’ end V5 tagged NFKB2 protein.
Coprecipitating proteins were analyzed by immunobloting. Significant levels of P62, ATG5-
ATG12 conjugate, caspase 8 and FADD were detected as early as 5 minutes in TNF (positive
control) or bortezomib treated cells (Figure 4C). Reciprocal co-immunoprecipitation with a


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FADD antibody showed that NFKB2, and p62 precipitated with FADD (Figure 4D). Similar
results were observed in cells expressing endogenous FADD and NFKB2 protein levels (Figure
4E). To determine, which of these potential NFKB2 binding partners were directly bound to
NFKB2, we immunoprecipated FADD in NFKB2 silenced OPM1 cells. Silencing NFKB2 led to
a reduction in FADD, P62, caspase 8 binding and increase Atg5/Atg12-FADD binding,
suggesting that NFKB2 plays a major role in FADD-P62-Caspase 8 complex formation (Figure
4E). Finally, p62 and caspase 8 colocalization was evaluated in a time course of OPM1 cells
treated with bortezomib (10 nM) and demonstrated that p62-caspase 8 complex formation lasted
for 6 hours before returning to baseline. Together, these results link NFKB2 with the initiating
signaling required for caspase 8 activation during bortezomib treatment (Figure 4F).
Figure 4. NF-kB2 (p100) is
important for bortezomib
induction
of
caspase
8
cleavage. A. Western blot
analysis
measuring
p62,
LC3-I and II, or caspase 8,
9 and 3 in OPM1 and
MM1S
(A)
or
in
OPM1control (Luciferase-
shRNA, LUC-shRNA) or
NF-kB2 silenced cells (B)
during
treatment
with
bortezomib.
C-D.
Immunoprecipitating
FADD
or
p100-V5
followed by Western blot
analysis measuring FADD,
caspase
8,
p62
and
ATG5/12 in OPM1 treated
cells with TNF(10 ng) or
bortezomib
F.
Immunoprecipiation
of
FADD and western blot
analysis of p62, ATG5/12
or caspase 8 was done in
control (LUC-shRNA) or
NF-kB2
(p100)
silenced
cells after treatment with
bortezomib.
F.
Immunofluorescence
of
p62
and
caspase
8
in
OPM1expressing
luciferase- or
NF-
kB2(p100)-
shRNA.
Bortezomib=10 nM.


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1.7 Study Rationale
Advances in therapeutic combinations have improved the outcome of MM. Although these
combination of agents are now improving the outcome, many patients fail in achieving an optimal
response and are accompanied with higher toxicities and health care cost. Hence, if we could
identify at diagnosis a subset of patients that would benefit from specific therapies, this could lead
to higher optimal responses and lower toxicities and healthcare cost. Our proposal answers this
need by identifying for the first time whether we can tailor the treatment of relapsed MM patients,
as defined below, based on their NFKB2 rearrangement status. To this end, we propose to conduct
a prospective; biomarker driven randomized controlled trial to compare the clinical response of
relapsed MM patients treated with ixazomib plus dexamethasone versus ixazomib, lenalidomide
and dexamethasone based on their diagnostic NFKB2 break apart FISH results. The objectives of
the trial are to address whether patients without NFKB2 rearrangements treated with Id can have
a similar outcome to those with NFKB2 rearrangements treated with IRd regimen as assessed by
their clinical response, monoclonal protein, serum kappa lambda light chains, and bone disease.
Correlative studies in this proposal will characterize the gain of new genetic abnormalities in
plasma cells of patients that are refractory or relapsed after Id or IRd treatment. To this end, we
will assess for transcribed mutations by performing RNA sequencing (RNA-seq) of plasma cells
acquired from bone marrow biopsies obtained pre-randomization and at relapse or in patients with
evidence of progression.
2.
STUDY OBJECTIVES
2.1
Primary Objectives
The primary objective of the study is to test whether the NFKB2 rearrangement can guide the
selection of treatment (Ixazomib plus dexamethasone (Id) or ixazomib plus lenalidomide and
dexamethasone (IRd)) by conducting the 3 following comparisons:
o
To compare the response rate at 4 cycles between patients treated with Id and patients
treated with IRd and confirm the lack of significant difference in overall response.
o
To compare the response rate at 4 cycles between non-rearranged and rearranged
NFKB2 treated with Id and confirm that NFKB2 rearrangement is associatedwith


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reduce response rate
o
To compare the responses rate at 4 cycles of patients with rearranged NFKB2 treated
with Id or IRd and confirm that adding lenalidomide increases the response rate inthis
population
We assume that adding lenalidomide in the treatment among non-rearranged patients will not
further improve the response rate, because our preliminary data suggest that the response rate of
non-rearranged patients with Id is expected toreach 95% and has little room to improve.
Therefore, the arm non-rearranged NFKB2 gene treated with IRd has been omitted in order to
save resources. Our preliminary data has shown that adding lenalidomide to bortezomib, another
inhibitor of the proteasome, resulted in response rates of 95% and published data has shown that
ixazomib in combination with lenalidomide (len) and dexamethasone (dex) in newly diagnosed
multiple myeloma achieved a 92%; hence, has little room for improvement.
2.2
Secondary Objectives

To determine time to treatment failure (TTF)

To determine the frequency and severity AE in IRd treated cohort

To identify novel transcribed mutations associated with Id and IRd resistance in patients with
MM.

To determine the prevalence of NFKB2 rearrangement in Relapsed/Refractory MM patients
screened in the study.

To determine the prevalence of NFKB2 rearrangement according to the type of previous
therapies received in all patients screened in the study.

To determine the toxicity profile of the study drugs according to the presence of NFKB2
rearrangement.

Delineate transcribed mutations associated with relapse or refractoriness to Id or IRd treatment
by RNA-sequencing.
2.3
Hypothesis:
Patients without NFKB2 rearrangement treated with Id will have better outcomes to those with
NFKB2 rearranged treated with Id and similar outcome to those NFKB2 rearranged patients
treated with IRd.


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3.
STUDY ENDPOINTS
3.1
Primary Endpoints

The primary objective of the study is to test whether the NFKB2 rearrangement canguide
the selection of treatment (Ixazomib plus dexamethasone (Id) or ixazomib plus lenalidomide
and dexamethasone (IRd)) by conducting the 3 following comparisons:
o
To compare the response rate at 4 cycles between patients treated with Id and patients
treated with IRd and confirm the lack of significant difference in overall response.
o
To compare the response rate at 4 cycles between non-rearranged and rearranged
NFKB2 treated with Id and confirm that NFKB2 rearrangement is associatedwith
reduce response rate
o
To compare the responses rate at 4 cycles of patients with rearranged NFKB2 treated
with Id or IRd and confirm that adding lenalidomide increases the response rate inthis
population
3.2
Secondary Endpoints

To compare response rates between arms at 8 cycles of treatment

To determine the frequency and severity AE in IRd treated cohort

To determine time to treatment failure (TTF)

To determine the prevalence of NFKB2 rearrangement in Relapsed/Refractory MM
patients screened in the study.

To determine the prevalence of NFKB2 rearrangement according to the type of
previous therapies received in all patients screened in the study.

To determine the toxicity profile of the study drugs according to the presence of
NFkB2 rearrangement.

Delineate transcribed mutations associated with relapse or refractoriness to IDL
treatment by RNA-sequencing.
4.
STUDY DESIGN
4.1
Overview of Study Design
This is an open-label, 3-arm, phase II clinical trial to study the differential effect in treatment


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efficacy in terms of response rate between treatment (Id vs IRd) and NFKB2 mutation status in
relapsed patients with multiple myeloma. The potential maximum sample for this study is 90
patients.
At the time of study initiation at a subsite, the coordinating center multi-site coordinator (with
additional staff as needed) will perform a site initiation teleconference. During this teleconference,
the Emory team will review the study, enrollment, reporting, and regulatory compliance.
4.2
Treatment Assignment
Eligible patients with relapsed MM will be assigned to each arm according to their NFKB2
rearrangement status. The first 30 patients without NFKB2 rearrangement will be enrolled into
Arm A and treated with ixazomib and dexamethasone (Id). On the other hand, the first 60 patients
with NFKB2 rearrangement will be subsequently randomized to receive in Arm B: ixazomib and
dexamethasone or in Arm C: Ixazomib, dexamethasone and lenalidomide (IRd) until the specific
arm is closed. Randomization is conducted with a block of 2 patients in order to balance the
enrollment in each arm (The first of the 2 patients entered consecutively is randomly assigned to
one of the 2 arms (Arm B or Arm C) with equal probability and the second one is assigned to the
other arm).
Patients will be administered Ixazomib orally at a dose of 4 mg on Days 1, 8, and 15 during a 28-
day treatment cycle. Dexamethasone will be administered orally at a dose of 40mg daily on Days
1, 8 ,15 and 22 of a 28 day treatment cycle. In the IRd arm, lenalidomide will be administered
orally at a dose of 25 mg daily on Days 1-21 of a 28 day cycle. Lenalidomide starting dose to be
adjusted according to baseline renal function according to Package Insert guidelines. Doses of
ixazomib, lenalidomide, or dexamethasone may be held or reduced in an attempt to manage
toxicity according to the guidelines outlined in Section 6.3.2. Treatment repeats every 28 days
for 4 cycles, or beyond, in the absence unacceptable toxicity or if at least a minimal response has
been achieved.
Patients will be evaluated at scheduled visits over 3 study periods: Screening, Treatment, and End
of Treatment (EOT). The duration of therapy is 4 cycles where patients will be assessed for
response after Cycles 1, 2, 3, and 4. Patients may have stem cells mobilized after a minimum of
4 cycles and frozen for future use. Patients deemed appropriate by treating physician for transplant
may elect to stop treatment after 4 cycles and proceed to ASCT. At any point during the first 4


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cycles of treatment, patients suspected of disease progression (PD) will have response assessments
repeated to confirm disease progression (ie, 2 sets of response assessments at least 1 week apart).
Patients who do not proceed to ASCT after 4 cycles may remain on trial according to the schedule
presented in the Schedule of Events for Cycle 2+ visits. These subjects will continue to be
evaluated for disease response at the end of each cycle. Patient without unacceptable toxicity and
with at least minimal response should continue treatment until 8 cycles. At the end of Cycle 8 and,
per the investigator’s discretion, the subject may continue the trial regimen as outlined in the
Schedule of Events (Cycle 9+) until withdrawal of consent, disease relapse; unacceptable toxicity
or no further clinical benefit is experienced. Toxicity will be evaluated according to the
investigators’ documentation of AEs using the National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI CTCAE), Version 4.03 and, for neurotoxicity, will be guided
by the patients’ completion of the Functional Assessment of Cancer Therapy/Gynecology
Oncology Group Neurotoxicity (FACT/GOG Ntx) questionnaire (Appendix 16.3). AEs will be
assessed, and laboratory values, vital signs, ECGs (at diagnosis) will be obtained to evaluate the
safety and tolerability of ixazomib.
Radiological evaluations (skeletal surveys, and as clinically indicated, plain films of symptomatic
sites,
positron
emission
tomography-computed
tomography
[PET-CT],
computed
axial
tomography [CT] scan or magnetic resonance imaging [MRI]) will be employed to assess the
status of the patient’s multiple myeloma in bone and in extramedullary sites.
Serial blood samples and 24-hour urine collections will be analyzed for M-protein quantification
(serum protein electrophoresis [SPEP] and urine protein electrophoresis [UPEP], respectively),
serum free light chain assay, immunofixation of serum and urine, and quantification of
immunoglobulins. Bone marrow biopsy and aspirate will be obtained before initiation of therapy
to evaluate the extent of plasma cell infiltration, NFkB2 rearrangement, cytogenetics and for
correlative studies. In addition, bone marrow biopsy and aspirate will be obtained to confirm
relapse/refractoriness of the disease and complete remission, as well as for correlative studies
(only in relapsed/refractory patients). Disease response will be assessed using modified and
updated by the International Myeloma Working Group (IMWG).(Rajkumar 2011, Durie 2006)
4.3
Number of Patients
Approximately 90 patients will be enrolled in this study. Enrollment in this study is defined as
the time the patient receives the first dose of ixazomib.
4.4
Duration of Study


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The study duration for an individual patient will include a screening period for inclusion of up to
21 days, the treatment period may continue until disease progression, unacceptable adverse
reaction or other reason for discontinuation. After study treatment discontinuation an end of
treatment (EOT) visit will be done at 30 days after the last dose of ixazomib. Patients who
discontinue treatment for reasons other than progression of disease will be followed monthly until
progression or initiation of subsequent therapy.


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5.
STUDY POPULATION
5.1
Inclusion Criteria
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
1.
Male or female patients 18 years or older.
2.
Voluntary written consent must be given before performance of any study related procedurenot
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.
3.
Females of childbearing potential (FCBP)* must have a negative serum or urine pregnancy test
with a sensitivity of at least 50 mIU/mL within 10 – 14 days prior to and again within 24 hours of
starting lenalidomide and Ixazomib and must either commit to continued abstinence from
heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective
method and one additional effective method AT THE SAME TIME, at least 28 days before she
starts taking lenalidomide through 90 days after the last dose of study drug. FCBP must also agree
to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with
a FCBP even if they have had a vasectomy from the time of signing the informed consent form
through 90 days after the last dose of study drug. In the event that the male patients choose to
agree to practice true abstinence, this must follow the timelines detailed above. All patients
assigned to the lenalidomide treatment group must be registered in and must comply with all
requirements of the Revlimid REMS™program.
4.
Multiple myeloma diagnosed according to standard criteria either currently or at the time of initial
diagnosis.
5.
The patient has confirmed relapsed or refractory MM.
6.
For patients that relapse following a response to prior treatment with bortezomib or carfilzomib,
six months must have elapsed since the last dose of treatment.
7.
The patient has received 1 to 3 prior lines of therapy. By definition, a single line of therapy may
consist of 1 or more agents, and may include induction, hematopoietic stem cell transplantation,
and maintenance therapy. Radiotherapy, bisphosphonate, or a single short course of steroids (ie,
less than or equal to the equivalent of dexamethasone 40 mg/day for 4 days) would not be
considered prior lines of therapy
8.
Patients must have measurable disease defined by at least 1 of the following measurements:
o
Serum M-protein ≥1.0 g/dL (≥10 g/L) for an IgG myeloma, ≥0.1 g/dL for an IgD myeloma or
0.5 g/dL (≥5g/L) for an IgA myeloma.


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o
Urine light chain ≥200 mg/24 hours
o
Serum free light chain ≥10 mg/dL provided the FLC ratio is abnormal.
o
Patients with oligo- or non-secretory disease must have bone marrow involvement with atleast
30% plasmacytosis on aspiration.
9.
Eastern Cooperative Oncology Group (ECOG) performance status and/or otherperformance
status 0, 1, or 2.
10. Patients must meet the following clinical laboratory criteria:
a.
Absolute neutrophil count (ANC) 1,000/mm3 and platelet count 75,000/mm3. In the
case that platelets are between 50,000 -75,000, the patient can be enrolled if the plasma
cell count in the bone marrow is superior to ≥50%. To meet this hematological eligibility
no transfusion support and hematological growth factor are not allowed within 7 days
before study enrollment.
b.
Total bilirubin 1.5 the upper limit of the normal range (ULN).
c.
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 2.5 ULN.
d.
Serum creatinine ≤2.5 mg/dL or a calculated creatinine clearance 50 mL/min.
* A female of childbearing potential is a sexually mature woman who: 1) has not undergone a
hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least24
consecutive months.
5.2
Exclusion Criteria
1. The patient is refractory to carfilzomib or bortezomib. (Refractory is defined as patients
who never achieved a response and progressed while on carfilzomib or bortezomib or
within 60 days of completing treatment).
2. Prior treatment with any investigational proteasome inhibitor within 6 months of study
entry.
3. Female patients who are breast feeding or have a positive serum pregnancy test during the
screening period.


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4. Failure to have fully recovered (ie, > Grade 1 toxicity) from the reversible effects of prior
chemotherapy.
5. Diarrhea > Grade 1 according to NCI CTCAE v4.03
6. Prior chemotherapy and/or immunotherapy within 14 days before enrollment. Major
surgery within 14 days before enrollment and minor surgery within 7 days prior to Cycle
1 Day 1
7. Radiotherapy within 14 days before enrollment. If the involved field covered ≤5% of the
bone marrow reserve, the patient may be enrolled irrespective of the end date of
radiotherapy.
8. Central nervous system involvement.
9. Infection requiring systemic antibiotic therapy or other serious infection within 14 days
before study enrollment.
10. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled
hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure,
unstable angina, or myocardial infarction within the past 6 months.
11. Systemic treatment, within 14 days before the first dose of ixazomib, with strongCYP3A
inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or
use of Ginkgo biloba or St. John’s wort.
12. Active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV)
positive.
13. Any serious medical or psychiatric illness that could, in the investigator’s opinion,
potentially compromise the paient’s ability to understand the patient information, to give
informed consent, to comply with the treatment according to this protocol or complete the
study.
14. Diagnosed or treated for another malignancy within 2 years before study enrollment 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.


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15. Patient has ≥Grade 2 peripheral neuropathy or neuropathy with pain, regardless of grade
that is seen on clinical examination during the screening period.
16. Known intolerance to IMiDs.
17. History of allergic reaction/hypersensitivity to any of the study medications, their
analogues or excipients in the various formulations.
18. Known GI disease or GI procedure that could interfere with the oral absorptionor tolerance
of ixazomib or lenalidomide, including difficulty swallowing.
19. Participation in other clinical trials, including those with other investigational agents not
included in this trial, such as monoclonal antibodies, within 30 days of the start of this trial
and throughout the duration of this trial.
20. Corticosteroid doses > 10 mg/day of prednisone or equivalent within 14 days prior to
Cycle 1 Day 1.
21. Autologous or allogeneic stem cell or bone marrow transplant within 3 months prior to
Cycle 1 Day 1.
22. Cytotoxic therapy within 21 days prior to Cycle 1 D1.
23. Patients that have previously been treated with ixazomib, or participated in a study with
ixazomib whether treated with ixazomib or not..
6.
STUDY DRUG
6.1
Description of Investigational Agents
6.1.1
Ixazomib Capsules
The ixazomib drug product is provided in strengths of 4.0, 3.0, and 2.3 mg capsules as stable
citrate ester drug substance, ixazomib citrate. The different dose strengths are differentiated by
both capsule size and color as described below:
For additional details, please see the ixazomib IB.


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6.2
Study Drug Administration
6.2.1
Ixazomib Administration
All protocol-specific criteria for administration of study drug must be met and documented before
drug administration. Study drug will be administered or dispensed only to eligible patients under
the supervision of the investigator or identified subinvestigator(s). Patients should be monitored
for toxicity, as necessary, and doses of ixazomib should be modified as needed to accommodate
patient tolerance to treatment; this may include symptomatic treatment, dose interruptions, and
adjustments of ixazomib dose (see Section 7).
The prescribed administration of ixazomib doses in this study is days 1, 8, 15 of ixazomib in a 28
day cycle.
Patients should be instructed to swallow ixazomib capsules whole, with water, and not to break,
chew, or open the capsules. Study drug should be taken on an empty stomach (no food or drink)
at least 1 hour before or 2 hours after a meal. Each capsule should be swallowed separately with
a sip of water. A total of approximately 8 ounces (240 mL) of water should be taken with the
capsules.
Every effort should be made to comply with the dose and schedule in cycle unless due to toxicity.
Missed doses can be taken as soon as the patient remembers if the next scheduled dose is 72 hours
or more away. A double dose should not be taken to make up for a missed dose. If the patient
vomits after taking a dose, the patient should not repeat the dose but should resume dosing at the
time of the next scheduled dose.
6.2.2
Ixazomib Destruction
Investigational ixazomib (expired or end of study) should be destroyed on site according to the
institution’s standard operating procedure. Be sure to document removal and destruction on drug
accountability logs.
6.3
Lenalidomide
Lenalidomide is an analogue of thalidomide with immunomodulatory, antiangiogenic, and
antineoplastic properties. Lenalidomide inhibits proliferation and induces apoptosis of certain
hematopoietic tumor cells including multiple myeloma, mantle cell lymphoma, and del (5q)
myelodysplastic syndromes in vitro. Lenalidomide causes a delay in tumor growth in some in
vivo nonclinical hematopoietic tumor models including multiple myeloma. Immunomodulatory


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properties of lenalidomide include activation of T cells and natural killer (NK) cells, increased
numbers of NKT cells, and inhibition of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by
monocytes. In multiple myeloma cells, the combination of lenalidomide and dexamethasone
synergizes the inhibition of cell proliferation and the induction of apoptosis.
6.3.1
Lenalidomide Administration
Lenalidomide should be taken once daily at about the same time each day, either with or without
food. The capsules should not be opened, broken, or chewed. Lenalidomide should be swallowed
whole with water.
Instruct patients that if they miss a dose of lenalidomide, they may still take it up to 12 hours after
the time they would normally take it. If more than 12 hours have elapsed, they should be instructed
to skip the dose for that day. The next day, they should take lenalidomide at the usual time.
Patients should not take 2 doses to make up for the one that they missed.
Commercial supplies of lenalidomide will be used for this study. Refer to the package insert for
full prescribing information
Prescribers must be certified with the REVLIMID REMS™program by enrolling and complying
with the REMS requirements.
Patients must sign a Patient-Prescriber agreement form and comply with the REMS requirements.
In particular, female patients of reproductive potential who are not pregnant must comply with
the pregnancy testing and contraception requirements.
Pharmacies must be certified with the REVLIMID REMS™program, must only dispense to
patients who are authorized to receive lenalidomide and comply with REMS requirements.
6.4
Dexamethasone
Commercial supplies of dexamethasone will be used in this study. Oral dexamethasone will be
given on an outpatient basis. Missed doses of dexamethasone will not be made up.
7. DOSE-MODIFICATION
The patient will be evaluated weekly for possible toxicities that may have occurred after the
previous dose(s). Toxicities are to be assessed according to the NCI CTCAE, version 4.03. Dose
modifications may be performed in all cycles of treatment. If toxicities cannot be managed
by


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dose modification or the patient cannot tolerate the lowest dose of study drug, the patient is to be
discontinued from study treatment. Exceptions may be made for patients that are experiencing
clinical benefit in discussion with the Lead Principal Investigator.
7.1
Dose Reduction Steps
7.1.1
Ixazomib Dose Reduction Steps
Ixazomib Dose Reduction Steps
Starting dose
First Dose reduction Step
Second dose reduction Step
4 mg
3 mg
2.3 mg
7.1.2
Lenalidomide Dose Reduction Steps
Lenalidomide Dose Reduction Steps
(Lenalidomide starting dose to be adjusted according to baseline renal
function according to Package Insert guideline).
Starting dose
First dose reduction
Step
Second dose reduction
Step
third dose reduction
Step
25 mg
15 mg
10 mg
5 mg
7.1.3
Dexamethasone Dose Reduction Steps
Dexamethasone Dose Reduction Steps
Starting dose
First Dose reduction Step
Second dose reduction Step
40 mg
20 mg
12 mg
Dexamethasone may be permanently discontinued for toxicity at the discretion of the investigator
but the patient can remain on study therapy with lenalidomide and/or ixazomib if tolerated.


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7.2
Dose Modification Guidelines during A Cycle Of Therapy
Each AE should be attributed to a specific drug, if possible, so that the dose modifications can be
made accordingly. Reduction of 1 agent and not the other is appropriate (for patients assigned to
IRd, if toxicity is related primarily to 1 of the agents. Prior to beginning the next cycle of
treatment, refer to the guidelines in Section 7.4. Further clarification can be obtained in
consultation with the Principal Investigator. If multiple toxicities are noted, the dose adjustments
and/or delays should be made according to guidelines of the most severe toxicity.
7.2.1 Ixazomib and Lenalidomide dose modification Guidelines During a
cycle of therapy
A decision regarding which study drug requires dose reduction will be dependent upon the
toxicity, its onset, and time course. Alternative dose modifications may be recommended after
discussion with the investigator and Principal Investigator to maximize exposure of study
treatment while protecting patient safety given that there may be overlapping dose limiting
toxicities (eg, thrombocytopenia, neutropenia, rash, and peripheral neuropathy.
Hematologic Toxicity during a cycle of therapy
Neutropenia
Absolute Neutrophil
Count
Action on Study
Drug (Ixazomib)
Action on
Lenalidomide
Action
First fall to < 0.5 ×
109/L
Interrupt treatment
Interrupt treatment
Follow CBC weekly;add
G-CSF
Return to ≥500 ×
103/mcL within the
same cycle
Resume and
maintain dose
level
Resume lenalidomide
at next lower dose
level
Eg, if lenalidomide dose was
25 mg, reduce to 15 mg
Second fall to < 0.5 ×
109/L
Interrupt treatment
Interrupt treatment
Follow CBC weekly; see
Section 6.10 for myeloid
growth factor recommendations
Return to ≥500 ×
103/mcL within the
same cycle
Resume study drug
at next lower dose
level
Resume and
maintain doselevel
Eg, if ixazomib dosewas
4 mg, reduce to 3 mg
Third fall to < 0.5 ×
109/L
Interrupt treatment
Interrupt treatment
Follow CBC weekly; see
Section 6.10 for myeloid
growth factor recommendations
Return to ≥500 ×
103/mcL within the
same cycle
Resume and
maintain dose
level lower
Resume lenalidomide
at next lower dose
level
Eg, if lenalidomide dose was
15 mg, reduce to 10 mg


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Fourth fall to < 0.5 ×
109/L
Interrupt treatment
Interrupt treatment
Follow CBC weekly;see
Section 6.7 for myeloid
growth factor
recommendations
Return to ≥500 ×
103/mcL within the
same cycle
Resume study drug
at next lower dose
level
Resume and
maintain doselevel
Eg, if ixazomib dose was
3 mg, reduce to 2.3 mg
Do not reduce below 2.3 mg.
Fifth fall to < 0.5 ×
109/L
Interrupt treatment
Interrupt treatment
Follow CBC weekly;see
Section 6.10 for
myeloid growth factor
recommendations.
Return to ≥500 ×
103/mcL within the
same cycle
Resume and
maintain dose
level lower
Resume lenalidomide
at next lower dose
level
Eg, if lenalidomide dose was
10 mg, reduce to 5 mg
Do not reduce below 5 mg
Thrombocytopenia
Platelet Count
Action on Study
Drug (ixazomib)
Action on
Lenalidomide
Action
First fall to <
30.000/mm3
Return to
≥30,000/mm3 within
the same cycle
Interrupt treatment
Resume and
maintain
dose level
Interrupttreatment
Resume
lenalidomide at next
lower dose level
Follow complete blood counts
(CBC) weekly
Eg, if lenalidomide dose
was 25 mg, reduce to 15 mg
Second fall to
< 30,000/mm3
Interrupt treatment
Interrupt treatment
Follow CBC weekly
Return to
≥30,000/mm3 within
the same cycle
Resume study
drug at next
lower dose level
Resume and maintain
dose level
Eg, if ixazomib dose was
4 mg, reduce to 3 mg
Third fall to
< 30,000/mm3
Interrupt treatment
Interrupt treatment
Follow CBC weekly
Return to
≥30,000/mm3 within
the same cycle
Resume and
maintain
dose level
Resume
lenalidomide at next
lower dose level
Eg, if lenalidomide dose
was 15 mg, reduce to 10 mg
Fourth fall to
< 30,000/mm3
Interrupt treatment
Interrupt treatment
Follow CBC weekly
Return to
≥30,000/mm3 within
the same cycle
Resume study
drug at next
lower dose level
Resume and maintain
dose level
Eg, if ixazomib dose was
3 mg, reduce to 2.3 mg
Do not reduce below 2.3 mg
Fifth fall to
< 30,000/mm3
Interrupt treatment
Interrupt treatment
Follow CBC weekly
Return to
≥30,000/mm3 within
the same cycle
Resume and
maintain
dose level
Resume
lenalidomide at next
lower dose level
Eg, if lenalidomide dose was
10 mg, reduce to 5 mg Do not
reduce below 5 mg
In some severe situations, both lenalidomide and study drug may be interrupted if needed, or alternative
dose modification management implemented based on discussion between the treating physician and
Principal Investigator Angioedema and Grade 4 rash have been reported with lenalidomide and should
result in lenalidomide discontinuation.


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Non-Hematologic toxicity during a cycle of therapy
CTCAE Category
AGENTS
Toxicity During a Cycle
Non-blistering rash
Grade 4
Lenalidomide/
Ixazomib
Discontinue lenalidomide and ixazomib.
Withdraw participant from the study.
Patient should be treated immediately following
institutional guidelines.
Desquamating (blistering)
rash-any Grade or
Erythema multiforme >
Grade 3
Lenalidomide/
Ixazomib
Discontinue treatment. Withdraw participant
from study.
Patient should be treated immediately following
institutional guidelines.
New onset of
Hyperthyroidism or
Hypothyroidism
Lenalidomide
Omit lenalidomide for remainder of cycle,
evaluate etiology, and initiate appropriate
therapy. Restart lenalidomide at investigator’s
discretion.
Neuropathy
Grade 2 peripheral
neuropathy with pain or
≥Grade 3
Grade 4
Lenalidomide
Ixazomib
Hold ixazomib. Follow weekly. If the toxicity
resolves to ≤grade 1(or baseline), restart
ixazomib at next lower dose level and continue
through the scheduled end of the cycle.
Otherwise, omit for remainder of cycle and
reduce the dose of ixazomib one dose level at the
start of the next cycle. Omitted doses are not
made up. For recurrent Grade 2 peripheral
neuropathy with pain or grade 3 neuropathy,
hold treatment. If the toxicity resolves to ≤grade
1(or baseline), reduce lenalidomide and /or
ixazomib at investigators discretion. (IRd
treatment group)
Discontinue treatment. Withdraw participant
from study.
Herpes Zoster
reactivation any grade
Lenalidomide
Ixazomib
Hold ixazomib and lenalidomide (IRd treatment
group) until lesions are dry. Initiate antiviral
therapy. (maintain dose level)
Venous
Thrombosis/embolism >
Grade 3
Lenalidomide/
Ixazomib
Hold therapy and start full anticoagulation as
appropriate; restart at investigator’s discretion
(maintain dose level).


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Other Lenalidomide or
Ixazomib related non-
hematologic toxicity
Grade > 3
Grade 4 related non-
hematologic toxicity
Lenalidomide
Ixazomib
Determine attribution (IRd treatment group) of
toxicity and hold appropriate therapy. Follow at
least weekly. If toxicity resolves to < grade 1 or
baseline, resume therapy with one level dose
reduction.
Consider permanent discontinuation of therapy.
Exceptions may be made following discussion
with the Lead Principal Investigator for patients
that are experiencing clinical benefit.
7.3
Dexamethasone dose modification Guidelines
Body System
Symptom
Recommended Action
Gastrointestinal
Dyspepsia, gastric or duodenal
ulcer, gastritis Grade 1–2
(requiring medical management)
Treat with H2 blockers, sucralfate, or
omeprazole. If symptoms persist
despite above measures, decrease
dexamethasone dose by 1 dose level.
Gastrointestinal
> Grade 3
(requiring hospitalization or
surgery)
Hold dexamethasone until symptoms
adequately controlled. Restart and
decrease one dose level of current
dose along with concurrent therapy
with H2 blockers, sucralfate, or
omeprazole. If symptoms persist
despite above measures, discontinue
dexamethasone and do not resume.
Gastrointestinal
Acute pancreatitis
Discontinue dexamethasone and do
not resume
Cardiovascular
Edema
>Grade 3 (limiting function and
unresponsive to therapy or
anasarca)
Diuretics as needed, and decrease
dexamethasone dose by 1 dose level;
if edema persists despite above
measures, decrease dose another dose
level. Discontinue dexamethasone and
do not resume if symptoms persist
despite second reduction.
Neurology
Confusion or Mood alteration
> Grade 2 (interfering with
function +/- interfering with
activities of daily living)
Hold dexamethasone until symptoms
resolve. Restart with one dose level
reduction. If symptoms persist despite
above measures, discontinue
dexamethasone and do not resume.
Musculoskeletal
Muscle weakness
Decrease dexamethasone dose by one
dose level. If weakness persists


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> Grade 2 (symptomatic and
interfering with function +/-
interfering with activities of
daily living)
despite above measures, decrease dose
by one dose level. Discontinue
dexamethasone and do not resume if
symptoms persist.
Metabolic
Hyperglycemia > Grade 3 or
higher
Treatment with insulin or oral
hypoglycemics as needed. If
uncontrolled despite above measures,
decrease dose by one dose level until
levels are satisfactory.
Dexamethasone may be permanently discontinued for toxicity at the discretion of the investigator
but the patient can remain on study therapy with Lenalidomide and/or ixazomib if tolerated.
7.4
Criteria for Initiation of A New Cycle of Therapy
For a new cycle of treatment to begin, the patient must meet the following criteria:

ANC must be ≥1,000/mm3.

Platelet count must be ≥75,000/mm3. For patients with to >50% plasma cells at baseline
and platelets count between 50 – 75,000/mm3, treatment should be adjusted according to
the dose modification guidelines described in section 7.2.1

All other non-hematologic toxicity (except for alopecia) must have resolved to ≤Grade 1
or to the patient’s baseline condition
If the patient fails to meet the above-cited criteria for initiation of the next cycle of treatment,
dosing should be delayed for 1 week. At the end of that time, the patient should be re-evaluated
to determine whether the criteria have been met. If the patient continues to fail to meet the above-
cited criteria, delay therapy and continue to reevaluate weekly. Should the start of the next cycle
need to be delayed for more than 2 weeks because of incomplete recovery or newly encountered
toxicity reduce the dose of the drug contributing to the toxicity by one dose level at the start of
the next cycle. Only one dose level reduction of one or both drugs should be made per cycle.
The maximum delay before treatment should be discontinued will be 4 weeks (including if there
is required stem cell harvesting where a 4 week delay is also acceptable). Patients in whom there
may be clinical benefit, in the absence of disease progression, as per their treating physician,
treatment may be continued after discussion with the Lead Principal Investigator and Millennium
Pharmaceuticals, Inc./Takeda


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7.5
Concomitant Medications
All concomitant medications administered from the time of informed consent signature through
30 days after the end of treatment (last dose or investigator/patient decision to discontinue,
whichever is later) are to be reported on the appropriate CRF for each patient.
7.5.1 Excluded Concomitant Medications and Procedures
Systemic treatment with any of the following metabolizing enzyme inducers should be avoided,
unless there is no appropriate alternative medication for the patient’s use (Rationale: If there were
to be a DDI with an inducer, ixazomib exposure would be less; therefore, there would be a reduced
chance of an AE. However, there may be less chance for an antitumor effect, but that is not an
absolute reason to be taken off ixazomib):

Strong CYP3A inducers: rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, and
phenobarbital

Excluded foods and dietary supplements include St. John’s wort and Ginkgo biloba
The following procedures are prohibited during the study.

Any antineoplastic treatment with activity against MM, other than study drugs

Radiation therapy (note that, in general, the requirement for local radiation therapy
indicates disease progression)

Platelet transfusions to help patients meet eligibility criteria are not allowed within 14 days
prior to study drug dosing for any dosing day
7.6
Permitted Concomitant Medications and Procedures
The following medications and procedures are permitted during the study:

Antiemetics, including 5-HT3 serotonin receptor antagonists, may be used at the discretion
of the investigator.

Loperamide or other antidiarrheal should be used for symptomatic diarrhea at discretion
of the investigator. The dose and regimen will be according to institutional guidelines. IVF
should be given to prevent volume depletion.


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
Growth factors (eg, granulocyte colony stimulating factor [G-CSF], granulocyte
macrophage-colony stimulating factor [GM-CSF], recombinant erythropoietin) are
permitted. Their use should follow published guidelines and/or institutional practice.
Erythropoietin will be allowed in this study. Their use should follow published guidelines
and/or institutional practice.

Patients should be transfused with red cells and platelets as clinically indicated and
according to institutional guidelines.

Treatment doses of antiviral therapy such as acyclovir may be administered if medically
appropriate.

Concomitant treatment with bisphosphonates will be permitted, as appropriate.

Patients who experience worsening neuropathy from baseline may be observed for
recovery and have dose reductions/delays as indicated in the protocol, and any supportive
therapy or intervention may be initiated as appropriate at the discretion of the investigator.

Supportive measures consistent with optimal patient care may be given throughout the
study.
7.7
Required/Recommended Concomitant Therapy

Prophylaxis against Risk of Infection: Antiviral therapy such as acyclovir
or
valacyclovir should be initiated at the onset of administration of ixazomib. Other antivirals
are also acceptable.

Prophylaxis against Risk of Deep Vein Thrombosis: Lenalidomide increases the risk of
thromboembolism. Anti-coagulation prophylaxis is required after an assessment of each
patient’s underlying risk factors, unless there is an excess risk of bleeding. Aspirin 81mg
daily is required to be initiated at the onset of administration of lenalidomide unless
contraindicated or alternate anti-coagulation (e.g. LMWH) is used for patient at high risk.

Prophylaxis against pathologic fractures: Bisphosphonates such as zoledronic acid
should be initiated at the onset of administration of ixazomib.
7.8
Precautions and Restrictions

Fluid deficit should be corrected before initiation of treatment and during treatment.


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
Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided with impaired renal
function given reported NSAID-induced renal failure in patients with decreased renal
function.

When digoxin was co-administered with lenalidomide, the digoxin AUC was not
significantly different; however, the digoxin Cmax was increased by 14%. Periodic
monitoring of digoxin plasma levels in accordance with clinical judgment and based on
standard clinical practice in patients receiving this medication is recommended during
administration of lenalidomide.
7.9
Pregnancy
It is not known what effects ixazomib has on human pregnancy or development of the embryo or
fetus. Lenalidomide can cause fetal harm when administered during pregnancy. Therefore,
female patients participating in this study should avoid becoming pregnant, and male patients
should avoid impregnating a female partner. Females of child bearing potential* and male
patients should use effective methods of contraception through defined periods during and after
study treatment as specified below.
*A female of child bearing potential is any sexually mature female who:
1) has not undergone a hysterectomy or bilateral oophorectomy; or
2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses
at any time in the preceding 24 consecutive months).
7.9.1
Females
Females of reproductive potential must commit either to abstain continuously from heterosexual
sexual intercourse or to use two methods of reliable birth control simultaneously (one highly
effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections,
hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective
contraceptive method – male latex or synthetic condom, diaphragm or cervical cap. Contraception
must begin 4 weeks prior to initiating treatment, during therapy, during dose interruptions and
continuing for 4 weeks following discontinuation of lenalidomide or 90 days following
discontinuation of ixazomib. Reliable contraception is indicated even where there has been a
history of infertility, unless due to hysterectomy. Females of reproductive potential should be
referred to a qualified provider of contraceptive methods, if needed.


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Females of reproductive potential must have 2 negative pregnancy tests before initiating therapy.
The first test should be performed within 10-14 days, and the second test within 24 hours prior to
prescribing lenalidomide and ixazomib. ARM A and B: FCBP on this arm will not be taking
lenalidomide. Females of reproductive potential in these arms must have 2 negative pregnancy
tests before initiating therapy. The first test should be performed within 10-14 days, and the
second test within 24 hours prior to the first dose of ixazomib. A pregnancy test will be formed at
day one on all future cycles. ARM C: This arm will be taking lenalidomide. Females of reproductive
potential must have 2 negative pregnancy tests before initiating therapy. The first test should be
performed within 10-14 days, and the second test within 24 hours prior to prescribing
lenalidomide and ixazomib. Repeat pregnancy test every week for the first 4 weeks and then every
28 days while on therapy and during interruptions in therapy and 28 days following
discontinuation of lenalidomide. Women with irregular menstruation must have pregnancy testing
every 14 days while on therapy and during interruptions and 14 and 28 days after discontinuation
of lenalidomide. All study participants on Arm C must be registered into the mandatory
Revlimid REMS™program, and be willing and able to comply with the requirements of the
Revlimid REMS™program.
7.9.2
Males
Lenalidomide is present in the semen of males who take lenalidomide. The effects of ixazomib
are unknown. Therefore, males must always use a latex or synthetic condom during any sexual
contact with females of reproductive potential while taking lenalidomide or ixazomib and for up
to 28 days after discontinuing lenalidomide or 90 days after discontinuation of ixazomib, even if
they have undergone a successful vasectomy. Male patients taking lenalidomide or ixazomib must
not donate sperm. In the event that the male patients choose to agree to practice true abstinence, this
must follow timelines detailed above. All study participants must be registered into the mandatory
Revlimid REMS™program, and be willing and able to comply with the requirements of the
Revlimid REMS™program.
7.10
Management of Clinical Events
Adverse drug reactions such as thrombocytopenia, diarrhea, fatigue, nausea, vomiting, and rash
have been associated with ixazomib and lenalidomide treatment. Management
guidelines
regarding these events are outlined below. Further details of management of ixazomib AEs are
described in Section 6 of the ixazomib IB and in the package insert for lenalidomide.
7.10.1
Thromboembolism Prophylaxis
Anti-coagulation prophylaxis is required after an assessment of each patient’s underlying risk
factors, unless there is an excess risk of bleeding. For patients at high risk, thromboprophylaxis


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according to ASCO guidelines or institutional standard of care is recommended.
7.10.2
Prophylaxis against Risk of Reactivation of Herpes Infection
Patients may be at an increased risk of infection including reactivation of herpes zoster and herpes
simplex viruses. Antiviral therapy such as acyclovir, valacyclovir, or other antivirals may be
initiated as clinically indicated. Other antivirals are also acceptable.
7.10.3
Nausea and/or Vomiting
Standard anti-emetics including 5-hydroxytryptamine 3 serotonin receptor antagonists are
recommended for emesis if it occurs once treatment is initiated; prophylactic anti-emetics may
also be considered at the physician’s discretion. Dexamethasone should not be administered as an
anti-emetic. Fluid deficit should be corrected before initiation of study drug and during treatment.
7.10.4
Diarrhea
Prophylactic antidiarrheals will not be used in this protocol. However, diarrhea should be
managed according to clinical practice, including the administration of antidiarrheals once
infectious causes are excluded. Fluid intake should be maintained to avoid dehydration. Fluid
deficit should be corrected before initiation of treatment and during treatment.
7.10.5
Erythematous Rash With or Without Pruritus
As with bortezomib, rash with or without pruritus has been reported with ixazomib, primarily at
the higher doses tested and when given with agents where rash is an overlapping toxicity such as
lenalidomide. The rash may range from limited erythematous areas, macular and/or small papular
bumps that may or may not be pruritic over a few areas of the body, to a more generalized eruption
that is predominately on the trunk or extremities. Rash has been most commonly characterized
as maculopapular or macular. To date, when it does occur, rash is most commonly reported within
the first 3 cycles of therapy. The rash is often transient, self-limiting, and is typically Grade 1 to
2 in severity.
Symptomatic measures such as antihistamines or corticosteroids (oral or topical) have been
successfully used to manage rash and have been used prophylactically in subsequent cycles. The
use of a topical, IV, or oral steroid (eg, prednisone ≤10 mg per day or equivalent) is permitted.
Management of a Grade 3 rash may require intravenous antihistamines or corticosteroids.
Administration of ixazomib (and/or other causative agent if given in combination) should be
modified per protocol and re-initiated at a reduced level from where rash was noted (also, per
protocol).
The lenalidomide induced rash is characterized as generalized, maculopapular, morbilliform,
urticarial, papular, often with pruritus. Per the package insert, discontinuation should be
considered for Grade 2-3 skin rash and discontinuation definitely for Grade 4 rash. However,


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serious skin reactions such as Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis and
Erythema Multiforme have been reported. Lenalidomide interruption or discontinuation should
be considered as described in the Package Insert/Summary of Product Characteristics.
(lenalidomide product label)
In line with clinical practice, dermatology consult and biopsy of Grade 3 or higher rash or any
SAE involving rash is recommended. Prophylactic measures should also be considered if a patient
has previously developed a rash (eg, using a thick, alcohol-free emollient cream on dry areas of
the body or oral or topical antihistamines). Punch biopsies for histopathological analysis are
encouraged at the discretion of the investigator.
7.10.6
Thrombocytopenia
Blood counts should be monitored regularly as outlined in the protocol with additional testing
obtained according to standard clinical practice. Thrombocytopenia may be severe but has been
manageable with platelet transfusions according to standard clinical practice. Ixazomib and/or
lenalidomide (IRd treatment group) administration should be modified as noted as per dose
modification recommendations in the protocol when thrombocytopenia occurs (see Table 6-2).
Therapy can be reinitiated at a reduced level upon recovery of platelet counts. A rare risk is
thrombotic thrombocytopenic purpura (TTP), a rare blood disorder where blood clots form in
small blood vessels throughout the body characterized by thrombocytopenia, petechiae, fever, or
possibly more serious signs and symptoms. TTP should be managed symptomatically according
to standard medical practice.
7.10.7
Neutropenia
Blood counts should be monitored regularly as outlined in the protocol with additional testing
obtained according to standard clinical practice. Neutropenia may be severe but has been
manageable. Growth factor support is not required but may be considered according to standard
clinical practice. Ixazomib and/or lenalidomide (IRd treatment group) administration should be
modified as noted as per dose modification recommendations in the protocol when neutropenia
occurs (see Section 7.2.1).
7.10.8
Fluid Deficit
Dehydration should be avoided since ixazomib may cause vomiting, diarrhea, and dehydration.
Acute renal failure has been reported in patients treated with ixazomib, commonly in the setting
of the previously noted gastrointestinal toxicities and dehydration.
Fluid deficit should be corrected before initiation of study drug and as needed during treatment to
avoid dehydration.


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7.10.9
Hypotension
Symptomatic hypotension and orthostatic hypotension with or without syncope have been
reported with ixazomib. Blood pressure should be closely monitored while the patient is on study
treatment and fluid deficit should be corrected as needed, especially in the setting of concomitant
symptoms such as nausea, vomiting, diarrhea, or anorexia. Patients taking medications and/or
diuretics to manage their blood pressure (for either hypo- or hypertension) should be managed
according to standard clinical practice, including considerations for dose adjustments of their
concomitant medications during the course of the trial. Fluid deficit should be corrected before
initiation of study drug and as needed during treatment to avoid dehydration.
7.10.10
Posterior Reversible Encephalopathy Syndrome
One case of posterior reversible encephalopathy syndrome, which ultimately resolved, has been
reported with ixazomib. This condition is characterized by headache, seizures and visual loss, as
well as abrupt increase in blood pressure. Diagnosis may be confirmed by magnetic resonance
imaging (MRI). If the syndrome is diagnosed or suspected, symptom-directed treatment should
be maintained until the condition is reversed by control of hypertension or other instigating
factors.
7.10.11
Transverse Myelitis
Transverse myelitis has also been reported with ixazomib. It is not known if ixazomib causes
transverse myelitis; however, because it happened to a patient receiving ixazomib, thepossibility
that ixazomib may have contributed to transverse myelitis cannot be excluded.
7.11
Preparation, Reconstitution, and Dispensing
ixazomib and lenalidomide are anticancer drug and as with other potentially toxic compounds
caution should be exercised when handling ixazomib and lenalidomide capsules.
7.12
Packaging and Labeling
7.12.1
Ixazomib
The study drug ixazomib capsules will be provided by Millennium/Takeda. The study drug will be
labeled and handled as open-label material, and packaging labels will fulfill all requirements
specified by governing regulations. The drug product is provided in strengths of 4.0, 3.0 and 2.3
mgcapsules.


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7.12.2
Lenalidomide
Lenalidomide is commercially available and will be labeled for commercial use.
7.12.3
Dexamethasone
Dexamethasone is commercially available and will be labeled for commercial use
7.13
Storage, Handling, and Accountability
7.13.1
Ixazomib
Upon receipt at the investigative site, ixazomib should remain in the blister and carton provided
until use or until drug is dispensed. The container should be stored at the investigative site
refrigerated (36°F to 46°F or 2°C to 8°C). Ensure that the drug is used before the retest expiry
date provided by Millennium/Takeda. Expiry extensions will be communicated accordingly with
updated documentation to support the extended shelf life.
Ixazomib capsules dispensed to the patient for take-home dosing should remain in the blister
packaging and refrigerated as noted above until the point of use. The investigative site is
responsible for providing the medication to the patient in the correct daily dose configurations.
Comprehensive instructions should be provided to the patient in order to ensure compliance with
dosing procedures. Patients who are receiving take-home medication should be given only 1 cycle
of medication at a time. Patients should be instructed to store the medication refrigerated (36°F to
46°F or 2°C to 8°C) for the duration of each cycle. Patients should be instructed to return their
empty blister packs to the investigative site, rather than discarding them. Reconciliation will occur
accordingly when the patient returns for their next cycle of take-home medication. Any extreme
in temperature should be reported as an excursion and should be dealt with on a case-by-case
basis.
Because ixazomib is an investigational agent, it should be handled with due care. Patientsshould
be instructed not to chew, break, or open capsules. In case of contact with broken capsules, raising
dust should be avoided during the clean-up operation. The product may be harmful by inhalation,
ingestion, or skin absorption. Gloves and protective clothing should be worn during cleanup and
return of broken capsules and powder to minimize skin contact.
The area should be ventilated and the site washed with soap and water after material pick-up is
complete. The material should be disposed of as hazardous medical waste in compliance with
federal, state, and local regulations.


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In case of contact with the powder (eg, from a broken capsule), skin should be washed
immediately with soap and copious amounts of water for at least 15 minutes. In case of contact
with the eyes, copious amounts of water should be used to flush the eyes for at least 15 minutes.
Medical personnel should be notified. Patients are to be instructed on proper storage,
accountability, and administration of ixazomib, including that ixazomib is to be taken as intact
capsules.
The study pharmacist or designee at the site will be responsible for handling, dispensing study
drug, completing associated documentary paperwork, handling dispensing log/accountability
form. Each time study medication is dispensed for a patient, the following information be
recorded: the patient’s initials, the patient’s study number, tablet strength, the number of tablets
dispensed with the corresponding lot number, and the initials of the person dispensing the drug.
These logs are to be maintained by the study pharmacist in the pharmacy throughout the duration
of the study. The Investigator is responsible for ensuring that the patient diary card(s) and study
drug provided to the patient and returned from the patient are accounted for and noted in source
documentation.
7.13.2
Lenalidomide
Care should be exercised by caretakers handling lenalidomide. Lenalidomide capsules should not
be opened or crushed. If powder from lenalidomide contacts the skin, wash the skin immediately
and thoroughly with soap and water. If lenalidomide contacts the mucous membranes, flush
thoroughly with water.
7.13.2.1 Storage
The study drug should be stored at room temperature away from direct sunlight and protected
from excessive heat and cold.
Only enough lenalidomide capsules for 1 cycle of therapy may be provided to the patient
each cycle.
7.14
Disposition of used supplies
All used bottles or packs of study drug must be destroyed in an appropriate manner according to
the standard practice. Destruction of such supplies will be documented. During the trial and at
termination, patients must return all unused study drug supplies and the return of these unused
study drug supplies must be recorded. Returned supplies must not be redispensed. No other
utilization of MLNN9708 or lenalidomide intended for use in this study will be authorized. The


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Principal Investigator or his/her designee will be responsible for the appropriate handling and
disposition of residual study drugs.
7.15
Other Safety Issues
7.15.1
Overdose
An overdose is defined as the accidental or intentional ingestion or infusing of any dose of a
product that is considered BOTH excessive AND medically important. All occurrences of
overdose must be reported as an SAE. Monitor adverse events as instructed in the schedule of
events and as clinically indicated.
8.
STUDY CONDUCT
8.1
Arrangements for Recruitment of Patients
Recruitment and enrollment strategies for this study may include recruitment from the
investigator’s local practice or referrals from other physicians. If advertisements become part of
the recruitment strategy, they will be reviewed by the institutional review board (IRB).
8.2
Enrollment
Enrollment in this study is defined as the time the patient receives the first dose of any study drug.
Procedures for completion of the enrollment information are described in the Study Manual.
8.3
Treatment Group Assignments
Patients will be segregated according to the results of the NFKB2 break apart FISH test. For those
patients without splits in NFKB2 will be assigned to ixazomib and dexamethasone. Patients with
evidence of a split in NFKB2 will be randomized to ixazomib and dexamethasone or ixazomib,
lenalidomide and dexamethasone as described in Section 4.1
9.
STUDY PROCEDURES
Patients will be evaluated at scheduled visits over 3 study periods: Screening, Treatment and End
of Treatment (EOT).
Refer to the Schedules of Events for timing of all assessments:
Additional details are provided as necessary in the sections that follow.


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9.1
Informed Consent
Each patient must provide written informed consent before any study-required procedures are
conducted, unless those procedures are performed as part of the patient’s standard care.
Patients will be registered after meeting all entry requirements and signing of the informed consent
document.
Study personnel will notify Winship Central Subject Registration (WCSR) by email at
winshipcsr@emory.edu, once subject has been consented for a trial.
Email notification must be done within 24 hours after consent has been obtained and it will include
scanned copies of:

Signed patient consent form

HIPAA authorization form

Emory Research Management System (ERMS; https://erms.emory.edu) Enrollment Fax
Cover
The WCSR will enter the subject into the OnCore Research Management System, which is the
system of record for Winship Cancer Institute Clinical Trials.
For participating institutions, after each subject signs consent, the Central Subject Registration
form is to be completed and sent to Winship within 24 hours of consent. This form, along with
the valid, signed informed consent form/HIPAA authorization form, is to be faxed or emailed to
Winship’s Central Subject Registrar per instructions on the form. Once a subject is registered,
each participating site will be notified via e-mail.
9.2
Inclusion and Exclusion Criteria
The inclusion and exclusion criteria (see Section 5.0) will be assessed during screening (up to 21
days before the first dose of study drug).
For multi-site institutions, The Eligibility checklist is to be printed from OnCore and verified by
2 people, of which one must be a clinical investigator or co-investigator. The completed and
signed eligibility checklist along with all redacted supporting source documentation must be
submitted to the Winship Multi-site Coordinator (MSC) or designee (fax 404-778-5071) within
14 days after pre-registration but no later than 2 business days prior to the scheduled treatment
visit. Eligibility will be confirmed by the site investigator or co-investigator and the MSC or
designee within 1 business day of receipt of all eligibility documentation and confirmation will
be sent to the participating site along with cohort assignment, if subject meets criteria.


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9.3
Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during screening.
9.4
Medical History and Physical Examination
A complete medical history is to be obtained at screening including diagnosis and staging of
multiple myeloma. The history should include a review of all current medications as well as any
prior radiation therapy and antineoplastic therapy.
A complete physical examination, including a neurologic examination, is to be conducted at the
Screening visit and at the EOT visit.
A symptom-directed physical examination, including a neurologic examination, is to be
conducted at the on Day 1 of each treatment.
9.5
Eastern Cooperative Oncology Group Performance Status
Performance status will be assessed using the ECOG scale at the following visits: Screening; Day
1 of each treatment cycle; and the EOT visit. [29]
9.6
Vital Signs, Body Weight and Height
Measurement of vital signs, including oral temperature, blood pressure, and heart rate will be
obtained during the following visits: Screening on Day 1 of each treatment cycle, blood pressure
and heart rate measurements will be taken and EOT.
Body weight (kg) will be determined at the Screening visit, on Day 1 of each treatment cycle, and
at the EOT visit. Height (cm) will be measured at the Screening visit only.


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9.7
Pregnancy Test
ARMs A and B: FCBP on this arm will not be taking lenalidomide. Females of reproductive
potential in these arms must have 2 negative pregnancy tests before initiating therapy. The first
test should be performed within 10-14 days, and the second test within 24 hours prior to the first
dose of ixazomib. A pregnancy test will be performed at day one on all future cycles or every 14
days if she has irregular menstruation.
ARM C: This arm will be taking lenalidomide. FCBP must have 2 negative pregnancy tests before
initiating therapy. The first test should be performed within 10-14 days, and the second test within
24 hours prior to prescribing lenalidomide and ixazomib. Repeat pregnancy test every week for
the first 4 weeks and then every 28 days while on therapy and during interruptions in therapy and
28 days following discontinuation of lenalidomide. Women with irregular menstruation must
have pregnancy testing every 14 days while on therapy and during interruptions and 14 and 28
days after discontinuation of lenalidomide.
* FCBP - A female of childbearing potential is a sexually mature woman who: 1) has not
undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal
for at least 24 consecutive months.
9.8
Clinical Laboratory Evaluations
The M-protein quantification (SPEP and UPEP), the serum free light chain assay, immunofixation
of serum and urine, quantification of Ig, and all safety laboratory assays are to be performed
locally.
9.8.1
Hematology
Hematology will be analyzed locally and includes the following:

Hemoglobin

Hematocrit

Platelet Count

WBC Count with Differential
A blood sample for hematology testing will be obtained at screening (within 21 days of the first
dose of study drug), prior to dosing on day one of each cycle, day 15 of cycle 1, and more


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frequently if clinically indicated and at the EOT visit.
9.8.2
Serum Chemistry
Serum chemistry samples will be analyzed locally and includes the following:
Blood urea nitrogen (BUN)
Albumin
Calcium
Creatinine
Total Bilirubin
Uric Acid
Lactate dehydrogenase (LDH)
Alkaline phosphatase
AST (SGOT)
ALT (SGPT)
Glucose
Sodium
Potassium
Chloride
CO2
Magnesium
Phosphorus
A blood sample for clinical chemistry testing will be obtained at screening (within 21 days of the
first dose of study drug), on Days 1 of each treatment cycle, on day 15 of cycle 1, and at the EOT
visit.
9.8.3
2-Microglobulin
A blood sample will be collected at screening for serum 2-microglobulin testing; results will be
analyzed locally.
9.8.4
Serum Kappa/ Lambda measurement
A blood sample will be collected at screening and before each cycle for serum Serum Kappa/
Lambda free light chain measurement; results will be analyzed locally.
9.8.5
Urinalysis
A urine sample for microscopic urinalysis will be collected at screening.
9.9
Computed Tomography/Magnetic Resonance Imaging
For patients with documented extramedullary disease, a PET-CT scan, CT scan, or MRI scan will
be performed at screening (within 4 weeks of the first dose of study drug) for evaluation of
disease. If disease is documented at screening, a repeat PET-CT scan, CT scan, or MRI scan
should be performed as required to document response or progression at the EOT visit.


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All follow-up scans should use the same imaging modality used at screening.
9.10
Skeletal Survey
A complete skeletal survey, using roentgenography, will be performed at screening (within 4
weeks of the first dose of study drug). If a patient has lytic lesions at screening, then a skeletal
survey, PET/CT, or plain film of symptomatic sites must be repeated at the End of Treatment
visit. In addition, if there are symptoms or signs that suggest increased or new bone lesions, the
skeletal survey or plain film of symptomatic sites may be repeated any time during the study and
at the EOT visit. A PET-CT may be done at screening in place of a skeletal survey provided that
the same modality for assessment is used throughout the study. Other assessments and scans for
extramedullary disease, such as a CT or MRI scan, may be required to better characterize some
lesions, especially at screening, to delineate the sites and measurements of extramedullary disease.
Radiographs will be analyzed locally and reports maintained with the patient record for retrieval
during monitoring visits.
9.11
Quantification of M-Protein
A blood and twenty-four (24)-hour urine sample will be obtained at screening, on Day 1 of Cycle
1, every treatment cycle (beginning at Cycle 2, Day 1) no later than the first dosing day, and at
the EOT visit. Thereafter it is left at the discretion of the local physician.
9.12
Serum Free Light Chain Assay
A blood sample will be obtained at screening, on Day 1 of Cycle 1, every treatment cycle
(beginning at Cycle 2, Day 1) no later than the first dosing day, and at the EOT visit for the serum
free light chain assay. Blood samples will be measured locally.
9.13
Immunofixation of Serum and Urine
Serum and urine samples will be obtained for serum and urine immunofixation tests at screening,
on Day 1 of Cycle 1, every treatment cycle (beginning at Cycle 2, Day 1) no later than the first
dosing day, and at the EOT visit.
9.14
Bone Marrow Biopsy/Aspiration
9.14.1
Morphology


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Bone marrow biopsy/aspiration (aspiration required biopsy optional) samples will be obtained at
screening (up to 4 weeks before the first dose of study drug) for evaluation of disease. Bone
marrow biopsy is to be repeated to assess suspected CR if applicable and at the EOT. This sample
will be evaluated locally. In addition, Empire genomics is receiving the baseline bone marrow
aspirate to do clinical grade FISH to check for NFKB rearrangements so patients can be assigned
to the different treatment groups. The remainder of the baseline sample will be shipped backed to
Emory and stored for future genomic analysis which will include RNA sequencing. Details
regarding the preparation, handling, and shipping of samples are provided in the Study Manual.
9.14.2
Cytogenetics
A bone marrow aspirate sample will be obtained at screening (up to 4 weeks before the firstdose
of study drug) for evaluation of cytogenetics. This evaluation will be performed locally.
9.14.3
Biomarkers
Bone marrow for the determination of NFKB2 split signal and RNA sequencing will beobtained
from screening bone marrows prior appointment to a treatment arm. The first is being performed
on the baseline sample which will be sent to Empire Genomics to have clinical grade FISH
analysis to look at the NFKB2 split and be able to assign patients to specific arms. In addition,
bone marrow samples will be obtained, at relapse or in refractory patients to evaluate for be
transcribed mutations associated with poor response to ixazomib and dexamethasone or ixazomib,
lenalidomide and dexamethasone. These samples will be shipped Emory to be purified and stored
for RNA sequencing analysis to look for additional biomarkers
9.15
Quantification of Immunoglobulins
A blood sample for quantification of immunoglobulins (IgM, IgG, and IgA) will be obtained at
screening, on predose Day 1 of Cycle 1, every treatment cycle (beginning at Cycle 2, Day 1) no
later than the first dosing day, and at the EOT visit.
9.15.1
Blood Sample for Genotyping- Germline DNA and RNA
One 5-mL blood sample will be collected during screening or on Cycle 1, Day 1 before the first
dose of Id or IRd is administered to assess potential biomarkers that predict response to Id vs IRd.
Details regarding the preparation, handling, and shipping of samples are provided in the Study
Manual.


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9.16
Pretreatment Events and Adverse Events
Monitoring of AEs will be conducted throughout the study. AEs will be reported from the first
dose of study drug through 30 days after the last dose of study drug or until the start of subsequent
antineoplastic therapy. Serious pretreatment events will be reported from the time of the signing
of the ICF up to first dose of study drug. SAEs will be reported from the first dose of study drug
up through 30 days after administration of the last dose of study drug or until the start of
subsequent antineoplastic therapy. All SAEs will be monitored until they are resolved or are
clearly determined to be due to a patient’s stable or chronic condition or intercurrent illness(es).
Refer to Section 10 for details regarding definitions, documentation, and reporting of pretreatment
events, AEs, and SAEs.
9.17
Stem Cell Collection and Autologous Stem Cell Transplantation
Patients who are eligible for and elect to undergo ASCT may undergo stem cell mobilization and
autologous peripheral blood stem cell (PBSC) collection at any time after the fourth treatment
cycle and ASCT at any time after the fourth treatment cycle. Stem cell mobilization and collection
will be performed according to the institutional guidelines at the respective investigative sites.
Patients may delay the start of a treatment cycle for a maximum of 4 weeks for stem cell
mobilization and collection. Patients may elect to stop treatment after 4 cycles and proceed to
ASCT at the discretion of the treating physician and participating institution. Patients going on to
ASCT must complete all EOT visit procedures prior to undergoing ASCT. Patients who undergo
ASCT(s) will provide blood and urine samples every 16 weeks following the ASCT(s) for the
assessments of SPEP, UPEP, immunofixation of serum and urine, and serum free light chains
until the occurrence of PD. If PD is determined, the date of progression should be recorded and
the patient should enter long-term follow-up for survival and alternate therapy.
9.18
Premedications and Concomitant Medications and Procedures
Premedications and concomitant medications and therapy will be recorded from the time that the
informed consent form (ICF) is signed through 30 days after the last dose of study drug or until
the start of subsequent antineoplastic therapy. See Section 7.5 for a list of prohibited and allowed
concomitant medications and therapies.
10.
STATISTICAL AND QUANTITATIVE ANALYSES
10.1
Statistical Methods


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10.1.1
Study design and Power Consideration
This is an open-label, 3-arm, phase II clinical trial to study the differential effect in the treatment
efficacy in term of response rate between treatment (Id vs IRd) and NFKB2 rearrangement status in
relapsed patients with multiple myeloma. The potential maximum sample for this study is 90
patients. This novel design is a hybrid of two biomarker designs, i.e. the target/enrichment and
stratified/interaction design that was necessary to address comparisons based on experimental
regimens and the focus on non-responsive (absence of rearrangement) patients. Eligible patients
will be first screened by their NFKB2 rearrangement status. The first 30 patients without NFKB2
rearrangement will be enrolled into Arm A and treated with Id. The first 60 patients with NFKB2
rearrangement will be randomly assigned to Arm B and be treated with Id or to Arm C and be
treated with IRd until the specific arm is closed. Randomization is conducted with a block of 2
patients in order to balance the enrollment in each arm (The first of the 2 patients entered
consecutively is randomly assigned to one of the 2 arms (Arm B or Arm C) with equal probability and
the second one is assigned to the other arm).
Within arms: Before the study is completed, the response rate of each arm is monitored separately
and compared to the historical RR of 30%. The Arm B is used as reference in the study, so that no
interim analysis is proposed for the arm and a total of 30 patients without rearragement will be
recruited without stopping. The sample size of 30 in Arm B will achieve a power of at least 80%
at the significance level of 0.05 to claim that Arm B has equivalent RR as the historical RR of 30%
assuming an equivalence tolerance of +/- 20% when the true RR of Arm B is approximately
30%.
Arm A or Arm C is designed to detect an improved RR of 60% vs. 30% using Simon’s 2-stage
Optimum design with a power of at least 90% and an alpha error of 5%., respectively. Ten (10)
evaluable patients will be enrolled into stage I. An interim analysis will be conducted after the
stage I. If 3 or less patients in the arm demonstrate objective response, then the arm is closed and
concluded with no potential better RR than the historical control RR of 30%. At least 4 objective
responses are required to proceed to stage II accrual of 20 additional patients for a total of 30
patients per arm. After the arm is closed with a maximum sample size of 30 patients, if 13 or less
patients with objective response, the arm is deemed as no potential better RR than the historical RR
of 30%. At least 14 patients must achieve objective response for the particular treatment arm A or
C to claim that their response rates are significantly better than the historical RR of 30%. Arm A
or Arm C has 65% probability of stopping early and 5% probability of declaring the treatment
effective if the true proportion is 30%. The probability of declaring the treatment effective is at
least 90% if the true RR is 60%.


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Table 8. Power and Sample Size for Testing the Equivalence between RR of Arm B and Historical
RR.
Maximum Sample Size
30
Lower Limit for Response Rate Rejecting
Equivalence
Upper Limit for Response Rate Rejecting
Equivalence
10%
50%
Table 9. Power and Sample Size for Arm A and C, Respectively.
Primary Efficacy Decision Using Simon’s Optimum Design Based on RR:
P0 = 30% vs. P1 = 60%
Power = 90%; α = 0.05
First Stage Sample Size
Upper Limit for First Stage Rejection of Drug
10
3
Maximum Sample Size
Upper Limit for Second Stage Rejection of
Drug
30
13
Between Arms: Any treatment arm closed to accrual after the first stage interim analysis will be
considered an inferior arm and will be excluded from final pairwise comparison. After the study
completes, Arm A and C are compared to Arm B using one sided t-test for the superiority in the
response rate, respectively. Assuming the expected RR for Arm A or C is about 60% and the
expected RR for Arm B is 30%, the sample size of 30 patients per arm will achieve a power of
80% at the significance level of 0.15 to detect the improvement in RR for Arm A or C from 30%
Equivalence is defined as within +/- 20% around the historical RR as of 30%:
P0 = 30% & D = +/-20%
Power = 80%; α = 0.15


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to 60%.
Arm A is compared to Arm C for the equivalence in response rate assuming the equivalence
tolerance in response rate is within +/-30% and their true response rates are around 60%. With
two sided t-test, the sample size of 30 patients per arm will achieve a power of at least 75% at the
significance level of 0.05 to claim that the Arm A and C have equivalent RR when their true RRs
are 60%.
Table 10. Power and Sample Size for Arm A or Arm C Compared to Arm B, Respectively.
Superior Response Rate for Arm A, or C than Arm B:
P0 = 30% vs. P1 = 60% (P1 > P0)
Power = 80%; α = 0.15
Sample Size of Arm B
Sample Size of Arm A or C
30
30
Table 11. Power and Sample Size for Testing the Equivalence in Response Rates between Arm
A and Arm C.
Equivalence is defined as within +/- 30% around the expected RR as of 60%:
P0 = 60% & D = +/-30%
Power = 76%; α = 0.05
Sample Size of Arm A
Sample Size of Arm C
30
30
10.1.2
Populations for Analysis
Evaluable for Toxicity: Patients will be considered evaluable for toxicity if they receive any study
drug. Patients will not be replaced based on toxicity.
Evaluable for Response: Patients will be considered evaluable for response if they have baseline
disease assessments, received at least one cycle of therapy and have had their disease re-evaluated.


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These patients will have their response classified according to the IMWG response criteria. All
patients who are not evaluable for response may be replaced.
Evaluable for RNA sequencing analysis:

Receive a bone marrow prior starting protocol-specified dosing regimen;

Receive the protocol-specified dosing regimen during Cycle 1 without dose reductions
or interruptions;

Do not receive any excluded concomitant medications through the completion of the
treatment;

Evidence of progression or stable disease of protocol-specified regimen; and

Have sufficient bone marrow and peripheral blood sample for RNA extraction and
sequencing analysis.
10.1.3
Response Assessment
Response assessments will be performed no later than the first day of every treatment cycle
beginning with Cycle 2, Day 1. Response and relapse categories are as follows:

Complete response
CR

Subcategory: stringent complete response
sCR

Partial response
PR

Subcategory: very good partial response
VGPR

Stable disease
SD

Minimal response
MR

Progressive disease
PD
CR should be confirmed with follow-up assessments of serum protein electrophoresis (SPEP),
UPEP, immunofixation of blood and urine, and serum free light chains. One bone marrow
assessment has to occur to document CR; no second bone marrow confirmation is needed. PD
may be confirmed per IMWG criteria. Please note that in order to determine a response of sCR,
bone marrow immunohistochemistry or immunofluorescence for kappa:lambda ratio, as well as
serum free light chain assay, should be performed for all patients suspected to be in CR to meet


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this response category’s requirements. Please see section 15.3 for further details.
10.1.4
Demographic and Baseline Characteristics
Patient demographic and baseline characteristics, including age, gender, medical history, and
prior therapy, will be summarized using descriptive statistics. For continuous variables,
descriptive statistics (number [n], mean, standard deviation, standard error, median [range]) will
be provided. For categorical variables, patient counts and percentages will be provided. Status of
NFKB2 rearrangement at baseline will be listed.
Response rates and depth of response will be calculated as the percent of evaluable patients that
have confirmed sCR/CR/VGPR or PR, and exact 95% confidence intervals will be calculatedfor
these estimates. Response defined as per modified IMWG criteria. Time to response, duration of
response, and survival will be estimated using the product-limit method of Kaplan and Meier. The
rate of MR will also be evaluated to determine the clinical benefit response.
10.1.5
Efficacy Analysis
The response criteria used in this study is the updated version of the IMWG (See Section 15.3).
[30] The efficacy analysis will mainly focus on the response rate at 4 cycles. Other efficacy
parameters, including but not limited to time to response and DOR, will be presented in listings
and summarized if appropriate.
10.1.5.1 Primary Efficacy
The primary endpoint is a response rate of VGPR or better after 4 cycles.
The primary efficacy analysis will be based on the Response-Evaluable population. Estimates of
the CR + VGPR rates will be presented with 2-sided 95% exact binomial confidence intervals.
10.1.5.2 Secondary Efficacy
The secondary efficacy parameters include the overall response rate (CR + VGPR + PR), PR,
stable disease (SD) or progression rate at cycle 4 and CR, sCR, VGPR, combined CR + VGPR
rate, and PR at cycle 8 (if patient continues on treatment), and time to response, DOR, TTP and
PFS.
Time to response is defined as the time from the date of first dose of study treatment to the date
of the first documentation of a confirmed response in a patient who responded.


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The DOR is defined as the time from the date of first documentation of a confirmed response to
the date of first documented PD.
TTP is defined as the time from the date of first dose of study treatment to the date of first
documentation of PD.
PFS is defined as the time from the date of first dose of study treatment to the date of first
documented PD or death.
The response rates, time to response, and DOR will be analyzed based on the Response-Evaluable
population. Time to response may also be measured in the population of patients with a confirmed
response. The response rates will be analyzed similarly to the primary endpoint. Time to response,
DOR will be analyzed using standard survival analysis techniques based on Kaplan-Meier
estimates.
10.1.5.3 ORR in the Subset of High-Risk Patients
ORR will be presented with 2-sided 95% exact binomial confidence interval in the subset of high-
risk patients determined by cytogenetics.
10.1.5.4 Autologous Stem Cell Transplant Evaluation
For patients who elect to proceed to stem cell harvesting and ASCT, summary tables will be
presented for the number of CD34+ cells (per kg) collected, as well as engraftment parameters if
available.
10.1.6.
Exploratory Biomarker Analysis
Gene expression and - RNA sequencing (RNA-seq). To assess for gene expression and transcribed
mutations associated with poor response to Id or IRd, we will extract RNA from plasma cells and
its corresponding normal counterpart using a Quiagen RNAeasy Kit. RNA quality will be
accessed using the Agilent RNA 6000 Nano kits with the Agilent 2100 Bioanalyzer. RNA-Seq
library preparation will be performed using a minimum of 100 ng of high quality (RIN≥8.0).
NGS
from
RNA
will
be
performed
in
our
Cancer
Genomics
Shared
Resource
(CLIA#11D1086150). The RNA-Seq sample library preparation will be performed using the
Illumina TruSeq kit with assisted automation using Beckman Coulter's SPRIworks HT system.
All isolates will be individually barcoded, and RNA-Seq data will be generated using 100x100
paired end reads for each sample using an Illumina HISeq2000 instrument.


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Gene expression. All sequencing reads will be evaluated for quality using FastQC software.
Depending on the quality control metrics of the data, the reads might be trimmed using SeqTK
software. Following trimming, pair end reads will be aligned to reference human genome
(GRCh37/hg19) using BWA software. Expression counts per gene will be obtained using
Cufflinks software by counting the number of reads or read pairs (also known as fragments)
aligning concordantly within a pair and uniquely to a given gene. Differential gene expression
will be computed by pairwise t-tests on the variance-stabilized counts followed by correction for
multiple testing using the Benjamini–Hochberg method.
Identify transcribed mutations. To determine the sequence of mutations associated with poor
response to Id or IRd, we will compare the mutational analysis of all samples against the results
obtained from time 0. To this end, we will first align paired-end reads using BWA pipeline and
detect splices representing translocations, inversions and other distant fusions within a single read
end using TopHat software. These distant splices provided one set of candidate fusions for the
subsequent testing stage. The other set of candidate fusions derived from: 1) unpaired unique
alignments, in which each end of the paired-end read aligned uniquely to a different chromosome,
and 2) paired reads, in which each end aligned uniquely to the same chromosome, but with an
apparent genomic distance that exceeded 200,000 bp or with genomic orientations that suggested
an inversion or scrambling event. Candidate fusions will then filtered against known transcripts
from RefSeq. We will require that both fragments flanking a distant splice, or both ends of an
unpaired or discordant paired-end alignment, map to known exon regions. This filtering step
eliminated approximately 90% of the candidates. For the goal of this project we will further
eliminate apparent read-through fusion events involving adjacent genes in the genome, which are
thought to be transcriptional rather than a genomic origin.
For the remaining candidate fusion events, we will construct artificial exon–exon junctions
consisting of the exons distal to the supported donor exon and the exons proximal to the supported
acceptor exon. The exons included in the proximal and distal computations will be limited so that
the cumulative length along each gene was within an estimated maximum insert length of 200 bp.
As a control, we will also construct all exon–exon junctions consisting of combinations of exons
within the same gene, for all genes contributing to a candidate fusion event. We will extract reads
that aligned to an intergenic junction corresponding to a candidate fusion, but not to a control
intragenic junction.
To filter the results of the re-alignment, we require that each candidate fusion have at least one
read with an overhang of 20 bp. We also require that each candidate fusion have at least 5
supporting reads. For each remaining candidate fusion, we will align the two component genes


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against each other using BWA and eliminate the fusion if the alignment had any region containing
60 matches in a window of 75 bp. We will also align the exon–exon junction against each of the
component genes and eliminate the fusion if the alignment had coverage greater than 90% of the
junction and identity greater than 95%.
10.1.7
Safety Analysis
Toxicity information recorded will include the type, severity, and the probable association with
the study regimen. Tables will be constructed to summarize the observed incidence by severity
and type of toxicity. Additional safety analyses may be performed to most clearly enumerate rates
of toxicities and to further define the safety profile of Id or IRd combinations.
Safety will also be evaluated by the incidence of treatment-emergent AEs, severity and type of
AEs, and by changes from baseline in the patient’s vital signs, weight, and clinical laboratory
results using the Safety population. Exposure to study drug and reasons for discontinuation will
be tabulated.
Treatment-emergent events will be tabulated. Treatment-emergent is defined as any AE that
occurs after administration of the first dose of study drug and up through 30 days after the last
dose of study medication or until the start of subsequent antineoplastic therapy, any event that is
considered drug related regardless of the start date of the event, or any event that is present at
baseline but worsens in severity after baseline or is subsequently considered drug related by the
investigator.
Additional safety analyses may be performed to most clearly enumerate rates of toxicities and to
further define the safety profile of Id or IRd combinations.
10.1.8
Interim Analysis
An interim analysis will be conducted after the stage I (Ten (10) evaluable patients). If 3 or less
patients in the arm demonstrate objective response, then the arm is closed and concluded with no
potential better RR than the historical control RR of 30%. At least 4 objective responses are
required to proceed to stage II accrual of 20 additional patients for a total of 30 patients per arm.
10.1.9
Early Stopping Rule
In this study, Grade 4 or greater nonhematological toxicity will be monitored starting from the
first 15 response-evaluable patients and then every 5 response evaluable patients. If the stopping
bounds of ≥5/15, ≥6/20, ≥7/25, ≥8/30, ≥9/35, ≥10/40, and ≥11/45 have been achieved, accrual


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to the study will be suspended to allow for investigation. After consideration by the study team
(Millennium/Takeda clinician, study chair, statistician), a decision will be made as to whether
accrual can be resumed.
The bounds are based on a Bayesian strategy to monitor outcomes in clinical trials. If the stopping
rule is met, there is 80% probability that the true toxicity rate is greater than 18% with a prior beta
distribution with parameters 0.4 and 1.6 for the binomially distributed toxicity rate. [31]


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11.
ADVERSE EVENTS
11.1
Definitions
11.1.1
Adverse Event Definition
Adverse event (AE) means any untoward medical occurrence in a patient or subject administered
a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign
(including an abnormal laboratory finding), symptom, or disease temporally associated with the
use of a medicinal (investigational) product whether or not it is related to the medicinal product.
This includes any newly occurring event, or a previous condition that has increased in severity or
frequency since the administration of study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered
by the investigator to be a clinically significant change from baseline.
11.1.2
Serious Adverse Event Definition
Serious AE (SAE) means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient was at risk of death at the time of
the event. It does not refer to an event which hypothetically might have caused death ifit
were more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization (see
clarification in the paragraph below on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined as a
substantial disruption of a person’s ability to conduct normal life functions).

Is a congenital anomaly/birth defect.

Is a medically important event. This refers to an AE that may not result in death, be
immediately life threatening, or require hospitalization, but may be considered serious
when, based on appropriate medical judgment, may jeopardize the patient, require medical
or surgical intervention to prevent 1 of the outcomes listed above, or involves suspected


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transmission via a medicinal product of an infectious agent. Examples of such medical
events include allergic bronchospasm requiring intensive treatment in an emergency room
or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization,
or the development of drug dependency or drug abuse; any organism, virus, or infectious
particle (e.g., prion protein transmitting Transmissible Spongiform Encephalopathy),
pathogenic or nonpathogenic, is considered an infectious agent.
Clarification should be made between a serious AE (SAE) and an AE that is considered severe in
intensity (Grade 3 or 4), because the terms serious and severe are NOT synonymous. The general
term severe is often used to describe the intensity (severity) of a specific event; the event itself,
however, may be of relatively minor medical significance (such as a Grade 3 headache). This is
NOT the same as serious, which is based on patient/event outcome or action criteria described
above, and is usually associated with events that pose a threat to a patient’s life or ability to
function. A severe AE (Grade 3 or 4) does not necessarily need to be considered serious. For
example, a white blood cell count of 1000/mm3 to less than 2000 is considered Grade 3 (severe)
but may not be considered serious. Seriousness (not intensity) serves as a guide for defining
regulatory reporting obligations.
11.2
Reporting Serious Adverse Events
AEs may be spontaneously reported by the patient and/or in response to an open question from
study personnel or revealed by observation, physical examination, or other diagnostic procedures.
Any clinically relevant deterioration in laboratory assessments or other clinical finding is
considered an AE. When possible, signs and symptoms indicating a common underlying
pathology should be noted as one comprehensive event. For serious AEs, the investigator must
determine both the intensity of the event and the relationship of the event to study drug
administration. For serious pretreatment events, the investigator must determine both the intensity
of the event and the relationship of the event to study procedures.
AEs which are serious must be reported from the first dose of study drug through 30 days after
administration of the last dost of ixazomib. Any SAE that occurs at any time after the first dose
of ixazomib treatment or after the designated follow-up period that the sponsor-investigator and/or
sub-investigator considers to be related to any study drug must be reported. In addition, new
primary malignancies that occur during the follow-up periods must be reported, regardless of
causality to study regimen, for a minimum of three years after the last dose of the investigational
product, starting from the first dose of study drug. All new cases of primary malignancy must be
reported.


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Planned hospital admissions or surgical procedures for an illness or disease that existed before the
patient was enrolled in the trial are not to be considered AEs unless the condition deteriorated in
an unexpected manner during the trial (e.g., surgery was performed earlier or later than planned).
All SAEs should be monitored until they are resolved or are clearly determined to be due to a
patient’s stable or chronic condition or inter-current illness.
Regardless of expectedness or causality, all SAEs (including serious pretreatment events) must
also be reported:
Fatal and Life Threatening SAEs within 24 hours of the investigator’s observation or
awareness of the event
All other serious (non-fatal/non life threatening) events within 24 hours of the
investigator’s observation or awareness of the event
The SAE report must include at minimum:

Event term(s)

Serious criteria

Intensity of the event(s): Investigator’s or sub-investigator’s determination.
Intensity for each SAE, including any lab abnormalities, will be determined by
using the NCI CTCAE version specified in the protocol, as a guideline,
whenever possible. The criteria are available online at
http://ctep.cancer.gov/reporting/ctc.html.

Causality of the event(s): Investigator’s or sub-investigator’s determination
of the relationship of the event(s) to study drug administration.
Follow-up information on the SAE may be requested by Winship Cancer Institute at Emory
University.
Intensity for each SAE, including any lab abnormalities, will be determined by using the NCI
CTCAE version 4.03 whenever possible.
Relationship to all study drugs for each SAE will be determined by the investigator or sub-
investigator by responding yes or no to the question: Is there a reasonable possibility that the AE
is associated with the study drug(s)?


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11.3
Procedures for AE and SAE Recording and Reporting
Reporting Participating investigators will assess the occurrence of AEs and SAEs at all participant
evaluation time points during the study.
All AEs and SAEs whether reported by the participant, discovered during questioning, directly
observed, or detected by physical examination, laboratory test or other means, will be recorded in
the participant’s research record and on the appropriate study-specific case report forms of the
EDC. All AEs must be recorded in the participant’s research record, stating the duration and
intensity of the event, action taken by the investigator and outcome of the event. The investigator
must evaluate the causal relationship between the study drug(s) and the adverse event.
• Related: There is a reasonable causal relationship between study drug administration and
the AE.
• Not Related: There is not a reasonable causal relationship between study drug
administration and the AE.
The investigator must evaluate all abnormal laboratory results to determine the clinical
significance. If an abnormal result appears to be clinically significant, it must be considered to be
an adverse event.
The descriptions and grading scales found in the CTEP Version 4.03 of the NCI CTCAE will be
utilized for AE reporting. The CTEP Version 4.03 of the CTCAE is identified and located on the
CTEP website at:
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf
11.4
Reporting Requirements
The study must be conducted in compliance with FDA regulations, local safety reporting
requirements, and reporting requirements of the study PI. All Serious Adverse Events (SAEs) that
occur following the subject’s first dose of study medication through 30 days of


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discontinuation of dosing must be reported. In addition, any SAE occurring after these time
periods that is believed to be related to study drug or protocol-specified procedure must be
reported.
Each adverse event will be assessed to determine if it meets the criteria for SAE reporting. Each
investigative site will be responsible to report SAEs that occur at that institution to their respective
IRB. It is the responsibility of each participating investigator to report serious adverse events as
described below.
For participating subsites, adverse events collected at weekly treatment visits are to be entered
into the EDC no later than 14 calendar days after data collection.
Subsites are not permitted to report directly to the coordinating center IRB or FDA. All external
site SAEs are to be reported to the coordinating center multi-site’s regulatory specialist. The
coordinating center multi-site coordinator will facilitate submission of external site SAEs to the
coordinating center IRB and FDA. All serious adverse events (SAEs) and other adverse events
must be recorded on case report forms. In addition, all SAEs must be reported to the coordinating
center principal investigator and coordinating center multi-site regulatory specialist within 24
hours of knowledge of the event using the PINR MMRC 060 Serious Adverse Event Report Form.
Copies of de-identified source documentation pertaining to the SAE must be submitted to the
coordinating center.
If a patient is permanently withdrawn from the study because of a SAE, this information must be
included in the initial or follow-up form. All SAEs must be submitted to the local IRB per local
IRB and institutional policy. Upon request of additional data or information that is deemed
necessary must be reported to the coordinating center as soon as possible but no later than 5
calendar days.
11.5
Reporting to the MMRC Lead Investigator
11.5.1
Serious Adverse Event Reporting
When the Investigator or his/her designee becomes aware that an SAE has occurred, the
Investigator must complete and submit a PINR MMRC 060 Serious Adverse Event Report Form,


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which will be used as the primary method for SAE reporting to Winship Cancer Institute. All SAE
reports that have the minimum data set for reporting should be submitted, even if only limited
information is available. This must occur within 24 hours of learning of the occurrence, regardless
of the relationship of the SAE to ‘Study Drug.’ In the event that the participating investigator
does not become aware of the serious adverse event immediately (e.g., participant sought treatment
elsewhere), the participating investigator is to report the event within 24 hours after learning of it
and document the time of his or her first awareness of the adverse event.
Follow-up reports must be submitted within 24 hours as additional information becomes available.
Investigators are responsible for notifying the Institutional Review Board (IRB) SAEs in
accordance with local regulations.
Each site is responsible for reporting all SAEs, regardless of expectedness or causality to Winship
Cancer Institute of Emory University within 24 hours of receiving the SAEs from investigator.
In addition, Winship Cancer Institute of Emory University will promptly provide MMRC Lead
Investigator and other MMRC participating Investigators with adverse events that require
expedited reporting to local IRBs.
Winship Cancer Institute of Emory University or the MMRC Lead Investigator may request
additional source documentation pertaining to the SAE. If a subject is permanently withdrawn
from the study because of a SAE, this information must be included in the initial or follow-up
report.
All serious adverse events that occur after the date of informed consent signature, during treatment
occurring or within 30 days of the last administered dose of study drug must also be reported.
All SAEs regardless of relationship to study drug must be followed to resolution or to stabilization
if improvement or resolution is not expected.
The initial report must be as complete as possible, including details of the current illness and
(serious) adverse event, and an assessment of the causal relationship between the event and the
investigational product(s). Information not available at the time of the initial report (e.g., an end
date for the adverse event or laboratory values received after the report) must be documented in
the paper PINR MMRC 060 Serious Adverse Event Report Form.


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Within the following 24 hours, the participating investigator must provide follow-upinformation
on the serious adverse event. Follow-up information should describe whether the event has
resolved or continues, if and how the event was treated, and whether the participant will continue
or discontinue study participation.
Information submitted in the paper PINR MMRC 060 Serious Adverse Event Report Form must be
added to the EDC within 24 hours. Follow up reports must be submitted within 24 hours as
additional information becomes available.
11.6
Non-Serious Adverse Event Reporting
Non-serious adverse events will be reported on the Adverse Event Case Report Form of the EDC,
stating the duration and intensity of the event, action taken by the investigator and outcome of the
event. The investigator must evaluate the causal relationship between the study and the adverse
event.
11.7
Reporting to the Institutional Review Board (IRB)
Investigators should report adverse events to their respective IRB according to the local IRB
policies and procedures in reporting adverse events.
11.8
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
Pregnancies and suspected pregnancies occurring while the participant is on study drug orwithin
28 days of the participant’s last dose of study drug should be reported immediately upon
investigator’s knowledge. If the participant is on study drug (Ixazomib and or lenalidomide, the
drug(s) are to be discontinued immediately and the participant is to be instructed to return any
unused portion of the study drug to the Investigator. The pregnancy, suspected pregnancy,
or positive pregnancy test must be reported immediately of the Investigator’s knowledge of
the pregnancy. Reporting to Celgene as required by the Revlimid REMS ® program for
patients taking lenalidomide. The patient should be referred to an obstetrician/gynecologist
experienced in reproductive toxicity for further evaluation and counseling.
The Investigator will follow the participant until completion of the pregnancy, and must report
the outcome of the pregnancy (including notification of false-positive tests) within 24 hours
of having knowledge of the event. Reporting to Celgene as required by the Revlimid
REMS® program.


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If the outcome of the pregnancy meets the criteria for immediate classification as a SAE (i.e.,
spontaneous abortion [any congenital anomaly detected in an aborted fetus is to bedocumented],
stillbirth, neonatal death, or congenital anomaly [including that in an aborted fetus]), the
Investigator should follow the procedures for reporting SAEs (i.e., report the event within
24 hours of the Investigator’s knowledge of the event).
All neonatal deaths that occur within 28 days of birth should be reported, without regard to
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is
related to the in utero exposure to the study drug should also be reported. Reporting to Celgene
as required by the Revlimid REMS® program.
If the patient is found not to be pregnant, any determination regarding the participant’s continued
participation in the study will be determined by the Investigator.
A female partner of a male taking investigational product should be advised to call their healthcare
provider immediately if they get pregnant. The male participant should notify the investigator of
his partner’s pregnancy and her healthcare provider information. If a woman becomes pregnant
or suspects that she is pregnant while participating in this study or within 90 days after the last
dose, she must inform the investigator immediately and permanently discontinue ixazomib and
lenalidomide (IRd treatment group).
12.
ADMINISTRATIVE REQUIREMENTS
12.1 Good Clinical Practice
The study will be conducted in accordance with the International Conference on Harmonisation
(ICH) for Good Clinical Practice and the appropriate regulatory requirement(s). The investigator
will be thoroughly familiar with the appropriate use of the study drug as described in the protocol
and Investigator’s Brochure.
12.2
Data Quality Assurance
Essential clinical documents will be maintained to demonstrate the validity of the study and the
integrity of the data collected. Study data will be entered into an eCRF by site personnel using a
secure, validated, web-based electronic data capture (EDC) application. Principal investigators
will have access to all data upon entry in the EDC application. Master files should be established
at the beginning of the study, maintained for the duration of the study and retained according to


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the appropriate regulations.
Study monitors will discuss instances of missing or uninterpretable data with the investigator for
resolution. Any changes to study data will be made to the eCRF and documented via an electronic
audit trail associated with the affected eCRF.
12.3
Ethical Considerations
The study will be conducted in accordance with applicable regulatory requirement(s) and will
adhere to GCP standards. The IRB will review all appropriate study documentation in order to
safeguard the rights, safety and well-being of the patients. The study will be conducted only at
sites where IRB approval has been obtained. The protocol, Investigator’s Brochure, informed
consent form, advertisements (if applicable), written information given to the patients (including
diary cards), safety updates, annual progress reports, and any revisions to these documents will
be provided to the IRB by the investigator.
This study must have the approval of a properly constituted IRB or IEC. Before the investigational
drug is shipped to the Site Investigator, the Site Investigator or designee will provide a copy
of the IRB/IEC approval letter stating that the study protocol and any subsequent amendments
and informed consent form have been reviewed and approved.
The Site Investigator is also responsible for notifying their IRB/IEC of any significant adverse
events that are serious, unanticipated and/or unexpected according to local IRB policies.
Millennium/Takeda will provide Investigators with any investigational new drug (IND) safety
reports generated, changes to the Investigator’s Brochure IB, and any safety updates. The Site
Investigators are responsible notifying their IRB/IEC of any such updates in accordance to their
IRB policies
The Lead Principal Investigator will initiate in writing any substantive changes to this protocol as
a protocol amendment. The amendment will be submitted to the IRB/IEC, together with a revised
informed consent, if applicable. Written documentation of IRB/IEC approval must be received
before the amendment is implemented. Upon completion of the trial, the Site Investigator must
provide the IRB/IEC with a summary of the trial’s outcome.
12.4
Patient Information and Informed Consent
After the study has been fully explained, written informed consent will be obtained from either
the patient or his/her guardian or legal representative before study participation. The method of


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obtaining and documenting the informed consent and the contents of the consent must comply
with the ICH-GCP and all applicable regulatory requirements.
Before implementing any study procedure, informed consent shall be documented by the use of a
written consent form approved by the IRB/IEC and signed and dated by the subject or the subject’s
legally authorized representative at the time of consent. A copy of the signed informed consent
will be given to the subject or subject’s legally authorized representative. The original signed
consent must be maintained by the Site Investigator.
12.5
Patient Confidentiality
In order to maintain patient privacy, all data capture records, drug accountability records, study
reports and communications will identify the patient by initials and the assigned patient number.
If requested, the investigator will grant monitor(s) and auditor(s) from Millennium/Takeda or its
designees and regulatory authority(ies) access to the patient’s original medical records for
verification of data gathered on the data capture records and to audit the data collection process.
The patient’s confidentiality will be maintained and will not be made publicly available to the
extent permitted by the applicable laws and regulations.
The investigator/institution will permit direct access to source data and documents by the FDA,
and other applicable regulatory authorities. The access may consist of trial-related monitoring,
including remote monitoring, audits, IRB/IEC reviews, and FDA/regulatory authority inspections.
Release of research results should preserve the privacy of medical information and must be carried
out in accordance with Department of Health and Human Services Standards for Privacy of
Individually Identifiable Health Information, 45 CFR 164.508.
12.6
Investigator Compliance
The investigator will conduct the study in compliance with the protocol given approval/favorable
opinion by the IRB and the appropriate regulatory authority(ies). Changes to the protocol will
require
approval
from
the
investigators
and
Millennium/Takeda
and
written
IRB
approval/favorable opinion prior to implementation, except when the modification is needed to
eliminate an immediate hazard(s) to patients. The IRB may provide, if applicable regulatory
authority(ies) permit, expedited review and approval/favorable opinion for minor change(s) in
ongoing studies that have the approval /favorable opinion of the IRB. The investigator will
submit all protocol modifications to Millennium/Takeda and the regulatory authority(ies) in
accordance with the governing regulations.


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Any departures from the protocol must be fully documented in the source documents.
Regulatory authorities, the IEC/IRB, and/or Millennium/ Takeda may request access to all source
documents, eCRFs, and other study documentation for on-site audit or inspection. Direct access
to these documents must be guaranteed by the investigator, who must provide support at all times
for these activities.
12.7
Study Documentation and Archives
12.7.1 Source Documents
Source Documents are original documents, data, and records (e.g., medical records, data
collection forms, pharmacy dispensing records, recorded data from automated instruments,
laboratory data) that are relevant to the clinical trial. The Site Investigator will prepare and
maintain adequate and accurate source documents. These documents are designed to record all
observations and other pertinent data for each subject enrolled in this clinical trial. Source
documents must be adequate to reconstruct all data transcribed onto the case report forms.
12.7.2 Case Report Form Completion
All data will be collecting using EDC system. All case report forms must be completed by
designated study personnel. The completed case report forms must be reviewed, signed and dated
by the Site Investigator or designee in a timely fashion.
12.7.3 Archival of Records
The Site Investigator must retain protocols, amendments, IRB/IEC approvals, signed and dated
consent
forms,
medical
records,
case
report
forms,
drug
accountability
records,
all
correspondence, and any other documents pertaining to the conduct of the study for a period of 2
years after the investigation is discontinued.
12.8
Data and Safety Monitoring Plan
The Data and Safety Monitoring Committee (DSMC) of the Winship Cancer Institute will provide
oversight for the conduct of this study. The DSMC functions independently within Winship
Cancer Institute to conduct internal monitoring functions to ensure that research being conducted
by Winship Cancer Institute Investigators produces high-quality scientific data in a manner
consistent with good clinical practice (GCP) and appropriate regulations that govern clinical
research.
Depending on the risk level of the protocol, the DSMC review may occur every 6


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months or annually. For studies deemed High Risk, initial study monitoring will occur within 6
months from the date of the first subject accrued, with 2 of the first 5 subjects being reviewed.
For studies deemed Moderate Risk, initial study monitoring will occur within 1 year from the
date of the first subject accrued, with 2 of the first 5 subjects being reviewed.
Subsequent
monitoring will occur in routine intervals per the Winship Data and Safety Monitoring Plan
(DSMP).
The DSMC will review pertinent aspects of the study to assess subject safety, compliance with
the protocol, data collection, and risk-benefit ratio. Specifically, the Winship Cancer Institute
Internal Monitors assigned to the DSMC may verify informed consent, eligibility, data entry,
accuracy and availability of source documents, AEs/SAEs, and essential regulatory documents.
Following the monitoring review, monitors will provide a preliminary report of monitoring
findings to the PI and other pertinent individuals involved in the conduct of the study. The PI is
required to address and respond to all the deficiencies noted in the preliminary report. Prior to
the completion of the final summary report, monitors will discuss the preliminary report responses
with the PI and other team members (when appropriate). A final monitoring summary report will
then be prepared by the monitor. Final DSMC review will include the final monitoring summary
report with corresponding PI response, submitted CAPA (when applicable), PI Summary
statement, and available aggregate toxicity and safety data.
The DSMC will render a recommendation and rating based on the overall trial conduct. The PI
is responsible for ensuring that instances of egregious data insufficiencies are reported to the IRB.
Continuing Review submissions will include the DSMC recommendation letter. Should any
revisions be made to the protocol-specific monitoring plan after initial DSMC approval, the PI
will be responsible for notifying the DSMC of such changes. The Committee reserves the right
to conduct additional audits if necessary.
12.9
Study Monitoring and Data Collection for Participating sites
Following initiation of the study site, remote monitoring will be completed by the Winship
DSMC and MSC. The Site Investigator will allocate sufficient time for the designated site staff
to submit source documentation as required to complete remote monitoring.
The purpose of trial monitoring is to verify the following:

The rights and well-being of human subjects are protected.


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
The reported data are accurate, complete, and verifiable from source documents.

The conduct of the trial is in compliance with the currently approved protocol,
amendment(s), ICH GCP, FDA CFR, and any other applicable regulatory requirements.
At the time of study initiation at a non-Emory site, the Emory Sponsor, Winship regulatory
specialist, and Winship research coordinators will perform a site initiation teleconference.
During this teleconference, the Emory team will review the study, enrollment, reporting, and
regulatory compliance. The participating site will have internal monitoring meetings. These
meetings, which will include the participating site investigator, the clinical research coordinator
and the regulatory affairs coordinator, will meet at least on a monthly basis to review and discuss
study data to ensure subject safety. The research coordinators will maintain a spreadsheet which
will be de-identified and will summarize all the patient data for subjects actively being treated on
the trial as well as a roadmap detailing pending tests/treatments for each individual subject. The
spreadsheet will be shared with the Emory PI via e-mail.
Winship’s MSC will perform an on-site or remote monitoring visit within the first three months
of enrollment of the first subject. Quarterly monitoring visits will occur (once annually onsite
and three times remotely) until subject follow-up is terminated. Monthly reviews of data in
OnCore will be conducted to ensure compliance or identify discrepancies; specifically, to assess
compliance with the protocol, verify informed consent forms, verify compliance with SAE
reporting procedures, monitor the tracking of study drug (pharmacy visit, storage and accounting
of study drug), retrieve regulatory documentation, and perform quality control by comparing
data from the CRF to the source documents of the center.
Study updates will occur at least once monthly between the PI at Emory and the research team at
the participating site(s). The purpose of the meetings is to discuss the enrollment, regulatory
updates, monitor toxicities, and evaluate the progress of the trial. Scheduled teleconferences
may stop after all patients have completed assigned protocol therapy. The coordinating center (or
designee) will communicate with participating sites via monthly email. The minutes from the
teleconference will be maintained in the regulatory binder for the study. In addition, electronic
copies will be sent via email to the principal investigators at each site.
12.10 Investigator and Site Responsibility for Drug Accountability
Accountability for the study drug at all study sites is the responsibility of the principal
investigator. The investigator will ensure that the drug is used only in accordance with this
protocol. Drug accountability records for ixazomib indicating the drug’s delivery date to thesite,


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inventory at the site, use by each patient, and amount returned to Millennium or a designee
or disposal of the drug (if applicable and if approved by Millennium) will be maintained by
the clinical site. Accountability records will include dates, quantities, lot numbers, expiration
dates (if applicable), and patient numbers.
12.11
Ixazomib Product Complaints
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who
identify a potential product complaint situation should immediately contact MedComm
Solutions (see below) and report the event. Whenever possible, the associated product should be
maintained in accordance with the label instructions pending further guidance from a
Millennium/Takeda Quality representative.
Phone: 1-844-ONC-TKDA (1-844-662-8532)
E-mail: GlobalOncologyMedinfo@takeda.com
FAX: 1-800-881-6092
Hours: Mon-Fri, 9 a.m. – 7 p.m. ET
Product complaints in and of themselves are not AEs. If a product complaint results in an SAE,
an SAE form should be completed and sent to Millennium/Takeda.
12.12 Study Termination
This study may be prematurely terminated, if in the opinion of the investigator or Millennium
if there is sufficient reasonable cause. Written notification documenting the reason for study
termination will be provided to the investigator or Millennium by the terminating party.
Circumstances that may warrant termination include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to patients

Failure to enter patients at an acceptable rate

Insufficient adherence to protocol requirements

Insufficient, incomplete and/or unevaluable data

Determination of efficacy based on interim analysis

Plans to modify, suspend or discontinue the development of the drug.
For Product Complaints,


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13.
INVESTIGATOR AGREEMENT
I have read Protocol Phase 2 Study of the Oral Form of ixazomib, a second-generation proteasome
inhibitor, in combination with dexamethasone with or without lenalidomide in Adult patients with
relapsed Multiple Myeloma.
I agree to conduct the study as detailed herein and in compliance with International Conference
on Harmonisation Guidelines for Good Clinical Practice and applicable regulatory requirements
and to inform all who assist me in the conduct of this study of their responsibilities and
obligations.
Principal Investigator printed name
Principal Investigator signature
Date
Investigational site or name of institution and location (printed)


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14.
REFERENCES
1.
Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer JClin.
2014;64(1):9-29
2.
Brenner H, Gondos A, Pulte D. Expected long-term survival of patients diagnosed with multiple
myeloma in 2006-2010. Haematologica. 2009;94(2):270-275.
3.
Martinez-Lopez J, Blade J, Mateos MV, et al. Long-term prognostic significance of response in
multiple myeloma after stem cell transplantation. Blood. 2011;118(3):529- 534.
4.
Chapman MA, Lawrence MS, Keats JJ, et al. Initial genome sequencing and analysis of multiple
myeloma. Nature. 2011;471(7339):467-472.esponse in multiple myelomaafter stem cell
transplantation. Blood. 2011;118(3):529-534.
5.
Gupta, N., et al., Clinical Pharmacokinetics of Intravenous and Oral MLN9708, An
Investigational Proteasome Inhibitor: An Analysis of Data From Four Phase 1 Monotherapy
Studies. in 52nd ASH Annual Meeting and Exposition, 2010. 116(21): p. abstr 1813.
6.
Gupta, N., M. Saleh, and K. Venkatakrishnan. Flat-Dosing Versus BSA-Based Dosing for
MLN9708, An Investigational Proteasome Inhibitor: Population Pharmacokinetic (PK) Analysis of
Pooled Data From 4 Phase-1 Studies in 53rd ASH Annual Meeting and Exposition. 2011. San
Diego, CA; p. abstr 1433
7.
Chow, L.Q., et al. MLN9708, an investigational proteasome inhibitor, in patients with solid tumors;
Updated Phase 1 results in Head and Neck Symposium. 2012. Phoenix,AZ
8.
Assouline, S., et al. Once-weekly MLN9708, an investigational proteasome inhibitor, in patients
with relapsed/refractory lymphoma: results of a Phase 1 dose-escalation study in 17th EHA Annual
Congress. 2012. Amsterdam, theNetherlands.
9.
Lonial, S., et al. Phase I study of twice-weekly dosing of the investigational oral proteasome
inhibitor MLN9708 in patients (pts) with relapsed and/or refractory multiple myeloma (MM)
in ASCO Annual Meeting. 2012. Chicago, Illinois.
10. Kumar S, et al. Weekly Dosing of the Investigational Oral Proteasome Inhibitor MLN9708 in
Patients with Relapsed and/or Refractory Multiple Myeloma: Results From a Phase 1 Dose-
Escalation Study In 53rd ASH Annual Meeting and Exposition; 2011 10- 13 Dec; San Diego, CA;
p. abstr 816..
11. Merlini, G., et al. MLN9708, a Novel, Investigational Oral Proteasome Inhibitor, in Patients with
Relapsed or Refractory Light-Chain Amyloidosis (AL): Results of a Phase 1 Study in 54th ASH
Annual Meeting and Exposition. 2012. Atlanta, Georgia.
12. Kumar, S. et al. A Phase 1/2 Study of Weekly MLN9708, an Investigational Oral Proteasome
Inhibitor, in Combination with Lenalidomide and Dexamethasone in Patients with Previously
Untreated Multiple Myeloma (MM). Lancet Oncology, 2014.15:1053-12.
13. Richardson, P.G., et al. MLN9708, an investigational proteasome inhibitor, in combination with
lenalidomide and dexamethasone in previously untreated multiple myeloma patients (pts):


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Evaluation of weekly and twice-weekly dosing in 17th EHA Annual Congress.2012. Amsterdam, the
Netherlands.
14. San Miguel, J., et al. Oral MLN9708, an an investigational proteasome inhibitor, in combination
with melphalan and prednisone in patients with previously untreated multiple myeloma: a Phase
1 study in 17th EHA Annual Congress. 2012.Amsterdam, the Netherlands.
15. Richardson P, Baz R, Wang L, Jakubowiak A, Berg D, Liu G, et al. Investigational Agent
MLN9708, An Oral Proteasome Inhibitor, in Patients (Pts) with Relapsed and/or Refractory
Multiple Myeloma (MM): Results From the Expansion Cohorts of a Phase1 Dose-Escalation
Study In: 53rd ASH Annual Meeting and Exposition; 2011 10-13Dec; San Diego, CA; p. abstr
301.
16. Lonial S, Baz R, Wang M, Talpaz M, Liu G, Berg D, et al. Phase I study of twiceweekly dosing of
the investigational oral proteasome inhibitor MLN9708 in patients (pts)with relapsed and/or
refractory multiple myeloma (MM). J Clin Oncol (ASCO Meeting Abstracts) 2012;30(15
suppl):abstr 8017.
17. Kumar S, Bensinger W, Reeder C, Zimmerman T, Berenson J, Berg D, et al.Weekly Dosing of the
Investigational Oral Proteasome Inhibitor MLN9708 in Patients with Relapsed and/or Refractory
Multiple Myeloma: Results From a Phase 1 Dose- Escalation Study In: 53rd ASH Annual Meeting
and Exposition; 2011 10-13 Dec; San Diego, CA;p. abstr 816.
18. Kumar S, Bensinger W, Reeder C, Zimmerman T, Berenson J, Liu G, et al. Weeklydosing of the
investigational oral proteasome inhibitor MLN9708 in patients (pts) with relapsed/refractory
multiple myeloma (MM): A Phase I study. Journal of Clinical Oncology 2012 ASCO Annual
Meeting Proceedings 2012:Abstract 8034.
19. Kumar S, Niesvizky R, Berdeja J, Bensinger W, Zimmerman T, Berenson J, et al.Safety and
Pharmacokinetics of Weekly MLN9708, an Investigational Oral Proteasome Inhibitor, Alone and
in Combination. Clinical Lymphoma Myeloma and Leukemia 2013;13(Supplement 1):S154;
abstr P-230
20. Common Terminology Criteria for Adverse Events (CTCAE). V.4.03
21. Kumar, S., Besinger W.I., Zimmerman, T.M., et al. Weekly dosing of the investigational oral
proteasome inhibitor MLN9708 in relapsed/refractory multiple myeloma – Results from a Phase 1
study. Blood 2014 Aug 14;124(7):1047-55
22. Richardson, P.G., Baz, R., Wang M., et al. Phase 1 study of twice-weekly dosing of
investigational oral proteasome inhibitor MLN9708 in patients with relapsed and/or refractory
multiple myeloma. Blood 2014 Aug 14;124(7):1038-46
23. Richardson, P.G., Hofmeister, C.C., Rosenbaum, C.A., et al. Twice Weekly Oral MLN9708 , An
Investigational Proteasome Inhibitor, in Combination withLenalidomide (Len) and Dexamethasone
(Dex) in Patients (Pts) with newly diagnosed Multiple Myeloma(MM): Final Phase 1 results and
Phase 2 Data. ASH 2013 Annual Meeting Abstract 535


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15.
APPENDICES
15.1 Eastern Cooperative Oncology Group (ECOG) Scale for Performance
Status
Grade
Description
0
Normal activity. Fully active, able to carry on all predisease performance withoutrestriction
1
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatoryand
able to carry out work of a light or sedentary nature (eg, light housework, officework)
2
In bed < 50% of the time. Ambulatory and capable of all self-care, but unable to carryout
any work activities. Up and about more than 50% of wakinghours.
3
In bed > 50% of the time. Capable of only limited self-care, confined to bed or chairmore
than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to
bed or chair
5
Dead
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET et al. Toxicityand
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5 (6):649-55.


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15.2
Cockcroft-Gault Equation
For males:
Creatinine Clearance = (140-age[years] weight [kg])
OR
(140–age[years] weight [kg])
72 (serum creatinine[mg/dL])
0.81 (serum creatinine[mol/L])
For females:
Creatinine Clearance = 0.85 (140-age[years] weight [kg]) OR 0.85 (140-age[years] weight [kg])
72 (serum creatinine[mg/dL])
0.81 (serum creatinine[mol/L])
Source: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine.Nephron
1976;16(1):31-41.


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FACT/GOG-Neurotoxicity Questionnaire, Version 4.0
By circling one (1) number per line, please indicate how true each statement has been for you
during the past 7 days.
ADDITIONAL CONCERNS
Not
at all
A little
bit
Some-
what
Quite
a bit
Very
much
I have numbness or tingling in my hands………
0
1
2
3
4
I have numbness or tingling in my feet…………
0
1
2
3
4
I feel discomfort in my hands………………….
0
1
2
3
4
I feel discomfort in my feet……………………
0
1
2
3
4
I have joint pain or muscle cramps……………
0
1
2
3
4
I feel weak all over……………………………
0
1
2
3
4
I have trouble hearing…………………………
0
1
2
3
4
I get a ringing or buzzing in my ears…………
0
1
2
3
4
I have trouble buttoning buttons………………
0
1
2
3
4
I have trouble feeling the shape of small objects
when they are in my hand………………………
0
1
2
3
4
I have trouble walking…………………………
0
1
2
3
4
Participant Signature:
Date:


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15.3 International Myeloma Working Group Response Criteria27
Response1
IMWG criteria
sCR
CR as defined below plus:

normal FLC ratio and

absence of clonal cells in bone marrow by immunohistochemistry or 2–
4 color flow cytometry
CR

Negative immunofixation on the serum and urine and

disappearance of any soft tissue plasmacytomas and

< 5% plasma cells in bone marrow.

In patients with only FLC disease, a normal FLC ratio of 0.26–1.65is
required.
VGPR

Serum and urine M-protein detectable by immunofixation but noton
electrophoresis or

> 90% reduction in serum M-protein plus urine M-protein level < 100
mg/24 h.

In patients with only FLC disease, >90% decrease in thedifference
between involved and uninvolved FLC levels is required.
PR

50% reduction of serum M-protein and reduction in 24 hours urinary M-
protein by >90% or to < 200 mg/24 h

If the serum and urine M-protein are unmeasurable,3 a > 50%decrease
in the difference between involved and uninvolved FLC levels is required
in place of the M-protein criteria

If serum and urine M-protein are not measurable, and serum freelight
assay is also not measureable, > 50% reduction in plasma cells is
required in place of M-protein, provided baseline bone marrow plasma
cell percentage was > 30%

In addition to the above listed criteria, if present at baseline, a >50%
reduction in the size of soft tissue plasmacytomas is alsorequired


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Stable
Disease

Not meeting criteria for CR, VGPR, PR or progressive disease
MR

25% but < 49% reduction of serum M protein and reduction in 24 hour
urine M-protein by 50 to 89% which still exceeds 200 mg per 24hr

In addition to the above criteria, if present at baseline, 25-49%
reduction in the size of soft tissue plasmacytomas is alsorequired

No increase in size or number of lytic bone lesions (developmentof
compression fracture does not exclude response)
Progressive
disease**
Increase of > 25% from lowest response value in any one of thefollowing:

Serum M-component (the absolute increase must be > 0.5 g/dL)4and/or

Urine M-component (the absolute increase must be > 200 mg/24 h)and/or

Only in patients without measurable serum and urine M-protein, the
difference between involved and uninvolved FLC levels. The absolute
increase must be > 10 mg/dL

Only in patients without measurable serum and urine M-protein and
without measurable disease by FLC levels, bone marrow plasma cell
percentage (absolute % must be ≥10%)

Definite development of new bone lesions or soft tissue plasmacytomasor
definite increase in the size of existing bone lesions or soft tissue
plasmacytomas

Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL)
that can be attributed solely to the plasma cell proliferative disorder
Adapted from Durie BGM, et al. Leukemia 2006; 20: 1467-1473; All response categories (CR, sCR,VGPR,
nad PD) require two consecutive assessments made at anytime before the institution of any newtherapy;
complete response and PR and SD categories also require no known evidence of progressive or newbone
lesions if radiographic studies were performed. VGPR and CR categories require serum and urinestudies
regardless of whether disease at baseline was measurable in serum, urine both or either. Radiographicstudies
are not required to satisfy these response requirements. Bone marrow assessments need not be confirmed. For
progressive disease, serum M-component increases of ≥I gm/dl are sufficient to define response if starting M-
component is ≥5 g/dl.
IMWG clarification for coding PD: Clarified that Bone marrow criteria for PD are to be used only inpatients
without measurable disease by M protein and by FLC levels. Clarified that 25% increase refers to Mprotein,
FLC, and bone marrow results and does not refer to bone lesions, soft tissue plasmacytomas orhypercalcemia.
Note the lowest response value does not need to be a confirmedvalue.

ICF_000.pdf: 
Informed Consent Form 
Phase II trial of IXAZOMIB and Dexamethasone versus IXAZOMIB, 
Dexamethasone and Lenalidomide, Randomized with NFKB2 rearrangement. 
(Proteasome Inhibitor NFKB2 Rearrangement Driven Trial, PINR) 
NCT Number: NCT02765854 
Document IRB Approval Date: 10/25/2022


PI: Leon Bernal-Mizrachi, MD   
    Page 1 of 20    
    Version Date: 12/03/2021
Protocol #: MMRC060         
     IRB Form 01292016
You Are Being Asked to Be in a Research Study
What Is a Research Study?
The main purpose of research studies is to gain knowledge. This knowledge may be used to help 
others. Research studies are not intended to benefit you directly, though some might.  
Do I Have to Do This?
No. Being in this study is entirely your choice.  If you decide to join this study, you can 
change your mind later on and withdraw from the research study. 
Taking part in a study is separate from medical care. The decision to join or not join the research 
study will not affect your status as a patient.  
What Is This Document?
This form is an informed consent document. It will describe the study risks, procedures, and any costs 
to you.
This form is also a HIPAA Authorization document. It will describe how your health information will be 
used and by whom.
Signing this form indicates you are willing to take part in the study and allow your health information 
to be used.
What Should I Do Next?
1. Read this form, or have it read to you.
2. Make sure the study doctor or study staff explains the study to you.
3. Ask questions (e.g., time commitment, unfamiliar words, specific procedures, etc.)
4. If there will be medical treatment, know which parts are research and which are standard care.
5. Take time to consider this, and talk about it with your family and friends.
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Protocol #: MMRC060                                                                                                                         IRB Form 01292016
Emory University and Grady Health System
Consent to be a Research Subject / HIPAA Authorization 
Title: MMRC060: Phase II trial of IXAZOMIB and Dexamethasone versus IXAZOMIB, 
Dexamethasone and Lenalidomide, Randomized with NFKB2 rearrangement
Principal Investigator:  Leon Bernal-Mizrachi, MD
Study-Supporter: Millennium: The Takeda Oncology Company
Introduction
You are being asked to be in a medical research study. This form is designed to tell you everything 
you need to think about before you decide if you want to be a part of the study.  It is entirely your 
choice.  If you decide to take part, you can change your mind later on and withdraw from the 
research study. The decision to join or not join the research study will not cause you to lose any 
medical benefits.  If you decide not to take part in this study, your doctor will continue to treat you.
Before making your decision:

Please carefully read this form or have it read to you

Please listen to the study doctor or study staff explain the study to you 

Please ask questions about anything that is not clear
You can take a copy of this consent form, to keep. Feel free to take your time thinking about whether 
you would like to participate. You may wish to discuss your decision with family or friends. Do not sign 
this consent form unless you have had a chance to ask questions and get answers that make sense 
to you.  By signing this form you will not give up any legal rights.
You are being asked to participate in a research study of an investigational genetic test and an 
investigational drug combination of ixazomib (MLN9708) and dexamethasone. Based on the results of 
the genetic test, you will be selected to receive Ixazomib in either a 2 drug combination of ixazomib and 
dexamethasone or in a 3 drug combination of Ixazomib, dexamethasone and lenalidomide.  The study 
will evaluate which drug combination is better for the treatment of patients with the particular genetic 
characteristic called “NF-kB2 rearrangement” identified by the test.  The test will be done on both your 
blood and your bone marrow. It will then evaluate if the test will be useful to choose the best treatment 
for patients in the future that have the same genetic characteristics. “Investigational” means the test 
and the drugs, ixazomib in combination of dexamethasone, have not been approved by any authority 
that regulates new medicines, including the US Food and Drug Administration (FDA).  Ixazomib, 
lenalidomide and dexamethasone in combination are approved by the US FDA and are commercially 
available for the treatment of multiple myeloma. The brand name for lenalidomide is Revlimid®.  
Ixazomib is a type of drug called a proteasome inhibitor. Proteasome inhibitors block the action of 
proteasomes which are found inside all cells, normal and cancerous.  They have the important role of 
identifying and marking damaged proteins so they can be broken down.  By blocking the action of 
proteasomes, damaged protein will accumulate within the cells and cause them to die.  Cancer cells 
are more susceptible to this effect than normal cells.  Ixazomib in combination of dexamethasone is 
considered “investigational” because it has not received approval from the FDA, although it has been 
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Protocol #: MMRC060                                                                                                                         IRB Form 01292016
previously tested in humans and there are many ongoing studies using ixazomib for the treatment of 
multiple myeloma. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
law. This Web site will not include information that can identify you. At most the Web site will include 
a summary of the results. You can search this Web site at any time.
What is the purpose of this study?
The purpose of this study is to evaluate the benefit of the 2 drug combination of Ixazomib and 
dexamethasone and the three drug combination of ixazomib, dexamethasone and lenalidomide in 
patients with the NF-kB2 rearrangement identified by the genetic test.   The study will evaluate the side 
effects of ixazomib when given with dexamethasone and of ixazomib when given with lenalidomide and 
dexamethasone.  It will also evaluate the effect the 2 drug or the three drug combination has on your 
cancer.  
People invited to participate in this study must be 18 years of age or older and, if female, cannot be 
pregnant.  They must have a diagnosis of multiple myeloma that has not responded or has come 
back after prior therapy. About 90 subjects will be enrolled in this study overall. 
About 90 patients will take part in this study.   We plan to enroll 60 patients at Emory and Grady. 
What will I be asked to do?
If you decide to take part in this research study, you will undergo the following procedures:
Screening Procedures:  
Procedures to determine if you are eligible to take part in a research study are called “screening” 
procedures.  For this research study, the screening procedures include those listed below.  These 
procedures may overlap with procedures you would undergo as part of your routine care, and may be 
done regardless of whether you join this study.  They will be done as an outpatient, and will involve 3-
4 hours of your time.  You will be seen by a physician, nurse practitioner or physician’s assistant, nurses 
and medical technicians.  All tests must be completed before you receive your first treatment (Cycle 1 
Day 1).  You must sign this informed consent form before any research procedures may be done. 

A review of your medical history

A review of any medication(s) you are currently taking; while in the study you should not 
take St. John’s wort and Ginkgo biloba.  Your study doctor will tell you if there are other 
drugs or dietary supplements you should avoid. Performance status (how well you are able 
to do your normal activities)

Vital signs (blood pressure, pulse, and temperature) will be recorded

A neurologic assessment including a physical evaluation and a questionnaire

Height and weight will be recorded

Blood samples (about 3 teaspoons) will be taken for routine tests to check your blood 
counts (numbers of each type of blood cell), chemistries (to evaluate your overall health 
status by checking things such as your kidney and liver function). Test to assess your blood 
clotting will be done. 

An EKG, or electrocardiogram (a test that measures the rhythm of your heart to make sure 
your heart is functioning properly) 
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Protocol #: MMRC060                                                                                                                         IRB Form 01292016

If you are a woman capable of having children, you will have another blood test to 
determine if you are pregnant before entering the study (about 1 teaspoon will be 
collected). This will be done 7-10 days prior to initiation of therapy and again within 24 
hours if you are selected to receive lenalidomide

Blood tests to assess the status of your myeloma. 

Blood test to obtain normal DNA. In this study we will collect about 2 tablespoons of blood 
during one of your regular lab draws so in that case there will not be an extra needle stick. 
If you are not scheduled for labs we will ask if you if you are willing to have an extra needle 
stick to the draw the blood. 

A 24 hour urine collection will be done

Standard radiologic imaging procedures may be done if you have a plasmacytoma (a solid 
tumor) to measure the size of your tumor(s) – this can include CT scans (computerized 
tomography), MRIs (magnetic resonance imaging), and/or other imaging tests

Skeletal survey - x-rays of the skull, long bones, pelvis and chest. This will be done if it has 
not been done in the past 4 weeks

Bone marrow biopsy and aspirate to assess disease status and to perform genetic testing. 
In addition, we will collect some extra bone marrow for research. We will collect about a half 
tablespoon of bone marrow, and this will mean at least one extra draw during your regular 
bone marrow biopsy.
Study Drug Administration:
If you qualify for the study and decide to take part in the study, you will be assigned to one of the 
treatment groups outlined based on the results of the genetic test 
If you DO NOT have NF-kB2 rearrangement identified by the genetic test you will receive treatment 
with the 2 drug combination of Ixazomib and dexamethasone.
If you DO HAVE NF-kB2 rearrangement identified by the genetic test, you will be randomly selected 
(like the flip of a coin) to receive either the 2 drug combination of ixazomib and dexamethasone or the 
3 drug combination of ixazomib, dexamethasone and lenalidomide.  
You and your study doctor will not have a choice in which treatment you will receive.  It will be 
determined by the test and the random selection.  
The treatments are described below.  Each treatment cycle is 28 days.
Treatment group – Ixazomib and dexamethasone:

Ixazomib will be given orally at 4.0 mg on days 1, 8 and 15 of each 28 day cycle. Ixazomib 
capsule should be swallowed whole and not chewed with an 8 oz. /240 ml glass of water on an 
empty stomach (no food or drink) at least 1 hour before or 2 hours after a meal.  Ixazomid should 
be stored refrigerated.

Dexamethasone will be given orally at 40 mg on Days 1, 8, 15, and 22 of each 28 day cycle. 
Treatment group – Ixazomib, dexamethasone and lenalidomide:
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Protocol #: MMRC060                                                                                                                         IRB Form 01292016

Ixazomib will be given orally at 4.0 mg on days 1, 8 and 15 of each 28 day cycle. Ixazomib 
capsule should be swallowed whole and not chewed with an 8 oz. /240 ml glass of water on an 
empty stomach (no food or drink) at least 1 hour before or 2 hours after a meal. Ixazomib should 
be stored refrigerated.

Dexamethasone will be given orally at 40 mg on Days 1, 8, 15, and 22 of a 28 day cycle.

Lenalidomide will be given orally at 25 mg on Days 1 through 21 of each 28-day cycle and should 
be taken once daily at about the same time each day, either with or without food. The capsules 
should not be opened, broken, or chewed. Lenalidomide should be swallowed whole with water.
All patients will be treated with up to 4 cycles of therapy and then your disease will be re-evaluated.  
Treatment may continue for 8 cycles or longer, as long as your disease is not getting worse, the side 
effects are acceptable and you agree to continue treatment. 
Monitoring / Follow-up Procedures:
During your treatment cycles, you will undergo the procedures listed below. They are considered part 
of your standard medical care and would be performed whether or not you were participating in a 
research study.  These procedures will all take place at the Winship Cancer Institute.  The tests are 
detailed below.
These procedures will be completed on Day One of each cycle (except Cycle One), unless otherwise 
indicated.  The monitoring/follow-up procedures include:

A review of any medication(s) you are currently taking

Performance status (how well you are able to do your normal activities)

A review of any symptoms or side effects you might be having

Physical examination and neurologic assessment including the questionnaire

Vital signs (blood pressure, pulse, and temperature) will be recorded

Weight will be recorded

Blood samples (about 3 teaspoons) will be taken for routine tests to check your blood counts 
(numbers of each type of blood cell) and chemistries (to evaluate your overall health status by 
checking things such as your kidney and liver function) (This can be done the day prior to each 
Day One.) 

Pregnancy test for women of child bearing potential on day 1 of each cycle.  If you are assigned 
to take lenalidomide, you will also be required to follow the pregnancy testing guidelines of the 
Revlimid REMS program. 

The skeletal survey will only be repeated yearly and as needed based on your symptoms. 

X-rays and/or scans to measure a plasmacytoma will be repeated every 12 weeks, to confirm a 
response or as needed based on your symptoms. 

Blood tests to assess the status of your myeloma will be repeated prior to every cycle

A 24 hour urine test to assess the status of your myeloma will be repeated prior to each cycle

A bone marrow aspirate may be repeated to confirm your response to treatment. In the event of 
relapsed or progression, we will collect one extra draw of about a half tablespoon of bone marrow 
during your regular bone marrow biopsy for research.
  
Routine blood tests to check your blood counts will be performed on days 1 and 15 of cycle one, then 
on day 1 of each cycle.  This includes blood counts (numbers of each type of blood cell) and chemistries. 
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Protocol #: MMRC060                                                                                                                         IRB Form 01292016
For the visits on Day 1 of each cycle, the procedures will take approximately 2 hours to complete and 
does not include time needed for the administration of your chemotherapy.
Research –Only procedures for all subjects in this study:
The following research-only procedures apply to all subjects involved in this research study.  
Blood tests and bone marrow samples will be obtained prior to initiation of treatment and in the event 
of relapse or progression. These studies will be done for research purposes to evaluate for genetic 
alterations that can be associated with response to treatment.  The tests are being done for research 
purposes only, and would not be conducted if you were not participating in this research study.  
Blood tests for pharmacodynamics will be drawn on day 1 and day 8 of the first combination cycle 
and on day 1 of the second cycle. 
End of Study Visit:
Once your participation in the study is stopped, for any reason, you will have an end of study visit with 
the tests noted below.  These procedures are part of your standard medical care (routine clinical care) 
that would be performed whether or not you were participating in a research study.  These tests will be 
performed by your study doctor, or a nurse, physician assistant, nurse practitioner, or lab technician 
under your study doctor’s supervision.  The tests will take about 3 to 4 hours, and will include:

Physical examination and neurologic assessment and questionnaire

Vital signs (blood pressure, pulse, and temperature) will be recorded

Weight will be recorded

Performance status (how well you are able to do your normal activities)

Blood samples (about 2 teaspoons) will be taken for routine blood tests to check your blood 
counts (numbers of each type of blood cell) and chemistries (to evaluate your overall health 
status by checking things such as your kidney and liver function)

A review of any symptoms or side effects that you may be having

If you have a plasmacytoma, standard radiologic imaging tests to measure the size of your 
tumor(s) – this can include CT scans, MRIs, and/or other imaging tests, such as x-rays

Blood tests to assess the status of your myeloma

A 24 hour urine test

Pregnancy test if you are a women of child bearing potential

Skeletal survey may be repeated based on your symptoms

Bone marrow aspirate and biopsy

You will be contacted every three months to check on the status of your health and treatments
Once you come off study for any reason beside disease progression, your condition will be 
followed monthly until progression or initiation of subsequent therapy.  If you are removed from 
the study for unacceptable side effects, you will be followed until resolution or stabilization of 
the side effects occurs.
How will my medicine be provided? 
Ixazomib that you will take will be dispensed by the pharmacy and delivered to the principal 
investigator or study team member.  The principal investigator or health care providers on his/her 
research team will provide the medicine to you.  If you have questions about the medicine, you should 
ask the principal investigator or study nurse.  You may also call the pharmacy if you have questions 
about the medicine. The number for the pharmacy is included on your medicine package.
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Protocol #: MMRC060                                                                                                                         IRB Form 01292016
Who owns my study information and samples?
If you join this study, you will be donating your samples and study information.  You will not receive 
any compensation if your samples or information to make a new product. If you withdraw from the 
study, data and samples that were already collected may be still be used for this study.  
What are the possible risks and discomforts?
Drugs for cancer are strong and have side effects.  As with any experimental procedure, there may be 
side effects that are currently unknown.  Side effects can go away shortly after drug administration is 
stopped, but some risks could be long-lasting, permanent, serious, life threatening, or even cause 
death.  You should talk to your study doctor about any side effects you have while taking part in the 
study.  The risks involved with this study are listed below:
Potential discomforts and risk of Ixazomib
Taking part in this study has risks. Some of these risks we know about. There is also a possibility of 
risks that we do not know about and have not been seen in humans to date. Please call the study doctor 
if you have any side effects even if you do not think it has anything to do with this study. Many 
discomforts and risks go away shortly after the study drug is stopped or with treatment for the 
discomforts and risks, but in some cases, discomforts and risks may be serious, long lasting, or 
permanent and may even result in hospitalization or death.
Based on studies of ixazomib it is possible to predict some of the discomforts and risks.  However, it is 
possible that ixazomib may cause risks that have not yet been observed in patients.  The following risks 
might be seen:
Low platelet count which may increase the chance of bleeding (30%)
Skin rash which may range from some red areas, small flat spots, or small raised bumps that may 
or may not be itchy in a few areas or all over the body (11%)
Nausea (53%)
Vomiting (38%)
Diarrhea (44%)
Numbness or tingling or pain feelings in hands and feet (10%)
Swelling or fluid buildup in the arms or legs 
Flu-like symptoms and other upper respiratory tract infections 
Arthralgia or joint pain 
Lung infections including pneumonia or pneumonitis 
Herpes Zoster that can sometimes cause local pain that may last after recovery from the skin rash 
and does not go away for some time
Other discomforts and risks reported in studies with Ixazomib, which may have been due to the 
patient’s disease, ixazomib, other medications, or some combination of these include:
Not feeling like eating 
Electrolyte imbalance (blood chemical imbalance)
Loss of water from the body (dehydration) because of vomiting and/or loose stools
High blood creatinine and renal failure which means your kidneys are having trouble working well; 
Patients who had lost body water (dehydration) because of vomiting and/or loose stools have had 
high levels of creatinine indicating that the kidneys were failing to function adequately. In some 
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Protocol #: MMRC060                                                                                                                         IRB Form 01292016
severe situations, less kidney function may require temporary treatment with a machine that supports 
the function of the kidney (dialysis)
Feeling short of breath or difficulty breathing
Lung infections including pneumonia or pneumonitis
Chills
Cough 
Fever
Pain in the abdomen or back
Muscle weakness
Feeling dizzy or dizziness
Lowered blood pressure that can commonly cause you to feel light headed, faint or pass out when 
you stand up
Lowered white blood cells called lymphocytes
Lowered red cells or anemia which may make you feel tired 
Lowered white blood cells called neutrophils that may increase your risk of infection and may be 
associated with fever 
Constipation 
Pain (muscular) in extremities
Distortion of the sense of taste i.e. an abnormal or impaired sense of taste
Trouble falling asleep, staying asleep or both
Some discomforts and risks occur with lesser frequency than those mentioned above, but should be 
noted because they are severe, life-threatening or fatal.  With limited experience and because these 
events occurred while patients were receiving other drugs as well, we do not know if ixazomib causes 
such problems.  Severe, life-threatening or deadly conditions that may involve rash, blistering, skin 
peeling and mouth sores including Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis, drug 
reaction with eosinophilia and systemic symptoms (DRESS syndrome), Acute febrile neutrophilic 
dermatosis (Sweet’s syndrome) and pemphigus vulgaris, have been reported in ixazomib studies when 
given in combination with other drugs.  These rashes are disorders of the immune system, which differ 
from regular skin rashes and are generally more severe.
In addition, two rare neurological conditions have been reported in patients on ixazomib. Posterior 
reversible encephalopathy syndrome (PRES) which affects the brain and may cause headaches, 
changes in your vision, changes in your mental status, or seizures (fits), but is usually reversible. 
Transverse myelitis, also a rare condition is an inflammatory disease-causing injury to the spinal cord 
which has been reported in a patient receiving ixazomib. This condition may cause varying degrees of 
muscle weakness, reduced movement in legs, changes in the feelings of the toes and feet unusual 
muscle tightness, feelings of pain, changes in bowel (constipation) or urinary (loss of control) function 
or loss of leg movement.  In general, recovery may be partial, complete, or not at all but most patients 
experiencing transverse myelitis have good to fair recovery of symptoms. We do not know whether 
ixazomib causes transverse myelitis, however, as it happened to a patient receiving ixazomib, we are 
not able to exclude the possibility that ixazomib may have contributed to transverse myelitis.
Progressive multifocal leukoencephalopathy (PML) is a rare, serious infection of the brain that is caused 
by a virus. Persons with a weakened immune system may develop PML. PML can result in death or 
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severe disability. PML has been observed rarely in patients taking ixazomib.  It is not known whether 
ixazomib may contribute to the development of PML
Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenia purpura (TTP) and 
hemolytic uremic syndrome (HUS), are rare, serious blood disorders that cause low levels of platelets 
and red blood cells, and result in blood clots in small vessels. Symptoms may include fatigue, fever, 
bruising, nose bleeds, and decreased urination. These disorders can occasionally be fatal. TMA, 
TTP, and HUS have been seen rarely (<0.1%) in patients treated with ixazomib.
Overdose has been reported in patients taking ixazomib. Reports of accidental overdose have been 
associated with risks such as nausea, lung infections including aspiration pneumonia, multiple organ 
failure, and death. It is important to take only one dose of ixazomib at a time, and only at the 
prescribed interval.
In addition, posterior reversible encephalopathy syndrome has also been reported with Ixazomib with 
lesser frequency (<1%).   This condition affects the brain and may cause headaches, changes in your 
vision, changes in your mental status, or seizures (fits), but is usually reversible.  
Additionally, it is worth noting that:
Ixazomib is similar to the drug known as VELCADE ® (bortezomib) for Injection which is approved 
for the treatment of multiple myeloma (a cancer of the plasma cell), as well as mantle cell lymphoma 
(a cancer of the lymph nodes) in patients who have received at least one prior therapy. 
Ixazomib, like VELCADE, should not be taken if you have ever had an allergic reaction to the active 
substance or any of the inactive ingredients used in its formulation.
The following side effects have been reported with VELCADE use and therefore may also be a risk with 
Ixazomib:
Rapid death of cancer cells that may let large amounts of the cells into the blood that injure organs, 
such as kidneys (this is referred to as tumor lysis syndrome).  Your study doctor can talk with you 
about other common side effects with VELCADE use. 
The more severe but rare side effects seen with VELCADE, include but are not limited to, worsening 
of your heart function (congestive heart failure), disorders that could affect the function of your lung 
that could be serious enough to result in death, and liver failure. Your study doctor can talk to you 
further about the risks of VELCADE.
Other drugs and supplements may affect the way Ixazomib works.  Tell your study doctor about all 
drugs and supplements you are taking while you are in this study.
One fatal case of progressive multifocal leukoencephalopathy (PML) has been reported with MLN9708 
in an oncology patient who had previously received a medication associated with PML. PML is a rare, 
serious infection of the brain that is caused by a virus. Persons with a weakened immune system may 
develop PML. PML can result in death or severe disability. It is not known whether MLN9708 may have 
contributed to the development PML in this patient.
Risk to the unborn child (Men and Women)
Female subjects: We do not know if the study drug combination will affect mother’s milk or an unborn 
child. Therefore, breast-feeding and pregnant women are not allowed to take part in the study.  Due to 
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unknown risks and potential harm to the unborn child/ infant, you should not become pregnant or nurse 
a baby while on this study and for at least 90 days after you have been discontinued from treatment. 
If you are a woman who is able to have children, you must have two negative pregnancy tests prior to 
enrolling in the study and agree to the pregnancy testing requirements and if randomized to receive 
lenalidomide, adhere to the appropriate guidelines per the Revlimid® Patient-Physician Agreement that 
will be provided to you by your physician.  You must also use two effective methods of birth control as 
noted in the Revlimid® Patient Physician Agreement form for at least 28 days before starting study 
treatment, for the entire study drug treatment period (including interruptions in treatment), and for 90 
days after treatment has been stopped. 
Please be aware that some of the follow up and contraception requirements for this protocol extend 
past those required in the Revlimid Patient-Physician Agreement and need to be followed as part of 
this study.
If you are unable to have children, you must still adhere to the appropriate guidelines of the Revlimid® 
Patient-Physician Agreement that will be provided to you by your physician.
Male subjects: We do not know if using the study drug combination will affect sperm.  Therefore, due 
to potential risk, you should not get your partner pregnant during the study drug treatment period.  Even 
if you are surgically sterilized (i.e. have had a vasectomy) you must agree to use an appropriate method 
of barrier contraception (latex or synthetic condom with or without a spermicidal agent) during the entire 
study drug treatment period (including interruptions in treatment), and for 90 days after completing 
study drug treatment.  Or, you should completely avoid having heterosexual intercourse.  You must 
also adhere to the appropriate guidelines of the Revlimid® Patient-Physician Agreement form that will 
be provided to you by your physician.
Please be aware that some of the follow up and contraception requirements for this protocol extend 
past those required in the Revlimid Patient-Physician Agreement and need to be followed as part of 
this study.
All subjects (male or female):  If you or your partner becomes pregnant during this study, you must 
tell the study doctor immediately.  The study doctor will advise you of the possible risks to your unborn 
child and discuss options for managing the pregnancy with you.  For female subjects who become 
pregnant while on this study, the study drug will be stopped immediately and the pregnancy will be 
followed until conclusion.
If you do not understand what any of these discomforts and risks mean, please ask the study doctor or 
study staff to explain these terms to you.
Study Drug risks
If you take home the study drug, you will be given complete instructions about dosing, storage, safe 
handling of the drug, and how to use the patient diary given to you.  Notify your study doctor immediately 
if the study drug capsule is broken or you are in contact with the capsule contents.
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Protocol #: MMRC060                                                                                                                         IRB Form 01292016
Possible discomforts and risk of Lenalidomide and Dexamethasone

Your study doctor will discuss with you the possible risks involved with the other medicines that 
you are required to take in this study, lenalidomide and dexamethasone, as they are commonly 
used to treat your type of cancer. Lenalidomide increases the risk of deep vein thrombosis and 
may require use of aspirin or alternate anti-coagulation.  Your study doctor has a listing of the 
risks associated with lenalidomide and will review this with you. 

All possible adverse effects from the combination therapy of lenalidomide, dexamethasone, and 
Ixazomib are unknown at this time.  

In order to participate in this study you must register in and follow the requirements of the 
Revlimid Risk Evaluation and Mitigation Strategy (REMS)™ program (formerly known as 
RevAssist® program) of Celgene Corporation.  This program provides education and counseling 
on the risks of fetal exposure, blood clots and reduced blood counts due to use of lenalidomide.
Risks and Side Effects of venipuncture/ intravenous needle insertion:
Infrequent (occurs in 1% to 10% of people - from 1 to 10 out of 100 people): mild pain and discomfort 
at the injection or needle insertion site as well as possible infection, bleeding, bruising, and soreness.
Rare (occurs in less than 1% or people - less than 1 out of 100 people): severe pain, swelling, 
infection from the actual injection, and fainting.
Risks and Side Effects of EKG (Electrocardiogram):
Rare – Occurs in less than 1% of people (less than 1 out of 100 people): 
Side effects that may be associated with the EKG electrode placement are skin irritation, redness, 
and chafing of the skin at the placement site.
Risks and Side Effects of Bone Marrow Aspirate and Biopsy
Possible side effects of a bone marrow aspirate and biopsy include bleeding, infection, bruising, pain 
or discomfort at the biopsy site and possible side effects from the local anesthetic (pain or bruising at 
the injection site).
The bone marrow test is performed by using a needle to obtain a small sample of bone marrow from 
the pelvic bone. The main discomfort associated with this test is pain when the bone marrow is being 
withdrawn. In order to make the procedure more comfortable, you will get a local anesthetic to numb 
the area. A mild sedative may also be given to you. While you are sedated, you will be able to 
respond to commands. 
Radiation Risks and Side Effects (CT Scan/X-ray):
You will be exposed to radiation from CT scans and other x-rays. These procedures are necessary 
for your medical care and will occur even if you do not participate in this study. The estimated 
radiation dose that you will receive is equal to or less than the annual radiation exposure limit allowed 
for persons who are occupationally exposed to radiation (for example, x-ray technologist, radiologist).  
The principal risk associated with a radiation dose is the possibility of developing a radiation-induced 
cancer later in life.  The risk for radiation-induced cancer from this study is minimal.  
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Protocol #: MMRC060                                                                                                                         IRB Form 01292016
Risks and Side Effects of MRI:
Rare – Occurs in less than 1% of subjects (less than 1 out of 100 subjects):  
Possible anxiety and claustrophobia related to being placed in the large body scanner; temporary 
discomfort related to having to lie still during the procedure; and possible pain, infection and bleeding 
related to venipuncture if contrast dye is used.  Because MRI works through a powerful magnetic 
field, it cannot be done if subjects have a pacemaker, intracranial aneurysm clips or other metal 
implants (for example, types of implants used in eye surgery or orthopedic [bone] surgery).  You will 
be questioned and examined, if necessary, to confirm that you may undergo MRI scanning without 
additional risk.  An x-ray may be performed to rule out the presence of a suspected foreign body prior 
to the MRI.
If you will be taking the study drug home, keep it out of the reach of children or anyone else who may 
not be able to read or understand the label.  Do not let anyone else take the study drug besides you.
It is possible that the researchers will learn something new during the study about the risks of being in 
it.  If this happens, they will tell you about it. Then you can decide if you want to continue to be in this 
study or not.  You may be asked to sign a new consent form that includes the new information if you 
decide to stay in the study.
Will I benefit directly from the study? 
This study is not designed to benefit you directly.  Your condition may improve while you are in this 
study but it may not, and it may even get worse.  This study is designed to learn more about how to 
select patients that will benefit the most from specific drug combination to treat their multiple 
myeloma. This information could help future myeloma patients.
Will I be compensated for my time and effort?
You will not be paid for taking part in this research study.  However, you may receive reimbursement 
of travel expenses for participating in the study. Your participation in this research study may contribute 
to the development of commercial products from which Millennium Pharmaceuticals, Inc., or others, 
may derive an economic benefit.   You have no rights to and will not receive payments of any kind for 
discoveries, patents or products that may be developed from this study. 
What are my other options?
Your study doctor will discuss with you any other treatments or other clinical trials, which may be 
available for the treatment of your disease and their risks and benefits. Your other choices may include:

Getting treatment or care for your cancer without being in a study

Receiving other standard therapies for newly diagnosed multiple myeloma 

Other clinical trials may be available that might have fewer side effects or might be better for 
your 
health. 
Talk to your study doctor about your choices before you decide if you will take part in this study.
Taking part in this study, however, may make you unable to participate in some other research 
studies, if they exclude people who have taken certain treatments.  You should discuss this with the 
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Protocol #: MMRC060                                                                                                                         IRB Form 01292016
researchers if you have concerns. You may wish to research other study options at websites like 
clinicaltrials.gov and ResearchMatch.org.
How will you protect my private information that you collect in this study?
Emory and Grady Health System will keep any research records that it creates private to the extent 
that this is required to do so by law.  Whenever possible, a study number, rather than your name, will 
be used on study records.  Your name and other identifying information will not appear when we 
present or publish the study results.
Study records can be opened by court order.  They also may be provided in response to a subpoena 
or a request for the production of documents. 
How is my Genetic Information Protected? What are the Risks?
The Genetic Information Nondiscrimination Act (GINA) is a federal law that generally makes it illegal 
for health insurance companies, group health plans, and most employers to discriminate against you 
based on your genetic information. This law generally will protect you in the following ways: 
•
Health insurance companies and group health plans may not request your genetic information 
that we get from this research.
•
Health insurance companies and group health plans may not use your genetic information 
when making decisions regarding your eligibility or premiums. 
•
Employers with 15 or more employees may not use your genetic information that we get from 
this research when making a decision to hire, promote, or fire you or when setting the terms of 
your employment.
Be aware that GINA does not protect you against genetic discrimination by companies that sell life 
insurance, disability insurance, or long-term care insurance, and does not apply to employers with 
less than 15 employees.
In addition to GINA, the State of Georgia has laws that prohibit insurers from using genetic testing 
information for any non-treatment purpose.  However, like GINA, this state law protection has 
exclusions: life insurance policies, disability income policies, accidental death or dismemberment 
policies, Medicare supplement policies, long-term care insurance policies, credit insurance policies, 
specified disease policies, hospital indemnity policies, blanket accident and sickness policies, 
franchise policies issued on an insurance policy written as a part of workers’ compensation equivalent 
coverage, or other similar limited accident and sickness policies.
Privilege 
In the State of Georgia, in some circumstances your genetic information has may have special legal 
protections called “privilege.” This means that the information cannot be used as evidence in a court. 
By allowing us to use and disclose your genetic information for this research study along with other 
information about you that genetic information used in the research may no longer have that legal 
protection. Other protections described in this form will still apply. There are also other confidentiality 
protections for research data in general under Georgia state law.  
Medical Record
If you have been an Emory Healthcare and Grady Health System patient before, then you already 
have an Emory Healthcare and Grady Health System medical record.  If you have never been an 
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Protocol #: MMRC060                                                                                                                         IRB Form 01292016
Emory Healthcare and Grady Health System patient, you do not have one.   An Emory Healthcare 
and Grady Health System medical record will be made for you if an Emory and Grady Health System 
provider or facility gives you any services or procedures for this study.  
Copies of the consent form/HIPAA authorization that you sign will be put in any Emory Healthcare 
and Grady Health System medical record you have now or any time during the study.  
Emory Healthcare and Grady Health System may create study information about you that can help 
with your care.  For example, the results of study tests or procedures.  These study results will be put 
in your Emory Healthcare and Grady Health System medical record. Anyone who has access to your 
medical records will be able to have access to all the study information placed there.  The 
confidentiality of the study information in your medical record will be protected by laws like the HIPAA 
privacy rule.  State and federal laws may not protect the research information from disclosure. 
The results of some study tests and procedures will be used only for research purposes and will not 
be placed in your medical record.  For this study, those items include: None
Tests and procedures done at non-Emory and Grady Health System places may not become part of 
your Emory medical and Grady Health System record. Also, if you decide to be in this study, it is up to 
you to let your other health providers know. 
In Case of Injury
If you get ill or injured from being in the study, Emory and Grady Health System will help you to get 
medical treatment.   Emory and Grady Health System and the sponsor have not, however, set aside 
any money to pay you or to pay for this medical treatment. The only exception is if it is proven that 
your injury or illness is directly caused by the negligence of an Emory and Grady Health System or 
sponsor employee.  “Negligence” is the failure to follow a standard duty of care. 
If you become ill or injured from being in this study, your insurer will be billed for your treatment costs. 
If you do not have insurance, or if your insurer does not pay, then you will have to pay these costs. If 
you believe you have become ill or injured from this research, you should contact Dr. Leon Bernal-
Mizrachi at telephone number 
. You should also let any health care provider who treats 
you know that you are in a research study. 
Costs
The study sponsor will pay for certain items and services that you may receive if you take part in this 
study.  
You will have to pay for the items or services for which the study sponsor does not pay. The sponsor 
will not pay for your regular medical care. If you have insurance, Emory and Grady Health System will 
submit claims to your insurance for items and services that the sponsor does not cover.  Emory and 
Grady Health System will send in only those claims for items and services that it reasonably believes 
your insurance will pay and that the sponsor has not paid. 
The actual amount that you have to pay depends on whether or not you have health insurance and 
whether or not that insurance will pay for any research study costs. Generally, insurance companies 
will not pay for items and services that are required just for a research study. Some insurance 
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Protocol #: MMRC060                                                                                                                         IRB Form 01292016
companies will not pay for regular medical treatment or treatment for complications if you are in a 
study.  How much you will have to pay for any co-payments, deductibles or co-insurance depends on 
your plan.  Emory and Grady Health System and the sponsor will not pay for these costs. 
It is a good idea to contact your insurance provider and tell them you want to be in this research 
study.  Ask them what they will pay for and what they will not pay for.  You can also ask the study 
team for help in figuring out what you will have to pay. 
If you do not have insurance, Emory and Grady Health System will review your case as part of its 
program for low-income patient care.  The standard policies of that program will apply.  The program 
will figure out if you have to pay any costs for taking part in the study and what those costs will be.
Withdrawal from the Study
You have the right to leave a study at any time without penalty.  
For your safety, however, you should consider the study doctor’s advice about how to go off the study 
treatment.  If you leave the study before the final planned study visit, the researchers may ask you to 
have some of the final steps done.  
The researchers also have the right to stop your participation in this study without your consent for any 
reason, especially if they believe it is in your best interest or if you were to object to any future changes 
that may be made in the study plan.
Authorization to Use and Disclose Protected Health Information
The privacy of your health information is important to us.  We call your health information that 
identifies you, your “protected health information” or “PHI.”  To protect your PHI, we will follow federal 
and state privacy laws, including the Health Insurance Portability and Accountability Act and 
regulations (HIPAA).  We refer to all of these laws as the “Privacy Rules.”  Here we let you know how 
we will use and disclose your PHI for the study 
PHI that Will be Used/Disclosed:  
The PHI that we will use or share for the main research study includes:

Medical information about you including your medical history and present/past 
medications.

Results of exams, procedures and tests you have before and during the study.

Laboratory test results.
Purposes for Which Your PHI Will be Used/Disclosed:
We will use and share your PHI for the conduct and oversight of the research study.  We will 
use and share your PHI to provide you with study related treatment and for payment for such 
treatment.  We will also use and share your PHI to conduct normal business operations.  We 
may share your PHI with other people and places that help us conduct or carry out the study, 
such as laboratories, data management centers, data monitors, contract research 
organizations, Institutional Review Boards (IRBs) and other study sites. If you leave the study, 
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Protocol #: MMRC060                                                                                                                         IRB Form 01292016
we may use your PHI to determine your health, vital status or contact information. We will use 
and disclose your PHI for the administration and payment of any costs relating to subject injury 
from the study.  
Use and Disclosure of Your Information That is Required by Law:  
We will use and disclose your PHI when we are required to do so by law. This includes laws 
that require us to report child abuse or abuse of elderly or disabled adults. We will also comply 
with legal requests or orders that require us to disclose your PHI. These include subpoenas or 
court orders.  
Authorization to Use PHI is Required to Participate:
By signing this form, you give us permission to use and share your PHI as described in this 
document. You do not have to sign this form to authorize the use and disclosure of your PHI.  
If you do not sign this form, then you may not participate in the research study or receive 
research-related treatment.  You may still receive non-research related treatment.  
People Who will Use/Disclose Your PHI:
The following people and groups will use and disclose your PHI in connection with the 
research study:

The Principal Investigator and the research staff will use and disclose your PHI to 
conduct the study and give you study related treatment.

Emory and Grady Health System may use and disclose your PHI to get payment for 
study related treatment and to run normal business operations. 

The Principal Investigator and research staff will share your PHI with other people and 
groups to help conduct the study or to provide oversight for the study.

Millennium Pharmaceuticals, Inc., (the makers of ixazomib) the Study Supporter.

The Multiple Myeloma Research Consortium, Inc. (an organization consortium that 
provides financial an administrative support for the conduct of clinical trials to member 
institutions) and its contractors or designees

Researchers at other institutions which are participating in this study.

Empire Genomics ( the makers of the NFKB2 FISH test evaluated in this study)

The following people and groups will use your PHI to make sure the research is done 
correctly and safely:
o
Emory and Grady Health System offices that are part of the Human Research 
Participant Protection Program and those that are involved in study 
administration and billing.  These include the Emory IRB, the Emory Research 
and Healthcare Compliance Offices, and the Emory Office for Clinical Research. 
o
Government agencies that regulate the research including:  Food and Drug 
Administration.
o
Public health agencies.
o
Research monitors and reviewer.
o
Accreditation agencies.
Expiration of Your Authorization
Your PHI will be used until this research study ends.
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Protocol #: MMRC060                                                                                                                         IRB Form 01292016
Revoking Your Authorization
If you sign this form, at any time later you may revoke (take back) your permission to use your 
information.  If you want to do this, you must contact the study team at:
Leon Bernal-Mizrachi, MD
Winship Cancer Institute, Emory University
1365-C Clifton Road NE
Atlanta, GA 30322
At that point, the researchers would not collect any more of your PHI.  But they may use or disclose 
the information you already gave them so they can follow the law, protect your safety, or make sure 
that the study was done properly and the data is correct.  If you revoke your authorization you will not 
be able to stay in the study. 
Other Items You Should Know about Your Privacy
Not all people and entities are covered by the Privacy Rules.  HIPAA only applies to health care 
providers, health care payers, and health care clearinghouses.  If we disclose your information to 
people who are not covered by the Privacy Rules, including HIPAA, then your information won’t be 
protected by the Privacy Rules.  People who do not have to follow the Privacy rules can use or 
disclose your information with others without your permission if they are allowed to do so by the laws 
that cover them.  The Sponsor, and people and companies working with the Sponsor on this study 
are not covered by the Privacy Rules.  They will only use and disclose your information as described 
in this Consent and Authorization. 
To maintain the integrity of this research study, you generally will not have access to your PHI related 
to this research until the study is complete.  When the study ends, and at your request, you generally 
will have access to your PHI that we maintain in a designated record set.  A designated record set is 
data that includes medical information or billing records that your health care providers use to make 
decisions about you. If it is necessary for your health care, your health information will be provided to 
your doctor. 
We may remove identifying information from your PHI.  Once we do this, the remaining information 
will not be subject to the Privacy Rules.  Information without identifiers may be used or disclosed with 
other people or organizations for purposes besides this study.  
In order to obtain lenalidomide through the Revlimid Risk Evaluation and Mitigation Strategy 
(REMS)™ program (formerly known as RevAssist® program), your name, address, phone, date of 
birth and the fact that you are participating in this trial will be disclosed to Celgene and its agents or 
vendors that supply lenalidomide and support the Revlimid REMS™ program.  By signing this 
consent form you agree to this disclosure.
 
What happens to my blood, samples or tissue?
The following samples will be used up in the testing performed for this study and any remaining 
sample will be stored for retesting until the study results have been reported:

Clinical Laboratory Evaluations (disease assessments) 

Hematology and Chemistry

Urine Samples 
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Protocol #: MMRC060                                                                                                                         IRB Form 01292016
The additional blood and bone marrow samples collected for this study will be stored at Emory 
University, Atlanta, GA, USA, its agents or its affiliated companies for up to 15 years from when the 
study results are reported or if less, the maximum period permitted under applicable law or until 
consent is withdrawn.  The samples will be sent to Empire Genomics which will process the sample 
and extracts the DNA, RNA or protein. Samples will then be transferred to Emory University for 
storage. Emory University, its agents and affiliated companies will have access to the samples 
collected. All samples collected during the study will be stored securely with limited access and 
Emory University will require anyone who works with the samples to agree to hold the research 
information and any individual results in confidence.  After that time, the samples will be destroyed.  
The study doctor will keep records linking your identity with your samples as required by applicable 
law.  The sample will be labeled with a unique sample identifier. The sample will be used in the 
analysis of Ixazomib and related disease states. The sample and data are linked to your personal 
health information with code numbers. This link means that you may be identified but only indirectly. 
The code numbers will be kept secure by the study doctor at Emory University.  
You may also request that your samples and material obtained from your samples be destroyed at 
any time by contacting your study doctor.  As long as the records linking your identity to your samples 
exist, your samples can still be destroyed.  However, Emory University will be entitled to keep and 
use any study results or information which it obtained from your samples prior to your request.  
You will have access to results of blood tests done as part of routine cancer care.  However, you will 
not have access to all your individual sample results from the study.
The samples collected may also be used in the future as part of research related to the development 
of ixazomib or involving additional biomarkers which may be relevant to your disease or response to 
ixazomib.  The blood samples collected from you and the information and results from tests 
performed with these samples may be used individually or combined with other data.   The tests 
performed with these samples are not intended to make determinations about your health or the 
likelihood you will develop any disease, so no test results will be provided to your doctor or put into 
your medical record.  By signing this consent form, you agree that we may store your blood samples 
and tumor tissue and may use it for studies going on right now, as well as Ixazomib or Multiple 
Myeloma related studies that are conducted in the future.
 
Disclosure
This study is evaluating a product manufactured by Celgene pharmaceuticals. Dr. Bernal-Mizrachi 
serves as a consultant to Celgene and receives compensation for these services. The terms of this 
arrangement have been reviewed and approved by Emory University in accordance with its conflict of 
interest policies.
Contact Information
Contact Dr. Leon Bernal-Mizrachi at 
:

if you have any questions about this study or your part in it,  

if you feel you have had a research-related injury or a bad reaction to the study drug, or

if you have questions, concerns or complaints about the research
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Protocol #: MMRC060                                                                                                                         IRB Form 01292016
Contact the Emory Institutional Review Board at 
:

if you have questions about your rights as a research participant.

if you have questions, concerns or complaints about the research.

You may also let the IRB know about your experience as a research participant through our 
Research Participant Survey at http://www.surveymonkey.com/s/6ZDMW75.
If you are a patient receiving care from the Grady Health System and have a question about your rights, 
you may contact the Office of Research Administration at research@gmh.edu.
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Protocol #: MMRC060                                                                                                                         IRB Form 01292016
Consent and Authorization
TO BE FILLED OUT BY SUBJECT ONLY
Please print your name, sign, and date below if you agree to be in the main study. By signing this 
consent and authorization form, you will not give up any of your legal rights. We will give you a copy of 
the signed form to keep.
Name of Subject 
       ________    ____:____ am / pm
Signature of Subject (18 years or older and able to consent)      Date        Time   (please circle)
TO BE FILLED OUT BY STUDY TEAM ONLY
__________________________________________________________
Name of Person Conducting Informed Consent Discussion
       ________    ____:____ am / pm
Signature of Person Conducting Informed Consent
Date      Time   (please circle)
Discussion
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