Phase 2 Trial of Ixazomib Combinations in Patients With Relapsed Multiple Myeloma
Phase: PHASE2
Conditions: Recurrent Plasma Cell Myeloma, Refractory Plasma Cell Myeloma
Sponsor: Mayo Clinic

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Mayo Clinic Cancer Center 
 
Phase 2 Trial of Ixazomib Combinations in Patients with Relapsed Multiple Myeloma  
 
 
Study Chair: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Study Co-chairs: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
Statistician: 
 
 
 
  
 
Drug Availability 
Commercial Agents:  Dexamethasone, Cyclophosphamide  
Drug Company Supplied:  Ixazomib, Daratumumab 
 
Study contributor(s) not responsible for patient care. 
 
Document 
History 
Effective Date 
Document 
History 
Effective Date 
Document 
History 
Effective Date 
Activation 
January 31, 2011
Addendum 10 
April 2, 2014
Addendum 20 
May 22, 2017
Addendum 1 
March 22, 2012
Addendum 11 
May 1, 2014
Addendum 21 
December 18, 2017
Addendum 2 
June 12, 2012
Addendum 12 
July 23, 2014
Addendum 22 
March 20, 2018
Addendum 3 
August 10, 2012
Addendum 13 
January 19, 2015
Addendum 23 
September 13, 2018
Addendum 4 
November 8, 2012
Addendum 14 
April 23, 2015
Addendum 24 
January 28, 2019
Addendum 5 
February 27, 2013
Addendum 15 
November 23, 2015
Addendum 25 
July 23, 2019
Addendum 6 
June 7, 2013
Addendum 16 
January 5, 2016
Addendum 26 
February 26, 2020
Addendum 7 
August 26, 2013
Addendum 17 
February 4, 2016
Addendum 27 
May 11, 2020
Addendum 8 
October 1, 2013
Addendum 18 
February 11, 2016
Addendum 28 
April 29, 2021
Addendum 9 
December 10, 2013
Addendum 19 
June 9, 2016
Addendum 29 
August 31, 2021
 
 
Addendum 30 
September 29, 2023
 
 
 

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Index 
Schema 
  1.0 
Background 
  2.0 
Goals 
 
  3.0 
Patient Eligibility 
  4.0 
Test Schedule 
  5.0  
Stratification Factor  
  6.0 
Registration/Randomization Procedures 
  7.0 
Protocol Treatment 
  8.0 
Dosage Modification Based on Adverse Events  
  9.0 
Ancillary Treatment/Supportive Care 
10.0 
Adverse Event (AE) Reporting and Monitoring  
11.0 
Treatment Evaluation   
12.0 
Descriptive Factors 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient  
14.0 
Body Fluid Biospecimens 
15.0 
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations/Tissue Biospecimens 
18.0 
Records and Data Collection Procedures 
19.0 
Budget 
20.0 
References 
 Appendix I - ECOG Performance Status 
Appendix II – Mayo Risk Stratification 
Appendix III – NYHA Classification 
Appendix IV – Multiple Myeloma Diagnostic Criteria 
Appendix V – Patient Medication Diary-Arm D   
Appendix V I – Pregnancy Reporting Form 
Appendix VII – Patient Medication Diary-Arms A-C (closed) 
Appendix VIII – Patient Medication Diary Arm E 

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Schema – Arm A (permanently closed to accrual per Addendum 5) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If a patient is deemed ineligible or a cancel, please refer to Section 13 for follow-up information. 
 
1 Cycle length = 28 days 
2 MR by 2 cycles and PR by 4 cycles can be unconfirmed responses 
3 Confirmation of PD is not required 
 
Generic name:    Ixazomib 
Brand name(s): Ninlaro® 
Mayo Abbreviation: MLN9708 
  
Availability:   Provided by Millennium Pharmaceutical
Generic name:  Dexamethasone 
Brand name(s):  Decadron 
Mayo Abbreviation:  DXM 
Availability:  Commercial
Active Treatment: 
Ixazomib x 2-4 cycles1 
Continue Treatment 
(Till progression)3 
Event Monitoring 
(per Section 18.0)
Add dexamethasone 
PD despite adding dexamethasone 
Unacceptable adverse events   
 
 
Event Monitoring 
Patient refusal  
 
 
 
(per Section 18.0) 
Registration 
< MR by 2 cycles or < PR by 4 
cycles2 or PD anytime3 
≥ MR by 2 cycles and ≥PR by 4 
cycles2
Continue Treatment 
(Till progression)3 

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Schema – Arm B and C (closed) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If a patient is deemed ineligible or a cancel, please refer to Section 13 for follow-up information. 
 
1 Cycle length = 28 days 
 
2 Confirmation of PD is not required 
 
Generic name:    Ixazomib 
Brand name(s): Ninlaro® 
Mayo Abbreviation: MLN9708  
  
Availability:   Provided by Takeda/Millennium 
Pharmaceuticals, Inc.
Generic name:  Dexamethasone 
Brand name(s):  Decadron 
Mayo Abbreviation:  DXM 
Availability:  Commercial 
 
 
 
Randomization 
Continue Treatment 
(Till progression)2 
Event Monitoring 
(per Section 18.0) 
PD at any time2
Unacceptable adverse events   
 
Event Monitoring 
Patient refusal 
 
 
 
(per Section 18.0) 
Registration 
Arm B 
Ixazomib 4mg and 
Dexamethasone 
Arm C 
Ixazomib 5.5mg and 
dexamethasone 

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Schema – Arm D 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If a patient is deemed ineligible or a cancel, please refer to Section 13 for follow-up information. 
 
1 Cycle length = 28 days 
 
2 Confirmation of PD is not required 
 
Generic name:     Ixazomib 
Brand name(s): Ninlaro® 
Mayo Abbreviation: MLN9708  
  
Availability:   Provided by Takeda/ 
Millennium Pharmaceuticals, Inc.
Generic name: cyclophosphamide 
Brand name(s):  Cytoxan 
Mayo Abbreviation:  CTX 
Availability:  Commercial 
Generic name:  Dexamethasone 
Brand name(s):  Decadron 
Mayo Abbreviation:  DXM 
Availability:  Commercial 
 
Continue Treatment 
(Till progression )2 
Event Monitoring 
(per Section 18.0) 
PD at any time2
Unacceptable adverse events   
 
Event Monitoring 
Patient refusal 
 
 
 
(per Section 18.0) 
Registration 
Arm D 
 Ixazomib 4mg, cyclophosphamide 300 
mg/m2 (cycles 1-18) and 
Dexamethasone

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Schema – Arm E (added as of Addendum 23) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If a patient is deemed ineligible or a cancel, please refer to Section 13 for follow-up information. 
 
1 Cycle length = 28 days 
 
2 Confirmation of PD is not required 
 
Note: Patients are allowed to be re-registered to a different arm due to progression. 
 
Generic name:    Ixazomib   
Brand name(s):  Ninlaro® 
Mayo Abbreviation: MLN9708    
Availability:   Provided by Takeda/Millennium, Inc.
Generic name:  cyclophosphamide 
Brand name(s):  Cytoxan 
Mayo Abbreviation:  CTX 
Availability:  Commercial 
Generic name:  Dexamethasone 
Brand name(s):  Decadron 
Mayo Abbreviation:  DXM 
Availability:  Commercial 
Generic name:  Daratumumab 
Brand name(s):  Darzalex 
Mayo Abbreviation:  DARA 
Availability:  Provided by Janssen 
 
 
 
Continue Treatment 
(Till progression)2 
Event Monitoring 
(per Section 18.0) 
PD at any time2
Unacceptable adverse events   
 
Event Monitoring 
Patient refusal 
 
 
 
(per Section 18.0) 
Registration 
Arm E 
Ixazomib, cyclophosphamide (cycles 1 
– 12 only), daratumumab, and 
dexamethasone 

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1.0 
Background 
 
1.1 
Treatment 
 
1.11 
Relapsed multiple myeloma: Multiple Myeloma (MM) is a plasma cell 
proliferative disorder characterized pathologically by accumulation of 
clonal plasma cells predominantly in the bone marrow, with circulating 
tumor cells seen usually in the late stages of the disease (Kyle, et al 
2003). Clinically, myeloma is manifested by destructive bone lesions that 
can result in pathological fractures, anemia and or thrombocytopenia, 
hypercalcemia, and renal insufficiency, which can be multifactorial in 
origin. In this country, the estimated annual diagnosed incidence is 
19,200, with approximately 50,000 prevalent cases. In Europe, the 
estimated annual diagnosed incidence is 21,611 with approximately 
54,536 prevalent cases. Multiple myeloma accounts for 10% of all 
hematologic malignancies and 1% of all malignancies. The median 
survival of patients with symptomatic MM treated with melphalan and 
prednisone or other combination chemotherapy medications was 3 to 4 
years (Kyle, et al 2003). Advances in high-dose chemotherapy and stem 
cell transplantation have improved overall survival and event-free 
disease periods in patients with MM, but relapses are inevitable.(Kumar, 
et al 2008) New therapeutic agents, such as bortezomib and thalidomide 
analogues, have shown promising clinical benefit in patients with 
relapsed or refractory disease. Despite these therapeutic advances, MM 
remains essentially incurable and is associated with high morbidity and 
mortality. 
 
1.12 
The ubiquitin proteasome pathway: The ubiquitin-proteasome pathway 
is critical to cellular homeostasis, playing a major role in maintaining 
appropriate levels of different proteins in the cell.(Adams, et al 1998, 
Adams, et al 1999) The ubiquitin-proteasome system is responsible for 
the orderly degradation of cellular proteins involved in virtually all 
aspects of cell growth and proliferation. The pathway degrades proteins 
involved in cell cycle regulation, cell survival, and metastasis such as 
p53, p21, p27 and NFkB. Ubiquitin is a 9kd protein that is abundantly 
present in the cell and is highly evolutionary conserved. Cellular proteins 
that are marked for degradation gets polyubiquitinated; where C-terminal 
glycine residues of the ubiquitin molecules attach covalently to specific 
lysine residues on the protein molecule. This three step process 
sequentially involves the ubiquitin activating enzyme E1, an ubiquitin 
conjugating enzyme E2 and an ubiquitin ligase E3. The first ubiquitin 
molecule forms the nidus for additional ubiquitin molecules to be 
attached. Once, polyubiquitinated, the protein is targeted by the 26S 
proteasome for degradation, an active energy requiring process that 
maintains protein levels in the cell. The 26S proteasome in the 
mammalian cells consists of a core 20S catalytic complex and a 19S 
regulatory complex. It is a cylindrical structure with an outer ring 
composed of 7 alpha subunits and an inner ring that is made up of seven 
beta subunits. The 20S catalytic portion has chymotryptic, tryptic and 
peptidylglutamyl like activities, with the catalytic sites located in the 
inner surface of the cylinder. The ubiquitinated protein is recognized by 

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the 19S subunit, the ubiquitin tags are cleaved, and the protein is 
hydrolyzed by the proteasome at six different catalytic sites present in 
the 20S catalytic complex. In vitro studies in a variety of cancers 
demonstrate the ability of proteasome inhibitors to selectively target the 
malignant cells supporting this strategy for cancer therapy. The 
mechanism of selectivity is not clear, but may be related to increased 
dependency of rapidly proliferating cells on the pathway. Bortezomib 
was the first proteasome inhibitor to enter human trials.(Adams 2002a) 
 
In the setting of MM, several in vitro studies have shown the ability of 
proteasome inhibitors to inhibit proliferation and induce apoptosis of 
MM cell lines and freshly isolated patient MM cells as well as overcome 
adhesion mediated resistance.(Richardson, et al 2003b) They can inhibit 
the paracrine growth of human MM cells by decreasing their adherence 
to bone marrow stromal cells (BMSCs) and related nuclear factor B-
dependent induction of interleukin-6 secretion by BMSCs. The 
mechanism of anti-MM activity of proteasome inhibitors are likely 
multiple. Transcriptional profiling of MM cells treated with bortezomib, 
a proteasome inhibitor currently in the clinic, demonstrated down-
regulation of growth/survival signaling pathways, and up-regulation of 
molecules implicated in pro-apoptotic cascades, as well as up-regulation 
of heat-shock proteins and ubiquitin/proteasome pathway members. In 
addition, treatment decreased the levels of several anti-apoptotic proteins 
and triggered the release of mitochondrial cytochrome c and caspase-9 
activation, all contributing to apoptosis of MM cells. One of the key 
effects is thought to be the inhibition of the NFkB pathway, which is 
critical to the MM cell proliferation induced by growth factors as well as 
adhesion to BMSC. Other purported mechanisms include (i) activation of 
classical stress response proteins such as heat shock proteins, Hsp27, 
Hsp70, and Hsp90; (ii) up regulation of c-Jun-NH2-terminal kinase 
(JNK); (iii) activation of extrinsic apoptotic signaling through Bid and 
caspase-8 cleavage; and (iv) inactivation of DNA-dependent protein 
kinase (DNA-PK), which is essential for the repair of DNA double-
strand breaks. 
 
1.13 
Clinical experience with bortezomib and combinations in Relapsed/ 
Refractory MM: Bortezomib (N-pyrazinecarbonyl-L-phenylalanine-L-
leucine boronic acid; Velcade; Millennium Pharmaceuticals) is a small, 
cell permeable molecule that specifically and selectively inhibits the 
proteasome by binding in a reversible manner.(Adams 2001, An, et al 
2000, Dai, et al 2003, Hideshima, et al 2001, Ling, et al 2002, Shah, et al 
2001, Sunwoo, et al 2001, Teicher, et al 1999)  Chemically, bortezomib 
is a modified dipeptidyl boronic acid derived from leucine and 
phenylalanine. Bortezomib inhibits the 20S proteasome with a Ki of 0.6 
nM and has a short plasma half-life following iv administration 
indicating rapid clearance.(Adams 2002b)  Bortezomib is metabolized by 
cytochrome P450 system into several inactive deboronated metabolites. 
Bortezomib is extensively bound to plasma proteins (83% in man).  
Tissue distribution of bortezomib, following IV infusion in rats, indicates 
that the highest levels are found in the adrenal glands, renal cortex, liver, 

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prostate and spleen.  When used at the recommended dosing schedule, 
nearly 60% proteasome inhibition is achieved.  
 
In a phase II multicenter trial of bortezomib in MM, 202 patients with 
progressive disease on treatment or disease progression within 60 days of 
completing therapy were treated with bortezomib alone, with addition of 
dexamethasone after 2 cycles in the absence of response.(Richardson, et 
al 2003a) Of the 193 assessable patients, 53 (27%) achieved a partial 
response to therapy including 4% of patients with a CR. The median 
survival for all patients was 16 months, and the median time to 
progression was 7 months. Responses were durable, with median 
response duration of 12 months in patients who achieved a CR, partial 
response, or minor response to therapy. Another randomized phase II 
trial in patients who failed to respond or relapsed after front-line therapy 
examined the two doses of bortezomib: 1.0 mg/m2 vs. 1.3 mg/m2 on days 
1, 4, 8, and 11 every 21 days. Responses (CR, partial response, or minor 
response) were seen in 33% of patients at the dose level of 1.0 mg/m2 and 
50% of patients at the dose level of 1.3 mg/m2. In a phase III trial 
comparing bortezomib with dexamethasone, the overall response rates 
were 38 percent for bortezomib and 18 percent for dexamethasone, and 
the complete response rates were 6 percent and less than 1 percent, 
respectively (Richardson, et al 2005). Median times to progression in the 
bortezomib and dexamethasone groups were 6.2 months and 3.5 months 
respectively. There was improvement in the overall survival in patients 
receiving bortezomib as well. Correlative studies from the initial studies 
suggest that bortezomib is able to overcome the adverse prognostic effect 
of the genetic abnormalities seen in MM such as deletion 13.(Jagannath, 
et al 2007). 
 
1.14 
Ixazomib: Ixazomib, which has been formulated for both intravenous 
(IV) and oral (PO) administration, is a small molecule proteasome 
inhibitor.  The proteasome is a large protein complex that degrades 
ubiquitinated proteins via the ubiquitin-proteasome pathway (UPP), 
which is responsible for the degradation of the majority of intracellular 
proteins.  Due to the accumulation of many different proteasome 
substrates, proteasome inhibition affects multiple signaling cascades 
within cells, resulting in downstream effects including antitumor activity, 
promotion of apoptosis, and antiangiogenic and antiproliferative 
activities.  These consequences of proteasome inhibition are of particular 
importance in plasma cells and multiple myeloma cells, which produce 
high levels of secreted Ig proteins.  Ixazomib is a small molecule 
proteasome inhibitor.   
 
Ixazomib is the citrate ester of the biologically active boronic acid form, 
MLN2238, which is structurally similar to borezomib.  In water or 
aqueous systems, ixazomib rapidly hydrolyzes to MLN2238, therefore 
all doses and concentrations are expressed as MLN2238.  Nonclinical 
studies were conducted with a solution of either MLN2238 or MLN2238 
in equilibrium with ixazomib.  Similar to bortezomib, MLN2238 
potently, reversibly, and selectively inhibits the 20S proteasome.  
However in contrast to bortezomib, it has a shorter dissociation half-life 

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(t1/2) that may contribute to increased tissue distribution.  Bortezomib 
has a slowly reversible dissociation rate from the red blood cell 
proteasome, while MLN2238 demonstrates a more rapidly reversible 
dissociation rate from the blood but sustained effects on bone marrow 
and tumor proteasomes suggesting better tissue distribution.  The 
pharmacologic implications of this difference in binding kinetics and 
tissue distribution may in turn result in differences in safety and efficacy 
profiles in a broader range of tumors.  In xenograft-bearing mice, the 
more rapid dissociation rate correlates with an increased ratio of tumor 
proteasome inhibition to blood proteasome inhibition, and ixazomib 
shows greater antitumor activity in several xenograft models, both solid 
tumor and bortezomib-resistant xenografts, than bortezomib.   
 
1.15    Nonclinical Pharmacology: MLN2238 refers to the biologically active, 
boronic acid form of the drug substance, ixazomib.  Ixazomib refers to 
the citrate ester of MLN2238.  In water or aqueous systems, the 
equilibrium shifts from ixazomib to the biologically active boronic acid 
form MLN2238.  All doses and concentrations are expressed as the 
boronic acid, MLN2238. 
 
In Vitro Pharmacology: MLN2238 preferentially binds the β5 site of the 
20S proteasome; at higher concentrations, it also inhibits the activity of 
the β1 and β2 sites.  MLN2238 inhibits ß5 site 20S proteasome activity 
in vitro, with a half-maximal inhibitory concentration (IC50) of 3.4 nM.  
Potency is reduced roughly 10-fold versus ß1 (IC50  31 nM) and 1,000-
fold versus ß2 (IC50 =3500 nM).  MLN2238 was also tested for 
inhibition against a panel of 103 kinases, 18 receptors (neurotransmitter, 
ion channel, brain and gut receptors), and 9 serine proteases.  In all cases, 
the IC50 values were > 10 μM.  MLN2238 and bortezomib have 
different β5 proteasome dissociation half-lives (t1/2), reflecting 
differences in their on-off binding kinetics (the β5 proteasome 
dissociation t1/2 for MLN2238 and bortezomib are 18 and 110 minutes, 
respectively).  Based on these favorable characteristics, ixazomib is 
anticipated to be effective against multiple myeloma (ixazomib 
Investigator’s Brochure (IB). 
 
Proteasome inhibition results in the accumulation of poly-ubiquitinated 
substrates within the cell and leads to cell cycle disruption, with 
concomitant activation of apoptotic pathways and cell death.  Consistent 
with inhibition of ß5 20S activity, MLN2238 demonstrated potent 
activity against cultured MDA-MB 231 human breast cancer cells in the 
WST cell viability assay.  In nonclinical models MLN2238 has activity 
against both solid tumor and bortezomib-resistant xenografts 
 
In Vivo Pharmacology: To determine the activity of MLN2238 in vivo, 
pharmacodynamic studies were performed in immunocompromised mice 
bearing either CWR22 human prostate or WSU-DLCL2 (human diffuse 
large B-cell lymphoma [DLBCL]) tumors.  Pharmacodynamic responses 
in xenograft tumors were analyzed by assessing 20S proteasome 
inhibition and by evaluating levels of accumulated protein markers such 
as deoxyribonucleic acid (DNA) damage-inducible protein 34 

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(GADD34) and activating transcription factor-3 (ATF-3) as well as 
measuring growth arrest.  Increased expression of GADD34 and ATF-3 
is indicative of a downstream biological response to proteasome 
inhibition.  After a single dose of MLN2238, a clear dose response was 
observed in CWR22 xenografts as seen in both tumor 20S proteasome 
inhibition and in changes in GADD34 and ATF-3 expression.  In WSU-
DLCL2 xenografts, greater tumor proteasome inhibition was observed 
with MLN2238 compared to bortezomib and resulted in increased 
expression of GADD34 and ATF-3. 
 
MLN2238 efficacy experiments demonstrated strong antitumor activity 
in 4 xenograft models: CWR22 (a human prostate cancer cell line) and 3 
human lymphoma cell lines (WSU-DLCL2, OCI-Ly7-7D1-luc, and 
PHTX-22L).  In the case of the CWR22 xenograft model, significant 
antitumor activity was seen with both IV and PO dosing, demonstrating 
that this molecule has antitumor activity when administered via different 
dosing routes.  In all 3 lymphoma lines, MLN2238 demonstrated 
stronger antitumor activity than did bortezomib. 
 
In summary, MLN2238, similar to bortezomib, is a dipeptide boronic 
acid proteasome inhibitor that potently, reversibly, and selectively 
inhibits the proteasome.  There are several features, such as sustained 
pharmacodynamic effects and activity in a bortezomib-refractory 
lymphoma xenograft model, that suggest that it may have activity that 
extends beyond that seen with bortezomib. 
 
1.16    Nonclinical Pharmacokinetics and Pharmacodynamics: Nonclinical 
Pharmacokinetics: The pharmacokinetic (PK) properties of MLN2238 
were studied in severe combined immunodeficient (SCID) mice bearing 
human CWR22 tumor xenografts, Sprague-Dawley rats, beagle dogs, 
and cynomolgus monkeys.  Because of the extensive red blood cell 
(RBC) partitioning of MLN2238, both blood and plasma PK parameters 
were determined in these studies.  MLN2238 had a very low blood 
clearance (CLb) and a moderate blood volume of distribution at steady-
state (Vss,b) after IV administration.  The concentration-versus-time 
curve of MLN2238 displayed a distinct bi-exponential profile with a 
steep initial distribution phase and a long terminal t1/2 (> 24 hr) in all 
species tested.  MLN2238 had higher plasma clearance (CLp) and a 
larger plasma volume of distribution at steady-state (Vss,p) than in 
blood, largely because of the extensive RBC partitioning. 
 
The PK properties of MLN2238 after oral administration were studied in 
rats and dogs.  The plasma oral bioavailability (F) was 41% in rats and 
nearly 100% in dogs.  A clinical prototype formulation of the ixazomib 
capsule demonstrated that MLN2238 had excellent oral F and an 
excellent absorption profile in dogs.  In addition, interindividual 
variability, as measured by %CV, in Cmax and AUC0-24hr after oral 
administration was low to moderate, similar to that after IV 
administration.  The terminal t1/2 after oral administration was also 
similar to that after IV administration.  Comparison of the PK profiles 

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after IV or PO administration in the dog is reported in further detail in 
the IB. 
 
MLN2238 is predicted to have very low CLb (0.0045 L/hr/kg) and a 
moderate Vss,b (0.79 L/kg) with a long terminal t1/2 (> 24 hours) in 
humans.  The human efficacious IV dose of MLN2238 is predicted to be 
2.0 mg/m2 (0.054 mg/kg) twice weekly. 
 
The human efficacious oral dose is predicted to be between 2 and 5 
mg/m2 twice weekly, based on a predicted oral F of between 41% (as 
seen in rats) and 100% (as seen in dogs).  The efficacious dose projection 
for once weekly oral would be higher than twice weekly oral (data not 
provided). 
 
Metabolism appears to be a major route of elimination for MLN2238 and 
urinary excretion of the parent drug was negligible (< 5% of dose).  In 
vitro in liver microsomes, the metabolism of MLN2238 was high in mice 
and low to moderate in all other species studied.  MLN2238 is 
metabolized by multiple cytochrome P450 (CYP) isozymes and non-
CYP enzymes and proteins.  The rank order of relative biotransformation 
activity of each of the 5 major human CYP isozymes in the in vivo 
studies was 3A4 (34.2%) > 1A2 (30.7%) > 2D6 (14.7%) > 2C9 (12.1%) 
> 2C19 (negligible). 
 
MLN2238 is neither an inhibitor of CYP isozymes 1A2, 2C9, 2C19, 
2D6, or 3A4 (IC50 > 30 μM, with an estimated inhibition dissociation 
constant [Ki] > 15 μM) nor a time dependent inhibitor of CYP3A4/5 (up 
to 30 μM).  The potential for ixazomib treatment to produce DDIs via 
CYP inhibition is inferred to be low. 
 
In a Caco-2 cell assay, MLN2238 showed medium permeability with a 
B-to-A/A-to-B permeability ratio of 2.9.  MLN2238 may be a low-
affinity substrate of para-glycoprotein (P-gp), breast cancer resistance 
protein (BCRP), and multidrug resistance protein 2 (MRP2) efflux pump 
transporters.  MLN2238 is not an inhibitor of P-gp, BCRP, and MRP2 
(IC50 > 100 μM).  Consequently, the potential for MLN2238 to cause 
DDIs with substrates or inhibitors of P-gp, BCRP, and MRP2 is low.   
 
See the IB for further details. 
 
1.17    Safety Pharmacology: In exploratory safety pharmacology studies, 
MLN2238 was a weak inhibitor of the cloned cardiac potassium (K+) 
human ether à-go-g o related gene (hERG) channel, with an IC50 of 59.6 
μM, which exceeds, by approximately 200-fold, the plasma Cmax (111 
ng/mL [0.3 μM]) predicted to occur in humans at the optimally 
efficacious dose after IV administration. 
 
In the GLP-compliant, 1-cycle, repeat-dose, PO toxicology study in 
beagle dogs, an increase in QTc was seen in male dogs at non-tolerated 
doses, and a potential increase in QTc was seen in male dogs at tolerated 
doses.  However, increased QTc was not seen in female dogs at any dose, 

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despite the fact that female dogs had plasma Cmax values similar to 
those of male dogs.  Additionally, in a GLP-compliant, 2-cycle, repeat-
dose, IV toxicology study in beagle dogs, no increase in QTc was seen in 
either male or female dogs at any dose, even though dogs in the IV study 
had higher MLN2238 plasma Cmax values than did the male dogs in the 
PO study.  These data suggest that MLN2238 has a low potential for 
prolonging the QT interval in vivo. 
 
1.18   Toxicology: All studies discussed in this section were conducted with a 
solution of either MLN2238 or MLN2238 in equilibrium with ixazomib.  
Because ixazomib was shown to dissociate immediately to MLN2238 
upon exposure to plasma in vitro and therefore could not be detected in 
plasma samples in vitro all doses, concentrations, and PK parameters 
noted, here and in the IB, are expressed as the boronic acid, MLN2238. 
 
The toxicology studies of MLN2238 were studied in SCID mice bearing 
human CWR22 tumor xenografts, Sprague-Dawley rats, beagle dogs,  
and cynomolgus monkeys.  Details of these studies are included in the 
IB. 
 
In Vitro Toxicology: MLN2238 was not mutagenic in a Good Laboratory 
Practice (GLP)-compliant bacterial reverse mutation assay (Ames assay).  
 
In Vivo Toxicology: Details of the in vivo toxicology IV dosing and oral 
dosing studies are provided in the IB.  To summarize, the toxicologic 
effects seen in the IV and PO studies are qualitatively similar to what 
was previously observed in rodents dosed with bortezomib, for which 
ixazomib is the next-generation molecule.  MLN2238 did not cause 
significant toxicities that have not been previously observed after dosing 
with bortezomib.  Therefore, on the basis of the similarity in the toxicity 
profile in rats between MLN22338 and bortezomib, MLN2238 is not 
known to present any additional safety risks beyond those that occur 
after treatment with bortezomib.  In addition, there were no significant 
findings at tolerated exposures in dogs observed after PO administration 
that were not seen after IV administration, and similar exposures were 
tolerated regardless of the route of administration. 
 
The potential risks identified from nonclinical studies in dogs and rats 
include: 
 
GI toxicity that could result in nausea, vomiting, diarrhea, 
dehydration, electrolyte imbalance, bleeding, bowel obstruction 
including ileus and intussusception, and sepsis. 
 
Reduced blood counts manifest as thrombocytopenia, 
neutropenia, and anemia.  Reticulocytopenia was described in 
animals and may be associated with anemia.  Reductions in 
blood counts may predispose to an increased susceptibility to 
infection, bleeding, and anemia. 
 
Peripheral nerve ganglia effects that may be associated with 
peripheral neuropathy that includes pain, burning sensation, and 
numbness.  Autonomic and motor neuropathy may be observed, 
as both have been reported for bortezomib. 

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 
Lymphoid cell depletion that may be associated with increased 
risk of infection, including re-activation of herpes zoster. 
 
Acute phase response that may result in fever and metabolic 
changes. 
 
All of the effects seen in the GLP-compliant PO toxicology studies in 
both dogs and rats at tolerated doses were reversible/reversing and can be 
monitored in the clinic with routine clinical observations (GI 
disturbances and infections secondary to lymphoid compromise), clinical 
pathology assessments (inhibition of erythropoiesis, thrombocytopenia, 
and inflammatory leukogram), and neurologic assessment, as are 
commonly done for patients treated with bortezomib.  The neurologic 
lesions in these studies are similar to what has been described after 
treatment with bortezomib and are believed to be the cause of the 
peripheral neuropathy observed in patients treated with bortezomib. 
Further details are presented in the IB. 
 
1.19a    Clinical Experience: Like bortezomib, ixazomib is a small molecule 
peptide boronic acid analog.  Clinical studies with bortezomib have 
yielded detailed understanding of its safety profile.  For details, refer to 
the package insert for bortezomib.  Ixazomib is in the early stages of 
clinical investigations, with 5 ongoing phase 1 trials and 3 planned phase 
1/2 trials in humans with safety, tolerability, PK, pharmacodynamics, 
electrocardiogram (ECG) parameters, and disease response assessed in 
each study.  Ixazomib is the first investigational proteasome inhibitor 
with substantial oral bioavailability in patients with multiple myeloma. 
 
As of 24 September 2010, 112 patients have been treated with single-
agent ixazomib in the 4 ongoing phase 1 studies (C16001, IV 
administration twice weekly in adult patients with advanced non-
hematologic malignancies, n = 67; C16002, IV administration weekly in 
adult patients with advanced lymphoma, n = 11; C16003 and C16004, 
PO administration twice weekly and weekly, respectively, in adult 
patients with relapse or refractory multiple myeloma, n = 19 and 15, 
respectively).  Regardless of the route of administration in the twice-
weekly dosing schedule, ixazomib is given on Days 1, 4, 8, and 11 of a 
21-day cycle, and in the weekly dosing schedule, the drug is given on 
Days 1, 8, and 15 of a 28-day cycle.  The emerging safety profile as 
presented in the IB and updated here, demonstrates that ixazomib is 
generally well tolerated with manageable and reversible adverse 
reactions and treatment emergent adverse events (TEAEs), irrespective 
of ixazomib causality.  In the non-hematologic malignancies study 
(C16001), the MTD for twice-weekly IV dosing in a 21-day treatment 
cycle is 1.76 mg/m2 based on transient Grade 4 thrombocytopenia in 2 
patients and reversible Grade 3 acute renal failure in 1 patient at 2.34 
mg/m2.  The MTD is yet to be determined in the other studies. 
 
Across the 4 ongoing clinical studies, 106/112 patients (95%) have 
experienced at least 1 TEAE, irrespective of causality and of grade of 
severity.  This frequency is similar in both the IV and oral formulations.  
However,  TEAEs Grade 3 or higher irrespective of cause, drug-related 

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adverse events both all grades and Grade 3 or higher are more frequent 
with the IV than oral formulation (56% vs 26%; 78% vs 68%; and 36% 
vs 18% respectively). 
 
Using the IV formulation, the TEAEs (any grade irrespective of causal 
relationship) observed most frequently (> 10% of patients) include:  
fatigue (56%), rash (45%), nausea (37%), thrombocytopenia (35%), 
vomiting (32%), anorexia (28%), diarrhea (27%), pyrexia (23%), 
constipation (22%), headache (21%), anemia (19%), abdominal pain, 
chill, and dyspnea (14% each) and cough and back pain (13% each).  
Using the oral formulation, the TEAEs (any grade irrespective of causal 
relationship) observed most frequently (> 10%) include fatigue (47%), 
rash 37%), nausea (26%), diarrhea (24%), anemia (21%), cough, 
dyspnea, and vomiting (15% each) and headache (12%).   
 
As of 24 September 2010, a total of 41/112 patients experienced serious 
adverse events (SAEs) while participating in ixazomib clinical studies.  
Sixteen of these 41 patients experienced SAEs considered by their 
investigator as related to ixazomib.  The most common (in ≥ 2 patients) 
treatment-emergent drug-related SAEs include thrombocytopenia (2 
patients, 1 each Grades 3 and 4), nausea (2 patients, Grade 3), 
dehydration (2 patients, Grade 3), transient renal toxicity (2 patients:  
Grade 4 elevated creatinine; Grade 3 acute renal failure), fatigue (2 
patients, Grade 3), pneumonia or pneumonitis (1 patient each, Grade 3).  
Both patients with acute renal insufficiency experienced vomiting and/or 
profuse diarrhea with poor oral intake immediately prior to the reported 
renal events as well as acute intake of nonsteroidal anti-inflammatory 
drugs (NSAIDs; NSAIDs acute intake).  These factors could be 
considered as potential precipitating factors of ischemic acute renal 
failure.  Both patients recovered from the renal toxicity and ultimately 
discontinued from study treatment.  The first occurrence of renal toxicity 
was a dose limiting toxicity (DLT) at the 2.34 mg/m2 dose in Study 
C16001.  The second renal event occurred in the MTD (1.76 mg/m2) 
expansion phase of Study C16001.  As a precautionary measure until 
more data are available, all ixazomib studies have been amended to 
include an adjustment of the relevant eligibility criterion, supplementary 
measures to monitor kidney function, as well as advice under Precautions 
and Restrictions (Section 3.7) regarding correction of volume depletion 
and concomitant medications.  There have been no reports of renal 
failure and/or elevated creatinine related to ixazomib in the 2 studies 
investigating the oral formulation in patients with MM or in the study 
investigating the IV formulation in patients with advanced lymphoma.  
Seven patients discontinued study drug for TEAEs (6 in Study C16001 
[IV formulation] due to progressive disease [2] and 1 each ileus, 
peripheral neuropathy, acute renal failure, and pneumonitis) and one in 
C16004 [weekly, oral formulation] due to progressive disease.  Five on-
study deaths were reported, all attributable to disease progression, none 
of which were considered by the investigator to be related to treatment 
with ixazomib.   
 

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To mitigate the inherent risks in clinical studies of ixazomib, patients 
will be monitored closely for anticipated potential toxicities, as well as 
for unanticipated toxicities when they receive ixazomib and for at least 
30 days after their last dose.  Patients are evaluated by routine outpatient 
procedures and tests every 1 to 3 weeks as outlined in each protocol 
while they are receiving treatment.  Additional evaluations can be 
conducted according to physician discretion.  Guidance for reducing 
doses is provided in the protocols, and drug dosage can be reduced by 
either reducing the planned dose administered or by interruption of the 
scheduled treatment within a cycle.  Each protocol, in addition to the IB, 
contains information regarding toxicity management.   
 
Based on observations from nonclinical toxicology studies of ixazomib 
and preliminary clinical observations from the 4 ongoing phase 1 clinical 
studies, the potential safety risks of ixazomib are generally consistent 
with the class-based effects of proteasome inhibition and are similar to 
what has been previously reported with bortezomib.  The emerging 
safety profile demonstrates that ixazomib is generally well tolerated with 
manageable and reversible adverse reactions and treatment-emergent 
adverse events, irrespective of ixazomib causality.  Thrombocytopenia 
and erythematous rash with or without pruritus have been listed as 
adverse drug reactions in the ixazomib IB.  Based on evidence from 
preliminary ixazomib clinical studies, potential risks could include:  
transient and manageable anemia, diarrhea, nausea, vomiting, anorexia, 
constipation, abdominal pain, fatigue, elevated creatinine, and peripheral 
neuropathy.  Additional safety risks may include fever, cough, dyspnea, 
peripheral edema, and headache.  Based on clinical evidence from 
bortezomib studies, lymphopenia and lymphoid cell depletion (increased 
risk of infection, re-activation of herpes zoster and herpes simplex 
viruses); acute phase response (fever and metabolic change), and tumor 
lysis syndrome may be reported in the future though these have not been 
seen to date. 
 
Like bortezomib, ixazomib is a small molecule peptide boronic acid 
analog.  Clinical studies with bortezomib have yielded detailed 
understanding of its safety profile.  For details, refer to the package insert 
for bortezomib.  Ixazomib is in the early stages of clinical investigations 
in humans with safety, tolerability, PK, pharmacodynamics, 
electrocardiogram (ECG) parameters and disease response assessed in 
each study.  Ixazomib is the first investigational proteasome inhibitor 
with substantial oral bioavailability in patients with multiple myelomas.   
 
As of 12 January 2011, 143 patients have been treated with ixazomib 
across 5 phase 1 studies with a twice weekly and a weekly dosing 
schedule being evaluated.  Regardless of the route of administration in 
the twice-weekly dosing schedule, ixazomib is given on Days 1, 4, 8, and 
11 of a 21-day cycle and, in the weekly dosing schedule, the drug is 
given on Days 1, 8, and 15 of a 28-day cycle: 
• 
C16001, single agent IV administration twice-weekly in adult 
patients with advanced non-hematologic malignancies, n = 78;  

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• 
C16002, single agent IV administration weekly in adult patients 
with advanced lymphoma, n = 15;  
• 
C16003 and C16004, single agent PO administration twice-
weekly and weekly, respectively, in adult patients with relapsed 
or refractory multiple myeloma [previous exposure to 
bortezomib, IMiD, and corticosteroid required], n = 26 and 22, 
respectively;  
• 
C16005, PO administration in combination with lenalidomide 
and low-dose dexamethasone q28 days, n=2).   
 
Currently, in addition to the trials noted above and this trial, there are 2 
additional planned trials (C16006, Phase 1/ 2, oral administration of 
ixazomib added to melphalan and prednisone in patients with NDMM; 
C16007, Phase 1, single-agent ixazomib oral administration weekly in 
patients with relapsed or refractory light chain amyloidosis).  None of 
these have begun to enroll patients. 
 
In the 3 enrolling studies investigating oral ixazomib in multiple 
myeloma, a total of 50 patients have been treated thus far at single agent 
doses of 0.24 to 2.23 mg/m2 twice-weekly (C16003) , 0.24 to 2.97 mg/m2 
weekly (C16004) and at the first dose level of 1.68mg/m2 in combination 
with lenalidomide and low-dose dexamethasone (C16005).  The most 
frequent (> 10%) TEAEs of any grade irrespective of causality to oral 
ixazomib [pooled oral data], include fatigue (40%), diarrhea (36%), 
nausea (30%), vomiting and anemia (20% each), upper respiratory 
infection (18%), thrombocytopenia (16%), cough (14%), and rash, 
headache and abdominal pain (12% each).  Two of the 3 studies are still 
in the dose escalation phase (C16004 and C16005), while the MTD has 
been determined in study C16003.  
 
As of 12 January 2011 in study 16003 (n=26), patients have received a 
median of 4 cycles of therapy (range 1-12); 7 patients are currently 
receiving therapy. One patient at the 1.2mg/m2 dose level achieved PR; 
17 patients achieved disease stabilization. The most common treatment 
emergent adverse events of any grade irrespective of causality (>20%) in 
this specific study are fatigue and diarrhea (42%), nausea (31%), 
thrombocytopenia, vomiting, anemia, cough, and upper respiratory 
infection (27% each), and rash (23%).  Nine patients had treatment-
related AEs ≥ Grade 3; only thrombocytopenia (n=4) and neutropenia 
(n=2) were seen in > 1 patient. Three patients have experienced drug 
related serious adverse events (SAEs) involving the following events 
thrombocytopenia, pancytopenia, nausea, vomiting, abdominal pain, 
chest pain [non-cardiac], or pneumonia. There has been one on-study 
death reported as not related to study drug.   
 
In Study C16003, 1 of 3 patients experienced a protocol-defined DLT 
(Grade 3 rash) at a dose of 2.23mg/m2.  An additional patient at this dose 
experienced Grade 4 thrombocytopenia (platelet count of 10,000/mm3).  
Per protocol, a DLT related to platelets required either a platelet count < 
10,000/mm3 or Grade 4 thrombocytopenia lasting more than 7 
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formally meet the protocol definition for DLT. Thrombocytopenia and 
rash are identified as adverse drug reactions in the Investigator’s 
Brochure, have predictable patterns, are reversible and can be monitored 
in the clinic with routine clinical observations and tests already outlined 
in the protocol.  Therefore after a discussion with the PIs, an intermediate 
yet lower dose was evaluated as allowed in the C16003 protocol and 
supported by available pharmacokinetic data in order to further 
characterize dose-related toxicities. Six patients were treated at the 
intermediate dose of 2.0 mg/m2, a dose approximately half way between 
the two existing dose levels of 2.23mg/m2 and 1.68mg/m2 (a dose 
without any DLTs). Given that no patient (0/6) experienced a DLT, the 
MTD of PO ixazomib administered twice-weekly is determined to be 
2.0mg/m2. This study is now accruing patients in 4 MTD expansion 
cohorts.  
 
As of 12 January 2011, in Study C16004 where ixazomib is administered 
weekly (n=22), patients have received a median of 2 cycles (range, 1–8); 
4 pts are currently receiving therapy. Dose escalation is continuing.  The 
most common treatment emergent adverse events of any grade 
irrespective of causality (>20%) in this specific study are fatigue (41%), 
nausea (27%), and diarrhea (27%).  There has not been any treatment 
related AEs ≥ Grade 3, any drug-related SAEs, or deaths on- study. In 
this heavily pretreated patient population, 4 patients have achieved 
stabilization of disease. 
 
In Study C16005, ixazomib is administered in combination with 
lenalidomide and low-dose dexamethasone.  This study has recently 
started to enroll patients (n=2 as of 12 January 2011) and dose escalation 
is ongoing.  To date, there have not been any treatment related AEs ≥ 
Grade 3, any drug-related SAEs, or deaths on-study.  Treatment 
emergent adverse events of any grade and irrespective of causality have 
been reported in 1 patient, and include nausea, vomiting, diarrhea, and 
anemia.  Both patients in this study have achieved a PR after 1 cycle of 
therapy.   
 
In the 2 ongoing studies investigating IV ixazomib in advanced solid 
tumors and advanced lymphoma (studies C16001 and C16002, 
respectively), a total of 93 patients have been treated thus far at single 
agent doses of 0.125 to 2.34 mg/m2 twice-weekly (C16001) and 0.125 to 
1.76 mg/m2 weekly (C16002).  The most frequent (> 10%) TEAEs of 
any grade irrespective of causality to IV ixazomib (pooled IV data), 
include fatigue (56%), thrombocytopenia (39%), nausea (33%), vomiting 
(32%), anorexia (31%), fever (29%), diarrhea (26%), constipation (22%), 
cough and headache (19% each), chills (18%), anemia (17%), abdominal 
pain (16%), shortness of breath (15%), and back pain and peripheral 
edema (14% each).  As described below, the MTD has been established 
in Study C16001 but dose escalation in Study C16002 is ongoing.  
 
As of 12 January 2011, in Study C16002 where ixazomib is administered 
weekly, (n=15), patients have received a median of 2 cycles (range, 1-
10); 6 patients have experienced treatment-related AEs ≥ Grade 3; only 

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thrombocytopenia (n=2) and neutropenia (n=2) were seen in > 1 patient 
at any point during the course of therapy.  One patient at the 1.76mg/m2 
dose level who experienced Grade 4 neutropenia that lasted more than 7 
days (meeting the definition of a DLT).  One patient at the 1.4mg/m2 
dose level achieved PR; and 5 patients have achieved disease 
stabilization.  The next dose level, 2.34mg/m2, is open for accrual. 
 
In Study C16001, 78 evaluable patients with advanced non-hematologic 
malignancies have been treated across 7 dose levels.  Patients have 
received a median of 2 cycles (range, 1-10); 6 patients are currently 
receiving therapy.  Thirteen patients have had stabilization of the 
underlying disease including tumor reductions of 14% and 18% in 2 
patients with renal cell carcinoma.  The MTD has been determined in 
this study.  At the 1.0 mg/m2 dose level, 1 out of 6 patients experienced a 
DLT (transient Grade 3 rash); no drug-related SAEs were reported.  No 
additional DLTs were reported as the dose was escalated up to 1.76 
mg/m2.  At the 2.34 mg/m2 dose level, 3 out of 3 patients were admitted 
to the hospital with DLTs (1 reversible Grade 3 acute renal failure and 2 
reversible Grade 4 thrombocytopenia).  All 3 patients recovered; 1 
patient, who had experienced thrombocytopenia, continued on study at a 
reduced dose of ixazomib for an additional 3 cycles before disease 
progression.  Given these AEs, the MTD of IV ixazomib administered 
twice-weekly is determined to be 1.76 mg/m2.  
 
As of 12 January 2011, 56 patients (6 in the dose escalation phase, 50 
from the dose expansion phase) have been treated at the MTD of 1.76 
mg/m2.  In these patients, fatigue, thrombocytopenia, nausea, vomiting, 
anorexia, fever, constipation, cough, diarrhea, chills, anemia, rash, 
headache, dehydration, shortness of breath, back pain, hyponatremia, 
abdominal pain, and peripheral edema are the most common treatment-
emergent AEs.  One patient treated at the MTD experienced renal 
toxicity, 1 patient experienced Grade 3 transient peripheral sensory 
neuropathy during Cycle 2, and 1 experienced Grade 3 peripheral 
neuropathy at the end of treatment after completion of 3 cycles. Fifteen 
SAE cases have been reported in the 1.76 mg/m2 dose cohort where the 
investigators considered ixazomib and alternative etiologies as a possible 
cause (1 each, Grade 3 reversible:  depressed level of consciousness, 
pneumonitis, pneumonia, ileus, pain in extremity, dyspnea, and acute 
renal failure; 3 each, Grade 3 reversible:  fatigue and dehydration; 1 
Grade 2 shingles and rash).  
 
During enrollment in the expansion cohort of Study C16001 (dosing at 
1.76 mg/m2), 1 patient (among 50 patients treated as of 10 December 
2010) has experienced acute renal failure (National Cancer Institute 
Common Terminology Criteria for Adverse Events [NCI CTCAE]i, 
version 3.0. Both cases of acute renal failure reported to date (the other 
patient was treated at the 2.34 mg/m2 dose level) share the following 
features: (1) a pre-existing kidney condition (status post-nephrectomy 
due to kidney cancer and prior hydronephrosis due to disease 
progression); (2) prior exposure to other antineoplastic drugs associated 
with nephrotoxic potential; (3) diarrhea and/or poor oral intake; (4) use 

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of nonsteroidal anti-inflammatory drugs (NSAIDs) during the 24 to 48 
hours before the onset of the AE; (5) the event occurred after a total of 4 
doses of study drug had been administered (1 patient received all 4 doses 
within Cycle 1 while the second patient received them over the course of 
2 treatment cycles); and (6) concomitant with event, the patient 
experienced thrombocytopenia. 
 
The emerging safety profile indicates that ixazomib is generally well 
tolerated with manageable and reversible treatment-emergent adverse 
events (TEAEs) or adverse reactions.  The MTD has been established in 
the 2 trials administering ixazomib twice-weekly (Study C16001; IV 
dosing and Study C16003; PO dosing) with dose escalation continuing in 
the 3 other studies.  As of 12 January 2011, the most common treatment-
related adverse drug reactions reported with ixazomib use, pooled from 
the 5 phase 1 early human studies (including both IV and oral 
formulations), include thrombocytopenia and maculopapular rash, with 
or without pruritus.  Other treatment-emergent side effects reported 
across these studies, which may have been due to either the patient’s 
disease or ixazomib, include nausea, vomiting, diarrhea, constipation, 
anorexia, fatigue, anemia, fever, abdominal pain, cough, headache, 
shortness of breath, upper respiratory infection, peripheral edema, chills, 
and back pain.  The most frequent (> 10%) TEAEs of any grade reported 
across the 3 phase 1 studies using the oral formulation of ixazomib (ie, 
C16003,  C16004, and C16005) , irrespective of causality to ixazomib, 
include fatigue (40%), nausea (30%), diarrhea (36%), vomiting and 
anemia (20% each), upper respiratory infection (18%), thrombocytopenia 
(16%), cough (14%), and headache, rash, and abdominal pain (12% 
each).  
  
Please refer to the IB for further information.  The most frequent AEs 
were anticipated based on preclinical data and previous experience with 
bortezomib and are noted in the informed consent documents.  While the 
potential toxicities may be severe, they are managed by routine clinical 
monitoring and standard medical interventions.  Based on bortezomib’s 
proven utility in the treatment of multiple myeloma and MCL and 
ixazomib’s increased tissue distribution and activity in several xenograft 
models, it is anticipated that ixazomib, directed against the same 
components of the ubiquitin-proteasome system (UPS), will prove 
efficacious in the treatment of similar, if not additional, malignancies. 
 
1.19b Potential Risks of ixazomib: ixazomib is structurally similar to 
bortezomib which has a well-defined safety profile. Bortezomib 
(VELCADE®) is approved by the FDA and EMA for the treatment of 
patients with multiple myeloma.  Based on observations from nonclinical 
toxicology studies of ixazomib and the preliminary clinical observations 
from the ongoing phase 1 studies, the potential safety risks of ixazomib 
are generally consistent with the class-based effects of proteasome 
inhibition, are similar to what has been previously reported with 
bortezomib, and are noted in the ixazomib IB.  
Thrombocytopenia, fatigue, nausea, vomiting, diarrhea and rash 
(erythematous, generalized, macular, macular-papular, and popular) with 

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or without pruritus have been listed in the ixazomib IB as adverse drug 
reactions reported with ixazomib.  However, it is possible that ixazomib 
will have toxicities that were not previously observed in or predicted 
from such sources.  Patients will be monitored closely for anticipated 
toxicities.   
 
This trial will be conducted in compliance with the protocol, good 
clinical practice (GCP), applicable regulatory requirements, and 
International Conference on Harmonisation (ICH) guidelines.  Essential 
clinical documents will be maintained to demonstrate the validity of the 
study and the integrity of the data collected.  Master files should be 
established at the beginning of the study, maintained for the duration of 
the study, and retained according to the appropriate regulations.  This is 
the responsibility of the sponsor-investigator. 
 
Additional details on the potential risks of ixazomib may be found in the 
current IB. 
 
1.19c 
Daratumumab in multiple myeloma 
 
 
Daratumumab is a human IgG1ĸ monoclonal antibody (mAb) that binds 
with high affinity to a unique epitope on CD38, a transmembrane 
glycoprotein. It is a targeted immunotherapy directed towards tumor cells 
that express high levels of CD38, such as plasma cells from patients with 
multiple myeloma. This target is distinct from those of other approved 
agents for multiple myeloma therapy. Daratumumab is currently 
approved for treatment of relapsed myeloma, that are refractory to a 
proteasome inhibitor and an IMiD and in combination with VMP for 
newly diagnosed MM.   
 
Nonclinical Studies with daratumumab 
Based on preclinical data, daratumumab may utilize multiple effector cell 
functions, resulting in immune mediated killing of tumor cells. In ex vivo 
experiments utilizing human bone marrow stromal cells co-cultured with 
primary multiple myeloma cells, complement-dependent cytotoxicity 
(CDC) occurs rapidly and demonstrates maximal myeloma cell killing by 
daratumumab within 1 hour of antibody-mediated activation of the 
complement proteins. Daratumumab-induced antibody-dependent cell-
mediated cytotoxicity (ADCC) is slower in its action, with maximal 
ADCC by daratumumab observed at 4 hours in vitro. Daratumumab has 
also been shown to induce antibody-dependent cellular phagocytosis 
(ADCP) in the presence of macrophages within 4 hours in vitro. The 
precise role of some or all of these effector functions in reducing tumor 
burden in patients is unknown. In toxicology studies in cynomolgus 
monkeys and chimpanzees, the major observed toxicities were cytokine 
release syndrome and thrombocytopenia. A minor decrease in red blood 
parameters was also observed. Cytokine release was seen only following 
the first dose and was markedly reduced following implementation of a 
10-mg predose of daratumumab. The effect on platelets and red blood 
cells was reversible. 

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For the most comprehensive nonclinical and clinical information as well 
as Reference Safety Information regarding daratumumab, refer to the 
latest version of the Investigator's Brochure (Daratumumab IB). 
 
Clinical studies with daratumumab 
 
Single agent studies: Two large single agent studies have been reported 
to date; GEN501 and MMY2002. In the GEN501 study, daratumumab 
was administered at doses of 0.005 to 24 mg per kilogram of body 
weight during the dose escalation phase.19 No maximum tolerated dose 
was identified. In the dose-expansion phase, 30 patients received 8 mg 
per kilogram of daratumumab and 42 received 16 mg per kilogram, 
administered once weekly (8 doses), twice monthly (8 doses), and 
monthly for up to 24 months. In the expansion phase, the median time 
since diagnosis was 5.7 years. Patients had received a median of four 
prior treatments; 79% of the patients had disease that was refractory to 
the last therapy received (64% had disease refractory to proteasome 
inhibitors and immunomodulatory drugs and 64% had disease refractory 
to bortezomib and lenalidomide), and 76% had received autologous 
stem-cell transplants. Infusion-related reactions were mild (71% of 
patients had an event of any grade, and 1% had an event of grade 3), with 
no dose-dependent adverse events. The most common adverse events of 
grade 3 or 4 (in ≥5% of patients) were pneumonia and thrombocytopenia. 
The overall response rate was 36% in the cohort that received 16 mg per 
kilogram (15 patients had a partial response or better, including 2 with a 
complete response and 2 with a very good partial response) and 10% in 
the cohort that received 8 mg per kilogram (3 had a partial response). In 
the cohort that received 16 mg per kilogram, the median progression-free 
survival was 5.6 months (95% confidence interval [CI], 4.2 to 8.1), and 
65% (95% CI, 28 to 86) of the patients who had a response did not have 
progression at 12 months. 
 
In the MMY2002 study, patients with multiple myeloma who were 
previously treated with at least three lines of therapy (including 
proteasome inhibitors and immunomodulatory drugs), or were refractory 
to both proteasome inhibitors and immunomodulatory drugs, were 
randomized to receive intravenous daratumumab 8 mg/kg or 16 mg/kg in 
in the initial part of the study.20 Patients received 8 mg/kg every 4 weeks, 
or 16 mg/kg per week for 8 weeks (cycles 1 and 2), then every 2 weeks 
for 16 weeks (cycles 3–6), and then every 4 weeks thereafter (cycle 7 and 
higher). In the second part of the study, the dose of 16 mg/kg was taken 
forward. One-hundred-six patients with a median of five previous lines 
of therapy (range 2–14) were treated at the 16-mg/kg dose. 85 (80%) 
patients had previously received autologous stem cell transplantation, 
101 (95%) were refractory to the most recent proteasome inhibitors and 
immunomodulatory drugs used, and 103 (97%) were refractory to the 
last line of therapy. Overall, responses were seen in 31 patients 
(29·2%,)—three (2·8%) with a stringent CR, ten (9·4%) with a VGPR, 
and 18 (17·0) with a PR. Median duration of response was 7·4 months 
(95% CI 5·5–not estimable) and progression-free survival was 3·7 
months and the 12-month overall survival was 64·8%. Daratumumab 

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was well tolerated; fatigue (40%) and anemia (33%) were the most 
common adverse events.  
 
Daratumumab-lenalidomide combinations: Preclinically, using bone 
marrow mononuclear cells from patients with multiple myeloma, 
increased killing of tumor cells was demonstrated when daratumumab 
was combined with lenalidomide as compared with that of either agent 
alone. 
 
In an open-label phase 1/2 study DARA 2-16 mg/kg was combined with 
standard dose of lenalidomide and dexamethasone, leading to a 
recommended phase 2 dose of daratumumab 16 mg/kg along with 
lenalidomide 25 mg days 1-21 and dexamethasone 40 mg weekly. 
Daratumumab 16 mg/kg was administered weekly during the first two 
28-day cycles, every other week during Cycles 3 through 6, and monthly 
in Cycle 7 and beyond until disease progression or unacceptable toxicity. 
LEN 25 mg was administered orally on Days 1 through 21 of each cycle, 
and DEX 40 mg was given weekly. Thirty two patients with median of 2 
prior lines of therapy were enrolled. 
 
The most common (>25%) TEAEs included neutropenia (81%), muscle 
spasms (44%), cough (38%), diarrhea (34%), fatigue and hypertension 
(28% each). Eighteen (56%) patients had IRRs and these were generally 
mild to moderate and occurred mostly during the first cycle. IRRs 
included cough (25%), allergic rhinitis, nausea, and vomiting (9% each), 
as well as dyspnea, nasal congestion, and hypertension (6% each). The 
overall response rate was 88%, with 11 (34%) partial responses and 17 
(53%) ≥very good partial responses (VGPRs) that included 7 (22%) 
stringent complete responses, 1 (3%) complete response, and 9 (28%) 
VGPRs. The median time to first and best response was 1 month and 4.5 
months, respectively. Results of this study confirm the efficacy of 
combining daratumumab with lenalidomide and dexamethasone.  
 
In a phase 3 trial, 498 patients with relapsed or relapsed and refractory 
multiple myeloma were randomly assigned to receive bortezomib and 
dexamethasone, alone or in combination with daratumumab. The 
progression-free survival was significantly higher in the daratumumab 
group than in the control group; the 12-month rate of progression-free 
survival was 60.7% in the daratumumab group versus 26.9% in the 
control group. After a median follow-up period of 7.4 months, the 
median progression-free survival was not reached in the daratumumab 
group and was 7.2 months in the control group (HR, 0.39; P<0.001). The 
overall response rate was higher in the daratumumab group than in the 
control group (82.9% vs. 63.2%, P<0.001), as were the rates of very 
good partial response or better (59.2% vs. 29.1%, P<0.001) and complete 
response or better (19.2% vs. 9.0%, P=0.001). The most common grade 3 
or 4 adverse events were thrombocytopenia, anemia, and neutropenia. 
Infusion-related reactions were associated with daratumumab in 45.3% 
of the patients; these reactions were mostly grade 1 or 2 (grade 3 in 8.6% 
of the patients), and in 98.2% of these patients, they occurred during the 
first infusion. 

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In another phase 3 trial, 569 patients with multiple myeloma who had 
received one or more previous lines of therapy were randomly assigned 
to receive lenalidomide and dexamethasone alone or in combination with 
daratumumab. At a median follow-up of 13.5 months OFS superior in 
the daratumumab arm. The Kaplan-Meier rate of progression-free 
survival at 12 months was 83.2% (95% CI, 78.3 to 87.2) in the 
daratumumab group, as compared with 60.1% (95% CI, 54.0 to 65.7) in 
the control group. Overall response rate was higher in the daratumumab 
group (92.9% vs. 76.4%, P<0.001), as was the rate of complete response 
or better (43.1% vs. 19.2%, P<0.001). In the daratumumab group, 22.4% 
of the patients were minimal residual disease negative (1 tumor cell per 
105 white cells), compared with 4.6% in the control group (P<0.001). 
The most common adverse events of grade 3 or 4 during treatment were 
neutropenia, thrombocytopenia, and anemia. Daratumumab-associated 
infusion-related reactions occurred in 47.7% of the patients and were 
mostly grade 1 or 2.  
 
1.19d Rationale for current study: Ixazomib represents the next generation 
proteasome inhibitor with several advantages including oral 
bioavailability as well as different proteasome binding characteristics. 
The trials so far have examined the activity of the drug in the setting of 
prior bortezomib treatment, since bortezomib is commonly used for 
relapsed patients. However, it is important to understand the single agent 
activity of the new drug in patients who have not received or received a 
limited amount of bortezomib and to further characterize the benefit of 
combining dexamethasone with ixazomib. 
 
 
Rationale for addition of cohorts B and C: Ixazomib as a single agent 
has shown activity in this cohort of relapsed, relatively proteasome 
inhibitor naive population. A proportion of patients had dexamethasone 
added to ixazomib as originally planned, for lack of optimal response or 
disease progression. The goal of this trial initially was to assess the 
efficacy of single agent ixazomib in this patient population. The current 
practice for most of the myeloma drugs including the newer drugs such 
as lenalidomide or bortezomib is to administer them in combination with 
dexamethasone. Given these factors, it would be of significant interest to 
assess the efficacy of dexamethasone added to ixazomib right from the 
beginning as that might provide better disease control and long-term 
efficacy as compared to adding it for suboptimal response. We propose 
to add another cohort of patients in order to assess the efficacy and 
tolerability of ixazomib in combination with dexamethasone. In addition, 
ixazomib trials that are ongoing or in development in combination with 
other myeloma agents are using a lower dose of ixazomib at 4 mg 
weekly.(Kumar, et al 2012) In the current trial, we are using a dose of 
5.5 mg based on the initial phase 1 single agent studies. Given that the 
future studies in combination with other active drugs like lenalidomide 
are going to use the 4 mg dose, it is of considerable interest to explore 
this dose also in the dexamethasone combination setting to better 
understand the contribution of the drugs being combined.  
 

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Rationale for addition of cohort D: One of the most effective 
combinations has been that of cyclophosphamide and bortezomib 
substantiating in vitro studies suggesting an excellent synergy between 
alkylating agents and proteasome inhibitors.4,5 Previously, we have 
shown that the combination of cyclophosphamide and dexamethasone 
with bortezomib provides a very effective regimen with responses 
comparable to that seen with IMiD combinations. This was also 
confirmed in the studies looking at combining melphalan with 
bortezomib.6 In fact, in the randomized EVOLUTION trial the 
combination of weekly cyclophosphamide with bortezomib and dex 
appeared to have higher response rate and depth of response compared to 
other three and four drug combinations that included bortezomib and 
lenalidomide.5 Ongoing trials are examining the combination of 
ixazomib, cyclophosphamide and dexamethasone in other settings, but 
the true clinical activity of this combination in the setting of minimal 
prior exposure to bortezomib is unknown and is an important question 
for continued development of an all-oral combination regimen in 
myeloma. 
 
Rationale for addition of cohort E: Daratumumab has been added to 
the current combinations such as Rd, Pd, VRd, KRd, and IRd in various 
clinical trials of newly diagnosed and relapsed myeloma, with excellent 
efficacy. The combination of ixazomib, cyclophosphamide and 
dexamethasone (ICd) has shown activity in newly diagnosed as well as 
relapsed MM. It is of scientific and clinical interest to examine the 
feasibility and efficacy of adding daratumumab to ICd. 
 
2.0 
Goals    
 
2.1 
Primary 
 
2.11  
Arm A (Permanently closed to accrual per Addendum 5):  To determine 
the confirmed overall response rate (>=PR) of ixazomib, used as a single 
agent in patients with relapsed multiple myeloma, who are proteasome 
inhibitor naive (including bortezomib) naïve OR have received less than 
6 cycles of therapy with bortezomib and had a better than PR with no 
progression at the time of discontinuation. 
 
2.12 
Arm B:  To determine the confirmed overall response rate (>=PR) of 
ixazomib at a 4 mg dose level in combination with dexamethasone in 
patients with relapsed multiple myeloma, who are proteasome inhibitor 
naive (including bortezomib) naïve OR have received less than 6 cycles 
of therapy with bortezomib and had a better than PR with no progression 
at the time of discontinuation  
 
2.13 
Arm C:  To determine the confirmed overall response rate (>=PR) of 
ixazomib at a 5.5 mg dose level in combination with dexamethasone in 
patients with relapsed multiple myeloma, who are proteasome inhibitor 
naive (including bortezomib) naïve OR have received less than 6 cycles 
of therapy with bortezomib and had a better than PR with no progression 
at the time of discontinuation 
 
2.14 
Arm D: To determine the confirmed overall response rate (>=PR) of 
ixazomib in combination with cyclophosphamide and dexamethasone in 

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patients with relapsed multiple myeloma, who are proteasome inhibitor 
naive (including bortezomib) naïve OR have received less than 6 cycles 
of therapy with bortezomib and had a better than PR with no progression 
at the time of discontinuation 
 
2.15 
Arm E (newly added with Addendum 23): To determine the confirmed 
overall response rate (>=PR) of ixazomib in combination with 
cyclophosphamide, daratumumab, and dexamethasone in patients with 
relapsed multiple myeloma 
 
2.2 
Secondary 
 
2.21 
Arm A:  To determine the overall response rate of ixazomib in 
combination with dexamethasone, when dexamethasone is added to 
ixazomib for lack of response or for progression. 
 
2.22 
Arm A:  To determine the event free survival and overall survival among 
patients with relapsed myeloma following treatment with ixazomib with 
dexamethasone added for lack of response or progression. 
 
 
2.23 
Arms B and C:  To determine the event free survival and overall survival 
among patients with relapsed myeloma following treatment with 
ixazomib at two different doses, in combination with dexamethasone. 
 
 
2.24 
Arm D:  To determine the event free survival and overall survival among 
patients with relapsed myeloma following treatment with ixazomib in 
combination with cyclophosphamide and dexamethasone. 
 
2.25 
Arm E (Addendum 23):  To determine the event free survival and overall 
survival among patients with relapsed myeloma following treatment with 
ixazomib in combination with cyclophosphamide, daratumumab, and 
dexamethasone. 
 
3.0 
Patient Eligibility 
 
3.1 
Registration - Inclusion Criteria  
 
3.11 
Age 18 years. 
3.12 
The following laboratory values obtained 14 days prior to registration. 
 
Calculated creatinine clearance (using Cockcroft-Gault equation 
below)* >=30 mL/min 
 
Absolute neutrophil count 1000/mL 
 
Untransfused Platelet count 75000/mL 
 
Hemoglobin ≥8.0 g/dL 
 
Total bilirubin <= 1.5 x the upper limit of the normal range (ULN). 
 
Aspartate aminotransferase (AST) <= 3x ULN 
 
Alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST) <= 3x  
 
*Cockcroft-Gault Equation: 
Creatinine clearance for males = (140 - age)(actual body weight in kg)  
(72)(serum creatinine in mg/dL) 

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Creatinine clearance for females = (140 - age)(actual body weight in kg)(0.85) 
(72)(serum creatinine in mg/dL) 
 
3.13 
Patients with relapsed multiple myeloma who have already received one 
or more standard treatment regimens.  
3.14 
Measurable disease of multiple myeloma as defined by at least ONE of 
the following: 
 
Serum monoclonal protein 1.0 g/dL (see Section 11.1 for 
definition) 
 
200 mg of monoclonal protein in the urine on 24 hour 
electrophoresis  
 
Serum immunoglobulin free light chain 10 mg/dL AND abnormal 
serum immunoglobulin kappa to lambda free light chain ratio. 
 
For patients with EMD measurable disease by CT or MRI or the CT 
portion of the PET/CT: Must have at least one lesion that has a single 
diameter of ≥2 cm. Skin lesions can be used if the area is ≥2cm in at 
least one diameter and measured with a ruler. 
 
Plasma cell count ≥0.5 X 109/L or 5 percent of the peripheral blood 
white cells  
 
Plasma cell count if determined by flow cytometry, ≥200/150,000 
events 
 
3.15 
ECOG performance status (PS) 0, 1, 2 (Appendix I). 
 
3.16 
Provide informed written consent. 
 
3.17 
Negative pregnancy test done ≤7 days prior to registration, for women of 
childbearing potential only. 
 
3.18 
Willing to return to consenting Mayo Clinic institution for follow-up 
during the active Monitoring Phase of the study. 
 
Note: During the Active Monitoring Phase of a study (i.e., active 
treatment and observation), participants must be willing to return to the 
consenting institution for follow-up. 
 
3.19a 
Recovered (ie, < Grade 1 toxicity) from the reversible effects of prior 
antineoplastic therapy. 
 
3.19b Arms A – D only:  
 
Patients should be proteasome inhibitor naïve (including bortezomib and 
carfilzomib) OR have received less than 6 cycles of therapy with a 
bortezomib or carfilzomib containing regimen and were not refractory to 
the bortezomib or carfilzomib based regimen (less than a PR or 
progression on or within 60 days of discontinuation)  
 
 
 
 

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3.19c 
Arm E only: 
 
Negative hepatitis B test (defined by a negative test for hepatitis B 
surface antigen [HBsAg], or antibodies to hepatitis B surface and/or core 
antigens [antiHBs or antiHBc)   
 
Note:   Patients with serologic findings suggestive of HBV vaccination 
(antiHBs positivity as the only serologic marker) AND a known history 
of prior HBV vaccination do not need to be tested for HBV DNA by 
PCR. Those who are PCR positive will be excluded. 
 
3.2 
Registration - Exclusion Criteria 
 
3.21  
Recent prior chemotherapy  
 
Alkylators (e.g. melphalan, cyclophosphamide) 14 days prior to 
registration.  
 
Anthracyclines  14 days prior to registration 
 
High dose corticosteroids, immune modulatory drugs (thalidomide or 
lenalidomide) 7 days prior to registration.  
 
3.22  
Prior therapy with any proteasome inhibitor other than bortezomib,  
carfilzomib, or ixazomib, 
 
3.23 
Concomitant high dose corticosteroids other than what is part of 
treatment protocol (concurrent use of corticosteroids).  EXCEPTION: 
Patients may be on chronic steroids (maximum dose 20 mg/day 
prednisone equivalent) if they are being given for disorders other than 
myeloma, i.e., adrenal insufficiency, rheumatoid arthritis, etc. 
 
3.24 
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 nonmelanoma skin 
cancer or carcinoma in situ of any type are not excluded if they have 
undergone complete resection.   
 
3.25 
Any of the following: 
 
Pregnant women or women of reproductive ability who are 
unwilling to use 2 effective methods of contraception from the 
time of signing the informed consent form through 90days after 
the last dose of study drug 
 
Nursing women  
 
Men who are unwilling to use a condom (even if they have 
undergone a prior vasectomy) while having intercourse with any 
woman, while taking the drug and for 30 days after stopping 
treatment. 
3.26 
Other co-morbidity which would interfere with patient's ability to 
participate in trial, e.g. uncontrolled infection, uncompensated heart or 
lung disease. 
3.27 
Other concurrent chemotherapy, radiotherapy, or any ancillary therapy 
considered investigational.  NOTE: Bisphosphonates are considered to 
be supportive care rather than therapy, and are thus allowed while on 

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protocol treatment.  
3.28 
Patient has ≥ Grade 3 peripheral neuropathy, or Grade 2 with pain on 
clinical examination during the screening period. 
3.29a 
Major surgery within 14 days before study registration. 
3.29b  Systemic treatment with strong CYP3A inducers (rifampin, rifapentine, 
rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo 
biloba or St. John’s wort within 14 days before the first dose of study 
treatment. 
3.29c 
Evidence of current uncontrolled cardiovascular conditions, including 
cardiac arrhythmias, congestive heart failure, angina, or myocardial 
infarction within the past 6 months.  Note: Prior to study entry, any ECG 
abnormality at screening must be documented by the investigator as not 
medically relevant. 
3.29d Known human immunodeficiency virus (HIV) positive. 
3.29e 
Known hepatitis B surface antigen-positive status, or known or suspected 
active hepatitis C infection. 
3.29f 
Any serious medical or psychiatric illness that could, in the investigator’s 
opinion, potentially interfere with the completion of treatment according 
to this protocol. 
3.29g Known allergy to any of the study medications, their analogues or 
excipients in the various formulations. 
3.29h Known GI disease or GI procedure that could interfere with the oral 
absorption or tolerance of ixazomib including difficulty swallowing. 
3.29i 
Diarrhea > Grade 1, based on the NCI CTCAE grading, in the absence of 
antidiarrheals. 
 
Arm E only:   
3.29j 
Refractory to any combination of a proteasome inhibitor and 
Daratumumab. 
 
3.29k  Known chronic obstructive pulmonary disease with a forced expiratory 
volume in 1second (FEV1) <50% of predicted normal. 
 
(Note that FEV1 testing is required for subjects suspected of having 
chronic obstructive pulmonary disease and subjects must be excluded if 
FEV1 <50% of predicted normal.) 
 
3.29l  Known moderate or severe persistent asthma within the past 2 years or 
currently has uncontrolled asthma of any classification (see Asthma 
Guidelines) 
  
 
 
 
 
 
 

 
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4.0 
Test Schedule  
 
Days Prior to 
Registration 
Days 8, 
15, 226 
Every Cycle 1 
End of treatment4
 
30 
days 
14 
days 
Complete medical history
X
X13
X
Adverse Event monitoring
X
X15
X
Physical exam, including 
weight and vital signs
 
X 
X13,15
X 
Height
X
Performance status (ECOG 
scale) 
 
X 
X15 
X 
CBC with diff. (includes 
hemoglobin, absolute 
neutrophil count and platelet 
count)
 
X 
X10
X15 
X 
Electrocardiogram
X
Forced expiratory volume in 1 
second (FEV1)   
Note: Arm E patients only
 
X 
 
 
 
Prothrombin time (PT)
X
Chemistry group to include 
sodium, potassium, glucose, 
alkaline phosphatase; Total 
and Direct bilirubin; SGOT 
(AST); ALT, serum creatinine, 
calcium
 
 
X 
 
 
 
X15 
 
 
X 
LDH, Beta2-microglobulin,  C-
reactive protein, circulating 
plasma cells
 
X 
 
 
 
Viral hepatitis panel including 
HBsAg, HB core antibody, 
and HB antibody 
Note:  Arm E only patients 
only
 
X14 
 
 
 
 X14 
 
X14  
Urinalysis
X
Electrophoresis of serum and 
urine
 
X 
 
X2,15
X2
Affected Immunoglobulin8
X
X15
X
Immunofixation serum and 
urine 
X 
 
  
X 5,15
X 
Immunoglobulin free light 
chain9
 
X 
 
X15 
X 
X-ray skeletal survey or 
WBLDCT; PET/CT, MRI 
X 
 
 
X16 
 

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Bone marrow aspirate and 
biopsy, myeloma FISH, 
metaphase cytogenetics, and 
flow cytometry  
X 
 
X5,11 
Chest x-ray
X
Serum pregnancy test
X3
Medication Diary7
X
 
 
1) All scheduled visits will have a window of  7 days unless otherwise stated. After completing 4 
cycles of therapy, patients can elect to come to the enrolling Mayo site every two cycles as long as all 
the required testing can be performed at local clinic and toxicity check can be performed over phone.  
2) Urine electrophoresis required only if used to assess disease response.. 
3) For women of childbearing potential only.  Must be done ≤7 days prior to registration. 
4)   End of treatment labs to be obtained at the time of study discontinuation or within 30 days. Tests used 
to confirm progression, if done can be used as end of treatment labs. Patients will go to event 
monitoring at progression while receiving dexamethasone with ixazomib. 
5)   Only required to document CR. 
6)  Only for first 2 cycles. 
7) The diary must begin the day the patient starts taking the medication and must be completed per 
protocol and returned to the treating institution.  
8)   Affected immunoglobulin refers to the baseline M-protein type, that is, IgG, IgA, or IgD.  Not 
applicable if patient “non-secretory” or if patient has no heavy chain, i.e. light chain myeloma. 
9)  Serum FLC to be followed in patients with light chain measurable disease. 
10) These tests may be obtained locally and results send to enrolling institution,  
11) Cytogenetics and FISH are not required. 
12) Urine electrophoresis required only if used to assess disease response. 
13) Medical history and physical examination can be performed every 2 cycles after the initial 4 
cycles and there are no ongoing toxicities. 
14) HBV-DNA testing required for patients with serologic evidence of prior HBV infection every 
12 weeks during treatment, at EOT, and 12 weeks after last dose of study treatment. 
15) Required evaluations can be done through local facility, phone contact, or by local lab as applicable if 
patient is unable to return to Mayo facility and is approved by study chair. 
16) For patients with EMD only: Same modality should be used at baseline and for serial evaluation. 
Assessment of EMD lesions should be performed at end of Cycle 1 and every three cycles or more 
frequently if clinically indicated. For patients with only skin involvement, skin lesions should be 
measured with a ruler with images maintained in the medical record. 
 
 

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5.0  
Stratification Factors:  
 
Stratification Factors – Arms B and C (closed) 
 
 
5.1 
Bortezomib or Carfilzomib exposure none versus limited 
 
5.2 
Lenalidomide refractory versus  no 
 
Grouping Factors as of Addendum 23  
 
 
5.3 
Treatment:  Arm D versus Arm E 
 
6.0  
Registration/Randomization Procedures 
6.1 
To register a patient, access the Research Registration Application at 
The Research Registration Application is available 24 hours a 
day, 7 days a week. Back up and/or system support contact information is available on 
the Web site. If unable to access the application, call the Mayo Clinic Site Management 
Team at 
between the hours of 8 a.m. and 4:30 p.m. Central Time 
(Monday through Friday) or email them at 
Quick 
Reference Guides (QRGs) for the application are available to study staff on the Mayo 
Clinic Office of Clinical Trials, Site Management Team website.  
Prior to initiation of protocol treatment, this process must be completed in its entirety and 
a MCCC patient  ID number must be provided The patient ID will begin with an ‘R’ and 
will be followed by 8 digits. It is the responsibility of the individual registering the 
patient to confirm the process has been successfully completed prior to release of the 
study agent. Patient registration via the Research Registration Application can be 
confirmed in any of the following ways: 
• 
Contact the Mayo Clinic Site Management Team. If the patient was fully registered, 
the MCCC Registration Office staff can access the information from the centralized 
database and confirm the registration. 
• 
View your list of registered patients via the Accruals Tile on the Patient Landing 
page of the Research Registration Application.  
 
 
6.11 
Documentation of IRB approval must be on file with the Site Management team 
before an investigator may register any patients.  
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office 
 If the necessary documentation is not submitted in advance 
of attempting patient registration, the registration will not be accepted and the 
patient may not be enrolled in the protocol until the situation is resolved. 
 
When the study has been permanently closed to patient enrollment, submission of annual 
IRB approvals to the Site Management Team is no longer necessary. 
 
 

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6.2 
Verification 
 
Prior to accepting the registration, the Registration Application will verify the following: 
 IRB approval at the registering institution 
 Patient eligibility 
 Existence of a signed consent form 
 Existence of a signed authorization for use and disclosure of protected health 
information  
 
6.3 
Treatment cannot begin prior to registration and must begin 14 days after registration.  
 
 
6.4 
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines 
specified on the test schedule. 
 
 
6.5 
All required baseline symptoms (see Section 10.3) must be documented and graded. 
 
 
6.6 
As of amendment 27: Treatment on this protocol must commence under the supervision 
of a medical oncologist or hematologist from the enrolling institution 
 
 
 
 
6.7 
Study drug availability checked.   
 
7.0 
Protocol Treatment 
 
As of Amendment 30, due to the commercial availability of Ixazomib, protocol treatment on this 
study will be discontinued. Patients may complete any current cycles in progress plus one 
additional cycle before being removed from protocol treatment.    
 
 
7.1 
Arm A (Permanently closed to accrual per Addendum 5) Treatment Schedule -  
 
Agent 
Dose Level 
Route 
Day 
Ixazomib  
5.5 mg 
PO 
1, 8, 15 
Dexamethasone* 
20 mg 
PO 
1, 2, 8, 9, 15, 16 
* Dexamethasone is added only for lack of a minor response by end of Cycle 2 or lack of 
a partial response by end of Cycle 4 (these responses can be unconfirmed) or if there is 
disease progression at any time (confirmation of PD is not required).  On-study 
measurements will be used throughout and no new baseline will be established. 
 
Arm B (Permanently closed to accrual per Addendum 14) Treatment Schedule –  
 
Agent 
Dose Level 
Route 
Day 
Ixazomib** 
4 mg 
PO 
1, 8, 15 
Dexamethasone* 
40 mg 
PO 
1, 8, 15 
* Dexamethasone is started Day 1 Cycle 1 
 

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Arm C (Permanently closed to accrual per Addendum 14) Treatment Schedule –  
 
Agent 
Dose Level 
Route 
Day 
Ixazomib** 
5.5 mg 
PO 
1, 8, 15 
Dexamethasone* 
40 mg 
PO 
1, 8, 15 
 
* Dexamethasone is started Day 1 Cycle 1 
 
Arm D Treatment Schedule –  
 
Agent 
Dose Level 
Route 
Day 
Ixazomib 
4 mg 
PO 
1, 8, 15 
Cyclophosphamide 
(Discontinue after 
18 cycles) 
300 mg/m2 
PO 
1, 8, 15, 22 
Dexamethasone* 
40 mg 
PO 
1, 8, 15, 22 
 
* Dexamethasone is started Day 1 Cycle 1 
 
  
 
The combination of ixazomib, cyclophosphamide and dexamethasone has been studied in 
newly diagnosed and relapsed patients in separate trials. Doses up to 500 mg/m2 weekly 
of cyclophosphamide have been combined with ixazomib, 4mg on days 1, 8, 15 and 
dexamethasone 40 mg weekly.  
 
Arm E Treatment Schedule –  
 
Agent 
Dose Level 
Route 
Day 
Ixazomib 
4 mg 
PO 
1, 8, 15 
Cyclophosphamide 
(Discontinue after 
12 cycles) 
300 mg/m2 
PO 
1, 8, 15, 22  
Daratumumab 
16 mg/kg 
IV 
Days 1, 8, 15, 22 for cycles 1-2;  
Days 1, 15 for cycles 3-6; and  
Day 1 for subsequent cycles 
Dexamethasone* 
40 mg 
PO/IV** 
1, 8, 15, 22 

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* Dexamethasone is started Day 1 Cycle 1 
**Dexamethasone should be given IV (PO only if IV is unavailable), approximately 1 
hour or less prior to daratumumab infusion. On days when subjects receive this dose 
of dexamethasone in the clinic, dexamethasone will not be self-administered at home. 
On days when daratumumab is not scheduled, PO may be taken at home (see Section 
9.9b). 
 
 
 
7.2 
Ixazomib  
 
 
Patients should be instructed to swallow ixazomib capsules whole, with water, and 
not to break, chew, or open the capsules. Ixazomib should be taken on an empty 
stomach, at least 1 hour before or at least 2 hours after food. 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.  
 
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 
 
Procedures for ixazomib dose reductions and delays are summarized in Section 8.2, 
along with the criteria that must be met for retreatment with study drug. If a dose is 
missed due to toxicity, the dose will not be made up. 
 
Oral ixazomib is supplied by Takeda Pharmaceuticals. See Section 15.1 for details on 
ixazomib description, formulation, storage, and accountability.  
 
7.3 
Cyclophosphamide (Cycles 1-18 for Arm D and cycles 1-12  for Arm E) 
  
 
Subjects will receive cyclophosphamide orally once weekly on days 1, 8, 15 and 22 
of the 28 day cycle. 
 
Cyclophosphamide is taken with water on a full or empty stomach. Subjects should 
not crush or chew capsules. Missed doses will not be made up. 
 
Procedures for dose reductions and delays are summarized in Section 8.3. 
 
Cyclophosphamide is commercially obtained 
 
7.4 
Daratumumab 
 
• 
Subjects will receive daratumumab intravenously weekly for 8 weeks, then every 
other week for 16 weeks and then every 4 weeks. 
 
Each subject’s dose will be calculated based on the subject’s weight rounded to the 
nearest kilogram. There is no cap on the absolute dose allowed, as long as the dose 
does not exceed 16 mg/kg. If a subject’s weight changes by more than 10% from 
baseline, the dose of daratumumab will be re-calculated. 
 
Vital signs should be monitored extensively on Cycle 1 Day 1 before, during, and 
after the first infusion of daratumumab. For all other infusions, vital signs should be 
measured immediately before the start of infusion and at the end of the infusion. 
• 
Missed doses will not be made up. Procedures for dose reductions and delays are 
summarized in Section 8.5. 

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• 
There are no planned dose reductions. 
• 
Daratumumab is provided by Janssen. See Section 15.4 for details on daratumumab 
description, formulation, storage, and accountability. 
 
As of amendment 27: 
In the event patient is unable to come to the enrolling site for daratumumab infusion 
due to extenuating circumstances, commercial drug can be used for administration at 
a facility accessible to the patient. In that event, the treating investigator will work 
closely with the external provider to ensure safe and appropriate delivery of the 
planned dose. This instance will have to be reported to the IRB as a deviation. 
 
• 
Daratumumab administration: See table below for general infusion guidelines.  
If patients tolerate the first 3 infusions, consideration can be given for a 90 minute 
infusion as per institutional guidelines. 
 
Refer to section 9 for prophylaxis and treatment of infusion reactions 
 
 
Dilution  
volume (mL) 
Initial rate 
 (first hour) 
Rate 
increment 
Maximum 
rate 
First infusion 
1000 mL 
50 mL/hour 
 
50 mL/hour 
every hour 
200 mL/hour 
Second infusiona 
500 mL 
50 mL/hour 
 
50 mL/hour 
every hour 
200 mL/hour 
Subsequent 
infusionsb 
500 mL 
100 mL/hour 
 
50 mL/hour 
every hour 
200 mL/hour 
a Escalate only if there were no Grade 1 (mild) or greater infusion reactions during the 
first 3 hours of the first infusion. 
b Escalate only if there were no Grade 1 (mild) or greater infusion reactions during a final 
infusion rate of ≥100 mL/hr in the first two infusions. 
 
7.5 
Dexamethasone  
 
• 
Dexamethasone may be self-administered by the subject on an outpatient basis. 
• 
Dexamethasone may be permanently discontinued after 12 cycles at the treating 
physician’s discretion or sooner if needed to manage toxicity related to 
dexamethasone.  Dexamethasone as pre-treatment prior to daratumumab should 
continue. 
• 
Missed doses of dexamethasone will not be made up. Procedures for dose reductions 
and delays are summarized in Section 8.2. 
• 
Dexamethasone is commercially available. Accurate records will be kept in the 
source documents of all drug administration (including dispensing and dosing).  
 
7.6 
Treatment at enrolling institution 
 
For this protocol, the patient must return to the consenting institution for daratumumab 
infusions as per treatment schedule and for evaluation prior to each cycle. Treatment by a 

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local medical doctor (LMD) is not allowed. As of amendment 27: Exception noted 
above in 7.4. 
 
  
 
As of amendment 27 
The patient must return to the enrolling institution for evaluation at least every third 
cycle, provided the drug can be sent to the patient and necessary interval evaluations as 
required by the protocol can be completed remotely or through local healthcare facilities. 
 
8.0 
Dosage Modification Based on Adverse Events  
 
Strictly follow the modifications in this table for the first two cycles, until individual treatment 
tolerance can be ascertained.  Individual drugs can be dose reduced as per the table below 
depending on the adverse event attribution. Thereafter, these modifications should be regarded as 
guidelines to produce mild-to-moderate, but not debilitating, side effects.  If multiple adverse 
events are seen, administer dose based on greatest reduction required for any single adverse event 
observed.  Reductions apply to treatment given in the preceding cycle and are based on adverse 
events observed since the prior dose. 
 
Omit = The current dose(s) for the specified drug(s) during a cycle is skipped.  The patient 
does not make up the omitted dose(s) at a later time 
Hold/Delay =  The current dose(s) of all drugs during a cycle is delayed.  The patient does 
make up the delayed dose(s) when the patient meets the protocol criteria to restart drugs. 
Discontinue = The specified drug(s) are totally stopped.    
 
 
NOTE: For Arms A-D, if ixazomib is discontinued, the patient will proceed to event 
monitoring (see Section 18.0). For Arm E, if ixazomib and daratumumab are discontinued, 
the patient will proceed to event monitoring (see Section 18.0).   
 
 
ALERT:  ADR reporting may be required for some adverse events (See Section 10) 
 
Instruction for initiation of a new cycle of therapy or restarting therapy after interruption 
during a cycle for toxicities 
 
A new cycle of treatment may begin on the scheduled Day 1 of a new cycle if: 
 
The ANC is ≥ 1000/μL 
 
The platelet count is ≥ 75,000/μL 
 
Any other non-hematologic treatment adverse event that may have occurred has 
resolved to ≤ Grade 1 or baseline severity. 
If these conditions are not met on Day 1 of a new cycle, the subject will be evaluated 
weekly and a new cycle of therapy will be held until the toxicity has resolved as described 
above.   
If any drug dosing was halted during the previous cycle and was restarted with a one-level 
dose reduction without requiring an interruption for the remainder of the cycle, then that 
reduced dose level will be initiated on Day 1 of the new cycle.  
If any drug dosing was omitted for the remainder of the previous cycle or if the new cycle 
is held due to known hematologic toxicity newly encountered on the scheduled Day 1, then 
the new cycle will be started with a one-level dose reduction.  If a new cycle of therapy 

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cannot be restarted within 4 weeks of the scheduled Day 1, the patient will be removed 
from protocol therapy and will go to event monitoring. 
 
8.1  
Dose Levels for ixazomib and cyclophosphamide (Based on Adverse Events in Tables  
8.11 and 8.12 ) 
 
 
Dose 
Level 
Ixazomib 
Cyclophosphamide
Arms A and C
Arm B 
Arm D  
Arm E 
Arms D and E 
Starting 
Dose 
5.5 mg Days 
1, 8, 15 
4.0 mg Days 
1, 8, 15 
4.0 mg 
Days 1, 8, 
15 
4.0 mg 
Days 1, 8, 
15 
300mg/m2/week 
Days 1,8,15,22 
-1 
4.0 mg Days 
1, 8, 15 
3.0 mg Days 
1, 8, 15 
3.0 mg 
Days 1, 8, 
15 
3.0 mg 
Days 1, 8, 
15 
300mg/m2/week 
Days 1,8,15 
-2 
3.0 mg Days 
1, 8, 15 
2.0 mg Days 
1, 8, 15 
2.0 mg 
Days 1, 8, 
15 
2.3 mg 
Days 1, 8, 
15 
200mg/m2/week 
Days 1,8,15 
-3 
2.0 mg Days 
1, 8, 15 
Discontinue 
2.0 mg 
Days 1, 15
Discontinue
100mg/m2/week 
Days 1,8,15 
-4 
Discontinue 
 
Discontinue
 
Discontinue 
 
 
 
 
 
 
  
  
 
 

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8.12  
Dose modifications based on adverse events during a cycle 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/Cl
ass (SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
BASED ON INTERVAL ADVERSE EVENT (Days 2-28 of each cycle) 
Investigations 
If platelet count ˂ 30  
109/L or ANC ˂1.0  
109/L or ANC > 1.0  
109/L (up to LLN) with 
fever (temperature 
> 38.5°C) 
Ixazomib / 
Cyclophos
phamide 
Days 2-22: Ixazomib and 
cyclophosphamide doses should be 
omitted.  Complete blood count (CBC) 
with differential should be followed 
weekly. If ANC is > 1.0  109/L and/or 
platelet counts > 30  109/L, ixazomib 
and cyclophosphamide may be reinitiated 
with 1 dose level reduction (see table 8.1). 
The subsequent cycle will use the reduced 
dose.  Dose reduction should be applied 
to only one drug at a time, starting with 
cyclophosphamide and alternating with 
ixazomib. If a patient is already at the 
lowest drug level, go to event monitoring.
Skin and 
subcutaneous 
tissue disorders 
Rash, maculopapular, 
≥Grade 2 
Ixazomib 
Omit ixazomib till rash resolves to ≤ 
Grade 1 (See Section 9.9b).  Restart at 
same dose. If the rash recurs, reduce dose 
by one dose level.  If a patient is already 
at the lowest drug level, go to event 
monitoring.
Any skin, Grade 4 
Ixazomib 
Discontinue ixazomib and go to event 
monitoring
Nervous System 
Disorders 
Newly developed Grade 1 
peripheral neuropathy 
with pain,  Grade 2 
peripheral neuropathy,
Ixazomib 
Reduce dose of ixazomib to the next 
lower dose level.  If a patient is already at 
the lowest drug level, go to event 
monitoring. 
Grade 2 neuropathy with 
pain or Grade 3 peripheral 
neuropathy 
Ixazomib 
Omit ixazomib until toxicity resolves or 
returns to baseline.  When toxicity 
resolves, re-initiate ixazomib at the next 
lower dose level.  If a patient is already at 
the lowest drug level, go to event 
monitoring.
Grade 4 peripheral 
neuropathy
Ixazomib 
Discontinue study drug for grade 4 
peripheral neuropathy.
Renal and urinary 
disorders 
Cystitis non infective 
 >Grade 2 
Cyclophos
phamide 
Omit cyclophosphamide until toxicity 
resolves or returns to baseline.  When 
toxicity resolves, re-initiate 
cyclophosphamide at the next lower dose 
level.   

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  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/Cl
ass (SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
Other 
Any other non-
hematological Grade 3 
attributable toxicity 
except: 
> Grade 3 nausea and/or 
emesis in the absence of 
optimal anti-emetic 
prophylaxis  
 
> Grade 3 diarrhea that 
occurs in the absence of 
optimal supportive therapy 
 
≥ Grade 3 fatigue
Ixazomib / 
Cyclophos
phamide 
Omit ixazomib and cyclophosphamide 
until resolution to Grade < 1 or baseline.  
If patient is also receiving Dex, hold both 
drugs.  Restart at next lower dose.  If a 
patient is already at the lowest drug level, 
go to event monitoring. 
Grade 4 Nonhematologic 
Toxicities 
Ixazomib 
Permanently discontinue 
cyclophosphamide.  
Consider permanently discontinuing 
ixazomib.  Exception, in the case where 
the investigator determines the patient is 
obtaining a clinical benefit. 
 
8.2  
Dose Levels for Dexamethasone (Based on Adverse Events in Tables 8.21) 
 
*In Arm A, Dexamethasone is added only for lack of a minor response by end of 
Cycle 2 or lack of a partial response by end of Cycle 4 (these responses can be 
unconfirmed) or if there is disease progression at any time (confirmation of PD is 
not required).   In Arms B, D, and E, Dexamethasone is started on Day 1 Cycle 1. 
 
 
8.21  
Dose modifications based on adverse events during a cycle 

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  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
BASED ON INTERVAL ADVERSE EVENT (Days 2-28 of each cycle) 
Gastrointestinal 
disorders 
Dyspepsia, gastric or 
duodenal ulcer, gastritis 
Grade 1-2 
(Symptomatic; altered 
GI function; medical 
intervention indicated; 
limiting instrumental 
ADL )
Dexamethasone 
Treat with H2 blockers, sucralfate, 
or omeprazole. If symptoms persist 
despite above measures, decrease 
dexamethasone dose by 1 dose 
level.   
Dyspepsia, gastric or 
duodenal ulcer, gastritis 
≥Grade 3 (Severely 
altered GI function; TPN 
indicated; elective 
operative or endoscopic 
intervention indicated; 
limiting self care ADL; 
disabling) 
Dexamethasone 
Omit dexamethasone until 
symptoms adequately controlled. 
Restart one dose level below along 
with concurrent therapy with H2 
blockers, sucralfate, or omeprazole. 
If symptoms persist despite above 
measures, discontinue 
dexamethasone and do not resume.  
Ixazomib should be continued. 
Pancreatitis 
≥ Grade 3 (Severe pain; 
vomiting; medical 
intervention indicated 
(e.g., analgesia, 
nutritional support))
Dexamethasone 
Discontinue dexamethasone and do 
not resume.  Ixazomib should be 
continued. 
Dose 
Level
Dexamethasone*
Arm A 
(Permanently closed 
to accrual) 
Arms B and C
(Permanently 
closed to accrual)
Arms D and E
0
20 mg Days 1, 2, 8, 
9, 15, 16 
40 mg Days 1, 8, 
15 
40 mg Days 1, 8, 15, 22
-1
20 mg Days 1, 8, 15
20 mg Days 1, 8, 
15
20 mg Days 1, 8, 15, 22
-2
10 mg Days 1, 8, 15
12 mg Days 1, 8, 
15
12 mg Days 1, 8, 15, 22
-3
5 mg Days 1, 8, 15
4 mg Days 1, 8, 
15
4 mg Days 1, 8, 15, 22

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  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION** 
General disorders 
and administration 
site conditions 
Edema 
≥ Grade 3 (limiting 
function and 
unresponsive to therapy 
or anasarca) 
Dexamethasone 
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.  Ixazomib should be 
continued. 
Psychiatric disorders 
Confusion or Mood 
alteration 
≥ Grade 2 (Severe 
disorientation; limiting 
selfcare ADL) 
Dexamethasone 
Omit dexamethasone until 
symptoms resolve. Restart with one 
dose level reduction. If symptoms 
persist despite above measures, 
discontinue dexamethasone and do 
not resume.  Ixazomib should be 
continued. 
Musculoskeletal and 
connective tissue 
disorders 
Muscle weakness 
> Grade 2  
 Weakness limiting self 
care ADL; disabling 
Dexamethasone 
Decrease dexamethasone dose by 
one dose level; if weakness persists 
despite above measures decrease 
dose by one additional dose level. 
Discontinue dexamethasone and do 
not resume if symptoms continue to 
persist.  Ixazomib should be 
continued. 
Metabolism and 
nutrition disorders 
Hyperglycemia Grade 3 
or higher, (>250 - 500 
mg/dL; >13.9 - 27.8 
mmol/L); hospitalization 
indicated 
Dexamethasone 
Treatment with insulin or oral 
hypoglycemics as needed. If 
uncontrolled despite above 
measures, decrease dose by one 
dose level at a time until levels are 
satisfactory. 
 
NOTE:  Adverse events requiring a dose-reduction step for any or all drugs beyond the three dose-
reduction steps (levels -1, -2 and -3) will be at the discretion of the Principal Investigator, if the 
decision is made for the patient to be kept on study.  These dose reductions must be clearly 
recorded in reported clinical data.  
 
8.3  
Daratumumab Dose Modification 
 
Dose modification of daratumumab is not permitted, but dose delay is the primary 
method for managing daratumumab-related toxicities. The attribution of the toxicity to 
individual drug (s) will be performed by the treating physician. 
 
 
8.31 
Daratumumab-Related Toxicity Management 

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Refer to Section 9.9i for details on management of infusion-related reactions. 
ONLY if any of the following criteria are met and the event cannot be ascribed to 
the other drugs, the daratumumab infusion must be omitted to allow for recovery 
from toxicity. The criteria for a dose omit are: 
 
Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding 
 
Grade 4 neutropenia, if this is the second occurrence despite growth factor 
support 
 
Febrile neutropenia of any grade 
 
Neutropenia with infection, of any grade 
 
Grade 3 or higher non-hematologic toxicities with the following exceptions: 
o Grade 3 nausea that responds to antiemetic treatment within 7 days 
o Grade 3 vomiting that responds to antiemetic treatment within 7 days 
o Grade 3 diarrhea that responds to antidiarrheal treatment within 7 days 
o Grade 3 fatigue that was present at baseline or that lasts for <7 days after 
the last administration of daratumumab 
o Grade 3 asthenia that was present at baseline or that lasts for <7 days 
after the last administration of daratumumab 
 
If a daratumumab administration does not commence within the prespecified 
window (Table) of the scheduled administration date, then the dose will be 
considered a missed dose. Administration may resume at the next planned dosing 
date. 
 
Table 8.6 
Daratumumab-Related Toxicity Management 
Cycles  
Frequency  
Dose Held  
Dosing Re-start  
1 and 2  
Weekly (q1wk)  
>3 days  
next planned weekly 
dosing date 
3 to 6  
Biweekly (q2wks)`  
>1 week  
next planned biweekly 
dosing date 
7+  
Every 4 weeks (Q4W)  
>2 weeks  
next planned every 4 
weeks dosing date 
 
A missed dose will not be made up. Doses of daratumumab may be delayed up to 4 
weeks. If a dose is delayed, then the dates of the subsequent doses must be adjusted. Any 
adverse event deemed to be related to daratumumab and unrelated to the other  drugs that 
requires a dose hold of more than 4 weeks will result in permanent discontinuation of 
daratumumab.  
 
 
 

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9.0    
Ancillary Treatment/Supportive Care 
 
9.1 
Patients may receive concurrent treatment with a bisphosphonate.  
 
9.2 
Patients may continue on low level/stable steroid doses for replacement or inhalation 
therapy. 
 
9.3 
The following medications are not permitted during the trial: 
 
Any other investigational treatment  
 
Any cytotoxic chemotherapy 
 
Any other systemic anti-neoplastic therapy including, but not limited to, 
immunotherapy, hormonal therapy or monoclonal antibody therapy. 
 
Any external beam radiotherapy 
 
9.4 
Antiemetics may be used at the discretion of the attending physician. Volume depletion 
should be corrected before initiation of study drug. 
 
9.5 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations.  The use of growth factors should 
follow published guidelines of the Journal of Clinical Oncology, Vol 24, No 18 (June 
20), 2006: pp. 2932-2947 
 
9.6 
Patients should receive full supportive care while on this study.  This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions.  All blood products and concomitant medications such 
as antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the 
medical records. 
 
Interference with Serological Testing:  Daratumumab binds to CD38 on red blood cells 
(RBCs) and results in a positive Indirect Antiglobulin Test (Coombs test). Daratumumab-
mediated positive indirect antiglobulin test may persist for up to 6 months after the last 
daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to 
minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh 
blood type are not impacted. Notify blood transfusion centers of this interference with 
serological testing and inform blood banks that a patient has received Daratumumab. 
Type and screen patients prior to starting Daratumumab. 
 
9.7 
Diarrhea:  This can be managed conservatively with loperamide.  The recommended dose 
of loperamide is 4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea free 
(maximum 16 mg/day). 
 
In the event of Grade 3 or 4 diarrhea, the following supportive measures are allowed:  
hydration, octreotide, and antidiarrheals.   
 
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or 
severe neutropenia (Grade 3 or 4), broad-spectrum antibiotics must be prescribed.  
Patients with severe diarrhea or any diarrhea associated with severe nausea or vomiting 
should be hospitalized for intravenous hydration and correction of electrolyte 
imbalances. 

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9.8  
Acute renal failure have been reported with ixazomib (see Section 1.4.3).  Volume 
depletion should be corrected before initiation of study drug. Nonsteroidal anti-
inflammatory drugs (NSAIDs) induced prevalence of nephrotoxicity is relatively low; 
however, given the wide use of these agents many persons are at risk, including for 
example, patients with cardio-renal disease, dehydration, and the aging kidney. NSAIDs 
should be avoided with impaired renal function given reported NSAID-induced renal 
failure in patients with decreased renal function  
 
9.9 
Herpes Zoster prophylaxis with acyclovir 400 mg PO BID is recommended while on 
study therapy and for 1 month beyond the end of therapy 
 
9.9a 
The following medications and procedures are prohibited during the study. 
 
Systemic treatment with strong CYP3A inducers (rifampin, rifapentine, rifabutin, 
 
carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John’s wort 
 
within 14 days before the first dose of study treatment 
 
The following procedures are prohibited during the study. 
 
Participation in clinical trials with other investigational agents, not included 
in this trial, within 14 days of the start of this trial and throughout the 
duration of this trial. 
 
9.9b      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. The rash may range from some erythematous areas, 
macular and/or small papular bumps that may or may not be pruritic over a few areas of 
the body or more generalized. The rash has been transient and has resolved either 
spontaneously or with standard symptomatic measures such as oral or topical steroids 
and/or antihistamines. Prophylactic measures should also be considered if a patient 
develops a rash (eg, using a thick, alcohol-free emollient cream on dry areas of the body).  
In the case of rash, the use of a topical or oral steroid (eg, prednisone ≤ 10 mg per day or 
equivalent) is permitted.  A rare risk is Stevens Johnson Syndrome, a severe, life-
threatening or deadly rash with skin peeling and mouth sores, which should be managed 
symptomatically according to standard medical practice. 
 
Thrombocytopenia: Thrombocytopenia has been reported to date primarily at the higher 
doses tested.  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. Thrombocytopenia nadirs commonly recover without intervention by 
the beginning of the next scheduled cycle. Ixazomib administration should be modified as 
noted as per dose modification recommendations in Table 8-2 when thrombocytopenia 
occurs.  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. 
 
Neutropenia: Neutropenia has been reported with ixazomib.  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 with  

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filgrastim according to standard clinical practice.  Neutropenic nadirs commonly recover 
without intervention by the beginning of the next scheduled cycle or with a short delay in 
treatment. Ixazomib dosing should be modified when neutropenia occurs, as noted in the 
dose modification recommendations in Table 8-2.  Therapy can be reinitiated at a reduced 
level upon recovery of absolute neutrophil counts. 
 
Fluid Deficits: Dehydration should be avoided because ixazomib may cause vomiting, 
diarrhea, and dehydration.  Acute renal failure has been reported with ixazomib.  Fluid 
deficits should be corrected before initiation of study drug and during treatment and as 
needed during therapy.  
 
Hypotension: Symptomatic hypotension and orthostatic hypotension 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.  
 
Posterior Reversible Encephalopathy Syndrome: One case of posterior reversible 
encephalopathy syndrome (PRES) has been reported with ixazomib.  While this case 
ultimately resolved, PRES has also been reported rarely with another proteasome 
inhibitor, VELCADE.  PRES is characterized by headache, seizures and visual loss, as 
well as abrupt increase in blood pressure.  Prompt diagnosis and initiation of 
antihypertensive and anticonvulsant therapy are important to prevent irreversible end-
organ damage. 
 
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, 
the possibility that ixazomib may have contributed to transverse myelitis cannot be 
excluded. 
 
Guidelines for Prevention of Infusion Reactions 
 
Pre-infusion Medication: On daratumumab infusion days, subjects will receive the 
following medications prior to infusion: 
 
Acetaminophen (paracetamol) 650-1000 mg IV or orally (PO) approximately 1 
hour or less prior to daratumumab infusion 
 
An antihistamine (diphenhydramine 25-50 mg IV or PO, or equivalent) 
approximately 1 hour (or less) prior to infusion 
 
Dexamethasone 40 mg IV or PO (only if IV is not available), approximately 1 
hour or less prior to daratumumab infusion. On days when subjects receive this 
dose of dexamethasone in the clinic, dexamethasone will not be self-administered 
at home. 
 
Post-infusion Medication: For subjects with higher risk of respiratory complications (ie, 
subjects who have a FEV1 <80%), the following postinfusion medications should be 
considered: 

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 
Antihistamine (diphenhydramine or equivalent) 
 
Dexamethasone 4 mg day after infusion 
 
Short-acting β2 adrenergic receptor agonist such as salbutamol aerosol 
 
Control medications for lung disease (eg, inhaled corticosteroids ± long-acting β2 
adrenergic receptor agonists for subjects with asthma; long-acting 
bronchodilators such as tiotropium or salbumatol ± inhaled corticosteroids for 
subjects with COPD) 
 
 
 
In addition, these at-risk subjects may be hospitalized for monitoring for up to 2 nights 
after an infusion. If subjects are hospitalized, then their FEV1 should be measured before 
discharge. If these subjects are not hospitalized, then a follow up telephone call should be 
made to monitor their condition within 48 hours after all infusions. If the subject has not 
experienced a significant medical event but is hospitalized overnight only for 
observation, then the hospitalization should not be reported as a serious adverse event. 
Investigators may prescribe bronchodilators, antihistamines, and corticosteroids that are 
deemed necessary to provide adequate supportive care in the event a bronchospasm 
occurs after subjects are released from the hospital/clinic.  
 
Management of Infusion-related Reactions (or any reaction during infusion) 
 
Subjects should be carefully observed during daratumumab infusions. Trained study staff 
at the clinic should be prepared to intervene in case of any infusion reactions occurring, 
and resources necessary for resuscitation must be available at the bedside. 
 
If any infusion-related reactions develop, then the infusion should be temporarily 
interrupted.  Subjects who experience adverse events during the infusion must be treated 
according to the investigator’s judgment and best clinical practice. The following 
guidelines may apply: 
 
Subjects should be treated with acetaminophen, antihistamine, or corticosteroids. 
Intravenous saline may be indicated. For bronchospasm, urticaria, or dyspnea, 
subjects may require antihistamines, oxygen, corticosteroids, or bronchodilators. 
For hypotension, subjects may require vasopressors. 
 
In the event of a life-threatening infusion-related reaction (which may include 
pulmonary or cardiac events), or anaphylactic reaction, daratumumab should be 
discontinued and no additional daratumumab should be administered to the 
subject. Aggressive symptomatic treatment should be applied. 
 
If an infusion is paused or the infusion rate is decreased, then a longer-than-
anticipated infusion time may occur. Overnight stays at the hospital because of 
slow infusion times should not be reported as a serious adverse event. However, 
if the underlying cause of the delayed infusion time is an adverse event or serious 
adverse event, then that should be reported as such. 
  
Infusion-Related Events of Grade 1 or Grade 2: If the investigator assesses an 
adverse event to be related to the daratumumab infusion, then the infusion should be 
paused. When the subject’s condition is stable, the infusion may be restarted at the 
investigator’s discretion. Upon restart, the infusion rate should be half of that used 

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before the interruption. Subsequently, the infusion rate may be increased at the 
investigator’s discretion. 
 
If the subject experiences a Grade 2 or higher event of laryngeal edema or a Grade 2 
or higher event of bronchospasm that does not respond to systemic therapy and does 
not resolve within 6 hours from the onset, then the subject must be withdrawn from 
treatment. 
 
Infusion-Related Reactions of Grade 3 or Higher: For infusion-related adverse events 
that are Grade 4, the infusion should be stopped and treatment with daratumumab 
will be discontinued for that subject. 
 
For infusion-related adverse events that are Grade 3, the daratumumab infusion must 
be stopped, and the subject must be observed carefully until the resolution of the 
adverse event or until the intensity of the event decreases to Grade 1, at which point 
the infusion may be restarted at the investigator’s discretion. Upon restart, the 
infusion rate should be half of that used before the interruption. Subsequently, the 
infusion rate may be increased at the investigator’s discretion. 
 
If the intensity of the adverse event returns to Grade 3 after restart of the infusion, 
then the procedure described in this section may be repeated at the investigator’s 
discretion. Should the intensity of the adverse event increase to Grade 3 for a third 
time, then treatment with daratumumab will be discontinued for that subject.  
 
 
 

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10.0 
Adverse Event (AE) Reporting and Monitoring  
 
10.1 
Adverse Event Characteristics 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site:  
    
 
10.11 Adverse event monitoring and reporting is a routine part of every clinical trial.  
First, identify and grade the severity of the event using the CTCAE version 4.0.  
Next, determine whether the event is expected or unexpected (see Section 10.2) 
and if the adverse event is related to the medical treatment or procedure (see 
Section 10.3).  With this information, determine whether the event must be 
reported as an expedited report (see Section 10.4). Expedited reports are to be 
completed within the timeframes and via the mechanisms specified in Sections 
10.4. All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.52 
and 18.0). 
 
10.12 Each CTCAE term in the current version is a unique representation of a specific event 
used for medical documentation and scientific analysis and is a single MedDRA 
Lowest Level Term (LLT).   
 
 
NOTE:  A severe AE, as defined by the above grading scale, is NOT 
the same as serious AE which is defined in the table in Section 10.4. 
 
10.2  
Expected vs. Unexpected Events  
 
 
The determination of whether an AE is expected is based on agent-specific 
information provided in Section 15.17 of the protocol. 
 
 
Unexpected AEs are those not listed in the agent-specific information 
provided in Section 15.17 of the protocol. 
 
NOTE: “Unexpected adverse experiences” means any adverse experience that is neither 
identified in nature, severity, or frequency of risk in the information provided for IRB 
review nor mentioned in the consent form.  
 
10.3 
Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or 
procedure, the following attribution categories are utilized: 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 

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Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly, probably or definitely attributed to a 
medical treatment suggest there is evidence to indicate a causal relationship 
between the drug and the adverse event.  
 
10.31 AEs Experienced Utilizing Investigational Agents and Commercial Agent(s) on 
the SAME Arm 
 
NOTE: The combination of an investigational agent with a commercial agent is 
considered investigational. 
 
Routine Reporting 
 
 Routine AE reporting for Phase 1 and Phase 2 clinical studies using an 
investigational agent /intervention in combination with a commercial agent 
is stated in the protocol.  See Section 10.52. 
 
NOTE:  When a commercial agent(s) is (are) used on the same 
treatment arm as the investigational agent/intervention (also, 
investigational drug, biologic, cellular product, or other 
investigational therapy under an IND), the entire combination (arm) is 
then considered an investigational intervention for reporting. 
 
Expedited Reporting 
 
 An AE that occurs on a combination study must be assessed in accordance with 
the guidelines for CTEP investigational agents/interventions in Section 10.4, and 
where indicated, an expedited report must be submitted. 
 
 An AE that occurs prior to administration of the investigational 
agent/intervention must be assessed as specified in the protocol. In general, 
only Grade 4 and 5 AEs that are unexpected with at least possible 
attribution to the commercial agent require an expedited report.  Refer to 
Section 10.4 for specific AE reporting requirements or exceptions. 
 
 Commercial agent expedited reports must be submitted by the Cooperative 
Group to the FDA via MedWatch. 
 
 An investigational agent/intervention might exacerbate the expected AEs 
associated with a commercial agent.  Therefore, if an expected AE (for the 
commercial agent) occurs with a higher degree of severity, expedited reporting 
is required.  The clinical investigator must determine severity. 
 
 

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10.32 
Special Situations for Expedited Reporting  
Exceptions to Expedited Reporting: EXPECTED Serious Adverse Events1 :  
 
An expedited report or notification form may not be required for specific Grade 
1, 2, 3 and 4 Serious Adverse Events where the AE is listed in Section 15.0 of the 
protocol or the consent form* as EXPECTED. Any protocol specific reporting 
procedures MUST BE SPECIFIED BELOW and will supercede the standard 
Expedited Adverse Event Reporting Requirements (Note:  These adverse events 
must still be reported through the routine reporting mechanism [i.e. 
Nadir/adverse events form Requirements (see footnote 1):  
  
System Organ Class 
(SOC) 
Adverse event/ 
Symptoms  
CTCAE Grade at 
which the event 
will not be 
expeditedly 
reported.
General disorders and 
administrations site 
conditions 
Fatigue 
Grade 3 
Gastrointestinal
Vomiting
Grade 3
Nausea
Grade 3
Diarrhea
Grade 3
Investigations
Neutrophil count 
decreased
Grade 3 
Platelet count 
decreased
Grade 3
White blood count
Grade 3
Lymphocyte count
Grade 3
Blood and lymphatic 
system disorders
Anemia 
Grade 3 
Metabolism and 
Nutrition disorders
Hyperglycemia 
Grade 3 
1 These exceptions only apply if the adverse event does not result in hospitalization.  If 
the adverse event results in hospitalization, then the standard expedited adverse events 
reporting requirements must be followed. 
 
Specific protocol exceptions to expedited reporting should be reported expeditiously by 
investigators ONLY if they exceed the expected grade of the event. 
 
*The consent form may contain study specific information at the discretion of the 
Principal Investigator; it is possible that this information may NOT be included in 
the protocol or the investigator brochure. 
 
10.321 Persistent or Significant Disabilities/Incapacities 
Any AE that results in persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions (formerly referred to 
as disabilities), congenital abnormities or birth defects, must be reported 
immediately if they occur at any time following treatment with an agent under 

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an IND/IDE since they are considered to be a serious AE and must be reported 
to the sponsor as specified in 21 CFR 312.64(b). 
 
10.322 Death 
 
 
Any death occurring within 30 days of the last dose, 
regardless of attribution to an agent/intervention under an 
IND/IDE requires expedited reporting within 24-hours. 
 
 
Any death occurring greater than 30 days with an attribution 
of possible, probable, or definite to an agent/intervention 
under an IND/IDE requires expedited reporting within 24-
hours. 
 
 
Reportable categories of Death  
 
 
Death attributable to a CTCAE term. 
 
 
Death Neonatal:  A disorder characterized by 
cessation of life during the first 28 days of life. 
 
 
Death NOS:  A cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
 
 
Sudden death NOS:  A sudden (defined as instant or 
within one hour of the onset of symptoms) or an 
unobserved cessation of life that cannot be attributed 
to a CTCAE term associated with Grade 5. 
 
 
Death due to progressive disease should be reported 
as Grade 5 “Neoplasms benigh, malignant and 
unspecified (incl cysts and polyps) – Other 
(Progressive Disease)” under the system organ class 
(SOC) of the same name.  Evidence that the death 
was a manifestation of underlying disease (e.g., 
radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a 
disease process) should be submitted. 
 
 
Any death occurring within 30 days of the last dose, 
regardless of attribution to the investigational 
agent/intervention requires expedited reporting within 24 
hours. 
 
 
Any death occurring greater than 30 days after the last does 
of the investigational agent/intervention requires expedited 
reporting within 24 hours only if it is possibly, probably, or 
definitely related to the investigational agent/intervention. 
 

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10.323 Secondary Malignancy 
 
 
A secondary malignancy is a cancer caused by treatment for a 
previous malignancy (e.g., treatment with investigational 
agent/intervention, radiation or chemotherapy).  A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
 
All secondary malignancies that occur following treatment with an 
agent under an IND/IDE be reported. Three options are available to 
describe the event: 
 
o Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myeloctyic Leukemia [AML]) 
 
o Myelodysplastic syndrome (MDS) 
 
o Treatment-related secondary malignancy 
 
 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting 
mechanisms outlined in each protocol. 
 
10.324 Second Malignancy 
 
 
A second malignancy is one unrelated to the treatment of a prior 
malignancy (and is NOT a metastasis from the initial malignancy).  
Second malignancies require ONLY routine reporting. 
 
10.4          Expedited Reporting Requirements for IND/IDE Agents 
 
 
 
 

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10.41  Expedited Reporting Requirements for Adverse Events that Occur on 
Studies under an IND/IDE within 30 Days of the Last Administration 
of the Investigational Agent/Intervention1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported within the timeframes 
detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes
Grade 2 
Timeframes
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes
Resulting in 
Hospitalization  
≥ 24 hrs 
7 Calendar Days 
24-Hour 3 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
7 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in section 
10.32 of the protocol. 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported within 24 hours of learning of the AE, 
followed by a complete expedited report within 3 calendar days of the initial 24-hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days 
of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
 All Grade 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
 Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
 Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
 
 

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Additional instructions: 
1. Contact Takeda/Millennium Pharmacovigilance and Janssen (see 10.6) 
 
Sponsor-investigator must report all SAEs, regardless of expectedness or relationship with any 
study drug, to Millennium Pharmacovigilance (or designee) as soon as possible, but no later 
than 5 calendar days of the sponsor-investigator’s observation or awareness of the event.  In 
the event that this is a multisite study, the sponsor-investigator is responsible to ensure that the 
SAE reports are sent to Millennium Pharmacovigilance (or designee) from all sites participating 
in the study.  Subinvestigators must report all SAEs to the sponsor-investigator so that the 
sponsor-investigator can meet his/her foregoing reporting obligations to Millennium 
Pharmacovigilance, unless otherwise agreed between the sponsor-investigator and 
subinvestigator(s).  Millennium Pharmacovigilance (or designee) may request follow-up 
information to a reported SAE, which the sponsor-investigator will be responsible for providing 
to Millennium Pharmacovigilance (or designee) 
 
The SAE report must include event term(s), serious criteria, and the investigator’s or sub-
investigator’s determination of both the intensity of the event(s) and the relationship of the 
event(s) to study drug administration. 
 
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, 
she must inform the investigator immediately and permanently discontinue study drug.  The 
sponsor-investigator must fax a completed Pregnancy Form to the Millennium Department of 
Pharmacovigilance or designee.  The pregnancy must be followed for the final pregnancy 
outcome. 
 
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor-investigator must also immediately fax a completed Pregnancy Form to 
the Millennium Department of Pharmacovigilance or designee Section.  Every effort should be 
made to follow the pregnancy for the final pregnancy outcome. 
 
Suggested Pregnancy Reporting Form: 
 
Pregnancy Report Form (a sample is provided in Appendix V) 
 
 
Suggested Reporting Form: 
 
SAE Report Form (provided by Takeda) 
 
US FDA MedWatch 3500A: 
 
 
Any other form deemed appropriate by the sponsor-investigator 
 
Mayo Clinic Cancer Center (MCCC) Institutions:  Provide copies, along with the UPIRTSO 
cover sheet, by fax 
to the MCCC Regulatory Affairs Unit (RAU) Risk 
Information Specialist who will determine and complete IRB reporting. The RAU will 
submit to the MCCC SAE Coordinator and the MCCC IND Coordinator to determine if 
FDA submission is needed. 
10.5 
Other Required Reporting 
 
10.51 Adverse events to be graded at each evaluation and pretreatment 
symptoms/conditions to be evaluated at baseline per the CTCAE v4.0 grading 
unless otherwise stated in the table below: 
 
Each

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SYSTEM ORGAN 
CLASS
Adverse event/Symptoms 
Baseline 
evaluation 
Investigations 
Creatinine increased
X
X
Neutrophil count decreased
X
X
Platelet count decreased
X
X
General disorders and 
administration site 
conditions
Edema limbs
X
X
Fatigue  
X 
X 
Gastrointestinal 
Disorders 
Nausea
X
X
Vomiting
X
X
# of Stools
X
Diarrhea
X
Constipation
X
Infections and 
infestations
Sepsis 
X 
X 
Blood and lymphatic 
system disorders 
Febrile neutropenia
X
X
Anemia 
X
X
Skin and 
subcutaneous tissue 
disorders
Rash, maculopapular 
X 
X 
Nervous system 
disorders 
 
Peripheral sensory neuropathy 
X
X
Peripheral motor neuropathy 
X
X
Cognitive disturbance
X
X
 
10.52 Submit via appropriate MCCC Case Report Forms (i.e., paper or 
electronic, as applicable) the following AEs experienced by a patient and 
not specified in Section 10.5: 
10.521 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
 
10.522 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
 
10.523 Grade 5 AEs (Deaths) 
 
10.5231  
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
treatment or procedure. 
 
10.5232 
Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, 
with a CTCAE type and attribution assigned. 
 
 

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10.53  Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion 
of the Active Monitoring Phase (i.e., compliance with Test Schedule in Section 
4.0). 
 
10.6 
Other Reporting Instructions for Industry Partners 
 
10.61 Special reporting requirements for Takeda 
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 if it 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 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 (eg, 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 

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may not be considered serious.  Seriousness (not intensity) serves as a guide for defining 
regulatory reporting obligations. 
 
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.  
 
AEs which are serious must be reported to Takeda Pharmacovigilance (or designee) from 
the first dose of study drug through 30 days after administration of the last dose of 
ixazomib. Any SAE that occurs at any time after completion 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 to Takeda Pharmacovigilance 
(or designee). 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 to Takeda 
Pharmacovigilance (or designee). 
 
 
 
 
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 
intercurrent illness(es). 
 
 
 
Since this is an investigator-initiated study, the principal investigator, Shaji Kumar, MD, 
also referred to as the sponsor-investigator, is responsible for reporting serious adverse 
events (SAEs) to any regulatory agency and to the sponsor- investigator’s EC or IRB. 
 
 
 
Regardless of expectedness or causality, all SAEs (including serious pretreatment events) 
must also be reported in English to Takeda Pharmacovigilance (or designee): 
 
 
 
Fatal and Life Threatening SAEs within 24 hours of the sponsor-investigator’s 
observation or awareness of the event 
 
 
 
All other serious (non-fatal/non-life-threatening) events within 4 calendar days of the 
sponsor-investigator’s observation or awareness of the event 
 
 
 
See below for contact information for the reporting of SAEs to Takeda 
Pharmacovigilance. 
 
 
The sponsor-investigator must fax or email the SAE Form per the timelines above. A 
sample of an SAE Form will be provided. 
 
 
 

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The SAE report must include at minimum: 
 Event term(s) 
 Serious criteria 
 Intensity of the event(s): Sponsor-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 
 
 Causality of the event(s): Sponsor-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 Takeda. 
  
Intensity for each SAE, including any lab abnormalities, will be determined by 
using the NCI CTCAE version used at your institution, as a guideline, whenever 
possible. The criteria are available online at 
 
  
In the event that this is a multisite study, the sponsor-investigator is responsible 
to ensure that the SAE reports are sent to Takeda Pharmacovigilance (or designee) from 
all sites participating in the study. Sub-investigators must report all SAEs to the 
sponsor-investigator so that the sponsor-investigator can meet his/her foregoing 
reporting obligations to the required regulatory agencies and to Takeda 
Pharmacovigilance, unless otherwise agreed between the sponsor-investigator and sub-
investigator(s). 
  
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)? 
  
Sponsor-investigator must also provide Takeda Pharmacovigilance with a copy 
of all communications with applicable regulatory authorities related to the study 
product(s), as soon as possible but no later than 4 calendar days of such 
communication. 
 
 
 
SAE and Pregnancy Reporting Contact Information 
 
 
 
 
 
 
 
  
 
 
 Suggested Reporting Form: 
 
SAE Report Form (provided by Takeda) 
 
US FDA MedWatch 3500A: 
 
 
Any other form deemed appropriate by the sponsor-investigator 
 
 
 
 
 
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 Takeda  and report the event. Whenever possible, the associated 
product should be maintained in accordance with the label instructions pending further 
guidance from a Takeda Quality representative. 
 
 
 
For Product Complaints 
 
 

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 
 
 
 
 
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 Takeda Pharmacovigilance 
 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events 
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 study drug.  The sponsor-investigator must immediately fax 
a completed Pregnancy Form to the Takeda Department of Pharmacovigilance or 
designee (see Section 8.2).  The pregnancy must be followed for the final pregnancy 
outcome. 
If a female partner of a male patient becomes pregnant during the male patient’s 
participation in this study, the sponsor-investigator must also immediately fax a 
completed Pregnancy Form to the Takeda Department of Pharmacovigilance or designee 
(see Section 8.2).  Every effort should be made to follow the pregnancy for the final 
pregnancy outcome. 
Suggested Pregnancy Reporting Form: 
Pregnancy Report Form (provided by Takeda) 
 
10.62 Special reporting requirements for Janssen 
 
Overview 
As the sponsor of the Study, PRINCIPAL INVESTIGATOR shall be solely responsible 
for complying, within the required timelines,  any safety reporting obligation to 
competent Health Authorities, IRB/ECs and any participating (co or sub) investigators, as 
defined in applicable laws and regulations.  For the purposes of this section, safety data 
includes adverse events, product quality complaints (PQCs), and special situations 
including pregnancies. 
 
The PRINCIPAL INVESTIGATOR will provide safety information to Janssen Scientific 
Affairs, LLC on adverse events, special situations including pregnancies and product 
quality complaints as defined within this section. 
 
1. 
Management of Safety Data 
This Study has been designated as an interventional study.  As such, all adverse events 
for Janssen Medicinal Products regardless of causality and special situations excluding 
those from subjects not exposed to a Janssen Medicinal Product and product quality 
complaints with or without an adverse event as described in this Exhibit will be reported 
from the time a subject has signed and dated an Informed Consent Form (ICF) until 
completion of the subject’s last study-related procedure (which may include contact for 
follow-up safety).  Serious adverse events will be reported for 30 days after the last dose 
of study drug. 
 
For the purposes of this study, the Janssen medicinal product is: DARZALEX™ 
(daratumumab)  
 

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2. 
Definitions 
2.1. 
Adverse Event (AE) 
An adverse event is any untoward medical occurrence in a clinical study subject 
administered a medicinal (investigational or non-investigational) product. An 
adverse event does not necessarily have a causal relationship with the treatment. 
An adverse event can therefore be any unfavorable and unintended sign 
(including an abnormal finding), symptom, or disease temporally associated with 
the use of a medicinal (investigational or non- investigational) product, whether 
or not related to that medicinal (investigational or non-investigational) product. 
(Definition per International Conference on Harmonisation [ICH]) 
This includes any occurrence that is new in onset or aggravated in severity or 
frequency from the baseline condition, or abnormal results of diagnostic 
procedures, including laboratory test abnormalities. 
 
2.2. 
Adverse Events of Special Interest (Arm E only) 
Adverse events of special interest are events that Janssen Scientific Affairs, LLC 
is actively monitoring as a result of a previously identified signal (even if non-
serious). These adverse events are: 
 
Infusion reactions ≥ grade 3 
 
Infections ≥ grade 4 
 
Cytopenias ≥ grade 4 
 
HBV Reactivation Other malignancies  
 
Any Adverse Event of Special Interest that is to be reported should be recorded 
on a Serious Adverse Event Report Form (MedWatch Form) and be reported 
within 24 hours of knowledge of the event. 
 
2.3. 
Individual Case Safety Report (ICSR) 
A valid ICSR must contain the four minimum criteria required to meet regulatory 
reporting requirements. 
 
an identifiable subject (but not disclosing personal information such as the 
subject’s name, initials or address) 
 
an identifiable reporter (investigational site) 
 
a Janssen medicinal product 
 
an adverse event, outcome, or certain special situations 
 
The minimum information required is: 
 
suspected Janssen medicinal product (doses, indication) 
 
date of therapy (start and end date, if available) 
 
batch or lot number, if available 
 
subject details (subject ID and country) 
 
gender 
 
age at AE onset 
 
reporter ID 
 
adverse event detail (AE verbatim in English), onset date, relatedness, 
causality, action taken, outcome, (if available) 
 
Janssen protocol ID 
 
2.4. 
Product Quality Complaint (PQC) 

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A product quality compliant is defined as any suspicion of a product defect 
related to a potential quality issue during manufacturing, packaging, release 
testing, stability monitoring, dose preparation, storage or distribution of the 
product, or delivery system.  Not all PQCs involve a subject.  Lot and batch 
numbers are of high significance and need to be collected whenever available. 
 
Examples of PQC include but not limited to: 
 
Functional Problem: e.g., altered delivery rate in a controlled release product 
 
Physical Defect:  e.g. abnormal odor, broken or crushed tablets/capsules 
 
Potential Dosing Device Malfunction: e.g.,  autoinjector button not working, 
needle detaching from syringe 
 
Suspected Contamination 
 
Suspected Counterfeit 
 
2.5. 
Serious Adverse Event (SAE) 
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance 
for Medicinal Products for Human Use is any untoward medical occurrence that 
at any dose: 
 
 
Results in death 
 
Is life-threatening 
(The subject was at risk of death at the time of the event. It does not refer to an 
event that hypothetically might have caused death if it were more severe.) 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity 
 
Is a congenital anomaly/birth defect 
 
Is a suspected transmission of any infectious agent via a medicinal product 
 
Is medically important* 
 
*Medical and scientific judgment should be exercised in deciding whether 
expedited reporting is also appropriate in other situations, such as important 
medical events that may not be immediately life threatening or result in death or 
hospitalization but may jeopardize the subject or may require intervention to 
prevent one of the other outcomes listed in the definition above. These should 
usually be considered serious. 
 
NOTE: DEATH FOR ANY REASON SHOULD BE REPORTED AS A SERIOUS 
ADVERSE EVENT. 
 
2.5.1. Hospitalization 
For reports of hospitalization, it is the sign, symptom or diagnosis which led 
to the hospitalization that is the serious event for which details must be 
provided. 
 
Any event requiring hospitalization or prolongation of hospitalization that occurs 
during the study must be reported as a serious adverse event, except 
hospitalizations for the following: 
 
Hospitalizations not intended to treat an acute illness or adverse event (e.g., 
social reasons such as pending placement in long-term care facility) 

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 
Surgery or procedure planned before entry into the study. [Note: 
Hospitalizations that were planned before the start of data collection and 
where the underlying condition for which the hospitalization was planned has 
not worsened will not be considered serious adverse events. Any adverse 
event that results in a prolongation of the originally planned hospitalization is 
to be reported as a new serious adverse event.] 
 
[For convenience the investigator may choose to hospitalize the subject for 
the duration of the treatment period.]  
 
 
2.5.2. Life-Threatening Conditions 
Disease progression should not be recorded as an adverse event or serious 
adverse event term; instead, signs and symptoms of clinical sequelae 
resulting from disease progression/lack of efficacy will be reported if they 
fulfill the serious adverse event definition. 
 
3. 
Unlisted (Unexpected) Adverse Event/Reference Safety Information 
An adverse event is considered unlisted if the nature or severity is not consistent 
with the applicable product reference safety information. For a medicinal 
product(s) with a marketing authorization, the expectedness of an adverse event 
will be determined by whether or not it is listed in the applicable product 
information.  
 
 
 
For DARZALEX™ (daratumumab),the expectedness of an adverse event will be 
determined by whether or not it is listed in the Investigator's Brochure 
 
4. 
Special Reporting Situations  
Safety events of interest for a Janssen medicinal product that require expediting 
reporting and/or safety evaluation include, but are not limited to: 
 
Drug exposure during pregnancy (maternal and paternal) 
 
Overdose of a Janssen medicinal product  
 
Exposure to a Janssen medicinal product from breastfeeding  
 
Suspected abuse/misuse of a Janssen medicinal product 
 
Inadvertent or accidental exposure to a Janssen medicinal product  
 
Any failure of expected pharmacological action (i.e., lack of effect) of a 
Janssen medicinal product 
 
Medication error involving a Janssen medicinal product (with or without 
patient exposure to the Janssen medicinal product, e.g., name confusion) 
 
Suspected transmission of any infectious agent via administration of a 
medicinal product 
 
 Unexpected therapeutic or clinical benefit from use of a Janssen medicinal 
product 
 
These safety events may not meet the definition of an adverse event; 
however, from a Janssen Scientific Affairs, LLC perspective, they are treated 
in the same manner as adverse events. Special situations should be recorded 
on the Adverse Event page of the CRF. 

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Any special situation that meets the criteria of a serious adverse event should 
be recorded on a Serious Adverse Event Report Form and be reported to 
Janssen Scientific Affairs, LLC within 24 hours of becoming aware of the 
event. 
 
Pregnancy  
 
All initial reports of pregnancy must be reported to Janssen Scientific Affairs, 
LLC by the PRINCIPAL INVESTIGATOR within 24 hours of becoming 
aware of the event using the Serious Adverse Event Form. Abnormal pregnancy 
outcomes (e.g. spontaneous abortion, fetal death, stillbirth, congenital anomaly, 
ectopic pregnancy) are considered serious adverse events and must be reported 
using the Serious Adverse Event Form.  
 
Any subject who becomes pregnant during the study must be promptly 
withdrawn from the study and discontinue further study treatment. 
 
Because the effect of the Janssen medicinal product on sperm is unknown, 
pregnancies in partners of male subjects exposed to a Janssen medicinal product 
will be reported by the PRINCIPAL INVESTIGATOR within 24 hours of their 
knowledge of the event using the Serious Adverse Event Form.  Depending on 
local legislation this may require prior consent of the partner. 
 
Follow-up information regarding the outcome of the pregnancy and any postnatal 
sequelae in the infant will be required. 
 
5. 
Maintenance of Safety Information 
All safety data should be maintained in a clinical database in a retrievable format. 
The PRINCIPAL INVESTIGATOR shall provide all adverse events, both serious 
and non-serious, in report format. However, in certain circumstances more 
frequent provision of safety data may be necessary, e.g. to fulfill a regulatory 
request, and as such the data shall be made available within a reasonable 
timeframe at Janssen Scientific Affairs, LLC request. 
 
6. 
Procedures for Reporting Safety Data and Product Quality Complaints 
(PQCs) for Janssen Medicinal Products to Janssen Scientific Affairs, LLC 
All adverse events and special situations, whether serious or non-serious, related 
or not related, following exposure to a Janssen medicinal product are to be 
documented by the investigator and recorded in the CRF and in the subject’s 
source records. Investigators must record in the CRF their opinion concerning the 
relationship of the adverse event to a Janssen medicinal product.  
All (serious and non-serious) adverse events reported for a Janssen medicinal 
product should be followed-up in accordance with clinical practice. 
 
6.1. 
SAEs, Adverse Events of Special Interest, and Special Reporting 
Situations 

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All serious adverse events that have not resolved by the end of the study, or that 
have not resolved upon discontinuation of the subject's participation in the study, 
must be followed until any of the following occurs: 
 
The event resolves 
 
The event stabilizes 
 
The event returns to baseline, if a baseline value/status is available 
 
The event can be attributed to agents other than the study drug or to 
factors unrelated to study conduct 
 
It becomes unlikely that any additional information can be obtained 
(subject or health care practitioner refusal to provide additional information, lost 
to follow-up after demonstration of due diligence with follow-up efforts) 
 
The PRINCIPAL INVESTIGATOR will transmit all SAEs, adverse events of 
special interest, and special situations following exposure to a Janssen product 
under study in a form provided by Janssen Scientific Affairs, LLC in accordance 
with Section 10,Transmission Methods, in English within 24-hours of becoming 
aware of the event(s). 
 
In the event the study is blinded, the PRINCIPAL INVESTIGATOR will submit 
an unblinded SAE or pregnancy exposure report to Janssen Scientific Affairs, 
LLC. 
 
All follow-up information for serious adverse events that are not resolved at the 
end of the study or by the time of patient withdrawal must be reported directly by 
the PRINCIPAL INVESTIGATOR, within 24 hours becoming aware, to 
Janssen Scientific Affairs, LLC using the Janssen Scientific Affairs, LLC Serious 
Adverse Event Report  
 
All available clinical information relevant to the evaluation of a related SAE or 
special situation is required. 
 
 
The PRINCIPAL INVESTIGATOR is responsible for ensuring that these 
cases are complete and if not are promptly followed-up. A safety report is not 
considered complete until all clinical details needed to interpret the case are 
received. Reporting of follow-up information should follow the same timeline as 
initial reports. 
 
 
Copies of any and all relevant correspondences with regulatory 
authorities and ethics committees regarding any and all serious adverse events, 
irrespective of association with the Janssen Product under study, are to be 
provided to Janssen Scientific Affairs, LLC using a transmission method in 
Section 10 from this Exhibit within 24 hours of such report or correspondence 
being sent to applicable health authorities. 
 
 
 
6.2. 
Non-Serious AEs 

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All non-serious adverse events should be reported to Janssen Scientific Affairs, 
LLC according to the timeframe outlined in the Research Funding Agreement 
section entitled Reporting of Data. 
 
6.3. 
PQC Reporting 
A PQC may have an impact on the safety and efficacy of the product. Timely, 
accurate, and complete reporting and analysis of PQC information from studies 
are crucial for the protection of patients, investigators, and Janssen Scientific 
Affairs, LLC, and are mandated by regulatory agencies worldwide. Janssen 
Scientific Affairs, LLC has established procedures in conformity with regulatory 
requirements worldwide to ensure appropriate reporting of PQC information. Lot 
and/or Batch #s shall be collected or any reports failure of expected 
pharmacological action (i.e., lack of effect). The product should be quarantined 
immediately and if possible, take a picture. 
 
All initial PQCs involving a Janssen medicinal product under study must be 
reported to Janssen Scientific Affairs, LLC by the PRINCIPAL 
INVESTIGATOR within 24 hours after being made aware of the event. The 
Janssen contact will provide additional information/form to be completed. 
 
If the defect for a Janssen medicinal product under study is combined with either 
a serious adverse event or non-serious adverse event, the PRINCIPAL 
INVESTIGATOR must report the PQC to Janssen Scientific Affairs, LLC 
according to the serious adverse event reporting timelines.  A sample of the 
suspected product should be maintained for further investigation if requested by 
Janssen Scientific Affairs, LLC. 
 
7. 
Reporting Procedures for Reporting Safety Data and Product Quality Complaints 
(PQCs) for Non-Janssen Medicinal Products  
For SAEs, special reporting situations and PQCs following exposure to a non-Janssen 
medicinal product under study, the PRINCIPAL INVESTIGATOR should notify the 
appropriate regulatory/competent authority or the manufacturer of that medicinal product 
(in the absence of appropriate local legislation) as soon as possible. 
 
8. 
Transmission Methods 
The following methods are acceptable for transmission of safety information to Janssen 
Scientific Affairs, LLC: 
 
Electronically via Janssen SECURE Email service (preferred) 
 
For business continuity purposes, if SECURE Email is non-functional: 
o Facsimile (fax), receipt of which is evidenced in a successful fax 
transmission report 
 
Telephone (if fax is non-functional). 
 
Please use the contact information and process information provided by Janssen 
Scientific Affairs, LLC.  
 
 

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11.0 
Treatment Evaluation 
11.1  
Terms and definitions 
Definitions for EMD response is similar to those used for patients with lymphoma 
(Cheson et al. Revised Response Criteria for Malignant Lymphoma). EMD 
measurements should be taken from the CT portion of the PET/CT, or MRI scans, or 
dedicated CT scans where applicable. For patients with only skin involvement, skin 
lesions should be measured with a ruler. Measurement of tumor size will be determined 
by adding the sum of the products of the maximal perpendicular diameters of measured 
lesions (SPD). 
Response is based on CT alone or the CT component of PET/CT or MRI where 
applicable and the PET. 
PET/CT scans are required at baseline for all patients with EMD. 
 
 
 
M-protein: synonyms include M-spike, monoclonal protein and myeloma protein, 
paraprotein, M-component. 
 
Serum M-protein level is quantitated using densitometry on SPEP except in cases 
where the SPEP is felt to be unreliable.   
 M-proteins migrating in the -region (usually IgA M-proteins)  
 Cases in which the M-spike is so large and narrow on agarose (some 
specimens >4 g/dL) that they underestimate the actual immunoglobulin level 
(by greater than 1500 mg/dL) due to technical staining properties of the 
agarose gel. 
 Cases in which there are multiple peaks of same monoclonal protein 
(aggregates or dimers) 
 
If SPEP is not available or felt to be unreliable (above examples) for routine M-
protein quantitation, then quantitative immunoglobulin levels derived from 
nephelometry or turbidometry can be accepted.  However, this must be explicitly 
reported at baseline, and only nephelometry can be used for that patient to assess 
response. SPEP derived M-spike values and quantitative nephelometric 
immunoglobulin values cannot be used interchangeably.   
 
Urine M-protein measurement is estimated using 24-h UPEP only.  Random or 24 h 
urine tests measuring kappa and lambda light chain levels are not reliable and are not 
recommended. 
 
FLC estimation is currently carried out using the serum FLC assay (Freelite, The 
Binding Site Limited, UK).  Patients with kappa/lambda FLC ratio <0.26 are defined 
as having monoclonal lambda FLC and those with ratios >1.65 as having a 
monoclonal kappa FLC.  The monoclonal light chain isotype is considered the 
involved FLC isotype, and the opposite light chain type as the uninvolved FLC type.  
 
 
Response terms: The following response terms will be used: stringent Complete 
Response (sCR), complete response (CR), very good partial response (VGPR), partial 

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response (PR), Minimal Response (MR), stable disease (SD), progressive disease 
(PD) and relapse from CR (RFCR).  
 
In addition, for each response category, there will be an “unconfirmed” response 
category, which will be for internal use, for the purpose of guiding decision making 
and test ordering. These designations will applied at the time of the first measurement 
at which the quantitative aspect of the response category has been satisfied without 
the confirmation step having been satisfied. The designation “u” will precede the 
standard abbreviations, and will include usCR, uCR, uVGPR, uPR, uMR, uPD.  
 
 
Measurable disease: Patients who have a measurable serum or urine M-protein.  
 
o Serum M-protein ≥1 g/dl  
o Urine M-protein ≥ 200 mg/24 h 
o Serum FLC assay: Involved FLC level ≥  10 mg/dl provided serum FLC ratio is 
abnormal 
 
The serum free light chain (FLC) assay is of particular use in monitoring response to 
therapy in patients who have oligo-secretory or non-secretory disease and should be used 
in assessing response only if the baseline serum and/or urine M proteins are not 
“measurable” as above, and the baseline level of the involved FLC is ”measurable.” 
When using this assay, it is important to note that the FLC levels vary considerably with 
changes in renal function and in patients with renal insufficiency, the levels of both the 
kappa and lambda may remain elevated, but the ratio normalizes with achievement of 
CR. Thus both the level of the involved and the uninvolved FLC isotype (i.e., the 
involved/uninvolved ratio or involved-uninvolved difference) should be considered in 
assessing response. Patients included on the study on the basis of FLC  alone (i.e. no 
measurable serum/urine) should be the only ones who are evaluated using FLC 
response criteria. The others should follow usual criteria and ignore FLC results. 
 
 
Evaluable disease: Patients who do not have a “measurable” serum M-spike, serum 
free light chain, or urine M-spike. 
 
 
Oligosecretory myeloma: Patient with multiple myeloma who has NEVER had 
“measurable” serum M-spike or urine M-spike, but has had a detectable monoclonal 
protein in his/her serum and/or urine and/or measurable serum free light chain.  
 
 
Non-secretory myeloma: Patient with multiple myeloma who has NEVER had a 
detectable monoclonal protein in his/her serum and/or urine. 
 
11.2  
Clarification of test indications 
 
Listed below are the minimal required tests required to assess response based on the 
characteristics of their disease at on study.   
 
Table 11.2 
Tests  Required To Assess Response (Must Be Done At Each Disease 
Measurement Visit except as indicated1,2) 
On Study Baseline Value 
SPEP 
24 hr UPEP2  
Ig FLC 

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Serum M-spike ≥1 g/dl, and urine M-spike≥ 200 
mg/24 hrs
X 
X 
 
Serum M-spike ≥ 1 g/dl, but urine M-spike < 200 
mg/24 hrs
X 
 
 
Serum M-spike<1 g/dl, and urine M-spike≥ 200 
mg/24 hrs
 
X 
 
Serum M-spike < 1 g/dl, urine M-spike < 200 
mg/24 hrs, but involved Ig FLC is ≥10 mg/dL
 
 
X 
1  Immunofixation studies of both serum and urine are required to document CR 
regardless of registration values, and in addition FLC measurement and bone marrow 
immunophenotyping is required to document sCR. 
2  For serum measurable patients, 24 hour urine does not need to be confirmed (i.e. 
repeated after documented response) for any response category 
3  Bone marrow biopsy results do not need to be confirmed (i.e. repeated after 
documented response). 
 
11.3 
Confirmed response  
 
In order to be classified as a hematologic response, confirmation of serum monoclonal 
protein, serum immunoglobulin free light chain (when primary determinant of response) 
and urine monoclonal protein (when primary determinant of response) results must be 
made by verification on two consecutive determinations.   
 
Bone marrow aspirate and biopsy are only required to document or confirm CR 
or sCR, except for patients with evaluable disease only, where a bone marrow is 
required to document all response categories including progression. However, a 
second confirmatory bone marrow is not required to confirm response. 
 
Radiographic studies are not required to satisfy these response requirements, 
however, if radiographic studies were performed there should be no evidence of 
progressive or new bone lesions. 
 
Appropriate tests required to document and confirm response are listed in Table 11.2 
 
11.4 
Bone progression  
 
Caution must be exercised to avoid rating progression or relapse on the basis of variation 
of radiologic technique alone.  Compression fracture does not exclude continued response 
and may not indicate progression.  When progression is based on skeletal disease alone, it 
should be discussed with the study chair before removing the patient from the study.  
 
 11.5 
 Response and Progression 
 
Criteria for response and progression are listed in Table 11.5. Progressive disease for all 
patients as defined in Table 11.5.  
 
 
 
 
 
 

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Table 11. 5 
CATEGORY
RESPONSE CRITERIA a
Stringent complete 
response (sCR)e   
 
 
CR as defined below plus all of the following 
 
Normal serum FLC ratio  
 
Absence of clonal cells in bone marrow by immunohistochemistry or 
immunofluorescence b 
 
Not applicable for those patients who do not have a “measurable” serum M-
spike, serum free light chain, or urine M-spike at baseline
Complete response 
(CR) 
 
Negative immunofixation of the serum and urine  
 
< 5% plasma cells in bone marrow  
 
Disappearance of any soft tissue plasmacytomas  
 
If at on study, the only measurable parameter was  FLC, normalization of 
FLC ratio 
 
For patients with extramedullary plasmacytoma present at baseline: a) FDG-
avid or PET positive prior to therapy: Mass of any size permitted if PET 
negative and b) Variably FDG-avid or PET negative: Regression to normal 
size on CT. For patients with only skin involvement, these same criteria apply 
to skin lesions measured with a ruler. 
 
For patients with plasma cell leukemia at baseline, complete absence of 
circulating plasma cells
Very good partial 
response (VGPR)d,e 
 
 
PR as defined below plus all of the following: 
 
Serum and urine M-component detectable by immunofixation but not on 
electrophoresis or 
 
If at on study, serum measurable, ≥ 90% or greater reduction in serum M-
component  plus urine M-component <100 mg per 24 h  
 
If at on study, the only measurable parameter was  FLC, ≥ 90% or greater 
reduction in the difference between involved and uninvolved free light chain 
levels 
 
Not applicable for those patients who do not have a “measurable” serum M-
spike, serum free light chain, or urine M-spike at baseline
Partial Response 
(PR) 
 
One of the following: 
 If at on study, serum and urine measurable, a ≥ 50% reduction of serum 
M-protein and reduction in 24-h urinary M-protein by ≥ 90% or to 
<200 mg per 24 h  
 If at on study, only serum measurable (but urine not), a ≥ 50% reduction 
of serum M-protein  
 If at on study, urine measurable (but serum not), a reduction in 24-h 
urinary M-protein by ≥ 90% or to <200 mg per 24 h  
 If at on study, the only measurable parameter was  FLC, a ≥ 50% decrease 
in the difference between involved and uninvolved FLC levels   
 
In addition to the above criteria, if a plasmacytoma present at baseline, ≥ 50% 
reduction in the size of soft tissue plasmacytomas is also required 
 
For patients with extramedullary plasmacytoma present at baseline: ≥50% 
decrease in SPD of up to 6 largest dominant masses and a) FDG-avid or PET 
positive prior to therapy: one or more PET positive at previously involved 
sites OR b) Variably FDG-avid or PET negative: regression on CT or by 
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Minor Response 
(MR) 
 
≥25% but < 49% reduction of serum M-protein and reduction in 24h urine M-
protein by 50-89%, which still exceeds 200 mg per 24 h 
 
In addition to the above criteria, if  a plasmacytoma present at baseline, 25-
49% reduction in the size of soft tissue plasmacytomas is also required 
Stable disease (SD) 
Not meeting criteria for CR, VGPR, PR, MR or progressive disease
Progressive disease 
(PD) 
Any one or more of the following:  
 
Increase of 25% from lowest value ind: 
 Serum M-component (absolute increase must be ≥ 0.5 g/dl)c  
 Serum M-component increase ≥ 1 g/dl, if lowest M component was ≥ 5 
g/dl 
 Urine M-component (absolute increase must be ≥ 200 mg/24 h) c 
 If at on study, the only measurable parameter was  FLC, the difference 
between involved and uninvolved FLC levels (absolute increase must be 
>10 mg/dl) c  
 Bone marrow plasma cell percentage (absolute % must be ≥10%)c 
 Appearance of a new lesion(s), ≥50% increase from nadir in SPD of more 
than one lesion, or ≥50% increase in longest diameter of a previous lesion 
>1 cm in short axis. Lesions PET positive if PET positive prior to therapy  
≥50% increase in circulating plasma cells (minimum of 200/mcl) 
Or any one or more of the following felt related to the underlying clonal plasma cell 
proliferative disorder 
 Development of new soft tissue plasmacytomas or bone lesions 
 Hypercalcemia (≥11.5 mg/dl) 
 Decrease in hemoglobin of ≥2 g/dl 
 Serum creatinine level ≥2 mg/dll
a All response categories require two consecutive assessments made at anytime before the institution of 
any new therapy; complete and PR, MR and SD categories also require no known evidence of progressive 
or new bone lesions if radiographic studies were performed. Radiographic studies are not required to 
satisfy these response requirements. Bone marrow assessments need not be confirmed. Each category, 
except for stable disease, will have a working subcategory of “unconfirmed” [prefix ‘u”] to designate first 
time point at which response category MAY have been achieved if confirmed. 
b Presence/absence of clonal cells is based upon the k/  ratio. An abnormal k/  ratio by 
immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells for analysis. 
An abnormal ratio reflecting presence of an abnormal clone is k/  of >4:1 or <1;2.  
c  Positive immunofixation alone in a patient previously classified as CR will not be considered 
progression. 
d In the case where a value is felt to be a spurious result per physician discretion (for example, a possible 
lab error), that value will not be considered when determining the lowest valueeDoes not apply to EMD or 
PCL 
 
 
12.0 
Descriptive Factors  
 
12.1  
Prior bortezomib treatment: Yes vs. no. 
12.2  
Prior stem cell transplant:  Yes vs. no. 

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12.3 
Parameters of hematologic response (pick all that apply): serum M-spike ≥ 1 g/Dl 
(distinguish between SPEP measurement versus quantitative IgA measurement), serum 
immunoglobulin free light chain ≥10 mg/dL, urine M-spike ≥200 mg/24 hours. 
12.4 
Prior carfilzomib treatment:  Yes vs. no 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient   
 
13.1 
Patients who are sCR, CR, VGPR, PR, MR or SD (or usCR, uCR, uVGPR, uPR, uMR) 
will continue treatment per protocol. 
 
13.2     Arm A only (Permanently Closed to Accrual:  Patients who do not achieve an MR (or 
uMR) by end of cycle 2 or a PR (or uPR) by end of cycle 4 (these responses can be 
unconfirmed) and those who develop progressive disease (confirmation of PD is not 
required) while receiving ixazomib alone will continue treatment with the addition of 
dexamethasone. 
 
13.3 
Arm A:  Patients who develop progressive disease (confirmed or unconfirmed per 
physician discretion) despite addition of dexamethasone while receiving therapy will 
go to the event-monitoring phase per Section 18.0.    
 
 
Arms B, C, D, E:  Patients who develop progressive disease (confirmed or unconfirmed 
per physician discretion) at any time will go to event-monitoring phase per Section 18.0. 
 
 
 
Note: Patients who develop progressive disease can be re-registered and move to a 
different arm. 
 
13.4 
Patients who go off protocol treatment for reasons other than PD will go to event-
monitoring phase per Section 18.0. 
   
13.5 
Criteria for Patient Discontinuation of Protocol Treatment 
 
Patients may discontinue protocol treatment and go to the event-monitoring phase per 
Section 18.0 for the following reasons: 
 
 
Progressive multiple myeloma despite addition of dexamethasone 
 
Patient withdraws consent to continue in the trial 
 
Patient develops an intercurrent illness that precludes further participation, or 
requires a prohibited concomitant treatment 
 
The Investigator withdraws the patient in the patient’s best interests 
 
Administrative reasons (e.g., the patient is transferred to hospice care) 
 
An adverse event, which in the opinion of the Investigator, precludes further trial 
participation  
 
All attempts should be made to complete the End of Treatment procedures per Section 
4.0 if a patient discontinues protocol treatment early. 
 
13.6 
Criteria for Study Discontinuation 
 

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The study may be temporarily or permanently discontinued at any site and at any time.  
Reasons for study discontinuation may include, but are not limited to, the following: 
 
 
Determination of unexpected, significant, or unacceptable risk to patients 
 
Poor enrollment 
 
Non-compliance with the protocol, Good Clinical Practice guidances or other 
regulatory requirements by the Investigator(s) 
 
Request to discontinue the trial by a regulatory or health authority or an IRB 
 
 Insufficient complete and/or evaluable data  
 
Manufacturing difficulties/concerns  
 
Plans to modify, suspend, or discontinue the development of the drug 
 
All Investigators and the requisite regulatory authorities will be notified if the study is 
suspended or terminated for safety reasons.  In the case of such termination, the 
Investigator will notify the IRB. 
 
13.7 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry.  
The patient may continue treatment off-protocol at the discretion of the physician as long 
as there are no safety concerns, and the patient was properly registered. The patient will 
go directly to the event-monitoring phase of the study (or off study, if applicable).  
 
 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted.  Event monitoring will be required per Section 18.0 
of the protocol.  
 
If the patient never received treatment, on-study material must be submitted.  No 
further data submission is necessary. 
 
13.8 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable.  All data up until the point of confirmation of a major violation must be 
submitted.  The patient will go directly to the event-monitoring phase of the study.  The 
patient may continue treatment off-protocol at the discretion of the physician as long as 
there are no safety concerns, and the patient was properly registered.  Event monitoring 
will be required per Section 18.0 of the protocol. 
 
13.9 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given.  On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted.  No further data submission is necessary. 
 
14.0 
Body Fluid Biospecimens   
 
No correlative studies planned 
 
15.0 
Drug Information 
 
15.1 
Ixazomib (MLN9708, Ninlaro®)  
 

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15.11 Background: Ixazomib   is a second-generation small molecule inhibitor of the 
20S proteasome that is under development for the treatment of multiple 
myeloma, other plasma cell dyscrasias, nonhematologic malignancies, and 
pediatric acute lymphoblastic leukemia and lymphoma. 
 
 
Ixazomib (MLN2238) refers to the biologically active, boronic acid form of the drug 
substance, ixazomib citrate. The transition to MLN2238 occurs in any aqueous 
system. 
 
15.12 Formulation: The ixazomib capsule drug product formulation consists of drug 
substance, microcrystalline cellulose, talc, and magnesium stearate.  Seven 
different capsule strengths are manufactured: 0.2, 0.5, 2.0, 2.3, 3.0, 4.0, and 5.5 
mg; each capsule strength has a unique color. Dosage strength is stated as 
ixazomib (the active boronic acid). Ixazomib capsules are individually packaged 
in blisters. 
 
 
Matching placebo capsules have been manufactured for the 2.3, 3.0, 4.0, and 5.5 
mg ixazomib capsules. The placebo capsules contain microcrystalline cellulose, 
talc, and magnesium stearate and are identical in color and size to the 
corresponding active dose. 
 
15.13 Preparation and storage:     Ixazomib capsules (0.2 mg, 0.5 mg, 2 mg), 
individually packaged in blisters:        
Do not store above 25°C. Do not freeze. Ixazomib capsules (2.3 mg, 3 mg, 4 mg, 
and 5.5 mg), individually packaged in blisters:  Do not store above 30°C. Do not 
freeze. 
 
 
Ixazomib that is dispensed to the patient for take-home dosing should remain in 
the blister packaging until the point of use. The investigative site is responsible 
for providing the medication to the patient in units that comprise the correct daily 
dose configurations.  Capsules should remain in the blisters until the point of use.  
Ixazomib capsules must be administered as intact capsules and must not be 
opened or manipulated in any way.  Comprehensive instructions should be 
provided to the patient in order to ensure compliance with dosing procedures. 
Patients will be instructed to store the medication in the refrigerator until the time 
of use. Reconciliation will occur accordingly when the patient returns for their 
next cycle of therapy. Any extremes in temperature should be reported as an 
excursion and will be managed on a case by case basis.  Returned unused 
capsules should be discarded in a proper biohazard container. 
 
Ixazomib is an anticancer drug. As with other potentially toxic compounds, 
caution should be exercised when handling ixazomib. It is recommended to wear 
gloves and protective garments during preparation when dispensed in clinic. 
(Please refer to published guidelines regarding the proper handling and disposal 
of anticancer agents. 
 
15.14 Administration:  Ixazomib capsules must be administered as intact capsules and 
are not intended to be opened or manipulated in any way.  Capsules should be 
taken on an empty stomach with approximately 8 oz (1 cup) of water at least 1 
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Ixazomib should not be taken if the patient has had a serious allergic reaction to 
boron or boron containing products. 
 
Health care providers should instruct patients and caregivers that only one dose 
of ixazomib should be taken at a time, and only at the prescribed interval (e.g. 
one capsule, once a week, on Days 1,8, and 15 of a 28-day cycle). The 
importance of carefully following all dosage instructions should be discussed 
with patients starting treatment. 
 
15.15 Pharmacokinetic (PK) information:   
a) Absorption:  After oral dosing, ixazomib is rapidly absorbed with a median 
Tmax of 1 hour.  The lack of a discernible relationship between BSA and ixazomib 
clearance over a relatively wide BSA range (1.4-2.6 m2) indicates that total 
systemic exposure (AUC) following fixed dosing should be independent of the 
individual patient’s BSA. The absolute oral bioavailability of ixazomib is ~58%.  
A high-fat meal decreased both the rate and extent of absorption.  Therefore, 
ixazomib should be administered on an empty stomach.   
b) Distribution: The steady state volume of distribution is large and is estimated 
to be 543 L.  Protein binding is 99% to plasma proteins and the extent of binding 
is not altered by severe renal impairment, moderate-severe hepatic impairment. 
c) Metabolism:  Metabolism is the primary route for elimination of ixazomib by 
both CYP and non-CYP enzymes. CYP3A4 and 1A2 comprise the major CYP 
isozymes that contribute to ixazomib metabolism. 
d) Excretion: The mean terminal half-life is 9.5 days.  Renal elimination is a 
minor clearance pathway for ixazomib.  Dosing adjustment is not required in 
patients with mild and moderate renal impairment in studies. However, in a 
dedicated renal impairment study (C16015), unbound AUC0-last was 38% higher 
in patients with severe renal impairment or end-stage renal disease (ESRD) 
requiring dialysis as compared to patients with normal renal function.  
Accordingly, a reduced starting dose of ixazomib is recommended in patients 
with severe renal impairment and ESRD requiring dialysis.  Ixazomib is not 
dialyzable and therefore can be administered without regard to the timing of 
dialysis.  Unbound systemic exposures of ixazomib are 27% higher in patients 
with moderate or severe hepatic impairment as compared to patients with normal 
hepatic function.  A reduced starting dose of ixazomib is recommended for 
patients with moderate or severe hepatic impairment. 
 
 
15.16 Potential Drug Interactions:   
The PK of ixazomib was similar with and without coadministration of 
clarithromycin, a strong CYP3A inhibitor, and therefore no dose adjustment is 
necessary when ixazomib is administered with CYP3A 
inhibitors. In the population PK analysis, coadministration of strong CYP1A2 
inhibitors did not affect ixazomib clearance. Thus, no dose adjustment is required 
for patients receiving strong CYP1A2 inhibitors. In a clinical rifampin DDI 
study, ixazomib Cmax and AUC0-last were reduced in the presence of rifampin by 
approximately 54% and 74%, respectively. As a result, the coadministration of 
strong CYP3A inducers with ixazomib is not recommended.  Ixazomib is neither 
a time-dependent nor reversible inhibitor of CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 
2D6, or 3A4/5, therefore the potential for ixazomib to produce DDIs via CYP 

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isozyme inhibition is low.  Ixazomib did not induce CYP1A2, CYP2B6, and 
CYP3A4/5 activity.  The potential for ixazomib to cause DDIs with substrates or 
inhibitors of P-gp, BCRP, MRP2, MATE-1, MATE2-K, OCT2, OAT1, OAT3, 
and OATPs is low. 
 
Pharmacokinetic parameters for ixazomib coadministered with 
lenalidomide and dexamethasone (LenDex) are like those observed when 
ixazomib is administered as a single agent. This suggests that there is no 
readily apparent effect of coadministration of LenDex on the clinical PK 
of ixazomib. 
 
Ixazomib should not be taken if the patient has had a serious allergic 
reaction to boron or boron containing products. 
 
15.17 Known potential toxicities:  See the current version of the Investigator’s 
Brochure for more complete information including potential risks, as well as 
recommendations for clinical monitoring and medical management of toxicity. 
 
Very common (≥10%): peripheral edema, peripheral neuropathy, 
peripheral sensory neuropathy, skin rash, diarrhea, constipation, nausea, 
vomiting, thrombocytopenia, neutropenia, back pain, eye disease, upper 
respiratory infection 
Common (≥1% to <10%):  Herpes zoster, hepatic insufficiency, blurred 
vision, conjunctivitis, xerophthalmia, pneumonia 
Uncommon (≥0.1% to <1%):  cholestatic hepatitis, hepatocellular 
hepatitis, hepatotoxicity, liver steatosis, peripheral motor neuropathy, 
reversible posterior leukoencephalopathy syndrome, Stevens-Johnson 
syndrome, Sweet’s syndrome, thrombotic thrombocytopenic purpura, 
transverse myelitis, tumor lysis syndrome, thrombotic microangiopathy 
 
 
Herpes zoster – antiviral prophylaxis should be considered in patients 
being treated with ixazomib to decrease the risk of herpes zoster 
reactivation. 
Overdose – There is no known specific antidote for ixazomib overdose.  .  
Symptoms of overdose are generally consistent with the known risks of 
ixazomib and reports have been associated with serious adverse events 
such as nausea, aspiration pneumonia, multiple organ failure, and death.   
In the event of an overdose in blinded studies, study medication 
assignment should be unblinded immediately.  The clinician should 
consider admitting the patient to the hospital for IV hydration, monitoring 
for adverse drug reactions, monitoring of vital signs, and appropriate 
supportive care.  Gastric lavage may be considered, but it should be kept in 
mind that ixazomib absorption is rapid.  Ixazomib is not readily dialyzable. 
 
15.18 Drug procurement:  Investigational product will be supplied free of charge to 
trial participants by Millennium Pharmaceuticals, Inc. 
 
 
 
 

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15.19  Nursing Guidelines 
 
15.191 Capsules must be administered intact and should not be opened or 
manipulated in any way. Additionally, capsules should remain in the 
blister packs until they are ready to be taken.  It is recommended to wear 
gloves and protective garments during preparation when dispensed in 
clinic 
 
15.192 Capsules should be taken on an empty stomach (either 1 hour before or 2 
hours after meals) with 8 oz of water. Make sure that patients are 
instructed to take exactly as directed to avoid overdose. 
 
15.193 Cytopenias have been observed. Monitor CBC w/diff.  Instruct patient to 
report any signs or symptoms of infection or bleeding to the study team. 
 
15.194 GI side effects have been seen (nausea, diarrhea, vomiting), treat 
symptomatically and monitor for effectiveness of intervention. 
 
15.195 Rash has been seen. Instruct patients to report any rash to study team. 
 
15.196 Assess patients concomitant medications, including over the counter and 
supplements. Ixazomib is metabolized through both CYP and non-CYP 
enzymes, and drug to drug interactions exist. Instruct patients not to start 
any new medications or supplements without checking with the study 
team first. 
 
15.197 Fatigue has been seen.  Instruct patient in energy conserving lifestyle. 
 
15.198 Insomnia can be seen.  Treat symptomatically and monitor for 
effectiveness. 
 
15.199a  Patients who have had an allergic reaction to boron or boron containing 
products should not take MLN9708. 
 
15.199b The following rare but life threatening conditions have been seen with 
agent: CHF, liver failure, TTP, TLS, renal failure, bowel obstruction, and 
RPLS, transverse myelitis, progressive multifocal leukoencephalopathy.  
Monitor labs closely, instruct patient to report any new or worsening 
symptoms to the study team and provide further assessment based on 
symptoms. 
 
15.199c Monitor LFT’s. Rarely hepatotoxicity has been seen. 
 
15.2 
Daratumumab (Darzalex®, Darzalex Faspro™, JNJ-54767414) 
  
Please consult the most current Investigator’s Brochure and package insert for complete 
drug information.  
 
15.21 Background: Daratumumab is an immunoglobulin G1 kappa (IgG1κ)  

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human monoclonal antibody against CD38 antigen, produced in a mammalian 
cell line (Chinese Hamster Ovary [CHO]) using recombinant DNA technology. 
The molecular weight of daratumumab is approximately 148 kDa.  
CD38 is a transmembrane glycoprotein (48 kDa) expressed on the surface of 
hematopoietic cells, including multiple myeloma and other cell types and tissues 
and has multiple functions, such as receptor mediated adhesion, signaling, and 
modulation of cyclase and hydrolase activity. Daratumumab is an IgG1κ human 
monoclonal antibody (mAb) that binds to CD38 and inhibits the growth of CD38 
expressing tumor cells by inducing apoptosis directly through Fc mediated cross 
linking as well as by immune-mediated tumor cell lysis through complement 
dependent cytotoxicity (CDC), antibody dependent cell mediated cytotoxicity  
(ADCC) and antibody dependent cellular phagocytosis (ADCP). Myeloid derived 
suppressor cells (MDSCs) and a subset of regulatory T cells (CD38+Tregs) 
expresses CD38 and is susceptible to daratumumab mediated cell lysis. 
 
 
15.22 Formulation:  
 
     . Study drug labels will contain information to meet the applicable 
regulatory requirements. Each vial will contain a study-specific label 
with a unique identification number  
 
15.23 Preparation and storage:  
 
  
 
Daratumumab IV and SC study drug vials must be stored in the original 
carton in a refrigerator ranging from 2°C to 8°C and must not be utilized 
after the expiry date printed on the label. The product must be protected 
from light and must not be frozen. Daratumumab IV or SC does not 
contain preservatives; therefore, any unused portion remaining in the vial 
must be discarded.  
 
Daratumumab IV will be diluted in a sterile, pyrogen-free physiological 
saline solution (0.9% NaCl) prior to IV administration.   
 
Daratumumab and hyaluronidase-fihj SC injection is directly drawn from 
the vial into a syringe and is compatible with polypropylene or 
polyethylene syringe material; polypropylene, polyethylene, or polyvinyl 
chloride (PVC) subcutaneous infusion sets; and stainless steel transfer 
and injection needles.  After the solution is withdrawn into the syringe, 
replace the transfer needle with a syringe cap.  To avoid needle clogging, 
attach the hypodermic injection needle or subcutaneous infusion set to 
the syringe immediately prior to injection. 
 
 
15.24 Administration:   
 
Administer pre-infusion and post-infusion medications. Refer to section 
7 of the protocol. 
 
IV administration: Administer the diluted solution by intravenous 
infusion using an infusion set fitted with a flow regulator and with an in-
line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) 

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filter (pore size 0.22 or 0.2 micrometer). Polyurethane (PU), 
polybutadiene (PBD), PVC, PP or PE administration sets must be used. 
o Infusion should be completed within 15 hours. 
o Refer to section 7 of the protocol for infusion rates 
o Do not store any unused portion of the infusion solution for 
reuse. Any unused product or waste material should be disposed 
of in accordance with local requirements. 
o Do not infuse daratumumab concomitantly in the same 
intravenous line with other agents. 
 
 
15.25 Pharmacokinetic information for IV administration: 
The pharmacokinetics (PK) of daratumumab following intravenous 
administration were evaluated in patients with relapsed and refractory multiple 
myeloma at dose levels from 0.1 mg/kg to 24 mg/kg, and included the 
recommended 16 mg/kg dose and regimen.  Over the dose range from 1 to 24 
mg/kg, increases in area under the concentration-time curve (AUC) were more 
than dose-proportional  The mean (SD) predose (trough) serum concentration at 
the end of weekly dosing was 573 (332) µg/mL. 
 
The mean (SD) predose (trough) serum concentration at the end of weekly dosing 
was 573 (332) µg/mL. At the recommended dose of 16 mg/kg, the mean ± SD 
central volume of distribution was 4.7 ± 1.3 L when daratumumab was 
administered as monotherapy and 4.4 ± 1.5 L when daratumumab was 
administered as combination therapy. 
 
Daratumumab showed target-mediated disposition with rapid clearance (CL) at 
low doses and slower CL at higher doses and with multiple doses.  Following the 
first administration at the recommended dose of 16 mg/kg, non-compartment 
model derived CL was 0.42 ± 0.42 mL/hr/kg and the half-life (t1/2) was 9.0 ± 4.3 
days.   
 
  The model-derived half-life associated with linear elimination was 
approximately 18±9 days.    Apparent steady state seems to be reached 
approximately 5 months into the every 4 week 
 dosing period of the 16 mg/kg with a schedule of weekly for 8 weeks, every 2 
weeks for 16 weeks, and then every 4 weeks thereafter.    
  
Following the administration of the recommended dose of 1,800 mg 
daratumumab and 30,000 units hyaluronidase subcutaneously once weekly for 8 
weeks, the mean ± standard deviation (SD) maximum trough concentrations 
(Ctrough following the 8th dose) were 593±306 μg/mL compared to 522±226 
μg/mL for daratumumab 16 mg/kg administered intravenously, with a geometric 
mean ratio of 108% (90% CI: 96, 122). The estimated median daratumumab area 
under the concentration-time curves (AUC0-7 days) and daratumumab peak 
concentration (Cmax) following the 8th dose were comparable between 
subcutaneous and intravenous daratumumab (4017 μg/mL•day vs. 4,019 
μg/mL•day for AUC0-7 days and 592 μg/mL vs. 688 μg/mL for Cmax). 
The absolute bioavailability of daratumumab-hyaluronidase is 69%, with peak 
concentrations occurring around 3 days (Tmax).  The estimated mean (coefficient 
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(37%) and peripheral compartment was 3.8 L with the daratumumab-
hyaluronidase formulation.  Daratumumab is cleared by parallel linear and 
nonlinear saturable target mediated clearances. The estimated mean (CV%) linear 
clearance of daratumumab is 119 mL/day. The estimated mean (CV%) 
elimination half-life associated with linear clearance is 20 days (22%). 
 
 
Special Populations 
Geriatric use:  Based on population PK analyses in patients receiving 
monotherapy or combination therapies, age (range: 31-93 years) had no clinically 
important effect on the PK or effectiveness of daratumumab.  The most common 
serious adverse events that occurred more frequently in elderly (≥ 65 years of 
age) were pneumonia and sepsis.   
Renal Impairment: The population PK analysis included 592 patients receiving 
IV daratumumab 16 mg/kg with normal renal function (creatinine clearance 
[CrCL] ≥90 mL/min), 757 patients with mild renal impairment (CrCL <90 and 
≥60 mL/min), 604 patients with moderate renal impairment (CrCL <60 and ≥30 
mL/min), and 6 patients with severe renal impairment or end stage renal disease 
(CrCL <30 mL/min). No clinical differences in exposure to daratumumab were 
observed between patients with renal impairment and those with normal renal 
function in both daratumumab IV and SC. . 
 
Hepatic Impairment: The population PK analysis included 1,742 patients with 
normal hepatic function (TB and AST ≤ULN) , 224 with mild hepatic 
impairment (TB 1.0× to 1.5× ULN or AST>ULN) patients, and 10 patients with 
moderate (TB>1.5 to 3xULN; n=9) or severe hepatic impairment (TB >3xULN; 
n=1). No clinical differences in the exposure to daratumumab were observed 
between patients with hepatic impairment and those with normal hepatic 
function. The effect of moderate (TB>1.5× to 3× ULN and any AST) or severe 
(TB>3× ULN and any AST) hepatic impairment on daratumumab IV or SC 
pharmacokinetics is unknown.  Population PK analysis demonstrated no 
clinically important differences in the exposure to daratumumab were observed 
between patients with normal hepatic function and mild hepatic impairment in 
studies of both daratumumab IV and SC.  There were few patients with 
moderate-severe hepatic impairment to make meaningful conclusions for these 
populations. 
  
 
 
15.26 Potential Drug Interactions:  Clinical PK assessments with daratumumab IV 
and SC formulations and lenalidomide, bortezomib, thalidomide, pomalidomide, 
melphalan ,prednisone, cyclophosphamide, dexamethasone, and carfilzomib  
indicated no clinically relevant drug-drug interactions.  
 
 
 
Effects on laboratory tests: 
 
Interference with Indirect Antiglobulin Tests: Daratumumab binds to CD38 on 
RBCs and interferes with compatibility testing, including antibody screening and 
cross matching and may persist for up to 6 months after the last daratumumab 
administration.   Daratumumab interference mitigation methods include treating 
reagent RBCs with dithiothreitol (DTT) to disrupt daratumumab binding or 
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treatment, K-negative units should be supplied after ruling out or identifying 
alloantibodies using DTT-treated RBCs. If an emergency transfusion is required, 
non-cross matched ABO/RhD compatible RBCs can be given per local blood 
bank practices. 
 
 
Interference with Serum Protein Electrophoresis and Immunofixation Tests: 
Daratumumab may be detected on serum protein electrophoresis (SPE) and 
immunofixation (IFE) assays used for monitoring disease monoclonal 
immunoglobulins (M protein). This can lead to false positive SPE and IFE assay 
results for patients with IgG kappa myeloma protein impacting initial assessment 
of complete responses by International Myeloma Working Group (IMWG) 
criteria. In patients with persistent very good partial response, where 
daratumumab interference is suspected, consider using a FDA approved 
daratumumab-specific IFE assay to distinguish daratumumab from any remaining 
endogenous M protein in the patient’s serum, to facilitate determination of a 
complete response. 
 
 
15.27 Known potential toxicities:   
Very common known potential toxicities, ≥ 10%: 
Blood and lymphatic system disorders: neutropenia, thrombocytopenia, anemia, 
lymphopenia 
Gastrointestinal disorders: nausea, vomiting, diarrhea, constipation 
Infections and infestations: upper respiratory tract infection, bronchitis 
pneumonia, nasopharyngitis 
Injury, poisoning, and procedural complications: infusion related reaction 
Metabolism and nutrition disorders:  hypokalemia, hyperglycemia, decreased 
appetite 
Musculoskeletal and connective tissue disorders: muscle spasms, back pain, 
arthralgia, pain in extremity, bone pain, musculoskeletal chest pain 
Nervous system disorders: dizziness, headache, tremor, headache 
Psychiatric disorders:  Insomnia, anxiety 
Respiratory, thoracic, and mediastinal disorders: cough, dyspnea, nasal 
congestion, upper respiratory tract infection, pneumonia 
Vascular disorders: hypertension 
General disorders and administration site conditions: fatigue, pyrexia, chills, 
peripheral edema, asthenia, non-cardiac chest pain, pain,  
 
  
Common known potential toxicities, 1% - <10%: 
General disorders and administration site conditions:  injection site reaction, 
peripheral edema 
Infections and infestations: respiratory tract infection, influenza, lower 
respiratory tract infection, sepsis, sinusitis, rhinitis, pharyngitis, viral respiratory 
tract infection, nasopharyngitis, respiratory syncytial virus infections, laryngitis, 
tonsillitis, lung infection, herpes zoster 
Blood and lymphatic disorders: febrile neutropenia 
Cardiac disorders: atrial fibrillation 
Respiratory, thoracic, and mediastinal disorders: pulmonary edema, hypoxia, 
laryngeal edema, pneumonitis, bronchospasm 

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Uncommon and rare known potential toxicities, <1%: 
Infections and infestations: pharyngitis, metapneumovirus infection, tracheitis, 
acute sinusitis, bronchiolitis, epiglottitis, oropharyngeal candidiasis, rhinovirus 
infection, tracheobronchitis, upper respiratory tract   bacterial infection, 
bronchitis bacterial, viral or bacterial laryngitis, pharyngitis, viral rhinitis, 
respiratory syncytial virus, infectious pneumonia 
Blood and Lymphatic Disorders: neutropenic sepsis, neutropenic infection 
Daratumumab IV and SC studies demonstrated that the incidence of anti-
daratumumab antibodies was low [<1%] following daratumumab administration 
in multiple myeloma (IV/SC) and amyloidosis (SC) participants.  Treatment 
emergent anti-rHuPH20 antibodies developed in 7.1% (60/840) of participants 
who received daratumumab SC in monotherapy and combination clinical studies. 
 
Hepatitis B virus (HBV) reactivation, in some cases fatal, have been reported in 
patients treated with daratumumab.  HBV screening should be performed in all 
patients before initiation of treatment with daratumumab and as clinically 
indicated.  Treatment interruption may be warranted in the event of HBV 
reactivation while on daratumumab. 
 
Please refer to the Investigator Brochure for a more comprehensive list of 
treatment-emergent adverse events. 
 
 
 
 
15.28 Drug procurement:  Daratumumab (Darzalex) will be provided to 
research subjects for the duration of their participation in this trial at no 
charge to them or their insurance providers. Note: patients will be charged 
for the administration of the Daratumumab. 
 
 
15.29 Nursing Guidelines:  
 
15.291 Daratumumab can cause severe infusion reactions, usually during the 
first infusion. Patients who have experience a reaction may experience 
further reactions with subsequent infusions. Most reactions occur during 
or within 4 hours of infusion, however may occur up to 48 hours after an 
infusion.  Warn patient of this possibility. Monitor patient throughout 
infusion for bronchospasm, hypoxia, SOB, and hypertension. Patients 
may also experience symptoms of anaphylaxis. Administer emergency 
medication as ordered.  
 
15.292 Patients may experience infections, including URI and pneumonia. 
Patients who have an ongoing infection should not receive agent. 
15.293 Patients may experience gastrointestinal side effects including diarrhea 
and nausea. Treat symptomatically and monitor for effectiveness. 
 
15.294 Warn patients about the possibility of peripheral neuropathy, dizziness, 
and insomnia.  
 
15.295 Fatigue is common. Instruct patient in energy conserving lifestyle. 
 

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15.296 Rarely patients may experience cardiac issues including, atrial-
fibrillation, peripheral edema, and hypertension. Instruct patient to report 
any chest pain, heart palpitations, and swelling to the study team.  
 
15.297 Monitor CBC w/diff as cytopenias (thrombocytopenia, neutropenia, 
anemia, and lymphopenia) have been seen. Instruct patient to report any 
unusual, bruising, bleeding and/or infections/fever to the study team. 
 
15.298 If using SQ, injection should be in the abdomen over 3-5 minutes. There 
is no data on SQ injections on other parts of the body. 
 
15.3 
Dexamethasone for Oral Administration (DXM) 
 
15.31 Background: Dexamethasone is an adrenal corticosteroid compound. 
Dexamethasone decreases inflammation by suppression of neutrophil migration, 
decreased production of inflammatory mediators, and reversal of increased 
capillary permeability; suppresses normal immune response. Dexamethasone’s 
mechanism of antiemetic activity is unknown. 
 
15.32 Formulation: Commercially available for oral administration as:  
 
Tablets [scored]: 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 4 mg, and 6 mg 
 
Solution, oral: 0.5 mg/mL (500 mL) 
Solution, oral concentrate: Dexamethasone Intensol: 1 mg/mL (30 mL) 
 
15.33 Preparation, storage, and stability: Refer to package insert for complete 
preparation and dispensing instructions. Store oral tablets at room 
temperature between 20ºC to 25ºC (60ºF to 77ºF). Protect from moisture. 
Dispense in a well-closed, light-resistant container as defined in the 
USP/NF. Store oral liquid at room temperature, do not freeze. Do not use 
if solution contains a precipitate. Refer to commercial package for drug 
expiration date. 
 
15.34 Administration:  Refer to the treatment section for specific administration 
instructions. May be taken with meals to decrease GI upset.  
 
 
15.35 Pharmacokinetic information: 
Onset of action: Prompt 
Duration of metabolic effect: 72 hours 
Metabolism: Hepatic 
Half-life elimination: Normal renal function: 1.8-3.5 hours; Biological 
half-life: 36-54 hours 
Time to peak, serum: Oral: 1-2 hours 
Excretion: Urine and feces 
 
 
15.36 Potential Drug Interactions: 
Cytochrome P450 Effect: Substrate of CYP3A4 (major); Induces 
CYP2A6 (weak), 2B6 (weak), 2C8 (weak), 2C9 (weak), 3A4 (strong) 
Increased Effect/Toxicity: Aprepitant, azole antifungals, calcium channel 
blockers, cyclosporine, estrogens, and macrolides may increase the serum 
levels of corticosteroids. Corticosteroids may increase the hypokalemic 

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effects of amphotericin B or potassium-wasting diuretics (loop or 
thiazide); monitor. Refer to the package insert for a listing of other drugs. 
Decreased Effect: Antacids and bile acid sequestrants may reduce the 
absorption of corticosteroids; may reduce the absorption of corticosteroids; 
separate administration by 2 hours. Aminoglutethimide, barbiturates, and 
CYP3A4 inducers may reduce the serum levels/effects of dexamethasone 
and dexamethasone may decrease the levels/effects of other CYP3A4 
substrates. Serum concentrations of isoniazid may be decreased by 
corticosteroids. Corticosteroids may lead to a reduction in warfarin effect. 
Corticosteroids may suppress the response to vaccinations. 
Ethanol/Nutrition/Herb Interactions:  
Ethanol: Avoid ethanol (may enhance gastric mucosal irritation). 
Food: Dexamethasone interferes with calcium absorption. Limit caffeine. 
Herb/Nutraceutical: Avoid cat’s claw (Uncaria tomentosa), echinacea 
(have immunostimulant properties) 
 
15.37 Known potential adverse events: Consult the package insert for the most 
current and complete information.  
 
Common known potential toxicities, frequency not defined:   
Fluid and electrolyte disturbances, congestive heart failure in susceptible 
persons, hypertension, euphoria, personality changes, insomnia, 
exacerbation of infection, exacerbation or symptoms of diabetes, 
psychosis, muscle weakness, osteoporosis, vertebral compression 
fractures, pancreatitis, esophagitis, peptic ulcer, dermatologic disturbances, 
convulsions, vertigo and headache, endocrine abnormalities, ophthalmic 
changes, and metabolic changes. Some patients have experienced itching 
and other allergic, anaphylactic or hypersensitivity reactions. Withdrawal 
from prolonged therapy may result in symptoms including fever, myalgia 
and arthralgia. 
 
15.38 Drug procurement:  Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
 
15.39 Nursing Guidelines: 
 
15.391 Monitor patient regularly for hypertension, CHF and other evidence of 
fluid retention. 
 
15.392 Advise patient of possible mood or behavioral changes, i.e., depression, 
euphoria, insomnia, even psychosis.  Instruct patient to report any 
suspected changes to healthcare team. 
 
15.393 Assess for symptoms of gastric ulcer, heartburn, or gastritis.  Suggest 
antacids.  Instruct patient to report symptoms to healthcare team if unable 
to control. 
 
15.394 Evaluate signs of infection, particularly local candidal infections and 
treat appropriately. 
 
15.395 Monitor blood glucose frequently. 
 

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15.396 Instruct patient to report frequent, unrelenting headaches or visual 
changes to healthcare team. 
 
15.397 Advise patient that easy bruising is a side effect. 
 
15.4 
Cyclophosphamide for Oral Administration (Cytoxan®, Neosar®, CTX) 
 
15.41 Background: Cyclophosphamide is an alkylating agent that prevents cell 
division by cross-linking DNA strands and decreasing DNA synthesis. It is a cell 
cycle phase nonspecific agent. Cyclophosphamide also possesses potent 
immunosuppressive activity. Cyclophosphamide is a prodrug that must be 
metabolized to active metabolites in the liver. 
 
15.42 Formulation: Commercially available for oral administration as:  
 
Tablets: 25 mg, 50 mg  
 
15.43 Preparation, storage, and stability: Refer to package insert for complete 
preparation and dispensing instructions. Store oral tablets at room 
temperature preferably below 25ºC (77ºF). This product will withstand 
brief exposure to temperatures up to 30ºC (86ºF), but should be protected 
from temperatures above 30ºC (86ºF). Dispense in a tight container as 
defined in the USP/NF. Refer to labeling on the bottle for expiration date 
of the commercial tablets. 
  
15.44 Administration:  Refer to the treatment section for specific administration 
instructions. Tablets are not scored and should not be cut or crushed. To 
minimize the risk of bladder irritation, do not administer tablets at bedtime. 
 
 
15.45 Pharmacokinetic information: 
Distribution: Vd: 0.48-0.71 L/kg; crosses placenta; crosses into CSF (not 
in high enough concentrations to treat meningeal leukemia) 
Protein binding: 10% to 60% 
Bioavailability: >75% 
Time to peak, serum: Oral: ~1 hour 
Metabolism: Hepatic to active metabolites acrolein, 4-aldophosphamide, 
4-hydroperoxycyclophosphamide, and nor-nitrogen mustard 
Half-life elimination: 3-12 hours 
Excretion: Urine (<30% as unchanged drug, 85% to 90% as metabolites) 
 
 
15.46 Potential Drug Interactions: 
Cytochrome P450 Effect: Substrate of CYP2A6 (minor), 2B6 (major), 
2C9 (minor), 2C19 (minor), 3A4 (major); Inhibits CYP3A4 (weak); 
Induces CYP2B6 (weak), 2C8 (weak), 2C9 (weak)  
Increased Effect/Toxicity: Allopurinol may cause an increase in bone 
marrow depression and may result in significant elevations of 
cyclophosphamide cytotoxic metabolites. CYP2B6 and CYP3A4 inducers 
may increase the levels/effects of acrolein (the active metabolite of 
cyclophosphamide); see package insert for example inducers. Etanercept 
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reduces serum pseudocholinesterase concentrations and may prolong the 
neuromuscular blocking activity of succinylcholine and mivacurium. 
Decreased Effect: Cyclophosphamide may decrease the absorption of 
digoxin tablets. CYP2B6 and CYP3A4 inhibitors may decrease the 
levels/effects of acrolein (the active metabolite of cyclophosphamide); see 
package insert for example inhibitors. 
Herb/Nutraceutical Interactions: Avoid black cohosh, dong quai in 
estrogen-dependent tumors.  
 
15.47 Known potential adverse events: Consult the package insert for the most 
current and complete information.  
 
Common known potential toxicities, > 10%:   
Dermatologic: Alopecia but hair will usually regrow although it may be a 
different color and/or texture. Hair loss usually begins 3-6 weeks after the 
start of therapy. 
Endocrine & metabolic: Fertility: May cause sterility; interferes with 
oogenesis and spermatogenesis; may be irreversible in some patients; 
gonadal suppression (amenorrhea) 
Gastrointestinal: Nausea and vomiting, usually beginning 6-10 hours after 
administration; anorexia, diarrhea, mucositis, and stomatitis are also seen 
Hematologic: Thrombocytopenia and anemia are less common than 
leukopenia 
 
Less common known potential toxicities, 1% - 10%:  
Cardiovascular: Facial flushing 
Central nervous system: Headache 
Dermatologic: Skin rash 
 
Rare known potential toxicities, <1% (Limited to important or life-
threatening):  
Cyclophosphamide may potentiate the cardiac toxicity of anthracyclines. 
Other adverse reactions include anaphylactic reactions, darkening of 
skin/fingernails, dizziness, hemorrhagic colitis, hemorrhagic ureteritis, 
hepatotoxicity, hyperuricemia, hypokalemia, jaundice, malaise, 
neutrophilic eccrine hidradenitis, radiation recall, renal tubular necrosis, 
secondary malignancy (e.g., bladder carcinoma), SAIDH, Stevens-Johnson 
syndrome, toxic epidermal necrolysis, weakness. 
 
15.48 Drug procurement:  Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
 
 
15.49 Nursing Guidelines:  
 
 
 
 
 
15.491 Myelosuppression is common. Monitor CBC including platelets. Instruct 
patient on signs/symptoms of infection and to inform health care team of 
any unusual bruising, or signs of bleeding. 
 

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15.492 Instruct patient to drink 2-3 liters of fluid per day for 2-3 days following 
treatment and to void frequently, not greater than every three hours to 
facilitate keeping the bladder clear of drug. 
 
 
 
 
15.493 Instruct patient to report any urinary urgency, frequency, dysuria, or 
hematuria. Administer mesna with high dose cytoxan to prevent 
hemorrhagic cystitis.  It may be necessary to catheterize and provide 
constant bladder irrigation. 
 
 
 
 
15.494 Advise patient in possible strong metallic taste associated with Cytoxan 
and suggest hard candy with a strong flavor (cinnamon, peppermint) to 
alleviate it. 
 
 
 
 
15.495 Administer antiemetics as necessary to minimize nausea and vomiting, 
which usually occurs 6-8 hours after administration. 
 
 
 
 
 
15.496 Report and record any complaint of lightheadedness, facial “heat 
sensation,” diaphoresis during administration. 
 
 
 
 
15.497 Use of an ice cap may be helpful in preventing or limiting alopecia. 
 
 
 
 
15.498 Corticosteroids, phenothiazine, imipramine, vitamin A succinylcholine, 
digoxin, thiazide diuretics, warfarin and allopurinol may inhibit Cytoxan 
metabolism and modify its’ effect.  They may also increase bone marrow 
suppression. 
 
 
 
 
 
 
15.499a Advise female patients of possible menstrual changes or amenorrhea. 
 
 
 
 
15.499b Patients on anticoagulant therapy should have INR levels 
carefully monitored as cytoxan increases their effect. 
 
 
 
 
15.499c Monitor electrolytes and for signs/symptoms of SIADH and 
tumor lysis syndrome. 
 
 
 
 
15.499d Monitor digoxin levels closely as cytoxan may decrease these levels. 
 
 
 
 
15.499e Cytoxan may potentiate doxorubicin-induced cardiomyopathy. Instruct 
patient to report any chest pain. 
 
 

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16.0  
Statistical Considerations and Methodology  
 
16.1  
Overview:  
 
This is a Phase II study designed to assess the proportion of confirmed responses as well 
as the toxicity associated with ixazomib with or without dexamethasone ,ixazomib with 
dexamethasone and cyclophosphamide, and ixazomib with dexamethasone, 
cyclophosphamide, and daratumumab  in patients with relapsed multiple myeloma.   
 
16.11  Primary Endpoint:  
 
The primary endpoint of this trial is the proportion of confirmed responses (sCR, 
CR, VGPR, PR) with single agent ixazomib (Arm A) or ixazomib in combination 
with dexamethasone (Arms B and C) or ixazomib in combination with 
dexamethasone and cyclophosphamide (Arm D) or ixazomib in combination with 
dexamethasone, cyclophosphamide, and daratumumab (Arm E).  Throughout 
Section 16.0, confirmed response will be considered synonymous with “success”, 
unless specified otherwise.  All patients meeting the eligibility criteria who have 
signed a consent form and have begun treatment will be evaluable for confirmed 
response, with the exception of patients who are determined to be a major 
treatment violation. 
 
16.12  Sample Size:  
 
The single stage study design to be used is fully described below.  Twenty-nine 
evaluable patients are required to assess the primary endpoint.  We anticipate 
accruing an additional 4 patients to account for ineligibility, cancellation, major 
treatment violation, or other reasons.  Therefore, the maximum total sample size 
will be 33 patients. 
 
As of Addendum 5 Arms B and C will be added to this study.  The single stage 
study design to be used for each arm is fully described below.  Thirty-two 
evaluable patients are required to assess the primary endpoint.  We anticipate 
accruing an additional 3 patients in each arm to account for ineligibility, 
cancellation, major treatment violation, or other reasons.  Therefore, the 
maximum total sample size in each arm will be 35 patients.  The overall 
maximum total sample size including all arms will be increased to 103 patients.  
 
As of Addendum 14, one additional patient will be randomized to Arm B or Arm 
C.  This is to account for a miscommunication that resulted in an extra patient 
being consented for the study.   
 
As of Addendum 15 Arm D will be added to this study.  The single stage study 
design to be used is fully described below.  Thirty-six evaluable patients are 
required to assess the primary endpoint.  We anticipate accruing an additional 4 
patients to account for ineligibility, cancellation, major treatment violation, or 
other reasons.  Therefore, the maximum total sample size in Arm D will be 40 
patients.  The overall maximum total sample size including all arms will be 
increased to 144 patients.   
 
As of Addendum 23 Arm E will be added to this study.  The single stage study 
design to be used is fully described below.  Thirty-five evaluable patients are 
required to assess the primary endpoint.  We anticipate accruing an additional 4 

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patients to account for ineligibility, cancellation, major treatment violation, or 
other reasons.  Therefore, the maximum total sample size in Arm E will be 39 
patients.  The overall maximum total sample size including all arms will be 
increased to 183 patients.   
 
16.13  Accrual Rate and Study Duration:  
 
Based on prior Mayo Clinic accrual in this patient population we expect an 
accrual of about 3-4 patients per month.  Therefore, accrual to this study should 
take about 9-12 months.  The analysis can begin as soon as the last patient has 
been observed for at least 6 months, or about 1.5 years after the trial opens. 
 
As of Addendum 5, accrual to Arm A has been completed and accrual will begin 
to Arms B and C.   Based on accrual to Arm A, we expect Arms B and C to have 
a similar accrual of about 3-4 patients per month.  Therefore, accrual to Arms B 
and C should take about 18-24 months.  The analysis can begin as soon as the 
last patient has been observed for at least 6 months, or about 2.5 years after 
Addendum 4 is implemented.  
 
As of Addendum 15, accrual to Arms B and C has been completed and accrual 
will begin to Arm D.  Based on accrual in the previous arms, accrual to Arm D is 
expected to take approximately 14 months. The analysis can begin as soon as the 
last patient has been observed for at least 6 months, or about 1.75 years after 
Addendum 15 is implemented. 
 
As of Addendum 23, accrual to Arm E will begin.  Based on accrual in the 
previous arms, accrual to Arm E is expected to take approximately 24 months. 
The analysis can begin as soon as the last patient has been observed for at least 6 
months, or about 2.5 years after Addendum 23 is implemented. 
 
16.2  
Statistical Design for Arm A (Permanently Closed to Accrual): 
 
16.21 Decision Rule:  
 
In a study including 193 evaluable relapsed multiple myeloma patients treated 
with single agent bortezomib, a proteasome inhibitor given by intravenous bolus, 
27% of patients achieved a confirmed response (Richardson, et al 2003a).  
Ixazomib is a next generation proteasome inhibitor with different proteasome 
binding characteristics that is given orally.   Since oral administration is 
preferred, a confirmed response rate at least equivalent to bortezomib in relapsed 
multiple myeloma patients treated with single agent ixazomib is of interest. 
 
Therefore, the largest success proportion where the proposed treatment regimen 
would be considered ineffective in this population is 10%, and the smallest 
success proportion that would warrant subsequent studies with the proposed 
regimen in this patient population is 30%. The following one-stage binomial 
design requires 29 patients to test the null hypothesis that the true success 
proportion in this patient population is at most 10%.  
 
16.211  Final Decision Rule:  If 5 or fewer successes are observed in the first 29 
evaluable patients, we will consider this regimen ineffective in this 

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patient population and terminate this study. Otherwise, if the number of 
successes is at least 6, this will be considered evidence of promising 
activity and the treatment may be recommended for further testing in 
subsequent studies. 
 
16.212  Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used 
in any decision making process.  Analyses involving over accrued 
patients are discussed in Section 16.54. 
 
16.22 Power and Significance Level: Assuming that the number of responses is 
binomially distributed, with a significance level of 6%, the probability of 
declaring that the regimen warrants further studies (i.e., statistical power) under 
various success proportions can be tabulated as a function of the true success 
proportion as shown in the table below. 
 
If the true success proportion is…
0.10
0.15
0.20
0.25
0.30
Then the probability of declaring that 
the regimen is promising and warrants 
further study is…
0.06
0.26
0.54
0.77
0.91
 
16.23 Other Considerations: Toxicity, quality/duration of response, and patterns of 
treatment failure observed in this study, as well as scientific discoveries or 
changes in standard care will be taken into account in any decision to terminate 
the study. 
 
16.3  
Statistical Design for Arms B and C (Permanently closed to accrual): 
 
16.31 Patients will be randomized to a treatment regimen using a dynamic allocation 
procedure, which balances the marginal distribution of the stratification factors 
(see Section 5.2) between the treatment regimens.(Pocock and Simon 1975)  The 
results of these studies will be analyzed independently and no direct comparisons 
will be made between the data from each of these treatment regimens. 
 
16.32 Decision Rule (to be assessed independently in each arm):  
 
The addition of dexamethasone to ixazomib from the beginning of treatment may 
result in improved response rates. Therefore, the largest success proportion where 
the proposed treatment regimen would be considered ineffective in this 
population is 20%, and the smallest success proportion that would warrant 
subsequent studies with the proposed regimen in this patient population is 40%. 
The following one-stage binomial design requires 32 evaluable patients to test 
the null hypothesis that the true success proportion in this patient population is at 
most 20%.  
 
16.321  Final Decision Rule:  If 9 or fewer successes are observed in the first 32 
evaluable patients, we will consider this regimen ineffective in this 
patient population and terminate this study. Otherwise, if the number of 
successes is at least 10, this will be considered evidence of promising 

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activity and the treatment may be recommended for further testing in 
subsequent studies. 
 
16.322  Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used 
in any decision making process.  Analyses involving over accrued 
patients are discussed in Section 16.54. 
 
 
16.33 Power and Significance Level: Assuming that the number of responses is 
binomially distributed, with a significance level of 9%, the probability of 
declaring that the regimen warrants further studies (i.e., statistical power) under 
various success proportions can be tabulated as a function of the true success 
proportion as shown in the table below. 
 
If the true success proportion is…
0.20
0.25
0.30
0.35
0.40
Then the probability of declaring that 
the regimen is promising and warrants 
further study is…
0.09
0.26
0.50
0.73
0.88
 
16.34 Other Considerations: Toxicity, quality/duration of response, and patterns of 
treatment failure observed in this study, as well as scientific discoveries or 
changes in standard care will be taken into account in any decision to terminate 
the study. 
 
 
16.4  
Statistical Design for Arm D: 
 
 
16.41 Decision Rule:  
 
The addition of cyclophosphamide to ixazomib and dexamethasone may result in 
improved response rates. Therefore, the largest success proportion where the 
proposed treatment regimen would be considered ineffective in this population is 
25%, and the smallest success proportion that would warrant subsequent studies 
with the proposed regimen in this patient population is 45%. The following one-
stage binomial design requires 36 evaluable patients to test the null hypothesis 
that the true success proportion in this patient population is at most 25%.  
 
16.411  Final Decision Rule:  If 12 or fewer successes are observed in the first 36 
evaluable patients, we will consider this regimen ineffective in this 
patient population and terminate this study. Otherwise, if the number of 
successes is at least 13, this will be considered evidence of promising 
activity and the treatment may be recommended for further testing in 
subsequent studies. 
 
16.412  Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used 
in any decision making process.  Analyses involving over accrued 
patients are discussed in Section 16.64. 
 

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16.42 Power and Significance Level: Assuming that the number of responses is 
binomially distributed, with a significance level of 9%, the probability of 
declaring that the regimen warrants further studies (i.e., statistical power) under 
various success proportions can be tabulated as a function of the true success 
proportion as shown in the table below. 
 
If the true success proportion is…
0.25
0.30
0.35
0.40
0.45
Then the probability of declaring that 
the regimen is promising and warrants 
further study is…
0.09
0.26
0.51
0.74
0.89
 
16.43 Other Considerations: Toxicity, quality/duration of response, and patterns of 
treatment failure observed in this study, as well as scientific discoveries or 
changes in standard care will be taken into account in any decision to terminate 
the study. 
 
16.5  
Statistical Design for Arm E: 
 
 
16.51 Decision Rule:  
 
The addition of cyclophosphamide and daratumumab to ixazomib and 
dexamethasone may result in improved response rates. Therefore, the largest 
success proportion where the proposed treatment regimen would be considered 
ineffective in this population is 50%, and the smallest success proportion that 
would warrant subsequent studies with the proposed regimen in this patient 
population is 70%. The following one-stage binomial design requires 35 
evaluable patients to test the null hypothesis that the true success proportion in 
this patient population is at most 50%.  
 
16.511  Final Decision Rule:  If 21 or fewer successes are observed in the first 35 
evaluable patients, we will consider this regimen ineffective in this 
patient population.  Otherwise, if the number of successes is at least 22, 
this will be considered evidence of promising activity and the treatment 
may be recommended for further testing in subsequent studies. 
 
16.512  Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used 
in any decision making process.  Analyses involving over accrued 
patients are discussed in Section 16.64. 
 
 
16.52 Power and Significance Level: Assuming that the number of responses is 
binomially distributed, with a significance level of 9%, the probability of 
declaring that the regimen warrants further studies (i.e., statistical power) under 
various success proportions can be tabulated as a function of the true success 
proportion as shown in the table below. 
 
 
 

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If the true success proportion is…
0.50
0.55
0.60
0.65
0.70
Then the probability of declaring that 
the regimen is promising and warrants 
further study is…
0.09
0.22
0.44
0.68
0.87 
 
16.53 Other Considerations: Toxicity, quality/duration of response, and patterns of 
treatment failure observed in this study, as well as scientific discoveries or 
changes in standard care will be taken into account in any decision to terminate 
the study. 
 
16.6 
Analysis Plan: 
 
16.61 Primary Endpoint:   
 
16. 611 Definition: The primary endpoint of this study is the proportion of 
confirmed responses with single agent ixazomib (prior to initiation of 
dexamethasone) (Arm A), with the combination of ixazomib plus 
dexamethasone from the start of therapy (Arms B and C), and with the 
combination of ixazomib plus dexamethasone and cyclophosphamide 
from the start of therapy (Arm D).  A confirmed response is defined as 
sCR, CR, VGPR, or PR noted as the objective status on 2 consecutive 
evaluations while receiving single agent ixazomib (Arm A) or ixazomib 
plus dexamethasone (Arms B and C) or ixazomib plus dexamethasone 
and cyclophosphamide (Arm D) or ixazomib in combination with 
dexamethasone, cyclophosphamide, and daratumumab (Arm E). All 
patients meeting the eligibility criteria who have signed a consent form 
and have begun treatment will be evaluable for response, with the 
exception of patients who are determined to be a major treatment 
violation. 
 
16. 612 Estimation:  The proportion of successes will be estimated in each arm 
independently by the number of successes divided by the total number of 
evaluable patients. 95% confidence intervals for the true success 
proportion will be calculated by the exact binomial method.   
  
16. 62 Definitions and Analyses of Secondary Endpoint (To be evaluated independently 
in each arm, except where noted): 
 
16. 621 Arm A Only - Confirmed response rate with the addition of 
dexamethasone:  The confirmed response rate for ixazomib with the 
addition of dexamethasone for lack of response or progression will be 
estimated by the number of patients who achieve a confirmed response at 
any time (with single agent ixazomib or ixazomib plus dexamethasone) 
divided by the number of evaluable patients.  95% confidence intervals 
for the true confirmed response rate will be calculated by the exact 
binomial method.  In addition, the number of patients who did not 
achieve a confirmed response with ixazomib alone then had a confirmed 
response after the addition of dexamethasone to ixazomib will be 
evaluated. 
 
 

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16. 622 Overall survival: Survival time is defined as the time from registration to 
death due to any cause.  The distribution of survival time will be 
estimated using the method of Kaplan-Meier (Kaplan and Meier, 1958).  
All evaluable patients will be included in this analysis. 
 
16. 623 Event-free survival: The event-free survival time is defined as the time 
from registration to disease progression while receiving ixazomib and 
dexamethasone, death due to any cause, or subsequent treatment for 
multiple myeloma.  Date of progression will be defined as the date that 
the criteria for progressive disease (per section 11.5) were first met after 
initiation of dexamethasone.  If a patient goes off study and never 
received dexamethasone, they will be censored on the date they went off 
study.  If a patient initiates dexamethasone but later discontinues 
dexamethasone due to toxicity and continues ixazomib alone, disease 
progression on ixazomib alone will be considered an event in this case.  
The distribution of event-free survival will be estimated using the 
method of Kaplan-Meier (Kaplan and Meier, 1958).  All evaluable 
patients will be included in this analysis. 
 
16. 63 Adverse Events: The maximum grade for each type of adverse event, regardless 
of causality, will be recorded and reported for each patient, and frequency tables 
will be reviewed to determine adverse event patterns.  Adverse events will 
continue to be recorded and reported up to 30 days after the last day of study 
drug treatment. 
 
16. 64 Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used in any 
decision making processes; however, they will be included in final point 
estimates and confidence intervals 
 
16. 65 Data & Safety Monitoring 
 
16. 651 The principle investigator(s) and the study statistician will review the 
study at least every quarter to identify accrual, adverse event, and any 
endpoint problems that might be developing. The Mayo Clinic Cancer 
Center (MCCC) Data Safety Monitoring Board (DSMB) is responsible 
for reviewing accrual and safety data for this trial at least twice a year, 
based on reports provided by the MCCC Statistical Office. 
 
16. 652 Adverse Event Stopping Rule (to be evaluated in each arm 
independently): The stopping rule specified below is based on the 
knowledge available at study development.  We note that the rule may be 
adjusted in the event of either (1) the study re-opening to accrual or (2) at 
any time during the conduct of the trial and in consideration of newly 
acquired information regarding the adverse event profile of the 
treatments under investigation.  The study team may choose to suspend 
accrual because of unexpected adverse event profiles that have not 
crossed the specified rule below. 
 

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Accrual will be temporarily suspended to this study if at any time we 
observe events considered at least possibly related to study treatment (i.e. 
an adverse event with attribute specified as “possible,” “probable,” or 
“definite”) that satisfy either of the following: 
 
 
if 4 or more patients in the first 15 treated patients experience a grade 
4 or higher non-hematologic adverse event at least possibly related to 
treatment. 
 
 
if after the first 15 patients have been treated, 25% of all patients 
experience a grade 4 or higher non-hematologic adverse event at 
least possibly related to treatment. 
 
We note that we will review grade 4 and 5 adverse events deemed 
“unrelated” or “unlikely to be related”, to verify their attribution and to 
monitor the emergence of a previously unrecognized treatment-related 
adverse event. 
 
16.7 
Inclusion of Women and Minorities 
 
16. 71 This study will be available to all eligible patients, regardless of race, gender, or 
ethnic origin. 
 
16. 72 There is no information currently available regarding differential effects of this 
regimen in subsets defined by race or gender, and there is no reason to expect 
such differences to exist.  Therefore, although the planned analysis will, as 
always, look for differences in treatment effect based on racial and gender 
groupings, the sample size is not increased in order to provide additional power 
for subset analyses. 
 
16. 73 The geographical region served by Mayo, has a population, which includes 
approximately 3% minorities. Based on prior Mayo studies involving similar 
disease sites, we expect about 3-5% of patients will be classified as minorities by 
race and about 33% of patients will be women.  Expected sizes of racial by 
gender subsets are shown in the following table: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino
1
2
0
3
Not Hispanic or Latino
60
120
0
180
Unknown
0
0
0
0
Ethnic Category: Total of all subjects* 
61
122
0
183 
Racial Category
American Indian or Alaskan Native
0
0
0
0
Asian
0
1
0
1
Black or African American
2
2
0
4
Native Hawaiian or other Pacific Islander
0
0
0
0
White
59
119
0
178
More than one race
0
0
0
0
Unknown
0
0
0
0
Racial Category: Total of all subjects
61
122
0
183 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa.
 
17.0  
Pathology Considerations/Tissue Biospecimens: None 
 
 

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18.0 
Records and Data Collection Procedures   
 
18.1 
Submission Timetable 
 
Initial Material(s) -  
 
 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
 
On-Study Form
 
 
 
2 weeks after registration
Baseline Adverse Event Form
Pretreatment Measurement Form 
SPEP, UPEP, FLC , Serum and Urine Immunofixation, 
Bone Marrow biopsy and aspirate, X-Ray skeletal 
survey, Cytogenetic, FISH on study reports 
 
End of Active Treatment/Cancel Notification Form 
Submit 2 weeks after registration if withdrawal/refusal 
occurs prior to beginning protocol therapy 
 
Test Schedule Material(s) -  
 
 
CRF
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
 
At each evaluation 
during treatment
At end of treatment 
Evaluation/Treatment Form
X1
X
Adverse Event Form
X
X
Measurement Form
X
X
SPEP, UPEP, FLC , Serum and Urine Immunofixation, 
Bone Marrow biopsy and aspirate, X-Ray skeletal survey
X2 
X2 
Interval Laboratory Form
X3
End of Active Treatment/Cancel Notification Form
X
ADR/AER 
At each occurrence 
(see Section 10.0)
 
 
1. Complete at each evaluation during Active Treatment (see Section 4.0). 
2. Submission of these reports is only required for documentation of CR or progression.  For 
documentation of CR, submit all of these reports at the first confirmation of CR.  For 
documentation of progression, submit one report for one of the measures where progression was 
seen.   Attention: QAS for MC1181. 
3. Only when required by the Test Schedule (see Section 4.0). 

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Follow-up Material(s)  
 
CRF 
Event Monitoring Phase1 
q. 6 months 
until PD or 
subsequent 
treatment for 
myeloma 2 
At PD or 
subsequent 
treatment 
for 
myeloma 2 
q. 12 months 
after PD or 
subsequent 
treatment for 
myeloma 
 
 
 
Death 
 
 
 
New Primary 
Event Monitoring Form
X
X
X
X
At each occurrence
 
1. If a patient is still alive 2 years after registration, no further follow-up is required. 
2. For documentation of progression, submit one report for one of the measures where progression was 
seen.   Attention: QAS for MC1181. 
 
19.0  
Budget 
 
 
19.1 
Costs charged to patient:  routine clinical care 
 
 
19.2 
Tests to be research funded: None 
 
19.3 
Ixazomib will be provided free of charge to study participants by Takeda/Millennium  
Pharmaceuticals, Inc.   Janssen Pharmaceuticals will provide the Daratumumab free of 
charge to the study participants (infusion and related costs will be charged to the 
patient/patients insurance).  
 
19.4 
Other budget concerns:  Protocol administration, study coordinator time, data 
management and statistical analysis efforts will be by funded by Millennium 
Pharmaceuticals, Inc.  
 
 
 

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20.0 
References 
 
Adams, J. (2001) Proteasome inhibition in cancer: development of PS-341. Semin Oncol, 28, 613-619. 
Adams, J. (2002a) Development of the proteasome inhibitor PS-341. The oncologist, 7, 9-16. 
Adams, J. (2002b) Development of the proteasome inhibitor PS-341. Oncologist, 7, 9-16. 
Adams, J., Behnke, M., Chen, S., Cruickshank, A.A., Dick, L.R., Grenier, L., Klunder, J.M., Ma, Y.T., 
Plamondon, L. & Stein, R.L. (1998) Potent and selective inhibitors of the proteasome: dipeptidyl 
boronic acids. Bioorganic & Medicinal Chemistry Letters, 8, 333-338. 
Adams, J., Palombella, V.J., Sausville, E.A., Johnson, J., Destree, A., Lazarus, D.D., Maas, J., Pien, C.S., 
Prakash, S. & Elliott, P.J. (1999) Proteasome inhibitors: a novel class of potent and effective 
antitumor agents. Cancer Research, 59, 2615-2622. 
An, W.G., Hwang, S.G., Trepel, J.B. & Blagosklonny, M.V. (2000) Protease inhibitor-induced apoptosis: 
accumulation of wt p53, p21WAF1/CIP1, and induction of apoptosis are independent markers of 
proteasome inhibition. Leukemia, 14, 1276-1283. 
Dai, Y., Rahmani, M. & Grant, S. (2003) Proteasome inhibitors potentiate leukemic cell apoptosis 
induced by the cyclin-dependent kinase inhibitor flavopiridol through a SAPK/JNK- and NF-
kappaB-dependent process. Oncogene, 22, 7108-7122. 
Hideshima, T., Richardson, P., Chauhan, D., Palombella, V.J., Elliott, P.J., Adams, J. & Anderson, K.C. 
(2001) The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug 
resistance in human multiple myeloma cells. Cancer Res, 61, 3071-3076. 
Jagannath, S., Richardson, P.G., Sonneveld, P., Schuster, M.W., Irwin, D., Stadtmauer, E.A., Facon, T., 
Harousseau, J.L., Cowan, J.M. & Anderson, K.C. (2007) Bortezomib appears to overcome the 
poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia, 21, 151-
157. 
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958; 
53:457-481. 
Kumar, S.K., Berdeja, J.G., Niesvizky, R., Lonial, S., Hamadani, M., Stewart, A.K., Roy, V., Hari, P., 
Vescio, R., Berg, D., Lin, J., Bacco, A.D., Gupta, N., Hui, A.-M. & Richardson, P.G. (2012) A 

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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). ASH Annual Meeting Abstracts, 120, 332-. 
Kumar, S.K., Rajkumar, S.V., Dispenzieri, A., Lacy, M.Q., Hayman, S.R., Buadi, F.K., Zeldenrust, S.R., 
Dingli, D., Russell, S.J., Lust, J.A., Greipp, P.R., Kyle, R.A. & Gertz, M.A. (2008) Improved 
survival in multiple myeloma and the impact of novel therapies. Blood, 111, 2516-2520. 
Kyle, R.A., Gertz, M.A., Witzig, T.E., Lust, J.A., Lacy, M.Q., Dispenzieri, A., Fonseca, R., Rajkumar, 
S.V., Offord, J.R., Larson, D.R., Plevak, M.E., Therneau, T.M. & Greipp, P.R. (2003) Review of 
1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc, 78, 21-33. 
Ling, Y.H., Liebes, L., Ng, B., Buckley, M., Elliott, P.J., Adams, J., Jiang, J.D., Muggia, F.M. & Perez-
Soler, R. (2002) PS-341, a novel proteasome inhibitor, induces Bcl-2 phosphorylation and 
cleavage in association with G2-M phase arrest and apoptosis. Mol Cancer Ther, 1, 841-849. 
Pocock, S.J. & Simon, R. (1975) Sequential treatment assignment with balancing for prognostic factors in 
the controlled clinical trial. Biometrics, 31, 103-115. 
Richardson, P.G., Barlogie, B., Berenson, J., Singhal, S., Jagannath, S., Irwin, D., Rajkumar, S.V., 
Srkalovic, G., Alsina, M., Alexanian, R., Siegel, D., Orlowski, R.Z., Kuter, D., Limentani, S.A., 
Lee, S., Hideshima, T., Esseltine, D.L., Kauffman, M., Adams, J., Schenkein, D.P. & Anderson, 
K.C. (2003a) A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med, 348, 
2609-2617. 
Richardson, P.G., Hideshima, T. & Anderson, K.C. (2003b) Bortezomib (PS-341): a novel, first-in-class 
proteasome inhibitor for the treatment of multiple myeloma and other cancers. Cancer Control, 
10, 361-369. 
Richardson, P.G., Sonneveld, P., Schuster, M.W., Irwin, D., Stadtmauer, E.A., Facon, T., Harousseau, 
J.L., Ben-Yehuda, D., Lonial, S., Goldschmidt, H., Reece, D., San-Miguel, J.F., Blade, J., 
Boccadoro, M., Cavenagh, J., Dalton, W.S., Boral, A.L., Esseltine, D.L., Porter, J.B., Schenkein, 
D. & Anderson, K.C. (2005) Bortezomib or high-dose dexamethasone for relapsed multiple 
myeloma. The New England journal of medicine, 352, 2487-2498. 

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Shah, S.A., Potter, M.W., McDade, T.P., Ricciardi, R., Perugini, R.A., Elliott, P.J., Adams, J. & Callery, 
M.P. (2001) 26S proteasome inhibition induces apoptosis and limits growth of human pancreatic 
cancer. J Cell Biochem, 82, 110-122. 
Sunwoo, J.B., Chen, Z., Dong, G., Yeh, N., Crowl Bancroft, C., Sausville, E., Adams, J., Elliott, P. & 
Van Waes, C. (2001) Novel proteasome inhibitor PS-341 inhibits activation of nuclear factor-
kappa B, cell survival, tumor growth, and angiogenesis in squamous cell carcinoma. Clin Cancer 
Res, 7, 1419-1428. 
Teicher, B.A., Ara, G., Herbst, R., Palombella, V.J. & Adams, J. (1999) The proteasome inhibitor PS-341 
in cancer therapy. Clin Cancer Res, 5, 2638-2645. 
 
 
 

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Appendix I 
ECOG Performance Status Scale 
 
SCORE  
DESCRIPTION  
0  
Fully active, able to carry on all pre-disease performance without 
restriction.  
1  
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light housework, office 
work.  
2  
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours.  
3  
Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours.  
4  
Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair.  
5  
Dead.  
 

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Appendix II 
 
Mayo Risk Stratification 
 
 
 
 
 
 
 
 
 
 
 
 
High Risk 
FISH deletion 17p 
FISH t(4:14) 
FISH t(14:16) 
Metaphase cytogenetic del 13 
Hypodiploidy 
PCLI >3% 
 

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Appendix III 
 
NYHA Classification 
 
Class I:  
NO Symptoms with ordinary activity  
Class II:  
Symptoms with ordinary activity  
Class III:  Symptoms with minimal activity 
Class IV:  Symptoms at rest 
 

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Appendix IV 
Multiple Myeloma Diagnostic Criteria 
 
 
Standard criteria for a diagnosis of multiple myeloma are as follows (Kyle et al British Journal of 
Haematology. 121(5):749-57, 2003)  
 
Multiple Myeloma 
Monoclonal protein present in serum ≥ 3 g/dl 
and/or 
Bone marrow clonal plasma cells ≥ 10% 
 
Myeloma-related organ or tissue impairment (ROTI) 
Calcium 1 mg/dL (0.25 mmol/L) above the upper limit of normal 
Creatinine > 2 mg/dL (173 mmol/L) 
Lytic bone lesions or osteoporosis 
 
Asymptomatic myeloma 
Multiple myeloma and absence of ROTI 
 
Symptomatic myeloma 
Multiple myeloma and presence of any ROTI that can be attributed to myeloma. 
 

 
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Name ______________________ 
 
 
 
Study No. MC1181 
Mayo Clinic No. ______________ 
Appendix V 
PATIENT MEDICATION DIARY Arm  D    
 
Please complete this diary on a daily basis. Write in the amount of the dose of dexamethasone that you took 
in the appropriate “Day” box. 
On the days that you do not take any study drug, please write in “0”. If you forget to take your daily 
dose, please write in “0”, but remember to take your prescribed dose at the next regularly scheduled 
time. 
Swallow ixazomib capsules whole, with water, and not to break, chew, or open the capsules. The study 
drug should be taken on an empty stomach, at least 1 hour before or no sooner than 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. 
The Cyclophosphamide will be discontinued after 18 cycles.  
If you experience any health/medical complaints or take any medication other than the study medications, 
please record this information. 
 
Week of:                                                    
 
Study Drug 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Ixazomib 
Cyclophosphamide 
Dexamethasone 
 
Week of:                                                    
 
Study Drug 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Ixazomib 
Cyclophosphamide
Dexamethasone 
 
Week of:                                                    
 
Study Drug 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Ixazomib 
Cyclophosphamide 
Dexamethasone 
 
Week of:                                                    
 
Study Drug 
Day 22 Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
Ixazomib 
Cyclophosphamide  
 
 
 
 
 
 
Dexamethasone 
My next scheduled visit is:                                                                
If you have any questions, please call:          
 
Patient signature: ______________________________________________ Date:_________________ 

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Appendix VI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Name ______________________ 
 
 
 
Study No. MC1181 
Mayo Clinic No. ______________ 
Appendix VII 
PATIENT MEDICATION DIARY (Arms A-C, closed) 
 
Please complete this diary on a daily basis. Write in the amount of the dose of ixazomib and 
dexamethasone that you took in the appropriate “Day” box. 
 
On the days that you do not take any study drug, please write in “0”. If you forget to take your daily dose, 
please write in “0”, but remember to take your prescribed dose at the next regularly scheduled time. 
 
Your study medication should be taken on an empty stomach, at least 1 hour before or no sooner than 2 
hours after a meal.  Each capsule should be swallowed separately with a sip of water.  A total of 
approximately 150 mL of water (5 fluid ounces or 2/3 cup) should be taken with the capsules. 
 
If you experience any health/medical complaints or take any medication other than ixazomib or 
dexamethasone, please record this information. 
 
Week of: _________________________ 
 
Study Drug
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Ixazomib
Dexamethasone
 
Week of: _________________________ 
 
Study Drug
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Ixazomib
Dexamethasone
 
Week of: _________________________ 
 
Study Drug
Day 15
Day 16
Day 17
Day 18
Day 19
Day 20
Day 21
Ixazomib
Dexamethasone
 
Week of: _________________________ 
 
Study Drug
Day 22
Day 23
Day 24
Day 25
Day 26
Day 27
Day 28
ixazomib
Dexamethasone
 
Patient signature: ______________________________________________ Date:_________________ 
 
 
My next scheduled visit is: _______________________________ 
If you have any questions, please call:  _____________________ 
 
 

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Name ______________________ 
 
 
 
Study No. MC1181 
Mayo Clinic No. ______________ 
Appendix VIII 
 PATIENT MEDICATION DIARY (Arm E) 
 
Please complete this diary on a daily basis. Write in the amount of the dose of ixazomib and 
dexamethasone that you took in the appropriate “Day” box. 
 
On the days that you do not take any study drug, please write in “0”. If you forget to take your daily dose, 
please write in “0”, but remember to take your prescribed dose at the next regularly scheduled time. 
 
Your study medication should be taken on an empty stomach, at least 1 hour before or no sooner than 2 
hours after a meal.  Each capsule should be swallowed separately with a sip of water.  A total of 
approximately 150 mL of water (5 fluid ounces or 2/3 cup) should be taken with the capsules. 
 
The Cyclophosphamide will be discontinued after 12 cycles. 
 
If you experience any health/medical complaints or take any medication other than ixazomib or 
dexamethasone, please record this information. 
 
Week of: _________________________ 
 
Study Drug
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Ixazomib
Cyclophosphamide
Dexamethasone
 
Week of: _________________________ 
 
Study Drug
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Ixazomib
Cyclophosphamide
Dexamethasone
 
Week of: _________________________ 
 
Study Drug
Day 15
Day 16
Day 17
Day 18
Day 19
Day 20
Day 21
Ixazomib
Cyclophosphamide
Dexamethasone
 
Week of: _________________________ 
 
Study Drug 
Day 22 
Day 23 
 
 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
 

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Ixazomib 
 
 
 
 
 
 
 
 
 
 
Cyclophosphamide 
 
 
 
 
 
 
 
 
 
Dexamethasone 
 
 
 
 
 
 
 
 
 
Patient signature: ______________________________________________ Date:_________________ 
 
 
My next scheduled visit is: _______________________________ 
If you have any questions, please call:  _____________________