Clinical trial NCT02547662
Conditions: Plasma Cell Leukemia Plasma Cell Myeloma Plasmacytoma
Sponsor: Mayo Clinic
Start date: 2015-12-24; Completion date: 2020-10-30
Enrollment: 17 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well pomalidomide, ixazomib citrate, and dexamethasone work in treating patients with previously treated multiple myeloma or plasma cell leukemia. Biological therapies, such as pomalidomide and dexamethasone, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop cancer cells from growing. Ixazomib citrate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving pomalidomide, ixazomib citrate, and dexamethasone together may be more effective in treating multiple myeloma.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the confirmed response rate (\>= partial response \[PR\]) of ixazomib citrate (ixazomib), used in combination with pomalidomide and dexamethasone in patients with previously treated multiple myeloma (MM) with extramedullary disease.

SECONDARY OBJECTIVES:

I. To determine the toxicities associated with ixazomib in combination with pomalidomide and dexamethasone in patients with previously treated MM with extramedullary disease.

II. To determine the differential response rates (biochemical versus extramedullary disease) with ixazomib in combination with pomalidomide and dexamethasone in patients with previously treated MM with extramedullary disease.

III. To determine the progression free survival following treatment with ixazomib in combination with pomalidomide and dexamethasone in patients with previously treated MM with extramedullary disease.

TERTIARY OBJECTIVES:

I. To assess the proportion of patients achieving minimal residual disease (MRD) negative status.

OUTLINE:

Patients receive ixazomib citrate orally (PO) on days 1, 8, and 15, pomalidomide PO on days 1-21, and dexamethasone PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 or 6 months for up to 3 years.

Arms: arm 1: Patients receive ixazomib citrate PO on days 1, 8, and 15, pomalidomide PO on days 1-21, and dexamethasone PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Dexamethasone intervention 2: Ixazomib Citrate intervention 3: Laboratory Biomarker Analysis intervention 4: Pomalidomide
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Correlative studies intervention 4: Given PO

Protocol documents:
Prot_SAP_ICF_000.pdf: 




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Table of Contents 
Phase 2 Trial of Pomalidomide, Ixazomib and Dexamethasone in Patients with Multiple 
Myeloma with Extramedullary Disease or Plasma Cell Leukemia ................................................ 1 
Protocol Resources.......................................................................................................................... 2 
Table of Contents ............................................................................................................................ 3 
Schema 
 ............................................................................................................................... 4 
1.0 
Background ...................................................................................................................... 5 
2.0 
Goals............................................................................................................................... 18 
3.0 
Patient Eligibility ............................................................................................................ 19 
4.0 
Test Schedule ................................................................................................................. 22 
5.0 
Grouping Factor: None................................................................................................... 24 
6.0 
Registration Procedures.................................................................................................. 24 
7.0 
Protocol Treatment ......................................................................................................... 26 
8.0 
Dosage Modification Based on Adverse Events ............................................................ 27 
9.0 
Ancillary Treatment/Supportive Care ............................................................................ 34 
10.0 
Adverse Event (AE) Reporting and Monitoring ......................................................... 37 
11.0 
Treatment Evaluation ................................................................................................. 47 
12.0 
Descriptive Factors ..................................................................................................... 52 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient ........................................... 52 
14.0 
Biospecimens .............................................................................................................. 54 
15.0 
Drug Information ........................................................................................................ 57 
16.0 
Statistical Considerations and Methodology .............................................................. 65 
17.0 
Pathology Considerations/Tissue Biospecimens ........................................................ 70 
18.0 
Records and Data Collection Procedures ................................................................... 70 
19.0  
Budget ..................................................................................................................... 7170 
20.0 
References .............................................................................................................. 7271 
Appendix I 
ECOG Performance Status .............................................................................. 7473 
Appendix II 
Patient Medication Diary ................................................................................ 7574 
Appendix III 
Drug Classification Guide ............................................................................... 7675 
Appendix IV 
Pomalidomide Education and Counselling Guidance Document ................... 7877 
Appendix V 
MC1487 Model Consent Form ....................................................................... 8382 
 




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1.0 
Background 
1.1 Multiple Myeloma: Multiple myeloma is a malignancy of the differentiated plasma cells that 
affect the older patient with a median age at onset of 65-70 years and a slight male 
predominance. Nearly 20,000 patients with myeloma are diagnosed in the United States each 
year, and despite considerable improvements in therapy remains incurable and uniformly 
fatal with a median overall survival of around 8 years. Recent improvements in therapies 
have significantly improved the survival outcomes, but given the inevitable relapses seen in 
these patients, new approaches to therapy are clearly needed. The highly effective drug 
combinations currently used are beset with a degree of toxicity that precludes long-term 
therapy and also can affect the quality of life metrics. Finally, some of these regimens require 
IV or subcutaneous administration, which can require frequent clinic, visits for patients. The 
highly effective multi-drug regimens currently in use typically include a proteasome 
inhibitor, either bortezomib given IV or SQ or carfilzomib given IV and an IMiD (typically 
lenalidomide or pomalidomide). 
 
1.2 Implications of extramedullary disease in multiple myeloma: MM is characterized by 
accumulation of the clonal plasmacytomas (PCs) predominantly in the bone marrow (BM), 
highlighting the dependence of the tumor on the marrow microenvironment. While all 
patients with monoclonal gammopathies have some level of circulating plasma cells, 
development of large numbers of plasma cells in the peripheral blood, referred to as plasma 
cell leukemia (PCL), has been uncommon.(Kumar et al. 2005) Rarely patients present with 
solid tumors (solitary or multiple) in the soft tissue and major organs called “extramedullary 
plasmacytomas” (EMP) or extramedullary disease (EMD). Recently, others and we have 
observed a disconcerting increase in the incidence of EMD in patients with MM.(Short et al. 
2011, Usmani et al. 2012) These patients abruptly develop soft tissue masses, effusions, and 
plasmacytomas in major organs and the central nervous system.(Rosinol et al. 2004, Madan 
et al. 2009, Varettoni et al. 2009) Patients with EMD have a poor prognosis, are often 
difficult to treat, and are refractory to most of the currently available drugs. In fact, 
development of EMD is associated with a very poor survival in patients with MM. Some 
studies have suggested that the malignant PCs in EMD have acquired additional genetic 
changes such as deletion of p53 gene.(Sheth et al. 2009, Lopez-Anglada et al. 2010) The 
increased occurrence of EMD may also reflect that patients are living longer thus allowing us 
to observe later stages of natural MM evolution that we were unable to witness in the past. 
However preliminary data from our studies indicate that this is not the sole explanation; in 
fact, the increased incidence of EMD may, in part, be related to specific therapies.(Short, 
Rajkumar et al. 2011) There is an urgent need to develop new treatment approaches for EMD 
and plasma cell leukemia with new as well as currently available drugs. 
 
We studied a large cohort of 1053 patients with MM seen at Mayo Clinic between January1, 
2001, and December 31, 2010, for development of EMD during routine clinical follow up. 
Among these, 93 patients (8.8%) were identified to have EMD at some point during the 
disease course, with median time to EMD detection of 11 months (range 0 – 10 years). 
Patients who developed EMD at any time during the disease course had a shorter overall 
survival compared with the rest (3.3 vs. 5.2 years, P <0.01). Development of EMD was 
associated with presence of high-risk FISH abnormalities, especially del17p, elevated serum 
LDH and high plasma cell labeling index at diagnosis; (P <0.05 for all comparisons). We 
then studied 174 MM patients with relapsed refractory MM who enrolled on a clinical trial of 
pomalidomide between 2007-2010, in order to estimate the incidence of EMD in recent 
years.(Short, Rajkumar et al. 2011) At trial entry, the rate of treatment-emergent EMD was 
7.5% (13 of 174 patients). EMD was associated with poor survival; median OS from trial 


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entry was 16 months with EMP versus not reached, in the rest, P=0.002). Following trial 
entry, 4 of the 13 patients with EMD responded to treatment. Clearly these studies suggest 
that tumor cell characteristics at the time of diagnosis that confer the myeloma cell with the 
ability to survive outside the marrow microenvironment. 
 
1.3 Ixazomib: Ixazomib, which has been formulated for both intravenous (IV) and oral (PO) 
administration, is a small molecule proteasome inhibitor. It is the citrate ester of the 
biologically active boronic acid form, MLN2238, which is structurally similar to bortezomib. 
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 (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. 
 
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 


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acid (DNA) damage-inducible protein 34 (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. 
 
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 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 


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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 
>30μM, with an estimated inhibition dissociation constant [Ki] >15μM), 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. 
 
Ixazomib 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, 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. 
 
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 


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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. 
• 
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. 
 
Clinical Experience with Ixazomib: Like bortezomib, ixazomib is a small molecule peptide 
boronic acid analog. Ixazomib is the first investigational proteasome inhibitor with 
substantial oral bioavailability in patients with multiple myeloma.  
 
Ixazomib has been evaluated as an oral single agent in phase 1 studies that have included 
patients with advanced solid tumors, lymphoma, relapse/refractory MM (RRMM), and 
relapsed or refractory light-chain (AL) amyloidosis and demonstrated early signs of activity. 
Ongoing studies continue to investigate both single-agent ixazomib and ixazomib in 
combination with standard treatments. Based on encouraging preliminary data observed in 
patients with MM requiring systemic treatment, two phase 3 trials in newly diagnosed MM 
(NDMM) (C16014) and RRMM (C16010) patient populations are currently evaluating 
ixazomib in combination with lenalidomide (Revlimid®) and dexamethasone (RevDex) 
versus placebo/RevDex. Both trials are combining ixazomib at a weekly dose of 4.0 mg on 
Days 1, 8, and 15 in a 28-day cycle to a standard dose of lenalidomide with a weekly 
dexamethasone dose of 40 mg. In addition, ongoing clinical pharmacology studies include 
evaluation of drug-drug interactions with ketoconazole and rifampin, effect of food, and oral 
bioavailability. Studies evaluating the safety and pharmacokinetic (PK) of ixazomib alone (in 
Japanese patients) and in combination with lenalidomide and dexamethasone in Asian adult 
patients (including Japanese patients) with a diagnosis of NDMM are ongoing. 
 


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As of 27 March 2013, preliminary clinical data are available for a total of 653 patients across 
13 studies. The emerging safety profile indicates that ixazomib is generally well tolerated. 
The adverse events (AEs) are consistent with the class-based effects of proteasome inhibition 
and are similar to what has been previously reported with bortezomib though the severity of 
some, for example peripheral neuropathy, is less. While some of these potential toxicities 
may be severe, they can be managed by clinical monitoring and standard medical 
intervention, or, as needed, dose modification or discontinuation. 
 
Fatigue was the most common AE reported among 384 patients treated in the oral (PO) 
studies (47%). Other common AEs reported in the pooled intravenous (IV) and PO safety 
populations include nausea, thrombocytopenia, diarrhea, and vomiting. Rash is also a 
commonly reported treatment-emergent event; however, there is some variety in its 
characterization and causality resulting in different preferred terms to describe it. A high-
level term outline of rash events includes rashes, eruptions and exanthems NEC; pruritus 
NEC; erythemas; papulosquamous conditions; and exfoliative conditions. The dose escalation 
phases of most trials reported in the IB have now completed enrollment, and gastrointestinal 
(GI) symptoms were the common dose-limiting toxicities (DLTs) when the use of 
prophylactic anti-emetics was not permitted per protocol. In the expansion cohorts or phase 2 
cohorts ( per each study), the incidence and severity of GI symptoms was mitigated by the 
use of the lower maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) ( per 
each study) and standard clinical usage of anti-emetics and/or antidiarrheal medications as 
deemed appropriate.  
 
The most frequent (at least 20%) treatment-emergent adverse events (TEAEs) reported with 
the PO formulation pooled from single-agent studies (n=201) irrespective of causality to 
ixazomib, include nausea (53%), fatigue (51%), diarrhea (44%), thrombocytopenia (34%), 
vomiting (38%), decreased appetite (32%), fever (21%), and anemia (21%). The most 
frequent (at least 20%) TEAEs reported with the PO formulation pooled from combination 
trials (irrespective of the combination) (n=173), irrespective of causality to ixazomib, include 
diarrhea (47%), fatigue (44%), nausea (38%), peripheral edema (35%), constipation (33%), 
insomnia (29%), thrombocytopenia (28%), anemia (26%), vomiting (26%), neutropenia 
(25%), back pain (24%), pyrexia (23%), peripheral edema (21%, each), fever (20%), cough 
(20%), hypokalemia (20%), neutropenia (20%), and upper respiratory tract infection (20%). 
Overall rash of all grades is reported in approximately 50% of patients and is more common 
when ixazomib is given in combination with lenalidomide, where rash is an overlapping 
toxicity. 
 
Pharmacokinetics and Drug Metabolism: Clinical IV and PO PK data show that 
ixazomib citrate (measured as the biologically active boronic acid form of ixazomib 
[MLN2238]) has multi-exponential disposition with a rapid initial phase that is largely over 
by 4 hours. Oral ixazomib citrate is rapidly absorbed with a median single-dose first time of 
occurrence of maximum (peak) concentration (Tmax) of approximately 0.5 to 2.0 hours and a 
terminal disposition half-life (t1/2) after multiple dosing of approximately 5 to 7 days. 
Results of a population PK analysis (n = 137) show that there is no relationship between body 
surface area (BSA) or body weight and clearance (CL). Also, based on stochastic simulations 
for fixed dose, exposures are independent of the individual patient’s BSA.(Gupta et al. 2011, 
Gupta et al. 2012) Based on these data, a recommendation was made for fixed dosing in 
clinical trials. An absolute bioavailability of 67% was determined for ixazomib using the 
population PK analysis. Please refer to the current ixazomib IB and Safety Management 
Attachment (SMA) for information on the PK for IV doses of ixazomib. 
 


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Clinical Study C16009 (Arm 1) with ketoconazole, a strong CYP3A4 inhibitor, showed a 2-
fold increase in area under the plasma concentration versus time curve (AUC) in the presence 
of ketoconazole. This resulted in the continued exclusion of strong CYP3A4 inhibitors in 
ongoing/planned clinical studies. 
 
Clinical Trial Experience Using the Oral Formulation of Ixazomib: As of 27 March 2013, a 
total of 507 patients with differing malignancies (multiple myeloma, AL amyloidosis, 
nonhematologic cancers, and lymphoma) have been treated in studies evaluating the oral 
ixazomib formulation. These patients have been treated with different doses of ixazomib 
either as a single-agent treatment (in 201 patients) or in combination with currently clinically 
available treatments (in 306 patients). Information regarding the ongoing studies, patient 
populations, and doses investigated is included in Table 1-1. 
Table 1-1 
Clinical Studies of Oral Ixazomib 
Trial/ 
Population 
Description 
Doses Investigated 
C16003 
RRMM 
N = 60 
PO, TW, single agent 
0.24-2.23 mg/m2 TW 
MTD:  2.0 mg/m2 
DLT:  rash, thrombocytopenia 
Closed to enrollment 
C16004 
RRMM 
N = 60 
PO, W, single agent 
0.24-3.95 mg/m2 W 
MTD:  2.97 mg/m2 
DLT:  rash, nausea, vomiting, diarrhea 
Closed to enrollment 
C16005 
NDMM 
N = 65 
PO, W, combination with LenDex 
28-day cycle 
1.68-3.95 mg/m2 W 
MTD:  2.97 mg/m2 
DLT:  nausea, vomiting, diarrhea, syncope 
RP2Da:  4.0 mg fixed (switched to fixed dosing in 
phase 2, equivalent  to 2.23mg/m2) 
Closed to enrollment 
C16006 
NDMM 
N = 20 
PO, TW (Arm A- 42 day cycle) and 
W (Arm B- 28 day cycle), 
combination with Melphalan and 
Prednisone 
Arm Aa:  3-3.7-mg fixed dose TW 
DLT:  rash, thrombocytopenia, subileus 
Arm Ba:  3-5.5-mg fixed dose, W 
DLT:  Esophageal ulcer nausea, vomiting, 
hematemesis, thrombocytopenia, ileus, 
neurogenic bladder 
MTD = 3.0 mg 
C16007 
RRAL 
N = 27 
PO, W, single agent 
4-5.5-mg fixed dosea W 
DLT:  thrombocytopenia, diarrhea, dyspnea, acute 
rise in creatinine, cardiac arrest  
MTD:  4.0  mg W 
C16008 
NDMM 
N = 64 
PO, TW, combination with LenDex 
21-day cycle 
3.0-3.7-mg fixed dosea W 
MTD:  3.0 mg 
Closed to enrollment 
C16009 
Solid tumors, 
Lymphomas 
PO, W, single agent 
5.5-mg fixed dosea W 


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Table 1-1 
Clinical Studies of Oral Ixazomib 
Trial/ 
Population 
Description 
Doses Investigated 
N = 54 
C16010 
RRMM 
N = 200 
PO, W, with LenDex versus placebo-
LenDex 
4.0 mg W 
C16011 
RRAL 
N = 4 
PO, W, with Dex versus physician’s 
choice of a Dex-based regimen 
4.0 mg W 
C16013 
RRMM 
N = 9 
PO, W, with LenDex 
4.0 mg W 
C16014 
Symptomatic MM 
N=701 
PO, combination with LenDex 
ixazomib 4.0 mg or matching placebo on Days 1, 
8, and 15, plus Len 25 mg on Days 1-21 (10 mg if 
low creatinine clearance, with escalation to 15 mg 
if tolerated) and Dex 40 mg (or 20 mg if 
>75 years old) on Days 1, 8, 15, and 22 
C16015 
Symptomatic MM 
with normal renal 
function or severe 
renal impairment 
N=28 
PO, combination with Dex 
Part A: ixazomib  3.0 mg on Day 1 
Part B: ixazomib  4.0 mg on Days 1, 8, and 15, 
plus Dex 40 mg (or 20 mg if >75 years old) on 
Days 1, 8, 15 and 22 of a 28-day cycle 
C16017 
RR follicular 
lymphoma 
N=58 
PO, W 
4.0, 5.3, and 7.0 mg, W 
Treatment at RP2D once determined. 
C16018 
Advanced solid 
tumors or 
hematologic 
malignancies with 
varying degrees of 
liver dysfunction 
N=45 
Part A: PO, Day 1 of 15-day cycle 
Part B: PO, W 
1.5 mg (severe hepatic impairment), 2.3 mg 
(moderate hepatic impairment), or 4.0 mg 
(normal hepatic function) 
TB-MC010034 
RRMM 
N = 10 
PO, W 
4.0 mg, W 
Single agent: 4.0 mg 
Combination with Rd 
Abbreviations: RRAL = Relapsed and/or refractory Primary systemic light chain (AL) amyloidosis; BSA = body 
surface area; Dex=dexamethasone; DLT = dose-limiting toxicity; IV = intravenously; LenDex = lenalidomide 
plus dexamethasone; MTD = maximum tolerated dose; NDMM = newly diagnosed multiple myeloma; PO = 
orally; RR= relapsed and/or refractory; RRAL= relapsed and/or refractory systemic light chain amyloidosis 
RRMM = relapsed and/or refractory multiple myeloma; TBD = to be determined; TW = twice weekly; W = 
weekly; RP2D= recommended phase 2 dose. 
Note that blinded data from pivotal Studies C16010 and C16011 are not included. 
a Approximate BSA and fixed dosing equivalence: 3 mg~ equivalent to 1.68 mg/m2 BSA dosing; 4.0 mg ~ 
equivalent to 2.23 mg/m2 BSA dosing; and 5.5 mg~ equivalent to 2.97 mg/m2 BSA dosing 


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1.4 Potential Risks of Ixazomib:  
The emerging safety profile indicates that ixazomib is generally well tolerated. The adverse 
events (AEs) are consistent with the class-based effects of proteasome inhibition and are 
similar to what has been previously reported with bortezomib, though the severity of some, 
for example peripheral neuropathy, is less. While some of these potential toxicities may be 
severe, they can be managed by clinical monitoring and standard medical intervention, or, as 
needed, dose modification or discontinuation. In the four ongoing studies (C16003, C16004, 
C16007, and C16009) investigating single-agent oral ixazomib in patients with differing 
malignancies (multiple myeloma, AL amyloidosis, non-hematologic cancers, and 
lymphoma), a total of 201 patients have been treated as of 27 March 2013. These patients 
have been treated with different doses of ixazomib, as they are all phase 1 trials. An overview 
of the most frequent (at least 10%) AEs occurring in the pooled safety population from 
single-agent oral ixazomib studies (C16003, C16004, C16007, and C16009) are shown in 
Table 1-2. 
Table 1-2 Most Common (At Least 10% of Total) Treatment-Emergent Adverse Events in 
Oral Single-Agent Studies 
Primary System Organ Class 
Preferred Term 
Oral Single Agent 
Total n=201 (n%) 
Subjects with at Least One Adverse Event 
197 (98) 
Gastrointestinal disorders 
160 (80) 
 Nausea 
106 (53) 
 Diarrhea 
88 (44) 
 Vomiting 
77 (38) 
 Constipation 
46 (23) 
 Abdominal pain 
33 (16) 
General disorders and administration site 
conditions 
151 (75) 
 Fatigue 
103 (51) 
 Pyrexia 
51 (25) 
 Edema peripheral 
27 (13) 
 Asthenia 
31 (15) 
Nervous system disorders 
92 (46) 
 Headache 
29 (14) 
 Dizziness 
26 (13) 
 Neuropathy peripheral 
21 (10) 
Metabolism and nutrition disorders 
107 (53) 
 Decreased appetite 
64 (32) 
 Dehydration 
37 (18) 
Blood and lymphatic system disorders 
98 (49) 
 Thrombocytopenia 
68 (34) 
 Anemia 
42 (21) 
 Neutropenia 
29 (14) 
 Lymphopenia 
20 (10) 
Skin and subcutaneous tissue disorders 
90 (45) 
 Rash maculara 
23 (11) 
Musculoskeletal and connective tissue disorders 
93 (46) 
 Back pain 
24 (12) 
 Arthralgia 
28 (14) 
Respiratory, thoracic and mediastinal disorders 
78 (39) 


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Table 1-2 Most Common (At Least 10% of Total) Treatment-Emergent Adverse Events in 
Oral Single-Agent Studies 
Primary System Organ Class 
Preferred Term 
Oral Single Agent 
Total n=201 (n%) 
 Cough 
28 (14) 
 Dyspnea 
30 (15) 
Infections and infestations 
89 (44) 
 Upper respiratory tract infection 
31 (15) 
Source: Ixazomib Investigator’s Brochure Edition 7 
Abbreviations: MedDRA = Medical Dictionary for Regulatory Activities, version 15.0. 
Subject Incidence: A subject counts once for each preferred term. Percentages use the 
number of treated subjects as the denominator. 
a 
Note that rash maculopapular and rash macular represent the two most common terms 
used to describe rash. 
 
As of 27 March 2013, there are 5 studies actively enrolling patients with multiple myeloma to investigate 
oral ixazomib in combination with standard combination regimens. The most frequent (at least 10%) AEs 
occurring in the pooled safety population from Studies C16005, C16006, C16008, and C16013 are shown 
for all grades (Table 1-3). Note that in combination trials, “related” is defined as related to any study drug 
in the combination regimen. 
 
Table 1-3 Most Common (At Least 10% of Total) Treatment-Emergent Adverse Events in Oral 
Combination Studies 
Primary System Organ Class 
Preferred Term 
Total Oral Combo Agent 
(5/6/8/13) 
n = 173 (n%) 
Subjects with at Least One Adverse 
Event 
163 (94) 
Gastrointestinal disorders 
139 (80) 
 Nausea 
65 (38) 
 Diarrhea 
81 (47) 
 Vomiting 
51 (29) 
 Constipation 
57 (33) 
General disorders and administration 
site conditions 
132 (76) 
 Fatigue 
76 (44) 
 Pyrexia 
39 (23) 
 Edema peripheral 
61 (35) 
 Asthenia 
20 (12) 
Nervous system disorders 
115 (66) 
 Headache 
28 (16) 
 Dizziness 
34 (20) 
 Neuropathy peripheral 
45 (26) 
Metabolism and nutrition disorders 
91 (53) 
 Decreased appetite 
25 (14) 
 Hypokalemia 
34 (20) 
Blood and lymphatic system disorders 
88 (51) 
 Thrombocytopenia 
49 (28) 
 Anemia 
45 (26) 
 Neutropenia 
43 (25) 
 Lymphopenia 
20 (12) 


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Table 1-3 Most Common (At Least 10% of Total) Treatment-Emergent Adverse Events in Oral 
Combination Studies 
Primary System Organ Class 
Preferred Term 
Total Oral Combo Agent 
(5/6/8/13) 
n = 173 (n%) 
Skin and subcutaneous tissue 
disorders 
102 (59) 
 Rash maculopapular 
29 (17) 
 Rash maculara 
22 (13) 
Musculoskeletal and connective tissue 
disorders 
99 (57) 
 Back pain 
42 (24) 
 Pain in extremity 
31 (18) 
 Arthralgia 
22 (13) 
Respiratory, thoracic and mediastinal 
disorders 
80 (46) 
 Cough 
36 (21) 
 Dyspnea 
26 (15) 
Infections and infestations 
92 (53) 
 Upper respiratory tract infection 
35 (20) 
Psychiatric disorders 
73 (42) 
 Insomnia 
50 (29) 
Source: Ixazomib Investigator’s Brochure Edition 7 
Abbreviations: MedDRA = Medical Dictionary for Regulatory Activities, version 15.0 
Subject Incidence: A subject counts once for each preferred term. Percentages use the 
number of treated subjects as the denominator.  
Data from ongoing blinded pivotal trials (C16010) are not included. 
a 
Note that rash maculopapular and rash macular represent the two most common terms 
used to describe rash 
 
The clinical experience with ixazomib also shows early signs of antitumor activity as 
evidenced by at least a 50% reduction in disease burden in some patients and prolonged 
disease stabilization in others across all ongoing trials. The antitumor activity has been seen 
with single-agent ixazomib, when combined with established therapies, and across the 
malignancies studied (advanced solid tumors, non-Hodgkin’s disease, Hodgkin’s disease, 
relapsed and/or refractory multiple myeloma, relapsed or refractory systemic light chain 
amyloidosis, and newly diagnosed multiple myeloma) to date.(Kumar et al. 2014, Kumar et 
al. 2014, Kumar et al. 2014, Richardson et al. 2014) 
 
1.5 Pomalidomide: Pomalidomide, a thalidomide analogue, is an immunomodulatory agent that 
displays similar anti-angiogenic activity, but far greater anti-proliferative and 
immunomodulatory activity compared to the parent drug. Pomalidomide has also been shown 
to stimulate antibody-dependent cytotoxic T-cell activity (ADCC). 
 
The efficacy of pomalidomide in relapsed myeloma has been shown in multiple 
trials.(Streetly et al. 2008, Lacy et al. 2009, Lacy et al. 2010, Lacy et al. 2011, San Miguel et 
al. 2013, Leleu et al. 2015) At tolerated doses (MTD=2 mg QD and 5 mg QOD), 
pomalidomide has been shown to be active in subjects with relapsed or refractory multiple 
myeloma (MM) (study CC-4047-00-001). In 45 subjects who received doses of 
pomalidomide ranging, by cohort, up to 10 mg daily, the most commonly occurring dose-
limiting toxicity (DLT) was reversible neutropenia. As with other IMiDs administered to 


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subjects receiving concomitant systemic steroids, deep vein thrombosis (DVT) was seen (in 
1subject each in this study and in its subsequent named patient supply rollover program). 
 
Preliminary efficacy and safety data from an ongoing phase II study, led by Martha Lacy, et 
al, at Mayo Clinic, were published. Sixty patients with relapsed or refractory multiple 
myeloma were enrolled. Pomalidomide (CC-4047) was given orally at a dose of 2 mg daily 
on days 1-28 of a 28-day cycle and dexamethasone was given orally at a dose of 40 mg daily 
on days 1, 8, 15, 22 of each cycle. Patient also received aspirin 325 mg once daily for 
thromboprophylaxis. The study endpoints were the response rate in patients taking 
pomalidomide plus dexamethasone including patients with lenalidomide resistant refractory 
multiple myeloma, and safety of pomalidomide plus dexamethasone. Responses were 
recorded using the criteria of the International Myeloma Working Group. Thirty eight 
patients achieved objective response (63%) including CR in 3 patients (5%), VGPR in 17 
patients (28%), and PR in 18 patients (30%). The CR + VGPR rate was 33%. Grade 3 or 4 
hematologic toxicity occurred in 23 patients (38%); and consisted of anemia in three patients 
(5%), thrombocytopenia in two patients (3%) and neutropenia in 21 (35%). Among those that 
developed grade 3/4 neutropenia, all first experienced the neutropenia in cycle 1-3; no new 
patients experienced grade 3/4 neutropenia in cycle 4 or later. The most common non-
hematological grade 3/4 toxicities were fatigue (17%) and pneumonia (8%). Other grade 3/4 
non-hematological toxicities that occurred in less than 5% included diarrhea, constipation, 
hyperglycemia, and neuropathy. One patient (1.6%) had a thromboembolic event of deep vein 
thrombosis. Lacy et al. have also demonstrated promising clinical activity of pomalidomide 
in myeloma patients with persistent disease following lenalidomide treatment. 
 
CC-4047-MM-002 is a Celgene sponsored phase 1b/2 multi-center, randomized, open-label, 
dose escalation study that is evaluating the safety and efficacy of oral pomalidomide alone 
and in combination with low-dose dexamethasone in patients with relapsed and refractory 
multiple myeloma. Eligible patients must have received at least 2 prior regimens and all 
patients must have received prior treatment that includes lenalidomide and bortezomib. This 
study consists of a phase 1 single agent pomalidomide (maximum tolerated dose [MTD]) 
segment and phase 2 randomized (pomalidomide plus low-dose dexamethasone versus 
pomalidomide alone) segment. The MTD was 4 mg 21/28 days (there were 4 drug-related 
DLTs [Grade 4 neutropenia] at 5 mg). Neutropenia and anemia were the most common grade 
3/4 toxicities; there was a dose-dependent increase in grade 4 neutropenia. Based on the 
preliminary safety and response data, 4 mg 21/28 days is the dose for the phase 2 segment. 
 
Pre-clinical data and the prior experience with thalidomide and lenalidomide in the treatment 
of patients with myelofibrosis with myeloid metaplasia (MMM) provide the rationale for the 
use of pomalidomide in patients with MMM. This is further supported by the results of a 
Celgene sponsored trial (MMM-001) which indicated that pomalidomide therapy at 0.5 mg or 
2 mg/day +/- an abbreviated course of prednisone is well tolerated in patients with 
myelofibrosis and active in the treatment of anemia. 
 
1.6 Rationale for the current trial: Clearly patients with EMD and PCL need newer therapies. 
The combination of pomalidomide and ixazomib provides a potentially powerful combination 
due to several reasons. We studied 174 consecutive patients with relapsed refractory multiple 
myeloma (MM) enrolled on a phase II clinical trial of pomalidomide plus low-dose 
dexamethasone at Mayo Clinic. Extramedullary disease (EMD) was present at the time of 
trial entry in 7.5% (13 of 174 patients). The response of EMD to pomalidomide plus low-dose 
dexamethasone included two complete and two partial responses among the 13 patients 


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(response rate, 31%). The results of this study suggest that pomalidomide can enter the 
extramedullary sites and attain therapeutic levels, with resultant disease response.  
 
Similar to bortezomib, MLN2238 potently, reversibly, and selectively inhibits the 20S 
proteasome. However in contrast to bortezomib, it has a shorter dissociation half-life (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. 
This particular property may enable ixazomib to attain higher levels in the extramedullary 
compartment, thus offer a particular advantage in this clinical situation. Finally, combinations 
of an IMiD and a proteasome inhibitor have been the most effective regimens in myeloma, as 
has been seen with bortezomib or carfilzomib combinations with thalidomide or 
lenalidomide. 


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2.0 
Goals 
 
2.1 
Primary 
 
To determine the confirmed response rate (>=PR) of ixazomib, used in combination with 
pomalidomide and dexamethasone in patients with previously treated multiple myeloma 
(MM) with extramedullary disease. 
 
2.2 
Secondary 
 
2.21 
To determine the toxicities associated with ixazomib in combination with 
pomalidomide and dexamethasone in patients with previously treated MM with 
extramedullary disease. 
 
2.22 
To determine the differential response rates (biochemical versus extramedullary 
disease) with ixazomib in combination with pomalidomide and dexamethasone in 
patients with previously treated MM with extramedullary disease. 
 
2.23 
To determine the progression free survival following treatment with ixazomib in 
combination with pomalidomide and dexamethasone in patients with previously 
treated MM with extramedullary disease. 
 
2.3 
Correlative Research 
 
2.31 
To assess the proportion of patients achieving minimal residual disease (MRD) 
negative status.  
 
 
 
 


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3.0 
Patient Eligibility 
3.1 
Registration - Inclusion Criteria  
3.11 
Age ≥18 years. 
3.12 
Previously treated myeloma, currently with extramedullary disease (defined as 
plasmacytoma outside bone marrow that is not contiguous with a bone lesion) 
with at least one lesion that has a single diameter of ≥2 cm or plasma cell 
leukemia (defined as circulating plasma cells exceeding 5% of peripheral blood 
leukocytes or 0.5 X 109/L or 200 cells/150000 events by flowcytometry). 
3.13 
The following laboratory values obtained ≤14 days prior to registration.  
• 
Calculated creatinine clearance (using Cockcroft-Gault equation below)* 
≥30 mL/min  
• 
Absolute neutrophil count (ANC) ≥1000/mm3  
• 
Platelet count ≥50,000/mm3 
• 
Hemoglobin ≥8.0 g/dL 
 
*Cockcroft-Gault Equation: 
Creatinine clearance for males = (140 - age)(actual body weight in kg)  
(72)(serum creatinine in mg/dL) 
 
Creatinine clearance for females = (140 - age)(actual body weight in kg)(0.85) 
(72)(serum creatinine in mg/dL) 
 
3.14 
Patients with measurable disease defined as at least one of the following: 
• 
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 or 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 
All study participants must be registered into the mandatory POMALYST 
REMS™ program, and be willing and able to comply with the requirements of 
the POMALYST REMS™ program. 
 
3.19a 
Willing to return to return to enrolling institution for follow-up (during the 
Active Monitoring Phase of the study). 
 
3.19b Willing to provide bone marrow and blood samples for correlative research 
purposes (see Sections 6.12 and 14.1). 
 
 
 


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3.2 
Registration - Exclusion Criteria 
 
3.21 
Other malignancy requiring active therapy. 
EXCEPTIONS: Non-melanoma skin cancer, DCIS or carcinoma-in-situ of the 
cervix.  
NOTE: If there is a history or prior malignancy, they must not be receiving other 
specific treatment for their cancer. 
 
3.22 
Any of the following because this study involves an investigational agent whose 
genotoxic, mutagenic and teratogenic effects on the developing fetus and 
newborn are unknown: 
• 
Females of childbearing potential (FCBP)† must have a negative serum 
pregnancy test with a sensitivity of at least 50 mIU/mL within 10 – 14 days 
prior to and again within 24 hours prior to prescribing pomalidomide for 
Cycle 1 (prescriptions must be filled within 7 days as required by RevAssist), 
and must either commit to continued abstinence from heterosexual 
intercourse or begin TWO acceptable methods of birth control, one highly 
effective method and one additional effective method.  
AT THE SAME TIME, at least 28 days before she starts taking 
pomalidomide FCBP must also agree to ongoing pregnancy testing. Men 
must agree to use a latex condom during sexual contact with a FCBP even if 
they have had a successful vasectomy.  
See Appendix IV: Pomalidomide Education and Counselling Guidance 
Document. Patient must follow pregnancy testing requirements as outlined 
in the POMALYST REMS™ program. 
• 
Nursing women  
• 
Men or women of childbearing potential who are unwilling to employ 
adequate contraception 
 
3.23 
Other co-morbidity which would interfere with patient's ability to participate in 
trial, e.g. uncontrolled infection, uncompensated heart or lung disease. 
 
3.24 
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 protocol treatment. 
3.25 
Patient has ≥Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical 
examination during the screening period. 
 
3.26 
Major surgery ≤14 days before study registration. 
 
3.27 
Systemic treatment with strong CYP3A4 inducers (e.g. rifampin, rifapentine, 
rifabutin, carbamazepine, phenytoin, phenobarbital, Gingko biloba, St. John’s 
wort) within 7 days before registration. 
                                                 
 
 
† A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any 
time in the preceding 24 consecutive months). 


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3.28 
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. 
 
3.29a 
QTc >470 milliseconds (msec) on a 12-lead ECG obtained during the Screening 
period. 
Note: If a machine reading is above this value, the ECG should be reviewed by a 
qualified reader and confirmed on a subsequent ECG. 
 
3.29b Known human immunodeficiency virus (HIV) positive. 
 
3.29c 
Known hepatitis B surface antigen-positive status, or known or suspected active 
hepatitis C infection. 
 
3.29d Any serious medical or psychiatric illness that could, in the investigator’s 
opinion, potentially interfere with the completion of treatment according to this 
protocol. 
 
3.29e 
Known allergy to any of the study medications, their analogues or excipients in 
the various formulations. 
 
3.29f 
Known GI disease or GI procedure that could interfere with the oral absorption 
or tolerance of ixazomib including difficulty swallowing. 
 
3.29g Diarrhea >Grade 1, based on the NCI CTCAE grading, in the absence of 
antidiarrheals. 
 


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4.0 
Test Schedule 
 
Days Prior to 
Registration 
Day 8, 15, 22 
(Cycles 1-3),  
Day 15 (Cycle 4 
onwards)1 
Every cycle, 
pre-
treatment1 
End of 
Cycle 41 
End of 
Treatment  
(+/-14 days)1 
Tests 
≤30 
days 
≤14 
days 
Complete medical history 
X 
 
 
 
 
 
Adverse Event monitoring 
 
X 
 
X16 
 
X 
Physical exam, including weight and vital signs 
 
X 
 
X16 
 
X 
Height 
 
X 
 
 
 
 
Performance status (ECOG scale)  
 
X 
 
X16 
 
X 
CBC with differential 
 
X 
X 
X16 
 
X 
Chemistry group: sodium, potassium, glucose, alkaline phosphatase; Total 
and Direct bilirubin; SGOT (AST); serum creatinine, calcium, magnesium 
 
X 
 
X16 
 
X 
LDH, Beta2-microglobulin, C-reactive protein 
X 
 
 
 
 
 
Electrophoresis of serum and urine (SPEP/UPEP) 
 
X 
 
X3,16 
 
X3 
Affected immunoglobulin2 
 
X 
 
X2,16 
 
X2 
Immunofixation serum and urine 
X 
 
 
X4,16 
 
X4 
Immunoglobulin free light chain (MML panel) 
 
X 
 
X5,16 
 
X5 
X-ray skeletal survey or low dose full body CT6 
X 
 
 
X6 
 
X 
Physical measurement (EMD lesion)7 
 
X 
 
X 
 
 
CT Scan, PET/CT, or MRI for measurement of EMD lesion8 
X 
 
 
X8 
 
 
Circulating plasma cell assessment (flow cytometry or peripheral smear)9 
 
X 
 
X9,16 
 
 
Bone marrow aspirate and biopsy, myeloma FISH, metaphase 
cytogenetics, plasma cell proliferation, and flow cytometry 
X 
 
 
X10 
X10 
X 
Biopsy of extramedullary lesion11 
X 
 
 
 
 
 
Chest x-ray 
X 
 
 
 
 
 
Serum pregnancy test12 
 
X12 
 
 
 
 
ECG, 12 lead with interpretation 
X 
 
 
 
 
 
Register patient for POMALYST REMS™ program13 
 
X13 
 
 
 
 
Patient Medication Diary (Appendix II)14 
 
 
 
X 
X 
X 
Mandatory tissue block11 
X 
 
 
 
 
 
Mandatory Research Bone marrow sampleR 
X 
 
 
X10 
 
X 
Mandatory Peripheral Blood sampleR 
X 
 
 
X15 
 
X15 
Cycle = 28 days  {FOOTNOTES CONTINUE ON NEXT PAGE} 


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Addendum 7 
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1) All scheduled visits will have a window of ±7 days unless otherwise stated. 
Note: Baseline labs can be used for Cycle 1, Day 1. 
2) 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. Affected immunoglobulin is required after baseline only if it used for disease monitoring instead of SPEP (e.g. IgA 
myeloma). 
3)  Urine Electrophoresis required only if used to assess disease response. 
4) Immunofixation (IF) needed only in the absence of M-protein to document sCR or CR. 
5) Serial light chain required if it is used for disease monitoring (measurable disease at baseline) 
6) Skeletal survey/low dose CT not needed at baseline or any other timepoint if PET/CT is done at that timepoint. Otherwise every 365 days (12 months) or 
more often if clinically indicated. 
7) For patients with a clinically palpable lesion. 
8) CT or MRI or the CT portion of the PET/CT, same modality should be used at baseline and for serial evaluation. PET/CT scans are required at baseline for 
all patients with EMD. 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. 
9) Number of circulating cells may be measured using flow cytometry or peripheral smear as is the standard practice for the institution, but same methodology 
should be used at every time point. This should be repeated after Cycle 1 and every 2 cycles after that or more often if clinically indicated. 
10) At the end of 4 cycles and only required to document CR after that. If a bone marrow was done to confirm CR prior to end of 4 cycles, no further bone 
marrow examination until the end of treatment. 
11) In patients with extramedullary soft tissue disease. 
12) For women of childbearing potential only. Must be done ≤7 days prior to registration.  
NOTE: Additional pregnancy testing is required as a condition of participation in the POMALYST REMS™ program. 
13) All study participants must be registered into the mandatory POMALYST REMS™ program, and be willing and able to comply with the requirements of the 
POMALYST REMS™ program. 
14) The diary must begin the day the patient starts taking the medication and must be completed per protocol and returned to the treating institution. 
15) At baseline, end of Cycle 4, and at end of treatment. See Section 14.0. 
16) Mayo Rochester only: 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. 
R 
Research funded (see Section 14.0). Will be charged to study and not to patient’s account. 
 
4.2 
Event Monitoring/Survival Follow-up 
 
Event Monitoring Phase1 
q. 3 months 
until PD 
At PD 
After PD  
q. 6 months 
Death 
New Primary 
Event Monitoring 
X 
X 
X 
X 
At each occurrence 
1. If a patient is still alive 3 years after registration, no further follow-up is required. 


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Addendum 7 
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5.0 
Grouping Factor: None 
6.0 
Registration Procedures 
6.1 
Registration Procedures-All Sites 
6.11 
Mayo Clinic sites: 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page 
and enter the registration/randomization application. The registration/ 
randomization 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 Web site, call the MCCC Registration Office at 
 
between the hours of 8 a.m. and 4:30 p.m. Central Time (Monday through 
Friday). 
The instructions for the registration/randomization application are available on 
the MCCC web page (http://ccswww.mayo.edu/training/) and detail the process 
for completing and confirming patient registration. Prior to initiation of protocol 
treatment, this process must be completed in its entirety and a MCCC subject ID 
number must be available as noted in the instructions. 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 
registration/randomization application can be confirmed in any of the following 
ways: 
• 
Contact the MCCC Registration Office 
. If the patient was 
fully registered, the MCCC Registration Office staff can access the 
information from the centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about A Registered Subject.” 
6.12 
Non Mayo Clinic sites 
To register a patient, fax 
 a completed eligibility checklist to the 
Mayo Clinic Cancer Center (MCCC) Registration Office between 8 a.m. and 
4:30 p.m. central time Monday through Friday. 
6.13 
(All Sites) Documentation of IRB approval must be on file in the Registration 
Office 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 
(fax: 
).  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 Registration Office is no longer necessary. 
6.2 
Verification 
Prior to accepting the registration, registration/randomization application will verify the 
following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 


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• 
Existence of a signed authorization for use and disclosure of protected health 
information  
6.3 
Correlative Research 
A mandatory correlative research component is part of this study, the patient will be 
automatically registered onto this component (see Sections 3.19b and 14.1).  
6.4 
Documentation 
Documentation of IRB approval must be on file in the Registration Office 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 (fax: 
507-284-0885). 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 Registration Office is no longer necessary. 
6.5 
Treating institution 
Treatment on this protocol must commence under the supervision of the hematologist 
from the enrolling institution. 
6.6 
Treatment start 
Treatment cannot begin prior to registration and must begin ≤14 days after registration. 
6.7 
Pretreatment 
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines 
specified on the test schedule. 
6.8 
Baseline symptoms 
All required baseline symptoms (see Section 10.62) must be documented and graded. 
6.9 
Study drug is available on site.  
 
 
 


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7.0 
Protocol Treatment 
7.1 
Treatment Schedule  
 
Table 7.1 
Agent 
Dose Level 
Route 
Day 
Retreatment 
Ixazomib 
4 mg 
PO 
1, 8, 15 
Every 28 
days 
Pomalidomide 
4 mg 
PO 
Days 1-21 
Every 28 
days 
Dexamethasone 
40 mg 
PO 
1, 8, 15, 22 
Every 28 
days 
 
7.2 
Dosing of ixazomib 
The doses of ixazomib used in this study are based on data from Millennium’s ongoing 
phase I and II trials, specifically the phase I/II trial of ixazomib (C16005) in combination 
with lenalidomide and dexamethasone, estimated 4 mg weekly of ixazomib as the RP2D 
in combination with weekly full dose of lenalidomide (25 mg) and dexamethasone 
(40 mg).  
 
7.3 
How to take ixazomib 
The ixazomib 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 240 mL (about 1 cup/8 oz) of water should be taken with 
the capsules. 
 
Missed doses can be taken as soon as the patient remembers as long as the next scheduled 
dose is 72 hours or more away. Patients who vomit a dose after ingestion will not receive 
an additional dose, but should resume dosing at the time of the next scheduled dose. 
 
Drug will be administered only to eligible patients under the supervision of the 
investigator or identified sub-investigator(s). The drug will be prepared under the 
supervision of a pharmacist, or appropriately qualified and trained personnel. 
 
7.4 
Treatment at enrolling institution  
 
As of Addendum 7, Mayo Rochester only 
For this protocol, the patient must return to the consenting 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.  
MMRC sites:  
For this protocol, the patient must return to the consenting institution for evaluation at 
least every 28 days. Treatment by a local medical doctor (LMD) is not allowed. 
 
7.5 
Pomalidomide supply - POMALYST REMS™ program 
All patients will be registered to the Celgene POMALYST REMS™ program to obtain 
pomalidomide, as required by the US Food and Drug Administration (FDA). Patients will 
receive pomalidomide every 28 days. All unused study drug must be returned to Mayo 


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Clinic to be recorded. Study drug is to be handed back to the patient to return per 
POMALYST REMS™ policy. Only enough pomalidomide for one cycle of therapy 
will be supplied to the patient each cycle. See Appendix IV for pomalidomide 
information. 
 
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. 
NOTE: If either of pomalidomide or ixazomib is discontinued, the patient can continue on 
the other drugs, unless specified otherwise in the dose modification tables. If both are 
discontinued, the patient will go to event monitoring (Section 18.0). 
 
ALERT: 
ADR reporting may be required for some adverse events (See Section 10) 
 
8.1 
Dose Levels for each drug in the combination 
(Based on Adverse Events in Tables 8.2-4) 
NOTE: One drug can be reduced each time based on the drug most likely related to the 
toxicity observed. 
Table 8.1 
Ixazomib 
(Days 1, 8, 15) 
Pomalidomide 
(Day 1-21) 
Dexamethasone 
(Days 1, 8, 15, 22) 
 
 
 
 
 
 
Starting 
dose 
4 mg 
Starting 
dose 
4 mg 
Starting 
dose 
40 mg 
-1 
3 mg 
-1 
3 mg 
-1 
20 mg 
-2 
2.3 mg 
-2 
2 mg 
-2 
12 mg 
-3 
2.3 mg days 1, 15 
-3 
1 mg 
-3 
4 mg 
-4 
Discontinue 
-4 
Discontinue 
-4 
Discontinue 
 
If patients cannot tolerate dose level – 3 of ixazomib AND pomalidomide they will go to 
event monitoring per Section 18.0. If dexamethasone is discontinued, the patient may 
continue treatment. 
8.11 
Instruction for initiation of a new cycle of therapy  
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 ≥50,000/μL 
• 
Any other non-hematologic treatment -related 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. 


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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 cannot be restarted within 4 weeks 
of the scheduled Day 1 due to non-resolution of drug related toxicities, the 
patient will be removed from protocol therapy and will go to event 
monitoring. 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
8.2 
Dose modifications for ixazomib based on adverse events during a cycle  
Table 8.2 
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT# 
ACTION** 
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 
Days 2-15: Ixazomib dose 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 may be 
reinitiated with 1 dose level reduction 
(see Table 8.1). The subsequent cycle will 
use the reduced dose.  
Skin and 
subcutaneous tissue 
disorders 
Rash, maculopapular, 
≥Grade 2 
Ixazomib 
Omit ixazomib till rash resolves to 
≤Grade 1 (See Section 9.9a). Restart at 
same dose. If the rash recurs, reduce dose 
by one dose level. 
Any skin, Grade 4 
Discontinue ixazomib 
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 
 
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. 


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Addendum 7 
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Table 8.2 
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT# 
ACTION** 
 
Grade 4 peripheral 
neuropathy 
Ixazomib 
Omit ixazomib. 
Peripheral neuropathy should be 
monitored until toxicity resolves or 
returns to baseline. 
Upon recovery, if the patient has received 
clinical benefit from therapy with 
ixazomib, the investigator may consider 
restarting ixazomib at the next lower dose 
level. 
 
Other 
Any other non-
hematological Grade 3 
attributable toxicity 
except: 
Ixazomib 
Pomalido
mide 
Omit ixazomib or pomalidomide or both 
depending on the attribution to either or 
both drugs, until resolution to Grade ≤1 or 
baseline 
Restart at next lower dose - If a patient is 
already at the lowest drug level, go to 
event monitoring 
If the toxicity can be attributed to either 
of the drugs, pomalidomide should be 
discontinued at first instance followed by 
ixazomib for recurrence of the same 
toxicity necessitating dose modification 
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 
 
Grade 4 
Nonhematologic 
Toxicities 
Ixazomib 
Pomalido
mide 
Permanently discontinue pomalidomide.  
Consider permanently discontinuing 
ixazomib – Exception if the investigator 
determines the patient is obtaining a 
clinical benefit 
If both ixazomib and pomalidomide are 
discontinued, the patient will go to event 
monitoring 
* 
Located
 
**  
Use the following to describe actions in the Action column: 
 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 toxicities attributable to both ixazomib and pomalidomide, only one of the drugs should be 
reduced for each incidence of toxicity severe enough to necessitate dose reduction. The drug reduced 
should alternate starting with pomalidomide for the first dose reduction. 
 
 


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8.3 
Dose modifications for pomalidomide based on adverse events during a cycle 
Table 8.3 
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Blood and lymphatic 
system disorders 
Febrile neutropenia 
associated with fever 
(≥38.5º C) 
Pomalido
mide 
• Omit pomalidomide dose. 
• Follow CBC weekly. 
• If neutropenia has resolved to ≤Grade 2 
prior to Day 21 and fever has resolved, 
restart pomalidomide at next lower dose 
level and continue the cycle through Day 
21 
• If febrile neutropenia is the only toxicity 
for which a dose reduction is required  
G-CSF may be used and the 
pomalidomide dose maintained 
Investigations 
Grade 3 neutrophil 
decreased and sustained 
for 7 days  
or 
Grade 4 neutropenia 
 
Platelet count decreased 
≥Grade 3 (platelet 
count <50,000/mm³) 
Pomalido
mide 
• Omit pomalidomide dose. 
• Follow CBC weekly. 
• Hold anticoagulation until platelets 
≥50,000/mm³ 
• If platelet count resolves to ≤Grade 2 
prior to Day 21, restart pomalidomide at 
next lower dose level and continue the 
cycle through Day 21 
• If neutropenia has resolved to ≤Grade 2 
prior to Day 21, restart pomalidomide at 
next lower dose level and continue the 
cycle through Day 21 
• If neutropenia is the only toxicity for 
which a dose reduction is required  
G-CSF may be used and the 
pomalidomide dose maintained 
Skin and subcutaneous 
tissue disorders 
Rash maculopapular  
Grade 2 or 3 
Pomalido
mide 
• Omit pomalidomide dose; follow weekly 
• If the toxicity resolves to ≤Grade 1 prior 
to Day 21, restart pomalidomide at next 
lower dose level and continue the cycle 
through Day 21 
Any rash  
Grade 4 
Pomalido
mide 
• Discontinue pomalidomide and remove 
patient from all study treatment 
Nervous system 
disorders 
Peripheral sensory 
neuropathy 
Grade 3 
Pomalido
mide 
• Omit pomalidomide dose and follow at 
least weekly 
• If the toxicity resolves to ≤Grade 1 prior 
to Day 21, restart pomalidomide at next 
lower dose level and continue the cycle 
through Day 21 


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Table 8.3 
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Grade 4 
Pomalido
mide 
• Discontinue pomalidomide and remove 
patient from all study treatment 
Immune system 
disorders 
Allergic reaction  
Grade 2-3 
Pomalido
mide 
• Omit dose and follow at least weekly 
• If the toxicity resolves to ≤Grade 1 prior 
to Day 15 restart at next lower dose level 
and continue the cycle until Day 21 
Grade 4 
Pomalido
mide 
• Discontinue pomalidomide and remove 
patient from all study treatment 
Vascular disorders 
Thromboembolic event 
≥ Grade 3 
Pomalido
mide 
• Omit dose and start anticoagulation 
• Restart at investigator’s discretion 
(maintain dose level) 
Endocrine disorders 
Hyperthyroidism or 
Hypothyroidism ≥ 
grade 2 
Pomalido
mide 
• Omit pomalidomide for remainder of 
cycle, evaluate etiology, and initiate 
appropriate therapy 
• See Instructions for Initiation of a New 
Cycle and reduce the dose of 
pomalidomide by 1 dose level 
Other non-hematologic 
adverse event 
Other non-hematologic 
toxicity ≥ Grade 3 
Pomalido
mide 
• Omit pomalidomide dose. Follow at least 
weekly 
• If the toxicity resolves to ≤Grade 2 prior 
to Day 21, restart pomalidomide at next 
lower dose level and continue the cycle 
through Day 21 
* 
Located at
 
**  Use the following to describe actions in the Action column: 
 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 toxicities attributable to both ixazomib and pomalidomide, only one of the drugs should be 
reduced for each incidence of toxicity severe enough to necessitate dose reduction. The drug reduced 
should alternate starting with pomalidomide for the first dose reduction. 
 
 
 


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8.4 
Dose modifications for dexamethasone based on adverse events during a cycle 
Table 8.4 
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 dexa-
methasone and do not resume 
Ixazomib and pomalidomide 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 and pomalidomide should 
be continued 
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 and pomalidomide should 
be continued 


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Table 8.4 
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Psychiatric disorders 
Confusion or Mood 
alteration 
≥Grade 2 (Severe 
disorientation; limiting 
self-care 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 and pomalidomide 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 and pomalidomide 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 
* 
Located at
 
**  Use the following to describe actions in the Action column: 
 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. 
 
 
 


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9.0 
Ancillary Treatment/Supportive Care 
9.1 
Steroid use 
Patients may continue on low level/stable steroid doses for replacement or inhalation 
therapy. 
 
9.2 
Disallowed concurrent treatment 
The following treatments are not permitted during the trial: 
• 
Any other investigational treatment  
• 
Any other systemic anti-neoplastic therapy including, but not limited to, 
immunotherapy, hormonal therapy or monoclonal antibody therapy. 
• 
Any external beam radiotherapy 
 
9.3 
Nausea and/or vomiting:  
Standard anti-emetics including 5-hydroxytryptamine 3 serotonin receptor antagonists are 
recommended for emesis if it occurs once treatment is initiated; prophylactic anti-emetics 
may also be considered at the physician’s discretion. Dexamethasone should not be 
administered as an anti-emetic. Fluid deficit should be corrected before initiation of study 
drug and during treatment. 
 
9.4 
Blood products and growth factors  
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. 
 
9.5 
Diarrhea 
Prophylactic antidiarrheals will not be used in this protocol. However, diarrhea should be 
managed according to clinical practice, including the administration of antidiarrheals 
such as loperamide once infectious causes are excluded. Fluid intake should be 
maintained to avoid dehydration. Fluid deficit should be corrected before initiation of 
treatment and during treatment. 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. 
 
9.6  
Renal failure and ixazomib 
Two cases of acute renal failure have been reported in patients treated at or above the 
MTD for intravenous ixazomib (see Section 1.4.3). Volume depletion should be corrected 
before initiation of study drug. Until further information is available, intake of 
nonsteroidal anti-inflammatory drugs immediately prior to the administration of ixazomib 
should be discouraged and requires consultation with the principal investigator. All 
necessary supportive care consistent with optimal patient care shall be available to 
patients as necessary. 


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Addendum 7 
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9.7 
Herpes Zoster prophylaxis 
Patients may be at an increased risk of infection including reactivation of herpes zoster 
and herpes simplex viruses. Prophylaxis with acyclovir 400 mg PO BID is recommended 
while on study therapy and for 1 month beyond the end of therapy 
 
9.8 
Prohibited medications 
Systemic treatment with any of the following metabolizing enzyme inducers should be 
avoided, unless there is no appropriate alternative medication for the patient’s use. 
(Rationale: Unlike with inhibitors if there were to be a drug-drug interaction with an 
inducer, MLN2238 exposure would be less - so there is a reduced chance of an adverse 
event. However, there may be less chance for an antitumor effect, but that is not an 
absolute reason to be taken off ixazomib):  
• 
Strong CYP3A inducers: rifampin, rifapentine, rifabutin, carbamazepine, 
phenytoin, and phenobarbital 
Extra caution should be exercised when using these medications concomitantly and 
incidence of any side effects should be carefully monitored. Because these medications 
are constantly changing, please review any medications for their potential to induce 
CYP3A4. Potential resources may include the FDA and/or IUPUI websites, or your local 
institution’s pharmacist. 
Excluded foods and dietary supplements include St. John’s wort and Ginkgo biloba. 
 
9.9a 
Erythematous Rash with or without Pruritus:  
As with bortezomib, rash with or without pruritus has been reported with ixazomib, 
primarily at the higher doses tested and when given with agents where rash is an 
overlapping toxicity. The rash may range from limited erythematous areas, macular 
and/or small papular bumps that may or may not be pruritic over a few areas of the body, 
to a more generalized eruption that is predominately on the trunk or extremities. Rash has 
been most commonly characterized as maculopapular or macular. To date, when it does 
occur, rash is most commonly reported within the first 3 cycles of therapy. The rash is 
often transient, self-limiting, and is typically Grade 1 to 2 in severity.  
Symptomatic measures such as antihistamines or corticosteroids (oral or topical) have 
been successfully used to manage rash and have been used prophylactically in subsequent 
cycles. The use of a topical, IV, or oral steroid (e.g., prednisone ≤10 mg per day or 
equivalent) is permitted. Management of a Grade 3 rash may require intravenous 
antihistamines or corticosteroids. Administration of ixazomib (and/or other causative 
agent if given in combination) should be modified per protocol and re-initiated at a 
reduced level from where rash was noted (also, per protocol). 
In line with clinical practice, dermatology consult and biopsy of Grade 3 or higher rash or 
any SAE involving rash is recommended. Prophylactic measures should also be 
considered if a patient has previously developed a rash (e.g., using a thick, alcohol-free 
emollient cream on dry areas of the body or oral or topical antihistamines). A rare risk is 
Stevens-Johnson Syndrome, a severe and potentially life-threatening rash with skin 
peeling and mouth sores, which should be managed symptomatically according to 
standard medical practice. Punch biopsies for histopathological analysis are encouraged 
at the discretion of the investigator. 
 


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9.9b 
Thrombocytopenia 
Blood counts should be monitored regularly as outlined in the protocol with additional 
testing obtained according to standard clinical practice. Thrombocytopenia may be severe 
but has been manageable with platelet transfusions according to standard clinical 
practice. Ixazomib administration should be modified as noted as per dose modification 
recommendations in the protocol when thrombocytopenia occurs (see Table 8.2). 
Therapy can be reinitiated at a reduced level upon recovery of platelet counts. A rare risk 
is thrombotic thrombocytopenic purpura (TTP), a rare blood disorder where blood clots 
form in small blood vessels throughout the body characterized by thrombocytopenia, 
petechiae, fever, or possibly more serious signs and symptoms. TTP should be managed 
symptomatically according to standard medical practice. 
 
9.9c 
Neutropenia 
Blood counts should be monitored regularly as outlined in the protocol with additional 
testing obtained according to standard clinical practice. Neutropenia may be severe but 
has been manageable. Growth factor support is not required but may be considered 
according to standard clinical practice. Ixazomib administration should be modified as 
noted as per dose modification recommendations in the protocol when neutropenia occurs 
(see Table 8.2). Therapy can be reinitiated at a reduced level upon recovery of ANCs. 
 
9.9d 
Fluid Deficit 
Dehydration should be avoided since ixazomib may cause vomiting, diarrhea, and 
dehydration. Acute renal failure has been reported in patients treated with ixazomib, 
commonly in the setting of the previously noted gastrointestinal toxicities and 
dehydration. Fluid deficit should be corrected before initiation of study drug and as 
needed during treatment to avoid dehydration. 
 
9.9e 
Hypotension 
Symptomatic hypotension and orthostatic hypotension with or without syncope have been 
reported with ixazomib. Blood pressure should be closely monitored while the patient is 
on study treatment and fluid deficit should be corrected as needed, especially in the 
setting of concomitant symptoms such as nausea, vomiting, diarrhea, or anorexia. 
Patients taking medications and/or diuretics to manage their blood pressure (for either 
hypo- or hypertension) should be managed according to standard clinical practice, 
including considerations for dose adjustments of their concomitant medications during 
the course of the trial. Fluid deficit should be corrected before initiation of study drug and 
as needed during treatment to avoid dehydration. 
 
9.9f 
Posterior Reversible Encephalopathy Syndrome 
One case of posterior reversible encephalopathy syndrome, which ultimately resolved, 
has been reported with ixazomib. This condition is characterized by headache, seizures 
and visual loss, as well as abrupt increase in blood pressure. Diagnosis may be confirmed 
by magnetic resonance imaging (MRI). If the syndrome is diagnosed or suspected, 
symptom-directed treatment should be maintained until the condition is reversed by 
control of hypertension or other instigating factors. 
 




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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). 
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.  
 
10.4 
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 10.5. 
 
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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10.41 Special Situations for Expedited Reporting and Submission of Notification 
Forms 
Exceptions to Expedited Reporting and Submission of Notification Forms: 
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 supersede the standard 
Expedited Adverse Event Reporting and Notification Form Requirements  
(Note: These adverse events must still be reported through the routine reporting 
mechanism [i.e. Nadir/adverse events form]; see footnote 1):  
  
Table 10.4 
System Organ Class (SOC) 
Adverse event/ 
Symptoms 
CTCAE Grade at 
which the event 
will not be 
expeditedly 
reported1. 
General disorders and 
administrations site conditions 
Fatigue  
≤Grade 3 
 
 
Gastrointestinal 
Vomiting 
≤Grade 3 
Nausea 
≤Grade 3 
Diarrhea 
≤Grade 3 
Investigations 
Neutrophil count 
decreased 
≤Grade 4 
Platelet count 
decreased 
≤Grade 4 
Lymphocyte count 
decreased 
≤Grade 4 
 
White blood cell count 
≤Grade 4 
Blood and lymphatic system 
disorders 
Anemia 
≤Grade 4 
 
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. 
 
 


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10.411 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 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). 
 
10.412 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 
benign, 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 dose 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. 
 
10.413 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 must 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 




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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 
 
10.43 Additional instructions: 
 
Special reporting requirements for Millennium 
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 Millennium 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 Millennium 
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 Millennium 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 Millennium 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 Millennium 
Pharmacovigilance. 
The sponsor-investigator must fax or email the SAE Form per the timelines above. A 
sample of an SAE Form will be provided. 
 
The SAE report must include at minimum: 








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10.6 
Required routine reporting 
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: 
Table 10.2 
SYSTEM ORGAN CLASS 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
Investigations 
Creatinine increased 
X 
X 
Neutrophil count decreased 
X 
X 
Platelet count decreased 
X 
X 
General disorders and 
administration site conditions 
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 
Skin and subcutaneous tissue 
disorders 
Rash, maculopapular 
X 
X 
Nervous system disorders 
 
Peripheral sensory neuropathy  
X 
X 
Peripheral motor neuropathy  
X 
X 
 
10.62 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: 
 
10.621 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
 
10.622 Grade 3 and 4 AEs regardless of attribution to the study treatment or procedure. 
 
10.623 Grade 5 AEs (Deaths) 
 
• 
Any death within 30 days of the patient’s last study treatment or procedure 
regardless of attribution to the study treatment or procedure. 
 
• 
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. 
 
10.63 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). 
 
 
 


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11.0 
Treatment Evaluation 
11.1  
Terms and definitions 
Serum or urine M spike of any level is not a requirement for entry into the study. If 
present, and meets criteria for measurable disease this will be followed for M protein 
response using IMWG uniform response criteria as described below. 
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 β-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. 
 
• 
CT, PET/CT or MRI should be performed on all patients with EMD at baseline. 
This should be repeated after 1 cycle and then every three cycles or more frequently 
if clinically indicated. The same modality should be used for serial assessment. 


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• 
Peripheral blood testing for circulating plasma cells should be performed in all 
patients with plasma cell leukemia at baseline and after 1 cycle and every two cycles 
thereafter. Peripheral smear or flow cytometry may be used to evaluate circulating 
plasma cells, but the same modality should be used throughout the study. 
 
• 
Response terms: The following response terms will be used to define M protein 
response: stringent Complete Response (sCR), complete response (CR), very good 
partial response (VGPR), partial response (PR), Minimal Response (MR), stable 
disease (SD), and progressive disease (PD). EMD or PCL response definitions/ 
criteria are detailed below. 
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 
o At least one plasmacytoma that has a single diameter of ≥2 cm.  
o Plasma cell count exceeding 500/microL or 5 percent of the peripheral blood 
white cells 
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 m-spike) 
should be the only ones who are evaluated using FLC response criteria. The others 
should follow usual criteria and ignore FLC results with the exception of defining 
stringent complete response. 
• 
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. 
 


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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 M protein Response (Must Be Done At Each Disease Measurement Visit 
except as indicated1,2) 
On Study Baseline Value 
SPEP 
24 hr 
UPEP2 
Ig FLC 
BM Bx 
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. SPEP and UPEP are required to 
document VGPR regardless of registration values. 
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 an M protein 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 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 in any case. 
• 
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.  
 
 


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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. Although the definition for “relapse from CR (or sCR) 
is listed, this will be documented as a response category in ONLY those protocols 
evaluating disease free survival. 
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  
• 
If at on study, the only measurable non-bone marrow 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)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 non-bone marrow 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 


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Table 11.5 
CATEGORY 
RESPONSE CRITERIA a 
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  
 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 measurements with a ruler in patients with only skin 
involvement  
 For patients with plasma cell leukemia at baseline, ≥50% reduction in the 
circulating plasma cell count 
Stable disease (SD) Not meeting criteria for sCR, CR, VGPR, PR, or progressive disease 
Progressive 
disease (PD) d 
Any one or more of the following:  
• 
Increase of 25% from lowest value in f 
 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 
 Hypercalcemia (≥11.5 mg/dl) if considered related to myeloma 
 Decrease in hemoglobin of ≥2 g/dl if considered related to myeloma 
 Serum creatinine level ≥2 mg/dl if considered related to myeloma 
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. 


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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 Progressive disease should be confirmed.  However, treatment may be discontinued for progressive disease that is 
unconfirmed per physician discretion. In this case, an objective status of PD should be entered on the measurement 
form and progressive disease should be reported on the event monitoring form. 
e Does not apply to EMD or PCL  
f 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 value. 
 
11.6 
Types of Response: 
11.61 Biochemical response will be defined as detailed above for serum, urine, and 
FLC. 
11.62  Extramedullary disease response will be defined as detailed above for 
plasmacytomas and plasma cell leukemia. 
12.0 
Descriptive Factors  
12.1 
Parameters followed for hematologic response (pick one):.serum M-spike ≥1 g/dL and 
urine M-spike ≥200 mg/24 hours vs. serum M-spike ≥1g/dL only vs. urine M-spike 
≥200 mg/24 hours only vs. serum immunoglobulin free light chain ≥10 mg/dL vs. 
extramedullary disease only. Distinguish between SPEP measurements versus 
quantitative IgA measurement for serum M-spike. 
12.2 
Parameter followed for extramedullary disease: extramedullary plasmacytoma vs. plasma 
cell leukemia  
13.0 
Treatment/Follow–up Decision at Evaluation of Patient  
13.1 
Patients who are sCR, CR, VGPR, PR, or SD (or usCR, uCR, uVGPR, uPR) will 
continue treatment per protocol. 
 
13.2 
Patients who develop progressive disease while receiving therapy will go to the event-
monitoring phase. 
 
13.3 
Patients who go off protocol treatment for reasons other than PD will go to the event-
monitoring phase per Section 18.0. 
 
13.4 
Criteria for Discontinuation of Treatment 
Patients may discontinue treatment for the following reasons: 
• 
Progressive multiple myeloma 
• 
Patient refuses further treatment on 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 
• 
Patient is lost to follow-up (defined as the inability to contact the patient on 3 
separate occasions) 
• 
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  


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All attempts should be made to complete the End of Study procedures when the patient 
discontinues treatment. Patients should go to event monitoring per Section 18.0, unless 
the patient refuses further study participation or is lost to follow-up. 
 
13.5 
Criteria for Study Discontinuation 
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: 
• 
Safety concerns 
• 
Poor enrollment 
• 
Non-compliance with the protocol, Good Clinical Practice guidance or other 
regulatory requirements by the Investigator(s) 
• 
Request to discontinue the trial by a regulatory or health authority or an IRB 
• 
Manufacturing difficulties/concerns 
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. 
 
13.6 
Ineligible 
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 at the discretion of the physician as long as there are 
no safety concerns, and the patient was properly registered.  
If the patient discontinues treatment, the patient will go 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 and the Off Treatment Form 
must be submitted. No further data submission is necessary. 
 
13.7 
Major violation 
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. The patient may continue treatment per protocol at the discretion of the 
physician as long as there are no safety concerns, and the patient was properly registered. 
If the physician decides treatment should be discontinued, the patient will go directly to 
the event monitoring phase per section 18.0 and all data up until the point of confirmation 
of a major violation must be submitted. 
13.8 
Cancel 
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 Off Treatment Form must be 
submitted. No further data submission is necessary. 
 


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14.0 
Biospecimens 
14.1  
Summary Table of Research Blood and Biospecimens to be collected for this Protocol 
Correlative Study  
(See Section 14.4 for 
more information) 
Mandatory 
or Optional 
Blood or 
Body Fluid 
being 
Collected 
Type of 
Collection 
Tube (color 
of tube top) 
Volume to 
collect per 
tube (# of 
tubes to be 
collected) 
Study 
Entry 
End of 
cycle 4 
At 
suspected 
CR 
At EOT 
Process 
at site? 
(Yes or 
No) 
Temperature 
Conditions 
for Storage 
/Shipping 
Flow cytometry, GEP 
Mandatory 
Bone 
marrow 
aspirate 
EDTA 
(lavender) 
4 mL 
(2) 
X 
X 
X 
X 
No 
Cool Pak 
Flow cytometry for 
adhesion molecules and 
circulating myeloma 
cells  
Mandatory 
Peripheral 
blood 
EDTA 
(lavender) 
6 mL 
(2) 
X 
X 
 
X 
No 
Cool Pak  
 
 
 
 
 
 
 
 
 
 
 
IHC, FISH 
Mandatory1 
Tissue 
biopsy block 
Paraffin 
block 
 (1) 
X 
 
 
 
No 
Ambient 
1 In patients with extramedullary soft tissue disease 
14.2  
Collection and Processing  
14.21 Bone Marrow and Peripheral Blood for Flow Cytometry 
This process will be performed on bone marrow aspirate and on peripheral blood samples following a wash no lyse 
method on fresh samples.  
Draw 8 mL of bone marrow aspirate into two lavender top EDTA tubes. Draw 12 mL of peripheral blood into 
two lavender top EDTA tubes. It is important to thoroughly mix the samples with the anticoagulant agent by 
gently inverting the tubes not less than five times. 
Samples are to be collected Monday through Thursday ONLY. Samples are to be shipped the same day 
they are collected. Please avoid Friday and holiday collections and shipments. 
14.22 Tissue Biopsy Block for Immunohistochemistry 
This procedure will be performed on paraffin embedded tissue biopsy sections. 
One core of the tissue biopsy (if multiple passes made) or half of the single core should be paraffin embedded 
and shipped ambient. NOTE: Blocks are not expected to be shipped the same day as the bone marrow and 
peripheral blood collections. 




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increased risk of EMD. Patients with plasma cell leukemia will have FISH 
performed on the peripheral blood.  
14.43 Gene expression profiling: We will perform GEP studies on the EMD tissue and 
BM samples on all patients who develop EMP and have adequate tissue/cells 
available. We hypothesize that the PCs in the EMD will exhibit a unique 
“microenvironment independence” signature suggesting the lack of continued 
need for the marrow microenvironment. The relative plasma cell gene expression 
proﬁles will be analyzed using high-density oligonucleotide microarrays 
containing probes for 50,000 transcripts and variants including 14,500 known 
genes (U133 Plus 2.0 array; Affymetrix, Santa Clara, CA). The arrays will be 
scanned using a Genechip 300 scanner and GeneChip 5.0 software (Affymetrix) 
will used to quantitatively analyze the scanned image. We have extensive 
experience with analysis. Functional analysis to determine the biological 
relevance of the data and to identify novel, dysregulated genes and biological 
pathways will be performed using a functional annotation and network mapping 
tool, Ingenuity Systems. 
14.44 Microvessel density: We will estimate the microvessel density (MVD) in the 
paraffin embedded biopsy tissue from EMD as well as BM samples from the 
time of trial entry and any subsequent samples. We hypothesize that increased 
BM angiogenesis reflects a plasma cell clone with increased capacity to modulate 
the microenvironment. We also hypothesize that the EMDs with high MVD will 
have a poor outcome, as tumor cells are likely more resistant to treatment.  
 
 


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15.0 
Drug Information 
15.1 
Ixazomib (MLN9708, Ninlaro®) 
15.11 Background 
Ixazomib (MLN9708) is a second-generation small molecule inhibitor of the 20S 
proteasome that is under development for the treatment of non-hematologic 
malignancies, lymphoma, and multiple myeloma. 
Ixazomib (MLN2238) refers to the biologically active, boronic acid form of the drug 
substance, ixazomib citrate (MLN9708). 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 (MLN9708) 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 (MLN9708) 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 (MLN9708) capsules (0.2 mg, 0.5 mg, 2 mg), individually packaged in 
blisters, can be stored at 2ºC to 8ºC or “Do not store above 25ºC. Do not freeze.” 
Ixazomib capsules (2.3 mg, 3 mg, 4 mg, and 5.5 mg), individually packaged in 
blisters, can be stored at “2ºC - 8ºC” or “Do not store above 25ºC. 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 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. 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 (MLN9708) 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 hour 
before or at least 2 hours after food. 


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Ixazomib should not be taken if the patient has had a serious allergic reaction to 
boron or boron containing products. 
15.15 Pharmacokinetic 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. 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. Ixazomib is 88-94% protein bound. 
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. 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 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 similar to those observed when ixazomib is 
administered as a single agent. This suggests that there is no readily apparent 
effect of coadministration of lenalidomide and dexamethasone on the clinical PK 
of ixazomib. 


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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%): anemia, neutropenia, thrombocytopenia, 
constipation, diarrhea, nausea, vomiting, fatigue, decreased appetite, 
dizziness, peripheral neuropathy 
Common (≥1% to <10%): Herpes zoster, peripheral sensory neuropathy, 
erythema, rash, erythematous rash, pruritic rash, macular rash, peripheral 
edema, upper respiratory tract infection, back pain, maculo-papular rash, 
popular rash 
Uncommon (≥0.1% to <1%): generalized pruritis, generalized rash 
Herpes zoster – antiviral prophylaxis should be considered in patients 
being treated with ixazomib to decrease the risk of herpes zoster 
reactivation. 
Rare but serious risks – intestinal obstruction, pneumonia, life-
threatening severe skin rash (Steven Johnson syndrome, TEN, DRESS 
syndrome), thrombotic thrombocytopenic purpura, tumor lysis syndrome, 
renal failure, posterior reversible encephalopathy syndrome, transverse 
myelitis, progressive multifocal leukoencephalopathy. 
Overdose- There is no known specific antidote for ixazomib overdose. 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 
reaction, monitoring of vital signs, and appropriate supportive care. 
Gavage 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. 
Ixazomib Destruction: Investigational ixazomib (expired or end of study) should 
be destroyed on site according to the institution’s standard operating procedure. 
Be sure to document removal and destruction on drug accountability logs. 
 
 
 


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15.2 
Pomalidomide (Pomalyst®, CC-4047)  
Please consult the most current Investigator’s Brochure and package insert for complete 
drug information. 
15.21 Background: Pomalidomide (CC-4047) is a novel drug in the class of 
immunomodulatory agents known as IMiDs compounds. Pomalidomide binds to 
its molecular target cereblon (CRBN), a protein that is part of an E3 ubiquitin 
ligase complex, which is responsible for the poly-ubiquitination of substrate 
proteins, targeting them for subcellular redistribution and destruction by the 
proteasome. The pharmacologic properties of pomalidomide are of potential 
therapeutic benefit in the treatment of various hematologic neoplasms (such as 
multiple myeloma and myeloproliferative neoplasm-associated myelofibrosis), 
non-neoplastic hematologic disorders (such as β-thalassemia and sickle cell 
disease) and non-hematologic disorders such as systemic sclerosis, as well as 
solid tumor neoplasms. 
15.22 Formulation: Pomalidomide (CC-4047) capsules can be 0.5-mg gelatin capsules 
(size 4 reddish brown), 1-mg hard gelatin capsules (size 4 reddish brown), 2-mg 
(size 2 reddish-brown), 3-mg and 4-mg hard gelatin capsules (size 2 reddish-
brown), and 5-mg hard gelatin capsules (size 1 reddish-brown), containing 
pomalidomide, mannitol, pregelatinized starch, and sodium stearyl fumarate. 
Pomalidomide (CC-4047) capsules are supplied in high density polyethylene 
(HDPE) containers fitted with induction seals and child-resistant plastic closures 
or PVC/PCTFE blister with push-through foil. 
15.23 Preparation and storage: Store drug at controlled room temperature, between 
68-77 ºF (20-25ºC) or as indicated on the manufacturer’s label. The expiration 
date is indicated on the label.  
Only enough study drug for one cycle of therapy (one month) may be dispensed. 
15.24 Administration: Pomalidomide is administered by mouth at approximately the 
same time each day with water. Pomalidomide should be taken without food, at 
least 2 hours before or 2 hours after a meal. Capsules should be swallowed 
whole, and should not be broken, chewed or opened. If a dose of pomalidomide 
is missed, it should be taken as soon as possible on the same day. If it is missed 
for the entire day, it should not be made up. Patients should be instructed never to 
give this medicinal product to another person and to return any unused capsules 
to the study doctor at the end of treatment. Patients who take more than the 
prescribed dose of pomalidomide should be instructed to seek emergency 
medical care if needed and contact study staff immediately. 
15.25 Pharmacokinetic information:  
a) Absorption – oral absorption has been moderately rapid with first dose- Cmax 
occurring in 1.5 to 4 hrs. More than 70% of the pomalidomide dose is absorbed 
in humans. A high fat meal decreased the rate of absorption but had minimal 
effect on overall extent of absorption; therefore drug may be administered 
without regard to food intake. 
b) Distribution – Apparent volume of distribution in healthy subjects ranged from 
74-138 L across a dose range of 1 to 10 mg daily. Pomalidomide protein binding 
in human plasma is low to moderate (15.8% for R-enantiomer, 42.2% for S-
enantiomer) and the binding is concentration independent in the concentration 
range of 30 and 1000 ng/mL. Drug distributes into semen. 


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c) Metabolism - Eight metabolites were detected in plasma, each at exposures 
<10% of the plasma pomalidomide. CYP-dependent metabolites accounted for 
approximately 43% of the excreted radioactivity, while non-CYP dependent 
hydrolytic metabolites accounted for 25%, and excretion of unchanged 
pomalidomide accounted for 10%. 
d) Excretion – In healthy patients, 72.8% of the dose was recovered in urine and 
15.5% was recovered in feces. Less than 3 % of the dose is excreted as 
unchanged pomalidomide in the urine. The geometric mean terminal elimination 
was approximately 7.5 hours. 
15.26 Potential Drug Interactions: Pomalidomide is partially metabolized by CYP1A2 
and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). 
Coadministration of pomalidomide with the strong CYP3A4/5 and P-gp inhibitor 
ketoconazole, or the strong CYP3A4/5 inducer carbamazepine, had no clinically 
relevant effect on exposure to pomalidomide.  Coadministration of the strong 
CYP1A2 inhibitor fluvoxamine with pomalidomide increased mean exposure to 
pomalidomide by 125% compared to pomalidomide alone. If strong inhibitors of 
CYP1A2 are coadministered with pomalidomide, the pomalidomide dose by 
should be reduced 50%. 
Smoking: Administration of pomalidomide in smokers, with smoking tobacco 
known to induce the CYP1A2 isoform, had no clinically relevant effect on 
exposure to pomalidomide relative to that exposure to pomalidomide observed in 
non-smokers. 
Dexamethasone: Co-administration of multiple doses of 4 mg pomalidomide 
with 20 mg to 40 mg dexamethasone (a weak inducer of CYP3A) to patients with 
multiple myeloma had no effect on the pharmacokinetics of pomalidomide 
compared with pomalidomide administered alone. 
15.27 Known potential toxicities: 
Very common known potential toxicities, ≥10%:  
Anemia, leukopenia, neutropenia, thrombocytopenia, constipation, diarrhea, 
nausea, fatigue, peripheral edema, pyrexia, bronchitis, pneumonia, upper 
respiratory tract infection, decreased appetite, bone pain, muscle spasm, 
dizziness, peripheral neuropathy, blood creatinine increased, acute renal failure, 
cough, dyspnea, pruritis 
Common known potential toxicities, ≥1% - <10%:  
Febrile neutropenia, pancytopenia, vertigo, vomiting, gastrointestinal 
hemorrhage, hemorrhoidal hemorrhage, rectal hemorrhage, hematochezia, 
gingival bleeding, bronchopneumonia, herpes zoster, nasopharyngitis, 
neutropenic sepsis, respiratory tract infection, alanine aminotransferase 
increased, increased liver function test, aspartate aminotransferase increased, 
gamma-glutamyltransferase increased, neutrophil count decreased, platelet count 
decreased, white blood cell count decreased, hyperkalemia, hyponatremia, 
depressed level of consciousness, peripheral sensory neuropathy, paresthesia, gait 
disturbance, polyneuropathy, hypoesthesia, neuralgia, peripheral motor 
neuropathy, tremor, confusional state, renal failure, renal impairment, 
hypercreatininemia, urinary retention, pelvic pain, pulmonary embolism, pruritus 
generalized, rash, swelling face, face edema, deep vein thrombosis 
 
 


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Uncommon and rare known potential toxicities, <1%:  
Melena, Mallory-Weiss syndrome, upper gastrointestinal hemorrhage, mucosal 
hemorrhage, hyperbilirubinemia, blood bilirubin increased, transaminases 
increased, blood alkaline phosphates increased, liver function test abnormal, basil 
cell carcinoma, dysethesia, areflexia, motor dysfunction, sensory disturbance, 
burning sensation, muscle atrophy, blood urea increased, creatinine renal 
clearance decreased, oliguria, glomerular filtration rate decreased, renal tubular 
necrosis, acute prerenal failure, azotemia, pneumonitis, interstitial lung disease, 
pruritis generalized, angioedema, urticarial, eyelid edema 
Frequency not defined:  
Hepatitis, hepatitis B viral reactivation, tumor lysis syndrome, squamous cell 
carcinoma of skin, eye swelling, periorbital edema, lip swelling, swollen tongue, 
mouth edema, pharyngeal edema, Stevens-Johnson syndrome, toxic epidermal 
necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS) 
  
All study participants must be registered into the mandatory POMALYST 
REMS™ program, and be willing and able to comply with the requirements of 
the POMALYST REMS™ program. Females of reproductive potential must 
adhere to the scheduled pregnancy testing. Females of childbearing potential 
should not handle or administer pomalidomide unless they are wearing gloves. 
15.28 Drug procurement: Pomalidomide (POMALYST®) will be provided to 
research subjects for the duration of their participation in this trial at no charge to 
them or their insurance providers. Pomalidomide will be provided in accordance 
with Celgene Corporation’s POMALYST REMS™ program. Per the standard 
POMALYST REMS™ program requirements, all physicians who prescribe 
pomalidomide for research subjects enrolled into this trial, and all research 
subjects enrolled into this trial, must be registered in and must comply with all 
requirements of the POMALYST REMS™ program. 
Drug will be shipped on a per patient basis by the contract pharmacy to the clinic 
site for IND studies. Only enough pomalidomide for one cycle of therapy will be 
supplied to the patient each cycle. 
 
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 


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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 
 
 
 


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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 
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. 
 
 
 


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16.0 
Statistical Considerations and Methodology 
16.1 
Overview 
This is a phase II study of a novel regimen of ixazomib with pomalidomide and 
dexamethasone for treatment of multiple myeloma with extramedullary disease and 
plasma cell leukemia. The study is designed to assess the confirmed response rate using a 
single stage phase II study design with an interim analysis. Accrual will be halted after 6 
patients to assess safety (see Section 16.4). We do not plan to halt accrual during the 
interim analysis (see Section 16.214). 
16.11 
Primary Endpoint: The primary endpoint of this trial is the rate of confirmed 
response. A confirmed response is defined as a patient who has achieved an sCR, 
CR, VGPR, or PR on two consecutive evaluations. All patients meeting the 
eligibility criteria, who have signed a consent form and have begun treatment, 
will be evaluable for response, unless they are determined to be a major 
violation. 
16.2 
Statistical Design 
16.21 Decision Rule: 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 50%. The following one–stage 
design with an interim analysis is based on a two-stage Simon optimum design 
and requires 27 evaluable patients to test the null hypothesis that the true success 
proportion in this patient population is at most 25%. 
16.211 Interim Analysis: Enter 10 evaluable patients into the study. If 2 or fewer 
successes are observed in the first 10 evaluable patients, we will consider 
this regimen ineffective in this patient population and terminate the 
study. Otherwise, if the number of successes is at least 3, we will 
continue accrual. 
16.212  Final Decision Rule: Enter an additional 17 evaluable patients into the 
study. If 9 or fewer successes are observed in the first 27 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 
activity and the treatment may be recommended for further testing in 
subsequent studies in this population.  
16.213 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 16.313. 
16.214 NOTE: We will not suspend accrual at the interim analysis to allow the 
first 10 patients to become evaluable, unless undue toxicity is observed.  
Given the limited overall sample size and the inclusion of an adverse 
events stopping rule, we feel it is ethical to not halt accrual for the 
interim analysis. However, if accrual is extremely rapid, we may 
temporarily suspend accrual in order to obtain safety data on these 
patients before re-opening accrual to further patients. 
 


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16.22 Sample Size: The one stage study design with an interim analysis to be used is 
fully described below. A minimum of 10 and a maximum of 27 evaluable 
patients will be accrued onto this phase II study unless undue toxicity is 
encountered. We anticipate accruing additional 3 patients to account for 
ineligibility, cancellation, major treatment violation, or other reasons for a total 
of 30 patients overall. 
16.23 Accrual Rate and Study Duration: The anticipated accrual rate is 1-2 evaluable 
multiple myeloma patients per month. At this rate, it will likely take about 18-24 
months to enroll, treat, and evaluate all patients. The maximum total study 
duration is expected to be approximately 2.5 years, or until the last patient 
accrued has been observed for at least 6 months. 
16.24 Power and Significance Level: Assuming that the number of successes is 
binomially distributed, the significance level is .10, i.e. there is a 10% chance of 
finding the drug to be effective when it truly is not. The probability of declaring 
that this regimen warrants further study (i.e. statistical power) and the probability 
of stopping at the interim analysis under various success proportions can be 
tabulated as a function of the true success proportion as shown in the following 
table. 
 
If the true success proportion is... 
0.25 
0.30 
0.35 
0.40 
0.45 
0.50 
Then the probability of declaring 
that the regimen warrants further 
study is… 
0.10 
0.24 
0.44 
0.64 
0.80 
0.90 
And the probability of stopping at 
the interim analysis is… 
0.53 
0.38 
0.26 
0.17 
0.10 
0.05 
 
16.25 Other considerations: Adverse events, 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 
Analysis Plan 
The analysis for this trial will commence at planned time points (see 16.2) and at the time 
the patients have become evaluable for the primary endpoint. The Statistician and Study 
Chair will make the decision, in accord with CCS Standard Operating Procedures, 
availability of data for secondary endpoints (e.g., laboratory correlates), and the level of 
data maturity. It is anticipated that the earliest date in which the results will be made 
available via manuscript, abstract, or presentation format is when last patient has been 
followed for at least 6 months. 
16.31 Primary Outcome Analyses: 
16.311 Definition: The primary endpoint of this trial is the proportion of the 
confirmed response rate. A success is defined as an sCR, CR, VGPR, or 
PR noted as the objective status on two consecutive evaluations. All 
patients meeting the eligibility criteria who have signed a consent form 
and have begun treatment will be evaluable for response, unless they are 
determined to be a major violation. 
16.312 Estimation: The proportion of successes will be estimated by the number 
of successes divided by the total number of evaluable patients. Ninety-


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Addendum 7 
Protocol version date: 30Mar2020 
five percent confidence intervals for the true success proportion will be 
calculated according to the approach of Duffy and Santner. 
16.313 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. 
16.32 Secondary Outcome Analyses 
16.321 Type of response will be differentiated as biochemical vs. 
extramedullary disease, as defined in Section 11.6. Biochemical 
response will be defined as a response by serum M-protein, urine M-
protein, or serum FLC assay parameters. For biochemical response, the 
response rate will be estimated by the number of responders divided by 
the number of evaluable patients who have measurable disease by serum 
M-protein, urine M-protein, or serum FLC assay at baseline. 
Extramedullary response will be defined as a response by 
extramedullary plasmacytoma or plasma cell count parameters. For 
extradmedullary response, the response rate will be estimated by the 
number of responders divided by the number of evaluable patients. 
Exact binomial confidence intervals will be calculated. 
16.322 Progression-free survival is defined as the time from registration to the 
earliest date of documentation of disease progression or death due to 
any cause. The distribution of progression-free survival will be 
estimated using the method of Kaplan-Meier. 
16.323 Adverse Events: All eligible patients that have initiated treatment will 
be considered evaluable for assessing adverse event rate(s). The 
maximum grade for each type of adverse event will be recorded for each 
patient, and frequency tables will be reviewed to determine patterns. 
Additionally, the relationship of the adverse event(s) to the study 
treatment will be taken into consideration. 
16.33 Correlative Analyses 
16.331 Minimal residual disease will be assessed on bone marrow aspirate in all 
patients achieving CR. The proportion of patients who achieve MRD 
negative status will be estimated by the number of patients who are MRD 
negative divided by the total number of evaluable patients who achieve 
an sCR or CR. Exact binomial 95% confidence intervals for the true 
MRD negative rate will be calculated. 
16.4 
Early Safety Analysis 
An early safety analysis will be performed after the first 6 patients have been accrued to 
the study and observed for one cycle. Accrual will be temporarily halted while these 
patients are evaluated. If 2 or more of the first 6 patients experience a DLT as defined 
below, then accrual to the study will continue to be temporarily halted while the study 
team determines if changes to the dosing schedule are warranted. 
Toxicity will be measured per NCI-CTCAE version 4. DLT is defined as an adverse 
event occurring during the first cycle of treatment that is possibly, probably, or definitely 
related to study treatment and that meets one of the following: 


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Addendum 7 
Protocol version date: 30Mar2020 
• 
Grade 3 diarrhea, nausea, and fatigue lasting > 3 days despite optimal supportive 
medications 
• 
Any other ≥Grade 3 non-hematological toxicity with the exceptions of electrolyte 
abnormalities that are reversible and asymptomatic 
• 
Febrile neutropenia 
• 
Grade 3 thrombocytopenia with clinically significant bleeding 
• 
Any ≥Grade 4 neutrophil count decreased or platelet count decreased that persists 
>7 days 
16.5 
Data & Safety Monitoring: 
16.51 The principal investigator(s) and the study statistician will review the study at 
least twice a year 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. 
16.52 Adverse Event Stopping Rules: The stopping rules specified below are based on 
the knowledge available at study development. We note that the Adverse Event 
Stopping 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 
treatment(s) under investigation. The study team may choose to suspend accrual 
because of unexpected adverse event profiles that have not crossed the specified 
rule below. 
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 
one of the following: 
• 
if 5 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, 30% 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. 
16.6  
Results Reporting on ClinicalTrials.gov 
At study activation, this study will have been registered within the “ClincialTrails.gov” 
website. The Primary and Secondary Endpoints along with other required information for 
this study will be reported on www.ClinicalTrials.gov. For purposes of timing of the 
Results Reporting, the initial estimated completion date for the Primary Endpoint of this 
study is 2.5 years after the study opens to accrual. The definition of “Primary Endpoint 
Completion Date” (PECD) for this study is at the time the last patient registered has been 
followed for at least 6 months. 
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. 


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16.72 There is no information currently available regarding differential effects of this 
regimen in subsets defined by race, gender, or ethnicity, 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 MCCC has a population which includes 
approximately 3% minorities. Based on prior MCCC 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: 
Accrual Estimates by Gender/Ethnicity/Race  
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
0 
1 
0 
1 
Not Hispanic or Latino 
10 
19 
0 
29 
Ethnic Category: Total of all subjects* 
10 
20 
0 
30 
Racial Category 
 
American Indian or Alaskan Native 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
Black or African American 
1 
1 
0 
2 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
0 
White 
9 
19 
0 
28 
Racial Category: Total of all subjects* 
10 
20 
0 
30 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rico, 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. 
 


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17.0 
Pathology Considerations/Tissue Biospecimens  
None 
 
18.0 
Records and Data Collection Procedures  
18.1 
Submission Timetable 
Data submission instructions for this study can be found in the Case Report Form 
packet. 
18.2 
Event monitoring 
See Section 4.2 for the event monitoring schedule. 
18.3 
CRF completion for non-Mayo Clinic sites 
This study will use Medidata Rave for remote data capture (rdc) of all study data. 
18.4 
Site responsibilities 
Each co-sponsor/participant will be responsible for insuring that all materials contain the 
patient’s initials, MCCC registration number, and MCCC protocol number. Patient’s 
name must be removed. 
18.5 
Supporting documentation 
This study requires supporting documentation for diagnosis and progression prior to 
study entry as well as for evidence of response to study therapy and progression after 
study therapy. Supporting documentation for diagnosis will include either a pathology 
report or a laboratory report demonstrating multiple myeloma with extramedullary 
disease or plasma cell leukemia (including bone marrow biopsy report; and SPEP, UPEP, 
FLC, FISH, and Cytogenetics reports). These reports should be submitted within 14 days 
of registration. 
For progression of disease prior to study entry, supporting documentation includes the 
evidence needed to determine the patient’s progression prior to enrollment. These 
documents should be submitted within 14 days of registration. 
For response to treatment, supporting documentation includes SPEP, UPEP, FLC, Serum 
and Urine Immunofixation, Bone Marrow Biopsy and aspirate, and X-ray skeletal survey. 
For patients who progress after study therapy supporting documentation may include any 
of the following: SPEP, UPEP, FLC, Serum and Urine Immunofixation, Bone Marrow 
Biopsy and aspirate, and X-ray skeletal survey. 
18.6 
Labelling of materials 
Each site will be responsible for insuring that all materials contain the patient’s 
initials, MCCC registration number, and MCCC protocol number. Patient’s name 
must be removed. 
18.7 
Incomplete materials 
Any data entered into a form will result in that form being marked as “received.” 
However, missing data will be flagged by edit checks in the database. 
18.8 
Overdue lists 
The list of overdue materials is available in the database at any time. A list of 
overdue materials and forms for study patients will be generated monthly. The 
listings will be sorted by location and will include the patient study registration 


MC1487 
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Addendum 7 
Protocol version date: 30Mar2020 
number. The appropriate co-sponsor/participant will be responsible to obtain the 
overdue material. 
18.9 
Corrections forms 
If a correction is necessary the QAS will query the site. The query will be sent to 
the appropriate site to make the correction in the database and respond back to the 
QAS.  
 
19.0  
Budget 
19.1 
Costs charged to patient: Routine clinical care 
19.2 
Tests to be research funded: None 
19.3 
Other budget concerns: None 
 
 


MC1487 
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Addendum 7 
Protocol version date: 30Mar2020 
20.0 
References 
Gupta, N., M. Saleh and K. Venkatakrishnan (2011). "Flat-dosing versus BSA-based dosing for 
MLN9708, an investigational proteasome inhibitor: population pharmacokinetic (PK) analysis of pooled 
data from 4 phase-1 studies. ." Blood 118(21): 1433. 
Gupta, N., M. Saleh and K. Venkatakrishnan (2012). "Switch from BSA-based dosing to fixed dosing for 
the investigational drug ixazomib citrate: Application of modeling and simulation to influence posology 
decisions in oncology drug development. ." Clin Pharmacol Ther 91(S86-S87 ). 
Kumar, S., S. V. Rajkumar, R. A. Kyle, M. Q. Lacy, A. Dispenzieri, R. Fonseca, J. A. Lust, M. A. Gertz, 
P. R. Greipp and T. E. Witzig (2005). "Prognostic value of circulating plasma cells in monoclonal 
gammopathy of undetermined significance." J Clin Oncol 23(24): 5668-5674. 
Kumar, S. K., W. I. Bensinger, T. M. Zimmerman, C. B. Reeder, J. R. Berenson, D. Berg, A. M. Hui, N. 
Gupta, A. Di Bacco, J. Yu, Y. Shou and R. Niesvizky (2014). "Phase 1 study of weekly dosing with the 
investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma." Blood 
124(7): 1047-1055. 
Kumar, S. K., W. I. Bensinger, T. M. Zimmerman, C. B. Reeder, J. R. Berenson, D. Berg, A. M. Hui, N. 
Gupta, A. Di Bacco, J. Yu, Y. Shou and R. Niesvizky (2014). "Weekly dosing of the investigational oral 
proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma: results from a phase 1 study." 
Blood. 
Kumar, S. K., J. G. Berdeja, R. Niesvizky, S. Lonial, J. P. Laubach, M. Hamadani, A. K. Stewart, P. Hari, 
V. Roy, R. Vescio, J. L. Kaufman, D. Berg, E. Liao, A. Di Bacco, J. Estevam, N. Gupta, A. M. Hui, V. 
Rajkumar and P. G. Richardson (2014). "Safety and tolerability of ixazomib, an oral proteasome inhibitor, 
in combination with lenalidomide and dexamethasone in patients with previously untreated multiple 
myeloma: an open-label phase 1/2 study." Lancet Oncol 15(13): 1503-1512. 
Lacy, M. Q., J. B. Allred, M. A. Gertz, S. R. Hayman, K. D. Short, F. Buadi, A. Dispenzieri, S. Kumar, P. 
R. Greipp, J. A. Lust, S. J. Russell, D. Dingli, S. Zeldenrust, R. Fonseca, P. L. Bergsagel, V. Roy, A. K. 
Stewart, K. Laumann, S. J. Mandrekar, C. Reeder, S. V. Rajkumar and J. R. Mikhael (2011). 
"Pomalidomide plus low-dose dexamethasone in myeloma refractory to both bortezomib and 
lenalidomide: comparison of 2 dosing strategies in dual-refractory disease." Blood 118(11): 2970-2975. 
Lacy, M. Q., S. R. Hayman, M. A. Gertz, A. Dispenzieri, F. Buadi, S. Kumar, P. R. Greipp, J. A. Lust, S. 
J. Russell, D. Dingli, R. A. Kyle, R. Fonseca, P. L. Bergsagel, V. Roy, J. R. Mikhael, A. K. Stewart, K. 
Laumann, J. B. Allred, S. J. Mandrekar and S. V. Rajkumar (2009). "Pomalidomide (CC4047) plus low-
dose dexamethasone as therapy for relapsed multiple myeloma." J Clin Oncol 27(30): 5008-5014. 
Lacy, M. Q., S. R. Hayman, M. A. Gertz, K. D. Short, A. Dispenzieri, S. Kumar, P. R. Greipp, J. A. Lust, 
S. J. Russell, D. Dingli, S. Zeldenrust, R. Fonseca, P. L. Bergsagel, V. Roy, J. R. Mikhael, A. K. Stewart, 
K. Laumann, J. B. Allred, S. J. Mandrekar, S. V. Rajkumar and F. Buadi (2010). "Pomalidomide 
(CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory 
multiple myeloma (MM)." Leukemia 24(11): 1934-1939. 
Leleu, X., L. Karlin, M. Macro, C. Hulin, L. Garderet, M. Roussel, B. Arnulf, B. Pegourie, B. Kolb, A. 
M. Stoppa, S. Brechiniac, G. Marit, B. Thielemans, B. Onraed, C. Mathiot, A. Banos, L. Lacotte, M. 
Tiab, M. Dib, J. G. Fuzibet, M. O. Petillon, P. Rodon, M. Wetterwald, B. Royer, L. Legros, L. 
Benboubker, O. Decaux, M. Escoffre-Barbe, D. Caillot, J. P. Fermand, P. Moreau, M. Attal, H. Avet-


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Loiseau and T. Facon (2015). "Pomalidomide plus low-dose dexamethasone in multiple myeloma with 
deletion 17p and/or translocation (4;14): IFM 2010-02." Blood. 
Lopez-Anglada, L., N. C. Gutierrez, J. L. Garcia, M. V. Mateos, T. Flores and J. F. San Miguel (2010). 
"P53 deletion may drive the clinical evolution and treatment response in multiple myeloma." Eur J 
Haematol 84(4): 359-361. 
Madan, S. and S. Kumar (2009). "Review: extramedullary disease in multiple myeloma." Clin Adv 
Hematol Oncol 7(12): 802-804. 
Richardson, P. G., R. Baz, M. Wang, A. J. Jakubowiak, J. P. Laubach, R. D. Harvey, M. Talpaz, D. Berg, 
G. Liu, J. Yu, N. Gupta, A. Di Bacco, A. M. Hui and S. Lonial (2014). "Phase 1 study of twice-weekly 
dosing of investigational oral proteasome inhibitor ixazomib in patients with relapsed and/or refractory 
multiple myeloma." Blood. 
Rosinol, L., M. T. Cibeira, J. Blade, J. Esteve, M. Aymerich, M. Rozman, M. Segarra, M. C. Cid, X. 
Filella and E. Montserrat (2004). "Extramedullary multiple myeloma escapes the effect of thalidomide." 
Haematologica 89(7): 832-836. 
San Miguel, J., K. Weisel, P. Moreau, M. Lacy, K. Song, M. Delforge, L. Karlin, H. Goldschmidt, A. 
Banos, A. Oriol, A. Alegre, C. Chen, M. Cavo, L. Garderet, V. Ivanova, J. Martinez-Lopez, A. Belch, A. 
Palumbo, S. Schey, P. Sonneveld, X. Yu, L. Sternas, C. Jacques, M. Zaki and M. Dimopoulos (2013). 
"Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with 
relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial." Lancet 
Oncol 14(11): 1055-1066. 
Sheth, N., J. Yeung and H. Chang (2009). "p53 nuclear accumulation is associated with extramedullary 
progression of multiple myeloma." Leuk Res 33(10): 1357-1360. 
Short, K. D., S. V. Rajkumar, D. Larson, F. Buadi, S. Hayman, A. Dispenzieri, M. Gertz, S. Kumar, J. 
Mikhael, V. Roy, R. A. Kyle and M. Q. Lacy (2011). "Incidence of extramedullary disease in patients 
with multiple myeloma in the era of novel therapy, and the activity of pomalidomide on extramedullary 
myeloma." Leukemia 25(6): 906-908. 
Streetly, M. J., K. Gyertson, Y. Daniel, J. B. Zeldis, M. Kazmi and S. A. Schey (2008). "Alternate day 
pomalidomide retains anti-myeloma effect with reduced adverse events and evidence of in vivo 
immunomodulation." British journal of haematology 141(1): 41-51. 
Usmani, S. Z., C. Heuck, A. Mitchell, J. Szymonifka, B. Nair, A. Hoering, Y. Alsayed, S. Waheed, S. 
Haider, A. Restrepo, F. Van Rhee, J. Crowley and B. Barlogie (2012). "Extramedullary disease portends 
poor prognosis in multiple myeloma and is over-represented in high-risk disease even in the era of novel 
agents." Haematologica 97(11): 1761-1767. 
Varettoni, M., A. Corso, G. Pica, S. Mangiacavalli, C. Pascutto and M. Lazzarino (2009). "Incidence, 
presenting features and outcome of extramedullary disease in multiple myeloma: a longitudinal study on 
1003 consecutive patients." Ann Oncol 21(2): 325-330. 


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Appendix I 
ECOG Performance Status 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
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 house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair. 
5 
Dead 
*As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-
655, 1982. 
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the 
scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
From 
 
 
 




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Appendix III Drug Classification Guide 
 
Class 
Generic name 
Other Names 
Alkylators 
 
 
 
Cyclophosphamide 
Cytoxan 
 
 
Melphalan 
Alkeran 
 
 
Carmustine 
BCNU 
 
 
Busulphan 
Myleran 
 
 
Chlorambucil 
 
 
 
Cisplatin 
 
 
 
Dacarbazine 
 
 
 
Ifosfamide 
 
 
 
Lomustine 
CCNU 
 
 
Mecholorethamine 
Nitrogen mustard  
 
Procarbazine 
 
 
 
 
 
 
Antimetabolites 
 
 
 
Asparaginase 
 
 
 
Chlorodeoxyadenosine 2-CDA 
 
 
Cytabarine 
Cytosar-U 
Tarabine 
 
Deoxycorormycin 
 
 
 
Floxuridine 
 
 
 
Fludarabine 
 
 
 
Flurouracil 
 
 
 
Hydroxyurea 
 
 
 
Mercaptopurine 
 
 
 
Methotrexate 
 
 
 
Thioguanine 
 
 
 
Thiotepa 
 
 
 
 
 
 
Anthracyclines/Antibiotics 
 
 
 
Bleomycin 
 
 
 
Dactinomycin 
 
 
 
Daunorubicin 
 
 
 
Doxorubicin 
Adriamycin 
 
 
Pegylated doxorubicin 
Doxyl 
 
 
Idarubicin 
 
 
 
Mitomycin 
 
 
 
Mitoxantrone 
 
 
 
 
 
 
Bisphosphonates 
 
 
 
Zoledronic acid 
Zometa 
 
 
Pamidronate 
Aredia 
 
 
 
 
 
Corticosteroids 
 
 
 
Prednisone 
 
 


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Protocol version date: 30Mar2020 
 
Methylprednisolone 
Solumedrol 
 
 
Dexamthasone 
Decadron 
Dex 
 
 
 
 
IMiDs (immune modulatory drugs) 
 
 
 
Thalidomide 
Thalidomid 
 
 
Lenalidomide 
Revlimid 
CC-5013 
 
Interferon 
 
 
 
Pomalidomide 
 
 
 
Levamisole 
 
 
 
 
 
 
Proteasome inhibitors 
 
 
 
Bortezomib 
Velcade 
 
 
Carfilzomib 
Kyprolis 
 
 
MLN9708 
Ixazomib 
 
 
Oprozomib 
 
 
 
 
 
 
Topoisomerases 
 
 
 
Etoposide 
VP-16 
 
 
 
 
 
 
 
 
 
Taxanes 
 
 
 
Paclitaxel 
Taxol 
 
 
Docetaxel 
 
 
 
 
 
 
 
 
 
 
Monoclonal Antibodies 
 
 
 
Anti-SLAMF7 
Elotuzumab 
 
 
Anti-38 
Daratumumab 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vinca Alkyloid 
 
 
 
Vinblastine 
 
 
 
Vincristine 
 
 
 
Vindestine 
 
 
 
Vinorelbine 
 
 
 
 
 
 
 
Last Updated 9/29/14 
 


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Appendix IV Pomalidomide Education and Counselling Guidance Document 
NOTE: This document will be completed as part of the Pomalyst REMS program. It is included 
here for informational purposes only. 
Protocol Number: MC1487_____________________________________ 
 
Patient Name (Print): __________________  
DOB: _____/_____/_____ (mm/dd/yyyy) 
(Check the appropriate box to indicate risk category) 
Female: 
 
If female, check one: 
  FCBP (Female of childbearing potential): sexually mature female who: 1) has not 
undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy 
(the surgical removal of both ovaries) or 2) has not been naturally postmenopausal 
(amenorrhea following cancer therapy does not rule out childbearing potential) for at 
least 24 consecutive months (i.e., has had menses at any time during the preceding 24 
consecutive months) 
  NOT FCBP 
Male: 
  
 
Do Not Dispense study drug if: 
• 
The patient is pregnant. 
• 
No pregnancy tests were conducted for a FCBP. 
• 
The patient states she did not use TWO reliable methods of birth control (unless 
practicing complete abstinence of heterosexual contact) [at least 28 days prior to 
therapy, during therapy and during dose interruption]. 
FCBP: 
1. 
I verified that the required pregnancy tests performed are negative. 
2. 
I counselled FCBP regarding the following: 
• 
Potential risk of fetal exposure to pomalidomide: If pomalidomide is taken during 
pregnancy, it may cause birth defects or death to any unborn baby. Females are advised to 
avoid pregnancy while taking pomalidomide. The teratogenic potential of pomalidomide in 
humans cannot be ruled out. FCBP must agree not to become pregnant while taking 
pomalidomide.  
• 
Using TWO reliable methods of birth control at the same time or complete abstinence from 
heterosexual contact [at least 28 days prior to therapy, during therapy, during dose 
interruption and 28 days after discontinuation of study drug]. 
• 
That even if she has amenorrhea she must comply with advice on contraception.  


MC1487 
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Protocol version date: 30Mar2020 
• 
Use of one highly effective method and one additional method of birth control AT THE 
SAME TIME. The following are examples of highly effective and additional effective 
methods of contraception:  
− Highly effective methods: 
o Intrauterine device (IUD) 
o Hormonal (birth control pills, injections, implants) 
o Tubal ligation 
o Partner’s vasectomy 
− Additional effective methods: 
o Male condom 
o Diaphragm 
o Cervical Cap 
• 
Pregnancy tests before and during treatment, even if the patient agrees not to have 
reproductive heterosexual contact. Two pregnancy tests will be performed prior to receiving 
study drug, one within 10-14 days and the second within 24 hours of the start of study drug. 
• 
Frequency of pregnancy tests to be done: 
− Every week during the first 28 days of this study and a pregnancy test every 28 days 
during the patient’s participation in this study if menstrual cycles are regular or every 14 
days if cycles are irregular. 
− If the patient missed a period or has unusual menstrual bleeding. 
− When the patient is discontinued from the study and at day 28 after study drug 
discontinuation if menstrual cycles are regular. If menstrual cycles are irregular, 
pregnancy tests will be done at discontinuation from the study and at days 14 and 28 
after study drug discontinuation. 
• 
Stop taking study drug immediately in the event of becoming pregnant and to call their study 
doctor as soon as possible.  
• 
NEVER share study drug with anyone else. 
• 
Do not donate blood while taking study drug and for 28 days after stopping study drug. 
• 
Do not breastfeed a baby while participating in this study and for at least 28 days after study 
drug discontinuation. 
• 
Do not break, chew, or open study drug capsules. 
• 
Return unused study drug to the study doctor. 
3.  
Provide Pomalidomide Information Sheet to the patient. 
 


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FEMALE NOT OF CHILDBEARING POTENTIAL (NATURAL MENOPAUSE FOR AT 
LEAST 24 CONSECUTIVE MONTHS, A HYSTERECTOMY, OR BILATERAL 
OOPHORECTOMY): 
1. 
I counselled the female NOT of childbearing potential regarding the following: 
• 
Potential risk of fetal exposure to pomalidomide (Refer to item #2 in FCBP) 
• 
NEVER share study drug with anyone else. 
• 
Do not donate blood while taking study drug and for 28 days after stopping study drug. 
• 
Do not break, chew, or open study drug capsules 
• 
Return unused study drug capsules to the study doctor. 
2. 
Provide Pomalidomide Information Sheet to the patient. 
MALE: 
1. 
I counselled the Male patient regarding the following: 
• 
Potential study drug fetal exposure to pomalidomide (Refer to item #2 in FCBP). 
• 
To engage in complete abstinence or use a condom when engaging in sexual contact 
(including those who have had a vasectomy) with a pregnant female or a female of 
childbearing potential, while taking study drug, during dose interruptions and for 28 days 
after stopping study drug. 
• 
Males should notify their study doctor when their female partner becomes pregnant and 
female partners of males taking study drug should be advised to call their healthcare 
provider immediately if they get pregnant 
• 
NEVER share study drug with anyone else. 
• 
Do not donate blood while taking study drug and for 28 days after stopping study drug. 
• 
Do not donate semen or sperm while taking study drug and for 28 days after stopping study 
drug. 
• 
Do not break, chew, or open study drug capsules. 
• 
Return unused study drug capsules to the study doctor. 
2. 
Provide Pomalidomide Information Sheet to the patient. 
 
Investigator/Counselor Name (Print): ____________________  
 (circle applicable) 
Investigator/Counselor Signature: _______________________  Date: _____/_____/_____ 
(circle applicable) 
 
**Maintain a copy of the Education and Counselling Guidance Document in the patient records.** 
 
 


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Pomalidomide Information Sheet  
FOR PATIENTS ENROLLED IN CLINICAL RESEARCH STUDIES 
Please read this Pomalidomide Information Sheet before you start taking study drug and each time you 
get a new supply. This Pomalidomide Information Sheet does not take the place of an informed consent 
to participate in clinical research or talking to your study doctor or healthcare provider about your 
medical condition or your treatment.  
What is the most important information I should know about pomalidomide? 
1. Pomalidomide may cause birth defects (deformed babies) or death of an unborn baby. 
Pomalidomide is similar to the medicine thalidomide. It is known that thalidomide causes life-
threatening birth defects. Pomalidomide has not been tested in pregnant women but may also 
cause birth defects. Pomalidomide was found to cause birth defects when tested in pregnant 
rabbits. If you are a female who is able to become pregnant: 
• 
Do not take study drug if you are pregnant or plan to become pregnant 
• 
You must either not have any sexual relations with a man or use two reliable, separate 
forms of effective birth control at the same time:  
− for 28 days before starting study drug 
− while taking study drug  
− during dose interruptions of study drug  
− for 28 days after stopping study drug  
• 
You must have pregnancy testing done at the following times: 
− within 10 – 14 days and again 24 hours prior to the first dose of study drug  
− weekly for the first 28 days 
− every 28 days after the first month or every 14 days if you have irregular menstrual 
periods 
− if you miss your period or have unusual menstrual bleeding 
− 28 days after the last dose of study drug (14 and 28 days after the last dose if menstrual 
periods are irregular) 
• 
Stop taking study drug if you become pregnant during treatment 
− If you suspect you are pregnant at any time during the study, you must stop study drug 
immediately and immediately inform your study doctor. The study doctor will report all 
cases of pregnancy to Celgene Corporation.  
• 
Do not breastfeed while taking study drug 
• 
The study doctor will be able to advise you where to get additional advice on contraception. 
If you are a female not of childbearing potential: 
In order to ensure that an unborn baby is not exposed to pomalidomide, your study doctor will 
confirm that you are not able to become pregnant. 
If you are a male: 


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The effect of pomalidomide on sperm development is not known and has not been studied. The 
risk to the foetus in females of child bearing potential whose male partner is receiving 
pomalidomide is unknown at this time.  
1. Male patients (including those who have had a vasectomy) must either not have any 
sexual relations with a pregnant female or a female who can become pregnant, or 
must use a condom during sexual contact with a pregnant female or a female that can 
become pregnant: 
o While you are taking study drug  
o During dose interruptions of study drug  
o For 28 days after you stop taking study drug  
2. Male patients should not donate sperm or semen while taking study drug and for 28 
days after stopping study drug.  
3. If you suspect that your partner is pregnant any time during the study, you must 
immediately inform your study doctor. The study doctor will report all cases of 
pregnancy to Celgene Corporation. Your partner should call their healthcare 
provider immediately if they get pregnant. 
2. Restrictions in sharing study drug and donating blood: 
1. Do not share study drug with other people. It must be kept out of the reach of 
children and should never be given to any other person. 
2. Do not donate blood while you take study drug and for 28 days after stopping study 
drug.  
3. Do not break, chew, or open study drug capsules. 
4. You will be supplied with no more than one cycle of study drug  
5. Return unused study drug capsules to your study doctor. 
Additional information is provided in the informed consent form and you can ask your study 
doctor for more information. 


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Appendix V 
MC1487 Model Consent Form 
*NOTES FOR LOCAL INVESTIGATORS:  
The goal of the informed consent process is to provide people with sufficient information for making 
informed choices. The informed consent form provides a summary of the clinical study and the 
individual’s rights as a research participant. It serves as a starting point for the necessary exchange of 
information between the investigator and potential research participant. This template for the informed 
consent form is only one part of the larger process of informed consent. For more information about 
informed consent, review the “Recommendations for the Development of Informed Consent Documents 
for Cancer Clinical Trials” prepared by the Comprehensive Working Group on Informed Consent in 
Cancer Clinical Trials for the National Cancer Institute. The website address for this document is 
http://cancer.gov/clinicaltrials/understanding/simplification-of-informed-consent-docs/ 
• 
A blank line, __________, indicates that the local investigator should provide the appropriate 
information before the document is reviewed with the prospective research participant.  
• 
Instructions and examples for informed consent authors are in [italics]. Remember to remove these 
items before finalizing your consent form. 
• 
The language should be written in 6th grade language. When proofreading the consent form, ask 
yourself if an average 6th grader would understand the study after reading this form. 
• 
Suggestion for Local Investigators: An NCI pamphlet explaining clinical trials is available for your 
patients. The pamphlet is entitled: “If You Have Cancer…What You Should Know about Clinical 
Trials.” This pamphlet may be ordered on the NCI website at https://cissecure.nci.nih.gov/ncipubs/ or 
call 1-800-4-CANCER (1-800-422-6237) to request a free copy. 
• 
Optional feature for Local Investigators: Reference and attach drug sheets, pharmaceutical 
information for the public, or other material on risks. Check with your local IRB regarding review of 
additional materials. 
*These notes for investigators are instructional and should not be included in the informed consent form 
given to the prospective research participant.  
 
RESEARCH PARTICIPANT CONSENT AND PRIVACY 
AUTHORIZATION FORM 
 
Study Title: MC1487: Phase 2 Trial of Pomalidomide, Ixazomib and Dexamethasone in 
Patients with Multiple Myeloma with Extramedullary Disease or Plasma Cell 
Leukemia {MMRC-052} 
 
IRB#:  
{Insert local IRB number here} 
 
Principal Investigator: {Insert name of local investigator here} 
 
Please read this information carefully. It tells you important things about this research study. A 
member of our research team will talk to you about taking part in this research study. If you have 
questions at any time, please ask us. 
 
Take your time to decide. Feel free to discuss the study with your family, friends, and healthcare 
provider before you make your decision. 


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To help you decide if you want to take part in this study, you should know: 
• Taking part in this study is completely voluntary.  
• You can choose not to participate.  
• You are free to change your mind at any time if you choose to participate.  
• Your decision won’t cause any penalties or loss of benefits to which you’re otherwise 
entitled. 
• Your decision won’t change the access to medical care you receive now or in the future if 
you choose not to participate or discontinue your participation.  
 
For purposes of this form, Mayo Clinic refers to Mayo Clinic in Arizona, Florida and Rochester, 
Minnesota; Mayo Clinic Health System; and all owned and affiliated clinics, hospitals, and 
entities. 
 
If you decide to take part in this research study, you will sign this consent form to show that you 
want to take part. We will give you a copy of this form to keep. A copy of this form will be put 
in your medical record. 
 
 
CONTACT INFORMATION 
 
You can contact … 
At … 
If you have questions or about … 
Principal 
Investigator: 
Insert local PI Name 
 
Study Team Contact: 
Insert local contact 
here 
 
Phone: 
Insert local telephone 
 
Phone: 
Insert local telephone 
 
Address: 
Insert local address 
 
 Study tests and procedures 
 Research-related injuries or 
emergencies 
 Any research-related concerns or 
complaints 
 Withdrawing from the research 
study 
 Materials you receive 
 Research-related appointments 
Institutional Review 
Board (IRB)/Research 
Ethics Board (REB) 
Phone: 
Insert IRB/REB 
telephone 
 
Toll-Free: 
 
 Rights of a research participant 
 
Research Subject 
Advocate 
(The RSA is 
independent of the 
Study Team) 
Phone: 
Insert local telephone 
 
 
E-mail: 
 
 Rights of a research participant 
 Any research-related concerns or 
complaints 
 Use of your Protected Health 
Information 
 Stopping your authorization to use 
your Protected Health Information 


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You can contact … 
At … 
If you have questions or about … 
Research Billing 
Insert local telephone 
 
 Billing or insurance related to this 
research study 
 
 
Other Information: 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Website will not include information that can identify you. At most, the 
Website will include a summary of the results. You can search this Website at any time. 
 
 
1. 
Why are you being asked to take part in this research study? 
 
 
You are being asked to take part in this study because you have been diagnosed with a type of 
blood cancer called “multiple myeloma” that requires treatment. 
 
About 30 people will take part in this research study.  
 
 
 
2. 
Why is this research study being done? 
 
 
You are being asked to take part in this research study because your multiple myeloma has 
gotten worse and is not responding to the standard drugs for multiple myeloma. 
 
In this study, you will be treated with an investigational drug called ixazomib (MLN9708), in 
addition to the standard regimen of pomalidomide and dexamethasone. It is thought that 
ixazomib will interfere with the process of protein breakdown in the multiple myeloma cells. The 
drug used in this study is considered investigational, which means it has either not been approved 
by the Food and Drug Administration (FDA) for routine clinical use or for the use described in 
this study. This study is being done to find out what effects (good and bad) the ixazomib has on 
you and your Multiple Myeloma. 
 
 
 
3. 
Information you should know 
 
 
Who is Funding the Study? 
 


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Takeda Pharmaceuticals/Millennium Pharmaceuticals, Celgene Corporation, and the Multiple 
Myeloma Research Foundation/Consortium (MMRF/MMRC) are funding the study. 
MMRF/MMRC will pay Mayo Clinic and other study sites to cover costs related to running the 
study. 
 
Information Regarding Conflict of Interest: 
 
Your doctor may be referring you to this study and if your doctor is also an Investigator in this 
study, he or she has a conflict by having two sets of interests (your well-being, and the scientific 
conduct of the study). If you are uncomfortable with your doctor working with you as part of this 
research study, but still wish to participate in the research, you may request to work with a 
different member of the research team. 
 
 
4. 
How long will you be in this research study? 
 
 
You will be in the study for approximately 3 years. 
 
 
5. 
What will happen to you while you are in this research study? 
 
 
Before you begin the study: 
 
If you agree to be in the study, you first sign this Informed Consent form, then you will be asked 
to participate in the following: 
 
Prior to Registration 
• Physical exam including complete medical history, height, weight and vital signs (blood 
pressure, heart rate, pulse, etc.) 
• Routine blood and urine tests 
• Skeletal survey (X-ray or low dose whole body CT) if needed 
• CT, MRI or CT-PET scan 
• Chest x-ray 
• Pregnancy test 
• Bone marrow aspirate and biopsy 
• ECG (a test to see how your heart is working) 
• Research blood tests 
• ECOG performance status (assessment of your ability to carry out daily activities) 
• Research samples (bone marrow and blood) 
 
As part of your clinical care, you will automatically be enrolled in the Pomalyst® REMS 
program in order to obtain pomalidomide. Before you can be enrolled in this program, you must 
read and agree to all the instructions. Due to the risks of the drug, pomalidomide is only 


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available through this program. More information is available on this website: 
http://www.pomalystrems.com/patient.html. 
 
Every Cycle Pre-treatment 
• Routine blood and urine tests 
• Physical exam including complete medical history, height, weight and vital signs 
• ECOG performance status (assessment of your ability to carry out daily activities) 
• CT, MRI or CT-PET scan (at the end of Cycle 1, then every third cycle) 
• Medication diary (please bring your medication diary with you to each visit) 
 
If you are a female of childbearing potential, you will need to have a blood or urine pregnancy 
test done weekly for the first four weeks of the study and every 28 days while on therapy with 
pomalidomide and/or ixazomib. In addition, you will need a pregnancy testing until 90 days after 
your last dose of ixazomib. 
 
Day 8, 15, 22 (Cycles 1-3); Day 15 (Cycle 4 onwards) 
• Routine blood tests 
 
End of Cycle 4 and every fourth cycle 
• Bone marrow aspirate and biopsy  
• Research samples (bone marrow and blood) 
 
End of Treatment 
• Physical exam including complete medical history, height, weight and vital signs 
• ECOG performance status (assessment of your ability to carry out daily activities) 
• Routine blood and urine tests 
• Skeletal survey (x-ray or CT) if needed 
• Medication diary 
• Bone marrow aspirate and biopsy  
• Research samples (bone marrow and blood) 
 
 
 
6. 
What are the possible risks or discomforts from being in this research 
study? 
 
 
You may have side effects while on the study. Everyone taking part in the study will be watched 
carefully for any side effects. However, doctors don’t know all the side effects that may happen. 
Side effects may be mild or very serious. Your health care team may give you medicines to help 
lessen side effects. In some cases, side effects can be serious, long lasting, or may never go 
away. 
 
You should talk to your study doctor about any side effects that you have while taking part in the 
study. 


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POTENTIAL DISCOMFORTS AND RISKS OF IXAZOMIB 
 
Based on early studies of ixazomib, it is possible to predict some of the discomforts and risks. 
The data suggest that the potential risks of ixazomib are likely to be manageable if monitored 
and treated. However, risks could become serious and potentially life-threatening. It is possible 
that ixazomib may cause side effects that were not seen in animal studies or yet seen in patients.  
 
 
Common risks of ixazomib (events occurring greater than 20% of the time) 
• Feeling sick to your stomach (nausea) 
• Throwing up (vomiting) 
• Loose stools (diarrhea) 
• Constipation 
• Feeling tired or weak 
• Decreased number of blood cells (platelets) that help to clot the blood, which could put 
you at increased risk of bleeding (thrombocytopenia) 
• Swelling of extremities 
• Fever 
• Decrease in red blood cells, which are the oxygen carrying cells which could make you 
feel tired (anemia) 
• A low number of white blood cells, which are the infection fighting cells, which could 
put you at risk for infection (neutropenia) 
• Infection including shingles 
• Skin rash 
• A low number of a particular white blood cell, which is important to the immune system 
(lymphopenia) 
• Numbness and tingling (also known as peripheral neuropathy) 
 
Less likely risks of ixazomib (events occurring less than or equal to 20% of the time) 
• Decreased appetite (not feeling hungry, not wanting to eat) 
• Cough 
• Joint pain 
• Abdominal pain or distension 
• Difficulty sleeping 
• Back pain 
• Shortness of breath 
• Upper respiratory tract infection  
• Sensation of lightheadedness or vertigo (spinning sensation) (dizziness) 
• Blood chemical imbalance (electrolyte imbalance) 
• Headache 
• Excessive or abnormal loss of body fluids (dehydration) 
• Pneumonia  
 


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Rare risks of ixazomib (events occurring less than 2-3% of the time) 
• Low or high blood pressure 
• A painful blistery red rash that is confined to one side of the body, similar to chicken pox 
(shingles - herpes zoster) 
• Effects on your nervous system that may cause painful feelings or numbness or tingling 
in hands and feet. The nerves that control things like your heart rate, gut movement, and 
urinary bladder may be affected. 
• Inflammatory response associated with an increase in your white blood cell count, fever, 
and a change in certain protein levels and chemistries in the body 
• Esophageal ulcer 
• Chest pain 
• Abnormal liver tests 
• Decreased weight 
• Fainting episodes 
• Decreased level of consciousness 
• Tremors 
• Blood clots 
• Inflammation of the lungs 
• Increased blood pressure in the lungs 
• Nosebleeds 
• Muscle weakness 
• Changes in mood 
• Swelling around the eyes 
• Muscle aches 
 
Rare but serious risks of ixazomib 
• Life threatening severe skin rash 
• Abnormal heart rhythms 
• Worsening of your heart function (congestive heart failure) 
• Disorders of your lungs that could be serious enough to result in death 
• Liver failure 
• Abnormal clotting of the blood in small blood vessels (Thrombotic Thrombocytopenic 
Purpura [TTP[) 
• A complication that may occur if the cancer cells die too quickly that includes 
inappropriate increase or decrease of various natural chemicals in the blood stream, 
called uric acid, phosphorus, potassium, creatinine, and calcium. Severe tumor lysis can 
result in kidney failure and may harm muscle or nerve function (Tumor lysis syndrome) 
• High creatinine and renal failure. The amount of creatinine (a waste product made by 
your body) in your blood helps your doctor understand how your kidneys are working. 
High creatinine means your kidneys are having trouble working well. Patients who had 
lost body water because of vomiting and/or loose stools have had high levels of creatinine 
indicating that the kidneys were failing to function adequately. In some severe situations, 
less kidney function may require temporary treatment with a machine that supports the 
function of the kidney (dialysis). 
• Blockage of your bowel function 


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• Severe rash that can lead to skin peeling and life-threatening complications (Stevens 
Johnson syndrome) 
• A condition that can be linked to abnormal nerve function and seizures (posterior 
reversible encephalopathy syndrome [PRES]) 
• Inflammation of the spinal cord (transverse myelitis) 
 
Progressive multifocal leukoencephalopathy (PML) has been reported with ixazomib in an 
oncology patient who had previously received a medication associated with PML. PML is a rare, 
serious infection of the brain that is caused by a virus. Persons with a weakened immune system 
may develop PML. PML can result in death or severe disability. It is not known whether 
ixazomib may have contributed to the development PML in this patient. 
 
Ixazomib should not be taken if you have ever had a serious allergic reaction to boron or boron 
containing products. 
 
POTENTIAL DISCOMFORTS AND RISKS OF POMALIDOMIDE (CC-4047, 
Pomalyst®) 
 
Likely risks of pomalidomide (events occurring greater than 20% of the time) 
• A low number of white blood cells, which are the infection fighting cells, which could 
put you at risk for infection (neutropenia or leukopenia) 
• A low number of a particular white blood cell, which is important to the immune system 
(lymphopenia) 
• Feeling tired (fatigue) 
• Difficulty passing stool (constipation) 
• Feeling sick to your stomach (nausea) 
• Decreased number of blood cells (platelets) that help to clot the blood (which could put 
you at increased risk of bleeding (thrombocytopenia) 
• Decrease in red blood cells, which are the oxygen carrying cells, which could make you 
feel tired (anemia) 
• Back pain 
• Shortness of breath or difficulty breathing (dyspnea) 
• Loose stools (diarrhea) 
• Bronchitis 
• Upper respiratory tract infection 
• Pneumonia 
• Dizziness 
• Nerve damage (peripheral neuropathy) 
• Decreased appetite 
• Swelling of limbs (peripheral edema) 
• Fever 
• Bone pain 
• Muscle spasm 
• Cough 
• Kidney failure (renal failure) 


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• Nausea 
• Generalized weakness (asthenia) 
 
Less likely risks of pomalidomide (events occurring less than or equal to 20% of the time) 
• When pomalidomide or related drugs (i.e. thalidomide and lenalidomide) have been used 
along with corticosteroids and certain other chemotherapy drugs, there has been an 
increased risk of individuals developing blood clots including blood clots in the big veins 
of the limbs (deep vein thrombosis) or in the lungs (pulmonary embolism).  Your doctor 
may request or require that you take aspirin or another blood thinner in this situation. 
• Abdominal pain 
• Sore mouth, nose, or throat (nasopharyngitis) 
• Drop in blood pressure  
• Headache 
• Chest pain 
• Feeling shaky (tremor) 
•  
• Infections including potentially life threatening infections 
• Muscle aches  
• Muscle weakness 
• Joint swelling or achiness 
• Dry or itchy skin 
• Blushing or redness to face (flushing) 
• Decreased function of the thyroid gland, which can result in feeling tired and weight gain 
that may first show up as an increased levels of thyroid stimulating hormone 
(hypothyroidism). If your thyroid function becomes abnormal, your doctor may have you 
take a thyroid replacement pill daily. 
• Difficulty emptying the bladder (urinary retention) 
• Pelvic pain 
• Rash 
• Throwing up (vomiting) 
• Decreased sodium levels in the blood (hyponatremia) 
• Abnormally high calcium in the blood stream, that can result in fatigue, confusion, 
feeling sick to your stomach, throwing up, difficulty passing stool, abnormal heartbeat, 
coma, and death (hypercalcemia) 
• Abnormally low calcium in the blood stream, that can result in muscle cramps, 
abdominal cramps, spasms (hypocalcemia) 
• Abnormal levels of potassium in the blood (hyper- or hypokalemia) 
• Death 
• Excessive sweating (hyperhidrosis) 
• High blood sugar (hyperglycemia) 
• Gastrointestinal bleeding 
• Airway and lung infection (bronchopneumonia) 
• Shingles (Herpes zoster) 
• Severe infection secondary to low neutrophil count (neutropenic sepsis) 


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• Respiratory tract infection 
• Elevated liver enzyme (alanine aminotransferase elevation) 
• Elevated liver function test 
• Confusion 
• Depressed level of consciousness 
• Drop in blood counts resulting in anemia, low white blood cell count (leucopenia), and 
low platelet count (thrombocytopenia) (pancytopenia) 
• Spinning sensation (vertigo) 
• Nosebleed (epistaxis) 
• General physical health deterioration 
 
Rare but serious risks of pomalidomide (events occurring less than 2-3% of the time) 
• Chest wall pain 
• Inability of the heart to properly pump blood to the lungs (right ventricular failure) 
• Bleeding from the stomach large intestine and/or small intestine (gastrointestinal 
bleeding) 
• Narrowing of the stomach or intestines (gastrointestinal stenosis) 
• Chest pain that occurs when your heart doesn't get enough oxygen, which can be a 
warning sign of a heart attack (angina - unstable) 
• An irregular heartbeat that results from the top/upper chambers of the heart “quivering” 
instead of beating normally (atrial fibrillation) 
• Fast heart rate (tachycardia) or slow heart rate (bradycardia) 
• Decrease in the ability of the heart to pump blood, because of weakening of the heart 
muscle (congestive heart failure) 
• Lack of oxygen to the heart muscle which can cause damage to the heart (heart attack) 
• Feeling like your heart is “fluttering or skipping” (heart palpitations) 
• Bleeding in the brain (cerebral hemorrhage) 
• Lack of oxygen to the brain caused by either bleeding in the brain or blood clot. Also 
called a stroke (cerebral vascular accident) 
• Memory impairment 
• Blood creatinine increased 
• Excessive or abnormal loss of body fluids (dehydration) 
• Failure to thrive 
• Anxiety 
• Feeling sad or blue (depression)  
• Difficulty falling or staying asleep (insomnia) 
• Changes in mood 
• Kidney stones (nephrolithiasis) 
• Collection of fluid in the space around the lung (pleural effusion) 
• Inability of the lungs to function properly (respiratory failure) 
• High blood pressure (hypertension) or low blood pressure (hypotension) 
• Acute inflammation of the liver including hepatitis, liver failure, jaundice (yellowing of 
skin and whites of eyes) (hyperbilirubinemia) 
• Inflammation of the lungs (interstitial lung disease) 


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• Possible second cancer with prolonged use 
• Blurred vision 
• Decreased level of phosphorus in the blood (hypophosphatemia) 
• Decreased albumin in the blood (hypoalbuminemia) 
• Low levels of magnesium in the blood (hypomagnesemia) 
• Night sweats 
• Changes in the voice or hoarseness (dysphonia) 
• Nose bleed (epistaxis) 
• Very sleepy, difficulty arousing (lethargy) 
• Fainting (syncope) 
• Excessive sleepiness (somnolence/depressed level of consciousness) 
• Change in taste sensation (dysgeusia) 
• Dry mouth 
• Chills 
• Recurrent areas of skin or mucosal swelling of sudden onset, usually disappearing within 
24 hours; an allergic reaction to the medication (angioedema) an exaggerated or 
inappropriate immune response (hypersensitivity) to pomalidomide 
• Hepatitis B viral activation 
• Kidney failure and blood chemistry abnormalities secondary to destruction of cancer cells 
by anti-cancer treatment (tumor lysis syndrome) 
• Skin cancer (basal cell carcinoma and squamous cell carcinoma) 
• Development of a new cancer during cancer treatment (secondary primary malignancies) 
including blood and bone marrow cancers (Hematologic malignancies), solid organ 
tumors (solid tumors), and skin cancers. 
• Inflammation of the lungs (pneumonitis) 
 
ANIMAL STUDIES 
In one study, a monkey developed a condition compatible with acute myelogenous leukemia 
after receiving high doses of pomalidomide for several months. The cause of this effect is being 
investigated and the risk of this finding to humans is unknown. 
 
As with any medication, allergic reactions are a possibility. 
 
Standard of Care Risks 
Your doctor will discuss the risks of biopsies, X-rays, scans, and blood and urine testing [include 
any tests/procedures performed as part of the participant’s standard care] as these tests and 
procedures are part of your standard clinical care. 
 
General risks 
The risks of drawing blood include pain, bruising, or rarely infection at the needle site. 
 
For more information about risks and side effects, ask your study doctor. 
 
Risks Associated with Pregnancy 
 


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Pomalidomide is related to thalidomide. Thalidomide is a known to cause severe life-threatening 
human birth defects. If pomalidomide is taken during pregnancy, it may cause birth defects or 
death to any unborn baby. Females must not become pregnant while taking pomalidomide. You 
have been informed that the risk of birth defects is unknown. If you are female, you agree not to 
become pregnant while taking pomalidomide. 
 
Pomalidomide is detected in trace quantities in human semen according to a study. The risk to 
the fetus in females of child bearing potential whose male partner is receiving pomalidomide is 
unknown at this time. For these reasons male patients receiving pomalidomide must use a latex 
condom while taking pomalidomide, when temporarily stopping pomalidomide, and for 90 days 
after permanently stopping pomalidomide treatment during any sexual contact with a pregnant 
female or a female of child bearing potential even if you have undergone a successful vasectomy.  
 
Patients should not donate blood during treatment therapy or for 28 days following 
discontinuation of pomalidomide. 
 
You must NEVER share pomalidomide with anyone else. 
 
POTENTIAL DISCOMFORTS AND RISKS OF DEXAMETHASONE 
 
Likely risks of dexamethasone: 
• Stomach and throat ulcers or worsening of any ulcers you had before treatment 
• Swelling and pain of the pancreas 
• Weight gain around the stomach 
• Puffiness (especially in the face) 
• Buildup of fluids and a rise in blood pressure 
• Possible rise in your blood sugar 
• Changes in the blood levels of potassium.   
• Infection 
 
Less likely risks of dexamethasone: 
• Muscle weakness 
• Brittle bones 
• Menstrual changes 
• Itching, and other allergic reactions, some severe.   
 
Rare but serious risks of dexamethasone: 
• Mood swings 
• Depression 
• Trouble sleeping 
• Changes in personality 
• Seizures 
• Dizziness 
• Patients who are more likely to get heart disease may have heart failure 
 


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BIRTH CONTROL, DANGERS OF PREGNANCY AND BREASTFEEDING 
You must not get pregnant while in this study. If you are or become pregnant, there may be 
unknown risks to the baby. If you may be able to have children, you will be given a pregnancy 
test at screening, and if the result is positive, you will not be able to be in the study. If you are 
sexually active, and able to have children, you and your partner must use two (2) highly effective 
forms of birth control throughout the study and for 90 days after your last dose of study drugs.  
 
Acceptable non-hormonal birth control methods include:  
• 
Total sexual abstinence. Abstinence must be for the total duration of the study i.e. from 
when you sign the informed consent form (ICF) until 90 days after the last dose of study 
drugs 
• 
Male sexual partner who has undergone a vasectomy plus male condom with spermicide. 
(You will need to confirm that your partner’s sperm was tested after the vasectomy 
procedure and that he was confirmed to be sterile.) 
• 
Tubal occlusion plus male condom with spermicide  
• 
Intrauterine Device (IUD) plus male condom with spermicide 
 
Acceptable hormonal methods include:  
• 
Etonogestrel implants (e.g., Implanon®, Norplan®) plus male condom with spermicide 
• 
Normal and low dose combined oral pills plus male condom with spermicide 
• 
Norelgestromin/ethinyl estradiol (EE) transdermal system plus male condom with 
spermicide 
• 
Intravaginal device (e.g., EE and etonogestrel) plus male condom with spermicide 
• 
Cerazette® (desogestrel) plus male condom with spermicide. (Cerazette® is currently the 
only highly efficacious progesterone based pill.) 
 
You should discuss with your study doctor which birth control methods are considered 
acceptable. 
 
A pregnancy test can be wrong. If you become pregnant or think you may be pregnant during the 
study, stop taking study capsules and contact the study doctor’s office immediately. You will be 
asked to withdraw from the study. You must not be breast-feeding an infant during the study. 
The study drug may cause unforeseeable risk to a breastfed baby. The study doctor must follow 
up and document the course and the outcome of all pregnancies, even if you withdraw from the 
study or if the study has finished. 
 
OTHER RISKS 
 
Additionally, you might also have side effects or discomforts that are not listed in this form. 
Some side effects are not yet known, and every risk or side effect cannot be predicted. You may 
experience unexpected side effects or be at risk for symptoms, illnesses, and/or complications 
that could not be predicted. Tell your study doctor or study staff right away if you have any 
problems. 
 
Many side effects go away shortly after the study drugs are stopped, but in some cases side 
effects can be serious, long lasting, or may never go away. There may be a risk of death. Some 


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side effects may not be known. Side effects may range from mild to life-threatening. Other drugs 
may be given to make side effects less serious and less uncomfortable. Talk to the researcher 
and/or your healthcare provider about side effects and ask any other questions. 
 
Standard of care risks 
Your doctor will discuss the risks of biopsies, X-rays, PET/CT and MRI scans, and blood and 
urine testing, as these tests and procedures are part of your standard clinical care. 
 
Blood Samples 
Blood samples will be taken using a needle from a vein in your arm during the study. The taking 
of a blood sample may cause some discomfort and bruising, and there is a potential for infection. 
Other risks, although rare, include dizziness and fainting. The maximum amount of blood that 
will be taken at any study visit is about 42 mL (less than 3 tablespoons). 
 
Blood loss from taking research samples and the side effects of the study drug may cause anemia 
(low red blood cell count). Anemia may make you feel tired. Some people may need iron 
supplements to compensate for the blood loss resulting from the procedures done during this 
study. Please make sure that you discuss this with the study doctor or your personal doctor. 
 
Non-Physical Risks 
You may lose time at work or home and spend more time in the hospital or study doctor’s office 
than usual. 
 
Genetic Testing 
This study involves testing your DNA, which is the genetic information you inherited from your 
parents (also known as genetic testing). You will not be notified of the genetic test results and 
they will not be put into your medical record.  
 
 
 
7. 
Are there reasons you might leave this research study early? 
 
 
Taking part in this research study is your decision. You may decide to stop at any time. You 
should tell the Principal Investigator if you decide to stop and you will be advised whether any 
additional tests may need to be done for your safety. We will tell you about new information or 
changes in the study that may affect your health or your willingness to continue in the study. 
 
In addition, the Principal Investigator, the companies supplying the drugs and funding or the 
medical institution may stop you from taking part in this study at any time: 
• If it is in your best clinical interest, 
• If you do not follow the study procedures, 
• If the study is stopped. 
 


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If you leave this research study early, or are withdrawn from the study, no more information 
about you will be collected; however, information already collected about you in the study may 
continue to be used. 
 
 
 
8. 
What if you are injured from your participation in this research study? 
 
 
Where to get help: 
 
If you think you have suffered a research-related injury, you should promptly notify the Principal 
Investigator listed in the Contact Information at the beginning of this form. 
 
Who will pay for the treatment of research related injuries: 
 
Care for such research-related injuries will be billed in the ordinary manner, to you or your 
insurance. You will be responsible for all treatment costs not covered by your insurance, 
including deductibles, co-payments and coinsurance. The study will not offer free medical care 
or payment for any bad side effects from taking part in this study. 
 
 
 
9. 
What are the possible benefits from being in this research study? 
 
 
This study may not make your health better. If you agree to take part in this study, there may or 
may not be direct medical benefit to you. We hope the information learned from this study will 
benefit other people with multiple myeloma in the future. 
 
 
 
10. 
What alternative do you have if you choose not to participate in this 
research study? 
 
 
You do not have to be in this study to receive treatment for your condition. Your other choices 
may include: 
• Taking part in another study 
• Getting treatment or care for your cancer without being in a study 
• Getting no treatment 
 
You should talk to the researcher and your regular physician about each of your choices before 
you decide if you will take part in this study. 
 
 


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11. 
What tests or procedures will you need to pay for if you take part in this 
research study?  
 
 
The study drugs, ixazomib and pomalidomide, will be given to you at no cost. You and/or your 
insurance might also have to pay for other drugs or treatments given to help control side effects. 
 
You won’t need to pay for tests and procedures which are done just for this research study. These 
tests and procedures are: 
o Research testing on your blood and bone marrow 
o Research testing on any biopsy tissue 
 
You and/or your insurance will need to pay for all other tests and procedures that are part of this 
research study because they are part of usual care for your cancer. Before you take part in this 
study, you should call your insurer to find out if the cost of these tests and/or procedures will be 
covered. You will have to pay for any costs not covered by your insurance. 
 
If you have billing or insurance questions call Research Billing at the telephone number 
provided in the Contact Information section of this form. 
 
 
 
 


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12. 
Will you be paid for taking part in this research study? 
 
 
You will not be paid for taking part in this study. 
 
Your participation in this research study may contribute to the development of commercial 
products from which Takeda/Millennium Pharmaceuticals, Inc. or others, may derive an 
economic benefit. You will have no rights to any patents or discoveries arising from this 
research, and you will receive no economic benefit. 
 
 
 
13. 
What will happen to your samples? 
 
 
Your samples will be sent to the Sponsor (Mayo Clinic). The Sponsor can use your samples for 
research purposes only as described in the research study and this consent form. Your sample 
will be sent to the Sponsor in a coded format, which protects your identity. Mayo Clinic may 
destroy the sample at any time without telling you. 
 
14. 
How will your privacy and the confidentiality of your records be protected? 
 
 
[Note to Local Investigators: The NCI has recommended that HIPAA regulations be addressed by the 
local institution. The regulations may or may not be included in the informed consent form depending on 
local institutional policy.] 
We will do our best to make sure that the personal information in your medical record will be 
kept private. However, we cannot guarantee total privacy. Your personal information may be 
given out if required by law. If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used.  
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include: 
• 
Mayo Clinic, the sponsor of this study 
• 
The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), involved in keeping research safe for people 
• 
Takeda Pharmaceuticals/Millennium Pharmaceuticals, Celgene Corporation, and the 
Multiple Myeloma Research Foundation and Consortium (MMRF/MMRC) 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
[Note to Local Investigators: The NCI has recommended that the above paragraph, containing 
language required by the FDA, be added in order to be in compliance with the Final Rule by the 
effective date of 07Mar2012.] 


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ENROLLMENT AND PERMISSION SIGNATURES 
 
Your signature documents your permission to take part in this research.  
 
 
 
/ 
/ 
: 
AM/PM 
Printed Name 
Date 
Time 
 
 
_______________________________ 
Signature 
 
 
Person Obtaining Consent  
• I have explained the research study to the participant. 
• I have answered all questions about this research study to the best of my ability. 
 
 
 
/ 
/ 
: 
AM/PM 
Printed Name 
Date 
Time 
 
 
_______________________________ 
Signature 
 
 
Local IRB changes to this document are allowed. Sections “What are the risks of the research 
study” or “What other choices do I have if I don’t take part in this research study?” should 
always be used in their entirety if possible. Editorial changes to these sections may be made as 
long as they do not change information or intent. If the institutional IRB insists on making 
deletions or more substantive modifications to these sections, they may be justified in writing by 
the investigator and approved by the IRB. Under these circumstances, the revised language and 
justification must be forwarded to the North Central Cancer Treatment Group Operations Office 
for approval before a patient may be registered to this study. 
 
Consent forms will have to be modified for each institution as it relates to where information 
may be obtained on the conduct of the study or research subject. This information should be 
specific for each institution.