Conditions: Recurrent Plasma Cell Myeloma Refractory Plasma Cell Myeloma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 8
Healthy volunteers: no

Brief summary:
This phase II trial studies how well ixazomib citrate, pomalidomide, dexamethasone, and stem cell transplantation works in treating patients with multiple myeloma that has come back or does not respond to treatment. Giving chemotherapy, such as pomalidomide and dexamethasone, before a stem cell transplant helps kill any cancer cells that are in the body and helps make room in the patient?s bone marrow for new blood-forming cells (stem cells) to grow. After treatment, stem cells are collected from the patient's blood and stored. More chemotherapy is then given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy. Giving ixazomib citrate in addition to pomalidomide, dexamethasone, and stem cell transplantation may work better in treating patients with relapsed or refractory multiple myeloma.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate the rate of progression free survival at 18 months from study entry after therapy with ixazomib citrate (ixazomib \[MLN9708\]) in combination with pomalidomide and dexamethasone followed by a single autologous stem cell transplantation (ASCT) and consolidation with ixazomib in combination with pomalidomide and dexamethasone and maintenance with ixazomib in relapsed refractory ASCT naive multiple myeloma (MM) patients.

SECONDARY OBJECTIVES:

I. To determine the best overall response rates (\>= partial response \[PR\]) and deep responses (very good partial response \[VGPR\], complete response \[CR\], stringent complete response \[sCR\]) at various stages of treatment: after induction, after stem cell transplantation (SCT), after consolidation and during maintenance.

II. To determine the overall survival from study entry.

TERTIARY OBJECTIVES:

I. Assessment of minimal residual disease (MRD) by flow cytometry at various stages of treatment: after induction, day # 100 after SCT, after consolidation and during maintenance at year 1 and 2 from initiation of maintenance therapy.

II. To determine the engraftment kinetics (white blood cells \[WBC\] and platelet) following single salvage ASCT for relapsed disease.

OUTLINE:

INDUCTION (COURSES 1-4): 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. Treatment repeats every 28 days (courses 1-3) and 56 days (course 4) for up to 4 courses in the absence of disease progression or unacceptable toxicity.

TRANSPLANTATION (COURSE 5): Between 2-4 weeks following Induction, patients undergo ASCT.

CONSOLIDATION (COURSES 6-9): Beginning 60-120 days following ASCT, patients receive ixazomib citrate, pomalidomide, and dexamethasone as in Induction. Treatment repeats every 28 days (courses 6-8) and 56 days (course 9) for up to 4 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE (COURSES 10+): Beginning 0-4 weeks following Consolidation, patients receive ixazomib citrate as in Induction. 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 months until progressive disease, and then every 6 months for 3 years.

Arms:
arm 1: INDUCTION (COURSES 1-4): 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. Treatment repeats every 28 days (courses 1-3) and 56 days (course 4) for up to 4 courses in the absence of disease progression or unacceptable toxicity.

TRANSPLANTATION (COURSE 5): Between 2-4 weeks following Induction, patients undergo ASCT.

CONSOLIDATION (COURSES 6-9): Beginning 60-120 days following ASCT, patients receive ixazomib citrate, pomalidomide, and dexamethasone as in Induction. Treatment repeats every 28 days (courses 6-8) and 56 days (course 9) for up to 4 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE (COURSES 10+): Beginning 0-4 weeks following Consolidation, patients receive ixazomib citrate as in Induction. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Autologous Hematopoietic Stem Cell Transplantation intervention 2: Dexamethasone intervention 3: Ixazomib Citrate intervention 4: Laboratory Biomarker Analysis intervention 5: Pomalidomide
Intervention descriptions: intervention 1: Undergo ASCT intervention 2: Given PO intervention 3: Given PO intervention 4: Correlative studies intervention 5: Given PO

Protocol document:
Prot_SAP_000.pdf: 




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Table of Contents 
Phase 2 Trial of Induction with Ixazomib, Pomalidomide, Dexamethasone Prior to Salvage 
Autologous Stem Cell Transplantation followed by Consolidation with Ixazomib, Pomalidomide, 
and Dexamethasone and Ixazomib Maintenance in Multiple Myeloma ........................................ 1 
Protocol Resources.......................................................................................................................... 2 
Table of Contents ............................................................................................................................ 3 
Schema ............................................................................................................................................ 4 
1.0 
Background ...................................................................................................................... 5 
2.0 
Goals............................................................................................................................... 23 
3.0 
Patient Eligibility ............................................................................................................ 24 
4.0 
Study Calendars .............................................................................................................. 27 
5.0 
Grouping Factor: None................................................................................................... 30 
6.0 
Registration Procedures.................................................................................................. 30 
7.0 
Protocol Treatment ......................................................................................................... 32 
8.0 
Dosage Modification Based on Adverse Events ............................................................ 33 
9.0 
Ancillary Treatment/Supportive Care ............................................................................ 43 
10.0 
Adverse Event (AE) Reporting and Monitoring ......................................................... 47 
11.0 
Treatment Evaluation ................................................................................................. 59 
12.0 
Descriptive Factors ..................................................................................................... 65 
14.0 
Biospecimens .............................................................................................................. 67 
15.0 
Drug Information ........................................................................................................ 68 
16.0 
Statistical Considerations and Methodology .............................................................. 77 
17.0 
Pathology Considerations/Tissue Biospecimens ........................................................ 83 
18.0 
Records and Data Collection Procedures ................................................................... 83 
19.0  
Budget ......................................................................................................................... 84 
20.0 
References .................................................................................................................. 85 
Appendix I ECOG Performance Status ..................................................................................... 89 
Appendix II 
Patient Medication Diary .................................................................................... 90 




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1.0 
Background 
1.1  
Multiple Myeloma: Multiple myeloma (MM) 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 27,000 patients with myeloma are diagnosed in the 
United States each year (seer.cancer.gov), and despite considerable improvements in 
therapy remains incurable and uniformly fatal, with a median overall survival of around 6 
years (Kumar SK et al. 2013). Recent improvements in therapies have significantly 
improved the survival outcomes (Kumar et al. 2013), but given the inevitable relapses 
seen in these patients, new approaches to therapy are clearly needed.  
1.2  
Implications of salvage ASCT approach in multiple myeloma: The management of MM 
has witnessed a substantial change over the past decade, primarily as a result of the use of 
effective novel agents. Previously, the conventional approach for SCT-eligible patients 
was induction therapy with dexamethasone alone or combination regimens like 
Vincristine, Adriamycin, and Dexamethasone (VAD) for 4–6 months, followed by high-
dose melphalan and peripheral autologous blood stem cell transplantation (SCT), as 
phase 3 trials had demonstrated a survival improvement with SCT approach compared to 
conventional chemotherapy, initially in patients younger than 65 (Kyle RA, Rajkumar 
SV 2004, Attal M et al. 1996 . Child JA et al. 2003) and subsequently in SCT-
eligible older patients as well. (Kumar SK. et al. 2008) Additionally, one randomized trial 
demonstrated comparable efficacy for SCT applied early in the course of the disease 
course or when used as salvage therapy following failure of primary therapy (Fermand JP 
et al, 1998).  
With the use of well-tolerated novel agents in combinations with dexamethasone, or with 
other conventional agents, response rates comparable to those witnessed in the context of 
SCT were noted (Rajkumar SV et al 2008., Harousseau JL et al. 2007. Cavo M, et al 
2009). Therefore, the advantages seen with early SCT have somewhat diminished and 
many patients prefer to defer SCT until relapse. (Lacy et al 2007, Rajkumar et al. 2008) 
The preliminary data analysis of the IFM/DFCI DETERMINATION trial showed no 
improvement in overall survival (OS) in patients who were randomized to early SCT 
underscoring again that SCT may be deferred in the context of current regimens (Attal M. 
et al. , 2015) . The theories that patients relapsing after induction with a novel agent-
based regimen will not be able to obtain a meaningful response from high-dose 
melphalan and that patients will be losing the opportunity to benefit from an effective 
treatment modality such as SCT have largely been debunked. In fact comparisons of 
patients going to early SCT to those who decided to stay on initial therapy in recent 
clinical trials have suggested favorable survival outcomes for both groups (Kumar SK et 
al., 2012)  
Autologous stem cell transplantation (ASCT) is increasingly being used as salvage 
therapy in patients with relapsed and refractory multiple myeloma. While utility of this 
approach has not been studied in a prospective fashion, sufficient evidence exists from 
retrospective studies to consider this therapy in patients with relapsed disease. It has been 
used as an effective salvage treatment, both for patients who have not had a prior 
transplant as well as those who have received a single ASCT as part of their initial 
treatment.  
The International Myeloma Working Group in collaboration with the Blood and Marrow 
Transplant Clinical Trials Network, the American Society of Blood and Marrow 
Transplantation, and the European Society of Blood and Marrow Transplantation recently 
summarized current knowledge regarding the role of ASCT in MM patients progressing 


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after primary therapy and proposed guidelines for the use of salvage HCT in MM. (Giralt 
et al, 2015). The expert committee recommended that salvage ASCT should be 
considered standard in transplantation-eligible patients relapsing after non SCT-based 
primary therapy and that the role of post salvage ASCT maintenance needs to be explored 
in the context of well-designed prospective trials that should include new agents, such as 
monoclonal antibodies, immune-modulating agents, and oral proteasome inhibitors 
(Giralt et al, 2015). Reinduction treatment with combination chemotherapy is the 
standard and most experts agree that high-dose therapy consolidation should be 
considered the standard of care at this time for this patient population. The experts agreed 
that this patient population of relapsed/refractory myeloma, although heterogeneous, is 
worthy of prospective trials designed to address the issue of optimal reinduction therapy 
and consolidation to determine whether their natural history is different than that for 
patients relapsing after a prior autograft. (Giralt et al. 2015). 
The Mayo Clinic Group retrospectively studied 290 patients with untreated MM who 
received IMiD-based initial therapy (Kumar S et al., 2012) Patients who underwent a 
stem cell harvest attempt were considered transplantation-eligible and were included. 
SCT within 12 months of diagnosis and within 2 months of harvest were considered early 
SCT (n=173). SCT >12 months after diagnosis was considered delayed SCT (n=112). In 
the delayed SCT group, 42 patients had undergone SCT, and the median estimated time 
to SCT was 5.3 months and 44.5 months in the early SCT and delayed SCT groups, 
respectively. The 4-year overall survival rate from diagnosis was 73% in both groups. 
The time to progression after SCT was similar between the early and delayed SCT 
groups. These results indicated that, in transplantation-eligible patients who receive 
IMiDs as initial therapy followed by early stem cell mobilization, delayed SCT results in 
similar overall survival compared with early SCT (Kumar S et al., 2012).  
Although, the introduction of newer, more effective therapies such as IMiDs and the 
proteasome inhibitor bortezomib has led to high response rates and deeper responses and 
has raised questions regarding the continued role of SCT in this disease, MM remains the 
most common indication for ASCT in North America according to data reported to the 
CIBMTR. The results of the S9321 trial suggested that the survival advantage of upfront 
SCT might not persist once the complete response rates of conventional therapy 
improved (Barlogie et al., 2006). As a result of the high response rates seen at the end of 
the induction therapy, and low toxicity profile of current regimens, patients are 
increasingly opting to delay SCT and continue with initial therapy. (Rajkumar et al., 
2008, Lacy et al, 2007)  
The Mayo Clinic study showed that the paradigm of comparable survival with early or 
delayed-SCT holds true in the context of newer therapies as it did with the alkylator 
based regimens of the past. The results were true irrespective of the specific IMiD used, 
whether thalidomide or lenalidomide, further confirming that the equivalence of SCT 
used in an early or deferred fashion is therapy independent. The differences in proportion 
of patients on the two drugs in the two groups likely reflects the better tolerability of 
lenalidomide and the increasing comfort on the part of physicians to defer transplant with 
the availability of more long term data with lenalidomide. (Kumar S, 2012). The 
comparable time to progression after early or delayed-SCT was in stark contrast to the 
results from the previous randomized trials that examined early versus delayed-SCT. In 
the MAG90 trial, a delayed-SCT was associated with a shorter TTP after SCT even 
though the overall survival was comparable with the two approaches (Fermand JP et al, 
1998). 


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An aspect of the early transplant approach that was traditionally used to favor an early 
transplant had been the reduced time with symptoms and side effects of therapy. 
However, this paradigm has been changed with the newer agents, which are much better 
tolerated and can often be continued for prolonged duration with minimal toxicity and 
impact on quality of life. Hence it is not surprising that there is increased acceptance of 
the delayed-SCT approach. This will have to be explored in the context of prospective 
trials comparing an early-SCT to delayed-SCT. The decision to go ahead with an early 
SCT or to defer transplant till relapse can be based on several factors including response 
to induction therapy, toxicity from treatment, physician bias, and patient perception 
among others. The Mayo study addressed the use of SCT primarily as the second line of 
therapy, as was the common practice in the period that was studied, and the results cannot 
be necessarily extrapolated to patients receiving an SCT after failing multiple lines of 
therapy with different newer drugs (Kumar S, 2012). 
In another study, the Mayo Clinic Group examined the outcomes in 98 patients 
undergoing salvage ASCT for relapsed MM after receiving an initial transplant. 
(Gonsalves W. et al., 2013). The median age at second ASCT was 60 years and the 
median time between the two ASCTs was 46 months. The median PFS from ASCT was 
10.3 months and the median OS was 33 months. In a multivariable analysis, a shorter 
time-to-progression (TTP) after initial ASCT, not achieving a CR after salvage ASCT, 
higher number of treatment regimens before second ASCT and a higher plasma cell 
labeling index at ASCT, predicted for shorter PFS. However, only a shorter TTP after 
first ASCT predicted for a shorter OS. From this study as well as the prior studies in the 
literature, it is clear that salvage ASCT is an effective and feasible therapeutic option for 
MM patients relapsing after other treatments. 
Investigators at the University of Arkansas, reported on 94 patients who had relapsed 
following ASCT, 31 of whom received a second ASCT at relapse. (Tricot G. et al., 1995) 
In this study, patients receiving a second autologous or allogeneic transplant had a better 
survival compared to those who received standard therapy, which may also reflect patient 
selection. Patients with low beta-2-microglobulin or a response lasting more than 12 
months from the first ASCT had better survival with salvage therapy.  
A group of investigators from the UK studied 172 patients who relapsed after one ASCT 
that was performed at maximal response from induction therapy with CVAMP regimen. 
(Alvares et al., 2006)  Among these, 118 patients received CVAMP at relapse and 54 
received alternative chemotherapy followed by a second ASCT in 83 of them, based on 
availability of stem cells and performance status. No difference was seen in EFS for 
patients receiving a second ASCT or alternative therapy at first relapse though there was 
a trend towards improved OS with repeat ASCT. In this study, there was no benefit to a 
second ASCT in those patients whose response from the initial transplant lasted less than 
18 months with a median survival of less than six months compared to nearly 3 years for 
those with longer response duration from the first transplant.  
Another study reported on patients who had up-front ASCT followed by a second ASCT 
in case of relapse or progression (Elice et al., 2006). Among the 70 patients who relapsed, 
26 went on to have a second ASCT at a median time of 20.4 months from first ASCT. 
Median OS and EFS after the second ASCT were 38.1 and 14.8 months. 
Studies have not systematically studied the impact of induction therapy prior to salvage 
ASCT or the role of post-transplant consolidation and maintenance. While the responses 
to the salvage transplant is overall encouraging, it still remains rather short and 
approaches such as consolidation and maintenance that have improved outcomes in the 


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setting of initial transplant should be evaluated in the context of salvage transplant. The 
combination of a proteasome inhibitor and an IMiD is one of the most effective treatment 
regimens in MM(Richardson PG et al., 2010, Richardson PG, 2009).The 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. Some of these regimens require IV 
or subcutaneous administration, which can require frequent clinic, visits for patients.  
Ixazomib is the first oral proteasome inhibitor to enter the clinic and has efficacy similar 
to bortezomib, with excellent activity seen in combination with lenalidomide in the 
setting of newly diagnosed disease. Pomalidomide is a new IMiD with activity seen in 
nearly a third of the patients who are refractory to lenalidomide. The combination offers a 
convenient oral regimen that is also a potentially effective combination in patients with 
relapsed disease who would have been exposed to prior IMiDs and proteasome inhibitors. 
The oral proteasome inhibitor also offers the opportunity to study a convenient 
maintenance therapy in the setting of relapsed disease. The current study proposes to 
examine the outcome following a salvage stem cell transplant, done following an 
effective induction therapy, and followed by consolidation and maintenance.  
1.3 
Ixazomib: MLN9708, 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. In water or aqueous systems, 
MLN9708 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 MLN9708. 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 citrate (MLN9708). 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 


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favorable characteristics, ixazomib is anticipated to be effective against multiple 
myeloma. (Ixazomib Investigator’s Brochure (IB). Proteasome inhibition results in the 
accumulation of poly-ubiquitinated substrates within the cell and leads to cell cycle 
disruption, with concomitant activation of apoptotic pathways and cell death. Consistent 
with inhibition of ß5 20S activity, MLN2238 demonstrated potent activity against 
cultured MDA-MB 231 human breast cancer cells in the WST cell viability assay. In 
nonclinical models MLN2238 has activity against both solid tumor and bortezomib-
resistant xenografts. 
In Vivo Pharmacology: To determine the activity of MLN2238 in vivo, 
pharmacodynamic studies were performed in immunocompromised mice bearing either 
CWR22 human prostate or WSU-DLCL2 (human diffuse large B-cell lymphoma 
[DLBCL]) tumors. Pharmacodynamic responses in xenograft tumors were analyzed by 
assessing 20S proteasome inhibition and by evaluating levels of accumulated protein 
markers such as deoxyribonucleic acid (DNA) damage-inducible protein 34 (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 


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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 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. 


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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. MLN2238 did not cause significant toxicities that have not been previously 
observed after dosing with bortezomib. Therefore, on the basis of the similarity in the 
toxicity profile in rats between MLN22338 and bortezomib, MLN2238 is not known to 
present any additional safety risks beyond those that occur after treatment with 
bortezomib. In addition, there were no significant findings at tolerated exposures in dogs 
observed after PO administration that were not seen after IV administration, and similar 
exposures were tolerated regardless of the route of administration. 
The potential risks identified from nonclinical studies in dogs and rats include: 
• 
GI toxicity that could result in nausea, vomiting, diarrhea, dehydration, electrolyte 
imbalance, bleeding, bowel obstruction (including ileus and intussusception), and 
sepsis. 
• 
Reduced blood counts manifest as thrombocytopenia, neutropenia, and anemia. 
Reticulocytopenia was described in animals and may be associated with anemia. 
Reductions in blood counts may predispose to an increased susceptibility to infection, 
bleeding, and anemia. 
• 
Peripheral nerve ganglia effects that may be associated with peripheral neuropathy 
that includes pain, burning sensation, and numbness. Autonomic and motor 
neuropathy may be observed, as both have been reported for bortezomib. 
• 
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: 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. 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 


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in several xenograft models, both solid tumor and bortezomib-resistant xenografts, than 
bortezomib. 
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, clinical 
pharmacology studies have evaluated drug-drug interactions with ketoconazole, 
clarithromycin, and rifampin, as well as the effect of food, renal impairment, and hepatic 
impairment on the PK of ixazomib. Studies evaluating the safety and pharmacokinetics 
(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 
RRMM are ongoing. 
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 


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(28%), anemia (26%), vomiting (26%), neutropenia (25%), back pain (24%), pyrexia 
(23%), peripheral edema (21%, each), fever (20%), cough (20%), hypokalemia (20%), 
neutropenia (20%), and upper respiratory tract infection (20%). Overall rash of all grades 
is reported in approximately 50% of patients and is more common when ixazomib is 
given in combination with lenalidomide, where rash is an overlapping toxicity. 
Additional detailed information regarding the clinical experience of ixazomib may be 
found in the IB, including information on the IV formulation.  
Pharmacokinetics and Drug Metabolism: After oral dosing, absorption of ixazomib is 
rapid with a median first time to maximum observed plasma concentration (Tmax) of 
approximately 1 hour postdose. The plasma exposure (AUC) of ixazomib increases in a 
dose-proportional manner over a dose range of 0.2 to 10.6 mg based on population PK 
analysis. The absolute oral bioavailability (F) of ixazomib is estimated to be 58% based 
on population PK analysis. A high-fat meal reduced ixazomib Cmax by 69% and 
AUC0-216 by 28%. This indicates that a high-fat meal decreases both the rate and extent 
of absorption of ixazomib. Therefore, ixazomib should be dosed at least 2 hours after 
food or 1 hour before food. 
The steady-state volume of distribution of ixazomib is large and is estimated to be 543 L 
based on a population PK model. Based on in vitro plasma protein binding measurements 
on samples from clinical studies (Studies C16015 and C16018), ixazomib is highly bound 
to plasma proteins (99%). Ixazomib concentrations are higher in whole blood than in 
plasma, indicating extensive partitioning of ixazomib into red blood cells, which are 
known to contain high concentrations of the 20S proteasome. 
Metabolism appears to be the major route of elimination for ixazomib. In vitro studies 
indicate that ixazomib is metabolized by multiple cytochrome P450 (CYP) and non-CYP 
proteins. At concentrations exceeding those observed clinically (10 µM), ixazomib was 
metabolized by multiple CYP isoforms with estimated relative contributions of 3A4 
(42.3%), 1A2 (26.1%), 2B6 (16.0%), 2C8 (6.0%), 2D6 (4.8%), 2C19 (4.8%), and 2C9 
(<1%). At 0.1 and 0.5 µM substrate concentrations, which are closer to clinical 
concentrations of ixazomib following oral administration of 4 mg ixazomib, non-CYP 
mediated clearance was observed and seemed to play a major role in ixazomib clearance 
in vitro. These data indicate that at clinically relevant concentrations of ixazomib, non-
CYP proteins contribute to the clearance of ixazomib and no specific CYP isozyme 
predominantly contributes to the clearance of ixazomib. Therefore, at clinically relevant 
concentrations of ixazomib, minimal CYP-mediated DDIs with a selective CYP inhibitor 
would be expected. 
Ixazomib is neither a time-dependent inhibitor nor a reversible inhibitor of CYPs 1A2, 
2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5. Ixazomib did not induce CYPs 1A2, 2B6, and 
3A4/5 activity or corresponding immunoreactive protein levels. Thus, the potential for 
ixazomib to produce DDIs via CYP isozyme induction or inhibition is low. 
Ixazomib is not a substrate of BCRP, MRP2 and OATPs. Ixazomib is not an inhibitor of 
P-gp, BCRP, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1 and 
MATE2-K. Ixazomib is unlikely to cause or be susceptible to clinical DDIs with 
substrates or inhibitors of clinically relevant drug transporters. 
The geometric mean terminal half-life (t1/2) of ixazomib is 9.5 days based on population 
PK analysis. For both IV and oral dosing, there is an approximately average 3-fold 
accumulation (based on AUC) following the Day 11 dose for the twice-weekly schedule 


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and a 2-fold accumulation (based on AUC) following the Day 15 dose for the 
once-weekly schedule. 
Mean plasma clearance (CL) of ixazomib is 1.86 L/hr based on the results of a population 
PK analysis. Taken together with the blood-to-plasma AUC ratio of approximately 10, it 
can be inferred that ixazomib is a low clearance drug. Using the absolute oral 
bioavailability (F) estimate of 58% (also from a population PK model), this translates to 
an apparent oral plasma clearance (CL/F) of 3.21 L/hr. The geometric mean renal 
clearance for ixazomib is 0.119 L/hr, which is 3.7% of CL/F and 6.4% of CL estimated in 
a population PK analysis. Therefore, renal clearance does not meaningfully contribute to 
ixazomib clearance in humans. Approximately 62% of the administered radioactivity in 
the ADME study (Study C16016) was recovered in the urine and 22% of the total 
radioactivity was recovered in the feces after oral administration. Only 3.2% of the 
administered ixazomib dose was recovered in the urine as unchanged ixazomib up to 
168 hours after oral dosing, suggesting that most of the total radioactivity in urine was 
attributable to metabolites.  
The PK of ixazomib was similar with and without co-administration of clarithromycin, a 
strong CYP3A inhibitor, and hence no dose adjustment is necessary when ixazomib is 
administered with strong CYP3A inhibitors. Consistently, in a population PK analysis, 
co-administration of strong CYP1A2 inhibitors did not affect ixazomib clearance. 
Therefore, no dose adjustment is required for patients receiving strong inhibitors of 
CYP1A2. Based on information from the clinical rifampin DDI study, ixazomib Cmax and 
AUC0-last were reduced in the presence of rifampin by approximately 54% and 74%, 
respectively. Therefore, the co-administration of strong CYP3A inducers with ixazomib 
is not recommended.  
Mild or moderate renal impairment (CrCL ≥ 30 mL/min) did not alter the PK of ixazomib 
based on the results from a population PK analysis. As a result, no dose adjustment is 
required for patients with mild or moderate renal impairment. In a dedicated renal 
impairment study (C16015), unbound AUC0-last was 38% higher in patients with severe 
renal impairment or ESRD patients requiring dialysis as compared to patients with 
normal renal function. Accordingly, a reduced starting dose of ixazomib is appropriate in 
patients with severe renal impairment or ESRD requiring dialysis. Pre- and post-dialyzer 
concentrations of ixazomib measured during the hemodialysis session were similar, 
suggesting that ixazomib is not readily dialyzable, consistent with its high plasma protein 
binding (99%). 
The PK of ixazomib is similar in patients with normal hepatic function and in patients 
with mild hepatic impairment, as defined by the National Cancer Institute Organ 
Dysfunction Working Group (total bilirubin <1.5 times the upper limit of normal [ULN]), 
based on the results from a population PK analysis. Consequently, no dose adjustment is 
required for patients with mild hepatic impairment. In a dedicated PK study in patients 
with moderate (total bilirubin >1.5 to 3 times the ULN) or severe (total bilirubin >3 times 
the ULN) hepatic impairment (Study C16018), unbound dose-normalized AUC0-last was 
27% higher in patients with moderate or severe hepatic impairment as compared to 
patients with normal hepatic function. Therefore, a reduced starting dose of ixazomib is 
appropriate in patients with moderate or severe hepatic impairment.  
There was no statistically significant effect of age (23-91 years), sex, body surface area 
(1.2-2.7 m2), or race on the clearance of ixazomib based on the results from a population 
PK analysis. 
Further details on these studies are provided in the IB. 


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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 
N = 54 
PO, W, single agent 
5.5-mg fixed dosea W 
C16010 
PO, W, with LenDex versus 
4.0 mg W 


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Table 1-1 
Clinical Studies of Oral Ixazomib 
Trial/ 
Population 
Description 
Doses Investigated 
RRMM 
N = 200 
placebo-LenDex 
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 


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Table 1-1 
Clinical Studies of Oral Ixazomib 
Trial/ 
Population 
Description 
Doses Investigated 
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 
 
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) 


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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%) 
 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) 
 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. 


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As of 27 March 2013, there are 5 studies that have completed enrollment or are 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) 


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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%) 
 Anemia 
45 (26) 
 Neutropenia 
43 (25) 
 Lymphopenia 
20 (12) 
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 


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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) 
Though additional data are needed to characterize the clinical benefit of this drug, the 
emerging data support the ongoing development of ixazomib. 
Relapsed and/or Refractory Multiple Myeloma:  
Please refer to the ixazomib IB for further information. 
 
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 
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 a 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 


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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 relapsed/refractory myeloma need 
newer therapies. The combination of pomalidomide and ixazomib provides a potentially 
powerful combination due to several reasons. Studies have not systematically studied the 
impact of induction therapy prior to salvage ASCT or the role of post-transplant 
consolidation and maintenance. While the responses to the salvage transplant is overall 
encouraging, it still remains rather short and approaches such as consolidation and 
maintenance that have improved outcomes in the setting of initial transplant should be 
evaluated in the context of salvage transplant. The combination of a proteasome inhibitor 
and an IMiD is one of the most effective treatment regimens in MM as has been seen 
with bortezomib or carfilzomib combinations with thalidomide or lenalidomide.6-8  A 
recently described mechanism of action of lenalidomide includes increased protein 
ubiquitination and brings into question mechanism of synergy between IMiDs and 
proteasome inhibitors. Despite this paradoxical preclinical data, clinical experience 
supports their synergistic activity.  
Ixazomib is the first oral proteasome inhibitor to enter the clinic and has efficacy similar 
to bortezomib, with excellent activity seen in combination with lenalidomide in the 
setting of relapsed refractory MM in a recently reported phase 3 trial (TOURMALINE- 
MM1 study) (reference ASH abstract 2015 Moreau) . Pomalidomide is new IMiD with 
activity seen in nearly a third of the patients refractory to lenalidomide. The combination 
offers a convenient oral regimen that is also a potentially effective combination in 
patients with relapsed disease who would have been exposed to prior IMiDs and 
proteasome inhibitors. The oral proteasome inhibitor also offers the opportunity to study 
a convenient maintenance therapy in the setting of relapsed disease.  
The current study proposes to examine the outcome following a salvage stem cell 
transplant, done following an effective induction therapy, and followed by consolidation 
and maintenance.  
1.7 
Potential Risks and Benefits of ixazomib 
Please refer to the current ixazomib IB. 
The clinical benefit of ixazomib continues to be studied in a comprehensive and global 
development plan that involves studies sponsored by Takeda. Ixazomib appears to show 
early signs of anti-tumor activity as evidenced by at least 50% reduction in disease 


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Protocol version date:  December 12, 2019 
burden in some patients, including patients that have been heavily pretreated as well as 
those with newly diagnosed MM, and prolongs stabilization of the underlying disease in 
other patients across all ongoing trials. The preliminary findings are favorable when 
considering historical and currently available therapies for the patient populations 
evaluated. Though additional data are needed to characterize the clinical benefit of this 
drug, the emerging data support expanded development of ixazomib for the treatment of 
patients with advanced malignancy. 
This study will be conducted in compliance with the protocol, good clinical practice 
(GCP), applicable regulatory requirements, and International Conference on 
Harmonisation (ICH) guidelines. 
 
 
2.0 
Goals 
2.1 
Primary 
To estimate the rate of progression free survival at 18 months from study entry after 
therapy with Ixazomib (MLN9708) in combination with pomalidomide and 
dexamethasone followed by a single ASCT and consolidation with ixazomib in 
combination with pomalidomide and dexamethasone and maintenance with ixazomib in 
relapsed refractory ASCT naïve MM patients. 
 
2.2 
Secondary 
2.21 
To determine the best overall response rates (≥ PR) and deep responses (VGPR, 
CR, sCR) at various stages of treatment: after induction, after SCT, after 
consolidation and during maintenance. 
2.22 
To determine the overall survival from study entry. 
 
2.3 
Correlative Research 
2.31 
Assessment of minimal residual disease (MRD) by flow cytometry at various 
stages of treatment: after induction, day # 100 after SCT, after consolidation and 
during maintenance at year 1 and 2 from initiation of maintenance therapy 
2.32 
To determine the engraftment kinetics (WBC and platelet) following single 
salvage ASCT for relapsed disease 
 
 
 


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Protocol version date:  December 12, 2019 
3.0 
Patient Eligibility 
3.1 
Inclusion Criteria  
3.11 
Age ≥18 years. 
3.12 
Previously treated ASCT naïve MM patients, currently with relapsed or 
refractory disease who are being considered for single ASCT for relapsed 
disease. Patients must be eligible to undergo a stem cell transplant as per 
institutional criteria for selection at the time of registration. 
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 ≥75x109/L unless the participant has ≥50% bone marrow 
infiltration in which case a platelet count of ≥50x109/L is allowed  
• 
Hemoglobin ≥9.0 g/dL 
• 
Total bilirubin ≤ 1.5 × the upper limit of the normal range (ULN) or if total 
bilirubin is >1.5 x ULN, the direct bilirubin must be ≤ 2.0 mg/dL.  
• 
Alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST) ≤ 3 × ULN or <5 x ULN if liver involvement 
*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:  
• 
Serum monoclonal protein ≥1.0 g/dL  by protein electrophoresis 
• 
≥200 mg of monoclonal protein in the urine on 24-hour electrophoresis  
• 
Serum immunoglobulin free light chain ≥10 mg/dL AND abnormal 
serum immunoglobulin kappa to lambda free light chain ratio. 
3.15 
ECOG performance status (PS) 0, 1 or 2 (Appendix I). 
3.16 
Willing to provide informed written consent. 
3.17 
Negative pregnancy test done ≤7 days prior to registration, for persons of 
childbearing potential only. 
3.18 
Willing to follow strict birth control measures. 
Persons of childbearing potential, agree to one of the following: 
• 
Practice 2 effective methods of contraception, at the same time, from the 
time of signing the informed consent form through 90 days after the last dose 
of study drug, AND must also adhere to the guidelines of any treatment-
specific pregnancy prevention program, if applicable, OR  
• 
Agree to practice true abstinence when this is in line with the preferred and 
usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, 
symptothermal, post-ovulation methods] and withdrawal are not acceptable 
methods of contraception.) 


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Protocol version date:  December 12, 2019 
Persons able to father a child: even if surgically sterilized (i.e., status post-
vasectomy), must agree to one of the following: 
• 
Agree to practice effective barrier contraception during the entire study 
treatment period and through 90 days after the last dose of study drug, OR 
• 
Must also adhere to the guidelines of any treatment-specific pregnancy 
prevention program, if applicable, OR 
• 
Agree to practice true abstinence when this is in line with the preferred and 
usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, 
symptothermal, post-ovulation methods] and withdrawal are not acceptable 
methods of contraception.) 
3.19a 
Negative human immunodeficiency virus (HIV), hepatitis B and C test.  
3.19b Willing to follow the requirements of the Pomalyst REMS program. 
3.19c 
Willing to return to return to enrolling institution for follow-up (during the 
Active Monitoring Phase of the study). 
3.19d Willing to provide bone marrow samples under IRB#521-93 for correlative 
research purposes (see Sections 6.2 and 14.0).  
 
3.2 
Exclusion Criteria 
3.21 
Diagnosed or treated for another malignancy ≤2 years prior to registration or 
previously diagnosed with another malignancy and have any evidence of residual 
disease.  
NOTE: If there is a history or prior malignancy, patient must not be receiving 
other specific treatment for their cancer. Patients with non-melanoma skin cancer 
or carcinoma in situ of any type, or low-risk prostate cancer after curative 
therapy, are not excluded if they have undergone complete resection. 
NOTE: Platelet transfusions to help patients meet eligibility criteria are not 
allowed ≤3 days prior to study registration.  
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: 
• 
Pregnant persons 
• 
Nursing persons  
• 
Persons of childbearing potential who are unwilling to employ adequate 
contraception 
3.23 
Co-morbid systemic illnesses or other severe concurrent disease which, in the 
judgment of the investigator, would make the patient inappropriate for entry into 
this study or interfere significantly with the proper assessment of safety and 
toxicity of the prescribed regimens. NOTE: this includes uncompensated heart or 
lung disease. 
3.24 
Receiving any other investigational agent which would be considered as a 
treatment for the primary neoplasm. NOTE: Bisphosphonates are considered to 
be supportive care rather than therapy and are allowed while on protocol 
treatment. 
3.25 
Patient has >Grade 2 peripheral neuropathy, or Grade 1 with pain on clinical 
examination during the screening period. 


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Protocol version date:  December 12, 2019 
3.26 
Major surgery ≤14 days prior to registration. 
3.27  
Systemic treatment with strong CYP3A inducers (rifampin, rifapentine, rifabutin, 
carbamazepine, phenytoin, phenobarbital) or use of Ginkgo biloba or St. John’s 
wort ≤14 days prior to registration.  
3.28 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements. NOTE: 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 allergy to any of the study medications, their analogues or excipients in 
the various formulations. 
3.29c 
Known GI disease or GI procedure that could interfere with the oral absorption 
or tolerance of study treatment including difficulty swallowing. 
3.29d Diarrhea >Grade 1, based on the NCI CTCAE v 4.0 grading, in the absence of 
antidiarrheals. 
3.29e 
Failure to have fully recovered (ie, ≤Grade 1 toxicity) from the reversible effects 
of prior chemotherapy. 
3.29f 
Radiotherapy ≤14 days prior to registration.  
NOTE: If the involved field is small, 7 days will be considered a sufficient 
interval between treatment and administration of the ixazomib. 
3.29g Central nervous system involvement with disease under study (myeloma), or 
concurrent AL amyloidosis or plasma cell leukemia. 
3.29hl Patients that have previously been treated with ixazomib, or participated in a 
study with ixazomib whether treated with ixazomib or not. 
3.29i 
Prior stem cell transplantation for myeloma 
 


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Protocol version date:  December 12, 2019 
4.0 
Study Calendars 
4.1 
Test Schedule (excluding routine investigations in the peri-ASCT period*) 
 
Prior to 
Registration 
 
Every cycle 
End of Cycle 4 of induction, 
post ASCT between Day 60- 
 
Tests and procedures 
≤30 
days 
≤14 
days 
Induction and 
consolidation16,1 
pre-treatment 
including 
maintenance1,7 
120, end of consolidation and 
1 year post initiation of 
maintenance1,14 
End of 
Treatment  
(±14 days)1 
Complete medical history 
X 
 
 
 
X 
 
Adverse Event monitoring 
 
X 
 
X 
X 
X 
Physical exam, including weight and vital signs 
 
X 
 
X 
X 
X 
Height 
 
X 
 
 
X 
 
Performance status (ECOG scale)  
 
X 
 
X 
X 
X 
Serum pregnancy test 
 
X11 
 
 
 
 
CBC with differential 
 
X 
X15 
X15 
X 
X 
Chemistry group: sodium, potassium, glucose, 
alkaline phosphatase; total and direct bilirubin; 
SGOT (AST); SGPT (ALT), serum creatinine, 
calcium 
 
X 
 
X 
X 
X 
HIV, hepatitis B and C  
X 
 
 
 
 
 
LDH, Beta2-microglobulin, C-reactive protein 
X 
 
 
 
X 
 
Electrophoresis of serum and urine 
(SPEP/UPEP) 
 
X 
 
X3 
X 
X3 
Affected immunoglobulin2 
 
X 
 
X2 
X 
X2 
Immunofixation serum and urine 
X 
 
 
X4 
X 
X4 
Immunoglobulin free light chain (MML panel) 
 
X 
 
X5 
X 
X5 
ECG  
X 
 
 
 
 
 
X-ray skeletal survey or whole-body low-dose 
CT 
X 
 
 
X6 
X6 
X 
CT Scan, PET/CT, or MRI for measurement if 
evidence of prior EMD lesion8 
X 
 
 
X8 
X8 
 
Circulating plasma cell assessment (flow 
cytometry or peripheral smear)9 
 
X 
 
X9 
X9 
 
Bone marrow aspirate and biopsy for 
myeloma17 
X 
 
 
X10 
X10 
X 


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Protocol version date:  December 12, 2019 
 
Prior to 
Registration 
 
Every cycle 
End of Cycle 4 of induction, 
post ASCT between Day 60- 
 
Tests and procedures 
≤30 
days 
≤14 
days 
Induction and 
consolidation16,1 
pre-treatment 
including 
maintenance1,7 
120, end of consolidation and 
1 year post initiation of 
maintenance1,14 
End of 
Treatment  
(±14 days)1 
Chest x-ray 
X 
 
 
 
 
 
Register patient for POMALYST REMS™ 
program 
 
X12 
 
 
 
 
Patient Medication Diary (Appendix II)13 
 
 
 
X 
X 
X 
Mandatory Research Bone marrow sample 18 
X14 
 
 
 
X14 
 
*Performed per institutional guidelines. Melphalan conditioning followed by stem cell infusion is being considered as ‘cycle 5’ in the 
protocol for logistical reasons only. No additional toxicity data will be collected in the immediate post ASCT period until day 60-100 
when the patient returns for routine post-ASCT reevaluation.  
1) All scheduled visits are while patient is receiving therapy will have a window of ±7 days unless otherwise stated. 
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) Every 365 days (12 months) or more often if clinically indicated. 
7) Does not need to be repeated at Cycle 1 Day 1. Baseline values can be used for cycle 1. 
8) This test is not mandatory. 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 suspected extra-medullary disease (EMD). Assessment of EMD lesions should be 
performed at end of induction, post ASCT (range:day 60-120), post consolidation (if persistent EMD noted previously) and every year on 
maintenance 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 and assess MRD. If a bone marrow was done to confirm CR prior to end of 
4 cycles, no further bone marrow examination until the end of the phase (induction/~ day 100 post –ASCT, consolidation and annually while 
on maintenance if CR suspected). 
11) For persons of childbearing potential only. Must be done ≤7 days prior to registration.  


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Protocol version date:  December 12, 2019 
12) 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. 
FOOTNOTES CONTINUE ON NEXT PAGE 
13) The diary must begin the day the patient starts taking the medication and must be completed per protocol and returned to the treating 
institution. 
14) At baseline, end of the phase induction, ~ Day 100 post ASCT, end of consolidation, and 1 year after initiation of maintenance while on 
maintenance. See Section 14.0. 
15) Can be performed at an outside facility 
16) Induction Day 8, 15, 22 (Cycles 1-3), Day 15 (Cycle 4); consolidation Day 8, 15, 22 (Cycles 6-8), Day 15 (Cycle 9) 
17) The following testing may be done if clinically indicated: Myeloma FISH, plasma cell proliferation, and flow cytometry (MRD). 
18) Research blood and bone marrow collection per protocol IRB 521-93 will be done after consenting for 521-93 and according to that protocol. 
All processing will be done on Stabile 6. 
 
 
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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Protocol version date:  December 12, 2019 
5.0 
Grouping Factor: None  
 
6.0 
Registration Procedures 
6.1 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page and 
enter the remote 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 5:00 p.m. Central Time (Monday through Friday). 
The instructions for the registration/randomization application are available on the 
MCCC web page
) 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 and institution 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.” 
 
6.2 
Correlative Research: A mandatory correlative research component is part of this study, 
the patient will be automatically registered onto this component (see Sections 3.19d and 
14.1).  
 
6.3 
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. 
 
6.4 
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 
• 
Existence of a signed authorization for use and disclosure of protected health 
information  
 
6.5 
Treatment on this protocol must commence at the recruiting institution under the 
supervision of a hematologist. 


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Protocol version date:  December 12, 2019 
 
6.6 
Treatment cannot begin prior to registration and must begin ≤14 days after registration. 
 
6.7 
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines 
specified on the test schedule. 
 
6.8 
All required baseline symptoms (see Section 10.6) must be documented and graded. 
 
6.9 
Study drug is available on site.  
 
 


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Protocol version date:  December 12, 2019 
7.0 
Protocol Treatment 
7.1 
Cycle lengths:  
Cycles 1-3 = 28 days 
Cycle 4 = up to 56 days  
Cycle 5 = up to 120 days  
Cycles 6-8 = 28 days 
Cycle 9 = up to 56 days  
Cycles 10 and beyond = 28 days 
 
7.2 
Treatment Schedule 
 
Doses and Schedule 
 
Agent 
Dose Level 
Route 
Day 
Retreatment 
Cycles 1-4 
Induction  
(x 4 cycles) 
  
 
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 
Cycle 5 
Transplantationa,e,f 
Stem cell mobilizationb followed by single ASCT  
Cycles 6-9 
Consolidationc 
(x 4 cycles) 
Ixazomib 
4 mg 
PO 
1, 8, 15 
Every 28 days 
Pomalidomide 
2 mg 
PO 
Days 1-21 
Every 28 days 
Dexamethasone 
40 mg 
PO 
1, 8, 15, 22 
Every 28 days 
Cycles 10 and Beyond 
Maintenance 
(until progression or 
unacceptable 
toxicity)d 
Ixazomib  
4 mg 
PO 
1, 8, 15 
Every 28 days  
a. SCT: Can be performed per institutional practice. Stem cells collected and cryopreserved ahead of 
time or collected immediately prior to transplant can be used. Conditioning regimen preference left to 
the treating physician, but should not be enrolled in any additional therapy trials. 
b. If not previously collected and cryopreserved. 
c  If a patient previously has a dose reduction in induction, the consolidation phase will start and 
continue at reduced dose. 
d.  Ixazomib maintenance would start at 4 mg unless dose has been previously reduced in the Induction 
or consolidation phase due to a non-hematologic toxicity specifically attributed to Ixazomib. 
e. Window period is 2-4weeks between Induction and ASCT; 60-120 days between ASCT and  
Consolidation and 0-4 weeks between the Consolidation and Maintenance phases. 
f. 
Melphalan conditioning followed by stem cell infusion is being considered as ‘cycle 5’ for logistical 
reasons only. No additional toxicity data will be collected in the immediate post ASCT period until 
day 60-100 when the patient returns for routine post ASCT-reevaluation. 
 
 
 


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Protocol version date:  December 12, 2019 
7.3 
Dosing of ixazomib 
The doses of ixazomib used in this study are based on data from Takeda’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).  
7.4 
How to take ixazomib 
Patients should be instructed to swallow ixazomib capsules whole, with water, and not to 
break, chew, or open the capsules The ixazomib should be taken on an empty stomach 
(no food or drink apart from 240 mL of water), at least 1 hour before or no sooner than 2 
hours after food. 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. 
 
7.5 
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 
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. 
 
7.6 
Treatment at enrolling institution 
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. 
 
 
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


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Protocol version date:  December 12, 2019 
 
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 4.2. 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 ≥1.0x109/L (=1000/microliter) 
• 
The platelet count is ≥75x109/L unless the participant has ≥50% bone 
marrow infiltration in which case a platelet count of ≥50x109/L is allowed 
• 
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 below 
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. 
 
 


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Protocol version date:  December 12, 2019 
  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 (for each 
cycle during induction and consolidation and maintenance)  
Table 8.2 
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT# 
ACTION** 
Blood and lymphatic 
system disorders 
Febrile neutropenia 
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 
 
Nervous System 
Disorders 
Peripheral motor neuropathy 
OR 
Peripheral sensory 
neuropathy 
Newly developed Grade 1 
with pain or ≥Grade 2  
Ixazomib 
Reduce dose of ixazomib to the 
next lower dose level 
Grade 2 with pain  
or Grade 3  
Ixazomib 
Omit ixazomib until AE resolves 
or returns to baseline. When AE 
resolves, re-initiate ixazomib at 
the next lower dose level. 
 
Grade 4 
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 
Skin and 
subcutaneous tissue 
disorders 
Rash, maculo-papular 
Rash, acneiform 
Grade 2 or 3 
Ixazomib 
Omit ixazomib until rash 
resolves to ≤Grade 1 (See 
Section 9.9a). Restart at same 
dose. If the rash recurs, reduce 
dose by one dose level. 
Grade 4 
 
Discontinue ixazomib 


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Table 8.2 
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT# 
ACTION** 
Other 
Any other non-hematological 
Grade 3 attributable adverse 
event except: 
Ixazomib 
Pomalidomide 
Dexamethasone 
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. 
Gastrointestinal 
Disorders 
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  
General disorders 
and administration 
site conditions 
Grade 3 fatigue 
(consider relatedness to one 
or all of the components of 
the combination) 
Other 
Grade 4 Nonhematologic 
adverse events (consider 
relatedness to one or all of 
the components of the 
combination) 
Ixazomib 
Pomalidomide 
Dexamethasone 
Consider permanently 
discontinuing ixazomib or 
pomalidomide or dexamethasone 
or all three depending on the 
attribution to either one, two or 
all three drugs (exception would 
be 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 at http:/ctep.cancer.gov/protocolDevelopment/electronic applications.ctc.htm 
**  
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 adverse events attributable to both ixazomib and pomalidomide, only one of the drugs should 
be reduced for each incidence of AEs severe enough to necessitate dose reduction. The drug reduced 
should alternate starting with pomalidomide for the first dose reduction. 
 
 


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Protocol version date:  December 12, 2019 
8.3 
Dose modifications for pomalidomide based on adverse events during a cycle 
(For each cycle during induction and consolidation and maintenance) 
Table 8.3 
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Investigations 
Neutrophil count decreased 
If ANC ˂1.0 × 109/L  
or ANC >1.0 × 109/L (up to 
LLN) with fever 
(temperature >38.5°C) 
Pomalidomide 
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 through 
Day 21of a 28-day cycle. 
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 
Platelet count decreased 
If platelet count ˂30 × 109/L 
Pomalidomide 
Omit pomalidomide dose 
Follow CBC weekly 
Hold anticoagulation/antiplatelet 
therapy 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 through 
Day 21 of each cycle 
Skin and 
subcutaneous tissue 
disorders 
Rash maculopapular  
Grade 2 or 3 
Pomalidomide 
Omit pomalidomide dose; follow 
weekly 
If the AE resolves to ≤Grade 1 
prior to Day 21, restart 
pomalidomide at next lower dose 
level and continue  through 
Day 21of each cycle 
Grade 3-4 Stevens –Johnson 
Syndrome 
Pomalidomide 
Discontinue pomalidomide and 
remove patient from all study 
treatment 
≥Grade 3 Erythema 
multiforme 
Pomalidomide 
Discontinue pomalidomide and 
remove patient from all study 
treatment 


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Table 8.3 
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Erythroderma  
≤Grade 3 
Pomalidomide 
Omit pomalidomide dose; follow 
weekly 
If the AE resolves to ≤Grade 1 
prior to Day 21, restart 
pomalidomide at next lower dose 
level and continue through 
Day 21of the 28-day cycle 
Rash, maculo-papular 
Rash, acneiform 
Grade 4 
Pomalidomide 
Discontinue pomalidomide and 
remove patient from all study 
treatment 
Nervous system 
disorders 
Peripheral sensory 
neuropathy 
Grade 3 
Pomalidomide 
Omit pomalidomide dose and 
follow at least weekly. 
If the AE resolves to ≤Grade 1 
prior to Day 21, restart 
pomalidomide at next lower dose 
level and continue through 
Day 21of the 28-day cycle 
Peripheral sensory 
neuropathy 
Grade 4 
Pomalidomide 
Discontinue pomalidomide and 
remove patient from all study 
treatment 
Immune system 
disorders 
Allergic reaction  
Grade 2-3 
Pomalidomide 
Omit dose and follow at least 
weekly 
If the AE resolves to ≤Grade 1 
prior to Day 15, restart at next 
lower dose level and continue 
through Day 21of the 28-day 
cycle 
Allergic reaction  
Grade 4 
Pomalidomide 
Discontinue pomalidomide and 
remove patient from all study 
treatment 
Vascular disorders 
Thromboembolic event 
≥ Grade 3 
Pomalidomide 
Omit dose and start 
anticoagulation 
Restart at investigator’s 
discretion (maintain dose level) 
Endocrine disorders 
Hyperthyroidism or 
Hypothyroidism ≥ Grade 2 
Pomalidomide 
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. 


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Table 8.3 
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Other non-
hematologic adverse 
event 
Other non-hematologic 
≥Grade 3 
Pomalidomide 
If the AE 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 
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 through 
Day 21of the 28-day cycle 
* 
Located at http:/ctep.cancer.gov/protocolDevelopment/electronic applications.ctc.htm 
**  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 adverse events 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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Protocol version date:  December 12, 2019 
8.4 
Dose modifications for dexamethasone based on adverse events during a cycle 
(for each cycle during induction and consolidation and maintenance) 
Table 8.4 
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Gastrointestinal 
disorders 
Dyspepsia 
Grade 1-2 
Dexamethasone 
Treat with H2 blockers, sucralfate, 
or omeprazole 
If symptoms persist despite above 
measures, decrease dexamethasone 
dose by 1 dose level 
Gastric or duodenal 
ulcer 
Grade 1-2 
Dexamethasone 
Treat with H2 blockers, sucralfate, 
or omeprazole 
If symptoms persist despite above 
measures, decrease dexamethasone 
dose by 1 dose level 
Gastritis  
Grade 1-2 
Dexamethasone 
Treat with H2 blockers, sucralfate, 
or omeprazole 
If symptoms persist despite above 
measures, decrease dexamethasone 
dose by 1 dose level 
Dyspepsia 
≥Grade 3 
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 
Gastric or duodenal 
ulcer 
≥Grade 3 
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 


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Table 8.4 
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Gastritis ≥Grade 3 
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 (any location) 
≥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 
Psychiatric disorders 
Delirium, delusion, 
depression, 
hallucination, euphoria  
≥Grade 2 
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 


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Protocol version date:  December 12, 2019 
Table 8.4 
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
AGENT 
ACTION** 
Musculoskeletal and 
connective tissue 
disorders 
Muscle weakness (any 
location) 
≥ 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 
(>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 http:/ctep.cancer.gov/protocolDevelopment/electronic applications.ctc.htm 
**  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 
Full supportive care 
Patients should receive full supportive care while on this study. This includes 
blood product support, antibiotic treatment, and treatment of other newly 
diagnosed or concurrent medical conditions. All blood products and concomitant 
medications such as antidiarrheals, analgesics, and/or antiemetics received from 
the first day of study treatment administration until 30 days after the final dose 
will be recorded in the medical records. 
9.2 
Steroid use 
Patients may continue on low level/stable steroid doses for replacement or inhalation 
therapy. 
9.3 
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 
9.4 
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. 
9.5 
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. 
NOTE: Platelet transfusions to help patients meet eligibility criteria are not allowed 
within 3 days prior to study registration or drug dosing for any dosing day. 
9.6 
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. 


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Protocol version date:  December 12, 2019 
Patients with severe diarrhea or any diarrhea associated with severe nausea or vomiting 
should be hospitalized for intravenous hydration and correction of electrolyte 
imbalances. 
9.7 
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. 
9.8 
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 
9.9a 
Prohibited medications  
The following medications, medicinal products and procedures are prohibited during the 
study. 
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 
(If there were to be a drug-drug interaction with an inducer, MLN2238 exposure would 
be decreased):  
• 
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.  
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). 


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Protocol version date:  December 12, 2019 
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. 
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. 
 
 


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Protocol version date:  December 12, 2019 
 
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. 
9.9g 
Pneumocystis jirovecii pneumonia [PJP (PCP)] prophylaxis 
Since   ixazomib  is immunosuppressive and associated with an increased risk of PJP, all    
may receive prophylaxis during   treatment.     The choice of prophylactic medications 
will be left to the discretion of the treating physician.   The decision to continue PJP 
prophylaxis beyond the time points noted is left to the discretion of the treating physician. 
Subjects who continue to demonstrate lymphopenia after the   dosing of ixazomib has 
been discontinued should be considered for ongoing prophylaxis.  
9.9g 
Transverse Myelitis 
Transverse myelitis has also been reported with ixazomib. It is not known if ixazomib 
causes transverse myelitis; however, because it happened to a patient receiving ixazomib, 
the possibility that ixazomib may have contributed to transverse myelitis cannot be 
excluded. 
9.9h 
Thromboprophylaxis 
All patients should receive ASA 325 mg daily for thromboprophylaxis. For patients 
considered high risk for thrombosis, therapeutic anticoagulation with warfarin or low 
molecular weight heparin should be used. 
 
 
 




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Protocol version date:  December 12, 2019 
 
Routine Reporting 
Events reported to sponsor via case report forms 
 
Events of Interest 
Events that would not typically be considered to meet the criteria for expedited reporting, 
but that for a specific protocol are being reported via expedited means in order to 
facilitate the review of safety data (may be requested by the FDA or the sponsor).  
 
Unanticipated Adverse Device Event (UADE) 
Any serious adverse effect on health or safety or any life-threatening problem or death 
caused by, or associated with, a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the investigational plan 
or application (including a supplementary plan or application), or any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects  
 
10.1 
Adverse Event Characteristics 
CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site: 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm)   
a. Identify the grade and severity of the event using the CTCAE version 4.0.  
b. Determine whether the event is expected or unexpected (see Section 10.2).  
c. Determine if the adverse event is related to the study intervention (agent, treatment or 
procedure) (see Section 10.3). 
d. Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4).  
e. Determine if other reporting is required (see Section 10.5). 
f. Note: All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.6 and 
18.0). 
NOTE: A severe AE is NOT the same as a serious AE, which is defined in Section 10.4. 
 
10.2  
Expected vs. Unexpected Events  
 
Expected events - are those described within the Section 15.0 of the protocol, the study 
specific consent form, package insert (if applicable), and/or the investigator brochure, (if 
an investigator brochure is not required, otherwise described in the general 
investigational plan).  
 
Unexpected adverse events or suspected adverse reactions are those not listed in Section 


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Protocol version date:  December 12, 2019 
15.0 of the protocol, the study specific consent form, package insert (if applicable), or in 
the investigator brochure (or are not listed at the specificity or severity that has been 
observed); if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan. 
 
Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have not 
been observed with the drug under investigation. 
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 or specificity, expedited reporting is 
required.  
 
10.3 
Attribution to agent(s) or procedure 
When assessing whether an adverse event (AE) is related to a medical agent(s) medical or 
procedure, the following attribution categories are utilized: 
 
Definite - The AE is clearly related to the agent(s)/procedure. 
Probable - The AE is likely related to the agent(s)/procedure. 
Possible - The AE may be related to the agent(s)/procedure. 
Unlikely - The AE is doubtfully related to the agent(s)/procedure. 
Unrelated - The AE is clearly NOT related to the agent(s)/procedure. 
 
10.31 AEs Experienced Utilizing Investigational Agents and Commercial Agent(s) on 
the SAME (Combination) Arm 
 
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. 
• An AE that occurs on a combination study must be assessed in accordance with the 
guidelines for investigational agents/interventions.  
• 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, unless hospitalization is required. Refer to Section 10.4 for 
specific AE reporting requirements or exceptions. 
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 or specificity, expedited reporting is 
required.  
• An increased incidence of an expected adverse event (AE) is based on the 
patients treated for this study at their site. A list of known/expected AEs is 
reported in the package insert or the literature, including AEs resulting from a 
drug overdose. 
• Commercial agent expedited reports must be submitted to the FDA via MedWatch 


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Protocol version date:  December 12, 2019 
3500A for Health Professionals (complete all three pages of the form). 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM0
48334.pdf 
or 
http://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/ListFormsAlphabe
tically/default.htm 
Instructions for completing the MedWatch 3500A: 
http://www.fda.gov/downloads/Safety/MedWatch/HowToReport/DownloadFor
ms/UCM387002.pdf 
 
10.32 EXPECTED Serious Adverse Events: Protocol Specific Exceptions to  
For this protocol only, the following Adverse Events/Grades are expected to occur 
within this population and do not require Expedited Reporting. These events must still 
be reported via Routine Reporting (see Section 10.6). * 
Table 10.32 
CTCAE 
System Organ Class (SOC) 
Adverse event/ 
Symptoms 
CTCAE Grade at 
which the event 
will not be 
expeditedly 
reported1 
Blood and lymphatic system 
disorders 
Anemia 
≤Grade 4 
Gastrointestinal disorders 
Vomiting 
≤Grade 3 
Nausea 
≤Grade 3 
Diarrhea 
≤Grade 3 
General disorders and 
administrations site conditions 
Fatigue  
≤Grade 3 
Investigations 
Lymphocyte count 
decreased 
≤Grade 4 
 
Neutrophil count 
decreased 
≤Grade 4 
 
Platelet count 
decreased 
≤Grade 4 
 
White blood cell 
decreased 
≤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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10.52 Death 
Note: A death on study requires both routine and expedited reporting 
regardless of causality, unless as noted below. Attribution to treatment or 
other cause must be provided. 
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 (including 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. 
10.53 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 will be reported. Three options are available to describe the event: 
o Leukemia secondary to oncology chemotherapy (e.g., Acute Myeloctyic 
Leukemia [AML]) 
o Myelodysplastic syndrome (MDS) 
o Treatment-related secondary malignancy 
• 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting 
mechanisms outlined in each protocol. 
10.54 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy). Second malignancies require ONLY 
routine reporting unless otherwise specified. 




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10.552 
Fetal Death 
Fetal death is defined in CTCAE as “A disorder characterized by death 
in utero; failure of the product of conception to show evidence of 
respiration, heartbeat, or definite movement of a voluntary muscle after 
expulsion from the uterus, without possibility of resuscitation.” 
Any fetal death should be reported expeditiously, as Grade 4 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy loss)” under the Pregnancy, puerperium and perinatal 
conditions SOC. 
10.553 
Death Neonatal 
Neonatal death, defined in CTCAE as “A disorder characterized by 
cessation of life occurring during the first 28 days of life” that is felt by 
the investigator to be at least possibly due to the investigational 
agent/intervention, should be reported expeditiously.  
A neonatal death should be reported expeditiously as Grade 4 
“General disorders and administration - Other (neonatal loss)” 
under the General disorders and administration SOC.  
10.6 
Required routine reporting 
10.61 Baseline and Adverse Events Evaluations 
Pretreatment symptoms/conditions to be graded at baseline and adverse events to 
be graded at each evaluation per CTCAE v4.0 grading unless otherwise stated in 
the table below: 
SYSTEM ORGAN CLASS 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
Investigations 
Creatinine increased 
X 
X 
Neutrophil count decreased 
X 
X 
Platelet count decreased 
X 
X 
White blood cell 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 maculo-papular 
X 
X 
Nervous system disorders 
 
Peripheral sensory neuropathy  
X 
X 
Peripheral motor neuropathy  
X 
X 
 
 


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10.62 All other AEs 
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 10.6: 
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) 
10.6231 
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the 
study treatment or procedure. 
10.6232 
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. 
 
10.7 
Late Occurring Adverse Events 
Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion 
of the Active Monitoring Phase (i.e., compliance with Test Schedule in Section 
4.0). 
 
10.8 
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). 


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Planned hospital admissions or surgical procedures for an illness or disease that existed 
before the patient was enrolled in the trial are not to be considered AEs unless the 
condition deteriorated in an unexpected manner during the trial (e.g., surgery was 
performed earlier or later than planned). All SAEs should be monitored until they are 
resolved or are clearly determined to be due to a patient’s stable or chronic condition or 
intercurrent illness(es). 
Since this is an investigator-initiated study, the principal investigator, Prashant Kapoor, 
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: 
• 
Event term(s) 
• 
Serious criteria 
• 
Intensity of the event(s): Sponsor-investigator’s or sub-investigator’s 
determination. Intensity for each SAE, including any lab abnormalities, will 
be determined by using the NCI CTCAE version specified in the protocol, as 
a guideline, whenever possible. The criteria are available online at 
http://ctep.cancer.gov/reporting/ctc.html. 
• 
Causality of the event(s): Sponsor-investigator’s or sub-investigator’s 
determination of the relationship of the event(s) to study drug administration.  
 
Follow-up information on the SAE may be requested by Millennium. 
 
Intensity for each SAE, including any lab abnormalities, will be determined by 
using the NCI CTCAE version used at your institution, as a guideline, whenever 
possible. The criteria are available online at 
http://ctep.cancer.gov/reporting/ctc.html. 
In the event that this is a multisite study, the sponsor-investigator is responsible 
to ensure that the SAE reports are sent to Millennium Pharmacovigilance (or 
designee) from all sites participating in the study. Sub-investigators must report 
all SAEs to the sponsor-investigator so that the sponsor-investigator can meet 
his/her foregoing reporting obligations to the required regulatory agencies and to 
Millennium Pharmacovigilance, unless otherwise agreed between the sponsor-
investigator and sub-investigator(s). 




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11.0 
Treatment Evaluation 
The International Myeloma Working Group (IMWG) uniform response criteria (Kumar et al, 
2016) will be used to assess response to therapy. 
 
11.1  
Terms and definitions 
• 
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-protein 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 M-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, with the exception that quantitative IgG may not be used. 
However, this must be explicitly reported at baseline, and only nephelometry can be used 
for that patient to assess response. SPEP derived M-protein values and quantitative 
nephelometric immunoglobulin values cannot be used interchangeably.  
Urine M-protein measurement is estimated using 24-h UPEP only. Random or 24 h urine 
tests measuring kappa and lambda light chain levels are not reliable and are not 
recommended. 
 
FLC estimation is currently carried out using the serum FLC assay (Freelite, The 
Binding Site Limited, UK). Patients with kappa/lambda FLC ratio <0.26 are defined as 
having monoclonal lambda FLC and those with ratios >1.65 as having a monoclonal 
kappa FLC. The monoclonal light chain isotype is considered the involved FLC isotype, 
and the opposite light chain type as the uninvolved FLC type.  
• 
Response terms: The following response terms will be used: stringent Complete 
Response (sCR), complete response (CR), very good partial response (VGPR), partial 
response (PR), Minimal Response (MR), stable disease (SD), and progressive disease 
(PD).  
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  
 
NOTE: Quantitative IgG may not be used for defining measurable disease 
o Urine M-protein ≥200 mg/24 h 


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o Serum FLC assay: Involved FLC level ≥10 mg/dl provided 
serum FLC ratio is abnormal 
o Bone marrow plasma cells ≥30% 
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-protein) 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-protein, 
serum free light chain, or urine M-protein. 
• 
Oligosecretory myeloma: Patient with multiple myeloma who has NEVER had 
“measurable” serum M-protein or urine M-protein, but has had a detectable M-
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 M-protein in his/her serum and/or urine. 
 
11.2 
Clarification of test indications 
Listed below are the minimal required tests required to assess response based on the 
characteristics of their disease at on study.  
Table 11.2 Tests Required To Assess Response (Must Be Done At Each Disease 
Measurement Visit except as indicated1,2) 
On Study Baseline Value 
SPEP4 
24 hr 
UPEP2 
Ig 
FLC 
BM Bx 
Serum M-protein ≥1 g/dl, and  
urine M-protein≥200 mg/24 hrs 
X 
X 
 
 
Serum M-protein ≥ 1 g/dl, but  
urine M-protein <200 mg/24 hrs 
X 
 
 
 
Serum M-protein <1 g/dl, and  
urine M-protein≥200 mg/24 hrs 
 
X 
 
 
Serum M-protein < 1 g/dl, urine M-protein <200 
mg/24 hrs, but involved Ig FLC is ≥10 mg/dL 
 
 
X 
 
Serum M-protein <1 g/dl, urine M-protein<200 
mg/24 hrs, involved Ig FLC is <10 mg/dL, bone 
marrow ≥30% plasma cells 
 
 
 
X3 
1  SPEP, UPEP, Immunofixation studies of both serum and urine, and Bone marrow biopsy 
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. 


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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  At a minimum, a bone marrow biopsy should be repeated every 3 months until documented 
response. Bone marrow biopsy results do not need to be repeated after documented response. 
4 If serum M-protein is being followed by quantitative immunoglobulin levels derived from 
nephelometry or turbidometry, quantitative immunoglobulins are required. SPEP is only 
required to document CR or VGPR.  
 
11.3 
Confirmed response  
In order to be classified as a hematologic response, confirmation of serum M- protein, 
serum immunoglobulin free light chain (when primary determinant of response) and 
urine M- 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 on the basis of variation of 
radiologic technique alone. Compression fracture does not exclude continued response 
and may not indicate progression. When progression is based on skeletal disease alone, it 
should be discussed with the Study Chair before removing the patient from the study.  
 
11.5 
Response and Progression 
Criteria for response and progression are listed in Table 11.5. Progressive disease for all 
patients as defined in Table 11.5.  
 
 


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Table 11.5 Response and Progression 
IMWG MRD 
NEGATIVITY 
CATEGORY  
 RESPONSE CRITERIA a 
Sustained MRD 
MRD negativity in the marrow (NGF or NGS, or both) and by 
imaging as defined below, confirmed minimum of 1 year apart. 
Subsequent evaluations can be used to further specify the duration of 
negativity (eg, MRD-negative at 5 years) 
Flow MRD k 
Absence of phenotypically aberrant clonal plasma cells by NGF on 
bone marrow aspirates using the EuroFlow standard operation 
procedure for MRD detection in multiple myeloma (or validated 
equivalent method) with a minimum sensitivity of 1 in 105 nucleated 
cells or higher 
Sequencing MRD k 
Absence of clonal plasma cells by NGS on bone marrow aspirates in 
which presence of a clone is defined as less than two identical 
sequencing reads obtained after DNA sequencing of bone marrow 
aspirates using the LymphoSIGHT platform (or validated equivalent 
method) with a minimum sensitivity of 1 in 105 nucleated cells or 
higher 
Imaging Plus MRD k 
MRD negativity as defined by NGF or NGS plus disappearance of 
every area of increased tracer uptake found at baseline or a preceding 
PET/CT or decrease to less than mediastinal blood pool SUV or 
decrease to less than that of surrounding normal tissue 
STANDARD IMWG 
RESPONSE 
CATEGORY 
RESPONSE CRITERIA a 
Stringent Complete 
Response (sCR) b 
• 
CR as defined plus 
• 
Normal FLC ratio and 
• 
Absence of clonal PCs by immunohistochemistry or 2- to 4- 
color flow cytometry i 
Complete Response 
(CR) b, l 
• Negative immunofixation of serum and urine c and 
• Disappearance of any soft tissue plasmacytoma and 
• <5% PCs in Bone Marrow and 
• If the only measurable disease is FLC, a normal FLC ratio d  
Very Good Partial 
Response (VGPR)  
• Serum and urine M-protein detectable by immunofixation but not 
on electrophoresis c or 
• ≥90% reduction in serum M-protein and urine M-protein <100 
mg/24 h c 
• If the only measurable disease is FLC, a >90% reduction in the 
difference between involved and uninvolved FLC levels 
Partial Response (PR) 
• If present at baseline, ≥ 50% reduction of serum M-protein and 
reduction in 24-hour urinary M-protein by ≥90% or to <200 
mg/24hrs c 
• If the only measurable disease is FLC, a ≥50% reduction in the 
difference between involved and uninvolved FLC levels 
• If the only measurable disease is BM, a ≥ 50% reduction in BM 
PCs (provided the baseline PCs was ≥ 30%) 
• If present at baseline, ≥ 50% reduction in the size (SPD) of soft 
tissue plasmacytomas j 
Minor Response (MR)  
• 
If present at baseline, ≥25% but ≤ 49% reduction of serum M 


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Table 11.5 Response and Progression 
protein and reduction in 24-hour urine M-protein by 50-89% 
which still exceeds 200mg/24 hours c and 
• 
If present at baseline, ≥50% reduction in the size (SPD) of soft 
tissue plasmacytoma j  
Stable Disease (SD) 
• 
Not meeting criteria for sCR, CR, VGPR, PR, MR or PD 
Progressive Disease 
(PD) b, h 
Increase of 25% from lowest value in any of the following f, g: 
• 
Serum M-protein (absolute increase must be ≥ 0.5 g/dL) and/or 
• 
Urine M-protein (absolute increase must be ≥ 200 mg/24 hrs) 
and/or 
• 
If the only measurable disease is FLC, the difference between 
involved and uninvolved FLC levels (absolute increase must be 
>10 mg/dL) and/or 
• 
If the only measurable disease is BM, bone marrow PC 
percentage (absolute increase must be ≥ 10%) e  
Or any one or more of the following: 
• 
Development of new bone lesion or soft tissue plasmacytoma or 
≥50% increase from nadir in the size (SPD) of existing bone 
lesions or soft tissue plasmacytoma or ≥ 50% increase in the 
longest diameter of a previous lesion >1 cm in short axis j 
• 
50% increase in circulating plasma cells (minimum of 200 cells 
per L) if this is the only measure of disease 
Clinical Relapse 
One or more of the following direct indicators of increasing disease 
and/or end-organ dysfunction that are considered related to the 
underlying plasma cell proliferative disorder: 
1.  Development of new soft tissue plasmacytomas or bone lesions on 
skeletal survey, magnetic resonance imaging, or other imaging 
2.  Definite increase in the size of existing plasmacytomas or bone 
lesions. A definite increase is defined as a 50% (and at least 1 cm) 
increase as measured serially by the sum of the products of the 
cross-diameters of the measurable lesion 
3.  Hypercalcemia (>11.5 mg/dL; >2.875mM/L) 
4.  Decrease in hemoglobin of more than 2 g/dL (1.25mM) or to less 
than 10 g/dL 
5.  Rise in serum creatinine by more than or equal to 2 mg/dL 
(≥177mM/L) 
6.  Hyperviscosity 
a All response categories require two consecutive assessments (sCR, CR, VGPR, PR, MR, 
PD) made at any time before the institution of any new therapy. MRD tests should be 
initiated only at the time of suspected complete response. sCR, CR, VGPR, PR, MR and 
SD categories and MRD require no known evidence of progressive or new bone lesions 
or extramedullary plasmacytomas if radiographic studies were performed. However, 
radiographic studies are not required to satisfy these response requirements except for the 
requirement of FDG PET if imaging MRD-negative status is reported. 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. The date of the initial test is 
considered as the date of response for evaluation of time dependent outcomes such as 
duration of response. 


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b CR patient will need to progress at the same level as VGPR and PR patients to be 
considered a PD. A positive immunofixation alone is not sufficient. 
c If more than one M protein spike meets the criteria for measurable disease at baseline, 
then both need to be followed for response. Otherwise, only follow the measurable M 
protein spike for response.  
d In patients in whom the only measurable disease is by serum FLC levels: CR in such 
patients indicates a normal FLC ratio of 0.26-1.65 in addition to the CR criteria listed 
above. 
e Bone marrow criteria for PD are only to be used in patients without measurable disease by 
M protein and by FLC 
f A "25% increase" refers to M protein, FLC and bone marrow results and does not refer to 
bone lesions, soft tissue plasmacytoma or hypercalcemia. The lowest value does not need 
to be a confirmed value. If the lowest serum M-protein is ≥5 g/dL, an increase in serum 
M-protein of ≥1 g/dL is sufficient to define disease progression. 
g 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. 
h Progressive disease should be confirmed on two consecutive evaluations, where the 
timing of confirmation is per the treating physician and can be done immediately within 
the same cycle or on the next cycle. 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. 
i Presence/absence of clonal cells is based upon the k/l ratio. An abnormal k/l ratio by 
immunohistochemistry requires a minimum of 100 plasma cells for analysis. An 
abnormal ratio reflecting presence of an abnormal clone is k/l of 4:1 or 1:2.  
j Plasmacytoma 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 the sum of the products of the maximal perpendicular diameters of 
measured lesions (SPD). 
k Requires a complete response as defined in table 11.5.  MRD tests should be initiated only 
at the time of suspected complete response. MRD requires no known evidence of 
progressive or new bone lesions if radiographic studies were performed. However, 
radiographic studies are not required to satisfy these response requirements except for the 
requirement of FDG PET if imaging MRD-negative status is reported. 
  
 
11.6 
Criteria for engraftment (for hematopoietic stem cell transplant studies only) 
Engraftment is defined as: 
•  The first day of three consecutive days on which the absolute neutrophil count (ANC) 
>500/mm3 
and  
•  The first of three consecutive days with an untransfused platelet count >20,000/mm3. 
 
 
 


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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. 
Distinguish between SPEP measurements vs. quantitative IgA measurement vs. 
quantitative IgD or IgM measurement for serum M-spike 
12.2  
Number of prior therapies: 1-3 vs. 4 or more 
12.3  
Revised international staging system (R-ISS): Stage I vs. Stage II vs. Stage III 
Risk Factors 
Serum β2 
microglobulin 
Serum 
albumin 
Del(17p) and/or t(4;14) 
and/or t(14;16) 
Abnormal 
LDH level 
Stage I (Criteria in all 
columns must be met) 
<3.5 mg/L 
≥3.5 g/dL 
No 
No 
Stage II 
All other possible combinations (not Stage I or Stage III) 
Stage III (Criteria in all 
columns must be met) 
>5.5 mg/L 
NA 
At least one = Yes 
12.4 
Extramedullary disease at the time of study entry: Yes vs. no 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient  
13.1 
Patients who are MRD negative, 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  
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 


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• 
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 off-protocol at the discretion of the physician as long 
as there are no safety concerns, and the patient was properly registered. The patient will 
go directly to the event-monitoring phase of the study (or off study, if applicable).  
• 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted. Event monitoring will be required per Section 18.0 of 
the protocol.  
• 
If the patient never received treatment, on-study material and the End of Active 
Treatment/Cancel Notification 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. All data up until the point of confirmation of a major violation must be 
submitted. The patient will go directly to the event-monitoring phase of the study. The 
patient may continue treatment off-protocol at the discretion of the physician as long as 
there are no safety concerns, and the patient was properly registered. Event monitoring 
will be required per Section 18.0 of the protocol. 
13.8 
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 End of Active Treatment/Cancel 
Notification 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 Body Fluid Specimens to be collected under IRB #521-93  
Note: Research blood and bone marrow collection per protocol IRB 521-93 will be done after consenting for 521-93 and 
according to that protocol. All processing will be done on Stabile 6. 
Correlative 
Study (Section 
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) 
End of 
Cycle 4 
(post 
Induction/ 
Pre ASCT 
~Day 100 
post 
ACST 
Post 
consolidation  
Ongoing  
Maintenance  
After 1 year 
from initiation 
of maintenance  
Minimal residual 
disease by Flow 
cytometry 
Mandatory 
In patients 
who have 
achieved at 
least CR  
Bone 
marrow 
aspirate 
ACD  
(yellow) 
6 mL 
(1) 
X 
X 
X 
X 
14.2  
Collection and Processing  
14.21 Flow cytometry: This will be performed on bone marrow aspirate following a wash no lyse method on fresh samples. 
14.3 
Background and Methodology 
14.3 1 Minimal residual disease evaluation: Currently 30-40% of patients achieve a CR with initial therapy. In most cases, 
patients classified as CR in reality have minimal residual disease (MRD) since (i) many such patients relapse, and (ii) 
residual clonal disease is detectable in most by more sensitive techniques such as multiparameter flow cytometry and PCR 
based techniques.(Sarasquete, Garcia-Sanz et al. 2005; Mateo, Montalban et al. 2008; Paiva, Vidriales et al. 2009). We 
will determine minimal residual disease positivity at various stages of treatment, among patients achieving a conventional 
complete response. Bone marrow aspirates will be evaluated for presence of clonal plasma cells a well as the ratio of 
clonal to non-clonal plasma cells after 4 cycles and whenever a CR is suspected and a marrow is done.  
MRD detection will be done on BM samples as previously described32. Plasma cells are identified by their characteristic 
CD45/CD38/CD138 staining pattern with light chain restriction and CD19/CD56 phenotype on each case. One ml 
(milliliter) of BM (bone marrow) is subjected to flow cytometry on a Cantos Flow Cytometer. Samples are collected 
ungated, up to one million events per tube.  
 


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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 (MLN9708) 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. 
 
15.13 Preparation and storage: Ixazomib capsules (0.2 mg, 0.5 mg,  
2.0 mg), individually packaged in blisters, can be stored at 2ºC to 8ºC  
or “Do not store above 25°C. Do not freeze." Ixazomib capsules (2.3 mg, 3.0 mg, 
4.0 mg, and 5.5 mg), individually packaged in blisters can be stored at “2°C - 
8°C” or “Do not store above 30°C. Do not freeze." 
Ixazomib that is dispensed to the patient for take-home dosing should remain in 
the blister packaging until the point of use. The investigative site is responsible 
for providing the medication to the patient in units that comprise the correct daily 
dose configurations. Capsules should remain in the blisters until the point of use. 
Ixazomib capsules must be administered as intact capsules and must not be 
opened or manipulated in any way. Comprehensive instructions should be 
provided to the patient in order to ensure compliance with dosing procedures. 
Patients will be instructed to store the medication in the refrigerator until the time 
of use. Reconciliation will occur accordingly when the patient returns for their 
next cycle of therapy. Any extremes in temperature should be reported as an 
excursion and will be managed on a case by case basis. Returned unused capsules 
should be discarded in a proper biohazard container. 
Ixazomib is an anticancer drug. As with other potentially toxic compounds, 
caution should be exercised when handling ixazomib. It is recommended to wear 
gloves and protective garments during preparation when dispensed in clinic. 
Please refer to published guidelines regarding the proper handling and disposal of 
anticancer agents. 
 
15.14 Administration: Ixazomib (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. 
Ixazomib should not be taken if the patient has had a serious allergic reaction to 
boron or boron containing products. 
 
15.15 Pharmacokinetic (PK) information:  


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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 should be avoided. 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 LenDex on the clinical 
PK of ixazomib. 
Ixazomib should not be taken if the patient has had a serious allergic 
reaction to boron or boron containing products. 
 


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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,   
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, papular 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 
reactions, 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 Takeda Pharmaceuticals, Inc. 
  
 15.19 Nursing guidelines 
15.191 Capsules must be administered intact and should not be opened or 
manipulated in any way. Additionally, capsules should remain in the 
blister packs until they are ready to be taken. 
15.192 Capsules should be taken on an empty stomach (either 1 hours before or 
2 hours after meals) with 8 oz of water. 
15.193 Cytopenias have been observed. Monitor CBC w/diff. Instruct patient to 
report any signs or symptoms of infection or bleeding to the study team. 
15.194 GI side effects have been seen (nausea, diarrhea, vomiting), treat 
symptomatically and monitor for effectiveness of intervention. 
15.195 Rash has been seen. Rarely Steven Johnson syndrome (SJS) has been 
seen with this agent. Instruct patients to report any rash to study team. 
15.196 Assess patients concomitant medications, including over the counter and 
supplements. MLN9708 is metabolized through both CYP and non-CYP 
enzymes, and drug to drug interactions exist. Instruct patients not to start 


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any new medications or supplements without checking with the study 
team first.  
15.197 Fatigue has been seen. Instruct patient in energy conserving lifestyle. 
15.198 Insomnia can be seen. Treat symptomatically and monitor for 
effectiveness. 
15.199a Patients who have had an allergic reaction to boron or boron containing 
products should not take MLN9708. 
15.199b The following rare but life threatening conditions have been seen with 
agent: CHF, liver failure, TTP, TLS, renal failure, bowel obstruction, and 
RPLS, transverse myelitis, progressive multifocal leukoencephalopathy. 
Monitor labs closely, instruct patient to report any new or worsening 
symptoms to the study team and provide further assessment based on 
symptoms. 
 
15.2 
Pomalidomide (Pomalyst®) 
15.21 Background: Pomalidomide 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 polyubiquitination 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 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 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 month of therapy may be dispensed. 
 
15.24 Administration: Pomalidomide is administered by mouth at approximately the 
same time each day. 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 


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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. 
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 half-life (t1/2) of pomalidomide was approximately 7.5 
hours. 
In pomalidomide renal studies, no dose adjustment was required for subjects with 
renal impairment. On hemodialysis days, subjects were instructed to take 
pomalidomide following hemodialysis. No dose adjustment of pomalidomide is 
required for patients with hepatic impairment as defined by the Child-Pugh 
criteria. 
15.26 Potential Drug Interactions: Pomalidomide is partially metabolized by 
CYP1A2 and CYP3A4/5. 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. 


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Protocol version date:  December 12, 2019 
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 
  
 
Uncommon known potential toxicities, ≥0.1% - <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, dysesthesia, 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 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. 


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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. 
15.29 Nursing Guidelines 
15.291 
Agent is known to be teratogenic in rabbits. Therefore all 
women who are pregnant or who could become pregnant, should 
not handle the agent outside of the original packaging. 
Chemotherapy gloves should be worn if contact is necessary. 
15.292 
Because of the similarity of this agent to thalidomide certain 
precautions MUST be employed by all subjects on protocol and 
for 4 weeks after discontinuation of agent. Instruct patients the 
following must be adhered to: No donation of 
tissue/blood/semen/sperm; sexually active males/ females must 
use protocol-specific contraception (regardless of fertility status-
i.e. history of vasectomy). 
15.293 
Cytopenias are common (neutropenia most common). Monitor 
CBC closely and instruct patient to report any signs/symptoms 
of infection or unusual bruising or bleeding to the study team. 
15.294 
Thrombotic events have been reported. Anticoagulation 
prophylaxis may be recommended. Instruct patients to report 
any problems with bleeding, extremity pain or swelling, or 
shortness of breath to the study team immediately.  
15.295 
Patients may experience cough, URI, pneumonia, or sinusitis. 
Instruct patients to report respiratory symptoms to the study 
team. 
15.296 
Gastrointestinal side effects consisting of diarrhea, constipation, 
stomatitis, nausea, decreased appetite, and abdominal pain have 
been seen. Treat symptomatically and monitor for effectiveness. 
15.297 
Drug should be taken without food (at least 2 hours before or 2 
hours after a meal). Do not open or crush capsules. 
15.298 
Patients may experience myalgias and muscle spasms. Treat 
symptomatically and monitor for effectiveness. 
15.299a Fatigue is common. Instruct patient in energy conserving 
lifestyle. 
15.299b Warn patients about the possibility of peripheral neuropathy, 
headache, confusion, and dizziness. 
15.299c Patients may experience URI, pneumonia, dyspnea, and cough. 
Instruct patients to report respiratory symptoms to the study 
team.  
15.299d Severe dermatologic reactions have been seen (including 
urticaria). Instruct patient to report and rash or skin changes to 
the study team. 
15.299e All patients must be registered in the POMALYST REMS 
program. See protocol for more details. 
 
 
 


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15.3 
Dexamethasone for Oral Administration (DXM) 
15.31 Background: Dexamethasone is an adrenal corticosteroid compound. 
Dexamethasone decreases inflammation by suppression of neutrophil migration, 
decreased production of inflammatory mediators, and reversal of increased 
capillary permeability; suppresses normal immune response. Dexamethasone’s 
mechanism of antiemetic activity is unknown. 
15.32 Formulation: Commercially available for oral administration as:  
Tablets [scored]: 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 4 mg, and 6 mg 
Solution, oral: 0.5 mg/mL (500 mL) 
Solution, oral concentrate: Dexamethasone Intensol: 1 mg/mL (30 mL) 
15.33 Preparation, storage, and stability: Refer to package insert for complete 
preparation and dispensing instructions. Store oral tablets at room 
temperature between 20ºC to 25ºC (60ºF to 77ºF). Protect from moisture. 
Dispense in a well-closed, light-resistant container as defined in the 
USP/NF. Store oral liquid at room temperature, do not freeze. Do not use 
if solution contains a precipitate. Refer to commercial package for drug 
expiration date. 
15.34 Administration: Refer to the treatment section for specific administration 
instructions. May be taken with meals to decrease GI upset.  
15.35 Pharmacokinetic information: 
Onset of action: Prompt 
Duration of metabolic effect: 72 hours 
Metabolism: Hepatic 
Half-life elimination: Normal renal function: 1.8-3.5 hours; Biological 
half-life: 36-54 hours 
Time to peak, serum: Oral: 1-2 hours 
Excretion: Urine and feces 
15.36 Potential Drug Interactions: 
Cytochrome P450 Effect: Substrate of CYP3A4 (major); Induces 
CYP2A6 (weak), 2B6 (weak), 2C8 (weak), 2C9 (weak), 3A4 (strong) 
Increased Effect/Toxicity: Aprepitant, azole antifungals, calcium channel 
blockers, cyclosporine, estrogens, and macrolides may increase the serum 
levels of corticosteroids. Corticosteroids may increase the hypokalemic 
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) 


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15.37 Known potential adverse events: Consult the package insert for the most 
current and complete information.  
Common known potential toxicities, frequency not defined:  
Fluid and electrolyte disturbances, congestive heart failure in susceptible 
persons, hypertension, euphoria, personality changes, insomnia, 
exacerbation of infection, exacerbation or symptoms of diabetes, 
psychosis, muscle weakness, osteoporosis, vertebral compression 
fractures, pancreatitis, esophagitis, peptic ulcer, dermatologic disturbances, 
convulsions, vertigo and headache, endocrine abnormalities, ophthalmic 
changes, and metabolic changes. Some patients have experienced itching 
and other allergic, anaphylactic or hypersensitivity reactions. Withdrawal 
from prolonged therapy may result in symptoms including fever, myalgia 
and arthralgia. 
 
15.38 Drug procurement: Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
15.39 Nursing Guidelines: 
15.391 Monitor patient regularly for hypertension, CHF and other evidence of 
fluid retention. 
15.392 Advise patient of possible mood or behavioral changes, i.e., depression, 
euphoria, insomnia, even psychosis. Instruct patient to report any 
suspected changes to healthcare team. 
15.393 Assess for symptoms of gastric ulcer, heartburn, or gastritis. Suggest 
antacids. Instruct patient to report symptoms to healthcare team if unable 
to control. 
15.394 Evaluate signs of infection, particularly local candidal infections and 
treat appropriately. 
15.395 Monitor blood glucose frequently. 
15.396 Instruct patient to report frequent, unrelenting headaches or visual 
changes to healthcare team. 
15.397 Advise patient that easy bruising is a side effect. 
 
 


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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 in combination with 
pomalidomide and dexamethasone for treatment of patients who are being considered for 
single ASCT for relapsed or refractory multiple myeloma. The study is designed to assess 
the progression-free survival at 18 months (PFS18) using a one-stage binomial study 
design.  
16.11 Primary Endpoint 
The primary endpoint of this trial is the proportion of patients alive and free from 
disease progression at 18 months from study entry. All patients meeting the 
eligibility criteria, who have signed a consent form and have begun treatment, 
will be evaluable for progression-free survival at 18 months (PFS18), unless they 
are determined to be a major violation. 
16.2 
Statistical Design:  
16.21 Decision Rule 
In a previous study including 112 patients who received a delayed autologous 
transplant after IMiD-based initial therapy, median progression-free survival 
from the time of transplant was 15.9 months (Kumar S 2012).  In two additional 
studies with 64 patients and 65 patients who received novel agents during the 
pre-ASCT induction, the median progression-free survival from time of 
transplant was 22.2 months and 18 months, respectively, in patients who received 
a delayed transplant (Dunavin NC, 2013; Remenyi P, 2016). 
Patients on the proposed study will also be undergoing delayed autologous 
transplantation; however, progression-free survival will be measured from study 
entry. Based on previous studies, a PFS18 rate from time of study entry of 50% 
would not be of interest. 
The largest success proportion where the proposed treatment regimen would be 
considered ineffective in this population is 50%, and the smallest success 
proportion that would warrant subsequent studies with the proposed regimen in 
this patient population is 75%. The following one-stage binomial design uses 21 
evaluable patients to test the null hypothesis that the true success proportion in a 
given patient population is at most 50%.  
16.212  Final Decision Rule: If 13 or fewer successes are observed in the first 21 
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 14, 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. 
 
 


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16.22 Sample Size 
The one stage study design to be used is fully described above. A maximum of 
21 evaluable patients will be accrued onto this phase II study unless undue 
toxicity is encountered. We anticipate accruing an additional 4 patients to 
account for ineligibility, cancellation, major treatment violation, or other reasons. 
Therefore, the total sample size will be 25 patients.  
16.23 Accrual Rate and Study Duration 
We anticipate accruing 2 patients per month to this study, and hence the 
enrollment period will be approximately 2 years. An individual patient is 
expected to complete induction, ASCT and consolidation phases within 15 
months of enrollment, after which ixazomib maintenance phase will start in 
which the drug is given until progression or unacceptable toxicity. The minimum 
duration before results may be reported is expected to be approximately 3.5 
years, or until the last patient accrued has been observed for at least 18 months.  
16.24 Power and Significance Level 
Assuming that the number of successes is binomially distributed, the significance 
level is 0.095. The probability of declaring that this regimen warrants further 
studies (i.e. statistical power) under various success proportions can be tabulated 
as a function of the true success proportion as shown in the following table. 
If the true success proportion is... 
0.50 
0.55 
0.60 
0.65 
0.70 
0.75 
Then the probability of declaring 
that the regimen warrants further 
study is… 
0.095 
0.197 
0.350 
0.537 
0.723 
0.870 
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 18 months. 
16.31 Primary Outcome Analyses: 
16.311 Definition: The primary endpoint of this trial is the proportion of patients 
alive and free from disease progression at 18 months from study entry. 
All patients meeting the eligibility criteria, who have signed a consent 
form and have begun treatment, will be evaluable for progression-free 
survival at 18 months unless they are determined to be a major violation. 
Definition of Success: An evaluable patient will be classified as a 


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treatment success for the primary endpoint if they are alive and free from 
disease progression at 18 months from registration. 
16.312 Estimation: The proportion of successes will be estimated by the number 
of successes divided by the total number of evaluable patients. Exact 
binomial 95% confidence intervals for the true success proportion will be 
calculated.  If patients are censored prior to 18 months post registration 
(which is unlikely given our data from past trials in a similar patient 
population), a Kaplan Meier (Kaplan, E. and Meier, P., 1958) estimate 
for PFS18 along with the 95% confidence intervals will be reported. We 
recognize that applying this approach will, however, reduce the stated 
statistical power of our primary analysis.   
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 The overall response rate will be estimated by the number of patients 
who achieve a sCR, CR,VGPR, or PR divided by the total number of 
evaluable patients. All evaluable patients will be used for this analysis. 
Exact binomial 95% confidence intervals for the true overall response 
rate will be calculated. 
16.322 The ≥VGPR response rate will be estimated by the number of patients 
who achieve a sCR, CR, or VGPR divided by the total number of 
evaluable patients.  All evaluable patients will be used for this analysis. 
Exact binomial 95% confidence intervals for the true overall ≥VGPR 
response rate will be calculated. 
16.323 Overall survival is defined as the time from registration to the last date 
of documentation of follow-up or death due to any cause. The 
distribution of overall survival will be estimated using the method of 
Kaplan-Meier (Kaplan, E. and Meier, P., 1958)  
16.322 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 in CR at various stages of treatment: after induction, day # 100 
after SCT, after consolidation and during maintenance at one year from 
initiation of maintenance therapy. 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. 


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16.324  Engraftment kinetics (WBC and platelet) following single salvage 
ASCT for relapsed disease will be measured by assessing the timing of 
recovery of bone marrow function. Neutrophil engraftment will be 
defined as the first of the three days of neutrophil count above 
500/microliter and platelet engraftment as the first day of >20,000 
platelets/microliter, untransfused.. The median time to engraftment of 
neutrophil count and platelet count from the day of infusion of 
autologous stem cells (day 0) will be summarized using descriptive 
statistics. 
16.4 
Data & Safety Monitoring 
16.41 Reviews 
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. 
16.42 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 3 or more patients in the first 10 treated patients experience a grade 4 or 
higher non-hematologic adverse event at least possibly related to treatment. 
• 
if after the first 10 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. 
16.5  
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 3.5 years after the study opens to accrual. The definition of “Primary Endpoint 


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Completion Date” (PECD) for this study is at the time the last patient registered has been 
followed for at least 18 months. 
16.6 
Inclusion of Women and Minorities 
16.61 This study will be available to all eligible patients, regardless of race, gender, or 
ethnic origin. 
16.62 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. 
16.63 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 
8 
16 
0 
24 
Ethnic Category: Total of all subjects* 
8 
17 
0 
25 
Racial Category 
 
American Indian or Alaskan Native 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
Black or African American 
0 
1 
0 
1 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
0 
White 
8 
16 
0 
24 
Racial Category: Total of all subjects* 
8 
17 
0 
25 
 
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 


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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 Data Submission 
Schedule. 
18.2 
Event monitoring 
See Section 4.2 and data submission table for the event monitoring schedule. 
18.3 
CRF completion 
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 pro gression 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 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. 
18.7 
Incomplete materials 
Any materials deemed incomplete by the MCCC Operations Office will be considered 
“not received” and will not be edited or otherwise processed until the missing 


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information is received. A list of the missing documents will be made available to the 
appropriate co-sponsor/participant. 
18.8 
Overdue lists 
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 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 co-sponsor/participant. The query will 
be sent to the appropriate co-sponsor/participant who will make the correction and return 
the query and documentation of correction back to the QAS.  
 
19.0  
Budget 
 
19.1 
Costs charged to patient: Routine clinical care 
 
19.2 
Tests to be research funded: Research testing on bone marrow specimens (per IRB #521-
93). 
 
19.3 
Other budget concerns: Ixazomib to be provided to the patient by Takeda free of charge.  
 
 
 


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20.0 
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88 
 
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Transplantation and Interferon Maintenance in Multiple Myeloma: Single-Center Experience of 18 Years. 
Transplant Proc. 2016 Jan-Feb;48(1):177-84. 
Palumbo, et al, JCO, Sept. 10, 2015: 33 (26):2863-2869 


MC168A  
89 
 
Protocol version date:  December 12, 2019 
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 http://www.ecog.org/general/perf stat.html