Clinical trial NCT03012880
Conditions: Plasma Cell Myeloma
Sponsor: Mayo Clinic
Start date: 2017-04-20; Completion date: 2022-12-15
Enrollment: 80 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well ixazomib citrate, lenalidomide, dexamethasone, and daratumumab work in treating patients with newly diagnosed multiple myeloma. Ixazomib citrate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as lenalidomide and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as daratumumab, may block cancer growth in different ways by targeting certain cells. Giving ixazomib citrate, lenalidomide, dexamethasone, and daratumumab may work better in treating patients with newly diagnosed multiple myeloma.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the complete response rate (CR) of the four-drug combination of ixazomib, lenalidomide, dexamethasone and daratumumab in patients with previously untreated symptomatic multiple myeloma (MM).

SECONDARY OBJECTIVES:

I. To determine the overall response rate (ORR), and very good partial response (VGPR) rate with the four drug combination of ixazomib, lenalidomide, dexamethasone and daratumumab, when used as initial therapy in patients with previously untreated symptomatic MM.

II. To determine the progression free survival and overall survival among patients with previously untreated symptomatic MM following treatment with the four drug combination of Ixazomib, lenalidomide, dexamethasone and daratumumab followed by ixazomib and daratumumab maintenance till progression.

II. To determine the toxicities associated with the four drug combination of ixazomib, lenalidomide, dexamethasone and daratumumab in patients with previously untreated symptomatic MM.

TERTIARY OBJECTIVES:

I. To examine the proportion of minimal residual disease (MRD) negativity following induction therapy with the four-drug combination of ixazomib, lenalidomide, dexamethasone and daratumumab.

II. To assess the quality of life using patient completed Functional Assessment of Cancer Treatment (FACT)/Gynecologic Oncology Group (GOG) questionnaires.

OUTLINE:

INDUCTION PHASE: Patients receive ixazomib citrate orally (PO) on days 1, 8, and 15 and lenalidomide PO on days 1-21. Patients receive daratumumab intravenously (IV) over 3-7 hours on days 1, 8, 15, and 22 of courses 1 and 2, on days 1 and 15 of courses 3, 4, and 5, and on day 1 of courses 7 and beyond. Patients also receive dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE PHASE: Patients receive ixazomib citrate PO on days 1, 8, and 15 and daratumumab IV over 3-7 hours on day 1. Courses repeat every 28 days for up to 36 months from registration in the absence of disease progression or unacceptable toxicity.

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

Arms: arm 1: INDUCTION PHASE: Patients receive ixazomib citrate PO on days 1, 8, and 15 and lenalidomide PO on days 1-21. Patients receive daratumumab IV over 3-7 hours on days 1, 8, 15, and 22 of courses 1 and 2, on days 1 and 15 of courses 3, 4, and 5, and on day 1 of courses 7 and beyond. Patients also receive dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE PHASE: Patients receive ixazomib citrate PO on days 1, 8, and 15 and daratumumab IV over 3-7 hours on day 1. Courses repeat every 28 days for up to 36 months from registration in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Daratumumab intervention 2: Dexamethasone intervention 3: Ixazomib Citrate intervention 4: Laboratory Biomarker Analysis intervention 5: Lenalidomide intervention 6: Questionnaire Administration
Intervention descriptions: intervention 1: Given IV intervention 2: Given PO intervention 3: Given PO intervention 4: Correlative studies intervention 5: Given PO intervention 6: Ancillary studies

Protocol documents:
Prot_SAP_000.pdf: 
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Version Date:  March 26, 2020 
    
Mayo Clinic Cancer Center 
 
Phase 2 trial of Ixazomib, lenalidomide, dexamethasone and daratumumab in patients with newly 
diagnosed multiple myeloma 
 
 
 
Study Chair: 
 
 
 
 
 
 
 
  
 
 
 
Study Co-Chairs:  
 
 
 
 
 
 
 
 
 
 
Statistician: 
 
 
 
√Study contributor(s) not responsible for patient care. 
 
Takeda Study: X16079 
Janssen Scientific Affairs (Janssen) Study: 54767414MMY2010 
IND #132345 
 
Drug Availability  
Commercial Agents: Dexamethasone, Lenalidomide 
Drug Company Supplied: Ixazomib (Takeda), Daratumumab (Janssen) 
 
Document History 
(Effective Date) 
  Activation 
 April 12, 2017 
Addendum 1 
 August 3, 2017 
Addendum 2 
Addendum 3 
 August 30, 2017 
 October 30, 2017  
Addendum 4 
 December 5, 2017 
Addendum 5 
 January 9, 2018 
Addendum 6 
 March 27, 2018 
Addendum 7 
June 11, 2018 
Addendum 8 
Addendum 9 
Addendum 10 
August 21, 2018 
January 23, 2019 
July 24, 2019 
 
 
 
      Addendum 11 
 
 January 13, 2020 
 
 
 
      Addendum 12 
 
 April 27, 2020 
 
 
 


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Protocol Resources 
Questions: 
Contact Name: 
Patient eligibility*, test schedule, 
treatment delays/ interruptions/adjustments, 
dose modifications, adverse events, 
forms completion and submission 
  
 
Drug administration, infusion pumps,  
nursing guidelines 
 
 
 
Forms completion and submission 
 
 
Protocol document, consent form, 
regulatory issues 
 
 
Adverse Events (MCCC SAE, paper AdEERS, 
MedWatch, AML/MDS) 
  
 
Biospecimens 
 
  
 
*No waivers of eligibility per NCI


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Version Date:  March 26, 2020 
Table of Contents 
Phase 2 trial of Ixazomib, lenalidomide, dexamethasone and daratumumab in patients with newly 
diagnosed multiple myeloma .......................................................................................................... 1 
Protocol Resources.......................................................................................................................... 1 
Table of Contents ............................................................................................................................ 3 
Schema 
 ............................................................................................................................... 4 
1.0 
Background ...................................................................................................................... 6 
2.0 
Goals............................................................................................................................... 17 
3.0 
Patient Eligibility ............................................................................................................ 17 
4.0 
Test Schedule ................................................................................................................. 21 
5.0 
Stratification Factors: None ........................................................................................... 24 
6.0  
Registration Procedures.................................................................................................. 24 
7.0 
Protocol Treatment ......................................................................................................... 26 
8.0 
Dosage Modification Based on Adverse Events ............................................................ 29 
9.0 
Ancillary Treatment/Supportive Care ............................................................................ 36 
10.0 
Adverse Event (AE) Reporting and Monitoring ......................................................... 41 
11.0 
Treatment Evaluation ................................................................................................. 57 
12.0 
Descriptive Factors ..................................................................................................... 63 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient ........................................... 64 
14.0 
Biospecimens .............................................................................................................. 66 
15.0 
Drug Information ........................................................................................................ 68 
16.0 
Statistical Considerations and Methodology .............................................................. 82 
17.0 
Pathology Considerations/Tissue Biospecimens: None ............................................. 88 
18.0 
Records and Data Collection Procedures ................................................................... 88 
19.0 
Budget ......................................................................................................................... 89 
20.0 
References .................................................................................................................. 90 
Appendix I 
Multiple Myeloma Diagnostic Criteria ............................................................... 92 
Appendix II 
Mayo Risk Stratification (mSMART) ................................................................. 93 
Appendix III 
NYHA Classification .......................................................................................... 94 
Appendix IV 
ECOG Performance Status Scale ........................................................................ 95 
Appendix V 
Revlimid REMS Required Pregnancy Information ............................................ 96 
Appendix VI 
PATIENT MEDICATION DIARY .................................................................... 98 
Appendix VII FACT/GOG NTX (Version 4) ............................................................................ 99 
Appencix VIII – Patient Information Sheet ................................................................................ 103 


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Version Date:  March 26, 2020 
Schema Arm A 
Closed to enrollment   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If a patient is deemed ineligible or a cancel, please refer to Section 13 for follow-up information. 
1 Cycle length = 28 days  
2 Confirmation of PD is not required.  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 Patient Status Form.  
3 Induction cycles 1-12 cycles 
4 Maintenance cycle 13 onwards 
5 Confirmation of MR or PR is not required. 
6 Patients may receive stem cell transplant (SCT) at physician discretion at any time after completion of 
treatment on  Cycle 4. If patient goes to SCT, they will go to Survival and Disease Status Follow-Up/ 
Event Monitoring per Section 4.2. Details should be recorded on the Stem Cell Harvest and Transplant 
and Engraftment  Forms  
Generic name: Ixazomib 
Brand name(s):Ninlaro 
Mayo Abbreviation: MLN9708    
Availability:   Provided by Takeda Pharmaceuticals, I
Generic name:  Dexamethasone 
Brand name(s):  Decadron 
Mayo Abbreviation:  DXM 
Availability:  Commercial 
Generic name:  Lenalidomide 
  
Brand name(s): Revlimid 
Mayo Abbreviation:  REVLIMID  
Availability:  Commercial  Revlimid REMS program
Generic name: Daratumumab  
Brand name(s): Darzalex 
Mayo Abbreviation: DARATUMUMAB  
Availability: Provided by Janssen   
Registration 
Induction3  
Ixazomib, lenalidomide, 
dexamethasone (cycles 1-12 only), 
daratumumab1 
Maintenance4  
Ixazomib, daratumumab till disease 
progression or maximum of 3 years1  
Optional: May interrupt 
therapy for stem cell 
collection any time after 
completion of treatment on 
Cycle  4   6 
PD at any time 2 
Unacceptable adverse events  
                       Event Monitoring (per section 4.2) 
Patient refusal 
Subsequent treatment for myeloma 
Patient will go off 
treatment to event 
monitoring if an MR 
is not seen after 2 
cycles and a PR is 
not seen after 4 
cycles.5 


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Version Date:  March 26, 2020 
Schema Arm B 
Open to enrollment as of Amendment 7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If a patient is deemed ineligible or a cancel, please refer to Section 13 for follow-up information. 
1 Cycle length = 28 days  
2 Confirmation of PD is not required.  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 Patient Status Form. 
3 Induction cycles 1-12 cycles 
4 Maintenance cycle 13 onwards 
5 Confirmation of MR or PR is not required. 
6 Patients may receive stem cell transplant (SCT) at physician discretion at any time after completion of 
treatment on Cycle 4. If patient goes to SCT, they will go to Survival and Disease Status Follow-Up/ 
Event Monitoring per Section 4.2. Details should be recorded on the Stem Cell Harvest and  Transplant 
and Engraftment Forms   
Generic name: Ixazomib 
Brand name(s):Ninlaro 
Mayo Abbreviation: MLN9708    
Availability:   Provided by Takeda Pharmaceuticals, I
Generic name:  Dexamethasone 
Brand name(s):  Decadron 
Mayo Abbreviation:  DXM 
Availability:  Commercial 
Generic name:  Lenalidomide 
  
Brand name(s): Revlimid 
Mayo Abbreviation:  REVLIMID  
Availability:  Commercial  Revlimid REMS program
Generic name: Daratumumab  
Brand name(s): Darzalex 
Mayo Abbreviation: DARATUMUMAB  
Availability: Provided by Janssen   
Registration 
Induction3  
Ixazomib, lenalidomide, 
dexamethasone (cycles 1 and 2 only), 
daratumumab1 
  
Maintenance4  
Ixazomib, daratumumab till disease 
progression or maximum of 3 years1  
Optional: May interrupt 
therapy for stem cell 
collection any time after 
completion of treatment on 
Cycle  4 6 
PD at any time 2 
Unacceptable adverse events  
                       Event Monitoring (per section 4.2) 
Patient refusal 
Subsequent treatment for myeloma 
Patient will go off 
treatment to event 
monitoring if an MR 
is not seen after 2 
cycles and a PR is 
not seen after 4 
cycles.5 


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1.0 
Background 
 
1.1 Multiple Myeloma: Multiple myeloma is a malignancy of the differentiated plasma cells, that 
affect the older patient with a median age at onset of 65-70 years and a slight male 
predominance. It is characterized by clonal expansion of plasma cells leading to increased 
production of monoclonal protein in the majority of patients accompanied by end organ 
damage in the form of lytic bone disease, hypercalcemia, anemia and renal insufficiency. 
Nearly 24,000 patients with myeloma are diagnosed in the United States each year, and 
despite considerable improvements in therapy, myeloma remains incurable and uniformly 
fatal with a median overall survival of around 8 years. Recent improvements in therapies 
have significantly improved the survival outcomes, but given the inevitable relapses seen in 
these patients, new approaches to therapy are clearly needed. As the efficacy of therapies 
have increased and newer classes of drugs have been approved for treatment of myeloma, 
there is increasing interest on improving the depth of response with the initial therapy of 
myeloma. 
 
1.2 Initial therapy of multiple myeloma: The treatment paradigms for multiple myeloma have 
undergone a significant change in the past decade.1,2 A decade ago, patients who were 
considered eligible for transplant underwent the procedure after a brief duration of therapy 
with a steroid based regimen with or without doxorubicin. Patients ineligible for transplant 
went on to receive melphalan and prednisone. With these treatment approaches patients had a 
median survival of 3-4 years, with nearly 10-20% of patients dying in the first year after 
diagnosis. During the last decade several new drugs were introduced such as thalidomide and 
its analogue lenalidomide and the proteasome inhibitor bortezomib and these along with 
continued use of transplant has led to improved survival in myeloma.3 In fact, in the recent 
clinical trials 3-year survival has approached 90% and 1-year mortality has dropped to under 
2%.4 This progress has come through a series of investigations examining the efficacy of the 
new drugs used in various combinations and sequences. Initial trials in the relapsed setting 
confirmed significant clinical activity for all these new drugs. This was followed by several 
clinical trials that examined the combination of novel agents with dexamethasone in the 
setting of newly diagnosed disease. The studies consistently demonstrated superior response 
rates, deeper responses, and improved progression-free survival for patients undergoing 
initial therapy with novel agents.4-7 The trials examined the role of the new drugs in the 
context of transplant eligible and ineligible patients. This has been followed by three drug 
regimens that either combined the new drugs together or incorporated an alkylator drug to the 
novel agent-dexamethasone combination. These have included combinations of bortezomib 
and dexamethasone with thalidomide (VTD), lenalidomide (VRd) or cyclophosphamide 
(VCD).5,6,8,9 
 
Of particular interest is the VRd regimen, which has shown high efficacy rates and is 
increasingly used for initial therapy in the community.5,9  VRd regimen has been associated 
with high response rates approaching 100% and deep responses with very good partial 
response rates and complete response rates of over 70 and 40% respectively. It has proven to 
be a highly effective initial therapy for patients planning stem cell transplantation with no 
significant effect on the ability to successfully mobilize stem cells.  
 
In the initial phase 1/2 trial of the VRD regimen, 66 patients with newly diagnosed myeloma  
received 3-week cycles of bortezomib (days 1, 4, 8, 11), lenalidomide (days 1-14), and 
dexamethasone (days 1, 2, 4, 5, 8, 9, 11, 12). Phase 2 dosing was determined to be 
bortezomib 1.3 mg/m2, lenalidomide 25 mg, and dexamethasone 20 mg. Most common 


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toxicities included sensory neuropathy, fatigue, lymphopenia, neutropenia and 
thrombocytopenia. All patients had a partial response 74% achieving very good partial 
response or better. In the EVOLUTION trial, patients were randomized to receive bortezomib 
1.3 mg/m2 d 1, 4, 8, 11 and dexamethasone 40 mg d 1, 8, 15, with either cyclophosphamide 
500 mg/m2 d 1, 8 and lenalidomide 15 mg d 1–14 (VDCR), lenalidomide 25 mg d1-14 
(VRd), cyclophosphamide 500 mg/m2 d 1, 8 (VCD) or cyclophosphamide 500 mg/m2 d 1, 8, 
15 (VCD-mod) in a 21 day cycle (maximum 8 cycles).9,10 This was followed by bortezomib 
1.3 mg/m2 (d 1, 8, 15, 22) for four 42-day maintenance cycles in all arms. VGPR or better 
was seen in 58, 51, 41 and 53% (CR rate of 25, 24, 22 and 47%) of patients (VDCR, VRd, 
VCD and VCD-mod arms, respectively); the corresponding progression-free survival (PFS) 
at 1 year was 86, 83, 93 and 100%, respectively. In a recently presented phase 3 trial, the 
combination of VRd was associated with increased response rates, deeper responses, 
increased PFS and improved overall survival compared with lenalidomide and 
dexamethasone. In the SWOG0777 trial, 525 patients with newly diagnosed myeloma were 
randomized to lenalidomide with or without bortezomib. Median PFS was 43 months (VRd) 
versus 30 months (Rd); log-rank P value = 0.0018. Median OS was 75 months (VRd) versus 
64 months (Rd); HR = 0.71; two-sided log-rank P value = 0.0250.  
 
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, Ixazomib 
citrate 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 citrate refers to the citrate ester 
of MLN2238.  In water or aqueous systems, the equilibrium shifts from ixazomib citrate 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 


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and 110 minutes, respectively).  Based on these favorable characteristics, ixazomib is 
anticipated to be effective against multiple myeloma. (ixazomib Investigator’s Brochure (IB). 
Proteasome inhibition results in the accumulation of poly-ubiquitinated substrates within the 
cell and leads to cell cycle disruption, with concomitant activation of apoptotic pathways and 
cell death.  Consistent with inhibition of ß5 20S activity, MLN2238 demonstrated potent 
activity against cultured MDA-MB 231 human breast cancer cells in the WST cell viability 
assay.  In nonclinical models MLN2238 has activity against both solid tumor and 
bortezomib-resistant xenografts. 
 
In Vivo Pharmacology: To determine the activity of MLN2238 in vivo, pharmacodynamic 
studies were performed in immunocompromised mice bearing either CWR22 human prostate 
or WSU-DLCL2 (human diffuse large B-cell lymphoma [DLBCL]) tumors.  
Pharmacodynamic responses in xenograft tumors were analyzed by assessing 20S proteasome 
inhibition and by evaluating levels of accumulated protein markers such as deoxyribonucleic 
acid (DNA) damage-inducible protein 34 (GADD34) and activating transcription factor-3 
(ATF-3) as well as measuring growth arrest.  Increased expression of GADD34 and ATF-3 is 
indicative of a downstream biological response to proteasome inhibition.  After a single dose 
of MLN2238, a clear dose response was observed in CWR22 xenografts as seen in both 
tumor 20S proteasome inhibition and in changes in GADD34 and ATF-3 expression.  In 
WSU-DLCL2 xenografts, greater tumor proteasome inhibition was observed with MLN2238 
compared to bortezomib and resulted in increased expression of GADD34 and ATF-3. 
MLN2238 efficacy experiments demonstrated strong antitumor activity in 4 xenograft 
models: CWR22 (a human prostate cancer cell line) and 3 human lymphoma cell lines 
(WSU-DLCL2, OCI-Ly7-7D1-luc, and PHTX-22L).  In the case of the CWR22 xenograft 
model, significant antitumor activity was seen with both IV and PO dosing, demonstrating 
that this molecule has antitumor activity when administered via different dosing routes.  In all 
3 lymphoma lines, MLN2238 demonstrated stronger antitumor activity than did bortezomib. 
In summary, MLN2238, similar to bortezomib, is a dipeptide boronic acid proteasome 
inhibitor that potently, reversibly, and selectively inhibits the proteasome.  There are several 
features, such as sustained pharmacodynamic effects and activity in a bortezomib-refractory 
lymphoma xenograft model, that suggest that it may have activity that extends beyond that 
seen with bortezomib. 
 
Nonclinical Pharmacokinetics and Pharmacodynamics: Nonclinical Pharmacokinetics: The 
pharmacokinetic (PK) properties of MLN2238 were studied in severe combined 
immunodeficient (SCID) mice bearing human CWR22 tumor xenografts, Sprague-Dawley 
rats, beagle dogs, and cynomolgus monkeys.  Because of the extensive red blood cell (RBC) 
partitioning of MLN2238, both blood and plasma PK parameters were determined in these 
studies.  MLN2238 had a very low blood clearance (CLb) and a moderate blood volume of 
distribution at steady-state (Vss,b) after IV administration.  The concentration-versus-time 
curve of MLN2238 displayed a distinct bi-exponential profile with a steep initial distribution 
phase and a long terminal t1/2 (> 24 hr) in all species tested.  MLN2238 had higher plasma 
clearance (CLp) and a larger plasma volume of distribution at steady-state (Vss,p) than in 
blood, largely because of the extensive RBC partitioning. The PK properties of MLN2238 
after oral administration were studied in rats and dogs.  The plasma oral bioavailability (F) 
was 41% in rats and nearly 100% in dogs.  A clinical prototype formulation of the ixazomib 
capsule demonstrated that MLN2238 had excellent oral F and an excellent absorption profile 
in dogs.  In addition, interindividual variability, as measured by %CV, in Cmax and AUC0-24hr 
after oral administration was low to moderate, similar to that after IV administration.  The 
terminal t1/2 after oral administration was also similar to that after IV administration.  
Comparison of the PK profiles after IV or PO administration in the dog is reported in further 


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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.   
 
In a Caco-2 cell assay, MLN2238 showed medium permeability with a B-to-A/A-to-B 
permeability ratio of 2.9.  MLN2238 may be a low-affinity substrate of para-glycoprotein (P-
gp), breast cancer resistance protein (BCRP), and multidrug resistance protein 2 (MRP2) 
efflux pump transporters.  MLN2238 is not an inhibitor of P-gp, BCRP, and MRP2 (IC50 > 
100 μM).  Consequently, the potential for MLN2238 to cause DDIs with substrates or 
inhibitors of P-gp, BCRP, and MRP2 is low.   
 
See the IB for further details. 
 
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 citrate.  Because ixazomib citrate 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 (ixazomib). 
 
The toxicology studies of MLN2238 were studied in SCID mice bearing human CWR22 
tumor xenografts, Sprague-Dawley rats, beagle dogs,  and cynomolgus monkeys.  Details of 
these studies are included in the IB. 
 
In Vitro Toxicology: MLN2238 was not mutagenic in a Good Laboratory Practice (GLP)-
compliant bacterial reverse mutation assay (Ames assay).  


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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 has been studied in several phase 1 and phase 1/2 studies evaluating both twice-
weekly and weekly dosing schedules.  Ixazomib as an intravenous and oral formulation. 
Regardless of the route of administration in the twice-weekly dosing schedule, ixazomib is 
given on Days 1, 4, 8, and 11 of a 21-day cycle; in the weekly dosing schedule, the drug is 
given on Days 1, 8, and 15 of a 28-day cycle. To date, the development of oral ixazomib has 
focused on multiple myeloma [relapsed and/or refractory and newly diagnosed] and a 
different yet related plasma cell dyscrasia, systemic light chain (AL) amyloidosis. A clinical 
pharmacology study looking at drug-drug interactions, the effect of food, and bioavailability 
also uses the oral formulation. Details of these trials can be found in ClinicalTrials.gov and 
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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 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. 


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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. 
 
 
Overview of the Oral Formulation of ixazomib 
The safety profile indicates that oral ixazomib is generally well tolerated with predominant 
toxicities largely reversible, able to be monitored by routine clinical examinations and 
manageable by dose reductions, discontinuation, or standard supportive care. From 
experience from phase 1 through 2 studies the major toxicities can be managed to allow 
repeat treatment cycles over periods extending beyond 24 months.  
Relapsed MM: Single-agent, Weekly ixazomib (Study C16004):13  


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Study C16004 is an open-label, dose-escalation, phase 1 study of ixazomib administered 
weekly on Days 1, 8, and 15 of a 28-day cycle in adult patients with RRMM. Patients with 
MM enrolled in the dose-escalation component of the study have relapsed following at least 2 
lines of therapy, which must have included bortezomib, thalidomide (or lenalidomide), and 
corticosteroids. In this study, 2 of 3 patients experienced protocol-defined DLTs (Grade 3 
rash and Grade 3 nausea, vomiting, and diarrhea) at a dose of 3.95 mg/m2. As per protocol, 
subsequent patients were treated at 1 dose level below (2.97mg/m2) where 1 of 6 patients 
experienced a DLT (Grade 3 nausea, vomiting, and diarrhea). The MTD of weekly oral 
ixazomib was determined to be 2.97 mg/m2. 
 
Once the MTD was established, cohorts of patients representing the heterogeneous patient 
population currently seen in clinical practice were enrolled in order to further evaluate the 
safety, tolerability, efficacy, PK, and pharmacodynamics of oral ixazomib and included: 
 
1. Relapsed and Refractory expansion cohort [refractory is defined as disease progression 
while on therapy or within 60 days after the last dose of therapy]; 
2. Carfilzomib expansion cohort 
3. Proteasome Inhibitor-Naïve expansion cohort 
4. VELCADE-Relapsed expansion cohort 
 
Sixty patients with relapsed and/or refractory multiple myeloma were enrolled. The MTD 
was determined to be 2.97 mg/m2. Dose-limiting toxicities were grade 3 nausea, vomiting, 
and diarrhea in 2 patients, and grade 3 skin rash in 1 patient. Common drug-related adverse 
events were thrombocytopenia (43%), diarrhea (38%), nausea (38%), fatigue (37%), and 
vomiting (35%). The observed rate of peripheral neuropathy was 20%, with only 1 grade 3 
event reported. Nine (18%) patients achieved a partial response or better, including 8 of 30 
(27%) evaluable patients treated at the MTD. Pharmacokinetic studies suggested a long 
terminal half-life of 3.6 to 11.3 days, supporting once-weekly dosing.  
 
Newly Diagnosed Multiple Myeloma (C16005): 14 
In Study C16005, ixazomib is given weekly (Days 1, 8, and 15), in combination with 
lenalidomide (Days 1-21), and dexamethasone (Days 1, 8, 15, and 22) in a 28-day cycle.15 
Patients with newly diagnosed MM were enrolled and treated with oral ixazomib (days 1, 8, 
and 15) plus lenalidomide 25 mg (days 1-21) and dexamethasone 40 mg (days 1, 8, 15, 22) 
for up to twelve 28-day cycles, then maintenance therapy with ixazomib (same schedule) 
every 28 days until progression. Patients were allowed to undergo stem cell collection after 3 
cycles and discontinue for autologous stem cell transplant (ASCT) after 6 cycles. Overall, 65 
patients were enrolled, 15 in Phase 1 and 50 in Phase 2. Patients received a median of 6 
cycles (range 1-19) with 27 (42%) remaining on treatment as of November 2012. Of those 
who have undergone stem cell mobilization, a median yield was 11.3 x 106 CD34+ cells/Kg 
(range 5-28). ixazomib MTD was established as 2.97 mg/m2 and RP2D was selected as 2.23 
mg/m2; RP2D translates to a 4.0 mg fixed dose based on population PK results. Among the 
64 evaluable patients, the overall response rate was 92%, including 55% VGPR and 23% CR 
(Figure 3 below).  Median time to first response was 0.92 months (range 0.89-6.44).  
 


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Potential Risks and Benefits of ixazomib:  
Please refer to the current ixazomib Investigator’s Brochure (IB)  
1.4 Lenalidomide in myeloma 
 
Lenalidomide has significant activity in the setting of multiple myeloma; both in relapsed and in 
newly diagnosed disease. Initial phase I/II study of lenalidomide in relapsed myeloma determined 
the ideal dose to be 25 mg once daily given for 3 of 4 weeks.16 The initial trial in the relapsed 
disease also demonstrated increased activity in combination with pulsed doses of dexamethasone. 
These findings led to the initial trials of the combination in newly diagnosed disease as well as 
randomized trials of the combination in relapsed myeloma.17 In the phase III trials of 
lenalidomide and dexamethasone, the combination was demonstrated to be superior to 
dexamethasone in terms of response rates and progression free and overall survival.18 The initial 
phase II study of lenalidomide and dexamethasone in newly diagnosed myeloma, conducted at 
the Mayo Clinic, also employed the combination of lenalidomide and pulsed dose dexamethasone 
(40 mg daily on four days on four days off schedule) for the first four cycles followed by 40 mg 
weekly for the subsequent cycles. The phase II study demonstrated significant response rates and 
long term follow up demonstrated sustained responses and 1-year survival rates of over 90%. The 
subsequent phase III trial in the ECOG (E4A03) compared the same dosing strategy to one that 
employed a lower dose of dexamethasone (40 mg weekly) right from the start of therapy.18 The 
results of the trial demonstrated a superior overall survival for the lower dose dexamethasone 
arm. 
 
 1.5 Daratumumab in myeloma 
Daratumumab is a human IgG1ĸ monoclonal antibody (mAb) that binds with high affinity to a 
unique epitope on CD38, a transmembrane glycoprotein. It is a targeted immunotherapy directed 
towards tumor cells that express high levels of CD38, such as plasma cells from patients with 
multiple myeloma. This target is distinct from those of other approved agents for multiple 
myeloma therapy. Daratumumab is currently approved for treatment of relapsed myeloma, that 
are refractory to a proteasome inhibitor and an IMiD. It is not approved for initial therapy of 
myeloma, and hence considered investigational for the current trial. 
 
Nonclinical Studies with daratumumab 
Based on preclinical data, daratumumab may utilize multiple effector cell functions, resulting in 
immune mediated killing of tumor cells. In ex vivo experiments utilizing human bone marrow 
45 
37 
32 
30 
26 
35 
19 
32 
23 
0 
10 
20 
30 
40 
50 
60 
70 
80 
90 
100 
After 4 cycles 
(n=47) 
After 8 cycles 
(n=19) 
Overall 
(n=52) 
CR 
VGPR 
PR 
% 
≥VGPR 
58% 
≥VGPR 
49% 
≥VGPR 
58% 
ORR 94% 
ORR 95% 
ORR 90% 


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stromal cells co-cultured with primary multiple myeloma cells, complement-dependent 
cytotoxicity (CDC) occurs rapidly and demonstrates maximal myeloma cell killing by 
daratumumab within 1 hour of antibody-mediated activation of the complement proteins. 
Daratumumab-induced antibody-dependent cell-mediated cytotoxicity (ADCC) is slower in its 
action, with maximal ADCC by daratumumab observed at 4 hours in vitro. Daratumumab has 
also been shown to induce antibody-dependent cellular phagocytosis (ADCP) in the presence of 
macrophages within 4 hours in vitro. The precise role of some or all of these effector functions in 
reducing tumor burden in patients is unknown. In toxicology studies in cynomolgus monkeys and 
chimpanzees, the major observed toxicities were cytokine release syndrome and 
thrombocytopenia. A minor decrease in red blood parameters was also observed. Cytokine release 
was seen only following the first dose and was markedly reduced following implementation of a 
10-mg predose of daratumumab. The effect on platelets and red blood cells was reversible. 
For the most comprehensive nonclinical and clinical information as well as Reference Safety 
Information regarding daratumumab, refer to the latest version of the Investigator's Brochure 
(Daratumumab IB). 
 
Clinical studies with daratumumab 
 
Single agent studies: Two large single agent studies have been reported to date; GEN501 and 
MMY2002. In the GEN501 study, daratumumab was administered at doses of 0.005 to 24 mg per 
kilogram of body weight during the dose escalation phase.19 No maximum tolerated dose was 
identified. In the dose-expansion phase, 30 patients received 8 mg per kilogram of daratumumab 
and 42 received 16 mg per kilogram, administered once weekly (8 doses), twice monthly (8 
doses), and monthly for up to 24 months. In the expansion phase, the median time since diagnosis 
was 5.7 years. Patients had received a median of four prior treatments; 79% of the patients had 
disease that was refractory to the last therapy received (64% had disease refractory to proteasome 
inhibitors and immunomodulatory drugs and 64% had disease refractory to bortezomib and 
lenalidomide), and 76% had received autologous stem-cell transplants. Infusion-related reactions 
were mild (71% of patients had an event of any grade, and 1% had an event of grade 3), with no 
dose-dependent adverse events. The most common adverse events of grade 3 or 4 (in ≥5% of 
patients) were pneumonia and thrombocytopenia. The overall response rate was 36% in the 
cohort that received 16 mg per kilogram (15 patients had a partial response or better, including 2 
with a complete response and 2 with a very good partial response) and 10% in the cohort that 
received 8 mg per kilogram (3 had a partial response). In the cohort that received 16 mg per 
kilogram, the median progression-free survival was 5.6 months (95% confidence interval [CI], 
4.2 to 8.1), and 65% (95% CI, 28 to 86) of the patients who had a response did not have 
progression at 12 months. 
 
In the MMY2002 study, patients with multiple myeloma who were previously treated with at 
least three lines of therapy (including proteasome inhibitors and immunomodulatory drugs), or 
were refractory to both proteasome inhibitors and immunomodulatory drugs, were randomized to 
receive intravenous daratumumab 8 mg/kg or 16 mg/kg in in the initial part of the study.20 
Patients received 8 mg/kg every 4 weeks, or 16 mg/kg per week for 8 weeks (cycles 1 and 2), 
then every 2 weeks for 16 weeks (cycles 3–6), and then every 4 weeks thereafter (cycle 7 and 
higher). In the second part of the study, the dose of 16 mg/kg was taken forward. One-hundred-
six patients with a median of five previous lines of therapy (range 2–14) were treated at the 16-
mg/kg dose. 85 (80%) patients had previously received autologous stem cell transplantation, 101 
(95%) were refractory to the most recent proteasome inhibitors and immunomodulatory drugs 
used, and 103 (97%) were refractory to the last line of therapy. Overall, responses were seen in 31 
patients (29·2%,)—three (2·8%) with a stringent CR, ten (9·4%) with a VGPR, and 18 (17·0) 
with a PR. Median duration of response was 7·4 months (95% CI 5·5–not estimable) and 


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progression-free survival was 3·7 months and the 12-month overall survival was 64·8%. 
Daratumumab was well tolerated; fatigue (40%) and anemia (33%) were the most common 
adverse events.  
 
Daratumumab-lenalidomide combinations: Preclinically, using bone marrow mononuclear cells 
from patients with multiple myeloma, increased killing of tumor cells was demonstrated when 
daratumumab was combined with lenalidomide as compared with that of either agent alone. 
 
In an open-label phase 1/2 study DARA 2-16 mg/kg was combined with standard dose of 
lenalidomide and dexamethasone, leading to a recommended phase 2 dose of daratumumab 16 
mg/kg along with lenalidomide 25 mg days 1-21 and dexamethasone 40 mg weekly. 
Daratumumab 16 mg/kg was administered weekly during the first two 28-day cycles, every other 
week during Cycles 3 through 6, and monthly in Cycle 7 and beyond until disease progression or 
unacceptable toxicity. LEN 25 mg was administered orally on Days 1 through 21 of each cycle, 
and DEX 40 mg was given weekly. Thirty two patients with median of 2 prior lines of therapy 
were enrolled. 
The most common (>25%) TEAEs included neutropenia (81%), muscle spasms (44%), cough 
(38%), diarrhea (34%), fatigue and hypertension (28% each). Eighteen (56%) patients had IRRs 
and these were generally mild to moderate and occurred mostly during the first cycle. IRRs 
included cough (25%), allergic rhinitis, nausea, and vomiting (9% each), as well as dyspnea, 
nasal congestion, and hypertension (6% each). The overall response rate was 88%, with 11 (34%) 
partial responses and 17 (53%) ≥very good partial responses (VGPRs) that included 7 (22%) 
stringent complete responses, 1 (3%) complete response, and 9 (28%) VGPRs. The median time 
to first and best response was 1 month and 4.5 months, respectively. Results of this study confirm 
the efficacy of combining daratumumab with lenalidomide and dexamethasone. A large phase 3 
trial of Daratumumab and Rd versus Rd has completed accrual. 
 
1.6 Rationale for the current trial: Ixazomib in combination with lenalidomide and dexamethasone 
results in high response rates and deep responses in patients with newly diagnosed myeloma. It is 
well tolerated and patients are able to stay on it long term as a maintenance therapy. More 
recently, addition of daratumumab to lenalidomide and dexamethasone has resulted in significant 
activity in relapsed myeloma. The combination of the ixazomib, lenalidomide, daratumumab and 
dexamethasone presents the potential to further enhance the response to therapy with four 
different drug classes with no significant overlapping toxicities. We hypothesize that this 
combination will lead to deep response including a higher proportion of MRD negative disease 
that will translate into longer survival in these patients. 
 
Rationale for Arm B: Long term therapy with dexamethasone is associated with various side 
effects including osteoporosis, adrenal suppression, muscle weakness, and increased risk of 
opportunistic infections. Given the efficacy of the daratumumab, ixazomib and lenalidomide, it is 
likely we will be able to decrease the dexamethasone doses and potentially eliminate it after the 
initial cycles. We will add a similar cohort of patients and treat them with dexamethasone only 
for the first two cycles of treatment and then discontinue. The endpoints of the trial will not be 
altered.  


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2.0 
Goals 
2.1 
Primary 
 
To determine the complete response rate (CR) of the four-drug combination of Ixazomib, 
lenalidomide, dexamethasone and daratumumab in patients with previously untreated 
symptomatic MM. 
 
2.2 
Secondary 
 
2.21 
To determine the overall response rate (ORR), and very good partial response 
(VGPR) rate with the four drug combination of ixazomib, lenalidomide, 
dexamethasone and daratumumab, when used as initial therapy in patients with 
previously untreated symptomatic MM  
 
2.22 
To determine the progression free survival and overall survival among patients 
with previously untreated symptomatic MM following treatment with the four 
drug combination of Ixazomib, lenalidomide, dexamethasone and daratumumab 
followed by ixazomib and daratumumab maintenance till progression. 
 
2.22 
To determine the toxicities associated with the four drug combination of 
Ixazomib, lenalidomide, dexamethasone and daratumumab in patients with 
previously untreated symptomatic MM. 
 
2.3 
Correlative Research 
 
2.31 
To examine the proportion of MRD negativity following induction therapy with 
the four-drug combination of Ixazomib, lenalidomide, dexamethasone and 
daratumumab 
 
2.32 
To assess the quality of life using patient completed FACT/GOG questionnaires. 
 
3.0 
Patient Eligibility 
3.1 
Inclusion Criteria  
3.11 
Age ≥18 years. 
 
3.12 
The following laboratory values obtained ≤14 days prior to registration.  
• 
Calculated creatinine clearance (using Cockcroft-Gault equation below)* 
>=30 mL/min 
• 
Absolute neutrophil count (ANC) ≥1500/mm3 
• 
Untransfused Platelet count ≥75000/mm3  
• 
Hemoglobin ≥8.0 g/dL 
• 
Total bilirubin ≤ 1.5 x ULN 
• 
ALT and AST ≤ 2.5 x ULN 
 
*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) 


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3.13 
Measurable disease of multiple myeloma as defined by at least ONE of the 
following: 
• 
Serum monoclonal protein ≥1.0 g/dL (see Section 11.1 for definition) 
• 
>200 mg of monoclonal protein in the urine on 24 hour electrophoresis  
• 
Serum immunoglobulin free light chain ≥10 mg/dL AND abnormal 
serum immunoglobulin kappa to lambda free light chain ratio. 
 
3.14 
ECOG performance status (PS) 0, 1 or 2 (Appendix IV) 
 
3.15 
Previously untreated for myeloma or have received no more than one cycle of 
any treatment regimen. NOTE: Prior radiation therapy for the treatment of 
solitary plasmacytoma is permitted. Prior therapy with clarithromycin, DHEA, 
anakinra, pamidronate or zoledronic acid is permitted. Any additional agents not 
listed must be approved by the Principal Investigator. 
 
3.16 
Provide informed written consent. 
 
3.17 
Negative pregnancy test done ≤7 days prior to registration, for women of 
childbearing potential only. 
 
3.18 
Willing to follow strict birth control measures. 
Female patients: If they are 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.) 
Male patients: 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 (eg, calendar, ovulation, 
symptothermal, post-ovulation methods] and withdrawal are not acceptable 
methods of contraception.) 
 
3.19a 
Negative hepatitis B test (defined by a negative test for hepatitis B surface 
antigen [HBsAg], or antibodies to hepatitis B surface and/or core antigens 
[antiHBs or antiHBc) (added as of addendum 9) 
Note:   Patients with serologic findings suggestive of HBV vaccination (antiHBs 
positivity as the only serologic marker) AND a known history of prior HBV 
vaccination do not need to be tested for HBV DNA by PCR. Those who are PCR 
positive will be excluded. 


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3.19b Willing to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study). 
 
3.19c 
Willing to follow the requirements of the Revlimid REMS program 
 
3.19d Willing to provide bone marrow and blood samples for planned research  
 
3.2 
Exclusion Criteria 
 
3.21  
MGUS or smoldering myeloma. 
 
3.22 
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: Patients with nonmelanoma skin cancer or carcinoma in situ of 
any type are not excluded if they have undergone complete resection.  
 
3.23 
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 women 
 
Nursing women  
 
Men or women of childbearing potential who are unwilling to employ adequate 
contraception 
 
3.24 
Other concurrent chemotherapy, or any ancillary therapy considered 
investigational.  NOTE: Bisphosphonates are considered to be supportive care 
rather than therapy, and are thus allowed while on protocol treatment. 
 
3.25 
Peripheral neuropathy ≥ Grade 2 on clinical examination or grade 1 with pain 
during the screening period. 
 
3.26 
Major surgery ≤14 days prior to registration. 
 
3.27 
Systemic treatment with strong CYP3A4 inducers (rifampin, rifapentine, 
rifabutin, carbamazepine, phenytoin, phenobarbital, St. John’s wort) ≤14 days 
prior to registration. 
 
3.28 
Evidence of current uncontrolled cardiovascular conditions, including 
hypertension, cardiac arrhythmias, congestive heart failure, unstable angina, or 
myocardial infarction ≤6 months.  Note: Prior to  entry, any ECG abnormality at 
screening must be documented by the investigator as not medically relevant. 
 
3.29a 
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 
 
3.29b Known human immunodeficiency virus (HIV) positive. 
 


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3.29c 
Known hepatitis B surface antigen-positive status, or known or suspected active 
hepatitis C infection. 
 
3.29d Any serious medical or psychiatric illness that could, in the investigator’s 
opinion, potentially interfere with the completion of treatment according to this 
protocol. 
 
3.29e 
Known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal 
antibodies or human proteins, or their excipients (refer to respective package 
inserts or Investigator's Brochure), or known sensitivity to mammalian-derived 
products. 
 
3.29f 
Known GI disease or GI procedure that could interfere with the oral absorption 
or tolerance of ixazomib, lenalidomide or dexamethasone including difficulty 
swallowing. 
 
3.29g Diarrhea > Grade 1, based on the NCI CTCAE grading, in the absence of 
antidiarrheals. 
 


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4.0 
Test Schedule  
4.1 
Schedule of assessments 
 
Days Prior to Registration 
Every 14 
days 
(cycles 1 - 
3)1 
Every cycle, 
Induction1,10,11  
Maintenance 
Phase: 
 
≤30 days 
≤14 days 
(every cycle)1, 10 
Complete medical history 
X 
 
 
 
 
Adverse Event monitoring 
 
X 
 
X 
X14 
Physical exam, weight and vital signs 
 
X 
 
X 
X14 
Height 
 
 
 
X 
 
 
 
Performance status (ECOG scale)  
 
X 
 
X 
X14 
CBC with diff. 
 
X 
X 
X 
X14 
Prothrombin time (PT) 
X 
 
 
 
 
Blood type and screen 
X 
 
 
 
 
Chemistry group to include sodium, 
potassium, glucose, alkaline phosphatase; 
Total and Direct bilirubin; SGOT (AST);ALT 
serum creatinine, calcium 
 
 
X 
 
X 
 
X 
 
X14 
 
sTSH, T3, T4 
X 
 
 
 
 
LDH, Beta2-microglobulin, C-reactive protein  
X 
 
 
 
 
Viral hepatitis panel including HBsAg, 
HB core antibody, and HB antibody  
X13 
 
 
X13 
X13 
Electrophoresis of serum and urine 
 
X 
 
X10 
X10,14 
Affected Immunoglobulin 
 
X 
 
X8 
X8,14 
Immunofixation serum and urine 
X 
 
 
X2 
X2,14 
Immunoglobulin free light chain 
 
X 
 
X5 
X5,14 
X-ray skeletal survey or WBLDCT 
X 
 
 
X4 
X 4 
Bone marrow aspirate and biopsy       
X 
 
 
X6 
X6 
Research bone marrow and blood sampleR,12 
X 
 
 
X6 
X 
Chest x-ray 
X 
 
 
 
 


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Version Date:  March 26, 2020 
 
Days Prior to Registration 
Every 14 
days 
(cycles 1 - 
3)1 
Every cycle, 
Induction1,10,11  
Maintenance 
Phase: 
 
≤30 days 
≤14 days 
(every cycle)1, 10 
Serum pregnancy test 
 
X3 
 
 
 
Patient Medication Diary (Appendix V)7. 
 
 
 
X 
X 
QOL questionnaire (Appendix VII) 
 
X 
 
X9 
X9 
1) All scheduled visits will have a window of ± 4 days unless otherwise stated 
2) Immunofixation (IF) needed only in the absence of M-spike to document CR or sCR. 
3) For women of childbearing potential only.  Must be done ≤7 days prior to registration. Pregnancy tests for females of childbearing potential.  
A female of childbearing potential (FCBP) is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; 
or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 
consecutive months). Pregnancy tests must occur within 10 – 14 days and again within 24 hours prior to prescribing lenalidomide for cycle 1.  
FCBP with regular or no menstruation must have a pregnancy test weekly for the first 4 weeks and then every 28 days while on therapy 
(including breaks in therapy); at discontinuation of lenalidomide and at Day 28 post the last dose of lenalidomide.  Females with irregular 
menstruation must have a pregnancy test weekly for the first 4 weeks and then every 14 days while on therapy (including breaks in therapy), at 
discontinuation of lenalidomide and at Day 14 and Day 28 post the last dose of lenalidomide (see Appendix VI: Risks of Fetal Exposure, 
Pregnancy Testing Guidelines and Acceptable Birth Control Methods) potential only. 
4) WBLDCT-whole body low dose CT, Every 12 cycles or if clinically indicated. 
5)    FLC is required only if used to assess disease response during active phase 
6)   At the end of 4 cycles, 12 cycles, after 12 and 24 cycles of maintenance (Cycles 24 and 36) and to document CR or disease progression.  
 
7)  The diary must begin the day the patient starts taking the medication and must be completed per protocol and returned to the treating 
institution. 
8)  Affected immunoglobulin refers to the baseline M-protein type, that is, IgG, IgA, IgD, or IgM.  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 (for e.g. IgA myeloma) 
9)  The QOL questionnaire will be filled out by the patient at baseline, every cycle for the first 4 cycles, and then every 3 cycles. 
10)  Urine Electrophoresis required only if used to assess disease response 
11)  Does not need to be repeated at Cycle 1 Day 1. Baseline values can be used for Cycle 1. 
12)  Not mandatory at baseline or disease progression 
13) Patients enrolled prior to amendment 9 and within the past 6 months, will be need to tested as soon as feasible.  Note:  HBV-DNA 
testing required for patients with serologic evidence of prior HBV infection every 12 weeks during treatment, at EOT, and 12 weeks 
after last dose of study treatment. 
14) As of amendment 12 Required evaluations can be done through local facility, phone contact, or by local lab as applicable if patient is unable 
to return to Mayo facility and is approved by study chair. 
R  Research funded (see Section 19.0).  Will be charged to study and not to patient’s account. 
 


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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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5.0 
Stratification Factors:  None 
6.0  
Registration Procedures 
6.1 
Registration 
 
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 3.19c and 14.0).  
 
6.3 
Verification 
 
Prior to accepting the registration, registration/randomization application will verify the 
following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information  
6.4 
IRB approval 
 
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 
 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. 


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When the study has been permanently closed to patient enrollment, submission of annual 
IRB approvals to the Registration Office is no longer necessary. 
 
6.5 
Treatment requirements 
As of amendment 12:  
Treatment on this protocol must commence under the supervision of a hematologist from 
the enrolling institution.  
 
6.6 
Treatment start 
 
Treatment cannot begin prior to registration and must begin ≤14 days after registration. 
 
6.7 
Pretreatment 
 
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines 
specified on the test schedule. 
 
6.8 
Baseline symptoms 
 
All required baseline symptoms (see Section 10.5) must be documented and graded. 
 
6.9a 
Study drug 
 
Study drug is available on site. 
 
6.9b 
Blood kits 
 
Blood kit is available on site for this patient. 
 
6.9c 
Patient questionnaire booklets  
 
Patient questionnaire booklet is available on site; copies are not acceptable for this 
submission. 
 
6.9d 
GCP 
The clinical trial will be conducted in compliance with regulations (21 CFR 312, 50, and 
56), guidelines for Good Clinical Practice (ICH Guidance E6), and in accordance with 
general ethical principles outlined in the Declaration of Helsinki; informed consent will 
be obtained from all participating patients; the protocol and any amendments will be 
subject to approval by the designated IRB prior to implementation, in accordance with 21 
CFR 56.103(a); and subject records will be stored in a secure location and subject 
confidentiality will be maintained. The investigator will be thoroughly familiar with the 
appropriate use of the study drug as described in the protocol and Investigator’s 
Brochure.  Essential clinical documents will be maintained to demonstrate the validity of 
the study and the integrity of the data collected.  Master files should be established at the 
beginning of the study, maintained for the duration of the study and retained according to 
the appropriate regulations.   
 
 
 


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7.0 
Protocol Treatment 
• 
Stem cell collection and transplant: Patients are allowed to collect stem cells at any time 
after completion of treatment on Cycle 4   if eligible for stem cell transplant. Details 
should be recorded on the Stem Cell Harvest form.  If patient goes to transplant, they will 
go directly to event monitoring per Section 4.2 and the transplant should be reported on 
the event monitoring and Transplant and Engraftment forms.  In the case that patients are 
unable to go to transplant due to other reasons, they can continue on study. In those cases, 
therapy may be interrupted for up to 4 weeks for the purpose of stem cell collection. Stem 
cells can be collected using standard institutional protocols. Any delay beyond 4 weeks 
should be discussed with the study PI prior to reinitiating protocol therapy. 
 
• 
Lack of Response:  Patients will go off treatment to event monitoring if an MR is not 
seen after 2 cycles and a PR is not seen after 4 cycles. Confirmation of MR or PR is not 
required. 
 
• 
Dose modifications for toxicity are outlined in Section 8.  
 
• 
An individual subject will be considered off-treatment following a 28-day safety follow-
up period after the last cycle of treatment. 
 
7.1 
Treatment Schedule  Arm A 
 
Table 7.1 
Induction phase (Cycles 1-12) 
Drug 
Route 
Dose 
Schedule 
Each cycle is 28 days 
Ixazomib 
Oral 
4 mg 
Days 1, 8 and 15 
Lenalidomide 
Oral 
25 mg (if CrCl >60 
ml/min) 
Days 1-21 
10 mg (if CrCl 30-60 
ml/min) 
Daratumumab 
IV 
16 mg/kg 
Cycles 1 and 2:   Days 1, 8, 15, 22 
Cycles 3, 4, 5, and 6:  Days 1, 15 
Cycles 7 and beyond:  Day 1 
 
Dexamethasone 
IV/ 
Oral* 
40 mg 
Days 1, 8, 15 and 22 
Arm A:  Cycles 1-12 
* On days when daratumumab is given, dexamethasone is given IV over 15 minutes within 1 
hour prior to daratumumab  
Maintenance Phase (Cycle 13 + up to 36 months from registration) 
Ixazomib 
Oral 
4 mg 
Days 1, 8 and 15 
Daratumumab 
IV 
16 mg/kg 
Day 1 
Cycle = 28 days 


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NOTE: Once the creatinine clearance is >60 mL/min during the course of the treatment, 
lenalidomide can be increased to 25 mg. 
Treatment Schedule  Arm B  
 
Table 7.1 
Induction phase (Cycles 1-12) 
Drug 
Route 
Dose 
Schedule 
Each cycle is 28 days 
Ixazomib 
Oral 
4 mg 
Days 1, 8 and 15 
Lenalidomide 
Oral 
25 mg (if CrCl >60 
ml/min) 
Days 1-21 
10 mg (if CrCl 30-60 
ml/min) 
Daratumumab 
IV 
16 mg/kg 
Cycles 1 and 2:   Days 1, 8, 15, 22 
Cycles 3, 4, 5, and 6:  Days 1, 15 
Cycles 7 and beyond:  Day 1 
Dexamethasone 
IV/ 
Oral* 
40 mg 
Days 1, 8, 15 and 22 
Arm B: Cycles 1-2    
* On days when daratumumab is given, Dexamethasone is given IV over 15 minutes within 1 
hour prior to daratumumab  
Maintenance Phase (Cycle 13 + up to 36 months from registration) 
Ixazomib 
Oral 
4 mg 
Days 1, 8 and 15 
Daratumumab 
IV 
16 mg/kg 
Day 1 
Cycle = 28 days 
 
 
NOTE: Once the creatinine clearance is >60 mL/min during the course of the treatment, 
lenalidomide can be increased to 25 mg. 
7.2 
Ixazomib  
• 
Patients should be instructed to swallow ixazomib capsules whole, with water, and 
not to break, chew, or open the capsules. Ixazomib should be taken on an empty 
stomach, at least 1 hour before or at least 2 hours after food. Each capsule should be 
swallowed separately with a sip of water. A total of approximately 8 ounces (240 
mL) of water should be taken with the capsules.  
• 
Missed doses can be taken as soon as the patient remembers if the next scheduled 
dose is 72 hours or more away. A double dose should not be taken to make up for a 
missed dose. If the patient vomits after taking a dose, the patient should not repeat the 
dose but should resume dosing at the time of the next scheduled dose 
• 
Procedures for ixazomib dose reductions and delays are summarized in Section 8.2, 
along with the criteria that must be met for retreatment with study drug. If a dose is 
missed due to toxicity, the dose will not be made up. 
• 
Oral ixazomib is supplied by Takeda Pharmaceuticals. See Section 15.1 for details on 
ixazomib description, formulation, storage, and accountability.  
 
 


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7.3 
Lenalidomide (Cycles 1-12 only) 
• 
Subjects will receive lenalidomide orally once daily on days 1-21 of the 28 day cycle. 
• 
Lenalidomide is taken with water on a full or empty stomach. Subjects should not 
crush or chew capsules. Missed doses will not be made up. 
• 
Procedures for dose reductions and delays are summarized in Section 8.3. 
• 
Lenalidomide is commercially obtained.  
7.4 
Daratumumab 
• 
Subjects will receive daratumumab intravenously weekly for 8 weeks, then every 
other week for 16 weeks and then every 4 weeks. 
• 
Each subject’s dose will be calculated based on the subject’s weight rounded to the 
nearest kilogram. There is no cap on the absolute dose allowed, as long as the dose 
does not exceed 16 mg/kg. If a subject’s weight changes by more than 10% from 
baseline, the dose of daratumumab will be re-calculated. 
• 
Vital signs should be monitored extensively on Cycle 1 Day 1 before, during, and 
after the first infusion of daratumumab. For all other infusions, vital signs should be 
measured immediately before the start of infusion and at the end of the infusion. 
• 
Missed doses will not be made up. Procedures for dose reductions and delays are 
summarized in Section 8.5. 
• 
There are no planned dose reductions. 
• 
Daratumumab is provided by Janssen. See Section 15.4 for details on daratumumab 
description, formulation, storage, and accountability. 
 
As of amendment 12: 
In the event patient is unable to come to the enrolling site for daratumumab infusion 
due to extenuating circumstances, commercial drug can be used for administration at 
a facility accessible to the patient. In that event, the treating investigator will work 
closely with the external provider to ensure safe and appropriate delivery of the 
planned dose. This instance will have to be reported to the IRB as a deviation. 
 
• 
Daratumumab administration: See table below for general infusion guidelines. If 
patients tolerate the first 3 infusions, consideration can be given for a 90 minute 
infusion as per institutional guidelines. Refer to section 9 for prophylaxis  and 
treatment  of infusion reactions 
 
 
Dilution  
volume (mL) 
Initial rate 
 (first hour) 
Rate 
increment 
Maximum 
rate 
First infusion 
1000 mL 
50 mL/hour 
 
50 mL/hour 
every hour 
200 mL/hour 
Second infusiona 
500 mL 
50 mL/hour 
 
50 mL/hour 
every hour 
200 mL/hour 
Subsequent 
infusionsb 
500 mL 
100 mL/hour 
 
50 mL/hour 
every hour 
200 mL/hour 
a Escalate only if there were no Grade 1 (mild) or greater infusion reactions during the 
first 3 hours of the first infusion. 
b Escalate only if there were no Grade 1 (mild) or greater infusion reactions during a final 
infusion rate of ≥100 mL/hr in the first two infusions. 


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7.5 
Dexamethasone (Cycles 1-12 for Arm A / Cycles 1 and 2 only for Arm B) 
• 
Dexamethasone may be self-administered by the subject on an outpatient basis. 
• 
Arm A: 
Dexamethasone may be permanently discontinued after 12 cycles at the treating 
physician’s discretion or sooner if needed to manage toxicity related to 
dexamethasone. 
 
Arm B: 
Dexamethasone will be discontinued after 2 cycles or sooner if needed to manage 
toxicity related to dexamethasone. Dexamethasone as part of infusion reaction 
prophylaxis may continue. 
• 
Missed doses of dexamethasone will not be made up. Procedures for dose reductions 
and delays are summarized in Section 8.2. 
• 
Dexamethasone is commercially available. Accurate records will be kept in the 
source documents of all drug administration (including dispensing and dosing).  
7.6 
Treatment at enrolling institution:  
For this protocol, the patient must return to the consenting institution for daratumumab 
infusions as per treatment schedule and for evaluation prior to each cycle. Treatment by a 
local medical doctor (LMD) is not allowed As of amendment 12: Exception noted 
above in 7.4. 
 
As of amendment 12:  
The patient must return to the consenting institution for ixazomib evaluation at least 
every third cycle, provided the drug can be sent to the patient and necessary interval 
evaluations as required by the protocol can be completed remotely or through local 
healthcare facilities.  
 
8.0 
Dosage Modification Based on Adverse Events   
Strictly follow the modifications in this table for the first two cycles, until individual treatment 
tolerance can be ascertained. Individual drugs can be dose reduced as per the table below 
depending on the adverse event attribution. If the toxicity is attributable to one drug, only that 
needs to be dose reduced. If overlapping toxicities are observed, the dose reductions can be 
alternated between the suspected drugs, starting with the drug most likely related to the adverse 
event. Thereafter, these modifications should be regarded as guidelines to limit to 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 ixazomib, lenalidomide or daratumumab is discontinued, the patient can continue 
on the other drugs, unless specified otherwise in the dose modification tables. If all 
three are discontinued, the patient will go to event monitoring (Section 4.2). 
 
 


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ALERT: 
ADR reporting may be required for some adverse events (See Section 10) 
8.1 
Dose Levels for each drug in the combination 
(Based on Adverse Events in Tables 8.2-5) 
 
NOTE: Toxicities attributable to dexamethasone should lead to dose reduction only for 
dexamethasone. 
 
 
Table 8.1 Dose reduction steps 
Step  
Ixazomib 
Lenalidomide Daratumumab 
Dexamethasone 
0 
 
4 mg 
25 mg 
NA 
40 mg 
-1 
 
3 mg 
15 mg 
 
24 mg 
-2 
 
2.3 mg 
10 mg 
 
12 mg 
-3 
 Discontinue 
5 mg 
 
4 mg 
-4 
 Discontinue 
Discontinue 
 
Discontinue 
 
 
 
8.11  
Instruction for initiation of a new cycle of therapy or restarting therapy after 
interruption during a cycle for toxicities 
 
 
 
 
 
 
 
A new cycle of treatment may begin on the scheduled Day 1 of a new cycle if: 
• 
The ANC is ≥1000/μL 
• 
The platelet count is ≥75,000/μL  
• 
Any other non-hematologic treatment -related adverse event that may have 
occurred has resolved to ≤Grade 1 or baseline severity. 
 
 
 
 
If these conditions are not met on Day 1 of a new cycle, the subject will be evaluated 
weekly and a new cycle of therapy will be held until the toxicity has resolved as 
described above. 
 
 
 
 
 
 
 
If any drug dosing was halted during the previous cycle and was restarted with a one-
level dose reduction without requiring an interruption for the remainder of the cycle, 
then that reduced dose level will be initiated on Day 1 of the new cycle. 
 
 
 
 
 
 
 
If any drug dosing was omitted for the remainder of the previous cycle or if the new 
cycle is held due to known hematologic toxicity newly encountered on the scheduled 
Day 1, then the new cycle will be started with a one-level dose reduction. If a new 
cycle of therapy cannot be restarted within 4 weeks of the scheduled Day 1 due to 
non-resolution of drug related toxicities, the patient will be removed from protocol 
therapy and will go to event monitoring. 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
 
 
 
 
 


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8.2 
Dose modifications for ixazomib based on adverse events during a cycle 
CTCAE 
System/Organ/
Class (SOC)* 
ADVERSE EVENT 
ACTION** 
Investigations 
If platelet count ˂30 × 109/L  
or ANC ˂1.0 × 109/L  
or ANC >1.0 × 109/L (up to LLN) 
with fever (temperature >38.5°C) 
 
Days 2-15: Ixazomib dose should be omitted on 
Day 8 and/or 15 as applicable 
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. The subsequent cycle will use the 
reduced dose.  
Skin and 
subcutaneous 
tissue disorders 
Rash, Any skin,  
≥Grade 2 
 
Omit ixazomib till rash resolves to ≤Grade 1 (See 
Section 9.9a). Restart at same dose. If the rash 
recurs, reduce dose by one dose level. 
Any skin, Grade 4 
Discontinue ixazomib and remove patient from all 
study treatment 
Nervous 
System 
Disorders 
Newly developed Grade 1 
peripheral neuropathy with pain, 
≥Grade 2 peripheral neuropathy 
Reduce dose of ixazomib to the next lower dose 
level 
Nervous 
System 
Disorders 
Grade 2 neuropathy with pain or 
Grade 3 peripheral neuropathy 
Omit ixazomib until toxicity resolves or returns to 
baseline. When toxicity resolves, re-initiate 
ixazomib at the next lower dose level. 
 
Grade 4 peripheral neuropathy 
 Permanently discontinue ixazomib. 
Other 
Any other non-hematological 
Grade 3 attributable toxicity 
except: 
Omit ixazomib depending on the attribution, 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 
Grade 3 nausea and/or emesis in 
the absence of optimal anti-emetic 
prophylaxis  
Grade 3 diarrhea that occurs in the 
absence of optimal supportive 
therapy  
Grade 3 fatigue 
 
Grade 4 Nonhematologic 
Toxicities 
Consider permanently discontinuing ixazomib – 
Exception  
if the investigator determines the patient is 
obtaining a clinical benefit 
 
* 
Located at
 
**  
Use the following to describe actions in the Action column: 
 
Omit = The current dose(s) for the specified drug(s) during a cycle is skipped. The patient does 
not make up the omitted dose(s) at a later time 


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 
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. 
8.3 
Dose modifications for lenalidomide based on adverse events during a cycle 
CTCAE 
System/Organ/Clas
s (SOC) 
ADVERSE EVENT 
ACTION 
Blood and lymphatic 
system disorders 
febrile neutropenia 
associated with fever 
(temperature ≥ 38.5º C) 
 
• 
Omit lenalidomide dose. 
• 
Follow CBC weekly. 
• 
If neutropenia has resolved to ≤ grade 2 prior 
to Day 21 and fever has resolved, restart 
lenalidomide at next lower dose level and 
continue the cycle through Day 21.  If febrile 
neutropenia is the only toxicity for which a 
dose reduction is required. G-CSF may be 
used and the lenalidomide dose maintained. 
Investigations 
If platelet count ˂30 × 
109/L  
or ANC ˂1.0 × 109/L  
or ANC >1.0 × 109/L 
(up to LLN) with fever 
(temperature >38.5°C) 
• 
Omit lenalidomide dose. 
• 
Follow CBC weekly. 
• 
Hold anticoagulation until platelets > 50,000 
• 
If platelet count resolves to ≤ grade 2 prior to 
Day 21, restart lenalidomide at next lower 
dose level and continue the cycle through 
Day 21. 
• 
If neutropenia has resolved to ≤ grade 2 prior 
to Day 21, restart lenalidomide at next lower 
dose level and continue the cycle through 
Day 21.  If neutropenia is the only toxicity 
for which a dose reduction is required. G-
CSF may be used and the lenalidomide dose 
maintained. 
Skin and 
subcutaneous tissue 
disorders 
Rash maculo papular  
Grade 2 or 3. 
 
• 
Omit lenalidomide dose.  Follow weekly. 
• 
If the toxicity resolves to ≤ grade 1 prior to 
Day 21, restart lenalidomide at next lower 
dose level and continue the cycle through 
Day 21. 
Any rash  
Grade 4 
• 
Discontinue lenalidomide.  Remove patient 
from all study treatment.  
• 
Go to event monitoring. 
 
 
Nervous system 
disorders 
Peripheral sensory 
Neuropathy 
 
Grade 3 
 
 
 
• 
Omit lenalidomide dose.  Follow at least 
weekly. 
• 
If the toxicity resolves to ≤ grade 1 prior to 
Day 21, restart lenalidomide at next lower 
dose level and continue the cycle through 
Day 21. 


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CTCAE 
System/Organ/Clas
s (SOC) 
ADVERSE EVENT 
ACTION 
Grade 4 
• 
Discontinue lenalidomide. Remove patient 
from all study treatment. 
• 
Go to event monitoring. 
Immune system 
disorders 
Allergic reaction  
Grade 2-3 
 
 
• 
Omit dose. Follow at least weekly. 
• 
If the toxicity resolves to ≤ grade 1 prior to 
Day 15 restart at next lower dose level and 
continue the cycle until Day 21. 
Grade 4 
• 
Discontinue lenalidomide.  Remove patient 
from all study treatment.   
• 
Go to event monitoring. 
Vascular disorders 
Thromboembolic event 
≥ Grade 3 
• 
Omit dose and start anticoagulation; restart at 
investigator’s discretion (maintain dose 
level). 
Hyperthyroidism or 
Hypothyroidism ≥ grade 
2 
• 
Omit lenalidomide for remainder of cycle, 
evaluate etiology, and initiate appropriate 
therapy.  
• 
See Instructions for Initiation of a New Cycle 
and reduce the dose of lenalidomide by 1 
dose level. 
Other non-
hematologic adverse 
event 
Other non-hematologic 
toxicity ≥ Grade 3 
• 
Omit lenalidomide dose.  Follow at least 
weekly.  
• 
If the toxicity resolves to ≤ grade 2 prior to 
Day 21, restart lenalidomide at next lower 
dose level and continue the cycle through 
Day 21. 
 
Lenalidomide dose modifications for renal impairment developing during treatment, considered not 
related to lenalidomide 
Renal Function 
Dose 
CrCl 30-60 ml/min 
10 mg daily 
CrCl < 30 mL/min (not requiring dialysis)  
 
15 mg every 48 hours 
CrCl < 30 mL/min (requiring dialysis)  
 
5 mg once daily. On dialysis days, administer 
the dose after dialysis  
 
 
* 
Located at
 
**  
Use the following to describe actions in the Action column: 
 
Omit = The current dose(s) for the specified drug(s) during a cycle is skipped. The patient does 
not make up the omitted dose(s) at a later time 
 
Hold/Delay = The current dose(s) of all drugs during a cycle is delayed. The patient does make 
up the delayed dose(s) when the patient meets the protocol criteria to restart drugs. 
 
Discontinue = The specified drug(s) are totally stopped. 
 


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8.4 
Dose modifications for dexamethasone (Dex) based on adverse events during a cycle 
CTCAE 
System/Organ/Cla
ss (SOC)* 
ADVERSE EVENT 
ACTION** 
Gastrointestinal 
disorders 
Dyspepsia, gastric or duodenal 
ulcer, gastritis Grade 1-2 
(Symptomatic; altered GI 
function; medical intervention 
indicated; limiting instrumental 
ADL) 
Treat with H2 blockers, sucralfate, or 
omeprazole 
If symptoms persist despite above measures, 
decrease dexamethasone dose by 1 dose level 
 
Dyspepsia, gastric or duodenal 
ulcer, gastritis ≥Grade 3  
(Severely altered GI function; 
TPN indicated; elective operative 
or endoscopic intervention 
indicated; limiting self-care ADL; 
disabling) 
Omit dexamethasone until symptoms 
adequately controlled 
Restart one dose level below along with 
concurrent therapy with H2 blockers, 
sucralfate, or omeprazole 
If symptoms persist despite above measures, 
discontinue dexamethasone and do not 
resume.  
Gastrointestinal 
disorders 
Pancreatitis 
≥Grade 3 (Severe pain; vomiting; 
medical intervention indicated 
(e.g., analgesia, nutritional 
support)) 
Discontinue dexamethasone and do not 
resume 
 
General disorders 
and administration 
site conditions 
Edema 
≥Grade 3 (limiting function and 
unresponsive to therapy or 
anasarca) 
Diuretics as needed, and decrease 
dexamethasone dose by 1 dose level 
If edema persists despite above measures, 
decrease dose another dose level 
Discontinue dexamethasone and do not 
resume if symptoms persist despite second 
reduction 
Psychiatric 
disorders 
Confusion or Mood alteration 
≥Grade 2 (Severe disorientation; 
limiting self-care ADL) 
Omit dexamethasone until symptoms resolve 
Restart with one dose level reduction 
If symptoms persist despite above measures, 
discontinue dexamethasone and do not resume 
Musculoskeletal 
and connective 
tissue disorders 
Muscle weakness 
≥ Grade 2  
Weakness limiting self-care ADL; 
disabling 
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 
Metabolism and 
nutrition disorders 
Hyperglycemia  
Grade 3 or higher  
(>250 - 500 mg/dL; >13.9 - 27.8 
mmol/L); hospitalization indicated 
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
 


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**  
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. 
 
8.5  
Daratumumab Dose Modification 
Dose modification of daratumumab is not permitted, but dose delay is the primary 
method for managing daratumumab-related toxicities. The attribution of the toxicity to 
individual drug (s) will be performed by the treating physician. 
 
8.51 
Daratumumab-Related Toxicity Management 
Refer to Section 9.9i for details on management of infusion-related reactions. 
ONLY if any of the following criteria are met and the event cannot be ascribed to 
the other drugs, the daratumumab infusion must be omitted to allow for recovery 
from toxicity. The criteria for a dose omit are: 
• 
Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding 
• 
Grade 4 neutropenia, if this is the second occurrence despite growth factor 
support 
• 
Febrile neutropenia of any grade 
• 
Neutropenia with infection, of any grade 
• 
Grade 3 or higher nonhematologic toxicities with the following exceptions: 
o Grade 3 nausea that responds to antiemetic treatment within 7 days 
o Grade 3 vomiting that responds to antiemetic treatment within 7 days 
o Grade 3 diarrhea that responds to antidiarrheal treatment within 7 days 
o Grade 3 fatigue that was present at baseline or that lasts for <7 days after 
the last administration of daratumumab 
o Grade 3 asthenia that was present at baseline or that lasts for <7 days 
after the last administration of daratumumab 
If a daratumumab administration does not commence within the prespecified 
window (Table) of the scheduled administration date, then the dose will be 
considered a missed dose. Administration may resume at the next planned dosing 
date. 
 
Table 8.6 
Daratumumab-Related Toxicity Management 
Cycles  
Frequency  
Dose Held  
Dosing Re-start  
1 and 2  
Weekly (q1wk)  
>3 days  
next planned weekly 
dosing date  
3 to 6  
Biweekly (q2wks)`  
>1 week  
next planned biweekly 
dosing date  
7+  
Every 4 weeks (Q4W)  
>2 weeks  
next planned every 4 
weeks dosing date  
 


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A missed dose will not be made up. Doses of daratumumab may be delayed up to 4 weeks. If a dose is 
delayed, then the dates of the subsequent doses must be adjusted. Any adverse event deemed to be related 
to daratumumab and unrelated to lenalidomide, ixazomib or dexamethasone that requires a dose hold of 
more than 4 weeks will result in permanent discontinuation of daratumumab.  
9.0 
Ancillary Treatment/Supportive Care 
9.1 
Oral hydration 
 
 
Patients are encouraged to drink at least 6 to 8 cups of liquid per day. 
 
9.2 
Disallowed concurrent treatment 
 
 
The following treatments are not permitted during the trial: 
 
 
• 
Any other investigational treatment  
 
 
• 
Any other systemic anti-neoplastic therapy including, but not limited to, 
immunotherapy, hormonal therapy or monoclonal antibody therapy. 
 
 
• 
Any external beam radiotherapy 
Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days  
prior to study drug dosing for any dosing day 
 
9.3 
Nausea and/or vomiting 
 
 
Standard anti-emetics including 5-hydroxytryptamine 3 serotonin receptor antagonists are 
recommended for emesis if it occurs once treatment is initiated; prophylactic anti-emetics 
may also be considered at the physician’s discretion. Dexamethasone should not be 
administered as an anti-emetic. Fluid deficit should be corrected before initiation of study 
drug and during treatment. 
 
9.4 
Blood products and growth factors 
 
 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations. The use of growth factors should 
follow published guidelines of the Journal of Clinical Oncology, Vol 24, No 18 (June 
20), 2006: pp. 2932-2947. 
 
 
 
 
 
Interference with Serological Testing:  Daratumumab binds to CD38 on red blood cells 
(RBCs) and results in a positive Indirect Antiglobulin Test (Coombs test). Daratumumab-
mediated positive indirect antiglobulin test may persist for up to 6 months after the last 
daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to 
minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh 
blood type are not impacted. Notify blood transfusion centers of this interference with 
serological testing and inform blood banks that a patient has received Daratumumab. 
Type and screen patients prior to starting Daratumumab. 
 
 
9.5 
Diarrhea 
 
 
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 


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initiation of treatment and during treatment. Additional doses of loperamide at 2 mg 
every 2-4 hours until diarrhea free (maximum 16 mg/day). 
 
 
In the event of Grade 3 or 4 diarrhea, the following supportive measures are allowed: 
hydration, octreotide, and antidiarrheals. 
 
 
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or 
severe neutropenia (Grade 3 or 4), broad-spectrum antibiotics must be prescribed. 
Patients with severe diarrhea or any diarrhea associated with severe nausea or vomiting 
should be hospitalized for intravenous hydration and correction of electrolyte 
imbalances. 
 
 
Please monitor patients carefully for development of ileus. 
 
 
9.6  
Renal failure and Ixazomib 
 
 
Two cases of acute renal failure have been reported in patients treated at or above the 
MTD for intravenous ixazomib (see Section 1.4.3). Volume depletion should be corrected 
before initiation of study drug. Until further information is available, intake of 
nonsteroidal anti-inflammatory drugs immediately prior to the administration of ixazomib 
should be discouraged and requires consultation with the principal investigator. All 
necessary supportive care consistent with optimal patient care shall be available to 
patients as necessary. 
 
9.7 
Herpes Zoster prophylaxis 
 
 
Patients may be at an increased risk of infection including reactivation of herpes zoster 
and herpes simplex viruses. Prophylaxis with acyclovir 400 mg PO BID is should be used 
while on study therapy and for 3 months beyond the end of therapy. 
 
9.8 
Prohibited medications 
9.81 
Prohibited enzyme inducers 
Systemic treatment with any of the following metabolizing enzyme inducers 
should be avoided, unless there is no appropriate alternative medication for the 
patient’s use. (Rationale: If there were to be a drug-drug interaction with an 
inducer, ixazomib exposure would be decreased)  
Strong CYP3A inducers: rifampin, rifapentine, rifabutin, carbamazepine, 
phenytoin, and phenobarbital.  
9.82 
Excluded foods and dietary supplements include St. John’s wort.  
9.9a 
Erythematous Rash with or without Pruritus 
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-


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limiting, and is typically Grade 1 to 2 in severity. Rash can also be seen with 
lenalidomide, and usually responds to dose interruption and dose decrease.  
 
 
 
 
 
Symptomatic measures such as antihistamines or corticosteroids (oral or topical) have 
been successfully used to manage rash and have been used prophylactically in subsequent 
cycles. The use of a topical, IV, or oral steroid (e.g., prednisone ≤10 mg per day or 
equivalent) is permitted. Management of a Grade 3 rash may require intravenous 
antihistamines or corticosteroids. Administration of ixazomib (and/or other causative 
agent if given in combination) should be modified per protocol and re-initiated at a 
reduced level from where rash was noted (also, per protocol). 
 
 
 
In line with clinical practice, dermatology consult and biopsy of Grade 3 or higher rash or 
any SAE involving rash is recommended. Prophylactic measures should also be 
considered if a patient has previously developed a rash (e.g., using a thick, alcohol-free 
emollient cream on dry areas of the body or oral or topical antihistamines). A rare risk is 
Stevens-Johnson Syndrome, a severe and potentially life-threatening rash with skin 
peeling and mouth sores, which should be managed symptomatically according to 
standard medical practice. Punch biopsies for histopathological analysis are encouraged 
at the discretion of the investigator. 
 
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 and lenalidomide administration should be modified as noted as per 
dose modification recommendations in the protocol when thrombocytopenia occurs (see 
Section 8). 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 Section 8). Therapy can be reinitiated at a reduced level upon recovery of ANCs. 
 
9.9d 
Fluid Deficit 
 
 
Vitals should be assessed prior to start of each cycle as per Table 4.1. Dehydration should 
be avoided since ixazomib may cause vomiting, diarrhea, and dehydration. Patients 
should be encouraged to maintain adequate fluid intake. Acute renal failure has been 
reported in patients treated with ixazomib, commonly in the setting of the previously 


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noted gastrointestinal toxicities and dehydration. Fluid deficit should be corrected before 
initiation of study drug and as needed during treatment to avoid dehydration. 
 
9.9e 
Hypotension 
 
 
Symptomatic hypotension and orthostatic hypotension with or without syncope have been 
reported with ixazomib. Blood pressure should be closely monitored while the patient is 
on study treatment and fluid deficit should be corrected as needed, especially in the 
setting of concomitant symptoms such as nausea, vomiting, diarrhea, or anorexia. 
Patients taking medications and/or diuretics to manage their blood pressure (for either 
hypo- or hypertension) should be managed according to standard clinical practice, 
including considerations for dose adjustments of their concomitant medications during 
the course of the trial. Fluid deficit should be corrected before initiation of study drug and 
as needed during treatment to avoid dehydration. 
 
9.9f 
Posterior Reversible Encephalopathy Syndrome 
 
 
One case of posterior reversible encephalopathy syndrome, which ultimately resolved, 
has been reported with ixazomib. This condition is characterized by headache, seizures 
and visual loss, as well as abrupt increase in blood pressure. Diagnosis may be confirmed 
by magnetic resonance imaging (MRI). If the syndrome is diagnosed or suspected, 
symptom-directed treatment should be maintained until the condition is reversed by 
control of hypertension or other instigating factors. 
 
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 
Guidelines for Prevention of Infusion Reactions 
Pre-infusion Medication: On daratumumab infusion days, subjects will receive the 
following medications prior to infusion: 
• 
Acetaminophen (paracetamol) 650-1000 mg IV or orally (PO) approximately 1 
hour or less prior to daratumumab infusion 
• 
An antihistamine (diphenhydramine 25-50 mg IV or PO, or equivalent) 
approximately 1 hour (or less) prior to infusion 
• 
Dexamethasone 40 mg IV or PO (only if IV is not available), approximately 1 
hour or less prior to daratumumab infusion. On days when subjects receive this 
dose of dexamethasone in the clinic, dexamethasone will not be self-administered 
at home. 
 
Post-infusion Medication: For subjects with higher risk of respiratory complications (ie, 
subjects who have a FEV1 <80%), the following postinfusion medications should be 
considered: 
• 
Antihistamine (diphenhydramine or equivalent) 


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• 
Dexamethasone 4 mg day after infusion 
• 
Short-acting β2 adrenergic receptor agonist such as salbutamol aerosol 
• 
Control medications for lung disease (eg, inhaled corticosteroids ± long-acting β2 
adrenergic receptor agonists for subjects with asthma; long-acting 
bronchodilators such as tiotropium or salbumatol ± inhaled corticosteroids for 
subjects with COPD) 
 
 
 
In addition, these at-risk subjects may be hospitalized for monitoring for up to 2 nights 
after an infusion. If subjects are hospitalized, then their FEV1 should be measured before 
discharge. If these subjects are not hospitalized, then a follow up telephone call should be 
made to monitor their condition within 48 hours after all infusions. If the subject has not 
experienced a significant medical event but is hospitalized overnight only for 
observation, then the hospitalization should not be reported as a serious adverse event. 
Investigators may prescribe bronchodilators, antihistamines, and corticosteroids that are 
deemed necessary to provide adequate supportive care in the event a bronchospasm 
occurs after subjects are released from the hospital/clinic.  
 
9.9i 
 Management of Infusion-related Reactions 
Subjects should be carefully observed during daratumumab infusions. Trained study staff 
at the clinic should be prepared to intervene in case of any infusion reactions occurring, 
and resources necessary for resuscitation must be available at the bedside. 
 
If an infusion-related reaction develops, then the infusion should be temporarily 
interrupted or slowed down. Subjects who experience adverse events during the infusion 
must be treated according to the investigator’s judgment and best clinical practice. The 
following guidelines may apply: 
• 
Subjects should be treated with acetaminophen, antihistamine, or corticosteroids. 
Intravenous saline may be indicated. For bronchospasm, urticaria, or dyspnea, 
subjects may require antihistamines, oxygen, corticosteroids, or bronchodilators. 
For hypotension, subjects may require vasopressors. 
• 
In the event of a life-threatening infusion-related reaction (which may include 
pulmonary or cardiac events), or anaphylactic reaction, daratumumab should be 
discontinued and no additional daratumumab should be administered to the 
subject. Aggressive symptomatic treatment should be applied. 
• 
If an infusion is paused or the infusion rate is decreased, then a longer-than-
anticipated infusion time may occur. Overnight stays at the hospital because of 
slow infusion times should not be reported as a serious adverse event. However, 
if the underlying cause of the delayed infusion time is an adverse event or serious 
adverse event, then that should be reported as such. 
  
Infusion-Related Events of Grade 1 or Grade 2: If the investigator assesses an 
adverse event to be related to the daratumumab infusion, then the infusion should be 
paused. When the subject’s condition is stable, the infusion may be restarted at the 
investigator’s discretion. Upon restart, the infusion rate should be half of that used 
before the interruption. Subsequently, the infusion rate may be increased at the 
investigator’s discretion. 
 


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If the subject experiences a Grade 2 or higher event of laryngeal edema or a Grade 2 
or higher event of bronchospasm that does not respond to systemic therapy and does 
not resolve within 6 hours from the onset, then the subject must be withdrawn from 
treatment. 
 
Infusion-Related Reactions of Grade 3 or Higher: For infusion-related adverse events 
that are Grade 4, the infusion should be stopped and treatment with daratumumab 
will be discontinued for that subject. 
For infusion-related adverse events that are Grade 3, the daratumumab infusion must 
be stopped, and the subject must be observed carefully until the resolution of the 
adverse event or until the intensity of the event decreases to Grade 1, at which point 
the infusion may be restarted at the investigator’s discretion. Upon restart, the 
infusion rate should be half of that used before the interruption. Subsequently, the 
infusion rate may be increased at the investigator’s discretion. 
 
If the intensity of the adverse event returns to Grade 3 after restart of the infusion, 
then the procedure described in this section may be repeated at the investigator’s 
discretion. Should the intensity of the adverse event increase to Grade 3 for a third 
time, then treatment with daratumumab will be discontinued for that subject.  
9.9j 
Thromboprophyaxis:  
All patients should be on 325 mg ASA daily while receiving lenalidomide. If they are 
unable to take ASA or are at high risk of VTE per investigator assessment, full dose 
anticoagulation is recommended.  
10.0 
Adverse Event (AE) Reporting and Monitoring 
10.1 
Adverse Event Characteristics 
CTCAE term (AE description) and grade: The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 
will be utilized for AE reporting. All appropriate treatment areas should have access to a 
copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded 
from the CTEP web site: 
 
10.11 Adverse event monitoring and reporting is a routine part of every clinical trial. 
First, identify and grade the severity of the event using the CTCAE version 4.0. 
Next, determine whether the event is expected or unexpected (see Section 10.2) 
and if the adverse event is related to the medical treatment or procedure (see 
Section 10.3). With this information, determine whether the event must be 
reported as an expedited report (see Section 10.4). Expedited reports are to be 
completed within the timeframes and via the mechanisms specified in Sections 
10.4. All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.2 and 
18.0). 
10.12 Each CTCAE term in the current version is a unique representation of a specific 
event used for medical documentation and scientific analysis and is a single 
MedDRA Lowest Level Term (LLT).  


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NOTE: A severe AE, as defined by the above grading scale, is NOT the same as 
serious AE, which is defined in the table in Section 10.4. 
 
10.2  
Expected vs. Unexpected Events  
• 
The determination of whether an AE is expected is based on agent-specific 
information provided in Section 15 of the protocol. 
• 
Unexpected AEs are those not listed in the agent-specific information provided in 
Section 15 of the protocol. 
 
NOTE: “Unexpected adverse experiences” means any adverse experience that is neither 
identified in nature, severity, or frequency of risk in the information provided for IRB 
review nor mentioned in the consent form.  
 
10.3 
Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or procedure, 
the following attribution categories are utilized: 
 
 
Definite - The adverse event is clearly related to the agent(s). 
 
 
Probable - The adverse event is likely related to the agent(s). 
 
 
Possible - The adverse event may be related to the agent(s). 
 
 
Unlikely - The adverse event is doubtfully related to the agent(s). 
 
 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
 
10.4 
Required Reporting 
 
AEs Experienced Utilizing Investigational Agents and Commercial Agent(s) on the 
SAME Arm 
 
NOTE: The combination of an investigational agent with a commercial agent is 
considered investigational. 
 
 
Routine Reporting 
 
Routine AE reporting for Phase 1 and Phase 2 clinical studies using an investigational 
agent /intervention in combination with a commercial agent is stated in the protocol. See 
Section 10.6. 
 
 NOTE: When a commercial agent(s) is (are) used on the same treatment arm as the 
investigational agent/intervention (also, investigational drug, biologic, cellular product, or 
other investigational therapy under an IND), the entire combination (arm) is then 
considered an investigational intervention for reporting. 
 
 
 
Expedited Reporting 
 
An AE that occurs on a combination study must be assessed in accordance with the 
guidelines for CTEP investigational agents/interventions in Section 10.4, and where 
indicated, an expedited report must be submitted. 
An AE that occurs prior to administration of the investigational agent/ intervention must 
be assessed as specified in the protocol. In general, only Grade 4 and 5 AEs that are 
unexpected with at least possible attribution to the commercial agent require an expedited 
report. Refer to Section 10.4 for specific AE reporting requirements or exceptions. 


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An investigational agent/intervention might exacerbate the expected AEs associated with 
a commercial agent. Therefore2, if an expected AE (for the commercial agent) occurs 
with a higher degree of severity, expedited reporting is required. The clinical investigator 
must determine severity. 
 
10.41 Special Situations for Expedited Reporting  
Exceptions to Expedited Reporting: EXPECTED Serious Adverse Events1 
An expedited report may not be required for specific Grade 1, 2, 3 and 4 Serious 
Adverse Events where the AE is listed in Section 15.0 of the protocol or the 
consent form* as EXPECTED. Any protocol specific reporting procedures 
MUST BE SPECIFIED BELOW and will supersede the standard Expedited 
Adverse Event Reporting Requirements  
(Note: These adverse events must still be reported through the routine reporting 
mechanism [i.e. Nadir/adverse events form]; see Footnote 1):  
 
System Organ Class (SOC) 
Adverse event/ 
Symptoms* 
CTCAE Grade at which 
the event will not be 
expeditedly reported1 
General disorders and  
administrations site conditions 
Fatigue  
≤Grade 3 
 
 
Gastrointestinal 
Vomiting 
≤Grade 3 
Nausea 
≤Grade 3 
Diarrhea 
≤Grade 3 
Investigations 
Neutrophil count  
decreased 
≤Grade 4 
Platelet count  
decreased 
≤Grade 4 
Lymphocyte count  
decreased 
≤Grade 4 
 
White blood cell count 
≤Grade 4 
Blood and lymphatic system 
disorders 
Anemia 
≤Grade 4 
Metabolism and Nutrition 
Disorders 
Hyperglycemia 
≤Grade 3 
 
 
1 These exceptions only apply if the adverse event does not result in hospitalization or 
any other serious criteria outlined in Section 10.42. If the adverse event results in 
hospitalization, then the standard expedited adverse events reporting requirements must 
be followed.  
Specific protocol exceptions to expedited reporting should be reported expeditiously by 
investigators ONLY if they exceed the expected grade of the event. 
 
 
*The consent form may contain study specific information at the discretion of the 
Principal Investigator; it is possible that this information may NOT be included in the 
protocol or the investigator brochure. 
 
 
10.411 Persistent or Significant Disabilities/Incapacities 
 
Any AE that results in persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions (formerly referred to as 


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disabilities), congenital abnormalities or birth defects, must be reported 
immediately if they occur at any time following treatment with an agent under an 
IND/IDE since they are considered to be a serious AE and must be reported to 
the sponsor as specified in 21 CFR 312.64(b). 
 
 
 
 
10.412 Death 
• 
Any death occurring within 30 days of the last dose, regardless of attribution 
to an agent/intervention under an IND/IDE requires expedited reporting 
within 24-hours. 
• 
Any death occurring greater than 30 days with an attribution of possible, 
probable, or definite to an agent/intervention under an IND/IDE requires 
expedited reporting within 24-hours. 
 
 
  
 
 
 Reportable categories of Death  
 
• 
Death attributable to a CTCAE term. 
• 
Death Neonatal: A disorder characterized by cessation of life during the first 
28 days of life. 
• 
Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5. 
• 
Sudden death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
• 
Death due to progressive disease should be reported as Grade 5 “Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) – Other 
(Progressive Disease)” under the system organ class (SOC) of the same 
name. Evidence that the death was a manifestation of underlying disease 
(e.g., radiological changes suggesting tumor growth or progression: clinical 
deterioration associated with a disease process) should be submitted. 
• 
Any death occurring within 30 days of the last dose, regardless of attribution 
to the investigational agent/intervention requires expedited reporting within 
24 hours. 
• 
Any death occurring greater than 30 days after the last does of the 
investigational agent/intervention requires expedited reporting within 24 
hours only if it is possibly, probably, or definitely related to the 
investigational agent/intervention. 
 
 
  
 
 
10.413 Secondary Malignancy 
• 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation 
or chemotherapy). A secondary malignancy is not considered a metastasis of 
the initial neoplasm. 
• 
All secondary malignancies that occur following treatment with an agent 
under an IND/IDE must be reported. Three options are available to describe 
the event: 
o Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myelocytic Leukemia [AML]) 
o Myelodysplastic syndrome (MDS) 


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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. 
 
 
  
 
 
10.414 Second Malignancy 
 
  
A second malignancy is one unrelated to the treatment of a prior malignancy (and 
is NOT a metastasis from the initial malignancy). Second malignancies require 
ONLY routine reporting. 
 
10.42 Expedited Reporting Requirements for IND/IDE Agents 
Expedited Reporting Requirements for Adverse Events that Occur on Studies 
under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention1 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:  
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported within the 
timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
timeframes 
Resulting in hospitalization 
≥24 hrs 
7 Calendar Days 
24-Hour/ 
3 Calendar 
Days 
Not resulting in hospitalization 
≥24 hrs 
Not required 
7 Calendar Days 
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in 
section 10.41 of the protocol. 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported within 24 hours of 
learning of the AE, followed by a complete expedited report within 3 calendar days of the 
initial 24-hour report. 


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o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require 
reporting as follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
 
10.43 Additional instructions: 
Mayo Clinic Cancer Center (MCCC) Institutions: Provide copies of 
MedWatch 3500A, along with the UPIRTSO cover sheet, by email to the MCCC 
Regulatory Affairs Unit (RAU) Risk Information Specialist at 
who will determine and complete IRB reporting. 
The RAU will submit to the MCCC SAE Coordinator and the MCCC IND 
Coordinator. 
 
10.5 
Required routine reporting 
10.51 Adverse events to be graded at each evaluation and pretreatment 
symptoms/conditions to be evaluated at baseline per the CTCAE v4.0 grading 
unless otherwise stated in the table below: 
CTCAE 
SYSTEM/ORGAN/CLASS 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
Investigations 
Creatinine increased 
X 
X 
Neutrophil count decreased 
X 
X 
Platelet count decreased 
X 
X 
General disorders and 
administration site conditions 
Fatigue  
X 
X 
Infusion related reaction 
 
X 
Gastrointestinal Disorders 
Nausea 
X 
X 
Vomiting 
X 
X 
# of Stools 
X 
 
Diarrhea 
 
X 
Infections and infestations 
Sepsis 
X 
X 
Blood and lymphatic system 
disorders 
Febrile neutropenia 
X 
X 
Skin and subcutaneous tissue 
disorders 
Rash- maculopapular 
X 
X 
Nervous system disorders 
Peripheral sensory neuropathy  
X 
X 
Peripheral motor neuropathy  
X 
X 


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10.52 Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.6: 
10.521 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
10.522 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
10.523 Grade 5 AEs (Deaths) 
• 
Any death within 30 days of the patient’s last study treatment or 
procedure regardless of attribution to the study treatment or 
procedure. 
• 
Any death more than 30 days after the patient’s last study treatment 
or procedure that is felt to be at least possibly treatment related must 
also be submitted as a Grade 5 AE, with a CTCAE type and 
attribution assigned. 
10.53 Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion 
of the Active Monitoring Phase (i.e., compliance with Test Schedule in 
Section 4.0). 
10.6 
Other Reporting Instructions for Industry Partners 
10.61 Special reporting requirements for Takeda 
Serious Adverse Event Definition 
Serious AE (SAE) means any untoward medical occurrence that at any dose: 
• 
Results in death. 
• 
Is life-threatening (refers to an AE in which the patient was at risk of death at the 
time of the event.  It does not refer to an event which hypothetically might have 
caused death if it were more severe). 
• 
Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph below on planned hospitalizations). 
• 
Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions). 
• 
Is a congenital anomaly/birth defect. 
• 
Is a medically important event.  This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered 
serious when, based on appropriate medical judgment, may jeopardize the patient, 
require medical or surgical intervention to prevent 1 of the outcomes listed above, or 
involves suspected transmission via a medicinal product of an infectious agent.   
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse; any organism, virus, or infectious particle (eg, prion protein transmitting 


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Transmissible Spongiform Encephalopathy), pathogenic or nonpathogenic, is 
considered an infectious agent.   
 
Clarification should be made between a serious AE (SAE) and an AE that is considered 
severe in intensity (Grade 3 or 4), because the terms serious and severe are NOT 
synonymous.  The general term severe is often used to describe the intensity (severity) of 
a specific event; the event itself, however, may be of relatively minor medical 
significance (such as a Grade 3 headache).  This is NOT the same as serious, which is 
based on patient/event outcome or action criteria described above, and is usually 
associated with events that pose a threat to a patient’s life or ability to function.  A severe 
AE (Grade 3 or 4) does not necessarily need to be considered serious.  For example, a 
white blood cell count of 1000/mm3 to less than 2000 is considered Grade 3 (severe) but 
may not be considered serious.  Seriousness (not intensity) serves as a guide for defining 
regulatory reporting obligations. 
 
AEs may be spontaneously reported by the patient and/or in response to an open question 
from study personnel or revealed by observation, physical examination, or other 
diagnostic procedures. Any clinically relevant deterioration in laboratory assessments or 
other clinical finding is considered an AE. When possible, signs and symptoms indicating 
a common underlying pathology should be noted as one comprehensive event. For 
serious AEs, the investigator must determine both the intensity of the event and the 
relationship of the event to study drug administration.  
 
AEs which are serious must be reported to Takeda Pharmacovigilance (or designee) from 
the first dose of study drug through 30 days after administration of the last dose of 
ixazomib. Any SAE that occurs at any time after completion of ixazomib treatment or 
after the designated follow-up period that the sponsor-investigator and/or sub-investigator 
considers to be related to any study drug must be reported to Takeda Pharmacovigilance 
(or designee). In addition, new primary malignancies that occur during the follow-up 
periods must be reported, regardless of causality to study regimen, for a minimum of 
three years after the last dose of the investigational product, starting from the first dose of 
study drug. All new cases of primary malignancy must be reported to Takeda 
Pharmacovigilance (or designee). 
 
 
 
 
Planned hospital admissions or surgical procedures for an illness or disease that existed 
before the patient was enrolled in the trial are not to be considered AEs unless the 
condition deteriorated in an unexpected manner during the trial (e.g., surgery was 
performed earlier or later than planned). All SAEs should be monitored until they are 
resolved or are clearly determined to be due to a patient’s stable or chronic condition or 
intercurrent illness(es). 
 
 
 
Since this is an investigator-initiated study, the principal investigator, Shaji Kumar, MD, 
also referred to as the sponsor-investigator, is responsible for reporting serious adverse 
events (SAEs) to any regulatory agency and to the sponsor- investigator’s EC or IRB. 
 
 
 
Regardless of expectedness or causality, all SAEs (including serious pretreatment events) 
must also be reported in English to Takeda Pharmacovigilance (or designee): 
 


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Fatal and Life Threatening SAEs within 24 hours of the sponsor-investigator’s 
observation or awareness of the event 
 
 
 
All other serious (non-fatal/non-life-threatening) events within 4 calendar days of the 
sponsor-investigator’s observation or awareness of the event 
 
 
 
See below for contact information for the reporting of SAEs to Takeda 
Pharmacovigilance. 
 
 
The sponsor-investigator must fax or email the SAE Form per the timelines above. A 
sample of an SAE Form will be provided. 
 
 
 
 
 
The SAE report must include at minimum: 
• Event term(s) 
• Serious criteria 
• Intensity of the event(s): Sponsor-investigator’s or sub-investigator’s determination. 
Intensity for each SAE, including any lab abnormalities, will be determined by using 
the NCI CTCAE version specified in the protocol, as a guideline, whenever possible. 
The criteria are available online at 
 
• Causality of the event(s): Sponsor-investigator’s or sub-investigator’s determination 
of the relationship of the event(s) to study drug administration.  
  
Follow-up information on the SAE may be requested by Takeda. 
  
Intensity for each SAE, including any lab abnormalities, will be determined by 
using the NCI CTCAE version used at your institution, as a guideline, whenever 
possible. The criteria are available online at 
 
  
In the event that this is a multisite study, the sponsor-investigator is responsible 
to ensure that the SAE reports are sent to Takeda Pharmacovigilance (or designee) from 
all sites participating in the study. Sub-investigators must report all SAEs to the 
sponsor-investigator so that the sponsor-investigator can meet his/her foregoing 
reporting obligations to the required regulatory agencies and to Takeda 
Pharmacovigilance, unless otherwise agreed between the sponsor-investigator and sub-
investigator(s). 
  
Relationship to all study drugs for each SAE will be determined by the 
investigator or sub-investigator by responding yes or no to the question: Is there a 
reasonable possibility that the AE is associated with the study drug(s)? 
  
Sponsor-investigator must also provide Takeda Pharmacovigilance with a copy 
of all communications with applicable regulatory authorities related to the study 
product(s), as soon as possible but no later than 4 calendar days of such 
communication. 
 
 
 
SAE and Pregnancy Reporting Contact Information 
 
 
 
 
  
 
 
 Suggested Reporting Form: 
• 
SAE Report Form (provided by Takeda) 
• 
US FDA MedWatch 3500A: 
 
• 
Any other form deemed appropriate by the sponsor-investigator 
 
 
 


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Product Complaints 
A product complaint is a verbal, written, or electronic expression that implies 
dissatisfaction regarding the identity, strength, purity, quality, or stability of a drug 
product. Individuals who identify a potential product complaint situation should 
immediately contact Takeda  and report the event. Whenever possible, the associated 
product should be maintained in accordance with the label instructions pending further 
guidance from a Takeda Quality representative. 
 
 
 
For Product Complaints 
 
 
 
 
 
 
 – 7 p.m. ET 
  
Product complaints in and of themselves are not AEs. If a product complaint results 
in an SAE, an SAE form should be completed and sent to Takeda Pharmacovigilance 
 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events 
If a woman becomes pregnant or suspects that she is pregnant while participating in this 
study or within 90 days after the last dose, she must inform the investigator immediately 
and permanently discontinue study drug.  The sponsor-investigator must immediately fax 
a completed Pregnancy Form to the Takeda Department of Pharmacovigilance or 
designee (see Section 8.2).  The pregnancy must be followed for the final pregnancy 
outcome. 
If a female partner of a male patient becomes pregnant during the male patient’s 
participation in this study, the sponsor-investigator must also immediately fax a 
completed Pregnancy Form to the Takeda Department of Pharmacovigilance or designee 
(see Section 8.2).  Every effort should be made to follow the pregnancy for the final 
pregnancy outcome. 
Suggested Pregnancy Reporting Form: 
Pregnancy Report Form (provided by Takeda) 
 
10.62 Special reporting requirements for Janssen 
 
Overview 
As the sponsor of the Study, PRINCIPAL INVESTIGATOR shall be solely responsible for 
complying, within the required timelines,  any safety reporting obligation to competent 
Health Authorities, IRB/ECs and any participating (co or sub) investigators, as defined in 
applicable laws and regulations.  For the purposes of this section, safety data includes adverse 
events, product quality complaints (PQCs), and special situations including pregnancies. 
 
The PRINCIPAL INVESTIGATOR will provide safety information to Janssen Scientific 
Affairs, LLC on adverse events, special situations including pregnancies and product quality 
complaints as defined within this section. 
 
1. Management of Safety Data 
This Study has been designated as an interventional study.  As such, all adverse events for 
Janssen Medicinal Products regardless of causality and special situations excluding those 
from subjects not exposed to a Janssen Medicinal Product and product quality complaints 
with or without an adverse event as described in this Exhibit will be reported from the time a 


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subject has signed and dated an Informed Consent Form (ICF) until completion of the 
subject’s last study-related procedure (which may include contact for follow-up safety).  
Serious adverse events will be reported for 30 days after the last dose of study drug. 
 
For the purposes of this study, the Janssen medicinal product is: DARZALEX™ 
(daratumumab)  
 
2. Definitions 
2.1. Adverse Event (AE) 
An adverse event is any untoward medical occurrence in a clinical study subject administered 
a medicinal (investigational or non-investigational) product. An adverse event does not 
necessarily have a causal relationship with the treatment. An adverse event can therefore be 
any unfavorable and unintended sign (including an abnormal finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational or non- investigational) 
product, whether or not related to that medicinal (investigational or non-investigational) 
product. (Definition per International Conference on Harmonisation [ICH]) 
This includes any occurrence that is new in onset or aggravated in severity or frequency from 
the baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities. 
 
2.2. Adverse Events of Special Interest  
Adverse events of special interest are events that Janssen Scientific Affairs, LLC is 
actively monitoring as a result of a previously identified signal (even if non-serious). 
These adverse events are: 
 
Infusion reactions 
 
Infections 
 
Cytopenias 
 
HBV Reactivation  
 
Other malignancies  
 
2.3. Individual Case Safety Report (ICSR) 
A valid ICSR must contain the four minimum criteria required to meet regulatory 
reporting requirements. 
• 
an identifiable subject (but not disclosing personal information such as the subject’s 
name, initials or address) 
• 
an identifiable reporter (investigational site) 
• 
a Janssen medicinal product 
• 
an adverse event, outcome, or certain special situations 
 
The minimum information required is: 
• 
suspected Janssen medicinal product (doses, indication) 
• 
date of therapy (start and end date, if available) 
• 
batch or lot number, if available 
• 
subject details (subject ID and country) 
• 
gender 
• 
age at AE onset 
• 
reporter ID 
• 
adverse event detail (AE verbatim in English), onset date, relatedness, causality, 
action taken, outcome, (if available) 
• 
Janssen protocol ID 


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


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


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


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• 
The event can be attributed to agents other than the study drug or to factors unrelated 
to study conduct 
• 
It becomes unlikely that any additional information can be obtained (subject or health 
care practitioner refusal to provide additional information, lost to follow-up after 
demonstration of due diligence with follow-up efforts) 
 
The PRINCIPAL INVESTIGATOR will transmit all SAEs and special situations 
following exposure to a Janssen product under study in a form provided by Janssen 
Scientific Affairs, LLC in accordance with Section 10,Transmission Methods, in English 
within 24-hours of becoming aware of the event(s). 
 
In the event the study is blinded, the PRINCIPAL INVESTIGATOR will submit an 
unblinded SAE or pregnancy exposure report to Janssen Scientific Affairs, LLC. 
 
All follow-up information for serious adverse events that are not resolved at the end of 
the study or by the time of patient withdrawal must be reported directly by the 
PRINCIPAL INVESTIGATOR, within 24 hours becoming aware, to Janssen Scientific 
Affairs, LLC using the Janssen Scientific Affairs, LLC Serious Adverse Event Report  
 
All available clinical information relevant to the evaluation of a related SAE or special 
situation is required. 
 
• 
The PRINCIPAL INVESTIGATOR is responsible for ensuring that these cases are 
complete and if not are promptly followed-up. A safety report is not considered 
complete until all clinical details needed to interpret the case are received. Reporting 
of follow-up information should follow the same timeline as initial reports. 
 
• 
Copies of any and all relevant correspondences with regulatory authorities and ethics 
committees regarding any and all serious adverse events, irrespective of association 
with the Janssen Product under study, are to be provided to Janssen Scientific Affairs, 
LLC using a transmission method in Section 10 from this Exhibit within 24 hours of 
such report or correspondence being sent to applicable health authorities. 
 
6.2. Non-Serious AEs 
All non-serious adverse events should be reported to Janssen Scientific Affairs, LLC 
according to the timeframe outlined in the Research Funding Agreement section entitled 
Reporting of Data. 
 
6.3. PQC Reporting 
A PQC may have an impact on the safety and efficacy of the product. Timely, accurate, 
and complete reporting and analysis of PQC information from studies are crucial for the 
protection of patients, investigators, and Janssen Scientific Affairs, LLC, and are 
mandated by regulatory agencies worldwide. Janssen Scientific Affairs, LLC has 
established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information. Lot and/or Batch #s shall be collected or any 
reports failure of expected pharmacological action (i.e., lack of effect). The product 
should be quarantined immediately and if possible, take a picture. 
 
All initial PQCs involving a Janssen medicinal product under study must be reported to 
Janssen Scientific Affairs, LLC by the PRINCIPAL INVESTIGATOR within 24 hours 


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after being made aware of the event. The Janssen contact will provide additional 
information/form to be completed. 
 
If the defect for a Janssen medicinal product under study is combined with either a 
serious adverse event or non-serious adverse event, the PRINCIPAL INVESTIGATOR 
must report the PQC to Janssen Scientific Affairs, LLC according to the serious adverse 
event reporting timelines.  A sample of the suspected product should be maintained for 
further investigation if requested by Janssen Scientific Affairs, LLC. 
 
7. Reporting Procedures for Reporting Safety Data and Product Quality Complaints 
(PQCs) for Non-Janssen Medicinal Products  
For SAEs, special reporting situations and PQCs following exposure to a non-Janssen 
medicinal product under study, the PRINCIPAL INVESTIGATOR should notify the 
appropriate regulatory/competent authority or the manufacturer of that medicinal product (in 
the absence of appropriate local legislation) as soon as possible. 
 
8. Transmission Methods 
The following methods are acceptable for transmission of safety information to Janssen 
Scientific Affairs, LLC: 
• 
Electronically via Janssen SECURE Email service (preferred) 
• 
For business continuity purposes, if SECURE Email is non-functional: 
o Facsimile (fax), receipt of which is evidenced in a successful fax transmission 
report 
• 
Telephone (if fax is non-functional). 
 
Please use the contact information and process information provided by Janssen Scientific 
Affairs, LLC.  
 
 
 


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11.0 
Treatment Evaluation 
The International Myeloma Working Group (IMWG) uniform response criteria21 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.  


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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 
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. 
 
 
 


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11.2  
Clarification of test indications 
 
Listed below are the minimal required tests required to assess response based on the 
characteristics of their disease at on study.   
 
Table 11.2 
Tests  Required To Assess 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. 
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 


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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.  
 
 
Table 11.5 
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 
• 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  


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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 
Minimal Response (MR)  
• If present at baseline, ≥25% but ≤ 49% reduction of serum M 
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 


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(≥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. 
 
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). 
 


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k Requires a complete response as defined in the table.  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. 
 
 
NOTE: Interference with Determination of Complete Response: Daratumumab is a 
human IgG kappa monoclonal antibody that can be detected on both, the serum protein 
electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring 
of endogenous M-protein. This interference can impact the determination of complete 
response and of disease progression in some patients with IgG kappa myeloma protein. 
  
12.0 
Descriptive Factors  
 
12.1 
Parameters followed for hematologic response (pick one): serum monoclonal protein ≥1 
g/dL and urine monoclonal protein ≥200 mg/24 hours vs. serum monoclonal protein  
≥1g/dL only vs. urine monoclonal protein  ≥200 mg/24 hours only vs. serum 
immunoglobulin free light chain ≥10 mg/dL. Distinguish between SPEP measurements 
versus quantitative IgA measurement for serum monoclonal protein  
 
12.2 
High risk vs. standard risk by mSMART (see Appendix II) 
 
 


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13.0 
Treatment/Follow–up Decision at Evaluation of Patient  
13.1 
Continuation 
 
 
Patients who are sCR, CR, VGPR, PR, or SD (or usCR, uCR, uVGPR, uPR) will 
continue treatment per protocol. Patients will go off treatment to event monitoring if an 
MR is not seen after 2 cycles and a PR is not seen after 4 cycles. Confirmation of MR or 
PR is not required. 
13.2 
Patients who receive transplant 
 
 
Patients who receive a transplant will go to event monitoring per Section 18.0. The 
transplant should be reported on the event monitoring form. Details should be recorded 
on the Stem Cell Harvest and Transplant and Engraftment  Forms. 
13.3 
Progressive Disease 
 
 
Patients who develop progressive disease while receiving therapy will go to the event-
monitoring phase. 
13.4 
Off protocol for reasons other than PD 
 
 
Patients who go off protocol treatment for reasons other than PD will go to the event-
monitoring phase per Section 18.0. 
13.5 
Discontinuation for unacceptable AEs 
 
 
Patients who discontinue therapy for an unacceptable adverse event(s) will be followed 
until resolution or stabilization of the AE(s). 
13.6 
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 over 2 years) 
• 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 4.2, unless the 
patient refuses further study participation or is lost to follow-up. 
 
13.7 
Criteria for Study Discontinuation 
 
 
The study may be temporarily or permanently discontinued at any site and at any time. 
Reasons for study discontinuation may include, but are not limited to, the following: 
• 
Safety concerns 
• 
Poor enrollment 


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• 
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. 
 
13.8 
Ineligible 
 
 
A patient is deemed ineligible 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 4.2 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. 
13.9a 
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 4.2 of the protocol. 
 
13.9b 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 for this Protocol 
 
Table 14.1 Summary Table of Research Blood and Body Fluid Specimens to be collected for this Protocol 
Correlative Study  
Mandatory 
or 
Optional 
Blood or 
Body 
Fluid 
being 
Collected 
Type of 
Collection 
Tube 
(color of 
tube top) 
Volume to 
collect per 
tube (# of 
tubes to be 
collected) 
Study 
Entry* 
End of 
cycle 4, 
12, 24, 
36 
At 
suspected 
CR 
At 
PD* 
Process 
at site? 
(Yes or 
No) 
Temperatu
re 
Conditions 
for Storage 
/Shipping 
Flow cytometry for 
circulating plasma 
cells 
Mandatory Peripheral 
blood 
ACD 
(yellow) 
6 mL 
(3) 
X 
X 
X 
X 
No 
Cool Pak 
Flow cytometry for 
MRD 
Mandatory 
Bone 
marrow 
aspirate 
ACD 
(yellow) 
6 ml 
(2) 
X 
X 
X 
X 
No 
Cool Pak 
 
* Samples at baseline and at time of disease progression are not mandatory


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14.2 
Shipping and Handling 
14.21 Kits 
14.211 Kits will be used for this study. Kits will contain supplies and 
instructions for collection, processing and shipping specimens 
14.212 Participating sites may obtain kits by emailing: 
Email requests should include address, 
contact information and number of kits being requested. 
14.213 Kits will be sent via FedEx Ground at no additional cost to participating 
sites. Allow 3-4 business days to receive kits. 
14.22 Shipping 
Bone marrow and blood samples can be shipped with Cool Pak the same day 
they are collected (Monday-Thursday). They should be shipped priority 
overnight taking care to avoid Friday collection and shipping. 
If unavoidable, Friday shipping with Saturday delivery can be arranged 
contacting the laboratory in advance. 
Please notify Mayo Clinic by email 
or phone 
 to notify laboratory when specimens are being shipped. 
  
 
  
   
 
 
 
 
 
 
 


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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. 
 
 
Matching placebo capsules have been manufactured for the 2.3, 3.0, 4.0, and 5.5 
mg ixazomib (MLN9708) capsules. The placebo capsules contain 
microcrystalline cellulose, talc, and magnesium stearate and are identical in color 
and size to the corresponding active dose. 
 
15.13 Preparation and storage: Ixazomib (MLN9708) capsules 0.2 mg, 0.5 mg,  
2.0 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 


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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:   
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 


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is no readily apparent effect of coadministration of LenDex on the clinical 
PK of ixazomib. 
 
Ixazomib should not be taken if the patient has had a serious allergic 
reaction to boron or boron containing products. 
 
15.17 Known potential toxicities:  See the current version of the Investigator’s 
Brochure for more complete information including potential risks, as well as 
recommendations for clinical monitoring and medical management of toxicity. 
 
Very common (≥10%): 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 Millennium Pharmaceuticals, Inc (Takeda) 
 
 


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15.19 Nursing guidelines 
15.191 Capsules must be administered intact and should not be opened or 
manipulated in any way. Additionally, capsules should remain in the 
blister packs until they are ready to be taken. It is recommended to wear 
gloves and protective garments during preparation when dispensed in 
clinic. 
15.192 Capsules should be taken on an empty stomach (either 1 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 
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 
Lenalidomide (Revlimid®, CC-5013, CDC-501)   
Please consult the most current Investigator’s Brochure and package insert for 
complete drug information. 
 
15.21 Background: Lenalidomide has a wide range of effects, including the inhibition 
of hematopoietic tumor cell proliferation, the enhancement of T cells and natural 
killer (NK) cell activity, the modulation of stem cell differentiation, the inhibition 
of angiogenesis, and the inhibition of inflammation. 
 
15.22 Formulation: For clinical study, lenalidomide is provided as 1.25-, 2.5-, 5-, 10-, 
15-, 20-, and 25-mg capsules for oral administration. Each capsule contains 


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lenalidomide as the active ingredient and the following inactive ingredients: 
anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, and 
magnesium stearate. 
 
Placebo capsules for the 1.25-, 2.5-, 5-, 10-, 15-, 20-, and 25-mg lenalidomide 
capsules are available for use in blinded studies. Each placebo capsule visually 
matches the drug product. 
 
The lenalidomide and placebo capsules are supplied in push-through blister foil 
or tamper-evident, child-resistant, opaque, high-density polyethylene (HDPE) 
containers with HDPE caps. 
 
15.23 Preparation and storage: Lenalidomide should be stored at room 
temperature, between 59 and 86ºF (15-30ºC).  Store drug away from direct 
sunlight.   
 
15.24 Administration:  Capsules are administered by mouth daily with water. Patients 
should not break, chew or open the capsules.   
 
 
15.25 Pharmacokinetic information: 
a)  Absorption – Lenalidomide is rapidly absorbed following oral administration 
to subjects with multiple myeloma or MDS, with maximum plasma 
concentrations occurring between 0.5 and  1.5 hours post-dose. 
Co-administration with a high-fat and high-calorie meal in healthy subjects 
reduced the extent of absorption, resulting in an approximately 20% decrease in 
AUC and 50% decrease in Cmax in plasma.   
 
In the pivotal MM and MDS registration trials where the efficacy and safety were 
established for lenalidomide, the drug was administered without regard to food 
intake. Thus, lenalidomide can be administered with or without food. 
 
Multiple dosing (up to 100 mg BID) did not cause marked drug accumulation.   
 
 
b)  Distribution – In vitro (14C)-lenalidomide binding to plasma proteins is 
approximately 30%. 
 
c)  Metabolism – Lenalidomide undergoes limited metabolism. Unchanged 
lenalidomide is the predominant circulating component in humans. Two 
identified metabolites are hydroxy-lenalidomide and N-acetyl-lenalidomide; each 
constitutes less than 5% of parent levels in circulation. 
 
d)  Excretion – Elimination is primarily renal.  Approximately 65% to 85% of 
lenalidomide is eliminated unchanged through urinary excretion in subjects with 
normal renal function. The half-life of elimination is approximately 3 to 4 hours 
(2 to 3 hours in patients 5 to 21 years) at the clinically relevant doses (5 to 50 
mg/day). Steady-state levels are achieved within 4 days. 
 
15.26 Potential Drug Interactions:  In vitro studies demonstrate that lenalidomide is 
not a substrate of CYP enzymes. In addition, lenalidomide shows little inhibitory 
or induction potential towards the CYP enzymes in vitro. Hence, 


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coadministration of CYP substrates, inhibitors, or inducers with lenalidomide is 
not likely to result in clinically relevant drug-drug interactions in humans.  
 
In vitro, lenalidomide is not a substrate of BCRP, MRP1, MRP2, MRP3, OAT1, 
OAT3, OATP1B1, OCT1, OCT2, MATE1, OCTN1, or OCTN2. Thus, it is 
unlikely that substrates or inhibitors of these transporters would affect 
lenalidomide disposition in humans. 
 
Lenalidomide is not an inhibitor of BSEP, BCRP, MRP2, OAT1, OAT3, 
OATP1B1, OATP1B3, or OCT2. Thus, lenalidomide is not anticipated to cause 
any significant drug-drug interactions due to inhibition of these transporters. 
 
Lenalidomide is not an inhibitor of UGT1A1 and is not anticipated to cause any 
significant drug-drug interactions due to UGT1A1 inhibition. 
 
In vitro, lenalidomide is a weak substrate, but not an inhibitor of P-glycoprotein 
(P-gp). 
 
Erythropoietic agents or other agents that may increase the risk of thrombosis, 
such as hormone replacement therapy and oral contraceptives, should be used 
with caution in patients with multiple myeloma receiving lenalidomide with 
dexamethasone. 
 
 
Periodic monitoring of digoxin plasma levels is recommended due to increased 
Cmax and AUC with concomitant lenalidomide therapy.  Close monitoring of PT 
and INR is recommended in multiple myeloma patients taking concomitant 
warfarin. 
 
15.27 Known potential toxicities:   
 
Pregnancy Warning: Lenalidomide, a thalidomide analogue, caused limb 
abnormalities in a developmental monkey study similar to birth defects caused by 
thalidomide in humans. If lenalidomide is used during pregnancy, a teratogenic 
effect of Lenalidomide in humans cannot be ruled out.  Pregnancy must be 
excluded before start of treatment. Prevent pregnancy during treatment by the use 
of two reliable methods of contraception. 
 
Very Common AEs (≥ 10%): anemia, febrile neutropenia, granulocytopenia, 
leukopenia, lymphopenia, neutropenia, thrombocytopenia, cataracts, blurred 
vision, abdominal pain, constipation, diarrhea, dyspepsia, nausea, vomiting, 
asthenia, chills, edema including peripheral, fatigue, pyrexia, abnormal liver 
function tests,  bronchitis, gastroenteritis, influenza,  nasopharyngitis, sinusitis, 
pneumonia, rhinitis, upper respiratory tract infection, urinary tract infection 
weight decreased, decreased appetite, hyperglycemia, hypocalcemia, 
hypokalemia, arthralgia, back pain, bone pain, muscle spasms, musculoskeletal 
pain, myalgia, pain in extremity, dizziness, dysgeusia, headache, hypoesthesia, 
neuropathy peripheral, neuropathy, paresthesia, tremor, depression, insomnia, 
renal failure, cough, dyspnea, epistaxis, pharyngitis, pulmonary embolism, dry 
skin, pruritus, rash, and deep vein thrombosis. 
 


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Common (≥ 1% and < 10%):   hemolytic anemia, pancytopenia, acute 
myocardial infarction, atrial fibrillation, cardiac failure, congestive heart failure, 
myocardial ischemia,  tachycardia, vertigo, upper abdominal pain, dry mouth, 
toothache, chest pain, fall, cholestasis, arthritis infective, bacteremia, cellulitis,  
erysipelas,  herpes simplex, herpes zoster, infection, lower respiratory infection, 
respiratory infection, lung infection, meningitis, ophthalmic herpes zoster,  
sepsis, contusion, alanine aminotransferase increased, c-reactive protein 
increased, gamma-glutamyltransferase increased, dehydration, diabetes mellitus, 
gout, hypercalcemia, hyperuricemia, hypophosphatemia, hypomagnesemia, 
hyponatremia, iron overload, muscular weakness, acute myeloid leukemia, basal 
cell carcinoma, Myelodysplastic syndrome, squamous cell carcinoma of skin, T-
call type acute leukemia, tumor flare, tumor lysis syndrome, cerebrovascular 
accident, lethargy, peripheral sensory neuropathy, syncope, mood altered,   
respiratory distress, erythema, hyperhidrosis, night sweats, hematoma, 
hypertension, hypotension, thrombosis, and vasculitis. 
 
Uncommon, limited to important or life-threatening (< 1%): appendicitis, 
bursitis infective, clostridium difficile colitis, infective exacerbation of chronic 
obstructive airways disease, pyelonephritis, hypersensitivity, Graft vs. Host 
Disease, viral reactivation (such as hepatitis B virus or herpes zoster), DRESS. 
 
The following additional adverse reactions have been reported in Celgene-
sponsored clinical studies and are considered by the company to be at least 
possibly related to the administration of lenalidomide: pneumonitis, transient 
abnormal liver laboratory tests, hyperthyroidism, viral reactivation (such as 
hepatitis B or herpes virus), acute graft-versus-host disease following allogeneic 
hematopoietic transplant, solid organ rejection, TLS, TFR, rhabdomyolysis, and 
allergic conditions, including angioedema,.  These reactions are reported 
voluntarily from a population of uncertain size, so it is not possible to reliably 
estimate their frequency. 
  
Lenalidomide may have minor or moderate influence on the ability to drive and 
use machines. Fatigue, dizziness, somnolence, vertigo and blurred vision have 
been reported with the use of lenalidomide. Therefore, caution is recommended 
when driving or operating machines. 
 
Please refer to the Investigator’s Brochure for a more comprehensive list of 
treatment-emergent adverse events. 
 
15.28 Drug procurement:  Commerical supply. Per standard requirements all 
physicians who prescribe lenalidomide 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 Celgene  REVLIMID REMS™  
program.  Prescriptions must be filled within 7 days.  Only enough lenalidomide 
for one cycle of therapy will be supplied to the patient each cycle. 
 
Any unused lenalidomide should be returned for disposition in accordance with 
the REVLIMID REMS™   program 
 


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15.29 Nursing Guidelines:  
 
• 
Myelosuppression is dose-dependent and reversible with treatment 
interruption and/or dose reduction. Monitor CBC w/diff regularly. Instruct 
patient to report any unusual bruising or bleeding (thrombocytopenia); signs 
and symptoms of infection (neutropenia); and energy conserving lifestyle 
(anemia). 
 
• 
Lenalidomide can have thrombotic adverse events (i.e DVT and PE). Instruct 
patient to report any limb swelling or pain, and to seek medical attention for 
shortness of breath or chest pain. 
 
• 
Because of the potential for birth defects patients should be instructed in 
effective methods of birth control. Female patients should use 2 forms of 
birth control during treatment and for 4 weeks after discontinuing therapy. 
Males must be instructed to use a latex condom during any sexual contact 
with a woman of child bearing potential (even if they have had a vasectomy), 
because it is unknown if lenalidomide is present in semen. 
 
• 
Patents may experience pruritus, rash and dry skin. Because of the rare risk 
of Steven’s Johnson Syndrome, patients should immediately report any rash 
to their provider. 
 
• 
Drug may cause hyperglycemia. Patients with diabetes or impaired fasting 
glucose may need to have their glucose levels monitored more closely. 
 
• 
Gastrointestinal side effects (diarrhea, constipation, nausea, dyspepsia, 
anorexia, etc) are commonly seen. Manage patient symptomatically and 
monitor for effectiveness. 
 
• 
Patients may experience myalgias, arthralgias, parasthesias and other 
generalized pain. Administer analgesics as ordered and monitor for their 
effectiveness. Rarely infective bursitis and arthritis have been reported. 
Instruct patients to report any joint pain or redness to study team 
immediately. 
 
• 
Upper respiratory symptoms (nasopharyngitis, cough, epistaxis, etc.) can be 
seen. Manage symptomatically and monitor for effectiveness. 
 
• 
Agent may cause fatigue, dizziness, vertigo or blurred vision. Instruct 
patients to use caution when driving or operating machines. 
 
• 
Monitor LFT’s and report any elevations to the study team. Instruct patient to 
report abdominal pain and/or jaundice to the study team. 
 
• 
All prescribers and patients must be enrolled into the REVLIMID REMS 
program. Only enough lenalidomide for one cycle of therapy will be supplied 
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• 
Rarely secondary malignancies have been seen after lenolidamide therapy, 
including MDS, squamous/basal cell carcinomas of the skin, T-cell type 
acute leukemia. 
 
• 
Monitor Renal function, renal failure has been reported. 
 
15.3 
Dexamethasone for Oral Administration  
 
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 
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administration by 2 hours. Aminoglutethimide, barbiturates, and CYP3A4 
inducers may reduce the serum levels/effects of dexamethasone and 
dexamethasone may decrease the levels/effects of other CYP3A4 substrates. 
Serum concentrations of isoniazid may be decreased by corticosteroids. 
Corticosteroids may lead to a reduction in warfarin effect. Corticosteroids may 
suppress the response to vaccinations. 
Ethanol/Nutrition/Herb Interactions:  
Ethanol: Avoid ethanol (may enhance gastric mucosal irritation). 
Food: Dexamethasone interferes with calcium absorption. Limit caffeine. 
Herb/Nutraceutical: Avoid cat’s claw (Uncaria tomentosa), echinacea (have 
immunostimulant properties) 
 
15.37 Known potential adverse events: Consult the package insert for the most 
current and complete information.  
Common known potential toxicities, frequency not defined:  
Fluid and electrolyte disturbances, congestive heart failure in susceptible persons, 
hypertension, euphoria, personality changes, insomnia, exacerbation of infection, 
exacerbation or symptoms of diabetes, psychosis, muscle weakness, osteoporosis, 
vertebral compression fractures, pancreatitis, esophagitis, peptic ulcer, 
dermatologic disturbances, convulsions, vertigo and headache, endocrine 
abnormalities, ophthalmic changes, and metabolic changes. Some patients have 
experienced itching and other allergic, anaphylactic or hypersensitivity reactions. 
Withdrawal from prolonged therapy may result in symptoms including fever, 
myalgia and arthralgia. 
 
15.38 Drug procurement: Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
 
15.4 
Daratumumab (Darzalex®) 
Please consult the most current Investigator’s Brochure and package insert for 
complete drug information. 
 
15.41 Background:. Daratumumab is an immunoglobulin G1 kappa (IgG1κ) human 
monoclonal antibody against CD38 antigen, produced in a mammalian cell line 
(Chinese Hamster Ovary [CHO]) using recombinant DNA technology. The 
molecular weight of daratumumab is approximately 148 kDa. 
 
CD38 is a transmembrane glycoprotein (48 kDa) expressed on the surface of 
hematopoietic cells, including multiple myeloma and other cell types and tissues 
and has multiple functions, such as receptor mediated adhesion, signaling, and 
modulation of cyclase and hydrolase activity. Daratumumab is an IgG1κ human 
monoclonal antibody (mAb) that binds to CD38 and inhibits the growth of CD38 
expressing tumor cells by inducing apoptosis directly through Fc mediated cross 
linking as well as by immune-mediated tumor cell lysis through complement 
dependent cytotoxicity (CDC), antibody dependent cell mediated cytotoxicity 
(ADCC) and antibody dependent cellular phagocytosis (ADCP). Myeloid derived 
suppressor cells (MDSCs) and a subset of regulatory T cells (CD38+Tregs) 
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15.42 Formulation:  
IV formulation:Daratumumab IV solution is a colorless to yellow liquid and 
sterile concentrate of 20 mg/mL in a vial with a nominal fill of 5 mL or 20mL. It 
will be manufactured and provided under the responsibility of Janssen Biotech. 
Refer to the Product Insert for a list of excipients. 
 
15.43 Preparation and storage:  
IV drug formulation: Daratumumab is supplied in glass vials containing 
daratumumab at a concentration of 20 mg/mL. Study drug labels will 
contain information to meet the applicable regulatory requirements. Each 
vial will contain a study-specific label with a unique identification number.   
 
All study drug vials must be stored in the original carton in a refrigerator 
ranging from 2°C to 8°C and must not be utilized after the expiry date 
printed on the label. The product must be protected from light and must 
not be frozen. Daratumumab does not contain preservatives; therefore, any 
unused portion remaining in the vial must be discarded. 
 
Daratumumab will be diluted in a sterile, pyrogen-free physiological saline 
solution (0.9% NaCl) prior to IV administration. Refer to Section 7 of the 
protocol, the Investigational Product Preparation Instructions or 
Investigational Product Procedures Manual for details regarding dose 
preparation, storage, and handling of diluted solutions. 
 
15.44 Administration:   
IV administration:  Administer the diluted solution by intravenous infusion using 
an infusion set fitted with a flow regulator and with an in-line, sterile, non-
pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.22 or 
0.2 micrometer). Polyurethane (PU), polybutadiene (PBD), PVC, PP or PE 
administration sets must be used. 
 
Infusion should be completed within 15 hours. 
 
Do not store any unused portion of the infusion solution for reuse. Any 
unused product or waste material should be disposed of in accordance with 
local requirements. 
 
Do not infuse daratumumab concomitantly in the same intravenous line 
with other agents. 
 
15.45 Pharmacokinetic information for IV administration: 
The pharmacokinetics (PK) of daratumumab following intravenous 
administration were evaluated in patients with relapsed and refractory multiple 
myeloma at dose levels from 0.1 mg/kg to 24 mg/kg, and included the 
recommended 16 mg/kg dose and regimen. Over the dose range from 1 to 24 
mg/kg, increases in area under the concentration-time curve (AUC) were more 
than dose-proportional. Clearance decreased with increasing dose and repeated 
dosing, indicating target-mediated pharmacokinetics. The mean (SD) predose 
(trough) serum concentration at the end of weekly dosing was 573 (332) µg/mL. 
 
The half-life of daratumumab is both concentration and time dependent. After the 
first dose of 16 mg/kg of daratumumab, the observed half-life was 9±4 days. The 
model-derived half-life associated with linear elimination was approximately 
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daratumumab. Apparent steady state seems to be reached approximately 5 
months into the every 4 weeks dosing period of the 16 mg/kg with a schedule of 
weekly for 8 weeks, every 2 weeks for 16 weeks, and then every 4 weeks 
thereafter (approximately 11 months of treatment in total). 
 
As expected with subcutaneous administration, concentration-time curves 
following administration in all cohorts indicate a later Tmax of approximately 72h 
post-dose, compared with IV administration when Tmax occurs at or near the end 
of infusion. The range of C3D1 Ctrough observations for the SC cohort is within 
the range observed following 16 mg/kg IV dosing, and the variability appeared to 
be similar for the daratumumab SC and 16 mg/kg IV cohorts.  The observed Cmax 
values from the daratumumab SC cohort is within the range observed for 
daratumumab 16 mg/kg IV.  
 
Special Populations 
Renal Impairment: The population PK analysis included 71 patients with normal 
renal function (creatinine clearance [CrCL] ≥90 mL/min), 78 patients with mild 
renal impairment (CrCL <90 and ≥60 mL/min), 68 patients with moderate renal 
impairment (CrCL <60 and ≥30 mL/min), and 6 patients with severe renal 
impairment or end stage renal disease (CrCL <30 mL/min). No clinical 
differences in exposure to daratumumab were observed between patients with 
renal impairment and those with normal renal function. 
 
Hepatic Impairment: The population PK analysis included 189 patients with 
normal hepatic function (TB and AST ≤ULN) and 34 with mild hepatic 
impairment (TB 1.0× to 1.5× ULN or AST>ULN) patients. No clinical 
differences in the exposure to daratumumab were observed between patients with 
mild hepatic impairment and those with normal hepatic function. Daratumumab 
has not been studied in patients with moderate (TB>1.5× to 3× ULN and any 
AST) or severe (TB>3× ULN and any AST) hepatic impairment. 
 
 
15.46 Potential Drug Interactions: No drug interaction studies have been performed. 
 
15.47 Known potential toxicities:   
 
Very common known potential toxicities, ≥ 10%: 
Injury, poisoning, and procedural complications: infusion related reaction 
Infections and infestations: pneumonia, upper respiratory tract infection, 
bronchitis, pneumonia  
Blood and lymphatic system disorders: neutropenia, thrombocytopenia, anemia, 
lymphopenia 
Vascular disorders: hypertension 
Nervous system disorders: headache, peripheral sensory neuropathy 
Respiratory, thoracic, and mediastinal disorders: cough, dyspnea 
Gastrointestinal disorders: nausea,vomiting, diarrhea 
Musculoskeletal and connective tissue disorders: muscle spasms 
General disorders and administration site conditions: fatigue, pyrexia, peripheral 
edema 
 
Common known potential toxicities, 1% - <10%: 
Injury, poisoning, and procedural complications: infusion related reaction 


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Infections and infestations: respiratory tract infection, influenza, lower 
respiratory tract infection, sepsis, sinusitis, rhinitis, pharyngitis, viral respiratory 
tract infection, tonsillitis, lung infection, herpes zoster 
Blood and lymphatic disorders: febrile neutropenia,  
Cardiac disorders: atrial fibrillation 
Respiratory, thoracic, and mediastinal disorders: pulmonary edema, hypoxia, 
laryngeal edema,  pneumonitis, bronchospasm  
Gastrointestinal disorders: diarrhea 
   
Uncommon and rare known potential toxicities, <1%: 
Infections and infestations: metapneumovirus infection, tracheitis, acute sinusitis, 
bronchiolitis, epiglottitis, oropharyngeal candidiasis, tracheobronchitis, upper 
respiratory tract infection bacterial, bronchitis bacterial, respiratory syncytial 
virus infections, laryngitis, streptococcal pharyngitis, viral rhinitis  
Blood and Lymphatic Disorders: neutropenic sepsis, neutropenic infection 
Please refer to the Investigator Brochure for a more comprehensive list of 
treatment-emergent adverse events. 
 
15.48 Drug procurement:  Daratumumab (Darzalex®) will be provided to 
research subjects for the duration of their participation in this trial at no 
charge to them or their insurance providers. 
 
15.49 Nursing Guidelines:  
 
 
Daratumumab can cause severe infusion reactions, usually during the first 
infusion. Patients who have experienced a reaction may experience further 
reactions with subsequent infusions. Most reactions occur during or within 4 
hours of infusion, however may occur up to 48 hours after an infusion.  Warn 
patient of this possibility. Monitor patient throughout infusion for 
bronchospasm, hypoxia, SOB, and hypertension. Patients may also 
experience symptoms of anaphylaxis. Administer emergency medication as 
ordered.  
 
 
Patients may experience infections, including URI and pneumonia. Patients 
who have an ongoing infection should not receive agent. 
 
 
Patients may experience gastrointestinal side effects including diarrhea and 
nausea. Treat symptomatically and monitor for effectiveness. 
 
Warn patients about the possibility of peripheral neuropathy, dizziness, and 
insomnia.  
 
 
Fatigue is common. Instruct patient in energy conserving lifestyle. 
 
 
 
Rarely patients may experience cardiac issues including, atrial-fibrillation, 
peripheral edema,  and hypertension. Instruct patient to report any chest pain, 
heart palpitations, and swelling to the study team. 
 
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15.51  Formulation and storage:  Dexamethasone sodium phosphate is supplied as 
4mg/ml IV solution in 5ml vials.  Store intact vials at controlled room 
temperature, do not refrigerate. Protect from heat and light. 
 
15.52  Preparation:  The sterile solution from the vial may be further diluted in D5W or 
NS (refer to the treatment section of the protocol). 
 
15.53   Stability:  Refer to expiration date on the vial. 
 
15.54   Administration:  IV push or infusion (see treatment section of the protocol). 
 
15.55   Known potential toxicities: 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. 
 
15.56   Drug procurement:  Commercially available from several commercial sources. 
 
15.57 Nursing guidelines: 
15.571 Monitor regularly for hypertension, CHF, and other evidence of fluid 
retention. 
15.572 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. 
 
15.573 Assess for symptoms of gastric ulcer, heartburn, or gastritis.  Suggest 
antacids.  Instruct patient to report symptoms to healthcare team if unable 
to control. 
 
15.574 Evaluate signs of infection, particularly local candidal infections and 
treat appropriately. 
 
15.575 Monitor blood glucose frequently. 
 
15.576 Instruct patient to report frequent unrelenting headaches or visual 
changes to healthcare team. 
 
15.577 Advise patient that easy bruising is a side effect.  
 
 


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16.0 
Statistical Considerations and Methodology  
16.1 
Overview 
 
 
This study is designed to assess the confirmed complete response rate with daratumumab 
added to ixazomib, lenalidomide and dexamethasone, when used as initial therapy in 
patients with previously untreated symptomatic MM using a one-stage binomial phase II 
study design in each arm. This study will include 2 treatment arms:  Arm A 
(Dexamethasone cycles 1-12) and Arm B (Dexamethasone cycles 1-2 only). 
 
 
 
 
 
16.11 Primary Endpoint 
 
 
 
 
 
The primary endpoint in each arm of this trial is the confirmed complete response rate.  A 
confirmed complete response is defined as objective status of CR or sCR that is 
maintained on two consecutive evaluations at least 2 weeks apart. All patients meeting 
the eligibility criteria, who have signed a consent form and have begun treatment will be 
evaluable for response, unless they are determined to be a major violation. 
 
 
 
16.12 Sample Size 
 
 
 
 
 
The one-stage binomial design to be used in each arm is fully described below.  A 
maximum of 36 evaluable patients will be accrued to each arm of this phase II study 
unless undue toxicity is encountered.  We anticipate accruing an additional 4 patients in 
each arm  to account for ineligibility, cancellation, major treatment violation, or other 
reasons for a maximum of 40 patients accrued in each arm, and 80 patients overall. 
 
 
 
16.13 Accrual Rate and Study Duration 
 
 
 
 
 
The anticipated accrual rate is 3 evaluable multiple myeloma patients per month, 
translating to a duration of approximately one year for accrual in each arm.  Accrual to 
Arm A will be completed before accrual is opened to Arm B.  In each arm, the total 
duration before any results may be available is expected to be approximately 1.5 years 
from the date of activation for that arm, or until the last patient accrued to that arm has 
been observed for at least 6 months. The maximum total study duration is expected to be 
5 years, or until the last patient accrued has been followed for 3 years. 
 
16.2  
Statistical Design (to be evaluated in each arm independently) 
 
 
 
 
 
16.21 Decision Rule 
 
 
 
 
 
In a prior phase I/II study of previously untreated multiple myeloma patients, the efficacy 
of a combination of ixazomib, lenalidomide and dexamethasone was evaluated.14  A total 
of 53 patients were treated at the recommended phase II dose of 4.0 mg ixazomib, where 
a complete response rate of 27% was seen.   This study will add daratumumab to the 
combination of ixazomib, lenalidomide and dexamethasone.  An increase in complete 
response rate with this four-drug combination would be of interest. 
 


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The largest success proportion where the proposed treatment regimen would be 
considered ineffective in this population is 25%, and the smallest success proportion that 
would warrant subsequent studies with the proposed regimen in this patient population is 
45%. The following one-stage binomial design requires 36 evaluable patients to test the 
null hypothesis that the true success proportion in this patient population is at most 25%.   
.  
 
 
16.211 Final Decision Rule: Enter 36 evaluable patients into the study. If 12 or 
fewer successes are observed in the first 36 evaluable patients, we will 
consider this regimen ineffective in this patient population. Otherwise, if 
the number of successes is at least 13, this will be considered evidence of 
promising activity and the treatment may be recommended for further 
testing in subsequent studies. 
 
 
 
 
 
16.212 Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the final decision rule or 
used in any decision making process. Analyses involving over accrued 
patients are discussed in Section 16.313. 
 
 
 
 
 
16.22 Power and Significance Level: Assuming that the number of successes is 
binomially distributed, the significance level is .09, i.e. there is a 9% chance of 
finding the drug to be effective when it truly is not. The probability of declaring 
that this regimen warrants further study (i.e. statistical power) under various 
success proportions can be tabulated as a function of the true success proportion 
as shown in the following table. 
 
If the true success proportion is... 
0.25 
0.30 
0.35 
0.40 
0.45 
Then the probability of declaring 
that the regimen warrants further 
study is… 
0.09 
0.26 
0.51 
0.74 
0.89 
 
 
 
16.23 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. In each arm, 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 in 
that arm  has been followed for at least 6 months. 
 
 
 
 
 
16.31 Primary Outcome Analyses (to be evaluated in each arm independently): : 
 
 
 


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16.311 Definition: The primary endpoint in each arm of this trial is the 
proportion of patients who achieve a confirmed complete response. A 
confirmed complete response is defined as an sCR or CR  noted as the 
objective status on two consecutive evaluations at least two weeks apart. 
All patients meeting the eligibility criteria who have signed a consent 
form and have begun treatment will be evaluable for response, unless 
they are determined to be a major violation. 
 
 
 
16.312 Estimation: The proportion of successes in each arm will be estimated by 
the number of successes divided by the total number of evaluable 
patients. An exact binomial 95% confidence interval for the true success 
proportion will be calculated. 
 
 
 
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 (to be evaluated in each arm independently) 
 
16.321 The overall response rate will be estimated by the number of patients 
who achieve an sCR, CR, VGPR or PR divided by the total number of 
evaluable patients. Exact binomial 95% confidence intervals for the true 
success proportions will be calculated. 
 
16.322 The rate of ≥ VGPR will be estimated by the number of patients with a 
VGPR, CR, or sCR divided by the total number of evaluable patients. 
Exact binomial 95% confidence intervals for the true success proportions 
will be calculated. 
 
16.323 Overall survival is defined as the time from registration to death due to 
any cause. The distribution of overall survival will be estimated using the 
method of Kaplan-Meier.22  
 
16.324 Progression-free survival is defined as the time from registration to the 
earliest date of documentation of disease progression or death due to any 
cause. The distribution of progression-free survival will be estimated 
using the method of Kaplan-Meier 
 
 
 
16.325 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: Due to the small overall sample size, the results of these 
analyses will be considered exploratory and hypothesis-generating in nature. 


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16.331 Minimal residual disease will be assessed on bone marrow aspirate in all 
patients achieving CR. The proportion of patients who achieve MRD 
negative status will be estimated by the number of patients who are MRD 
negative divided by the total number of evaluable patients. Exact 
binomial 95% confidence intervals for the true MRD negative rate will 
be calculated. 
 
 
16.332  The FACT/GOG neurotoxicity questionnaire will be completed by 
patients at baseline, after each cycle for the first 4 cycles, and then every 
three cycles. Patients will be evaluated by overall score for each 
questionnaire at each time point and changes over time will be 
calculated. These measures will be correlated with outcome using 
Fisher’s exact test and Kaplan-Meier methods where appropriate. 
 
 
16.4 
Data & Safety Monitoring: 
 
 
 
16.41 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 (to be evaluated in each arm independently):  
 
 
 
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 with an attribution of possibly, probably, or definitely related to study 
treatment that satisfy one of the following: 
 
• 
if 5 or more patients in the first 13 treated patients experience a grade 4 or 
higher non-hematologic adverse event  
• 
if after the first 13 patients have been treated, 40% of all patients experience 
a grade 4 or higher non-hematologic adverse event.  
 
 
 
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. 
 


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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 
For purposes of timing of the 
Results Reporting, the initial estimated completion date for the Primary Endpoint of this 
study is  5 years after the study opens to accrual. The definition of “Primary Endpoint 
Completion Date” (PECD) for this study is at the time all patients registered have 
achieved a confirmed complete response or have discontinued treatment without 
achieving a confirmed complete response.  
 
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: 
 
 


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16.631 Accrual Estimates by Gender/Ethnicity/Race 
Ethnic Category 
Sex/Gender 
Females Males 
Unknown Total 
Hispanic or Latino 
0 
2 
0 
2 
Not Hispanic or Latino 
28 
50 
0 
78 
Ethnic Category: Total of all subjects* 
28 
52 
0 
80 
Racial Category 
 
American Indian or Alaskan Native 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
Black or African American 
2 
2 
0 
4 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
0 
White 
26 
50 
0 
76 
Racial Category: Total of all subjects* 
28 
52 
0 
80 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rico, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial  
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations 
or community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, 
China, India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, 
and Vietnam. (Note: Individuals from the Philippine Islands have been recorded as 
Pacific Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 


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


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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: None 
 
 
19.3 
Other budget concerns: None 
 
 
 


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20.0 
References 
 
 
1. 
Kumar S: Multiple myeloma - current issues and controversies. Cancer Treat Rev 36 
Suppl 2:S3-11, 2010 
 
2. 
Kumar SK, Mikhael JR, Buadi FK, et al: Management of newly diagnosed symptomatic 
multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) 
consensus guidelines. Mayo Clin Proc 84:1095-110, 2009 
 
3. 
Kumar SK, Rajkumar SV, Dispenzieri A, et al: Improved survival in multiple myeloma 
and the impact of novel therapies. Blood 111:2516-20, 2008 
 
4. 
Rajkumar SV, Jacobus S, Callander NS, et al: Lenalidomide plus high-dose 
dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed 
multiple myeloma: an open-label randomised controlled trial. Lancet Oncol 11:29-37, 2010 
 
5. 
Richardson PG, Weller E, Lonial S, et al: Lenalidomide, bortezomib, and dexamethasone 
combination therapy in patients with newly diagnosed multiple myeloma. Blood 116:679-86, 2010 
 
6. 
Cavo M, Tacchetti P, Patriarca F, et al: Bortezomib with thalidomide plus dexamethasone 
compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy 
after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised 
phase 3 study. Lancet 376:2075-85, 2010 
 
7. 
San Miguel JF, Schlag R, Khuageva NK, et al: Bortezomib plus melphalan and 
prednisone for initial treatment of multiple myeloma. N Engl J Med 359:906-17, 2008 
 
8. 
Reeder CB, Reece DE, Kukreti V, et al: Cyclophosphamide, bortezomib and 
dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II 
clinical trial. Leukemia 23:1337-41, 2009 
 
9. 
Kumar SK, Flinn I, Noga SJ, et al: Bortezomib, dexamethasone, cyclophosphamide and 
lenalidomide combination for newly diagnosed multiple myeloma: phase 1 results from the multicenter 
EVOLUTION study. Leukemia 24:1350-6, 2010 
 
10. 
Kumar S, Flinn IW, Richardson PG, et al: Novel Three- and Four-Drug Combination 
Regimens of Bortezomib, Dexamethasone, Cyclophosphamide, and Lenalidomide, for Previously 
Untreated Multiple Myeloma: Results From the Multi-Center, Randomized, Phase 2 EVOLUTION 
Study. ASH Annual Meeting Abstracts 116:621-, 2010 
 
11. 
Gupta N, Liu G, Berg D, et al: Clinical Pharmacokinetics of Intravenous and Oral 
MLN9708, An Investigational Proteasome Inhibitor: An Analysis of Data From Four Phase 1 
Monotherapy Studies. Blood (ASH Annual Meeting Abstracts) 116:abstr 1813, 2010 
 
12. 
Gupta N, Saleh M, Venkatakrishnan K: Flat-Dosing Versus BSA-Based Dosing for 
MLN9708, An Investigational Proteasome Inhibitor: Population Pharmacokinetic (PK) Analysis of 
Pooled Data From 4 Phase-1 Studies 53rd ASH Annual Meeting and Exposition. San Diego, CA, 2011, 
pp abstr 1433 
 
13. 
Kumar SK, Bensinger WI, Zimmerman TM, et al: Phase 1 study of weekly dosing with 
the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma. Blood 
124:1047-55, 2014 
 
14. 
Kumar SK, Berdeja JG, Niesvizky R, et al: Safety and tolerability of ixazomib, an oral 
proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously 
untreated multiple myeloma: an open-label phase 1/2 study. Lancet Oncol 15:1503-12, 2014 
 
15. 
Kumar SK, Berdeja JG, Niesvizky R, et al: A Phase 1/2 Study of Weekly MLN9708, an 
Investigational Oral Proteasome Inhibitor, in Combination with Lenalidomide and Dexamethasone in 
Patients with Previously Untreated Multiple Myeloma (MM). ASH Annual Meeting Abstracts 120:332-, 
2012 
 
16. 
Richardson P, Jagannath S, Schlossman R, et al: A Multi-center, Randomized, Phase 2 
Study to Evaluate the Efficacy and Safety of 2 CDC-5013 Dose Regimens When Used Alone or in 


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Combination with Dexamethasone (Dex) for the Treatment of Relapsed or Refractory Multiple Myeloma 
(MM). Blood 102:235a, 2003 
 
17. 
Lacy M, Gertz M, Dispenzieri A, et al: Lenalidomide Plus Dexamethasone (Rev/Dex) in 
Newly Diagnosed Myeloma: Response to Therapy, Time to Progression, and Survival. Blood 108:798-, 
2006 
 
18. 
Rajkumar SV, Jacobus S, Callander N, et al: Phase III trial of lenalidomide plus high-
dose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly diagnosed multiple 
myeloma (E4A03): a trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 2007 
ASCO Annual Meeting Abstracts 25 (18S):LBA8025, 2007 
 
19. 
Lokhorst HM, Plesner T, Laubach JP, et al: Targeting CD38 with Daratumumab 
Monotherapy in Multiple Myeloma. N Engl J Med, 2015 
 
20. 
Lonial S, Weiss BM, Usmani SZ, et al: Daratumumab monotherapy in patients with 
treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet, 2016 
  
21. 
Kumar et al: International Myeloma Working Group consensus criteria for response and 
minimal residual disease assessment in multiple myeloma. Lancet Oncol 2016 Aug:17(8): e328-46 
 
22. 
Kaplan E, Meier P: Nonparametric estimation from incomplete observations. J Am Stat 
Assoc 53:457-81, 1958 
 
 
 


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Appendix I 
Multiple Myeloma Diagnostic Criteria 
 
Clonal BMPC ≥10% or biopsy-proven plasmacytoma PLUS  
-Either a myeloma defining event:  
C: Hypercalcemia: serum calcium >1 mg/dL higher than the upper limit of normal or >11 mg/dL 
R: Renal insufficiency: creatinine clearance <40 mL per min or serum creatinine >2 mg/dL 
A: Anemia: hemoglobin >20 g/L below the lower limit of normal, or a hemoglobin <100 g/L 
B: Bone lesions: osteolytic lesions on x-ray, CT, or PET-CT 
-OR a biomarker of early progression 
• 
Clonal bone marrow plasma cell percentagen≥60% 
• 
Involved: uninvolved serum free light chain ratio ≥100 
• 
>1 focal lesion on MRI studies 
 
 


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Appendix II 
Mayo Risk Stratification (mSMART) 
 
 
High Risk 
FISH deletion 17p 
FISH t(4:14) 
FISH t(14:16) 
Hypodiploidy 
PCLI >3% 
 
Standard Risk 
Not high risk as defined above 
 


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


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


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Appendix V 
Revlimid REMS Required Pregnancy Information 
 
Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods 
Risks Associated with Pregnancy 
 
The use of lenalidomide in pregnant females and nursing mothers has not been studied nor has the effect 
of the lenalidomide on human eggs and sperm.  The risks to a fetus are not known.  However, because 
lenalidomide is related to thalidomide, and thalidomide is known to cause severe birth defects, the 
following requirements must be observed. 
Females of childbearing potential (FCBP)† must agree to use two reliable forms of contraception 
simultaneously or to practice complete abstinence from heterosexual intercourse during the following 
time periods related to this study: 1) for at least 28 days before starting study drug; 2) while participating 
in the study; and 3) for at least 28 days after discontinuation from the study. The two methods of reliable 
contraception must include one highly effective method (i.e. intrauterine device (IUD), hormonal [birth 
control pills, injections, or implants], tubal ligation, partner’s vasectomy) and one additional effective 
(barrier) method (i.e. latex condom, diaphragm, cervical cap).  FCBP must be referred to a qualified 
provider of contraceptive methods if needed.   
 
Before starting study drug:   
Female Subjects:   
• 
FCBP must have two negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior to 
starting lenalidomide.  The first pregnancy test must be performed within 10-14 days prior to the 
start of lenalidomide and the second pregnancy test must be performed within 24 hours prior to 
the start of lenalidomide.  The subject may not receive study drug until the Investigator has 
verified that the results of these pregnancy tests are negative. 
• 
Will be warned that sharing study drug is prohibited and will be counseled about pregnancy 
precautions and potential risks of fetal exposure.. 
• 
Must agree to abstain from donating blood during study participation and for at least 28 days 
after discontinuation from the study. 
 
Male Subjects:   
• 
Must agree to use a latex condom during sexual contact with females of childbearing potential 
while participating in the study and for at least 28 days following discontinuation from the study 
even if he has undergone a successful vasectomy.  
• 
Will be warned that sharing study drug is prohibited and will be counseled about pregnancy 
precautions and potential risks of fetal exposure,  
• 
Must agree to abstain from donating blood, semen, or sperm during study participation and for at 
least 28 days after discontinuation from the study. 
 
During study participation and for 28 days following discontinuation from the study: 
All Subjects: 
                                                 
 
† A female of childbearing potential is a sexually mature woman who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive 
months (i.e., has had menses at any time in the preceding 24 consecutive months). 
 
 
 
 


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• 
Only enough lenalidomide for one cycle of therapy may be dispensed with each cycle of 
therapy.  
• 
If pregnancy or a positive pregnancy test does occur in a study subject or the partner of a male 
study subject during study participation, lenalidomide must be immediately discontinued. 
 
Female Subjects:   
• 
FCBP with regular or no menstrual cycles must agree to have pregnancy tests weekly for the 
first 28 days of study participation and then every 28 days while on study, at study 
discontinuation, and at day 28 following discontinuation from the study. If menstrual cycles are 
irregular, the pregnancy testing must occur weekly for the first 28 days and then every 14 days 
while on study, at study discontinuation, and at days 14 and 28 following discontinuation from 
the study.   
• 
In addition to the required pregnancy testing, the Investigator must confirm with FCBP that she 
is continuing to use two reliable methods of birth control at each visit.   
• 
Counseling about pregnancy precautions and the potential risks of fetal exposure must be 
conducted at a minimum of every 28 days. During counseling, subjects must be reminded to not 
share study drug and to not donate blood, . 
 
Pregnancy testing and counseling must be performed if a subject misses her period or if her pregnancy 
test or her menstrual bleeding is abnormal.  Study drug treatment must be discontinued during this 
evaluation. 
• 
Females must agree to abstain from breastfeeding during study participation and for at least 28 
days after discontinuation from the study. 
 
Male Subjects: 
• 
Counseling about the requirement for latex condom use during sexual contact with females of 
childbearing potential and the potential risks of fetal exposure must be conducted at a minimum 
of every 28 days. During counseling, subjects must be reminded to not share study drug and to 
not donate blood, sperm, or semen, . 
 
 


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Appendix VI PATIENT MEDICATION DIARY FOR ARM A  
 
 
Please complete this diary on a daily basis. Write in the amount of the dose of lenalidomide, ixazomib 
and dexamethasone that you took in the appropriate “Day” box. 
 
On the days that you do not take any study drug, please write in “0”. If you forget to take your daily 
dose, please write in “0”, but remember to take your prescribed dose at the next regularly scheduled 
time. 
 
Please swallow the ixazomib capsules whole, with water, and not to break, chew, or open the capsules. 
They should be taken on an empty stomach, at least 1 hour before or at least 2 hours after food.  Each 
capsule should be swallowed separately with a sip of water. A total of approximately 8 ounces (240 mL) 
of water should be taken with the capsules.   
 
If you experience any health/medical complaints or take any medication other than ixazomib or 
dexamethasone, please record this information. 
 
Week of: _________________________ 
Study Drug 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Lenalidomide 
 
 
 
 
 
 
 
Ixazomib 
 
 
 
 
 
 
 
Dexamethasone 
 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Lenalidomide 
 
 
 
 
 
 
 
Ixazomib 
 
 
 
 
 
 
 
Dexamethasone 
 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Lenalidomide 
 
 
 
 
 
 
 
Ixazomib 
 
 
 
 
 
 
 
Dexamethasone 
 
 
 
 
 
 
 
 
Week of: _________________________ 
 
Patient signature: ___________________________________________ 
Date:_____________________________________________________ 
 
My next scheduled visit is: _______________________________ 
If you have any questions, please call: ______________________  
 
 
Study Drug 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
Lenalidomide 
 
 
 
 
 
 
 
Ixazomib 
 
 
 
 
 
 
 
Dexamethasone 
 
 
 
 
 
 
 


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Appendix VI PATIENT MEDICATION DIARY FOR ARM A (Maintenance)  
 
Please complete this diary on a daily basis. Write in the amount of the dose of ixazomib that you took in 
the appropriate “Day” box. 
 
On the days that you do not take any study drug, please write in “0”. If you forget to take your daily 
dose, please write in “0”, but remember to take your prescribed dose at the next regularly scheduled 
time. 
 
Please swallow the ixazomib capsules whole, with water, and not to break, chew, or open the capsules. 
They should be taken on an empty stomach, at least 1 hour before or at least 2 hours after food.  Each 
capsule should be swallowed separately with a sip of water. A total of approximately 8 ounces (240 mL) 
of water should be taken with the capsules.   
 
If you experience any health/medical complaints or take any medication other than ixazomib, please 
record this information. 
 
Week of: _________________________ 
Study Drug 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Ixazomib 
 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Ixazomib 
 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Ixazomib 
 
 
 
 
 
 
 
 
Week of: _________________________ 
 
Patient signature: ___________________________________________ 
Date:_____________________________________________________ 
 
My next scheduled visit is: _______________________________ 
If you have any questions, please call: ______________________  
 
 
Study Drug 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
Ixazomib 
 
 
 
 
 
 
 


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PATIENT MEDICATION DIARY FOR ARM B (Cycles 1 & 2)   
 
Please complete this diary on a daily basis. Write in the amount of the dose of lenalidomide, ixazomib 
and dexamethasone that you took in the appropriate “Day” box. 
 
On the days that you do not take any study drug, please write in “0”. If you forget to take your daily 
dose, please write in “0”, but remember to take your prescribed dose at the next regularly scheduled 
time. 
 
Please swallow the ixazomib capsules whole, with water, and not to break, chew, or open the capsules. 
They should be taken on an empty stomach, at least 1 hour before or at least 2 hours after food.  Each 
capsule should be swallowed separately with a sip of water. A total of approximately 8 ounces (240 mL) 
of water should be taken with the capsules.   
 
If you experience any health/medical complaints or take any medication other than ixazomib or 
dexamethasone, please record this information. 
 
Dexamethasone will be taken for cycles 1 and 2 only (unless your doctor instructs you otherwise) 
 
Week of: _________________________ 
Study Drug 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Lenalidomide 
 
 
 
 
 
 
 
Ixazomib 
 
 
 
 
 
 
 
Dexamethasone 
 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Lenalidomide 
 
 
 
 
 
 
 
Ixazomib 
 
 
 
 
 
 
 
Dexamethasone 
 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Lenalidomide 
 
 
 
 
 
 
 
Ixazomib 
 
 
 
 
 
 
 
Dexamethasone 
 
 
 
 
 
 
 
 
Week of: _________________________ 
 
Patient signature: ___________________________________________ 
Date:_____________________________________________________ 
 
My next scheduled visit is: _______________________________ 
If you have any questions, please call: ______________________  
Study Drug 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
Lenalidomide 
 
 
 
 
 
 
 
Ixazomib 
 
 
 
 
 
 
 
Dexamethasone 
 
 
 
 
 
 
 


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PATIENT MEDICATION DIARY FOR ARM B (Cycles 3 and beyond)   
Please complete this diary on a daily basis. Write in the amount of the dose of lenalidomide, ixazomib 
and dexamethasone that you took in the appropriate “Day” box. 
 
On the days that you do not take any study drug, please write in “0”. If you forget to take your daily 
dose, please write in “0”, but remember to take your prescribed dose at the next regularly scheduled 
time. 
 
Please swallow the ixazomib capsules whole, with water, and not to break, chew, or open the capsules. 
They should be taken on an empty stomach, at least 1 hour before or at least 2 hours after food.  Each 
capsule should be swallowed separately with a sip of water. A total of approximately 8 ounces (240 mL) 
of water should be taken with the capsules.   
 
If you experience any health/medical complaints or take any medication other than ixazomib or 
dexamethasone, please record this information. 
 
Week of: _________________________ 
Study Drug 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Lenalidomide 
 
 
 
 
 
 
 
Ixazomib 
 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Lenalidomide 
 
 
 
 
 
 
 
Ixazomib 
 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Lenalidomide 
 
 
 
 
 
 
 
Ixazomib 
 
 
 
 
 
 
 
 
Week of: _________________________ 
 
Patient signature: ___________________________________________ 
Date:_____________________________________________________ 
 
My next scheduled visit is: _______________________________ 
If you have any questions, please call: ______________________  
 
 
Study Drug 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
Lenalidomide 
 
 
 
 
 
 
 
Ixazomib 
 
 
 
 
 
 
 


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PATIENT MEDICATION DIARY (Cycles 13 and beyond)   
 
Please complete this diary on a daily basis. Write in the amount of the dose of lenalidomide, ixazomib 
and dexamethasone that you took in the appropriate “Day” box. 
 
On the days that you do not take any study drug, please write in “0”. If you forget to take your daily 
dose, please write in “0”, but remember to take your prescribed dose at the next regularly scheduled 
time. 
 
Please swallow the ixazomib capsules whole, with water, and not to break, chew, or open the capsules. 
They should be taken on an empty stomach, at least 1 hour before or at least 2 hours after food.  Each 
capsule should be swallowed separately with a sip of water. A total of approximately 8 ounces (240 mL) 
of water should be taken with the capsules.   
 
If you experience any health/medical complaints or take any medication other than ixazomib  , please 
record this information. 
 
  
 
Week of: _________________________ 
Study Drug 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Ixazomib 
 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Ixazomib 
 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Ixazomib 
 
 
 
 
 
 
 
 
Week of: _________________________ 
 
 
Patient signature: ___________________________________________ 
 
Date:_____________________________________________________ 
 
My next scheduled visit is: _______________________________ 
If you have any questions, please call: ______________________  
 
 
 
Study Drug 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
Ixazomib 
 
 
 
 
 
 
 


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Version Date:  November 20, 2019 
Appendix VII FACT/GOG NTX (Version 4) 
 
 


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Appencix VIII – Patient Information Sheet  
 
Patient Completed Booklet 
________________________________________________________________________ 
 
You have been given a booklet to complete for this study. The booklet contains some 
questions about your health as a patient receiving treatment for cancer. You answers will 
help us to better understand how the treatment you are receiving is affecting the way you 
feel. 
 
 
1. This booklet contains one set of questions: 
FACT GOG NTX (Version 4) Questionnaire (38 questions) 
 
2. Please select one answer for each question. 
 
3. Please complete the booklet during your scheduled clinical visit and return it to your 
nurse or your physician. 
 
Thank you for taking the time to help us.