Clinical trial NCT01718743
Conditions: Hematopoietic Cell Transplantation Recipient Plasma Cell Myeloma
Sponsor: M.D. Anderson Cancer Center
Start date: 2012-12-03; Completion date: 2023-04-12
Enrollment: 64 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well ixazomib citrate and lenalidomide after stem cell transplant 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. Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. Giving ixazomib citrate together with lenalidomide may be effective in treating multiple myeloma.

Detailed description:
PRIMARY OBJECTIVES:

I. Establish safety and efficacy of oral ixazomib citrate (MLN 9708) and lenalidomide in the maintenance setting post autologous stem cell transplant (ASCT) in myeloma patients.

SECONDARY OBJECTIVES:

I. Incidence of secondary primary malignancy.

II. Evaluate the best response rate (stringent complete response \[sCR\]/near complete response \[nCR\]/very good partial response \[VGPR\]/partial response \[PR\]).

III. Evaluate time to progression.

IV. Evaluate time to next therapy.

V. Evaluate the tolerability and toxicity.

VI. Evaluate M. D. Anderson Symptom Inventory (MDASI)-myeloma symptom evaluation.

OUTLINE:

Beginning 60-180 days post-transplant, patients receive ixazomib citrate orally (PO) on days 1, 8, and 15 and lenalidomide PO on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

Arms: arm 1: Beginning 60-180 days post-transplant, patients receive ixazomib citrate PO on days 1, 8, and 15 and lenalidomide PO on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Ixazomib Citrate intervention 2: Lenalidomide intervention 3: Questionnaire Administration
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Ancillary studies

Protocol documents:
Prot_SAP_000.pdf: 
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MD Anderson IND Sponsor Cover Sheet 
Protocol ID 
2012-0277 
Protocol Title 
Phase II Study of the Combination of MLN 9708 with Lenalidomide as 
Maintenance Therapy post Autologous Stem Cell Transplant in Patients 
with Multiple Myeloma 
Phase 
Phase I 
Protocol Version 
9 (Institutional Version 34) 
Version Date 
12/06/2019 
Protocol PI 
Krina Patel, MD 
Department 
Lymphoma/Myeloma 
Investigational 
Products 
MLN 9708 with Lenalidomide 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
116,747 
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Phase II Study of the combination of MLN 9708 with Lenalidomide 
as Maintenance Therapy post Autologous Stem Cell Transplant in 
Patients with Multiple Myeloma 
 
 
Protocol History 
Original 
June 25, 2012 
 
 
Version 1 
September 26, 2012 
Version 2 
November 6, 2012 
Version 3 
July 29, 2013 
Version 4 
Sept 29, 2014 
Version 5 
September 2, 2015 
Version 6 
October 29, 2015 
Version 7 
October 5, 2016 
Version 8 
January 11, 2018 
Version 9 
December 6, 2019 
 
Principal Investigator and Study Center: 
Krina Patel, MD 
Assistant Professor 
Department of Lymphoma/Myeloma 
Unit 429 
M.D. Anderson Cancer Center 
Houston, Texas 77030 
(o) 713 792-2860 
(f) 713 794-5656 
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1. 
INTRODUCTION AND STUDY RATIONALE 
 
1.1 
Overview of the Disease 
 
Management of Myeloma has changed significantly over the past 10 years. The use 
consolidation of induction therapy with autologous stem cell transplantation (ASCT) has 
become an important part of the therapeutic plan for transplant eligible patients with 
multiple myeloma [1-5] demonstrating improvements in responses and translated to PFS and 
OS benefits. Based on the findings of 6 international trials looking at ASCT, the ASCT 
regimen of melphalan 200 mg/m2 has become the standard of care. 
 
Despite the clinical benefit with the use of ASCT, myeloma continues to remain incurable, 
and patients progress within 2-3 years of single ASCT. 
 
Several strategies, have attempted to improve on the single autologous transplant, using 
either consolidation or maintenance therapy. Various consolidation strategies include use of 
a second autologous stem cell transplant or combination chemotherapy/ 
 
A second strategy uses chemotherapy either as a single agent bortezomib or combinations 
regimens including bortezomib/thalidomide/dexamethasone or bortezomib/ lenalidomide/ 
dexamethasone. An ongoing national intergroup trial is designed to answer the role of 
consolidation therapy and the best strategy. 
 
The second strategy to improve outcomes post transplant have been the use of long term 
maintenance therapy. Initial trials evaluated the use of alpha-interferon, prednisone with no 
significant benefit in survival and significant toxicity. 
 
Multiple trials have studied immunomodulatory therapy with thalidomide to improve 
progression free survival post ASCT. All of the trials showed improvement in progression 
free survival however only 3 showed benefit in overall survival. Subset analysis showed 
benefit limited to patients in a partial remission post transplant and no benefit for patients 
with high risk cytogenetics and patients in a deeper remission including complete remission. 
The use of thalidomide has been limited by development of toxicity with long term use 
including neuropathy, somnolence and fatigue. 
 
A second generation Imid, lenalidomide has been developed with improved side effect 
profile with limited neuropathy and somnolence. Lenalidomide has been approved in the 
relapsed myeloma in combination with dexamethasone. 
 
Two trials have evaluated the role of lenalidomide in the post- transplant setting as 
maintenance therapy, in the US as an intergroup effort led by the CALBG, and the IFM 
group (1, 2). Continuous low dose lenalidomide demonstrated similar results between both 
studies with significant benefit in progression free survival. There was an absolute18-20 
month increase in PFS, with an increase from 22+ months to 40+ months .  The CALBG 
trial more recently and importantly has demonstrated early overall survival benefit. 
The benefit in PFS with lenalidomide,  has also present in patients with high risk 
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cytogenetics and patient in complete remission post ASCT, which was not seen with 
maintnenace thalidomide. The use of maintenance lenalidomide has been very well 
tolerated with minimal neuropathy. The major toxicity has been leucopenia with limited 
neutropenic fevers. The second emerging signal has been development of second primary 
malignancies with use of lenalidomide and  additional followup and data is needed. 
In congregate the significant clinical benefit with improvement in PFS, limited side effect 
profile has established lenalidomide as an important therapeutic option. 
 
Proteaseome inhibition has been studied post transplant in a hybrid consolidation 
/maintenance model with predefined course of bortezomib based therapy, which was well 
tolerated and led to significant improvement in response rates and benefit in PFS. However 
long term proteasome inhibitor therapy has been limited by the necessary IV administration. 
 
The combination of proteasome inhibitors and immunomodulatory agents have strong 
preclinical rationale which have been confirmed with high response rates with all 
combinations of PI+IMid in both newly diagnosed and relapsed/refractory myeloma. 
 
MLN9708 offers an exciting new opportunity as an active proteasome inhibitor with oral 
administration of therapy to be studied in the maintenance therapy. Multiple ongoing studies 
of MLN9708 as single agent and in combination with lenalidomide therapies are onging. 
 
New treatment strategies to continue to improve progression free survival with maintenance 
therapy in an important window of opportunity to improve survival in patients with 
myeloma. We propose the addition of MLN9708 to lenalidomide as maintenance therapy 
will be a well tolerated regimen and lead to significant improvement in duration of 
remission post- transplant. 
 
 
1.2 
MLN9708 
 
1.2.1 
Scientific Background 
 
1.2.2 Please refer to the current MLN9708 Investigator’s Brochure (IB) and Safety 
Management AttacNonclinical Pharmacology 
 
Please refer to the current MLN9708 Investigator’s Brochure (IB) and Safety Management 
Attachment (SMA). 
 
1.2.3 
Nonclinical Pharmacokinetics and Pharmacodynamics 
 
Please refer to the current MLN9708 Investigator’s Brochure (IB) and Safety Management 
Attachment (SMA). 
 
1.2.4 Safety Pharmacology 
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Please refer to the current MLN9708 Investigator’s Brochure (IB) and Safety Management 
Attachment (SMA). 
 
1.2.5 
Toxicology 
 
Please refer to the current MLN9708 Investigator’s Brochure (IB) and Safety Management 
Attachment (SMA). 
1.2.6 Clinical Experience 
 
As of 12 October 2011, 247 patients have been treated with MLN9708 across 7 enrolling, 
sponsor-led phase 1 or phase 1/2 studies evaluating both twice-weekly and weekly dosing 
schedules. Regardless of the route of administration in the twice-weekly dosing schedule, 
MLN9708 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. Ongoing and planned studies 
include: 
 
• Study C16001: phase 1, single-agent intravenous (IV) administration twice weekly 
in adult patients with advanced nonhematologic malignancies; N = 111 
 
• Study C16002: phase 1, single-agent IV administration weekly in adult patients with 
advanced lymphoma; N = 21 
 
• Studies C16003 and C16004: phase 1, single-agent oral (PO) administration twice 
weekly and weekly, respectively, in adult patients with relapsed or refractory MM 
(RRMM) (previous exposure to bortezomib, IMiD, and corticosteroid required); N = 
56 and 32, respectively 
 
• Study C16005: phase 1/2, PO administration weekly in combination with 
lenalidomide and low-dose dexamethasone every 28 days in adult patients with 
previously untreated transplant eligible MM; N = 15 
 
• Study C16006: phase 1/2, PO administration twice weekly and weekly in 
combination with melphalan and prednisone (MP) in patients with previously 
untreated transplant ineligible MM; N = 6 
 
• Study C16007: phase 1, single-agent PO administration weekly in patients with 
relapsed or refractory light-chain amyloidosis; N = 6 
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In addition to the trials noted above, there are currently 4 planned trials, each of which will 
use the PO formulation of MLN9708.  These studies include: 
 
• Study C16008: PO twice-weekly administration in combination with lenalidomide 
and low-dose dexamethasone every 21 days in adult patients with newly diagnosed 
multiple myeloma (NDMM) 
 
• Study C16009: PO administration on Days 1 and 15 of the first 28-day cycle to 
assess drug-drug interactions (DDIs) with ketoconazole, relative bioavailability, and 
food effect in patients with advanced solid tumor malignances, lymphoma, or 
Waldenström’s macroglobulinemia; in subsequent cycles, PO administration on 
Days 1, 8, and 15 
 
Both Study C16008 and Study C16009 are in the process of institutional review board (IRB) 
and independent ethics committee (IEC) reviews and have not yet begun to enroll patients 
(for additional information, please refer to ClinicalTrials.gov). 
 
The 2 planned phase 3 trials are: 
 
• Study C16010: phase 3 trial of lenalidomide and dexamethasone with MLN9708 or 
placebo given weekly in patients with relapsed or refractory MM; currently in the 
development stage 
 
• Study C16011: phase 3 trial of dexamethasone with MLN9708 given weekly versus 
physician’s choice from a preselected list of available therapy in patients with 
relapsed or refractory AL amyloidosis; currently in the development stage 
 
1.2.6.1 
Pharmacokinetics and Drug Metabolism 
 
Clinical IV and PO pharmacokinetic (PK) data show that MLN9708 (measured as the 
biologically active boronic acid form of MLN9708 [MLN2238]) has multi-exponential 
disposition with a rapid initial phase that is largely over by 4 hours. Oral MLN9708 is 
rapidly absorbed with a median time to first maximum plasma concentration (Tmax) of 
approximately 0.5 to 2.0 hours and terminal t1/2 after multiple dosing of approximately 5 to 7 
days.[1] Results of a population PK analysis (N = 137) show that there is no relationship 
between body surface area (BSA) or body weight and clearance (CL). Also, based on 
stochastic simulations for fixed dose, exposures are independent of the individual patient’s 
BSA.[2]  Based on these data, a recommendation was made for fixed dosing in clinical 
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trials. An absolute bioavailability of 67% was determined for MLN9708 using the 
population PK analysis.  See the IB for information on the PK for IV doses of MLN9708. 
 
Metabolism appears to be the major route of elimination for MLN9708, with negligible 
urinary excretion of the parent drug (< 3% of dose). In vitro studies of liver microsomes 
show that MLN9708 is metabolized by multiple cytochrome P450 enzymes (CYPs) and 
non-CYP enzymes/proteins. The rank order of relative biotransformation activity of the 5 
major human CYP isozymes is 3A4 (34.2%) > 1A2 (30.7%) > 2D6 (14.7%) > 2C9 (12.1%) 
> 2C19 (< 1%). MLN9708 is not an inhibitor of CYPs 1A2, 2C9, 2C19, 2D6, or 3A4, nor is 
it a time-dependent inhibitor of CYP3A4/5.  The potential for MLN9708 treatment to 
produce DDIs via CYP inhibition is inferred to be low; however, there may be a potential 
for DDIs with a concomitant strong CYP3A4 or CYP1A2 inhibitor because of the potential 
for first-pass metabolism when MLN9708 is administered via the PO route and because of 
the moderate contribution of CYP3A4- and CYP1A2-mediated metabolism of MLN9708 in 
human liver microsomes. MLN9708 may be a weak substrate of P-glycoprotein (P-gp), 
breast cancer resistance protein (BCRP), and multidrug resistance associated protein 
(MRP2) efflux pump transporters. MLN9708 is not an inhibitor of P-gp, BCRP, and MRP2. 
The potential for DDIs with substrates or inhibitors of P-gp, BCRP, and MRP2 is, therefore, 
inferred to be low. 
 
1.2.6.2 
Clinical Trial Experience Using the Oral Formulation of MLN9708 
 
As of 12 October 2011, a total of 115 patients have been treated with escalating doses of 
MLN9708 in 5 enrolling studies designed to investigate PO MLN9708 in patients with MM 
and amyloidosis.  These studies are outlined in Table 1-1. 
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Table 1-1 
Ongoing Studies of Oral MLN9708 
Trial/ 
Population 
Description 
Doses Investigated 
C16003 
RRMM 
N = 56 
PO, twice weekly (TW), single agent 
0.24-2.23 mg/m2, TW 
MTD:  2.0 mg/m2 
DLT:  rash, thrombocytopenia 
C16004 
RRMM 
N = 32 
PO, weekly (W), single agent 
0.24-3.95 mg/m2, W 
MTD:  2.97 mg/m2 
DLT:  rash, nausea, vomiting 
C16005 
NDMM 
N = 15 
PO, W, combination with LenDex 
1.68-3.95 mg/m2, W 
MTD:  2.97 mg/m2 
DLT: nausea, vomiting, diarrhea, syncope 
RP2D*: 4.0 mg fixed (switch to fixed dosing in 
phase 2) 
C16006 
NDMM 
N = 6 
PO, TW (Arm A) and W (Arm B), 
combination with melphalan and 
prednisone 
Arm A*: 3-3.7 mg, fixed dose, TW 
Arm B*:  3-4.0 mg, fixed dose, W 
C16007 
RR-AL 
N = 6 
PO, W, single agent 
4-5.5 mg, fixed dose*, W 
Abbreviations: AL = Primary systemic light chain (AL) amyloidosis ; DLT = dose-limiting toxicity; 
LenDex = lenalidomide plus dexamethasone; MTD = maximum tolerated dose; NDMM = newly 
diagnosed multiple myeloma; PO = orally; RRAL = relapsed refractory amyloidosis; RRMM = 
relapsed and/or refractory multiple myeloma. 
* Approximate body surface area (BSA) and fixed dosing equivalence: 3 mg ~ equivalent to 1.68 mg/m2 
BSA dosing; 4.0 mg ~ equivalent to 2.23 mg/m2 BSA dosing; and 5.5 mg ~ equivalent to 2.97 mg/m2 
BSA dosing. 
 
The emerging clinical safety profile pooled from the ongoing trials indicates that PO 
MLN9708 is generally well tolerated with manageable, reversible, dose-dependent treatment 
emergent adverse events (TEAEs) that are consistent with class-based effects of proteasome 
inhibition though frequencies differ. As of 12 October 2011, the most frequent (> 10%) 
TEAEs irrespective of causality to PO MLN9708 (pooled data) are listed in Table 1-2. 
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Table 1-2 
Oral MLN9708 Potential Risks Irrespective of Causality 
12 October 2011 (N = 115) 
 
 
Adverse Drug Reactions 
Fatigue (53%) 
Thrombocytopenia (36%) 
Skin rash (all terms) (36%) 
Nausea (35%), diarrhea (34%), vomiting (30%) 
Potential Risks Reported (> 10%) Due to 
MLN9708 or Disease Under Study 
Anemia (24%), neutropenia (17%) 
Anorexia (17%), fever (17%) 
Peripheral neuropathy (16%) 
Upper respiratory infection (15%) 
Cough (15%), arthralgias (15%) 
Dizziness (14%) 
Constipation (13%), headache (13%) 
Dehydration (10%), shortness of breath (10%) 
Abdominal (10%) or back pain (10%) 
Peripheral edema (10%) 
 
 
 
 
1.2.6.3 
Relapsed and/or Refractory Multiple Myeloma 
 
As of 12 October 2011, there are 2 ongoing, phase 1 clinical trials investigating PO 
MLN9708 in RRMM. In Study C16003 of twice-weekly MLN9708 (21-day cycle, Days 1, 
4, 8, and 11), the MTD is 2.0 mg/m2. In Study C16004 of weekly MLN9708 (28-day cycle, 
Days 1, 8, and 15), the MTD is 2.97 mg/m2. In both trials, patients are enrolled into the 
following defined expansion cohorts: RRMM, bortezomib relapsed, proteasome inhibitor 
naïve, and carfilzomib exposed.  Study C16003 (single agent, twice weekly) has completed 
accrual and Study C16004 (single agent, weekly) is enrolling patients into the expansion 
cohorts. 
 
Study C16003:  Single-agent, Twice-Weekly MLN9708 
 
Study C16003 has enrolled 56 patients with the following characteristics:  median age of 
65.5 years (range 50–86); median time since initial MM diagnosis of 4.7 years 
(range 1.1-24.3); median number of prior therapies of 4 (range 1–28); 57% of patients had 
received stem cell transplant; 88%, 79%, 59%, and 4% had prior therapy with bortezomib, 
lenalidomide, thalidomide, and carfilzomib, respectively; and 52% were refractory to last 
therapy, including 28% who were bortezomib-refractory.  Patients have received a median 
of 3.5 cycles of therapy (range 1-23+). Six patients have achieved at least a partial response 
(PR) (1 very good partial response [VGPR] and 5 PRs); additionally, 1 patient has achieved 
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a minor response (MR), and 28 patients have achieved durable disease stabilization for up to 
12.9 months.[3] 
 
In Study C16003, 1 of 3 patients experienced a protocol-defined dose-limiting toxicity 
(DLT) (Grade 3 rash) at a dose of 2.23 mg/m2. Another patient at this dose experienced 
Grade 4 thrombocytopenia (platelet count of 10,000/mm3). Per protocol, a DLT related to 
platelets required either a platelet count < 10,000/mm3 or Grade 4 thrombocytopenia lasting 
more than 7 consecutive days; therefore, a platelet count equal to 10,000/mm3 did not 
formally meet the protocol definition for DLT.  Although thrombocytopenia and rash have 
been identified as adverse drug reactions (see the IB), both events have predictable patterns, 
are reversible (spontaneously or with standard medical treatment), and can be monitored in 
the clinic with routine clinical observations and tests. Therefore, after a discussion with the 
participating investigators, an intermediate yet lower dose was allowed in the C16003 
protocol and supported by available PK data to further characterize dose-related toxicities. 
Six patients were treated at the intermediate dose of 2.0 mg/m2, a dose approximately half 
way between the 2 existing dose levels of 2.23 mg/m2 and 1.68 mg/m2 (a dose without any 
DLTs). Given that not 1 patient (0/6) has experienced a DLT, the MTD of MLN9708 
administered PO, twice weekly was determined to be 2.0 mg/m2.[3] 
A summary of the safety profile of patients treated in Study C16003 is outlined in Table 1-3. 
Overall, 98% of patients experienced a TEAE of any grade and of any cause. 
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Table 1-3 
Study C16003, Twice–Weekly, Single–agent, Oral MLN9708: Most 
Common Treatment-Emergent Adverse Events as of 12 October 2011 
(N= 56) 
 
 
Most Common (> 20%) Any Grade and Irrespective 
of Cause 
Fatigue (57%) 
Skin rash (all terms) (50%) 
Thrombocytopenia (41%) 
Nausea (34%), diarrhea (36%) 
Vomiting and fever (30% each) 
Cough (25%) 
Anorexia (23%) 
Neutropenia (21%) 
 
 
Drug-Related Peripheral Neuropathy (PN) (n = 6) 
4 patients with worsening to Grade 1 
2 patients with worsening to Grade 2 
All 6 had baseline Grade 1 PN at study entry 
Drug-Related Grade ≥ 3 in more than 2 Patients 
(Overall 34 patients with at least 1 drug-related Grade 
3 or higher adverse event) 
Thrombocytopenia (n = 19) 
Neutropenia (n = 8) 
Fatigue (n = 5) 
Rash (all terms) (n = 5) 
Abdominal pain, anemia, hypophosphatemia, and 
leucopenia (n = 2 each) 
 
 
 
Fifteen patients have experienced drug-related serious adverse events (SAEs) involving the 
following events: thrombocytopenia; anemia; neutropenia; febrile neutropenia; nausea; 
vomiting; abdominal pain; chest pain (noncardiac); orthostatic hypotension, hypotension, or 
hypophosphatemia; hyperuricemia; febrile neutropenia; fever; chills; rash, pneumonia; 
hypoxia; pulmonary hypertension; fall; headache; fatigue; and dehydration. Five patients 
discontinued therapy due to TEAEs (thrombocytopenia, pulmonary hypertension, and 
pruritic rash) that were considered at least possibly related to MLN9708, and spinal cord 
compression and bone pain, both considered related to disease progression. The 2 on-study 
deaths reported were not related to study drug.[3] 
 
Study C16004:  Single-agent, Weekly MLN9708 
 
In Study C16004, where MLN9708 is administered weekly, 28 patients have been enrolled 
to the dose-escalation phase as of 12 October 2011. Patient characteristics included median 
age of 64 years (range 40–76), median time since initial MM diagnosis of 4.9 years (range 
1.5–18.8), and median number of prior therapies of 6 (range 2–14); 72% of patients had 
received SCT; 97%, 91%, 56%, and 6% had prior bortezomib, lenalidomide, thalidomide, 
and carfilzomib, respectively; and 56% were refractory to last therapy, including 28% 
refractory to bortezomib and 41% refractory to lenalidomide-thalidomide.  Patients have 
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received a median of 2 cycles of therapy (range 1-11+). Two patients in the dose-escalation 
phase have achieved an objective response: 1 achieved a VGPR (relapsed after 4 prior lines 
of therapy including SCT, thalidomide, bortezomib, lenalidomide, and carfilzomib); and 1 
achieved a PR (relapsed after 4 prior lines of therapy including SCT, thalidomide, 
lenalidomide, perifosine, and bortezomib) . Additionally, 6 patients achieved durable 
disease stabilization for up to 9.5 months. At data cut-off, 2 patients remain on treatment; 
discontinuation has been due mainly to progressive disease (69%).[4] 
 
In Study C16004, 2 of 3 patients experienced a protocol-defined DLT (Grade 3 rash and 
Grade 3 nausea, vomiting, and diarrhea) at a dose of 3.95 mg/m2. Per the protocol, 
subsequent patients were treated at 1 dose level below (2.97 mg/m2) where 1 of 6 patients 
experienced a protocol-defined DLT (Grade 3 nausea, vomiting, and diarrhea).  Based on 
this information and other safety data, the MTD of weekly PO MLN9708 was determined to 
be 2.97 mg/m2. This dose cohort is currently being expanded to further evaluate the safety 
and activity of MLN9708.[4] 
 
Table 1-4 provides a summary of the safety profile of patients treated in Study C16004. 
Overall, 97% of patients experienced a TEAE of any grade and of any cause. 
 
Table 1-4 
Study C16004, Weekly Single-agent Oral MLN9708:  Most Common 
Treatment-Emergent Adverse Events as of 12 October 2011 (N = 32) 
 
 
Most Common (> 20%) 
Any Grade and Irrespective of Cause 
Fatigue (50%) 
Thrombocytopenia (34%) 
Nausea (38%), diarrhea (31%) 
Vomiting (28%) 
 
 
Drug-Related Peripheral Neuropathy (PN) (n = 3) 
1 patient with worsening to Grade 1 
2 patients with worsening to Grade 2 
All 3 events were baseline Grade 1 PN at study entry 
Drug-Related Grade ≥ 3 in more than 2 Patients 
(Overall, there have been 8 patients with at least 1 
drug-related Grade 3 or higher adverse event) 
Thrombocytopenia (n = 4; 1 Grade 4 and 3 Grade 3) 
Neutropenia and diarrhea (n = 3 each) 
Nausea and Fatigue (n = 2 each) 
Anemia, dehydration, vomiting, dizziness, rash 
(erythema multiforme) (n = 1 each) 
 
 
 
There have been 2 drug-related SAEs involving diarrhea, dehydration, and dizziness. Six 
patients discontinued therapy due to a TEAE (thrombocytopenia, rash, neutropenia, 
diarrhea, nausea, vomiting, and abdominal pain) that was considered at least possibly related 
to MLN9708. The 1 on-study death reported was determined to be related to disease 
progression.[4] 
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1.2.6.4 
Newly Diagnosed Multiple Myeloma (NDMM) 
 
Study C16005 has completed enrollment to the phase 1 portion of the study and is enrolling 
into the phase 2 portion. MLN9708 is given weekly on Days 1, 8, and 15 with lenalidomide 
on Days 1 through 21 and dexamethasone on Days 1, 8, 15, and 22 of a 28-day cycle. This 
study has enrolled 15 patients as of the clinical data cut (12 Oct 2011) to 4 dose cohorts. No 
DLTs were seen at doses up to 2.23 mg/m2. Three of 3 patients treated at the 3.95 mg/m2 
dose cohort experienced Grade 3 nausea and vomiting despite adequate antiemetic therapy; 
1 patient additionally experienced Grade 2 syncope, and, in another patient the dose of 
lenalidomide was compromised such that < 80% of the planned doses were received.  Per 
the protocol, subsequent patients were treated at 1 dose level below (2.97 mg/m2),  at which 
1 of 6 patients experienced a protocol-defined DLT (Grade 3 rash). The MTD of weekly 
MLN9708 in combination with a 28-day cycle of lenalidomide and dexamethasone was 
established at 2.97 mg/m2. The recommended phase 2 dose (RP2D) estimation was 
established following evaluation of the available data from the phase 1 portion of the trial, 
which included, but were not limited to, analyses of efficacy results (response rates: 
complete response [CR] and VGPR) and toxicity characterization (Grade 3/4 AEs, SAEs, all 
grades peripheral neuropathy, and treatment discontinuation). For the purpose of the RP2D 
estimation, Cycle 1 data from 6 evaluable patients were used in addition to the available 
clinical data supporting tolerance over multiple treatment cycles. Based on this review, the 
RP2D dose was determined to be 2.23 mg/m2 in this combination. The clinical development 
of MLN9708 included a population PK analysis evaluating the feasibility of switching from 
BSA-based dosing to fixed dosing.[2] The results of this analysis support this transition; 
therefore, in Study C16005, all patients treated in the phase 2 portion of the trial will receive 
PO MLN9708 at a dose of 4.0 mg (the RP2D dose of 2.23 mg/m2 × the mean patient BSA of 
1.86 m2).[5] 
 
As of 12 October 2011, patients in Study C16005 have completed a median of 5 cycles 
(range 1-9). To date, all 15 response-evaluable patients have achieved at least a PR to 
therapy, including 4 CRs, 4 VGPRs, and 7 PRs; 14/15 of patients achieved at least a PR by 
the end of  Cycle 1, and all 15 achieved at least a PR after Cycle 2.[5] 
 
Table 1-5 provides a summary of the safety profile of patients treated in Study C16005. 
Overall, 100% of patients experienced a TEAE of any grade and of any cause. 
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Table 1-5 Study C16005, Weekly Oral MLN9708 Administered in Combination 
With Lenalidomide and Dexamethasone: Most Common Treatment- 
Emergent Adverse Events as of 12 October 2011 (N = 15) 
 
 
Most Common (> 20%) 
Any Grade and Irrespective of Cause 
Fatigue (60%) 
Vomiting (53%) 
Anemia (40%) 
Diarrhea and nausea (33% each) 
Insomnia, peripheral edema, and thrombocytopenia 
(27% each) 
 
 
Drug-Related Peripheral Neuropathy (PN) (n = 3) 
2 patients developed Grade 1 PN 
Drug-Related Grade ≥ 3 in ≥ 2 Patients (Overall, 8 
patients with at least 1 drug-related Grade 3 or higher 
adverse event) 
Rash and vomiting (n = 2 each) 
 
 
 
Related means to ANY drug in the study drug combination. 
 
 
There have been no on-study deaths. One patient has discontinued study drug due to a 
TEAE deemed unrelated to study drug. Four patients have experienced drug-related SAEs 
involving nausea, vomiting, dehydration, dizziness, fainting, orthostatic hypotension, 
hypotension, deep vein thrombosis (DVT), atrial fibrillation, and muscle weakness.[5] 
 
An additional study is being conducted in patients with NDMM, Study C16006, “An Open- 
Label, Dose-Escalation, Phase 1/2 Study of the Oral Form of MLN9708, a Next-Generation 
Proteasome Inhibitor, Administered in Combination With a Standard Care Regimen of 
Melphalan and Prednisone in Patients With Newly Diagnosed Multiple Myeloma Requiring 
Systemic Treatment”. In this study, PO MLN9708 is being administered on the twice- 
weekly schedule in 1 group and on the weekly schedule in a second group. This study 
recently started to enroll patients. As of 12 October 2011, 6 patients, 3 per treatment group, 
have been treated, and all patients have received a fixed starting dose of 3.0 mg with 
standard doses of melphalan and prednisone. 
 
1.2.6.5 
Clinical Trial Experience Using the Intravenous Formulation of MLN9708 
 
See the IB for descriptions of the 2 ongoing studies investigating IV MLN9708 in advanced 
solid tumors and advanced lymphoma (Studies C16001 and C16002, respectively). 
 
1.2.6.6 
Clinical Trial Safety Experience: Pooled Intravenous and Oral Formulation 
 
The potential risks reported with MLN9708 use, pooled from the enrolling 7 phase 1 and 
phase 1/2 clinical studies (including both IV and PO formulations) are shown in Table 1-6. 
Although the predominant potential toxicities may be severe in some cases, they are largely 
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reversible and can be managed by routine clinical monitoring and standard medical 
interventions, which may include dose reduction or supportive care. There is also 
consistency in the type of TEAE reported regardless of the MLN9708 formulation, even 
though there are differences in the frequency and severity of the reported events. Over all, 
the weekly schedule is active and has milder toxicities than the twice-weekly schedule. The 
most frequent AEs, listed in Table 1-6, were anticipated based on nonclinical data and 
previous experience with bortezomib. 
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Table 1-6 
 MLN9708 Potential Risks (Pooled Intravenous and Oral Formulations) 
as of 12 October 2011 
 
 
Adverse Drug Reactions 
Thrombocytopenia 
Skin rash (Includes terms: erythematous, generalized, 
pruritic, macular, macula-papular, papular) 
Nausea, vomiting, diarrhea 
Fatigue 
Potential Risks Reported (> 10%) Due to 
MLN9708 or Disease Under Study 
Fever 
Anorexia, constipation, dehydration 
Anemia, neutropenia 
Headache 
Dizziness 
Upper Respiratory Infection, dyspnea, cough 
Chills 
Arthralgia 
Abdominal or back pain 
Peripheral edema 
 
 
 
Please refer to the current MLN9708 Investigator’s Brochure (IB) and Safety Management 
Attachment (SMA) for more information. 
 
 
1.2.7         Potential Risks of MLN9708 
 
Please refer to the current MLN9708 Investigator’s Brochure (IB) and Safety Management 
Attachment (SMA). 
 
1.3         Lenalidomide (CC-5013) 
REVLIMID® (lenalidomide), a thalidomide analogue, is an immunomodulatory agent with 
anti-angiogenic properties. The chemical name is 3-(4-amino-1-oxo 1,3-dihydro -2H- 
isoindol-2-yl) piperidine-2,6-dione and it has the following chemical structure: 
Chemical Structure of Lenalidomide 
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O 
H 
N 
 
 
O 
 
N 
O 
 
NH2 
3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione 
The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight is 
259.3. 
Lenalidomide is off-white to pale-yellow solid powder. It is soluble in organic solvent/water 
mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in organic solvents 
and low pH solutions. Solubility was significantly lower in less acidic buffers, ranging from 
about 0.4 to 0.5 mg/ml. Lenalidomide has an asymmetric carbon atom and can exist as the 
optically active forms S(-) and R(+), and is produced as a racemic mixture with a net optical 
rotation of zero. 
REVLIMID® (lenalidomide) is available in 5 mg capsules for oral administration. Each 
capsule contains lenalidomide as the active ingredient and the  following  inactive 
ingredients: lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, and 
magnesium stearate. The 5 mg capsule shell contains gelatin, titanium dioxide and black ink. 
The 10 mg capsule shell contains gelatin, FD&C blue #2, yellow iron  oxide,  titanium 
dioxide and black ink. 
REVLIMID® (lenalidomide) is indicated for the treatment of patients with transfusion- 
dependent anemia due to Low- or Intermediate-1-risk myelodysplastic syndromes associated 
with a deletion 5q cytogenetic abnormality with or without additional cytogenetic 
abnormalities. Revlimid® is also approved in combination with dexamethasone for the 
treatment of patients with multiple myeloma that have received at least  one prior  therapy. 
All other uses are considered investigational. 
Clinical Pharmacokinetics and Pharmacodynamics 
Absorption: 
Lenalidomide, in healthy volunteers, is rapidly absorbed following oral administration with 
maximum plasma concentrations occurring between 0.625 and 1.5 hours post-dose. Co-
administration with food does not alter the extent of absorption (AUC) but does reduce the 
maximal plasma concentration (Cmax) by 36%. The pharmacokinetic disposition of 
lenalidomide is linear. Cmax and AUC increase proportionately with increases in dose. 
Multiple dosing at the recommended dose-regimen does not result in drug accumulation. 
Pharmacokinetic sampling in myelodysplastic syndrome (MDS) patients was not performed. 
In multiple myeloma patients maximum plasma concentrations occurred between 0.5 and 
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4.0 hours post-dose both on Days 1 and 28. AUC and Cmax values increase proportionally 
with dose following single and multiple doses. Exposure (AUC) in multiple myeloma 
patients is 57% higher than in healthy male volunteers. 
1.3.1 Pharmacokinetic Parameters 
 
Distribution: 
In vitro (14C)-lenalidomide binding to plasma proteins is approximately 30%. 
Metabolism and Excretion: 
The metabolic profile of lenalidomide in humans has not been studied. In healthy volunteers, 
approximately two-thirds of lenalidomide is eliminated unchanged  through  urinary 
excretion. The process exceeds the glomerular filtration rate and therefore is partially or 
entirely active.  Half-life of elimination is approximately 3 hours. 
 
Supplier(s) 
Revlimid® (lenalidomide) will be billed to the patients insurance through  commercial 
supply to study participants. 
 
Dosage form 
Lenalidomide will be supplied as capsules for oral administration. 
 
Packaging 
.   Bottles will contain a sufficient number of capsules for one cycle of dosing. 
 
Storage 
Lenalidomide should be stored at room temperature away from direct sunlight and protected 
from excessive heat and cold. 
 
Prescribing Information 
Lenalidomide will be provided in accordance with the RevAssist® program. Per standard 
RevAssist® 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 Celgene’s RevAssist® program. Only enough 
lenalidomide for one cycle of therapy will be supplied to the patient each cycle. 
 
 
Special Populations: 
Patients with Renal Insufficiency: The pharmacokinetics of lenalidomide in MDS patients 
with renal dysfunction has not been determined. In multiple myeloma patients, those with mild 
renal impairment had an AUC 56% greater than those with normal renal function. (See 
PRECAUTIONS: Renal Impairment). 
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Patients with Hepatic Disease: The pharmacokinetics of lenalidomide in patients with 
hepatic impairment has not been studied. 
Age: The effects of age on the pharmacokinetics of lenalidomide have not been studied. 
Pediatric: No pharmacokinetic data are available in patients below the age of 18 years. 
Gender: The effects of gender on the pharmacokinetics of lenalidomide have not been 
studied. 
Race: Pharmacokinetic differences due to race have not been studied. 
 
 
1.3.2 Deep Venous Thrombosis and Pulmonary Embolism 
 
This drug has demonstrated a significantly increased risk of DVT and PE in patients with 
multiple myeloma who were treated with REVLIMID® (lenalidomide) combination therapy. 
Patients and physicians are advised to be observant for the signs and symptoms of 
thromboembolism. Patients should be instructed to seek medical care if they develop 
symptoms such as shortness of breath, chest pain, or arm or leg swelling 
OTHER ADVERSE EVENTS 
Most frequently reported adverse events reported during clinical studies  with  lenalidomide 
in oncologic and non-oncologic indications, regardless of presumed relationship to study 
medication include: anemia, neutropenia, thrombocytopenia and pancytopenia, abdominal 
pain, nausea, vomiting and diarrhea, dehydration, rash, itching, infections,  sepsis, 
pneumonia, UTI, Upper respiratory infection, cellulites, atrial fibrillation, congestive heart 
failure, myocardial infarction, chest pain, weakness, hypotension, hypercalcemia, 
hyperglycemia, back pain, bone pain, generalized pain, dizziness, mental status changes, 
syncope, renal failure, dyspnea, pleural effusion, pulmonary embolism, deep  vein 
thrombosis, CVA, convulsions, dizziness, spinal cord compression, syncope, disease 
progression, death not specified and fractures. 
 
 
1.3.3 INDICATIONS AND USAGE: 
 
Revlimid® (lenalidomide) is indicated for the treatment of patients with transfusion- 
dependent anemia due to Low- or Intermediate-1-risk myelodysplastic syndromes associated 
with a deletion 5q cytogenetic abnormality with or without additional cytogenetic 
abnormalities. Revlimid® is also approved in combination with dexamethasone for the 
treatment of patients with multiple myeloma that have received at least one prior therapy. 
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1.3.4 Clinical Experience 
 
A Phase I study in subjects with refractory or relapsed MM was conducted to identify the 
maximum tolerated dose (MTD) and to evaluate the safety of lenalidomide given orally for 
up to 4 weeks at 5 mg/day, 10 mg/day, 25 mg/day and 50 mg/day. Secondary objectives 
included evaluation of response to lenalidomide, as well as pharmacokinetics and identification 
of surrogate markers to aid in defining mechanisms of action. Subjects who tolerated study 
drug with acceptable toxicity and were without disease progression were permitted to continue 
on therapy beyond 28 days as part of an extension phase for over 1 year. Twenty-seven 
subjects were enrolled, of whom 15 had undergone prior autologous  stem  cell 
transplantation and 16 had received prior thalidomide, with a median of 3 prior regimens 
(range 2-6). All subjects had relapsed MM and 18 (72%) were refractory to salvage 
therapy. Two subjects were removed from study on the first day of treatment due to rapid 
disease progression, which resulted in renal dysfunction and rendered them ineligible. The first 
group of 3 subjects were treated for 28 d at 5 mg/d without any dose limiting toxicity (DLT). 
The second cohort of 3 subjects commenced therapy at 10 mg/day. In one subject, DLT was 
encountered with grade (G) 2 fever as well as G3 leukopenia and neutropenia, resulting in 
removal from study before day 28. Two subjects tolerated drug. Three additional subjects 
were treated at 10 mg/day with no attributable toxicity within the first 28 days. In the third 
cohort of 3 subjects at 25mg/day, drug was well tolerated within the first 28 days but G3 
thrombocytopenia and G3 and G4 neutropenia occurred during the second month,  resulting 
in 2 subjects being removed from study. In the fourth cohort at 
50mg/day, the first 3 subjects tolerated treatment without DLT in the first 28 days and a 
subsequent 10 subjects also tolerated drug without DLT within the first 28 days. However, 
subsequent G3 thrombocytopenia and G3/4 neutropenia in the extension phase has prompted 
dose reduction and GCSF support in all subjects. No significant somnolence, constipation or 
neuropathy has been seen in any cohort. Median duration of therapy is currently 4 months 
[range 2 weeks – 14 months] and 11 subjects continue on treatment. Maximal protein 
reductions seen during therapy in subjects who have received > 28d of treatment are 
summarized below: 
 
Table 1-2 
M Protein Reductions in a Phase I Study with Lenalidomide 
 
Dose [mg] 
Pts 
[n] 
< 25% 
> 25% <50% 
>50% 
Progression 
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5 
3 
- 
2 
1 
- 
10 
5 
- 
- 
1 
4 
25 
3 
1 
2 
- 
- 
50 
13 
3 
5 
4 
1 
Subtotals 
24 
4 (17%) 
9 (37%) 
6 (25%) 
5 (21%) 
 
 
 
Thus, best responses in protein of > 25% have been seen in 15 of 24 evaluable pts (63%), 
and a <25% reduction has been seen in 4 subjects to achieve stable disease or better in 19 of 
24 (79%). Pharmacokinetics [days 1-4, and 28] have been completed in 24 subjects and 
reveal rapid absorption (t max: 1-1.5 h); monophasic elimination (t ½: 3.1-4.2 h), and low to 
moderate inter-subject variability for AUC (11-52%) and C  max  (3-33%). Furthermore, 
there  was  no  significant  accumulation  by day 28. 
In  conclusion,  these  studies suggest 
Lenalidomide 
at 
the 
dose 
levels 
studied 
has 
anti-tumor 
activity, 
continuous 
pharmacokinetics (PK) with convenient daily oral dosing and acceptable toxicity in subjects 
with relapsed and refractory multiple myeloma. (Richardson et al., 2002) 
 
Given the myelosuppression beyond day 28 seen in all subjects at 50 mg/day, this dose was 
considered to be the DLT, and thus the 25 mg/day dose level as a continuous daily schedule 
of administration was considered MTD. Given the activity of the drug seen at lower dose 
levels and the PK characteristics observed, 30 mg/day in divided or single daily dose was 
assessed for activity and safety, and to determine whether a divided dose schedule  is 
superior. In addition, a 3-week on and one-week off schedule was assessed to determine if a 
cycling schedule would decrease the myelosuppression that was observed in earlier trials 
with daily dosing. In this phase II study, 70 subjects with relapsed and refractory Myeloma 
were enrolled at several centers in the U.S. Richardson et al reported that 26% of subjects 
required  dose  reduction  due  to  myelosuppression  in  this   study. 
Responses  that  were 
observed included 4% of subjects with complete responses, 17% with partial responses and 
33% with minimal responses. Progressive disease occurred in 15% of subjects (Richardson et 
al., 2002). It was concluded that daily dosing was better tolerated than twice daily dosing 
because of a lower incidence and severity of myelosuppression. 
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Data from two phase III trials comparing lenalidomide + dexamethasone to single agent 
dexamethasone in patients with relapsed and/or refractory multiple myeloma were presented 
at the 10th International Multiple Myeloma Workshop in Sydney Australia (Weber et al., 
2005;  Dimopoulos  et  al.,  2005). 
Patients  who  had  received  1-3  prior  therapies,  and 
progressing on their last therapy were randomized to receive lenalidomide, 25 mg/d x 21 d, 
placebo d22-28 plus dexamethasone, 40 mg, d 1-4, 9-12, 17-20, q 28d or placebo daily x  28 
d plus dexamethasone, 40 mg,  d 1-4,  9-12, 17-20,    q28d. 
The  responses  reported are 
summarized in Table 1-4 while the incidence of DVT and pulmonary embolism are 
summarized in Table 1-5. Anemia, thrombocytopenia, neutropenia, fatigue, neuropathy, and 
constipation were also observed more often in lenalidomide + dexamethasone group compared 
to dexamethasone only group, however these events were generally manageable. 
 
Table 1-3 
Response Rates in Phase III Trials of Relapse refractory MM (Celgene 
MM-009 and MM-010) 
 
Weber 
et 
al 
(ASCO 
05 
oral 
presentation) 
Dimopoulos et al (ASH 2005 # 6) 
Lenalidomide + 
Dexa (n=170) 
Dexa Alone 
(n=171) 
P Value 
Lenalidomide + 
Dexa (n=176) 
Dexa 
Alone 
(n=175) 
P Value 
Overall 
Response 
Rate (%) 
61% 
23% 
≤0.001 
59% 
24% 
≤0.001 
TTP (mo.) 15 
5 
≤0.00001 11.3 
4.7 
≤0.00001 
 
 
 
Table 1-4 
DVT & PE Risks in Phase III Trials of Relapse refractory MM  (Celgene 
MM-009 and MM-010) 
 
Weber et al* 
Dimopoulos et al* 
Lenalidomide 
+ 
Dexa 
Dexa Alone Lenalidomide 
+ 
Dexa 
Dexa Alone 
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Deep Vein Thrombosis 
(%) 
13.5 
3.5 
5.0 
5.0 
Pulmonary 
Embolism 
(%) 
2.9 
0.6 
4.0 
1.0 
Oral presentation from Dimopoulos ASH 2005 
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1.4         Study Rationale and Selection of Drug Doses 
 
There have significant advances in the management of multiple both in the relapsed/refractory, 
newly diagnosed patients with subsequent improvements in response rates,  and   survival. 
The role of maintenance therapy and the optimal regimen post autologous stem cell 
transplant (ASCT) in the myeloma paradigm continues to evolve. 
 
Both lenalidomide and bortezomib have been evaluated as maintenance therapy post   ASCT. 
 
CALBG 100104 was a phase III trial which randomized patients post ASCT to maintenance 
lenalidomide  10  mg/day  or placebo. 
Maintenance lenalidomide  on  an  intention to  treat 
analysis lead to a 20.5 month improvement in time to progression (TTP) from 21.8 months 
to 42.3 months with 17 months of followup. This benefit in TTP was seen in patients with 
prior thalidomide or lenalidomide based induction therapies. The major toxicity was 
hematologic toxicity, with 43% of patients experiencing grade 3/4 neutropenia, 13% with 
G3/4 thrombocytopenia with 12% patients discontinuing therapy due to any adverse event. 
 
A second trial, IFM 2005-02 trial randomized patients post ASCT to placebo or 2 months of 
consolidation with lenalidomide 25 mg/day for days 1-21 for 2  months  followed 
maintenance lenalidomide 10-15 mg daily. This led to an improvement in progression free 
survival post transplant from 24 months to 42 months. 
 
These two trials have established maintenance lenalidomide as an important therapeutic option 
leading to significant improvements in PFS and potentially overall survival. 
 
The combination of proteasome inhibitors and lenalidomide have been studied preclincally 
demonstrating synergy and clinically in both induction therapy as well as relapsed myeloma 
with promising activity. 
 
The combination also warrant further exploration as the  maintenance  therapy post 
transplant. Specifically the addition of oral MLN 9708 to lenalidomide, is attractive as an 
all oral regimen with expected improvements in PFS/TTP compared to single agent 
lenalidomide. 
 
The dosage of lenalidomide will be based on the CALBG experience with 10 mg and modified 
as tolerated. The dose of MLN 9708 will be based on the single agent experience as well 
combination studies. We will start 3 mg orally on day 1, 8, and 15 and dose modifications 
based on tolerability. 
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2. 
STUDY OBJECTIVES 
 
2.1 
Primary Objective 
 
• Establish safety and efficacy of oral MLN 9708 and lenalidomide in the 
maintenance setting post ASCT in myeloma patients 
• Primary endpoint: 
o Progression free survival (PFS) 
2.2 
Secondary Objectives 
 
The secondary objectives of this study are to: 
 
• Incidence of secondary primary malignancy 
• Evaluate the best response rate (sCR/nCR/VGPR/PR) 
• Evaluate time to progression 
• Evaluate time to next therapy 
• Evaluate the tolerability and toxicity 
• Evaluate MDASI- Myeloma symptom evaluation. 
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3. 
INVESTIGATIONAL PLAN 
 
3.1 
Overall Design and Plan of the Study 
 
Eligible patients will be enrolled and maintenance therapy on protocol no less than 60 days 
and must be initiated no more the 180 days post ASCT. 
 
Patients will have standard restaging studies prior to initiation of therapy. 
 
Standard post transplant therapy per institutional guidelines will be unaltered including 
prophylaxis therapy, vaccinations and restaging. 
 
Patients who have completed ASCT and meet eligibility criteria will initiate maintenance 
therapy based on time on enrollment either in the phase dose escalation or expansion portion 
of trial. 
 
Patients’ clinical laboratory values and toxicity must be as specified below within 5 days 
before the first dose of study drug: 
 
• Platelet count ≥ 100,000/mm3 
 
• Neutrophil count ≥ 1000/mm3 (No growth factors within 5 days) 
 
• Total bilirubin ≤ 1.5 × ULN 
 
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤ 3 × ULN 
 
• Creatinine < 2.5 mg/dL 
 
Recovered (ie, ≤ Grade 1 toxicity) from the reversible effects of autologous stem cell 
transplant. 
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Each cycle will be defined as a 28 day cycle. Drug holidays and break in therapy including 
those due to holidays, physician discretion and drug delivery are allowed as needed. Study 
drug will begin at Lenalidomide (10 mg/day); after three cycles , provided the ANC is ≥ 
1000/μL, platelet count ≥ 100,000/μL, and all nonhematologic toxicity is ≤ grade 1, then the 
dose may be increased to 15 mg/day at discretion of physician. 
 
MLN 9708 will be dosed at  3  mg flat dose on days 1, 8, 15 administered orally. 
 
 
Patients will be allowed to receive radiotherapy for palliation of symptoms during the course of 
maintenance therapy 
Study visits and procedures are detailed in the study table in the Appendix. 
 
3.2 
Selection of Patients 
 
The total number of patients to be treated in this study is up to 64 patients (48 total patients 
dosed at 3 mg). 
 
3.2.1 
Inclusion Criteria 
 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
 
1.Patient must have undergone autologous stem cell transplantation, with melphalan as a 
preparative regimen, within 12 months of initiation of induction therapy for newly 
diagnosed myeloma. 
 
2. Time to initiation of maintenance therapy. 
 
Patients may start maintenance therapy as early as 60 days post transplant and up to - 
180 post transplant; as long as they meet the following criteria: 
 
• 
Platelet count ≥ 100,000/mm3 
 
• Neutrophil count ≥ 1000/mm3. (No growth factors within 5 days) 
 
• Total bilirubin ≤ 1.5 × ULN 
 
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤ 3 × ULN 
 
• Creatinine < 2.5 mg/dL 
 
• Recovered (ie, ≤ Grade 1 toxicity) from the reversible effects of autologous 
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stem cell transplant. 
 
 
3. Patients whose primary therapy was changed due to suboptimal response of toxicity will 
be eligible, however no more than 2 regimens will be allowed prior to ASCT. 
 
4. Male or female patients 18 years or older. 
 
5. Patients must have an Eastern Cooperative Oncology Group (ECOG) status of 0 to 2. 
 
6. Voluntary written informed consent before performance of any study-related 
procedure not part of normal medical care, with the understanding that consent may be 
withdrawn by the subject at any time without prejudice to future medical care. 
 
7. Female patients who: 
 
• Are postmenopausal for at least 1 year before the Screening visit, OR 
 
• Are surgically sterile, OR 
 
• If they are of childbearing potential, agree to practice 2 effective methods of 
contraception, at the same time, from the time of signing the informed consent, 
during study treatment and for 28 days after the last dose of study treatment, OR 
agree to completely abstain from heterosexual intercourse 
 
Male patients, even if surgically sterilized (ie, status postvasectomy), who: 
 
• Agree to practice effective barrier contraception during the entire study treatment 
period and through 28 days after the last dose of study treatment, OR 
 
• Agree to completely abstain from heterosexual intercourse 
 
 
3.2.2 
Exclusion Criteria 
 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
 
1. Patient has ≥ Grade 2 peripheral neuropathy. 
 
2. Major surgery within 14 days before the first dose of study drug. 
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3. Radiotherapy within 14 days before enrollment 
 
4. Known active central nervous system involvement 
 
5. Systemic treatment, within 14 days before study enrollment, with strong inhibitors of 
CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of CYP3A 
(clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, 
nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, 
rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. 
John’s wort 
 
6. Inability to swallow oral medication, inability or unwillingness to comply with the 
drug administration requirements, or GI procedure that could interfere with the oral 
absorption or tolerance of treatment. 
 
7. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled 
hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart 
failure, unstable angina, or myocardial infarction within the past 6 months. 
 
8. Female subject is pregnant or lactating. 
 
9. Serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with participation or completion of treatment according to this 
protocol. 
 
10. QTc B> 470 milliseconds (msec) on a 12-lead ECG obtained during the Screening 
period. If a machine reading is above this value, the ECG should be reviewed by a 
qualified reader and confirmed on a subsequent ECG. 
 
11. Ongoing or active systemic infection, known human immunodeficiency virus (HIV) 
positive, known active hepatitis B virus hepatitis, or known active hepatitis C virus 
hepatitis. 
 
12. Infection requiring systemic antibiotic therapy or other serious infection within 
14 days before study enrollment. 
 
13. Known allergy to any of the study medications, their analogues, or excipients in the 
various formulations. 
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14. Participation in clinical trials with other investigational agents not included in this 
trial, within 21 days of the start of this trial and throughout the duration of this trial. 
 
15. Failure to have fully recovered (ie, ≤ Grade 1 toxicity) from the effects of prior 
chemotherapy regardless of the interval since last treatment. 
 
16. Co-morbid systemic illnesses or other severe concurrent disease that, in the judgment 
of the investigator, would make the patient inappropriate for entry into this study or 
interfere significantly with the proper assessment of safety and toxicity of the 
prescribed regimens. 
 
3.3 
Study Treatments 
 
3.3.1 
Clinical Trial Materials 
MLN9708 
MLN9708 will be provided by Millenium at no cost. 
 
Lenalidomide (REVLIMID®) 
Lenalidomide (REVLIMID®) is commercially available oral drug supplied in 25mg, 10mg 
and 5mg capsules. 
3.3.2 
Preparation, Handling, Storage, and Destruction of Drugs 
Drug Administration 
Lenalidomide (Revlimid®) Administration: 
 
For study participants, commercial supply of lenalidomide will be utilized and administered 
through the RevAssist® program. 
 
Women of childbearing potential should not handle or administer the clinical dosage forms 
unless they are wearing gloves. 
 
Only enough lenalidomide for 1 cycle may be provided to the patient each cycle. 
If a dose of lenalidomide is missed, it should be taken as soon as possible on the same day. 
If it is missed for the entire day, it should not be made up. 
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Patients who take more than the prescribed dose of lenalidomide should be instructed to 
seek emergency medical care if needed and contact study staff immediately. 
Accurate records will be kept in the source documents of all drug administration (including 
prescribing and dosing). 
 
Research center personnel will review the dosing instructions with subjects. Subjects will be 
asked to maintain a diary to record the drug administration. Subjects will be asked to bring 
any unused drug and empty drug containers to the research center at their next  visit. 
Research personnel will count and record the number of used and unused drug at each visit 
and reconcile with the patient diary. 
MLN9708 
 
All protocol-specific criteria for administration of study drug must be met and documented 
before drug administration. Patients should be monitored for toxicity, as necessary, and 
doses of MLN9708 should be modified as needed to accommodate patient tolerance to 
treatment; this may include symptomatic treatment, dose interruptions, and adjustments of 
MLN9708 dose (see Section 3.3.3) and per PI discretion. 
 
MLN9708 Administration 
 
Capsules of MLN9708 will also be referred to as study drug. Study drug will be supplied by 
Millennium as capsules of 0.2, 0.5, and 2.0 mg MLN9708. 
 
The prescribed administration of MLN9708 doses in this study is 3 mg MLN9708 on days 
1, 8, 15 on a 28 day cycle. 
 
Patients should be instructed to swallow MLN9708 capsules whole, with water, and not to 
break, chew, or open the capsules. Study drug should be taken on an empty stomach (no 
food or drink) at least 1 hour before or 2 hours after a meal. Each capsule should be 
swallowed separately with a sip of water. A total of approximately 8 ounces (240 mL) of 
water should be taken with the capsules. 
 
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. 
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MLN9708 Destruction 
 
Investigational MLN9708 (expired or end of study) should be destroyed on site according to 
the institution’s standard operating procedure. Be sure to document removal and destruction 
on drug accountability logs. 
 
3.3.3 
Dose Modification and Delay 
 
Before each cycle the patient will be evaluated for possible toxicities that may have 
occurred after the previous dose(s). Toxicities are to be assessed according to the NCI 
Common Toxicity Criteria for Adverse Events (CTCAE), Version 4.0 
(http://ctep.cancer.gov/reporting/ctc.html). Each AE should be attributed to a specific 
drug, if possible, so that the dose modifications can be made accordingly. If multiple 
toxicities are noted, the dose adjustments and/or delays for lenalidomide and MLN9708 are 
per PI discretion  and suggest refer  to guidelines that address the most severe toxicity. 
 
3.3.3.1 Criteria for Beginning or Delaying a Subsequent Treatment Cycle 
 
Treatment with Lenalidomide and MLN9708 will use a cycle length of 28 days. For a new 
cycle of treatment to begin, the patient must meet the following criteria: 
 
• ANC must be ≥ 1,000/mm3. 
• Platelet count must be ≥ 75,000/mm3. 
In addition, all other toxicity considered to be related to treatment with MLN9708 must have 
resolved to ≤ Grade 1, to the patient’s baseline values, or to a level considered acceptable by 
the physician (eg, hypokalemia that can be managed by replacements) before a new cycle of 
MLN 9708  treatment may begin. 
 
If greater than > 4 week delay in starting subusequent cycle due to recovery from 
toxicity, consider dose reduction in attributable drug. 
 
If the patient fails to meet the above-cited criteria for initiation of the next cycle of 
treatment, dosing should be delayed until recovery. The maximum delay before treatment 
should be discontinued will be 6 weeks or at the discretion of the Principal Investigator. 
 
Intracyle dosing : 
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Lenalidomide should be held if plt < If platelet count ≤ 30 × 109/L or ANC ≤ 0.75 × 109/L 
If platelet count ≤ 30 × 109/L or ANC ≤ 0.75 × 109/L  until recovered to platelet > 
75,000 and ANC > 1.0 
 
 
Suggested  Dose Modification  patients if on Lenalidomide 10 mg 
 
 
 
 
Lenalidomide 
MLN 9708 
Dose -1 
unchanged 
2.4 mg 
Dose -2 
10 mg q 21 
2.4 mg 
Dose -3 
10 mg q 21 
1.5 mg 
Dose -4 
5 mg q 21 
1.5 mg 
 
 
 
Suggested  Dose Modification If on lenalidomide 15 mg 
 
After 3 cycle is if the Lenalidomide has been increased to 15 mg daily use the 
following dose modification: 
 
 
 
Lenalidomide 
MLN 9708 
Dose – 1 
10 mg q 28 
3mg 
Dose -2 
10 mg q 28 
2.4mg 
Dose -3 
10 mg q 21 
2.4mg 
Dose -4 
10 mg po q 21 
1.5mg 
Dose -5 
5 mg q 21 
1.5mg 
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For dosing recommendations upon recovery, refer to Table 3-2 and Table 3-3. 
Table 3-1 
Dose Reduction Steps for MLN9708 
 
Starting Dose 
First Dose Reduction 
Second Dose Reduction 
Third Dose Reduction 
3.0 mg 
2.4mg 
1.5mg 
Discontinue MLN9708 
 
 
3.3.4 Dose Adjustments for Hematologic Toxicity 
 
MLN9708 Dose Adjustments for Hematologic Toxicity 
 
Dosage adjustments for hematologic toxicity are outlined in Table 3-2. 
 
Table 3-2 
MLN9708 Dose Adjustments for Hematologic Toxicities 
 
 
Criteria 
Action 
 
 
Within-Cycle Dose Modifications 
• 
If platelet count ≤ 30 × 109/L or ANC ≤ 0.75 × 
109/L on a MLN9708 dosing day (other than 
Day 1) 
• 
MLN9708 dose should be withheld. 
• 
Complete blood count (CBC) with differential 
should be repeated as clinically indicated 
• 
Upon recovery, MLN9708 may be reinitiated 
with 1 dose level reduction. 
 
 
 
• 
• 
 
 
Dose Modifications for Subsequent Treatment 
Cycles 
• 
All hematologic toxicities 
• 
For hematologic toxicity that occurs during 
a cycle but recover in time for the start of 
the next cycle,: 
o 
If dose was reduced within the 
cycle, start the next cycle at that 
same dose. 
o 
If due to toxicity timing, ie, after 
Day 15 dosing thus a dose 
reduction was not required at 
that point in the cycle, reduce 
MLN9708 by 1 dose level at the 
start of that cycle. 
o 
Do not reduce the dose both 
within a cycle and at the start of 
the cycle for the same most 
severe toxicity. 
 
 
 
 
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3.3.5 Treatment Modifications for MLN9708-related AEs (Non-Hematologic Toxicities) 
Treatment modifications due to MLN9708-related AEs are outlined in Table 3-3. 
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Table 3-3 
MLN9708 Treatment Modification (Delays, Reductions, and 
Discontinuations) Due to Adverse Events (Non-Hematologic Toxicities) 
 
Adverse Event (Severity) 
Action on Study Drug 
Further Considerations 
Grade 1 peripheral neuropathy 
• No action 
Grade 1 signs and symptoms: 
asymptomatic; without pain or 
loss of function; clinical or 
diagnostic observations only[6] 
 
 
New or worsening Grade 1 
peripheral neuropathy with pain 
or Grade 2 
• Hold study drug until 
resolution to Grade ≤ 1 or 
baseline 
Grade 2 signs and symptoms: 
Moderate symptoms; limiting 
instrumental activities of daily 
living (ADL)[6] 
 
 
 
New or worsening Grade 2 
peripheral neuropathy with pain 
or Grade 3 
 
• Hold study drug until 
resolution to Grade ≤ 1 or 
baseline 
• Reduce study drug to next 
lower dose upon recovery 
 
Grade 3 signs and symptoms: 
severe symptoms; limiting self- 
care ADL; assistive device 
indicated[6] 
 
 
New or worsening Grade 4 
peripheral neuropathy 
• Discontinue study drug 
 
 
 
 
Grade 3 nonhematologic toxicity 
judged to be related to study 
drug 
If not recovered to 
< Grade 1 or baseline 
within 4 weeks 
 
• Hold study drug until 
resolution to Grade < 1 or 
baseline 
• Reduce study drug 1 to next 
lower dose upon return to 
< Grade 1 or baseline 
 
Symptomatic recommendations 
noted in Section 3.4 
 
 
Subsequent recurrence 
Grade 3 that does not 
recover to < Grade 1 or 
baseline within 4 weeks 
• Hold study drug until 
resolution to Grade < 1 or 
baseline 
• Reduce study drug to next 
lower dose 
Monitor closely, take 
appropriate medical 
precautions, and provide 
appropriate symptomatic care 
 
 
Grade 4 nonhematologic 
toxicities judged to be related to 
study drug 
• Ppermanently discontinuing 
study drug 
 
 
Once MLN9708 is reduced for any toxicity, the dose may not be re-escalated 
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3.3.5 
Packaging and Labeling 
MLN9708 
For blistered material, the capsules are packaged in cold form foil-foil blisters with a paper 
backing for child-resistance. 
 
MLN9708 is an anticancer drug and as with other potentially toxic compounds caution 
should be exercised when handling MLN9708 capsules. 
 
The study drug MLN9708 capsules will be provided by Millennium. The study drug will be 
labeled and handled as open-label material, and packaging labels will fulfill all requirements 
specified by governing regulations. The formulation consists of 0.2-, 0.5-, and 2.0-mg 
capsules for oral administration. 
 
MLN9708 capsules may be stored unopened at 2°C to 8°C (36°F-46°F). The capsules are 
individually packaged in cold form foil-foil blisters with a paper backing for child 
resistance. The capsules are in 1 × 4 blister strips that are individually perforated. The 
strips (1 × 4) are placed in cartons containing 6 strips (24 total capsules) of the same 
strength. 
 
Storage, Handling, and Accountability 
 
Upon receipt at the investigative site, MLN9708 should remain in the blister and carton 
provided until use or until drug is dispensed. The container should be stored at the 
investigative site refrigerated (36°F to 46°F, 2°C to 8°C). All excursions should be brought 
to Millennium’s attention for assessment and authorization for continued use. Ensure that 
the drug is used before the retest expiry date provided by Millennium. Expiry extensions 
will be communicated accordingly with updated documentation to support the extended 
shelf life. 
 
In countries where local regulations permit, MLN9708 capsules dispensed to the patient for 
take-home dosing should remain in the blister packaging and refrigerated as noted above 
until the point of use. The investigative site is responsible for providing the medication to 
the patient 52in the correct daily dose configurations. Comprehensive instructions should be 
provided to the patient in order to ensure compliance with dosing procedures. Patients who 
are receiving take-home medication should be given only 1 cycle of medication at a time. 
Patients should be instructed to store the medication refrigerated (36°F to 46°F, 2°C to 8°C) 
for the duration of each cycle. Patients should be instructed to return their empty blister 
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packs to the investigative site, rather than discarding them. Reconciliation will occur 
accordingly when the patient returns for their next cycle of take-home medication. Any 
extreme in temperature should be reported as an excursion and should be dealt with on a 
case-by-case basis. 
 
Because MLN9708 is an investigational agent, it should be handled with due care. Patients 
should be instructed not to chew, break, or open capsules. In case of contact with broken 
capsules, raising dust should be avoided during the clean-up operation. The product may be 
harmful by inhalation, ingestion, or skin absorption. Gloves and protective clothing should 
be worn during cleanup and return of broken capsules and powder to minimize skin contact. 
 
The area should be ventilated and the site washed with soap and water after material pick-up 
is complete. The material should be disposed of as hazardous medical waste in compliance 
with federal, state, and local regulations. 
 
In case of contact with the powder (eg, from a broken capsule), skin should be washed 
immediately with soap and copious amounts of water for at least 15 minutes. In case of 
contact with the eyes, copious amounts of water should be used to flush the eyes for at least 
15 minutes. Medical personnel should be notified. Patients are to be instructed on proper 
storage, accountability, and administration of MLN9708, including that MLN9708 is to be 
taken as intact capsules. 
 
3.4 
Management of Clinical Events 
 
Prophylaxis Against Risk of Infection 
 
If lymphopenia is noted, patients may be at an increased risk of infection. In particular, 
lymphopenia can be associated with reactivation of herpes zoster and herpes simplex 
viruses. Antiviral therapy such as acyclovir or valacyclovir may be initiated as clinically 
indicated.  Other antivirals are also acceptable. 
 
Thromboembolism Prophylaxis 
For patients at high risk, thromboprophylaxis according to ASCO guidelines or institutional 
standard of care is recommended. 
Nausea and/or Vomiting 
 
Standard anti-emetics, including 5-HT3 antagonists, are recommended for emesis occurring 
upon treatment initiation; prophylactic anti-emetics may also be considered. 
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Dexamethasone should not be administered as an anti-emetic. Fluid deficits should be 
corrected before initiation of study drug and during treatment. 
 
Diarrhea 
 
Diarrhea should be managed according to clinical practice, including the administration of 
antidiarrheals once infectious causes are excluded. Fluid intake should be maintained to 
avoid dehydration. Fluid deficits should be corrected before initiation of treatment and 
during treatment. 
 
Erythematous Rash With or Without Pruritus 
 
Rash has been reported with both lenalidomide and MLN9708. The lenalidomide- 
Induced rash is characterized as generalized, maculopapular, morbilliform, urticarial, papular, 
often with pruritus, and is noted as a warning/precaution in the lenalidomide package insert 
(PI). Serious skin reactions such as Stevens-Johnson Syndrome, toxic epidermal necrolysis, 
and erythema multiforme have been reported. Lenalidomide interruption 
Or discontinuation should be considered as described in the PI/Summary of Product 
Characteristics (SmPC). 
 
As with VELCADE, rash with or without pruritus has been reported with MLN9708, 
primarily at the higher doses tested. The rash may range from some erythematous areas to 
macular and/or small papular bumps that may or may not be pruritic over a few areas of the 
body or more generalized, or it may have been transient and resolved either spontaneously 
or with standard symptomatic measures such as oral or topical antihistamines. Prophylactic 
measures should also be considered if a patient develops a rash (eg, using a thick, 
alcohol-free emollient cream on dry areas of the body). In the case of rash, the use of a 
topical or oral steroid (eg, prednisone ≤ 10 mg per day or equivalent) is permitted. 
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Thrombocytopenia 
 
Thrombocytopenia has been reported with both MLN9708 and lenalidomide. 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. MLN9708 or 
lenalidomide administration should be modified as noted as per dose modification 
recommendations when thrombocytopenia occurs. Therapy can be reinitiated at a reduced 
level upon recovery of platelet counts. 
 
Neutropenia 
 
Neutropenia has been reported with both MLN9708 and lenalidomide. Blood counts should 
be monitored regularly as outlined in the protocol with additional testing obtained according 
to standard clinical practice.  Neutropenia may be severe but has been manageable with 
G-CSF according to standard clinical practice. MLN9708 or lenalidomide administration 
should be modified when neutropenia occurs, as noted in the dose modification 
recommendations in Table 3-2. Therapy can be reinitiated at a reduced level upon recovery 
of absolute neutrophil counts. 
 
Fluid Deficits 
Dehydration should be avoided because lenalidomide is substantially excreted by 
kidney, and MLN9708 may cause vomiting, diarrhea, and dehydration. Two cases of acute 
renal failure have been reported in patients treated at or above the MTD with IV 
administration of MLN9708. There has been no treatment-related renal failure reported in 
patients treated with PO MLN9708. Fluid deficits should be corrected before initiation of 
study drug and during treatment. Until further information is available, intake of NSAIDs 
while on this protocol should be avoided. 
 
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 
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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. 
 
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. 
 
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. 
 
 
 
3.5 
Concomitant Treatment 
 
3.5.1 
Permitted Concomitant Medications and Procedures 
 
All necessary supportive care consistent with optimal patient care shall be available to 
patients as necessary. 
 
The following are examples of those permitted during the study: 
 
• Growth factors (eg, granulocyte colony stimulating factor [G-CSF], granulocyte 
macrophage-colony stimulating factor [GM-CSF], recombinant erythropoietin). 
• Patients may be transfused with red cells and platelets as clinically indicated. 
• Prophylactic antibiotics for pneumocystis prophylaxis (such as Bactrim) is 
allowed. 
• Antiviral therapy such as acyclovir is recommended for all patients. 
• Concomitant treatment with bisphosphonates will be permitted. 
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• Patients who experience worsening neuropathy from baseline may be observed 
for recovery, and any supportive therapy or intervention may be initiated as 
appropriate at the discretion of the investigator. Dose reduction is suggested, 
when and if the patient resumes MLN9708 therapy. 
 
 
 
3.5.2 
Prohibited Concurrent Therapy 
 
The following medications and procedures are prohibited during the study. 
 
Systemic treatment with any of the following metabolizing enzyme inhibitors is not 
permitted in this study A DDI with a strong inhibitor would increase MLN2238 exposure. 
(rationale: if there were to be a drug-drug interaction with an inhibitor, the MLN2238 
exposure would be increased leading to a high probability of an adverse event): 
 
• Strong inhibitors of CYP1A2: fluvoxamine, enoxacin, ciprofloxacin 
 
• Strong inhibitors of CYP3A: clarithromycin, telithromycin, itraconazole, 
voriconazole, ketoconazole, nefazodone, and posaconazole 
 
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 . A DDI 
with a strong inducer would decrease MLN2238 exposure Strong CYP3A inducers: 
rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, and phenobarbital 
 
The dietary supplements St John’s wort and Ginkgo biloba are not permitted. 
The following procedures are prohibited during the study: 
• Any antineoplastic treatment with activity against MM except for drugs in this 
treatment regimen. 
 
• Platelet transfusions to help patients meet eligibility criteria are not allowed 
within 3 days before study drug dosing. 
 
• Adjuvant hormone therapy for breast or prostate cancer 
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3.6 
Treatment Compliance 
 
Patients will keep a pill diary. 
 
3.7 
Precautions and Restrictions 
 
• Fluid deficits should be corrected before and throughout treatment. 
 
3.8 
Contraception Requirements 
 
The effects of MLN9708 on human pregnancy or development of the embryo or fetus are 
unknown. Therefore, female patients participating in this study should avoid becoming 
pregnant, and male patients should avoid impregnating a female partner. Nonsterilized 
female patients of reproductive age and male patients should use effective methods of 
contraception through defined periods during and after study treatment as specified below. 
 
Female patients must meet the following eligibility criteria: 
 
• Are postmenopausal for at least 1 year before the screening visit, OR 
 
• Are surgically sterile, OR 
 
• Agree to completely abstain from heterosexual intercourse 
 
• If they are of childbearing potential, agree to practice 2 effective methods of 
contraception, at the same time, for at least 30 days before starting study drug 
through 28 days after the last dose of study treatment. 
 
o The 2 methods of reliable contraception must include 1 highly effective 
method and 1 additional effective (barrier) method. Females of childbearing 
potential must be referred to a qualified provider of contraceptive methods if 
needed. The following are examples of highly effective and additional 
effective methods of contraception: 
 
Highly effective methods: 
 
• Intrauterine device (IUD) 
 
• Hormonal (birth control pills, injections, implants) 
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• Tubal ligation 
 
• Partner’s vasectomy 
 
Additional effective methods: 
 
• Male condom 
 
• Diaphragm 
 
• Cervical Cap 
Male patients, even if surgically sterilized (ie, status postvasectomy), must meet the 
following eligibility criteria: 
 
• Agree to completely abstain from heterosexual intercourse, OR 
 
• Agree to practice effective barrier contraception during the entire study treatment 
period and through 28 days after the last dose of study treatment if their partner is of 
childbearing potential, even if they have had a successful vasectomy. 
 
3.9 
Duration of Treatment and Patient Participation 
 
. Patients will be informed that they have the right to withdraw from the study at any time 
for any reason, without prejudice to their medical care. Patients will be removed from study 
for the following reasons. 
 
• Progression of disease 
• Patient's request to withdraw from the study or refusal of further therapy 
• Unacceptable toxicity 
• Pregnancy 
• Physicians discretion 
• Lost to long term follow up after 12 months of no contact 
 
 
Definition of Progressive Disease: 
Progressive disease (for patients not in CR) requires one or more of the following: 
 
• >25% increase in the level of the serum monoclonal paraprotein, which must 
also be an absolute increase of at least 0.5 g/dL and confirmed by at least 
one repeated investigation. 
• >25% increase in the 24 hour urinary light chain excretion, which must also 
be an absolute increase of at least 200 mg/24 hour and confirmed by at least 
one repeated investigation. 
• >25% increase in plasma cells in a bone marrow aspirate or trephine biopsy, 
which must also be an absolute increase of at least 10%. 
• Definite increase in the size of existing bone lesions or soft tissue 
plasmacytomas. 
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• Development of new bone lesions or soft tissue plasmacytomas (development 
of a compression fracture does not exclude continued response). 
• Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL or 2.8 
mmol/L) not attributable to any other cause. 
 
 
Relapsed disease (for patients who were in CR) requires at least one or more of 
the following (to be used for analyzing disease free survival). 
 
• Reappearance of serum or urine monoclonal paraprotein by immunofixation 
or electrophoresis. 
• Development of at least 5% plasma cells in the bone marrow. 
• A difference between involved and uninvolved FLC levels of >10 mg/dL, only 
in patients without measurable paraprotein in the serum and urine. 
• Development of new lytic bone lesions or soft tissue plasmacytomas or 
definite increase in the size of residual bone lesions (development of a 
compression fracture does not exclude continued response and may not 
indicate progression). 
• Development of hypercalcemia (corrected serum calcium > 11.5 g/dL or 2.8 
mmol/L) not attributable to any other cause. 
• Appearance of any other sign of progression. 
 
Patients with relapsed disease (recurrence of disease after attaining a CR) should 
continue on treatment if they do not fulfill criteria for progressive disease. This would apply to patients at any 
time following initiation of maintenance therapy. 
 
3.10 
Efficacy, Correlative Studies, and Safety Measurements 
 
 
3.10.1 
Efficacy Measurements 
 
Patients will be staged every 1-3 cycles +/- 7 days while on protocol. Efficacy evaluations 
will be based on changes in myeloma protein measurements in serum and 24-hour urine, 
bone marrow examination as indicated, skeletal survey as indicated clinically, 
extramedullary plasmacytomas as clinically indicatedA serum sample for FreeLite TM testing 
will be obtained. 
 
 
3.10.2 
Correlative/ QOL Questionnaire 
 
 Mandatory blood samples one 50 ml in green top tube and 10 ml in Purple top will 
 
   
be obtained at time of routine blood collection and banked in the MDACC Plasma   
Cell Dyscrasia Tissue Bank every 1-3 cycles on day 1 +/- 7 days. 
The blood samples will be used for future research to better understand myeloma biology, 
diagnostic and prognostic features and immunoprofiling 
M. D. Anderson Symptom Inventory (MDASI-MM module) scores. The core MDASI- 
MM module is a brief, easily understood instrument that provides a measure of the 
intensities of 13 cancer-related symptoms. Patients will be asked to rate the intensity of 
physical, affective, and cognitive symptoms on 0 to 10 numeric scales from “not present" 
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(score of 0) to "as bad as you can imagine" (score of 10). Patients will also rate the amount 
of interference with daily activities caused by symptoms on 0 to 10 numeric scales from "did 
not interfere" (score of 0) to interfered completely (score of 10). Six symptom items 
determined by physicians and nurses in the Lymphoma/Myeloma and Blood and Marrow 
Transplantation Departments to be important for the assessment of patients with multiple 
myeloma and patients who are post-transplant will be added to the core MDASI-MM 
module for this study. The symptoms to be assessed by the core MDASI-MM module 
include: pain, fatigue, nausea, disturbed sleep, distress, shortness of breath, difficulty 
remembering, lack of appetite, drowsiness, dry mouth, sadness, vomiting, numbness, 
constipation, muscle weakness, diarrhea, mouth or throat sores, rash, and trouble 
concentrating. The six additional items assessing symptom-related interference in general 
activity, mood, work, relation with others, enjoyment of life and walking. The MDASI-MM 
module will be administered in person, by an interactive voice response (IVR) telephone 
system, or through the use of tablet PCs. The IVR system will asks patients to rate each 
symptom and interference item on the 0-10 numeric scales using the keypad of a touch-tone 
telephone. 
 
 
While on study, patients will complete MDASI on day 1 (+/- 7 days) of every 1-3 
cycles of therapy 
 
 
 
3.10.3 
Safety Measurements 
 
Before starting each cycle, patients will be evaluated for toxicity. Safety evaluations will be 
based on changes in physical examinations, ECOG Performance Status scores, clinical 
laboratory findings from pretreatment to the End-of-Treatment Visit, and on the observation 
or report of any AEs (including laboratory abnormalities reported as AEs) that occur after 
starting study drug until 30 days after the last dose of study agent and those SAEs (including 
laboratory abnormalities reported as AEs) occurring after 30 days if considered related to 
Lenalidomide or MLN 9708. The intensity (severity) of AEs will be assessed using the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI- 
CTCAE), Version 4.0. 
 
 
 
4. 
ADVERSE EVENTS 
 
4.1 Adverse Event Definition 
 
An adverse event (AE) is any untoward medical occurrence in a patient administered a 
pharmaceutical product, which does not necessarily have a causal relationship with the 
treatment. An adverse event can be any unfavorable and unintended sign (eg, including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of the 
drug, whether or not it is considered to be drug related. This includes any newly occurring 
event or previous condition that has increased in severity or frequency since the administration 
of drug. 
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 The Investigator or physician designee is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for each event for all 
subjects enrolled on the trial.” 
 PDMS/CORe will be used as the electronic case report form (eCRF) and protocol 
specific data will be entered into PDMS/CORe for patients at MDACC. 
We will only capture clinically relevant AE as determined by the treating physician. 
 
For this protocol an abnormal laboratory value will not be assessed as an AE unless 
that value leads to discontinuation or delay in treatment, dose modification, 
therapeutic intervention, or is considered by the investigator to be a clinically 
significant change from baseline. 
 
We will per GCP have an AE log. 
 
 
 
4.1.1 
Serious Adverse Event Definition/ Reporting 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or the sponsor, it results in any of the following outcomes: 
 
• Death 
• A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it 
occurred in a more severe form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant disability/incapacity – a substantial disruption of a 
person’s ability to conduct normal life functions. 
• A congenital anomaly/birth defect. 
• Suspected transmission of infectious agents by a medicinal product 
 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate 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. 
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 (21 
CFR 312.32). 
 
• Important medical events as defined above, may also be considered serious 
adverse events. Any important medical event can and should be reported as an 
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SAE if deemed appropriate by the Principal Investigator or the IND Sponsor, 
MDACC IND Office. 
 
• All events occurring during the conduct of a protocol and meeting the definition of a 
SAE must be reported to the IRB in accordance with the timeframes and procedures 
outlined in “University of Texas M. D. Anderson Cancer Center Institutional Review 
Board 
 
• All life-threatening or fatal events, that are unexpected, and related to the study 
drug, must have a written report submitted within 24 hours 
 
 
• Serious adverse events will be captured from the time the patient therapy and 
until 30 days after therapy discontinues. Serious adverse events  must  be 
followed until clinical recovery is complete and laboratory tests have returned 
to baseline, progression of the event has stabilized, or there has been acceptable 
resolution of the event. 
 
• Additionally, any serious adverse events that occur after the 30 day time period 
that are related to the study treatment must be reported to MDACC  IND 
Office. This may include the development of a secondary malignancy. 
 
Reporting to FDA: 
 
• Serious adverse events will be forwarded to FDA by the IND  Sponsor (Safety 
Project Manager MDACC IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse events 
are reported according to the Code of Federal Regulations,  Good Clinical  Practices, 
the protocol guidelines, the sponsor’s guidelines, and Institutional  Review  Board 
policy. 
 
 
Reporting to Millennium: 
 
This is an investigator-initiated study. The principal investigator (who may also sometimes 
be referred to as the sponsor-investigator), is conducting the study and acting as the sponsor. 
Therefore, the legal/ethical obligations of the principal investigator include both those of a 
sponsor and those of an investigator. 
 
Sponsor-investigator must report all SAEs, regardless of expectedness or relationship 
with any study drug, to Millennium Pharmacovigilance (or designee) as soon as 
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possible, but no later than 5 calendar days of the sponsor-investigator’s observation or 
awareness of the event. In the event that this is a multisite study, the sponsor- 
investigator is responsible to ensure that the SAE reports are sent to Millennium 
Pharmacovigilance (or designee) from all sites participating in the study. 
Subinvestigators must report all SAEs to the sponsor-investigator so that the sponsor- 
investigator can meet his/her foregoing reporting obligations to Millennium 
Pharmacovigilance, unless otherwise agreed between the sponsor-investigator and 
subinvestigator(s). Millennium Pharmacovigilance (or designee) may request follow- 
up information to a reported SAE, which the sponsor-investigator will be responsible 
for providing to Millennium Pharmacovigilance (or designee). 
 
The SAE report must include event term(s), serious criteria, and the investigator’s or 
sub-investigator’s determination of both the intensity of the event(s) and the 
relationship of the event(s) to study drug administration. 
 
Intensity for each SAE, including any lab abnormality, will be determined by using the 
NCI CTCAE, version used at your institution, as a guideline, whenever possible. The 
criteria are available online at http://ctep.cancer.gov/reporting/ctc.html. 
 
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 Millennium Pharmacovigilance with a copy of 
all communications with applicable regulatory authorities related to the study or study 
drug(s), including, but not limited to, telephone conversation logs, as soon as possible 
but no later than 5 calendar days of such communication. 
 
SAE and Pregnancy Reporting Contact Information 
Fax Number: 1-800-963-6290 
Email: TakedaOncoCases@cognizant.com 
 
Suggested Reporting Form: 
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• SAE Report Form (a sample is provided in Section 7.10) 
 
• US FDA MedWatch 3500A: 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.h 
tm 
 
• Any other form deemed appropriate by the sponsor-investigator 
 
 
4.2 
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 must permanently discontinue study drug(s). All pregnancies and 
suspected pregnancies must be reported to Millennium Pharmacovigilance (or 
designee; see Section 4.2 for contact information) immediately. The pregnancy must 
be followed for the final pregnancy outcome (ie, delivery, still birth, miscarriage) and 
Millennium Pharmacovigilance will request this information from the investigator. 
 
If a female partner of a male patient becomes pregnant during the male patient’s 
participation in this study, this must be reported to Millennium Pharmacovigilance (or 
designee) immediately (see Section 4.2 for contact information). Every effort should be 
made to follow the pregnancy for the final pregnancy outcome. 
 
 
4.3 Long Term Follow-Up Phase   
Following end of therapy on this trial, all subjects will be followed until death, withdrawal of 
consent for study participation, or removal from study. Subjects will return to the site or be 
contacted by telephone every 6 months (+/- 4 weeks) for follow up assessments of the 
following:  
• Second primary malignancies  
• Next-line of therapy  
• Progressive disease on next line of therapy  
• Overall survival  
 
Following disease progression on the next-line of therapy, subjects will only be followed for 
overall survival and development of 2nd primary malignancies.
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5. 
STATISTICAL CONSIDERATIONS 
 
Design 
This is a single-arm, open label, phase II trial to determine the progression free survival (PFS) of 
patients with multiple myeloma treated with the combination of MLN 9708 with Lenalidomide as 
maintenance therapy post autologous stem cell transplant. 
 
Analysis plan, Sample Size and Power 
 
The primary endpoint is PFS, defined as the time from autologous stem cell transplantation (ASCT) 
to the time of clinical progression, death, whichever occurs first or the time of last contact. It is 
hypothesized that the combination will prolong PFS compared to the current standard regimen. A total 
of 48 patients (dosed at 3 mg of Ixazomib) will be enrolled at an accrual rate of 2 patients per month 
over 24 months. Additional 48 months of follow-up  is  planned  after the  last  patient  is recruited 
into the trial. Assuming that PFS time follows an exponential distribution, and patients treated with the 
current standard regimens had a median PFS of 40 months, we will monitor the PFS using the method 
of Thall et al. (Thall, 2005). Let Ts and Te represent the time to progression for the standard regimens 
and the proposed treatment regimen, respectively. We assume Ts|Ms and Te|Me follow an exponential 
distribution with respective median Ms and Me. Furthermore, we assume that the prior for Ms follows 
an inverse gamma distribution IG (100, 3960) to reflect our knowledge of PFS for the patients treated 
with the standard  regimens.  This  has  a  mean  of  40  months,  and  a variance  of  16.3. The prior 
for Me is  assumed to be  IG  (3, 80), which has the same  mean  of  40 months and a larger  variance 
of 1600 to reflect the uncertainty about the median PFS of the proposed treatment regimen. 
 
The PFS will be monitored every six months, and the study will be terminated early if there is little 
evidence based on the available data that the median PFS of the patients treated with the proposed 
treatment regimen is 12 months or more than that of the patients treated with the standard regimens. 
The formal stopping rule is 
 
Pr(Me > Ms+12 | data) < 0.035 
 
Specifically, the trial will be stopped early if there is less than 3.5% chance that the median PFS for 
the patients treated with the proposed treatment regimen is 12 months or more than the median PFS 
for the patients treated with the standard regimens. The probability cutoff 0.035 was chosen to obtain 
an early stopping probability around 10% (0.091) if the true median PFS for the proposed treatment 
regimen results in a 12 months improvement over the historical median PFS of 40 months. 
 
The operating characteristics of this decision rule are summarized in Table 1 using the onearmTTE 
software developed at the Department of Biostatistics at M.D. Anderson. 
 
 
Table 1. Operating characteristics for the design (based on 2000 simulations) 
True median 
Progression Free 
Survival (month) 
Pr(stop early) 
Average Number of Patients 
Treated 
(25th, 75th percentiles) 
30 
0.92 
39.6 ( 32, 48 ) 
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36 
0.64 
42.9 ( 42, 48 ) 
40 
0.41 
44.4 ( 48, 48 ) 
48 
0.16 
46.0 ( 48, 48 ) 
52 
0.091 
46.5 ( 48, 48 ) 
60 
0.053 
46.9 ( 48, 48 ) 
 
 
 
This monitoring will be carried out via the Clinical Trial Conduct (CTC) website 
(https://biostatistics.mdanderson.org/ClinicalTrialConduct) which is housed on a secure server at 
MDACC and maintained by the MDACC Department of Biostatistics. Access to the website will be 
gained through usernames and passwords provided by the MDACC Department of Biostatistics. 
Training on the use of the CTC will be provided by the biostatistical collaborator of the study, with 
emphasis on the importance of timely updating of follow-up times and recording of events. The 
monitoring rules for the PFS will be applied every six months with the probability criterion recomputed 
based on the most recent data available at that time. If the stopping rule is met, the study statistician, 
research nurse, and principal investigator will each receive an email notification that the stopping 
boundary has been met. 
 
Because of the limited number of patients who have received the combination treatment, we 
will monitor the toxicity of the combination while we monitor the efficacy of it. Due to the 
lack of detailed information about the association between toxicity and efficacy, independency 
between the efficacy endpoints and toxicity endpoints is assumed, and the toxicity events are 
monitored continuously (Thall et al., 1996). The toxicity endpoint is defined as treatment- 
related unmanageable toxicities, including grade 3 non-hematologic effects, or grade 4 
hematologic effects, that require delay or termination of the treatment during cycle 1 A toxicity 
rate of 30% or higher will not be considered acceptable. The prior probability of toxicity is 
assumed to follow a Beta (0.3, 0.7) distribution with one patient worth of information. The 
toxicity will be monitored by a cohort size of 4. At any time after at least 4 patients have 
completed toxicity evaluations, the trial will be stopped if the following statement is true 
 
 
 
Pr[toxicity rate > 30% | data]  > 0.95, 
 
 
 
which means that the trial will be stopped for toxicity if the posterior probability of the toxicity rate 
being greater than 30% is greater 95%. The early stopping boundaries for toxicity, shown in the 
format of 
 
(The number of patients with toxicities) / (The number of patients treated), 
are ≥3/4,  5/8, 7/12, 9/16, 10/20, 12/24, 13/28, 15/32, 16/36, 18/40, 19/44, and 21/48. 
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Table 2. Operating characteristics for the stopping rules 
For excessive toxicity monitoring 
 
 
 
 
 
 
 
 
Early termination of the trial can be caused by either lack of efficacy or excessive toxicity. If the 
efficacy and toxicity are considered jointly, the early stopping probabilities as shown in Table 3 will 
be higher than the probabilities shown in Tables 1 to 2. 
 
Table 3: Operating characteristics considering efficacy and toxicity jointly 
True median 
True toxicity rate 
Probability Stop Early 
36 
0.2 
0.65 
36 
0.3 
0.70 
36 
0.5 
0.97 
52 
0.2 
0.12 
52 
0.3 
0.25 
52 
0.5 
0.92 
60 
0.2 
0.086 
60 
0.3 
0.22 
60 
0.5 
0.91 
 
 
 
Patients’ demographic and clinical characteristics at baseline will be summarized using 
descriptive statistics such as frequency distribution, mean (± s.d.) and median (range) 
accompanied by graphical analysis. Student t-test/Wilcoxon test and ANOVA/Kruskal- 
Wallis test will be used to compare continuous variables between different patient groups. The 
chi-square test or the Fisher’s exact test will be applied to assess the association between 
two categorical variables (Woolson, 2002). 
 
 
 
The response rates and incidence of new primary malignancy will be estimated along with 
95% confidence intervals. Time-to-event outcomes, including PFS and  overall  survival 
(OS), will be estimated using the Kaplan-Meier method (Kaplan, 1958). log-rank test will 
be performed to test the difference in time-to-event distributions between patient groups 
(Mantel, 1966). Cox proportional hazards model will be used to include multiple  covariates 
in the time-to-event analysis (Cox, 1972). 
True 
DLT Rate 
Probability Stop 
Early 
Mean sample 
size 
0.20 
0.035 
46.5 
0.30 
0.18 
41.8 
0.40 
0.56 
30.7 
0.45 
0.77 
23.8 
0.50 
0.91 
17.8 
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Toxicity data will be summarized by frequency tables. For the toxicity endpoint, per-treated 
analysis will be used to include any patient who received the treatment regardless of the 
eligibility nor the duration or dose of the treatment received. 
 
The MDASI –myeloma symptom evaluation will be analyzed with descriptive analysis. 
 
 
 
6. 
PRODUCT COMPLAINTS 
 
A product complaint is a verbal, written, or electronic expression which implies 
dissatisfaction regarding the identity, strength, purity, quality, or stability of a drug product. 
Individuals who identify a potential product complaint situation should immediately contact 
MedComm Solutions (see below) and report the event. Whenever possible, the associated 
product should be maintained in accordance with the label instructions pending further 
guidance from a Millennium quality representative. 
 
For Product Complaints, 
Phone: 1-877-TAKEDA7 (1-877-825-3327) 
• 
E-mail: medicalinformation@tpna.com 
• 
FAX: 1-800-247-8860 
• 
Hours: Mon-Fri, 8 a.m. – 6 p.m. ET 
 
Product complaints in and of themselves are not AEs. If a product complaint results in an 
SAE, an SAE form should be completed and sent to Millennium Pharmacovigilance. 
 
7. ADMINISTRATIVE REQUIREMENTS 
 
7.1 
Good Clinical Practice 
 
The study will be conducted in accordance with the International Conference on 
Harmonization (ICH) for Good Clinical Practice (GCP) and the appropriate 
regulatory requirement(s). The investigator will be thoroughly familiar with the 
appropriate use of the drug as described in the protocol and IB.  Essential clinical 
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documents will be maintained to demonstrate the validity of the study and the integrity 
of the data collected. Master files should be established at the beginning of the study, 
maintained for the duration of the study, and retained according to the appropriate 
regulations.  This is the responsibility of the sponsor-investigator. 
 
7.2 
Ethical Considerations 
 
The study will be conducted in accordance with ethical principles founded in the 
Declaration of Helsinki. The Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) will review all appropriate study documentation in order to 
safeguard the rights, safety, and well-being of the patients. The study will only be 
conducted at sites where IRB/IEC approval has been obtained. The protocol, IB, 
informed consent, advertisements (if applicable), written information given to the 
patients (including diary cards), safety updates, annual progress reports, and any 
revisions to these documents will be provided to the IRB/IEC by the investigator. 
Millennium requests that the protocol and informed consent documents be reviewed by 
Millennium prior to IRB/IEC submission. 
 
7.3 
Patient Information and Informed Consent 
 
The principles of informed consent are described by Federal Regulatory Guidelines 
(Federal Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for 
Protection from Research Risk Reports: Protection of Human Subjects (Code of 
Federal Regulations 45 CFR46). They must be followed to comply with FDA 
regulations for the conduct and monitoring of clinical investigations. 
 
7.4 
Institutional Review 
 
This study must be approved by an appropriate institutional review committee as 
defined by Federal Regulatory Guidelines (Ref. Federal Register Vol. 46, 17, January 
27, 1981, part 56) and the Office for Protection from Research Risks Reports: 
Protection of Human Subjects (Code of Federal Regulations 45 CFR 46). 
 
7.5 
Patient Confidentiality 
 
In order to maintain patient privacy, all data capture records, drug accountability 
records, study reports, and communications will identify the patient by initials and the 
assigned patient number. The investigator will grant monitor(s) and auditor(s) from 
Millennium or its designees and regulatory authority(ies) access to the patient’s 
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original medical records for verification of data gathered on the data capture records 
and to audit the data collection process. The patient’s confidentiality will be 
maintained and will not be made publicly available to the extent permitted by the 
applicable laws and regulations. 
 
7.6 
Protocol Compliance 
 
The investigator will conduct the study in compliance with the protocol given 
approval/favorable opinion by the IRB/IEC and the appropriate regulatory 
authority(ies). Changes to the protocol will require approval from Millennium and 
written IRB/IEC approval/favorable opinion prior to implementation, except when the 
modification is needed to eliminate an immediate hazard(s) to patients. The IRB/IEC 
may provide, if applicable regulatory authority(ies) permit, expedited review and 
approval/favorable opinion for minor change(s) in ongoing studies that have the 
approval /favorable opinion of the IRB/IEC. The investigator will submit all protocol 
modifications to Millennium and the regulatory authority(ies) in accordance with the 
governing regulations. 
 
Any departures from the protocol must be fully documented in the source documents. 
 
7.7 
On-site Audits 
 
Regulatory authorities, the IEC/IRB, and/or Millennium may request access to all 
source documents, data capture records, and other study documentation for on-site 
audit or inspection. Direct access to these documents must be guaranteed by the 
investigator, who must provide support at all times for these activities. 
 
7.8 
Drug Accountability 
 
Accountability for the drug at all study sites (including all subsites, if applicable) is the 
responsibility of the sponsor-investigator.  The sponsor-investigator will ensure that 
the drug is used only in accordance with this protocol. Drug accountability records 
indicating the drug’s delivery date to the site (if applicable), inventory at the site (if 
applicable), use by each patient, and return to Millennium or disposal of the drug will 
be maintained by the site and/or subsites. Accountability records will include drug 
receipt/destruction dates, quantities, lot numbers, expiration dates (if applicable), and 
corresponding registered patient numbers. 
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All material containing MLN9708 will be treated and disposed of as hazardous waste 
in accordance with governing regulations. 
 
 
7.9 
Record Retention 
 
The sponsor-investigator will maintain all study records according to ICH-GCP and 
applicable regulatory requirement(s). 
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8. 
APPENDICES 
 
8.1 
Study Flow Chart 
 
 
Procedure 
Screening 
≤ 28 days 
from 
Initiation 
of therapy 
(may 
include 
Day 1) 
Baseline 
Cycle 1:  (except cycle 1 day 18)8 
all 
cycles 
beyond 
cycle 1 
End of 
study 
Follow 
up 
Cycle 
1 
Day 1 
+/- 7 days 
Day  8 +/-3 days 
(only 
dose 
escalation 
phase) 
Day 15 
+/-3 days ( only 
dose 
escalation 
phase) 
Day 1 
+/-7 days 
within 
30 
days after 
last   dose 
+/- 7 days 
 
 
Every 6 
months (+/- 
4 weeks) 
Informed consent 
X 
Inclusion/Exclusion criteria 
X 
Complete Medical Hx 
X 
Confirmation Dx and status of disease and prior Rx 
X 
MDASSI Questionnaire and Correlative Samples6 
X 
X6 
Record concurrent therapies/procedures 
X 
Record adverse events 
X 
X 
X 
X 
 
Physical examination, vital signs Score7 
X 
X 
X 
X 
X 
X 
 
Skeletal survey( as clinically indicated) 
X 
X 
 
Bone Marrow aspiration and biopsy 
X 
X1 
X 
 
12 Lead ECG 
X 
Hematology3 
X 4 
X 
X 
X 
X 
X 
 
Serum chemistry2 
X4 
X 
X 
X 
X 
X4 
TSH 
x 
Ht, Wt, BSA 
X 
X 
X 
X 
 
Pregnancy test  for females of child bearing potential 
X 
X5 
X5 
X 
 
Register Patient into Rev Assist® Program 
X 
Serum and urine M component quantification 
X 
X (every 1-3 cycles 
X 
 
24hour urine for protein measurement 
X 
X (every 1-3 cycles 
X 
 
Prescribe lenalidomide via RevAssist® 
X 
X 
Serum for FreeLite Testing 
X 
X (every 1-3 cycles 
X 
 
Dispense study drug for next cycle 
X 
X 
Perform drug accountability 
X 
X 
X 
 
Survival status 
 
 
 
X8 


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1. A repeat bone marrow biopsy will only be done at time of suspected complete remission to document complete 
remission per standard clinical practice and at physician discretion. 
2. To include Na, K, Cl, Co2, Ca, Mg, Phosphorous, BUN, Cr., glucose, albumin, alk phos, total Bili, ast/alt. 
3. WBC, differential, Hgb, Hct and platelet count 
4. Screening CBC and Chemistry parameters need to meet criteria to initiate dosing in section 3.1 within 5 days of starting 
protocol directed therapy. 
5. Pregnancy testing will be done 10-14 days prior to starting therapy and within 24 hours prior of starting lenalidomide 
on day 1 
6. These will be done ever 1-3 cycles. 
7. DAY 8 AND DAY 15 (+/-) 3 DAYS ASSESSMENTS ARE TO BE DONE DURING CYCLE 1 AND DURING THE 
CYCLE THE PHYSICIAN DOSE ESCALATES 
8. Subjects will return to the site or be contacted by telephone every 6 months (+/- 4 weeks) for follow up assessments, 
refer to section 4.3.  
 
 
 
 
 
8.2 
Eastern Cooperative Oncology Group Performance Status 
 
 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all predisease performance 
without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (eg, light 
housework, office work). 
2 
In bed < 50% of the time. 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 
In bed > 50% of the time. Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair. 


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5 
Dead. 
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5 (6):649-55. 


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MDACC 2012-0277 
MLN9708 
 
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