Investigator-Initiated Phase I/II Clinical Trial of Selinexor (KPT-330) and Liposomal Doxorubicin for Relapsed and Refractory Multiple Myeloma
Phase: PHASE1
Conditions: Multiple Myeloma
Sponsor: H. Lee Moffitt Cancer Center and Research Institute

 
 INVESTIGATOR-INITIATED PHASE I/II CLINICAL TRIAL OF SELINEXOR (KPT-330) 
AND LIPOSOMAL DOXORUBICIN FOR RELAPSED AND REFRACTORY MULTIPLE 
MYELOMA 
 
 
NCT02186834  
 
Version 8 
March 31, 2017 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 1 
CLINICAL STUDY PROTOCOL 
TITLE: INVESTIGATOR-INITIATED PHASE I/II CLINICAL TRIAL OF SELINEXOR (KPT-330) AND 
LIPOSOMAL DOXORUBICIN FOR RELAPSED AND REFRACTORY MULTIPLE MYELOMA 
CLINICAL TRIAL PROTOCOL NUMBER: MCC17814 
 
PROTOCOL VERSION: 8 
PROTOCOL DATE: 3/31/2017 
INVESTIGATIONAL PRODUCT: Selinexor (KPT-330) 
SPONSOR: H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE 
DRUG PRODUCT SUPPLIER: KARYOPHARM THERAPEUTICS 
PRINCIPAL INVESTIGATOR: 
RACHID BAZ, M.D.  
 
  
  
  
 
12902 MAGNOLIA DRIVE, FOB 3 
  
  
  
 
TAMPA, FL 33612 
  
  
  
 
 
  
  
  
 
 
  
  
  
 
  
CLINICAL TRIAL COORDINATOR: 
 
  
  
  
 
 
  
  
  
 
  
STATISTICIAN:  
  
 
 
CO-INVESTIGATORS:  
 
 
 
 
 
 
 
 
  
Table of Contents 
Synopsis 
....................................................................................................................................... 6
 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................... 
19 
1 Introduction .................................................................................................................... 
21 
1.1 Overview 
.................................................................................................................................. 21 
1.2 Selinexor:  Mechanism of Action and Preclinical Summary 
.................................. 
21 
1.3 Selinexor:  Clinical Summary 
............................................................................................ 
23 
1.4 Doxorubicin for Patients with Multiple Myeloma 
..................................................... 
26 
1.5 Investigator-initiated Phase I/II Clinical Trial of , Liposomal Doxorubicin and 
Dexamethasone for Relapsed and Refractory Multiple Myeloma 
.................................. 
27 
1.5.1 
Rationale for the Study 
...........................................................................................................
 
27 
1.5.2 
Rationale for Starting Dose and Dosing Schedule 
....................................................... 
38 
1.5.3 
Study Population and Sample Size 
.................................................................................... 
41 
1.5.4 
Assessment for Response 
...................................................................................................... 
41 
2 OBJECTIVES 
...................................................................................................................... 
41 
2.1 Primary Objective 
................................................................................................................. 41 
2.2 Secondary Objectives 
........................................................................................................... 41 
3 INVESTIGATIONAL PLAN 
............................................................................................. 
41 
3.1 Overview of Study Design and Dosing Regimen ........................................................ 
41 
3.1.1 
Definition of Treatment Cycle and Duration 
................................................................. 
42 
3.1.2 
Criteria to Proceed with a New Cycle of Therapy During Induction 
................... 
42 
3.1.3 
Criteria to Proceed with a New Cycle of Therapy During Maintenance............. 
43 
3.1.4 
End of Treatment Visit 
............................................................................................................
 
44 
3.2 Study Duration 
....................................................................................................................... 44 
4 PATIENT SELECTION..................................................................................................... 
44 
4.1 Inclusion Criteria 
.................................................................................................................. 44 
4.2 Exclusion Criteria 
.................................................................................................................. 45 
4.3    Patient Registration ……………………………………………………………………………………44 
5 STUDY CALENDAR 
......................................................................................................... 
47 
6 TREATMENT PLAN ........................................................................................................ 
49 
6.1 Study Assessments................................................................................................................ 49 
6.1.1 
Efficacy Assessments............................................................................................................... 
49 
6.1.2
 
Translational Analyses 
...........................................................................................................
 
49 
6.1.3 
Safety Assessments 
..................................................................................................................
 
50 
6.1.4 
Definition of a Dose Limiting Toxicity (DLT) 
................................................................ 
50 
6.1.5 
Laboratory Assessments........................................................................................................ 
50 
6.2 Study Procedures 
.................................................................................................................. 50 
6.2.1 
Screening Procedures 
............................................................................................................. 
50 
6.2.2 
Treatment Phase 
....................................................................................................................... 
52 
6.2.3 
End of Treatment 
......................................................................................................................
 
52 
6.3 End of Study............................................................................................................................. 53 
6.3.1 
Planned Treatment of the Patients After End of Treatment Phase 
...................... 
53 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 3 
6.3.2 
Removal of Patients from Treatment 
............................................................................... 
53 
6.4 Study Discontinuation 
......................................................................................................... 54 
7 INVESTIGATIONAL MEDICINAL PRODUCT 
............................................................ 
54 
7.1 Selinexor .................................................................................................................................. 54 
7.1.1 
Preparation and Administration of Selinexor 
............................................................... 
54 
7.1.2 
Formulation 
................................................................................................................................
 
54 
7.1.3 
Labelling 
.......................................................................................................................................
 
54 
7.1.4 
Storage 
..........................................................................................................................................
 
55 
7.1.5 
Drug Accountability 
.................................................................................................................
 
55 
7.1.6 
Selinexor Dosing Information.............................................................................................. 
55 
7.2  liposomal Doxorubicin 
....................................................................................................... 55 
7.2.1 
Preparation of Liposomal doxorubicin 
............................................................................ 
55 
7.2.2 
Formulation and Administration of Liposomal doxorubicin.................................. 
56 
7.2.3 
Storage of Liposomal doxorubicin 
..................................................................................... 
56 
7.2.4 
Dosing Information 
..................................................................................................................
 
56 
7.3 Dexamethasone 
..................................................................................................................... 56 
7.3.1 
Dosing Information 
..................................................................................................................
 
56 
8 TOXICITIES, RISKS, AND AE-RELATED DOSE MODIFICATIONS 
...................... 
57 
8.1 Selinexor .................................................................................................................................. 57 
8.1.1 
Selinexor Toxicity Overview 
................................................................................................ 
57 
8.1.2 
Risks Associated with Selinexor 
......................................................................................... 
57 
8.1.3 
Dose Modifications for Selinexor 
....................................................................................... 
58 
8.1.4 
Dose Adjustment Guidelines for Selinexor-Related Toxicities 
.............................. 
60 
8.2 Liposomal doxorubicin 
..................................................... Error! Bookmark not defined. 
8.2.1 
Liposomal doxorubicin Toxicity Overview 
.................................................................... 
63 
8.2.2 
Risks Associated with Liposomal doxorubicin 
............................................................. 
63 
8.2.3 
Dose Modifications for Liposomal doxorubicin 
........................................................... 
63 
8.2.4 
Dose Adjustment Guidelines for Liposomal doxorubicin 
........................................ 
64 
8.3 Dexamethasone 
..................................................................................................................... 66 
8.3.1 
Dexamethasone Toxicity Overview 
................................................................................... 
66 
8.3.2 
Risks Associated with Dexamethasone 
........................................................................... 
66 
8.3.3 
Dose Modifications for Dexamethasone 
.......................................................................... 
66 
8.3.4 
Dose Adjustment Guidelines for Dexamethasone 
....................................................... 
66 
9 SAFETY GUIDANCE FOR INVESTIGATORS ............................................................. 
68 
9.1 Concomitant Medication and Treatment ..................................................................... 
68 
9.1.1 
Permitted Concomitant Medication 
.................................................................................. 
68 
9.1.2 
Prohibited Medication 
............................................................................................................
 
69 
9.2 Supportive Care Guidelines 
............................................................................................... 
70 
9.2.1 
Anorexia 
.......................................................................................................................................
 
70 
9.2.2 
Fatigue 
...........................................................................................................................................
 
71 
9.2.3 
Emesis 
...........................................................................................................................................
 
71 
9.2.4 
Diarrhea 
........................................................................................................................................
 
72 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 4 
9.2.5 
Thrombocytopenia 
...................................................................................................................
 
72 
9.2.6 
Hyponatremia 
............................................................................................................................ 
72 
9.2.7 
Liver Enzyme Increase 
........................................................................................................... 
73 
10 CORRELATIVE STUDIES AND PHARMACOKINETICS 
...................................... 73
 
10.1 Exploratory Correlative Studies 
...................................................................................... 
73 
10.2 Limited Pharmacokinetic Studies 
................................................................................... 
77 
11 STATISTICAL CONSIDERATIONS 
........................................................................... 
77 
11.1 Endpoints 
................................................................................................................................. 
77 
11.1.1 Primary Endpoint 
..................................................................................................................... 
77 
11.1.2 Secondary Endpoints 
.............................................................................................................. 
77 
11.2 Sample Size Justification .................................................................................................... 
77 
11.3 Study Population Definition 
.............................................................................................. 
77 
11.4 Study Design ........................................................................................................................... 78 
11.5 Analysis of the Phase I 
......................................................................................................... 79 
11.6 Analysis of the Phase II 
....................................................................................................... 79 
12 REGULATORY CONSIDERATIONS 
......................................................................... 
80 
12.1 Institutional Review Board/Ethics Committee Approval 
....................................... 
80 
12.2 Informed Consent ................................................................................................................. 80 
12.3 Subject Confidentiality 
........................................................................................................ 80 
12.4 Study Record Requirements 
............................................................................................. 
80 
12.5 Premature Discontinuation of the Study 
...................................................................... 
81 
13 REGULATORY AND REPORTING REQUIREMENTS 
.......................................... 
81 
13.1 Adverse Events 
....................................................................................................................... 81 
13.2 Serious Adverse Event (SAE) Definition 
....................................................................... 
81 
13.3 Adverse Drug Reporting 
..................................................................................................... 
82 
13.4 Karyopharm Drug Safety Contact information .......................................................... 
82 
13.5 Investigator Reporting Responsibilities 
....................................................................... 
82 
13.5.1 Reporting to FDA 
...................................................................................................................... 
82 
13.5.2
 Reporting to Sponsor (NPM) 
............................................................................................... 
83 
13.5.3 Reporting to the IRB 
................................................................................................................ 
84 
13.6 Adverse Events Updates / IND Safety Reports 
............................................................ 
84 
14 DATA MANAGEMENT 
................................................................................................ 
84 
14.1 Data Collection 
....................................................................................................................... 84 
14.2 Protocol Monitoring Committee 
...................................................................................... 
84 
14.3 Study Monitoring and Auditing 
........................................................................................ 
85 
14.3.1 Investigator Responsibilities 
............................................................................................... 
85 
14.3.2 Site Responsibilities.................................................................................................................
 
85 
14.3.3 Monitoring 
...................................................................................................................................
 
86 
15 PROTOCOL AMENDMENTS OR DEVIATIONS..................................................... 
86 
15.1 Protocol Amendments 
......................................................................................................... 86 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 5 
15.2 Protocol Deviations 
.............................................................................................................. 86 
16   REFERENCES 
.................................................................................................................... 
87 
APPENDIX A: Response Criteria ....................................................................................... 
91 
APPENDIX B: Performance Status Criteria 
................................................................... 
92 
APPENDIX C: Laboratory PK/PD Events Schedule – Blood Draws ....................... 
93 
 
 
 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 6 
Synopsis 
Study Title 
Investigator-initiated Phase I/II Clinical Trial of Selinexor 
(KPT-330) and liposomal doxorubicin for relapsed and 
refractory multiple myeloma 
Study Rationale 
Multiple myeloma accounts for 10% of all hematologic 
neoplasms, and approximately 20,000 patients were 
diagnosed with multiple myeloma in the United States in 
2012[1]. Advances in therapy have resulted in the 
availability of novel immunomodulatory agents and 
proteasome inhibitors with a resultant improved survival of 
patients[2-7]. Despite those advances
, the disease remains 
uniformly fatal. The outcomes of patients with multiple 
myeloma who have failed lenalidomide and bortezomib 
remains poor and the development of new active therapies 
for this group of patients represents an unmet medical need. 
There is extensive experience with the use of doxorubicin 
and  liposomal doxorubicin (LD) for the treatment of 
multiple myeloma.  Historically, patients with multiple 
myeloma received infusion doxorubicin in a regimen called 
VAD (vincristine
, doxorubicin, and dexamethasone).  
Because LD is associated with shorter infusion times and less 
cardiotoxicity, it was incorporated into the induction 
regimen instead of doxorubicin resulting in the DVD 
regimen.  Outpatient DVD has been compared to VAD and 
resulted in similar response rates to VAD—with less 
alopecia
, neutropenia and obviating the need for 
hospitalization[8]. However, it was associated with greater 
incidence of palmar plantar erythrodysesthesias or hand-
foot syndrome (HFS).  More recently, LD in combination with 
bortezomib was found to be superior to bortezomib alone—
showing a significant increased time to progression
, 15-
month survival rate, and duration of response for the 
LD/bortezomib arm[2]
. This led to the approval by the US 
Food and Drug Administration of LD for patients with 
relapsed and refractory multiple myeloma in 2007
. We have 
previously evaluated the addition of LD to thalidomide and 
lenalidomide in patients with relapsed and refractory 
myeloma as well as in the newly diagnosed setting with 
evidence of clinical synergy[9-11]. 
 
Selinexor, a Selective Inhibitor of Nuclear Export / SINE™ 
Compound, forces multiple tumor suppressor proteins to 
accumulate in the cell nucleus where they perform their 
growth inhibiting function.  Selinexor has shown potent 
broad anti-cancer
 cytotoxicity
 in vitro and robust anti-cancer 
activity against multiple tumors in preclinical animal models
.  
Selinexor is being evaluated in several Phase I studies, 
including patients with advanced hematological 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 7 
malignancies (NCT01607892), advanced metastatic solid 
tumors (NCT01607905), and in a food effect study in 
patients with sarcomas (NCT01607905). Initial results have 
shown that selinexor has acceptable tolerability with clear 
anti-tumor activity in these studies.  
The laboratory of Dr. Sullivan has demonstrated that high-
density human myeloma cell lines and patient myeloma cells 
export DNA topoisomerase IIα from the nucleus to the 
cytoplasm
, thus rendering the myeloma cells resistant to the 
cytotoxic effects of topoisomerase II inhibitors—for example, 
doxorubicin[12].  The export of human topoisomerase II
α 
has been shown to be mediated by two CRM1 (XPO1)-
dependent nuclear export signals[13].  More recently, the 
same lab has shown that XPO1 inhibitors (leptomycin B and 
ratjadones) and XPO1 siRNA block the nuclear export of 
topoisomerase IIα and re-sensitize these cells to 
doxorubicin[14].  Finally, 
this lab has demonstrated that 
selinexor (and other SINE™ XPO1 antagonists)  sensitize 
high-density human myeloma cell lines and patient myeloma 
cells to doxorubicin and have little effect on normal PBMN’s 
and bone marrow cells[15]. These recent results also 
demonstrated that optimal myeloma cell kill occurs when 
the administration of selinexor precedes that of doxorubicin. 
Thus, the present study aims to evaluate the safety and 
efficacy of selinexor in combination with LD and 
dexamethasone in patients with relapsed and refractory 
multiple myeloma. 
Primary Objective 
For the phase I portion, the primary objective is to determine 
the safety and recommended phase II dose of selinexor in 
combination with LD and dexamethasone in patients with 
relapsed and refractory myeloma. 
In the phase II portion, the primary objective is to evaluate 
the efficacy (overall response rate—partial response and 
better) of selinexor, LD, and dexamethasone in patients with 
relapsed and refractory myeloma. 
Secondary Objectives 
 
To estimate the progression-free (PFS) and overall survival 
(OS) in patients with relapsed and refractory myeloma 
treated with this combination. 
To estimate the clinical benefit rate (minimal response and 
better) of the combination in relapsed and refractory 
myeloma. 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 8 
Endpoints 
Primary Endpoints: 
1. Phase I: determine the MTD and RP2D of the 
combination 
2. Phase II: determine the overall response according to 
the uniform criteria of the IMWG (partial response 
and better) 
 
Secondary Endpoints: 
1. Clinical benefit rate (minimal response and better) 
2. Progression-free survival of the combination 
3. Duration of response 
4. Overall survival 
5. Adverse event profile as assessed by the NCI CTC 
version 4.  
Exploratory correlative analyses (see below) 
Correlative / Exploratory 
studies 
Patients will have a bone marrow aspirate and biopsy 
performed on screening
, within the loading phase (day -7) at 
least 2 hours after the selinexor administration, and at the 
time of disease progression. The bone marrow biopsies will 
be used to construct a tumor microarray for the analyses 
below.  Bone marrow aspirates will be aliquoted and a 
portion will be CD138 selected. If a patient has <5% 
involvement plasma cells in the bone marrow in screening
, a 
repeat bone marrow biopsy is not needed on day -7 
(loading).  
Myeloma Patient Bone Marrow Biopsy Microarrays 
Plasma cells in tumor microarrays (produced from patient 
bone marrow biopsies) will be identified by lambda or kappa 
light-chain staining and examined for the expression and 
intracellular location (nucleus versus cytoplasm) of 
topoisomerase IIα, topoisomerase IIβ, p53, XPO1
, IkB, NF-kB, 
and possibly other biomarker of relevance before and after 
in vivo treatment with selinexor and at the time of disease 
progression.  
 
Myeloma Patient Bone Marrow Aspirates 
Patient bone marrow aspirates collected during screening 
will be used to evaluate the predictive value of baseline ex 
vivo sensitivity testing with selinexor and LD.  The 
lymphocyte fraction of patient bone marrow aspirates will 
be isolated by ficoll-gradient centrifugation and incubated 
overnight in the presence of selinexor (0, 0
.156
, 0.625, 2.5, 
10 and 40 µM), +/- doxorubicin (2µM), and if adequate 
sample is available, KPT8602 (0, 0.156, 0.625, 2
.5, 10 and 40 
µM) +/- dexamethasone (10µM) . .  Ex vivo sensitivity to will 
be assayed in CD-138/light chain double positive myeloma 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 9 
cells by flow cytometry and activated caspase 3 apoptosis 
assay for EC50 analysis.
 
 
A portion of the lymphocyte fraction will be incubated 
overnight in the presence of selinexor (100 nM and 300 nM) 
and cytospin slides made to assay the intracellular location 
(nucleus versus cytoplasm) of topoisomerase IIα, 
topoisomerase IIβ, p53
, XPO1, IkB and NF-kB and possibly 
other biomarker of relevance with or without treatment with 
selinexor.The intracellular location of topoisomerase IIα, 
topoisomerase IIβ, p53
, XPO1, IkB and NF-kB seen in plasma 
cells from the aspirates will be compared to that seen in the 
biopsy tissue arrays.  
 
A portion of the cells from the lymphocyte fraction of the 
bone marrow aspirate will be isolated using CD-138 
magnetic bead selection. In the future
, DNA from CD-138 
positive myeloma cells will be isolated and interrogated for 
specific mutations by targeted exome sequencing
.  In 
addition, gene expression of RNA isolated from CD-138 
positive myeloma cells will be assayed by microarray 
analysis. 
 
Myeloma Patient Blood Samples for PK Analyses (Appendix 
C) 
Patients enrolled on the phase I and phase II parts of this 
study will also have peripheral blood collected for limited PK 
analyses of selinexor and LD.  Samples will be collected after 
administration of selinexor (to measure peak plasma 
concentrations) and at the time of bone marrow aspirates.  
Blood samples will also be collected post-LD administration 
to measure free doxorubicin to estimate overall patient 
exposure to free doxorubicin.  We will correlate blood levels 
of selinexor and LD with the expression and intracellular 
location of the proteins described above
. 
 
Myeloma Patient Blood Samples for PD Analyses (Appendix 
C) 
1. XPO1 Inhibition.  Leukocytes will be isolated from 
patient blood samples collected pre- and post-dosing 
(≥4hr) and total RNA will be isolated to study 
changes in gene expression before and after 
exposure to selinexor
. Inhibition of XPO1(selinexor 
target) will be assessed by qRT-PCR of XPO1 and 
other genes, which are upregulated once XPO1 is 
inactivated (based on Karyopharm gene chip 
studies)(e.g
., ARRDC3, NGFR, SLC family, PCLO)
. 
2.  Cytokines. Blood samples (1 ml) will be collected 
pre- and post-dosing and analyzed for plasma 
cytokine concentrations.  Cytokines include: IL1α, 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 10 
TNFα, IL-6
, MCP1, IFNγ, VEGFα, IL-8
, IFNα, IL-10 
Sample Size 
Approximately 6-24 adult patients will be enrolled in the 
phase I portion and 7 to 23 patients (excluding patients 
treated at the RP2D in the phase I) will be enrolled in the 
phase II portion. Overall, up to 47 patients may be enrolled. 
Study Design 
A Phase I/II Study of oral selinexor in combination with LD 
and dexamethasone in patients with relapsed and refractory 
multiple myeloma.  
Phase I: 
The phase I portion will be a standard 3+3 dose escalation 
design.  
Briefly, 3 patients will be enrolled on each dose level.  
• If no patient develops a dose limiting toxicity (DLT), 
the next 3 patients are enrolled at a higher dose level.  
• If 1/3 develops a DLT, the cohort is expanded and 3 
additional patients are enrolled to that dose level. If 0 
of 3 (total 1/6) patients experience DLT, proceed to 
the next higher dose level. If >1 patient suffers a DLT 
(≥2/6), then the dose will be de-escalated to the 
previous lower level. Three additional patients will 
be enrolled to that lower dose cohort unless 6 
patients had been treated at that lower dose
. If ≤1 of 
6 patients experience DLT
, this lower dose level will 
be declared the maximum tolerated dose (MTD).  
• If 2 or more patients (≥2/3) develop a DLT, 3 
additional patients will be enrolled at a lower dose 
cohort unless 6 patients had been treated at that 
lower dose.  
 
Loading phase 
Selinexor will be administered orally at 80 mg on day, -7 
during a loading phase and then once weekly on days 1, 8, 
and 15 (twice weekly for cohort 3m and 4m). 
Dexamethasone will be administered at 40 mg weekly (or 20 
mg in case of intolerance or in patients 75 years or older).    
Treatment phase and dose escalation: 
Patients will received liposomal doxorubicin (20-30 mg/m2 
IVPB on D1) at least 2 hours but less than 4hours after 
selinexor administration, and dexamethasone (40 mg PO 
weekly).  Cycle 1 is the cycle when all 3 drugs are given. A 
cycle is 21 days 
Dexamethasone will be given at 40 mg weekly during the 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 11 
treatment phase. 
The dose escalation for the phase I will be as follow: 
Dose level -1: 40mg on days 1,8, 15  in
 combination
 with 20 
mg/m2 LD 
Dose level 1: 40 mg/m2 (~68 mg) on days 1,8
, 15 in 
combination with 20 mg/m2 LD includes a 2 week loading 
phase (4 total doses in loading) 
Dose level 2: 80 mg on days 1, 8, 15 in combination with 20 
mg/m
2 LD (includes a 2 week loading phase (4 total doses in 
loading) 
Dose level 1m: 60 mg on days 1, 8, 15 in combination with 20 
mg/m2 LD (Includes a single loading dose on day -7) 
Dose level 2m: 80 mg on days 1, 8, 15 in combination with 20 
mg/m2 LD (Includes a single loading dose on day -7) 
Dose level 3m: 80 mg on days 1,3,8, 10  in
 combination
 with 
20 mg/m2 LD (Includes a single loading dose on day -7) 
Dose level 4m: 80 mg on days 1,3,8, 10  in
 combination
 with 
30 mg/m2 LD (Includes a single loading dose on day -7) 
After amendment 5, patients will start dosing on dose level 
2m 
Intra-patient dose escalation 
Intra-patient dose escalation of selinexor will be allowed at 
the discretion of the principal investigator and treating 
physician, provided that dose level has been found to be well 
tolerated(cleared DLT with 6 patients treated at that dose 
level). Intrapatient dose escalation would only occur after 
patients have completed the first cycle and can also occur in 
the maintenance setting
.  
Maintenance phase:  
After 8 cycles of therapy with selinexor, LD, and 
dexamethasone, patients will be eligible to proceed on 
maintenance with the tolerated dose of weekly selinexor and 
dexamethasone until disease progression. In maintenance, 
cycles are 28 days.   
Definition of dose limiting toxicity (DLT) 
DLT is defined as any of the following occurring in the first 
cycle (excluding the selinexor loading period from D-14 to D-

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 12 
1) that is not due to an a cause other than study drug toxicity 
• ≥ 1 missed doses (out of 3 doses) in 21 days at the 
               target dose due to study drug toxicity 
• Discontinuation of a patient due to a toxicity that is 
not due to a cause other than drug toxicity before 
completing cycle 1 
 
• Grade ≥ 3 nausea/vomiting
, diarrhea or dehydration 
while taking
 optimal supportive medications 
 
• Any other Grade ≥3 non-hematological toxicity 
except alopecia, steroid induced hyperglycemia or 
electrolyte abnormalities correctable with 
supportive therapy 
 
• Grade ≥ 3 AST or ALT elevation  
 
• Grade 4 neutropenia [absolute neutrophil count 
(ANC) < 500/mm3] lasting ≥7 days  
 
• Febrile neutropenia (ANC<1000/mm3 with a single 
temperature ≥ 38.3ºC or sustained temperature of 
>38°C for over 1 hour); 
 
• Grade ≥3 thrombocytopenia associated with 
clinically significant bleeding  
 
 
Determination of maximum tolerated dose (MTD) and 
recommended phase II dose (RP2D) 
The MTD is defined as the highest dose level in which ≤ 1 of 6 
patients experience a DLT
. In general, we anticipate that the 
MTD will be the RP2D. However, based on evaluation with 
co-investigators, and a focus on those patients tolerating 
longer-term treatment, the RP2D dose may be less than the 
MTD.  
Phase II: 
Simon Two stage phase II.  
Thirteen eligible patients will be enrolled in the first stage 
(including the 6 patients from the phase I treated at the 
RP2D). If 3 or more partial responses are noted
, another 16 
patients will be enrolled. If 8 or more patients achieve a 
partial response or better among the 29 subjects, the 
combination is deemed active.  Under this two-stage 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 13 
optimum design, there would be a 90.7% chance of detecting 
a tumor response rate of at least 40% and a response rate of 
15% or less would lead to the conclusion that the regimen 
lacks antitumor activity at
 a 0.05 significance level
. The 
probability of early stopping (in stage I) is 0
.058 if the true 
response rate of the combination is 40%.  
Dose Schedule  
Loading phase: Patients will receive selinexor at 80 mg on D-
7 orally. This dose was shown to be tolerable in a study of 
patients with chronic hematologic malignancies including 
myeloma (NCT01607892). In addition, patients will receive 
dexamethasone 40 mg
 on day -7. The loading phase lasts 1 
week.  
Induction phase:  Patients will be treated initially with 
selinexor at the RP2D PO weekly dose (on days 1, 8, 15) (or 
twice weekly dosing on cohort 3m and 4m),  liposomal 
doxorubicin at the RP2D IVPB on D1 (at least 2 hours (and 
no longer than 4 hours) after the selinexor dose), and 
dexamethasone 40 mg PO weekly (on days 1, 8, 15).  Cycles 
are repeated every 3 weeks (21 days) and patients will 
receive a maximum of 8 cycles of therapy with this 
combination. For patients with prior doxorubicin exposure, 
after a total dose of 450 mg/m2, patients will be required to 
have cardiac assessments (echocardiograms or MUGA) every 
2 cycles.  Any patient with a decrease in ejection fraction of ≥ 
20% from baseline will have LD discontinued.  
Maintenance phase: After 8 cycles of therapy with selinexor, 
LD and dexamethasone, patients will be eligible to proceed 
on maintenance with the tolerated dose of selinexor and 
dexamethasone until disease progression. Cycles are 
repeated every 28 days 
Discontinuation Criteria: 
At the discretion of the Investigator, the investigator may 
remove a patient from the study for the following reasons: 
• Due to disease progression 
• Noncompliance with study procedures 
• Patient no longer consents to participate in the study 
• Intercurrent illness that interferes with study 
assessments 
• Investigator discretion 
• Incidence or severity of AEs in this study indicates a 
potential health hazard to the patient 
• Termination of the study by the sponsor 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 14 
• Pregnancy 
Duration of Treatment 
After 8 cycles of the combination of LD, dexamethasone, and 
selinexor, patients may continue to receive selinexor and 
dexamethasone until disease progression or occurrence of 
an unacceptable toxicity in the phase I and II.  
Inclusion /Exclusion Criteria 
Inclusions: 
1. Written informed consent
 in accordance with federal, 
local
, and institutional guidelines 
2. Age ≥ 18 years 
3. Patients with relapsed and refractory multiple 
myeloma who have received at least 2 prior 
therapies which must include lenalidomide and a 
proteasome inhibitor. Patients must have disease 
refractory to the most recent therapy. Refractory 
myeloma is defined as progressive disease during or 
within 60 days of last therapy. Patients must have 
previously received or be ineligible for (or refused) 
autologous stem cell transplant. 
4. Patients must have measurable myeloma paraprotein 
levels in serum (≥ 0
.5 g/dL) or urine (≥ 0.2 g excreted 
in a 24-hour urine collection sample) or by free light 
chain (involved free light chain greater than 100 
mg/L). 
5. ECOG performance status of 0-1
.  ECOG 2 allowed if 
due to bone disease. 
6. Must have an echocardiogram or MUGA indicating 
LVEF ≥ 50% within 42 days prior to first dose of 
study drug
.   
7. Adequate hematological function:  
a. In the phase I portion:  absolute neutrophil 
count (ANC) ≥1000/mm
3, platelet count 
≥50,000mm3.  GCSF is not allowed during 
screening or during the first cycle for phase I 
patients
.  
b. In the phase II portion, if the patient has 
significant bone marrow involvement (BM 
plasma cells ≥ 50%), platelet count 
≥30,000mm3 and (ANC) ≥ 1000/mm
3 are 
required.  GCSF is allowed
 during screening 
and therapy for all phase II patients. 
Alternatively, with less BM involvement, an 
absolute neutrophil count (ANC) ≥ 
1000/mm3, and platelet count ≥50,000mm
3 
are required.   
8. Adequate hepatic function within 14 days prior to 
loading phase (day -14): total bilirubin <2 times the 
upper limit of normal (ULN) (except patients with 
Gilbert’s syndrome who must have a total bilirubin of 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 15 
< 3 times ULN), and alanine aminotransferase (ALT) 
or aspartate aminotransferase (AST) <2
.5 times ULN.  
9. Adequate renal function within 14 days prior to 
loading phase (day-14): measured or estimated 
creatinine clearance of ≥ 30 mL/min, (Cockroft and 
Gault)  
10. Female patients of child-bearing potential must agree 
to use dual methods of contraception and have a 
negative serum pregnancy test at screening
.  Male 
patients must use an effective barrier method of 
contraception if sexually active with a female of 
child-bearing potential.  Acceptable methods of 
contraception are condoms with contraceptive foam, 
oral, implantable or injectable contraceptives
, 
contraceptive patch, intrauterine device, diaphragm 
with spermicidal gel, or a sexual partner who is 
surgically sterilized or post-menopausal.  For both 
male and female patients
, effective methods of 
contraception must be used throughout the study 
and for three months following the last dose. 
 
Exclusions: 
Patients meeting any of the following exclusion criteria are 
not eligible to enroll in this study. 
1. Patients who are pregnant or lactating 
2. Radiation, chemotherapy, or immunotherapy or 
any other approved anticancer therapy ≤2 weeks 
prior to loading phase (day -7)  
3. Major surgery within four weeks before loading 
phase (day -7) 
4. Myocardial infarct within 6 months before 
enrollment, New York Heart Association (NYHA) 
Class II or greater heart failure
, uncontrolled 
angina, severe uncontrolled ventricular 
arrhythmias, clinically significant pericardial 
disease, or electrocardiographic evidence of 
acute ischemic or active conduction system 
abnormalities 
5. Prior cumulative exposure to doxorubicin 
(including liposomal preparation) > 350mg/m2 
6. Uncontrolled infection requiring parenteral 
antibiotics, antivirals, or antifungals within one 
week prior to first dose; patients with controlled 
infection or on prophylactic antibiotics are 
permitted in the study 
7. Known to be HIV seropositive 
8. Known active hepatitis A, B, or C infection; or 
known to be positive for HCV RNA or HBsAg 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 16 
(HBV surface antigen) 
9. Any underlying condition that would significantly 
interfere with the absorption of an oral 
medication 
10. Grade >2 peripheral neuropathy at baseline 
(within 14 days prior to loading phase (day -7)) 
11. Serious psychiatric or medical conditions that 
could interfere with treatment 
12. Participation in an investigational anti-cancer 
study within 3 weeks prior to loading phase (day 
-7) 
13. Concurrent therapy with approved or 
investigational anticancer therapeutic.  Patients 
are allowed to receive corticosteroids for the 
treatment of non-malignant disorders in doses 
not to exceed the equivalent of prednisone 20 
mg/day 
14. Patients with coagulation problems and active 
bleeding in the last month (peptic ulcer
, epistaxis, 
spontaneous bleeding) 
15. Patients who have had a previous allogeneic 
transplant for treatment of multiple myeloma 
within the past 6 months or have evidence of 
clinically significant GVHD  
Screening Assessments 
Signed written informed consent 
Demographics and medical history (prior therapy) 
Pregnancy test (if applicable) (within a week of loading 
phase) 
Physical examination and vital signs (within 2 weeks of 
loading phase) 
Ophthalmologic exam (within 4 weeks of loading phase) 
Cardiac evaluation: echocardiogram or MUGA(within 6 
weeks of loading phase), ECG
 
Hematology (CBC) (within 2 weeks of loading phase) 
Clinical chemistry (with LDH, b2microglobulin,) (within 2 
weeks of loading phase) 
Urinalysis (within 4 weeks of loading phase) 
Coagulation (within 2 weeks of loading phase) 
Assessment of disease status (within 4 weeks of loading 
phase) (SPEP, 24h UPEP, serum free light chain) 
Bone marrow aspiration and biopsy with cytogenetics, FISH, 
MyPRS (gene expression profile) and correlative endpoints 
described above (within 4 weeks of loading phase) 
Chest radiograph (within 4 weeks of loading phase) 
Skeletal survey (within 4 weeks of loading phase) 
Concomitant medication 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 17 
Treatment and Post-Treatment 
Assessments 
Loading Phase 
Physical examination and vital signs (includes weight and 
ECOG performance status) (on day -7 only) 
Hematology (on day -7 only) 
Clinical chemistry
 (on day -7 only) 
Assessment of disease status (Day -7) (SPEP, 24h UPEP, 
serum free light chain) 
PK of selinexor (appendix
 C) 
Adverse events and concomitant medication 
Pregnancy test (if applicable) 
Bone Marrow aspiration and biopsy at least 2 hours post 
selinexor dosing on day -7 
 
Cycle 1 
Physical examination and vital signs (includes weight and 
ECOG performance status) 
Hematology  
Complete clinical chemistry (weekly in cycle 1) 
Assessment of disease status (SPEP, 24h UPEP, serum free 
light chain) 
PK of doxorubicin, and selinexor and PD (appendix C) 
Adverse events and concomitant medication 
Pregnancy test (if applicable) 
Cycle 2 and Beyond 
Physical examination and vital signs (on day 1) (includes 
weight and ECOG performance status) 
Cardiac evaluation (echocardiogram or MUGA every 2 cycles 
if patient has prior anthracycline exposure with greater than 
450 mg/m2) 
Hematology  (on day 1) 
Complete clinical chemistry
 (on day 1) 
Assessment of disease status (SPEP, 24h UPEP, serum free 
light chain) (on day 1) 
Adverse events and concomitant medication 
Pregnancy test (if applicable) 
PK of doxorubicin, and elinexor and PD (appendix C) 
Final Visit (end of study) 
Physical examination and vital signs (includes weight and 
ECOG performance status) 
Pregnancy test (if applicable) 
Cardiac evaluation (echocardiogram or MUGA) 
Hematology  

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 18 
Complete clinical chemistry
  
Assessment of disease status (SPEP, 24h UPEP, serum free 
light chain) 
Bone marrow aspiration and biopsy (in the event of 
discontinuation due to disease progression) 
Adverse events and concomitant medication 
Pregnancy test (if applicable) 
Response 
Response will be assessed
 per the uniform response criteria 
of the IMWG incorporating minimal response (≥25% 
decrease in serum M protein and ≥50% decrease in the 24h 
urine m spike). 
Safety Variables & Analysis 
The safety and tolerability of the combination of selinexor, 
LD and dexamethasone will be evaluated by means of drug 
related DLT, AE reports, physical examinations, and 
laboratory safety evaluations.  Common Terminology 
Criteria for Adverse Events (CTCAE) V 4.03 will be used for 
grading of AEs.  Investigators will provide their assessment 
of causality as 1) unrelated, 2) unlikely related 3) possibly 
related, or 4) probably or 5) definitely related for all AEs to 
one of or all three study drugs.   

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 19 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
  
AE 
Adverse event 
ALT (SGPT) 
Alanine aminotransferase 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
AST (SGOT) 
Aspartate aminotransferase 
AUC 
Area under the curve 
BMI 
Body
 mass index 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CHF 
Congestive heart failure 
CI 
Confidence interval 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
CRM1 
Chromosome region maintenance protein 1 
CTCAE 
Common terminology criteria for adverse events 
CT Scan 
Computed
 Tomography
 Scan 
CYP450 
Cytochrom P450 
D 
Day 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
End of treatment 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GLP 
Good laboratory practice 
H 
HFS 
Hour 
Hand foot syndrome 
HR 
Hazard ratio 
ICH 
International Conference on Harmonization 
IMWG 
International myeloma working group 
INR 
International normalized ratio 
IRB 
Institutional review board 
ITT 
Intent to treat 
IV 
Intravenous 
LDH 
Lactate dehydrogenase 
m² 
Square metre (body surface area) 
Mg 
Milligram 
Min 
MyPRS 
MCRN 
Minute 
Myeloma Prognostic Risk Signature 
Moffitt Clinical Research Network 
Ml 
Milliliter 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 20 
NCI 
National Cancer Institute  
NES 
Nuclear export signal 
NYHA 
New York Heart Association 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Pharmacodynamics  
PFS 
Progression-free survival 
PK 
LD 
Pharmacokinetics  
 liposomal Doxorubicin 
PO 
Per oral  
PR 
Partial response 
PTT 
RP2D 
Partial thromboplastin time 
Recommended phase II dose 
Topo II 
Topoisomerase II 
SAE 
Serious adverse event 
SD 
Stable disease 
SINE 
Selective inhibitor of nuclear export 
SUSAR 
Suspected unexpected serious adverse reaction 
TSH 
Thyroid stimulating hormone 
TSP 
Tumor suppressor protein 
TTP 
Time to progression 
UNL 
Upper normal limit 
WBC 
White blood cell count 
XPO1 
Exportin 1 
 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 21 
1 Introduction 
1.1 Overview 
Multiple myeloma accounts for 10% of hematologic malignancies and about 2% of all 
cancer death in the United States[1]. The United States Food and Drug Administration
 
recently approved 6 agents for the treatment of myeloma including immunomodulators 
(thalidomide
,  lenalidomide,  pomalidomide),  proteasome  inhibitors  (bortezomib
,  
carfilzomib), and an anthracycline ( liposomal doxorubicin)[2, 4-7, 16, 17]. Despite 
advances in therapy the disease remains uniformly fatal and finding novel agents to 
overcome drug resistance represents an unmet medical need.  
Cancer cells must inactivate their tumor suppressor proteins (TSPs) in order to perpetuate 
their neoplastic phenotype. TSPs require nuclear localization in order to function. Like most 
proteins, TSPs are shuttled into the nucleus by carrier proteins called importins
, and they 
are carried out of the nucleus by exportins. Exportin 1 (XPO1), also called CRM1, is one of 
seven major nuclear exporters responsible for carrying ~220 cargo proteins out of the 
nucleus into the cytoplasm[18].  Nearly all TSPs are transported out of the nucleus 
exclusively by XPO1. Furthermore, XPO1 is overexpressed by 2-4 fold in nearly all cancer 
cells, and its levels correlate with poor prognosis and/or chemotherapy resistance[19]. 
Current research suggests that cancer cells have co-opted XPO1 in order to neutralize their 
TSPs. In addition, DNA topoisomerase II is a substrate for
 XPO1[19]. Topoisomerase II alpha 
is located in the cytoplasm of high density myeloma cells consistent with XPO1 activity and 
lack of response to doxorubicin[14]. 
 
Selinexor is a small molecule, drug-like, orally available Selective Inhibitor of Nuclear 
Export / SINE™ compound that is a slowly reversible covalent antagonist of XPO1.  By 
blocking XPO1
, selinexor induces the accumulation of TSPs in the cell nucleus, leading to 
activation of their tumor suppressing function.  Cells with marked genomic (DNA) damage, 
including cancer cells, undergo apoptotic cell death; normal cells, with little or no genomic 
damage
, undergo transient, reversible cell cycle arrest. Consistent with its novel mechanism 
of broadly inducing TSP function, selinexor has shown broad anti-tumor in preclinical 
mouse models and spontaneous canine cancers.  Selinexor is currently being studied in 
three Phase 1 clinical trials in patients with advanced hematologic or solid tumor 
malignancies, and in patients with treatment refractory sarcomas.  Preliminary evidence of 
anti-tumor activity in humans with a diverse set of cancers formed the basis for studying 
the effect of selinexor on patients with myeloma. In addition, we have shown that selinexor 
and other XPO1 inhibitors are able to restore topoisomerase II alpha location into the 
nucleus and hence susceptibility to doxorubicin, forming the basis of this clinical trial.  
1.2 Selinexor:  Mechanism of Action and Preclinical Summary 
A brief summary of key aspects the preclinical evaluation of selinexor is presented below.  
Further detailed information is provided in the Investigator’s Brochure.  
Selinexor is an orally available, irreversible, potent and Selective Inhibitor of Nuclear Export  
/ SINE™ compound that specifically blocks XPO1
.  Selinexor restores many of the TSP and 
other growth regulatory proteins to the nucleus where they can carry out their normal 
functions
.  It is selectively cytotoxic for cells with genomic damage, i.e., for tumor cells, both 
in vitro and in vivo.  All cell types exposed to SINE™ compounds in vitro undergo G1 ± G2 
cell cycle arrest, followed by a ‘genomic fidelity’ review, and cells with significant genomic 
(DNA) damage are induced to undergo apoptosis
.  Normal cells, with minimal or no DNA 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 22 
damage
, remain in transient, reversible cell cycle arrest until the export block is relieved.  
Selinexor and other SINE™ compounds are not intrinsically cytotoxic; rather, they can 
restore the highly effective tumor suppressing pathways that lead to selective elimination of 
genomically damaged (i
.e., neoplastic) cells.  Tumors of hematopoietic lineage are 
particularly susceptible to induction of apoptosis by XPO1 inhibition; normal hematopoietic 
cells and their functions are largely spared.  
Preclinical Safety 
Sprague-Dawley rats and cynomolgus monkeys were chosen as the toxicology species for 
the selinexor nonclinical safety program.  In both species, the primary effects of oral 
selinexor were dose-dependent reductions in food intake and body weight (or reductions in 
body weight gain), with minimal clinical symptoms (no or mild non-bloody diarrhea)
, 
associated primarily with gastrointestinal atrophy.  Similar effects are observed in mice and 
dogs.  At high repeated doses of selinexor associated with marked weight loss, there were 
changes in cerebellar granular layer neurons in both rats (≥300 mg/m
2) and monkeys (≥72 
mg/m2), but only monkeys showed any CNS symptoms.  No central nervous system (CNS)-
related adverse side effects were observed in the GLP, rat and monkey 4-cycle toxicity 
studies. A GLP, rat neurofunctional study (Irwin test) has also been performed at dose levels 
of 12, 60, or 300 mg/m2 (2, 10, and 50 mg/kg).  No behavioral changes were observed at all 
doses tested.   
In the pivotal, GLP, 4-week monkey study, there was no evidence of a direct or indirect 
effect of selinexor on the morphology and intervals of the ECG at up to 36 mg/m2 (3 
mg/kg).  Based on these results, QT prolongation or other cardiac effect does not appear to 
be a safety
 concern
 for selinexor.  
In summary, dose limiting toxicity (DLT)/mortality in both rats and monkeys is related 
primarily to marked weight loss with atrophy of the gastrointestinal (GI) tract and 
noncritical effects on other major organs. 
Preclinical Efficacy    
In vitro experiments with continuous (~72 hour) exposure to selinexor demonstrated 
potent pro-apoptotic activity across a broad panel of tumor-derived cell lines and patient 
samples in culture, including multiply-resistant cancers, with the majority of IC50s for 
cytotoxicity <800 nM and most hematologic tumor lines having IC50s of 20-400 nM for 
selinexor.  In contrast, normal cells typically underwent (or remained in) cell cycle arrest 
but were resistant to apoptosis-induction; cytotoxicity IC50s were typically >5 µM.  As 
noted above, selinexor had little effect on normal (nonmalignant) lymphocytes or other 
nontransformed cells, which correlated with the low incidence in animals of the typical side 
effects seen with most anti-cancer therapies such as significant myelosuppression, alopecia, 
mucositis and other GI dysfunction
.  
Selinexor and other SINE™ compound analogs have been administered in efficacy studies to 
mice and dogs and in toxicology studies to rats and monkeys. Efficacy was demonstrated in 
mouse models of myeloma, mantle cell lymphoma, and T-cell acute lymphocytic leukemia  
xenografts.  Moreover, efficacy, including significant survival advantages, was demonstrated 
in acute myeloid leukemia (AML) [MV4-11 (FLT3-ITD)] [20, 21] and chronic lymphocytic 
leukemia (TCL-1) leukemografts.  Efficacy was also demonstrated in solid tumor xenografts 
including prostate, breast, liver, glioblastoma
, kidney, and colon cancers.   

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 23 
1.3 Selinexor:  Clinical Summary  
A brief summary of key aspects of the clinical evaluation of selinexor is presented below
.  
Further detailed information is provided in the Investigator’s Brochure.  
Study Designs 
Karyopharm Therapeutics is currently conducting three open-label Phase I clinical trials to 
assess the safety, tolerability, and efficacy of selinexor given orally 2-3 times per week.   The 
first study (KCP-330-001) is in patients with advanced hematological malignancies, the 
second (KCP-330-002) is in patients with advanced or metastatic solid tumor malignancies, 
and the third (KCP-330-003), a food effect study, is in patients who have metastatic, locally 
advanced or locally recurrent soft tissue or bone sarcomas.  All patients entering these 
single-agent phase I studies have relapsed after available therapies and have objectively 
progressing tumors at time of study drug initiation.  To date selinexor has been 
administered to over 200 patients
.     
KCP-330-001 is a dose escalation study in patients with advanced hematologic 
malignancies.  KCP-330-002 is a dose escalation study in patients with advanced metastatic 
solid tumors.  Dose escalation began at 3mg/m
2 given at 10 doses per cycle 
(Monday/Wednesday/Friday on weeks 1 and 3; Monday/Wednesday on weeks 2 and 4).  
The dose limiting toxicities (DLTs) were anorexia/nausea and fatigue at 40mg/m
2 (10 times 
per 4-week cycle) in KCP-330-002 and the maximum tolerated dose (MTD) was 30mg/m2. 
Based on similar adverse events in KCP-330-001
, escalation beyond 30mg/m2 (10 times per 
cycle) was not performed
. The recommended phase II dose (RP2D) for 10 times per cycle 
dosing is 30mg/m2. Reduced intensity dosing at twice weekly (8 times per cycle, Days 1 & 3 
of each week) has shown improved tolerability.  Dose escalation on this schedule in KCP-
330-002 is currently proceeding at 50mg/m2; 40mg/m
2 cleared DLT.  Escalation on this 
twice-weekly schedule in KCP-330-001 is currently proceeding at 35mg/m2 and is 
anticipated to increase to 40mg/m
2 in patients with non-AML hematologic malignancies
.  In 
patients with relapsed AML, escalation is currently ongoing at 40mg/m
2 on the twice 
weekly (Day 1, 3) schedule. 
KCP-330-003 (OZM-050) is an open label Phase Ib trial to evaluate the effects of food and 
formulation on pharmacokinetics of selinexor in patients with advanced soft-tissue or bone 
sarcoma.   
 
Clinical Safety 
In ongoing clinical trials, the most common AEs suspected to be related to selinexor 
are anorexia, fatigue, nausea, vomiting
, diarrhea, and weight loss.  Most of these side effects 
can be managed effectively with dose modification and/or supportive care initiated prior to 
first dosing
. Overall, the most frequently observed laboratory abnormalities include 
mild/moderate thrombocytopenia, hyponatremia, and a decrease in red blood cells (RBC).  
Less common adverse events include:  changes in taste, changes in vision including 
blurred vision, low platelets, decrease in red blood cells, low sodium without symptoms and 
rare side effects include worsening of pre-existing cataracts, elevated levels of bilirubin
, 
elevated liver enzyme levels (ALT and AST), and acute cerebellar syndrome. 
In a previous study, one patient, heavily pre-treated for recurrent pancreatic cancer, 
developed acute cerebellar syndrome following 4 doses of selinexor at 85 mg/m2 BSA twice 
weekly. The patient experienced abnormal speech, loss of coordination, and was unable to 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 24 
walk. Since the date of the initial reported event, this patient is recovering
, with both speech 
and mobility recovered to near baseline over ~6 weeks. No other patients have reported 
similar symptoms to date. 
Patients should avoid alcohol consumption or any products containing ethanol (such 
as certain cough suppressant medications) on days that selinexor is administered. Alcohol 
and ethanol may interfere with the breakdown of selinexor in the body; therefore, alcohol 
consumption, particularly on days of selinexor therapy, should be minimized
. 
Acetaminophen use on the days of selinexor dosing
 should be limited. Selinexor should be 
taken within 30 minutes of eating
. 
Patients should not become pregnant or father a child while on this study because 
the drugs in this study can affect an unborn baby. Women should not breastfeed a baby 
while on this study.  It is important patients understand the need to use birth control while 
on this study.  It is not anticipated that female patients enrolling in this study will be able to 
conceive.  However, in the rare event that this is possible
, female patients of child-bearing 
potential must agree to use dual methods of contraception and have a negative serum 
pregnancy test at screening
, and male patients must use an effective barrier method of 
contraception if sexually active with a female of child-bearing potential
. Acceptable 
methods of contraception are condoms with contraceptive foam; oral, implantable or 
injectable contraceptives; contraceptive patch; intrauterine device; diaphragm with 
spermicidal gel; or a sexual partner who is surgically sterilized or post-menopausal. Total 
(true) abstinence (when this is in line with the preferred and usual lifestyle of the patient), 
is an acceptable method of contraception. Periodic abstinence (e.g
., calendar, ovulation, 
symptothermal
, post- ovulation methods) and withdrawal are not acceptable methods of 
contraception. For both male and female patients, effective methods of contraception must 
be used throughout the study and for three months following the last dose. 
 
Please see the selinexor Investigator’s Brochure for additional information.  
Clinical Evidence of Anti-Cancer Activity 
Hematological Malignancies   In the dose escalation phase of study KCP-330-001, tumor 
load reductions and disease stabilization have been noted across many tumor types
, 
consistent with the broad anti-tumor mechanism and results observed in preclinical 
studies.  Responses have been documented in patients with multiple myeloma (MM), mantle 
cell and diffuse large B cell (DLBCL) lymphomas
, chronic lymphocytic leukemia, Richter’s 
Syndrome, and acute myeloblastic leukemia (AML).  Durability for 6-12 months has been 
observed
.  Dose expansion is planned at 35mg/m2 twice weekly in patients with 
relapsed/refractory DLBCL (N=15), MM (N=10) and at 40 mg/m
2 in AML (N=24)
.  A 
separate Arm will evaluate the safety and tolerability of selinexor in patients with relapsed 
T-cell lymphomas (PTCL and CTCL). Additional cohorts exploring optimal twice weekly 
dosing (e.g
., dosing on Days 1, 2 vs. 1, 3 versus 1, 4) are being enrolled
. 
Solid Tumor Malignancies In the dose escalation phase of study KCP-330-002, disease 
stabilization or responses for >4 months has been observed in patients with colon cancer
, 
cervical adeno- and squamous cancers, and endometrial stromal sarcoma
.  Tumor shrinkage 
has also been observed in patients with melanoma, head and neck cancers, and Ewing 
sarcoma.  Dose expansion at 35mg/m
2 twice weekly in patients with prostate
, ovarian, 
squamous (head and neck, lung
, and cervical), colon, and high-grade malignant gliomas are 
ongoing
.  Additional cohorts exploring twice weekly dosing as described above are being 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 25 
explored.  In addition, preliminary observations indicate that many of the progression 
events in the (primarily colorectal cancer) patients in the escalation portion of the phase I 
are related to liver (vs. lung or other non-liver) lesions.  Therefore
, the protocol for KCP-
330-002 was amended to explore whether pre-treatment with low-dose acetaminophen, 
which reduces liver glutathione (GSH)-mediated metabolism of selinexor, can boost hepatic 
levels of selinexor (as observed in rats), and induce local tumor
 lesion
 shrinkage. 
As of January 20, 2014
, interim clinical data from nineteen patients enrolled in KCP-330-
003 (OZM-050) were available. All patients received standard treatment for sarcoma and 
had progressive disease at study entry. Selinexor 30 mg/m2 was dosed orally twice weekly 
and showed similar tolerability following administration of both capsules and tablets when 
given under fasting conditions or with high or low fat meals. Of the 19 patients that received 
at least one dose of selinexor, 9 patients achieved stable disease by their first or second CT 
scan. In addition, 9 patients remained on study (>2 cycles) as of January 20, 2014. 
 
Clinical Pharmacokinetics 
Detailed pharmacokinetic (PK) and pharmacodynamic (PD) analyses and serial tumor 
biopsies were performed in both KCP-330-001 and -002 studies and suggested a fairly 
proportional increase in Cmax and AUC with increasing dose
, with no accumulation and 
without affecting half-life or clearance of selinexor
. At 30 mg/m2, AUC
0-last. (4375 ng*h/mL) 
was comparable to the anti-tumor exposure observed in mice and dogs.  Tmax (~3 h) and 
T1/2 (6-7 h) were consistent across doses.  A significant increase (2-20x) in XPO1 messenger 
ribonucleic acid (mRNA) levels (PD marker) in circulating leukocytes was observed at all 
doses, with higher doses demonstrating higher levels of XPO1 mRNA induction.  Analysis of 
tumor  biopsies  confirmed  nuclear  localization  of  TSPs  (e.g
.,  p53
,  FOXO3A,  IκB)  and 
apoptosis of cancer cells following selinexor administration. 
Selinexor PK data from eleven patients in study KCP-330-003 (OZM-050), suggest that oral 
selinexor in capsule or tablet forms show a clear difference between fasted and fed 
treatments, regardless of fat content of the meal. Patients being administered oral selinexor 
in clinical trials should be instructed to always take selinexor with food in order to prevent 
variations in plasma selinexor exposure related to prandial state. As there were no 
detectable differences between a high-fat or low-fat meal, no specific instructions with 
regard to meal size or content are required. There were no detectable differences in plasma 
selinexor exposure between the tablet and capsule formulations (p >0.05); as such, all 
previous selinexor trials conducted with the capsule formulation should be considered 
supportive of safety in future trials conducted with tablets at a similar dose range. 
Moreover
, these data indicate that the use of selinexor tablets at the same doses as 
previously used for capsules is appropriate. 
 
Patients in this study will be dosed based on a fixed oral dose of selinexor rather than 
dosing per body surface area. This dosing regimen is supported by the accumulated PK data 
to date (see Investigator Brochure). 
The 5th and 95th percentile for BSA values encountered to date in Phase 1 trials KCP-330-
001 and KCP-330-002 are 1.5 and 2.3 m2, respectively (N=331).  For this range, flat doses of 
60 mg and 100 mg selinexor translate to BSA normalized dose ranges of 27-40 mg/m2 and 
43-70 mg/m2, respectively.  To evaluate PK for flat doses of 60 mg and 100 mg selinexor, 
Cmax and AUC
(0-∞) values were compared for the equivalent
, typical BSA-normalized dose 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 26 
ranges  Both C
max and AUC
(0-∞) were found to be significantly different (p<0.0001) for 60 mg 
and 100 mg selinexor.   
 
 
 
 
1.4 Doxorubicin for Patients with Multiple Myeloma 
There is extensive experience with the use of doxorubicin and  liposomal doxorubicin for 
the treatment of multiple myeloma.  Historically, patients with multiple myeloma received 
infusion doxorubicin in a regimen called VAD (vincristine, doxorubicin and 
dexamethasone).  Because  liposomal doxorubicin (LD) is associated with shorter infusion 
times and less cardiotoxicity, it was incorporated into the induction regimen instead of 
doxorubicin resulting in the DVD regimen.  Outpatient DVD has been compared to VAD and 
resulted in similar response rates to VAD—with less alopecia, neutropenia and obviating 
the need for hospitalization[8]. However, it was associated with greater incidence of palmar 
plantar dysesthesias or hand-foot syndrome.  More recently, LD in combination with 
bortezomib was found to be superior to bortezomib alone—showing a significant increased 
time to progression, 15-month survival rate and duration of response for the 
LD/bortezomib arm[2]. This led to the approval by the US Food and Drug Administration of 
LD for patients with relapsed and refractory multiple myeloma in 2007
. We have evaluated 
the addition of LD to thalidomide and lenalidomide based therapy in the relapsed / 
refractory setting as well as in newly diagnosed myeloma with evidence of synergy[10, 22]. 
 
Given the erratic availability of LD preparations , this trial will utilize commercial sources of 
Liposomal doxorubicin. Commercial sources of liposomal doxorubicin  are  
  drugs with the 
same active ingredient, dosage, strength, and route of administration as the FDA-approved 
drug Doxil. 
 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 27 
1.5 Investigator-initiated Phase I/II Clinical Trial of Selinexor,   Liposomal 
Doxorubicin and Dexamethasone for Relapsed and Refractory Multiple 
Myeloma 
1.5.1 Rationale for the Study  
In our pre-clinical studies, we have observed that high-density drug resistant multiple 
myeloma cells
, similar to those found in the bone marrow of myeloma patients
, export 
topoisomerase II alpha (topo  IIα)  from  the  nucleus  to  the  cytoplasm[12]. Under normal 
conditions, topoisomerases remove DNA tangles and relieve torsional stress and are also 
necessary  for  chromatin  condensation  during  mitosis.  Topo  IIα  does  this  by  creating 
double-strand DNA breaks called cleavable complexes,  allowing the DNA to unwind
, 
essentially removing torsional stress. Topoisomerase directed drugs arrest Topo IIα protein 
in this cleavable complex formation, ultimately resulting in double-strand DNA breaks and 
induce apoptosis of the cancer cell
. However, when Topo IIα is exported into the cytoplasm 
and is no longer in contact with nuclear DNA, it cannot form cleavable complexes thereby 
making the myeloma cells resistant to topoisomerase directed therapeutics such as 
doxorubicin[12, 13, 23].  
The  molecule  that  exports  topo  IIα  from  the  nucleus  to  the  cytoplasm  is  a  chaperone  / 
receptor protein called chromosome maintenance protein 1 (CRM1), or XPO1. CRM1 binds 
to a leucine-rich (hydrophobic) nuclear export signal peptide on the topo  
IIα  protein [12, 
13, 23] and escorts it through the nuclear pore complex where it is released into the 
cytoplasm
. We have found that if we block CRM1 binding to topo IIα at the nuclear export 
signal peptide, topo IIα stays in the cell nucleus and the cells are made sensitive to 
topoisomerase inhibitors, essentially a reversal of density-dependent drug-resistance.  

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 28 
In general, the intracellular location of a protein is crucial to its normal functioning in a cell
. 
Cancer cells utilize the processes of nuclear-cytoplasmic transport through the nuclear pore 
complex to effectively evade anti-cancer mechanisms [14, 18, 19]. Examples of nuclear 
proteins  
that  are  exported  
into  
the  cytoplasm  
in  cancer  
include  
the  drug  
targets  
topo  
IIα  
and BCR-ABL [24] and tumor-suppressor proteins such as retinoblastoma [25], APC [26], 
p53 [27], p21 [28], and p27 [29]. In addition, CRM1-mediated export is increased in various 
cancers (reviewed in [18, 19]). The therapeutic potential of various CRM1 inhibitors has 
begun to be addressed in the laboratory. Compounds under investigation include ratjadone 
compounds [14, 30-33], KOS-2464 [34], FOXO export inhibitors[35], valtrate [36], 
acetoxychavicol acetate [37], and most recently CBS9106 [38] and small-molecule selective 
inhibitors of nuclear export / SINE™ compounds[21]. Recent publications have indicated 
that SINE™ compounds may be effective against various malignancies including leukemia 
[20, 21, 39-41], kidney cancer [42], mantle cell lymphoma [43], melanoma [44], and 
multiple myeloma (MM) [40]. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1. Drug Resistance in multiple myeloma and intracellular localization of 
topoisomerase IIα Human multiple myeloma cells grown at high densities; (A) export topo 
IIα to the cytoplasm and (B)(next page) are resistant to topo II inhibitors. High density cells 
were grown at 2 x10
6 for 20 hours and either stained with DAPI (blue) and topo IIα (green) 
(A) or treated with doxorubicin and assayed for apoptosis (B)(next page).
 
 
A 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 29 
 
 
 
 
 
 
 
 
 
 
In multiple myeloma (MM), de novo drug resistance to topoisomerase II inhibitors 
occurs at high cell densities due to trafficking of topo IIα from the nucleus to the cytoplasm 
(Figure 1A) where it is no longer in contact with the DNA and thus unable to induce 
apoptotic cell death [12, 13, 23, 45] (Figure 1B). We have previously demonstrated that 
topo  IIα  is  exported  from  the  nucleus  of  human  myeloma  cells  by  a  CRM1-dependent 
mechanism [12], and we have also identified the nuclear export signals (NES) for topo IIα at 
amino acids 1017-28 (site A) and 1054-66 (site B) [13](Figure 2). We found that site-
directed mutation of NES 1017-28 (site A) blocked nuclear export of topo IIα [13] (Figure 
2).  
Figure 2. Site-directed mutagenesis. The figure compares nucleotide sequences from the 
wild-type topo IIα gene and the mutated sequences used in this study. Hydrophobic amino 
acid residues thought to be necessary for nuclear export were mutated to alanine using site-
directed mutagenesis (gray boxes). Putative NES amino acid sequences are in boxes below 
their
 corresponding
 nucleotide sequences. 
 
B 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 30 
CRM1 inhibition using siRNA or ratjadone to block nuclear export of topoisomerase 
IIα and sensitize high-density drug resistant myeloma cells to doxorubicin 
In these experiments, we repeated the finding that that myeloma cells grown
 at high density 
are highly resistant to topo II–directed chemotherapeutic drugs (Figure 1) and that drug 
resistance correlated with nuclear export  of  
topo  
IIα  (Figure  1). Based on these data, we 
proposed that blocking CRM1-mediated export of topo IIα may make myeloma cells more 
sensitive to topo II–active agents.  
To evaluate whether blocking topo IIα export would sensitize cells, we knocked down CRM1 
mRNA and protein expression in cells by transfection with CRM1-specific siRNAs and by 
using the CRM1-inhibiting drug ratjadone C (Figures 3 and 4) [14]. Ratjadone C was used in 
this study because it is a potent inhibitor of CRM1, has been shown to have anticancer 
properties, and has reduced toxicity in vitro compared to leptomycin B when used at low 
concentrations. CRM1 inhibition by siRNA and ratjadone C in human myeloma cells was 
found to prevent nuclear export of topo IIα in plateau density cell cultures (Figure 3)
. 
Depletion or inhibition of CRM1 by siRNA or ratjadone C caused high-density myeloma cells 
to become 4-fold more sensitive to the topo II inhibitors doxorubicin and VP-16 as 
measured by apoptosis (Figure 4)[14]
. Depletion of topo IIα protein by specific topo IIα 
siRNA knockdown reversed this synergistic effect, indicating that topoIIα was the targeted 
molecule for CRM1 synergistic activity (data not shown). In addition, we found that blocking 
CRM1-mediated export sensitized patient myeloma cells obtained from bone marrow 
aspirates to the topo II poison doxorubicin (Figure 5). Normal peripheral blood 
mononuclear cells were not sensitized by CRM1inhibition (Figure 11). It is likely that these 
cells were not sensitized because they are not replicating at a high rate, unlike the myeloma 
cells, which double approximately every 24 h. In addition, normal cells do not export topo 
IIα; therefore, ratjadone C treatment would not affect intracellular localization.  
When additional drugs were used in combination with ratjadone C, we found that myeloma 
cells were sensitized to the topo II inhibitors doxorubicin and VP-16 but not to the 
alkylating agent melphalan, or other myeloma chemotherapeutics such as dexamethasone 
and lenalidomide (data not shown). In conclusion, maintaining topo IIα in the nucleus by 
inhibition of CRM1 greatly enhanced the cytotoxic effect of the topo II inhibitors 
doxorubicin and VP-16 in high-density myeloma cells. Band depletion assays indicated that 
more DNA-topo IIα complexes were stabilized in cells when CRM1 was inhibited and these 
increased cleavable complexes resulted in increased strand breaks as measured by the 
comet assay and subsequent apoptosis[14]. 
 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 31 
 
Figure 3. H929 topo IIα immunofluorescence. H929 human myeloma cells were grown at 
log and plateau densities, fixed with 4% paraformaldehyde, permeabilized with 0.25% 
Triton X-100
, and stained for cytoskeletal protein (phalloidin-green), topo IIα (red), and 
DNA (DAPI-blue). Results indicate that topo IIα is present in the nucleus of log density cells 
and is exported from the nucleus in plateau density cells. However, nuclear export is 
blocked in plateau cells by a CRM1 inhibitor ratjadone C and by transfection with CRM1 
specific siRNA. Under the conditions of this experiment, CRM1 siRNA knockdown was 69%.  
 
 
 
 
 
 
 
Figure 4. A) CRM1 knockdown using siRNA makes myeloma cells more sensitive to 
the topo IIα poison doxorubicin. H929 cells were transfected with siRNA
, incubated at 
log-phase for 20 hours, and concentrated at plateau-phase conditions. At 48 hours cells 
were treated with the topo II inhibitor doxorubicin (2 µM) and assayed for apoptosis by 
Annexin V staining using flow cytometry, n=2
. Inset, Western blot data for siRNA 
transfection. Percent knockdown was compared to control siRNA (scramble).  CRM1 
knockdown renders plateau density cells more sensitive to topo  IIα inhibitors. B) CRM1 
inhibitor and topo IIα inhibitor synergy. Myeloma cell line U266 was grown in culture for 
20 hours at 2x106 cells/ml. Cells were incubated with the CRM1 inhibitor ratjadone C (5 
nM) for 20 hours. Cell were then treated with doxorubicin (0, 0.5, 1, and 2 µM) for four 
hours and assayed for caspase 3 staining by flow cytometry. Myeloma cells are made more 
sensitive to topo IIα inhibitors in a dose-dependent manner by inhibiting CRM1 export.  
B 
A 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 33 
Figure 6. CRM1-targeted 
nuclear
 export
 
inhibitors. Similar  in  
mechanism to LMB, the 
SINE™ CRM1 inhibitors 
(KPT-127, KPT-185
, KPT-
249, KPT- 276, and KPT-
330(Selinexor)) bind to 
the active site (CRM1 
cysteine residue 528) and 
prevent transport receptor 
binding  to  the  cargo  
protein. KPT-185T is the 
inactive trans-isomer of 
KPT-185.  
 
Figure 7. CRM1, p53, and topo IIα  
localization  
in  SINE™ compound-treated cells.   A) 
Immuno-fluorescence microscopy. Human H929 MM cells were treated with SINE™ 
compound or leptomycin B for 20 hours
. Samples assayed for p53 and CRM1 were treated 
with 100 nM SINE™ compound and 10 nM LMB. Samples assayed for topoisomerase (topo) 
IIα were treated with 300 nM SINE™ compound and 100 nM LMB.  Intracellular localization 
and  expression  of  p53
,  CRM1,  and  topo  IIα  were  examined  by  immunofluorescence 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 34 
microscopy. Nuclei were counter-stained using DAPI (blue). Column 1: CRM1 (green) 
nuclear localization in low-density log-phase cells (2 x 105/ml) was increased in untreated 
controls, in KPT-185T treated cells, and in LMB-treated cells, but not in KPT-185, KPT
-249, 
or KPT-330 treated cells
. Column 2: p53 (red) was exported from the nucleus in low-
density log-phase (2 x 105/ml) untreated control
, and KPT-185T treated cells; however, 
cells treated with KPT-185, KPT-249, KPT-330, and LMB had increased nuclear 
accumulation of p53. Column 3: high-density (3 x 10
6/ml) untreated control cells exported 
topo IIα (green) to the cytoplasm (as did KPT-185T treated cells) and had low levels of topo 
IIα  in  the  nuclei (blue/DAPI). KPT-185, KPT-249, KPT-330, and LMB prevented nuclear 
export of topo IIα; therefore, the nuclei were green (topo IIα).  
B) CRM1, p53, and topo IIα protein expression in SINE™ compound -treated cells. H929 
cells were treated with 100 nM of each CRM1 inhibitor for 20 hours at high-density (3 x 
106/ml) growth conditions. Whole cell lysates assayed  
for  
topo  
IIα  protein  demonstrated 
minimal change in total amount of topo IIα; however, cytoplasmic fractions showed that the 
nuclear  export  of  
topo  
IIα  was  
inhibited  by  KPT-185, KPT-249, and LMB. GAPDH protein 
(loading control) showed that equal amounts of protein were loaded for topo IIα. H929 cells 
were also treated with 100 nM of each CRM1 inhibitor for 20 hours at log-phase growth 
conditions. Whole cell lysates assayed for p53 showed that total cellular p53 increased in 
cells treated with CRM1 inhibitors when compared to untreated and KPT-185T treated 
control samples. Nuclear fractions isolated from treated cells and assayed by Western blot 
demonstrated that nuclear p53 increased when cells were exposed to the active CRM1 
inhibitors KPT-185
, KPT-249, and LMB. KPT-185 and KPT-249, but not LMB or KPT-185T
, 
decreased CRM1 protein expression in whole cell lysates. However, when cells were treated 
with the proteasome inhibitor bortezomib, CRM1 protein levels did not decrease. Treated 
cells were also assayed for CRM1 mRNA levels. We found that all CRM1 inhibitors had 
significantly (P < 0.05) increased mRNA levels as compared to untreated and KPT-185T 
treated controls. 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 35 
 
 
Figure 8. SINE™ compound molecules work synergistically with doxorubicin, 
bortezomib, and carfilzomib in H929 cells. SINE™ compound KPT-185 was serially 
diluted, added to the wells containing H929 MM cells grown at plateau densities (2 x 
106/ml), and incubated overnight at 37°C and 5% CO
2. Doxorubicin (A), bortezomib (B), 
carfilzomib (C), lenalidomide (D), dexamethasone (E), and melphalan (F) were serially 
diluted and added the following day, and the plates were incubated an additional 24 hours. 
Samples were assayed for cell viability (CellTiter-Blue reagent) in replicates of 2-4. Percent 
viability versus drug concentration was plotted. SINE™ compounds were found to be 
synergistic with doxorubicin (CI=0
.377), bortezomib (CI=0.410), and carfilzomib
 
(CI=0.322), additive with melphalan (CI=0.849), and non-synergistic/antagonistic for 
lenalidomide (CI>2.0) and dexamethasone (CI>2.0) in H929 cells
.  
 
 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 36 
 
 
 
 
 
 
 
 
 
 
Figure 9. Human myeloma cells are sensitized to doxorubicin. High-density (3.0 x 106 
cells/ml) H929 cells were treated concurrently with 300 nM SINE™ compound and 
doxorubicin (dox; 0.1
, 0.5, or 1 µM) for 20 hours and assayed for apoptosis by activated 
caspase 3. Apoptosis was induced in SINE™ compound /doxorubicin-treated cells in a dose-
dependent 
manner (P 
< 0.021).  
 
 
 
 
 
 
 
 
 
 
 
Figure 10. Stromal cell co-culture induced drug resistance. H929 myeloma cells (5 
x10
5) co-cultured with HS-5 cells (5 x105) are drug-resistant to CRM1 inhibitors (P=0.0001) 
and doxorubicin (P=0.0002) when used as a single agent compared with H929 cells grown 
in suspension. When compared to doxorubicin alone (columns 1 and 3 of the VC group 
(vehicle control)) (P<0.0001) or the inactive trans-isomer KPT-185T (P<0.02), both KPT-

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 37 
185 and KPT-249 sensitized H929 cells when used in combination with doxorubicin. SINE™ 
compounds sensitized both suspension cells and co-cultured myeloma cells to doxorubicin. 
  
 
Figure 11: CRM1 inhibition sensitized MM cell lines and patient myeloma cells to 
doxorubicin but did not affect peripheral blood mononuclear or non-myeloma bone 
marrow mononuclear cells. A) H929 myeloma cells were incubated concurrently with 
SINE™ compound (100 nM) and 1 µM doxorubicin over a time course of 4, 8, 16, 20, and 24 
hours. MM cells demonstrated significant (P < 0.05) apoptosis beginning at 8 hours with co-
treatment of SINE™ compound and doxorubicin. B)  Human peripheral blood mononuclear 
cells (PBMC) from normal donors (n=3) were unaffected by treatment with SINE™ 
compound (300 nM) and were not sensitized to doxorubicin. C and D) CRM1 inhibitors 
sensitize patient myeloma cells (n=12) to doxorubicin (C) but do not sensitize non-
myeloma cells (D). This indicates that SINE™ compound  may specifically inhibit neoplastic 
cells in MM patients
.  
Summary: Rationale 
Drug resitance in multiple myeloma is correlated to the nuclear export of topo IIα by the 
export receptor CRM1. Blocking nuclear export sensitizes drug-resistant human myeloma 
cells to chemothearpeutic agents. In a study published recently in our lab [46]we examined 
the cytotoxic effects of selinexor in MM cells. We showed by immunofluorescence 
microscopy and nuclear-cytoplasmic fractionation that these molecules were able to 
prevent nuclear export of the tumor suppressor protein p53 and the nuclear drug target 
topo  IIα.  Cell viability data demonstrated that selinexor was effective as a single agent 
against human myeloma H929 and 8226 and HL-60 AML cells at nanomolar concentrations 
but was up to 239-fold less toxic to normal cells. Selinexor, when used in combination with 
the anti-MM agents doxorubicin, was found to sensitize drug-resistant MM cells in both the 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 38 
high-density cell culture model and in co-culture with HS-5/GFP bone marrow stromal 
cells[46]. 
Combining selinexor with doxorubicin induced apoptosis and decreased cell viability of 
myeloma cells synergistically. The synergistic effects of selinexor with the myeloma drug 
doxorubicin was dose dependent, and time-course studies performed in high-density drug-
resistant MM cultures showed that apoptosis was induced after a 8-hour co-treatment with 
doxorubicin/ selinexor. Normal human peripheral blood mononuclear cells were unaffected 
by selinexor treatment and were not sensitized to doxorubicin. In studies done on MM 
patient  bone  marrow  mononuclear  cells,  selinexor-doxorubicin  co-incubation 
synergistically induced activated caspase 3 in CD138/light-chain double-positive myeloma 
cell populations but not in CD138/light-chain double-negative non-myeloma cells, 
indicating that selinexor may specifically inhibit neoplastic cells in MM patients. We found 
that CRM1 protein levels are decreased by selinexor. Interestingly, CRM1 mRNA levels were 
increased by both selinexor and LMB even with the concurrent decrease of CRM1 protein 
found in selinexor -treated cells[46]. 
Recent publications on the effects of selinexor on AML have shown that selinexor has anti-
proliferative effects on AML cell lines and primary AML samples. In addition, when used as a 
single agent, selinexor induced apoptosis and accumulation of p53 in the nucleus of AML 
cells. We found parallel results in human MM cell lines and in patient MM bone marrow 
mononuclear cells with selinexor as a single agent; in addition, selinexor sensitized MM cells 
both in vitro and ex vivo to doxorubicin[46].   
High-density drug-resistant MM cell lines and cells made resistant by stromal cell co-culture 
were sensitive to selinexor treatment.  Selinexor induced apoptosis both as a single agent 
and in combination with doxorubicin as compared to the inactive trans-isomer (P<0.02) or 
DMSO vehicle control (P<0.0001).  Selinexor was found to sensitize both suspension cells 
and co-cultured
 myeloma cells to doxorubicin. 
These data support the current clinical study investigating the combination of selinexor 
with doxorubicin in MM 
1.5.2 Rationale for Starting Dose and Dosing Schedule 
In this trial, we propose weekly dosing of selinexor in combination with LD and 
dexamethasone. Dexamethasone will be given at a total of 40 mg weekly per myeloma 
therapy standard. The starting dose of LD will be 20 mg/m2 IV on D1. Selinexor will be given 
orally on days 1
, 8, and 15 of the cycle. The starting dose of selinexor will be 40  mg/m2 
(~68 mg) weekly, taking into account for the potential overlapping toxicities with LD 
(thrombocytopenia
, nausea). In  the ongoing Phase 1 study (KCP-330-001) in patients with 
hematological malignancies, a dose of 45 mg/m
2 twice weekly (90 mg/m2 weekly) cleared 
DLT; currently dosing at 60 mg/m2 (120 mg/m2 weekly). Therefore, the starting dose in 
this study of 40 mg/m2 selinexor twice weekly, based on prior regimens, would correspond 
to a weekly dose of 80 mg/m2, which was found to be tolerable in prior studies. Of note, 
doses as low as 3 mg/m2 have shown biological and clinical activity. 
Importantly, our preclinical studies suggest synergism between doxorubicin and selinexor 
when selinexor is given prior to doxorubicin, and we have recommended a loading dose of 
selinexor for the first 2 weeks on the trial.  

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 39 
Of note, cohort 2m and 3m have used a one week (one dose of selinexor 80 mg) loading 
phase only.  
 
The following dose levels will be evaluated in this trial: 
Dose 
level 
Number of selinexor doses 
during loading 
LD IV on 
D1 
Selinexor PO  
Dexamethasone* 
PO D1, 8, 15 
-1 
4 (Days-14, -11,-7, -4) 
20 mg/m2 40 mg D1, 8
, 15 
40 mg  
1 
4 (Days-14, -11,-7, -4) 
20 mg/m2 40 mg/m2 (~68 
mg) D1, 8, 15 
40 mg  
2 
4 (Days-14, -11,-7, -4) 
20 mg/m2 80 mg D1, 8
, 15 
40 mg 
1m 
1 (day -7 only) 
20 mg/m2 60 mg D1, 8
, 15 
40 mg 
2m 
1 (day -7 only) 
20 mg/m2 80 mg D1, 8
, 15 
40 mg 
3m 
1 (day -7 only) 
20 mg/m2 80 mg D1,3,8, 10 40 mg 
4m 
1 (day -7 only) 
30 mg/m2 80 mg D1,3,8, 10 40 mg 
* For patients with intolerance to 40 mg of dexamethasone or who are older than 75 years, 
the starting dose of dexamethasone will be 20 mg on the same schedule   
LD is administered at least 2 hours (but less than 4hours) after selinexor administration on 
day 1 of each induction cycle 
Patients enrolled on cohort 2m will have a 1 week loading phase and selinexor will be 
administered on days 1,8
,15 of the cycle (see below). 
 
Dose level 2m was found to be the recommended phase II dose and will be the dose level 
used in the phase II / expansion cohort.  

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 41 
After amendment 5, patients will start dosing on dose level 2m 
1.5.3 Study Population and Sample Size  
Up to 47 patients with relapsed and refractory myeloma will be the included in this trial: up 
to 24 patients on the phase I study and 23 on the phase II trial.  Responses in 3 or more of 
the 13 patients treated at the RP2D will establish the rationale for enrollment of 16 
additional patients
.  
1.5.4 Assessment for Response  
The uniform response criteria of the international myeloma working group (IMWG) will be 
used for response assessment (see Appendix A) [47]. 
2 OBJECTIVES  
2.1 Primary Objective 
For the phase I portion, the primary objective is to determine the safety and recommended 
phase II dose (RP2D) of selinexor in combination with LD and dexamethasone in patients 
with relapsed and refractory myeloma. 
In the phase II portion, the primary objective is to evaluate the efficacy (overall response 
rate—partial response and better) of selinexor and LD and dexamethasone in patients with 
relapsed and refractory myeloma. 
2.2 Secondary Objectives 
To estimate the progression-free (PFS), duration of response (DOR), and overall survival 
(OS) in patients with relapsed and refractory myeloma treated with this combination. 
To estimate the clinical benefit rate (minimal response and better) of the combination in 
relapsed and refractory myeloma. 
3 INVESTIGATIONAL PLAN 
3.1 Overview of Study Design and Dosing Regimen 
This is a investigator-sponsored phase I/II study to evaluate the effectiveness and 
tolerability of oral selinexor in combination with  liposomal doxorubicin and 
dexamethasone in patients with relapsed and refractory multiple myeloma. This study will 
be conducted at H. Lee Moffitt Cancer Center and Research Institute, Wayne State University 
/ Karmanos cancer center and Virginia Commonwealth University Massey Cancer Center
.   
After the initial screening visit and registration in the study, eligible patients will receive 
selinexor on day -7= at a dose of 80 mg in addition to dexamethasone 40 mg. After 1 week of 
dosing with selinexor and dexamethasone, patients will receive weekly selinexor at a 
starting dose of 80 mg (cohort 2m) in combination with  liposomal doxorubicin at a starting 
dose of 20 mg/m2, and dexamethasone at 40 mg orally weekly.  
During the treatment period, patients will undergo physical examination and assessment of 
tumor response (paraprotein assessment) every 3 weeks per the IMWG uniform response 
criteria. 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 43 
investigator, however the patient will not be considered evaluable for DLT and will be 
replaced during the phase I.  
 
Any other drug-related adverse events that may have occurred have resolved to ≤ grade 2 
severity.  
For the phase II patients: For patients with baseline (at the time of eligibility) grade 3 
thrombocytopenia or neutropenia
, a new cycle of therapy (or cycle 1 day 1) can be started 
when the ANC is greater than 800/mm3 and the platelet count is than 30
,000/ mm3. In 
addition, non-hematologic toxicities must have recovered as described in Section 6.1. For 
example
, if a patient initial platelet count was 40,000/mm3, the patient may be able to 
restart another cycle on day 1 if his/her platelet count is greater than 30,000/mm
3.  
For patients without baseline grade 3 thrombocytopenia or neutropenia, a new cycle of 
therapy (or cycle 1 day 1) can be initiated when the ANC is greater than 800/mm3 and the 
platelet count is greater than 50
,000/mm3. In addition, 
non-hematologic toxicities must 
have recovered as described in Section 6.1 
For patients who do not meet criteria to start cycle 1 day 1 because of hematologic adverse 
events encountered during the loading phase, patients may be allowed to proceed with 
cycle 1 after discussion between the treating physician and principal investigator provided 
the patient will receive growth factor and /or transfusion support during cycle 1.  
Any other drug-related adverse events that may have occurred have resolved to ≤ grade 2 
severity.  
If these conditions are not met on Day 1 of a new cycle, the subject will be evaluated weekly 
and a new cycle of treatment will not be initiated until the toxicity has resolved as described 
above. If study drug dosing was halted during the previous cycle and was restarted with a 
one-level dose reduction without requiring an interruption for the remainder of the cycle, 
then that reduced dose level will be initiated on Day 1 of the new cycle
. If study drug 
dosing was omitted for the remainder of the previous cycle or if the new cycle is 
delayed due to toxicity newly encountered on the scheduled Day 1, then the new cycle 
will be started with a one-level dose reduction of the causative agent. 
 
If recovery from toxicities is prolonged beyond 7 days, then the dose of selinexor, Liposomal 
doxorubicin or dexamethasone will be decreased by one dose level depending on which 
agent is felt to be the causative factor or more likely contributing factor. 
3.1.3 Criteria to Proceed with a New Cycle of Therapy During Maintenance 
It is expected that responding patients  (stable disease or better) will proceed to 
maintenance therapy with selinexor and dexamethasone, and typically this would be 
associated with an improvement of disease-related parameters
. In addition, long-term 
maintenance therapy needs to be associated with less long-term toxicities
. To start a new 
cycle of maintenance, the following criteria must be met: 
ANC is greater or equal to 1,000/mm3 
Platelet count is greater or equal to 30,000/mm3 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 44 
In addition, non-hematologic toxicities must have recovered as described in Section 6.1 
3.1.4 
End of Treatment Visit  
Patients that discontinue from treatment will undergo an end of treatment visit, regardless 
of the reason of discontinuation, 28 days after the last dose of study
 medication. 
3.2 Study Duration 
The study is planned to start in Q2 2014 with respect to first patient in (FPI). With an 
expected accrual rate of 3 patients every 5 weeks, and a total number of 47 patients planned, 
the anticipated enrolment period is 20 months. Hence, the last patient will be included not 
later than Q1 2016. The length of treatment period will be approximately 3 months, leading 
to the last patient off study-treatment in Q2 2016. 
4 PATIENT SELECTION 
This Investigator Initiated trial will be conducted in compliance with the protocol, GCP and 
all applicable regulations.   
4.1 Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible to enroll in this study. 
1. Written informed consent in accordance with federal
, local, and institutional 
guidelines 
2. Age ≥ 18 years 
3. Patients with relapsed and refractory multiple myeloma who have received at least 
2 prior therapies, which must include lenalidomide and  a proteasome inhibitor. 
Patients must have disease refractory to the most recent therapy.  Refractory 
myeloma is defined as progressive disease during or within 60 days of last therapy
. 
Patients must have previously received or be ineligible for (or refused) autologous 
stem cell transplant. 
4. Patients must have measurable myeloma  paraprotein  
levels in serum  
(≥  0.5  g/dL) 
or urine (≥ 0.2 g excreted in a 24-hour urine collection sample) or by free light chain 
(involved free light chain greater than 100 mg/L). 
5. ECOG performance status of 0-1
.  ECOG 2 allowed if due to bone disease. 
6. Must have an echocardiogram or MUGA indicating LVEF ≥ 50% within 42 days prior 
to first dose of study drug
.   
7. Adequate hematological function:  
a. In  the  phase  I  portion:    absolute  neutrophil  count  (ANC)  ≥1000/mm
3, 
platelet count ≥50,000mm3.  GCSF is not allowed during screening or during 
the first cycle for phase I patients
.  
b. In the phase II portion, if the patient had significant bone marrow 
involvement  (BM  plasma  cells  ≥  50%),  a platelet  count  ≥30,000mm3 and 
absolute neutrophil count (ANC) ≥ 1000/mm
3 is required.  GCSF is allowed 
during screening and therapy for all phase II patients. Alternatively, with 
less BM involvement, an ANC ≥ 1000/mm3, and platelet count ≥50,000mm
3 
is required. 
8. Adequate hepatic function within 14 days prior to loading phase (day -14): total 
bilirubin <2 times the upper limit of normal (ULN) (except patients with Gilbert’s 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 45 
syndrome who must have a total bilirubin of < 3 times ULN), and alanine 
aminotransferase (ALT) <2.5 times ULN
.  
9. Adequate renal function within 14 days prior to loading: measured or estimated 
creatinine clearance of ≥ 30 mL/min, (Cockroft and Gault)  
10. Female patients of child-bearing potential must agree to use dual methods of 
contraception and have a negative serum pregnancy test at screening
.  Male patients 
must use an effective barrier method of contraception if sexually active with a 
female of child-bearing potential.  Acceptable methods of contraception are 
condoms with contraceptive foam, oral, implantable or injectable contraceptives, 
contraceptive patch, intrauterine device
, diaphragm with spermicidal gel, or a 
sexual partner who is surgically sterilized or post-menopausal.  For both male and 
female patients, effective methods of contraception must be used throughout the 
study and for three months following the last dose. 
4.2 Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not eligible to enroll in this 
study. 
1. Patients who are pregnant or lactating 
2. Radiation, chemotherapy, or immunotherapy or any other approved anticancer 
therapy ≤2 weeks prior to day -7 (beginning of loading phase)  
3. Major surgery within four weeks before Day -7 
4. Myocardial infarct within 6 months before enrollment, New York Heart 
Association (NYHA) Class II or greater heart failure
, uncontrolled angina, severe 
uncontrolled ventricular arrhythmias, clinically significant pericardial disease
, 
or electrocardiographic evidence of acute ischemic or active conduction system 
abnormalities  
5. Prior cumulative exposure to doxorubicin (including liposomal preparation) > 
350mg/m2 
6. Uncontrolled infection requiring parenteral antibiotics, antivirals
, or antifungals 
within one week prior to first dose; patients with controlled infection or on 
prophylactic antibiotics are permitted in the study; 
7. Known to be HIV seropositive; 
8. Known active hepatitis A, B, or C infection; or known to be positive for HCV RNA 
or HBsAg (HBV surface antigen) 
9. Any underlying condition that would significantly interfere with the absorption 
of an oral medication. 
10. Grade >2 peripheral neuropathy at baseline. 
11. Serious psychiatric or medical conditions that could interfere with treatment 
12. Participation in an investigational anti-cancer study within 3 weeks prior to day 
-7 (beginning of loading phase) 
13. Concurrent therapy with approved or investigational anticancer therapeutic.  
Patients are allowed to receive corticosteroids for the treatment of non-
malignant disorders in doses not to exceed the equivalent of prednisone 20 
mg/day 
14. Patients with coagulation problems and active bleeding in the last month (peptic 
ulcer
, epistaxis, spontaneous bleeding) 
15. Patients who have had a previous allogeneic transplant within 6 months and 
have evidence of clinically
 significant graft versus host disease
. 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 46 
4.3 Patient registration 
All  subjects must  be registered with the MCRN Coordinating Center  to  be able  to 
participate in  a trial. The participating  site must fax  or email the completed study 
specific eligibility checklist and registration forms, supporting documents and signed 
informed consent  to the Coordinating Center. Unsigned  or  incomplete forms will  be 
returned  to  the site
. Once documents are received, the MCRN Research Coordinator will 
review them  to confirm eligibility  and  to complete the registration process.  If 
eligibility cannot  be confirmed, the research  coordinator will query  the site for 
clarification  or additional documents  as needed. Subjects failing  to meet all study 
eligibility requirements will  not  be registered and will be unable to participate in the 
trial
. 
 
Upon completion  of registration, the MCRN Research Coordinator will provide the 
participating site with the study sequence number and randomization information,  if 
indicated. Within 24-48 hours after registration, it is the site’s responsibility 
to: 
• Enter the demographic and on-study patient information into the Oncore 
database 
• Order investigational agent(s) if indicated per protocol 
   
It  is the responsibility  of the participating Investigator  or designee  to inform the 
subject  of the research treatment plan and  to conduct the study  in compliance 
with the protocol  as agreed upon with Moffitt  Cancer Center and approved  by the 
site’s IRB
. 
To register a patient send the completed signed eligibility checklist along with 
supporting documentation to the MCRN via email at
 
, Mo
nday through Friday between 8:00AM and 5:00PM (EST)
. 
 
 
 
 
 
 
 
 
 
 
 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 47 
5 STUDY CALENDAR 
 
Screening 
Loadin
g 
Cycle 1 
Cycles 
2-8 
Maintenance 
Final 
Visit 
EOT 
Visit window (+/-3 working 
days) 
Within 
28 days 
prior to 
start of 
therapy 
Within 
14 days 
prior to 
start of 
therapy 
Day 
--7 
Da
y 1 
D
a
y 
8 
D
a
y 
1
5 
Day 1, 8 
and 15 
Day 1 
30 
days 
± 2 days 
± 2 days 
± 7 
days 
Informed consent
1 
x 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
 
x 
 
 
 
 
 
 
 
Demographics / Medical history
2 
x 
 
 
 
 
 
 
 
 
Pregnancy test (if applicable)3 
 
x 
x 
x 
 
 
x 
x 
x 
Body height, weight, & BSA4,  
 
x 
x19 
x19  
 
x19 
x19 
x19 
Vital signs5, 19 
x 
 
x 
x x x 
x 
x 
x 
Physical examination and 
ECOG6 
x 
 
x19 
x19 
 
 
x19 
x19 
x19 
Ophthalmologic exam7 
x7 
 
 
 
 
 
 
 
 
12-lead ECG
19, echocardiogram 
(or MUGA)
8  
x 
 
 
 
 
 
 
x 
x 
Urine analysis9, 19 
x 
 
 
 
 
 
 
 
 
Hematology10, 19 
 
x 
x 
x x x 
x 
x 
x 
Serum chemistry
11, 19 
 
x 
x 
x x x 
x 
x 
x 
Coagulation test (PT, PTT) 12, 19 
 
x 
 
 
 
 
 
 
 
Bone marrow aspiration and 
biopsy13 
x 
 
x 
 
 
 
 
 
x 
Assessment of disease status14 
x 
 
x 
x 
 
 
x 
x 
x 
Chest radiograph15, 19 
x 
 
 
 
 
 
 
 
 
Selinexor dosing in clinic16 
 
 
x 
x 
x x 
x 
x 
 
LD dosing in clinic17 
 
 
 
x 
 
 
x 
 
 
Pharmacokinetics and 
pharmacodynamics18 
 
 
x 
x 
x x 
x 
 
 
Adverse events 
 
 
x 
x x x 
x 
x 
x 
Concomitant medication
19 
 
x 
x 
x x x 
x 
x 
x 
 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 48 
Study Assessment Footnotes 
1 Prior to the first study-specific measures 
2 Medical history includes baseline symptoms as well as a detailed history of prior cancer therapies including 
types and number of prior regimen, refractoriness to immunomodulatory agents and / or proteasome inhibitors, 
prior anthracycline and total cumulative dose, disease progression during or after therapy, as well as 
discontinuations due to intolerability or any other serious illness. 
3 Applicable for women of childbearing potential. Serum β-HCG test within 7 days before the first dose of study 
drug. To be repeated by urine test, if date of first result exceeds the 7-day window. During cycles 2-8, a 
pregnancy test is obtained on day 1 of the cycle only. 
4 Height will be measured at screening only. During cycles 2-8 and maintenance, weight is obtained on day 1 of 
the cycle only. 
5 Vital signs: blood pressure, pulse and temperature. During loading, vital signs are obtained on day -7. During 
cycles 2-8, vital signs are obtained on day 1 of the cycle only. During maintenance, vital signs are obtained on 
day 1 of the cycle only.  
6 Full physical examination for baseline and end of study visit
. Physical examinations during the study should be 
symptom directed. During cycles 2-8 and maintenance, physical exam is obtained on day 1 of the cycle only. 
During loading, physical exam is only on day -7 
7 Full ophthalmological exam: required at screening and if clinically indicated (change in symptoms develop and 
especially if there is a baseline cataract or age related macular degeneration). Prior to dilation: best corrected 
visual acuity, visual field examination via automated perimetry
, tonometry, color vision test
. Dilated fundoscopy 
and slit lamp exam 
8Echocardiogram or MUGA is required at baseline, at the completion of induction, at discontinuation from the study 
and as clinically indicated. In addition, in patients who have received a cumulative anthracycline dose >350 mg/m2, an 
echocardiogram will be obtained after every 2 cycles of LD. 
9 Urine analysis will include appearance, color, urine bilirubin, glucose, hemoglobin, ketones, pH
, protein, 
specific gravity, urobilinogen. Microscopy will only be performed if clinically indicated.  This will be obtained on 
screening and as clinically indicated 
10 Hematology: hemoglobin, white blood cell (WBC) count
, absolute neutrophil counts and platelets.  During 
loading, a hematology sample is obtained on day -7. 
During cycles 2-8 and maintenance, hematology sample is 
obtained on day 1 of the cycle only. 
11 Serum Chemistry: Sodium, Potassium, Chloride, Bicarbonate, BUN, Creatinine, and Glucose, Calcium
, ALT
, AST, 
Alkaline Phosphatase, Total Bilirubin, LDH
, Total Protein, Albumin. During screening only, this will also include 
amylase, lipase, uric acid, TSH and creatine kinase. During loading, a chemistry sample is obtained on day -7. 
During cycles 2-8 and maintenance, chemistry sample is obtained on day 1 of the cycle only. 
12 Coagulation test include prothrombin time (PT), international normalization ratio (INR), and activated partial 
thromboplastin time (aPTT)
 
13 A bone marrow aspirate and biopsy will be performed at baseline, on day-7  (at least 2 hours after selinexor 
administration) and at the end of treatment in case of progressive disease. The screening bone marrow will 
include standard cytogenetics, FISH and gene expression profiling by MyPRS. In addition, bone marrow biopsy 
and aspirate on screening and day-7 will be used for PD markers. Finally, CD138 positive cells from the 
screening bone marrow aspirate and the end of treatment bone marrow aspirate will be frozen in pellets for 
future molecular characterization by next generation sequencing. If a patient has <5% involvement plasma cells 
in the bone marrow in screening, a repeat bone marrow biopsy is not needed on day -7 (loading). 
14 Disease status will be measured by assessment of myeloma paraprotein and measurement of plasmacytomas 
(if applicable). Specifically patients will have a serum protein electrophoresis, 24h urine for protein 
electrophoresis and serum free light chain assay during screening, start of the loading phase, on day 1 of every 
cycle. In addition, patients will have a skeletal survey at baseline, and at progression. Finally, patients with 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 49 
plasmacytomas should have measurement of their plasmacytomas at baseline, and every 2 cycles using a 
modality at the discretion of the treating physician.  
15 Both posteroanterior and lateral films should be obtained for baseline. Note: this test does not need to be 
repeated if results are available from a test performed 30 days prior to start of therapy. This test serves as a 
baseline in the event that patients develop any adverse events during the study. 
16   Selinexor will be administered in the clinic on day -7, cycle 1 days 1,8,15, cycle 2-8 days 1, and day 1 of 
maintenance cycles. Patients will self-dose with selinexor on other days. Dexamethasone will be taken at home by the 
patients with breakfast. Patients on cohort 3m and 4m will receive Selinexor in the clinic on day -7, cycle 1 day 1and 8 
and cycle 2-8 and maintenance cycles day 1.      
17  LD will be administered intravenously in the clinic on day 1 of cycle 1-8.  
18 Blood for selinexor (PK) will be obtained on day -7, cycle 1 day 1, 8 and 15. Blood for free doxorubicin (PK) will be 
obtained on cycle 1 day 1, 8 and 15. Plasma and blood leukocytes for pharmacodynamics (XPO1 inhibition and select 
cytokine assays) will be obtained on day -7, Cycle 1 day 1 and 15, and Cycle 2 day 1.  Please see Appendix C for 
detailed blood sampling plan. 
19 These assessments will not be collected in the electronic case report forms (eCRF) but continue to be performed for 
safety. Adverse events related to laboratory assessment or ECG will continue to be captured in the adverse event eCRF 
6 TREATMENT PLAN 
Please refer to the Study Calendar (Section 5) for an overview. 
The investigator should confirm eligibility of the patient according to the inclusion and 
exclusion criteria of the study. All patients have to provide written Informed Consent before 
any study specific assessment is performed. A study-specific assessment is defined as a 
procedure that is not part of the routine assessments performed for diagnostic purposes or 
standard care.  
Patients not meeting the eligibility criteria will not be enrolled into the study.  
6.1 
Study Assessments 
6.1.1 Efficacy Assessments  
The clinical activity of selinexor will be evaluated for its effects on disease response criteria 
in terms of best response, duration of response, progression-free survival (PFS) and overall 
survival (OS).  Disease status will be measured by the uniform response assessment of the 
International Myeloma Working Group. 
The baseline disease assessment must be recorded and measured within 28 days prior to 
treatment start. During the treatment period, disease assessments will be performed every 
cycle, and as clinically indicated.  
6.1.2 Translational Analyses 
We will evaluate the ex vivo efficacy of selinexor and doxorubicin in patient specimens. In 
addition, we will evaluate the impact of cellular localization of topo IIα at baseline and post 
treatment on the efficacy of the combination.  
In addition, we plan to measure levels of XPO mRNA by qRT-PCR (as well as ARRDC3, NGFR, 
SLC family, PLCO) as well as levels of selected plasma cytokines after therapy with selinexor 
(IL1α, TNFα, IL-6, MCP1, INFγ, VEGFα, IL-8, IFNα, IL-10).  

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 50 
6.1.3 Safety Assessments 
Throughout the treatment period until one month after the last dose of study medication, 
patients will be assessed for all adverse events. National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE v4.03) will be used for grading
. If 
necessary, the patient may be withdrawn from the study treatment.  
• Medical history will include baseline symptoms as well as a detailed history of prior 
cancer therapies including types and number of prior regimens, refractoriness to 
immunomodulatory agents and / or proteasome inhibitors, prior anthracycline and 
total cumulative dose, disease progression during or after therapy, as well as 
discontinuations due to intolerability or any other serious illness. 
• Concomitant medications will be documented throughout treatment phase until the 
EOT visit
.  
• Adverse events (see also Section 7.1): All patients will be closely monitored for 
adverse events during the course of the trial and for up to one month after the last dose 
of study medication.
  
6.1.4 Definition of a Dose Limiting Toxicity (DLT)  
DLT is defined as any of the following occurring in the first cycle that is not due to cause 
other than drug toxicity (the loading phase dosing has already cleared DLT and found to be 
tolerable and will not be included in the DLT evaluation) 
• ≥ 1 missed doses (out of 3 doses) in 21 days at the target dose due to study drug 
toxicity 
• Discontinuation of a patient due to a toxicity that is not due to cause other than 
drug toxicity before completing cycle 1 
• Grade ≥ 3 nausea/vomiting or diarrhea while taking optimal supportive medication 
• Any  other  Grade  ≥3  non-hematological toxicity except alopecia, steroid induced 
hyperglycemia or electrolyte abnormalities correctable with supportive therapy 
• Grade ≥ 3 AST or ALT elevation lasting longer than 7 days  
• Grade 4 neutropenia [absolute neutrophil count (ANC) < 500/mm3] lasting ≥7 days  
• Febrile  neutropenia  (ANC<1000/mm3  with  a  single  temperature  ≥  38.3ºC  or 
sustained temperature of >38°C for over 1 hour); 
• Grade ≥3 thrombocytopenia associated with clinically significant bleeding  
6.1.5 Laboratory Assessments 
Safety blood samples include complete blood count, clinical chemistry, including liver 
function test
, and coagulation. 
6.2 
Study Procedures 
6.2.1 Screening Procedures  
All patients will be screened and screening procedures performed within 28 days prior to 
the start of induction treatment. These include the following:  
Signed written informed consent 
Obtained prior to any study specific assessments 
Demographics and medical history • Age, gender, ethnic background, and race 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 51 
• Details on prior cancer therapy, including types 
and number of prior regimens
, refractoriness to 
immunomodulatory agents and / or proteasome 
inhibitors, prior anthracycline and total 
cumulative dose, as well as discontinuations due 
to intolerability or any other serious illness
. 
• Previous and concurrent relevant diseases 
• Current symptoms and/ or residual toxicities 
from prior therapies 
Pregnancy test (if applicable) 
(within 1 week of loading
 phase) 
A serum pregnancy test will be performed in pre-
menopausal women and women who are post-
menopausal for < 2 years. In case the sampling date 
for the serum pregnancy test exceeds 7 days before 
treatment start, a urine test is required for 
confirmation 
Physical examination and vital 
signs (within 4 weeks of loading 
phase) 
• Body height and weight 
• BSA 
• Blood pressure, pulse
, temperature 
• Physical examination 
Ophthalmologic exam (within 4 
weeks of loading phase) 
Full ophthalmologic exam: required at screening and 
when clinically indicated. Prior to dilation: best 
corrected visual acuity, visual field examination via 
automated perimetry, tonometry, color vision test. 
Dilated fundoscopy and slit lit exam. 
Cardiac evaluation (within 4 weeks 
of loading phase) 
12-lead ECG, echocardiogram or MUGA will be 
obtained at screening  
Urine analysis (within 4 weeks of 
loading phase) 
Urine bilirubin, glucose, hemoglobin, ketones, pH, 
protein 
Hematology (CBC) (within 2 weeks 
of loading phase) 
Hemoglobin, white blood cell (WBC) count, absolute 
neutrophil count and platelet count  
Serum chemistry (within 2 weeks 
of loading phase) 
Sodium, potassium, chloride, bicarbonate, BUN
, 
creatinine, glucose, calcium, phosphate, magnesium
, 
ALT, AST
, alkaline phosphatase
, total bilirubin, total 
protein, albumin, uric acid, amylase, lipase, creatinine 
kinase
, LDH, TSH 
Coagulation (within 2 weeks of 
loading phase) 
Prothrombin time (PT), international normalization 
ratio (INR), and activated partial thromboplastin time 
(aPTT) 
Assessment of disease status 
(within 4 weeks of loading phase) 
The disease status will be assessed by serum protein 
electrophoresis, 24h urine for protein electrophoresis 
and serum free light chain assay 
Chest radiograph (within 4 weeks 
of loading phase) 
Both, posteroanterior and lateral films should be 
obtained for baseline. Note: this test does not need to 
be repeated if results are available from a test 
performed 30 days prior to start of therapy.  

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 52 
Concomitant medication 
Concomitant medication currently used 
Bone Marrow Biopsy and Aspirate 
(within 4 weeks of loading phase) 
A bone marrow aspiration and biopsy will be 
obtained at screening
  
 
6.2.2 Treatment Phase 
During the treatment phase the following assessments are to be performed: 
Physical examination and vital 
signs 
• Body weight 
• BSA 
• Blood pressure, pulse
, temperature 
• Physical examination (symptom directed) 
Cardiac evaluation  
12-lead ECG and echocardiogram as clinically 
indicated. Echocardiogram or MUGA is required at at 
the completion of induction. In addition, in patients 
who have received a cumulative anthacycline dose 
>350 mg/m2, an echocardiogram will be obtained 
after every 2 cycles of LD 
Pregnancy test (if applicable) 
A serum pregnancy test will be performed in pre-
menopausal women and women who are post-
menopausal for < 2 years to exclude that a pregnancy 
occurred under treatment 
Hematology  
Hemoglobin, white blood cell (WBC) count, absolute 
neutrophil count and platelet count 
Serum chemistry  
 
Sodium, potassium, chloride, bicarbonate, BUN
, 
creatinine, glucose, calcium, phosphate, magnesium
, 
ALT, AST
, alkaline phosphatase
, total bilirubin, total 
protein, albumin, LDH 
Assessment of disease status 
The disease status will be assessed by serum protein 
electrophoresis, 24h urine for protein electrophoresis 
and serum free light chain assay on day -14 and every 
cycle 
Adverse events and concomitant 
medication 
Assessed on an ongoing basis 
Bone Marrow Biopsy and Aspirate  A bone marrow aspiration and biopsy will be obtained 
during the loading phase at least 2 hours after the 
administration of selinexor  
 
6.2.3 End of Treatment 
Patients who discontinue therapy for any reason must have and end of treatment (EOT) 
visit
 completed
 30 days (± 7 days) after the last application of study drug
. 
At the EOT visit
, the patients will undergo the following assessments: 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 53 
Pregnancy test (if applicable) 
A serum pregnancy test will be performed in pre-
menopausal women and women who are post-
menopausal for < 2 years to exclude that a pregnancy 
occurred under treatment 
Physical examination and vital 
signs 
• Body weight 
• Blood pressure, pulse
, temperature 
• Physical examination 
Cardiac evaluation  
12-lead ECG, echocardiogram or MUGA
 
Hematology  
Hemoglobin, white blood cell (WBC) count, absolute 
neutrophil count and platelet count 
Clinical chemistry
  
Sodium, potassium, chloride, bicarbonate, BUN
, 
creatinine, glucose, calcium, phosphate, magnesium
, 
ALT, AST
, alkaline phosphatase
, total bilirubin, total 
protein, albumin, LDH 
Assessment of disease status 
The disease status will be assessed by serum protein 
electrophoresis, 24h urine for protein electrophoresis 
and serum free light chain assay 
Adverse events and concomitant 
medication 
Assessed on an ongoing basis 
Bone Marrow biopsy and Aspirate  A bone marrow aspiration and biopsy will be obtained 
at the end of treatment and before the initiation of 
another therapy in patients with progressive disease 
6.3 
End of Study 
6.3.1 Planned Treatment of the Patients after End of Treatment Phase 
After completion of the study at routine follow-up (EOT), patients will generally be treated 
at the discretion of the investigator according to medical routine. 
6.3.2 Removal of Patients from Treatment 
Subjects will be free to discontinue treatment or withdraw from the study at any time, for 
any reason, or they may be withdrawn/ removed if necessary in order to protect their 
health (see reasons for withdrawal below). It is understood by all concerned that an 
excessive rate of withdrawals can render the study uninterpretable; therefore, unnecessary 
withdrawal of subjects should be avoided.  
Patients will be removed from further treatment for the following reasons: 
• Disease progression 
• Non-compliance with visits and assessment which indicates a potential health 
hazard to the patient 
• Patient no longer consents to participate in the study 
• Intercurrent illness that interferes with study assessments 
• Incidence or severity of AEs in this study indicates a potential health hazard to the 
patient 
• Investigator discretion 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 54 
• Pregnancy 
• Termination of the study by the sponsor 
 
If there is a medical reason for withdrawal of treatment, the patient will remain under the 
supervision of the investigator until the AEs have been resolved or declined to baseline 
values
.  
In case of premature discontinuation of the study treatment, the investigations scheduled 
for the EOT should be performed, if possible. Should a patient decide to withdraw
, every 
effort will be made to complete and report the observations as thoroughly as possible. The 
investigator should contact the patient to determine as completely as possible the reason 
for the withdrawal. A complete final evaluation at the time of the patient’s withdrawal 
should be made, with an explanation of why the patient is withdrawing from the study. If 
the reason for removal of a patient from the study is an adverse event or an abnormal 
laboratory test result, the principal specific event or test will be recorded on the case report 
form
. 
6.4 
Study Discontinuation 
The whole study may be discontinued at the discretion of the sponsor in the event of any of 
the following: 
• Medical or ethical reasons affecting the continued performance of the study 
• Difficulties in the recruitment of patients 
7 INVESTIGATIONAL MEDICINAL PRODUCT 
7.1 Selinexor 
7.1.1 Preparation and Administration of Selinexor  
Product:   Selinexor (KPT-330)  
Classification: 
Cell biological modifier: Apoptosis inducing agent 
Mechanism of action: 
Selinexor is a Selective Inhibitor of Nuclear Export / SINE™ 
compound that specifically blocks nuclear export by slowly-reversible covalent binding to 
XPO1 (also called CRM1) protein.  
7.1.2 Formulation 
Tablets for selinexor oral administration will be supplied in 20 mg tablets in wallet-sized 
blister packs (12 tablets per blister pack). 
7.1.3 Labelling 
Each wallet size blister package of selinexor tablets will be labelled in accordance with 
current ICH GCP, FDA and specific national requirements
. Blister packages for take-home 
use will require additional in-pharmacy labeling with take-home and patient-
specific instructions (such as exact dose).  

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 55 
7.1.4 Storage 
Selinexor tablets will be stored at ambient or refrigerated temperatures between (36 – 
86 °F) or (2–30 °C) in a locked and secured area with restricted access to study staff. The 
tablets should not be stored at freezer temperatures or allowed to freeze
. All medication 
must be stored in a secure area under the proper storage requirements with access 
restricted to the site staff pharmacist or designee(s). 
7.1.5 Drug Accountability 
Study drug for the study are provided by the Karyopharm Therapeutics Inc. and will be 
labeled as per the applicable regulations.  Sites must request study drug by submitting an 
order form directly to the drug depot in order for the study drug to be shipped to the site 
pharmacy.   
Study drug accountability records will be maintained at the pharmacy and will be available 
for review
. 
All medication must be stored in a secure area under the proper storage requirements with 
access restricted to the site staff pharmacist or designee(s). 
The Investigational medicinal product should not be used for any purpose outside the scope 
of this protocol
, nor can Investigational medicinal product be transferred or licensed to any 
party not participating in the clinical study. Data for Investigational medicinal product are 
confidential and proprietary and shall be maintained as such by the Investigators. 
The Investigator, or a responsible party designated by the Investigator, must maintain a 
careful record of the inventory and disposition of unused material.  
All clinical drug supplies must be kept in an appropriate, limited access, secure place until 
used or returned to Karyopharm Therapeutics or designee for destruction. Drug supplies 
will be counted and reconciled at the site before being returned. The study site will be 
required to maintain a log
 of the temperature where the study medication is stored
.  
7.1.6 Selinexor Dosing Information 
After the initial screening visit and registration in the study, patients will receive selinexor –
at a dose of 80 mg on day -7. After the loading phase, patients will receive 
selinexor at a 
starting dose of 40 mg/m
2 on D1, 8, 15 for cohort 1. 
 
Selinexor is to be taken within 30-minutes of solid food consumption together with ≥120 
mL (8 ounces) of water. 
7.2  Liposomal Doxorubicin  
7.2.1 Preparation of Liposomal doxorubicin 
Commercial supply of Liposomal doxorubicin will be used for this trial 
Liposomal doxorubicin is available as 2 mg/ml concentrate solution for infusion in 25 ml 
and 10 ml vials. 
The appropriate dose of liposomal doxorubicin up to a maximum of 90 mg must be diluted 
in 250 ml of 5% Dextrose Injection USP prior to administration. Doses exceeding 90 mg 
should be diluted in 500 ml of 5% dextrose injection USP prior to administration. Diluted 
liposomal doxorubicin should be refrigerated at 2°C to 8°C and administered within 24 
hours. Liposomal doxorubicin should not be used with in line filters and should not be 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 56 
mixed with other drugs. It should not be used with any other diluent other than Dextrose 
injection 5%. Partially used vials should be discarded. 
Liposomal doxorubicin is not a clear solution but a translucent, red liposomal dispersion. 
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit. Do not use if 
a precipitate or foreign matter is present. 
7.2.2 Formulation and Administration of Liposomal doxorubicin 
When administering Liposomal doxorubicin, precautions should be taken to avoid 
extravasation, which may occur with or without a stinging or burning sensation, even if 
blood returns well on aspiration of the infusion needle. 
Liposomal doxorubicin must not be given by the intramuscular or subcutaneous route. 
Liposomal doxorubicin is not a clear solution but a translucent, red liposomal dispersion. 
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit.  Do not use 
if a precipitate or foreign matter is present.  
Serious and sometimes life-threatening or fatal allergic/anaphylactoid like infusion 
reactions have occurred.  Medications to treat such reactions, as well as emergency 
equipment should be available for immediate use. To minimize the risk of infusion-related 
reactions
, the initial rate of administration is 1 mg/min. If no infusion related adverse 
events are observed, the rate of infusion can be increased to complete administration of the 
drug over one hour. 
7.2.3 Storage of Liposomal doxorubicin 
Liposomal doxorubicin is stored at 2°C-8°C and is not frozen 
7.2.4 Dosing Information 
During the induction phase, patients will receive liposomal doxorubicin at a starting dose of 
20 mg/m2 on Day 1 of the cycle at least 2 hours (but less than 4 hours) after the 
administration of selinexor.  
7.3 Dexamethasone 
Commercial dexamethasone will be used for this trial. Dexamethasone is available in 4 mg 
tablets.  Dexamethasone should be stored at room temperature away from direct sunlight 
and protected from excessive heat and cold. 
7.3.1 Dosing Information 
Patients will be instructed to take Dexamethasone 40 mg (10 tablets) orally once weekly 
with meals (ideally with breakfast to minimize insomnia). Patients 75 years or older and 
patients previously intolerant to 40 mg dosage will be allowed to receive 20 mg (5 tablets) 
once a week
. 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 57 
8 TOXICITIES, RISKS, AND AE-RELATED DOSE MODIFICATIONS  
8.1 Selinexor  
8.1.1 Selinexor Toxicity Overview 
Selinexor is currently in clinical development and has not been FDA-approved for use. 
Human experience with selinexor is currently limited and the entire safety profile is not 
known at this time. Measures will be taken to ensure the safety of the patients participating 
in this trial, including the use of stringent inclusion and exclusion criteria and close 
monitoring
. Toxicity grading will be performed in accordance with NCI CTCAE 4.03. If more 
than one different type of toxicity occurs concurrently, the most severe grade will 
determine the modification. 
If toxicities are encountered, adjustments will be made to the study treatment as detailed in 
the sections below. All AEs grade >1 and SAEs will be recorded during the trial and for up to 
30 days after the last dose of study treatment or until the initiation of another anti-cancer 
therapy, whichever occurs first. 
8.1.2 Risks Associated with Selinexor 
As of June 2013, 96 human patients have been treated with selinexor. Across these trials, 9 
patients of 97 (9.3%) have reported at least one SAE that is at least possibly related to study 
drug
. Side effects observed in these patients include: 
 
Very common side effects (≥10%):  
Nausea  
Vomiting  
Diarrhea  
Anorexia  
Hyponatremia  
Dehydration  
Blurred vision  
Thrombocytopenia  
Anemia  
Neutropenia  
Leucopenia  
Fatigue  
Weight Loss  
Dysgeusia  
Dizziness  
 
Common side effects (≥1-10%):  
Constipation  
Dry mouth  
Creatinine Increased  
Worsening of pre-existing cataracts  
Febrile neutropenia  
Dyspnea  
Syncope   
Confusion  
Pneumonia  

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 58 
Sepsis  
 
Uncommon side effects (>0.1-1%):  
Cognitive disturbance  
Altered balance  
 
Rare side effects (>0.1-1%):  
Acute cerebellar syndrome – symptoms can include a sudden loss of coordination, balance, 
or slurred speech 
 
Reproductive risks  
Patients should not become pregnant or father a baby while on this study because the drugs 
in this study can affect an unborn baby.  Women should not breastfeed a baby while on this 
study.  It is important patients understand the need to use birth control while on this study. 
8.1.3 Dose Modifications for Selinexor 
Based on observations from the ongoing Phase I studies in patients with advanced 
hematological and solid tumors, selinexor shows a reasonably wide therapeutic range, with 
activities from ~12mg/m
2 to 35mg/m2.  At the present time, we do not know how to predict 
which patient's tumors will respond to lower doses
, nor can we predict 
tolerability.  
 Therefore, in order to optimize specific anti-tumor activity and the patient’s 
tolerability, therapy is initiated at 80mg weekly
. In patients with tolerability issues on 
selinexor, we recommend reducing the selinexor dose. In addition, if patient is experiencing 
one or more Grade ≤2 toxicities such as fatigue or anorexia, then 1-2 doses of selinexor can 
be held, and dosing resumed at current dose.   
Toxicity will be graded according to NCI CTCAE, version 4.03; the therapy modifications 
described below are applied according to this severity grading
. If drug-related toxicity 
requires a treatment delay of more than 4 weeks, then the patient is taken off protocol 
treatment. Each dose modification or treatment delay has to be documented in the CRF, 
including the respective reason
. 
Phase I data in patients with both solid and hematologic malignancies indicate that 
selinexor is associated with minimal laboratory abnormalities. Therefore
, provided that it is 
clinically indicated, patients should be treated aggressively with supportive care to reduce  
 
toxicities and permit selinexor dosing to be maintained at the same or reduced 
doses/frequency as indicated below. 
Dose levels 1 
60 mg D1,8, 15 
Dose levels -1 
40 mg D1,8,15 
Dose levels -2 
20 mg-D1,8
,15 
 
 
 
Table 1: Prespecified dose modifications for adverse events related to study drug 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 59 
Dose levels 2 
80 mg D1,8, 15 
Dose levels 3 
80 mg D1,3,8, 10 
 
Intra-patient dose escalation for selinexor will be allowed at the discretion of the treating 
physician and principal investigator provided the above dose level was found to be 
tolerable (cleared DLT)
. This will apply to patients in the induction (after cycle 1) and 
maintenance phase only.  
 
 
 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 63 
8.2 Liposomal doxorubicin 
8.2.1 Liposomal doxorubicin Toxicity Overview 
 liposomal doxorubicin is approved for the treatment of patients with multiple myeloma
. 
The toxicity profile has been well described overall. Measures to ensure patients’ safety, 
including the use of stringent inclusions and exclusion criteria
, will be taken.  
8.2.2 Risks Associated with Liposomal doxorubicin 
The toxicity profile of Liposomal doxorubicin has been well established and includes the 
following common toxicities 
 Dermatologic: Alopecia, Hand-foot syndrome (multiple myeloma, 19% ), Rash 
(multiple myeloma, 22% ) 
 Gastrointestinal: Constipation (multiple myeloma
, 31% ), Diarrhea (multiple 
myeloma, 46% ), Loss of appetite (multiple myeloma, 19% ), Nausea (multiple 
myeloma, 48% ), Stomatitis, 
Vomiting (multiple myeloma, 32% ) 
 Neurologic: Asthenia (multiple myeloma
, 22% ) 
 Other: Fatigue (multiple myeloma, 36% ), Fever (multiple myeloma, 31% ) 
Serious toxicities include the following: 
 Cardiovascular: Cardiomyopathy, Heart failure (multiple myeloma
, 3%) 
 Dermatologic: Radiation recall syndrome 
 Hematologic: Anemia (multiple myeloma
, 25% ), Myelosuppression, Neutropenia 
(multiple myeloma, 36% )
, Thrombocytopenia (multiple myeloma, 33% ) 
 Hepatic: Hyperbilirubinemia  
 Immunologic: Anaphylactoid reaction, Infusion reaction  
 
8.2.3 Dose Modifications for Liposomal doxorubicin 
Prespecified dose modification for Liposomal doxorubicin ( liposomal doxorubicin) 
guideline for Liposomal doxorubicin will be as shown below: 
Dose Level 1: LD 20 mg/m2 
Dose Level 2: LD 30 mg/m2 
Dose Level -1: LD 15 mg/m2 
Dose level -2:  LD 10 mg/m2 
A dose of Liposomal doxorubicin below 10 mg/m2 will not be planned 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 68 
 
9 SAFETY GUIDANCE FOR INVESTIGATORS 
9.1 Concomitant Medication and Treatment 
Concomitant medication is defined as any prescription or over-the-counter preparation, 
including vitamins and supplements. Patients may continue their baseline medication(s)
. 
Patients should minimize the use of products containing acetaminophen, which can 
interfere with the metabolism of selinexor. For combination painkillers containing 
acetaminophen it is recommended that single agent opiates (when clinically acceptable) be 
substituted. 
All patients will receive prophylactic proton pump inhibitors. In addition, all patients will 
receive prophylactic treatment to prevent anorexia
, fatigue and nausea which includes one 
of the following:  
1- Olanzepine 5 mg PO qhs or 2.5 mg PO BID, 0-3 days before the first dosing day of 
selinexor 
2- Mirtazapine 15 mg PO qhs, 0-3 days before the first
 dosing day of selinexor 
3- Neurokinin 1 receptor blockers such as Aprepitant, 
phosaprepitant or similar 
If an increased risk of adverse effects due to olanzepine is anticipated, olanzepine can be 
omitted. However it is recommended that mirtazapine or other appetite stimulating 
serotonergic agent be used. Additional standard supportive care agents may be used as 
needed (prn). Specifically
, it is recommended (although not mandated, that patient receive 
antimicrobial prophylaxis given the increased risk of infections seen in patients with 
advanced myeloma. For example, fluoroquinolone prophylaxis could be considered. 
Supportive care may be tapered or discontinued in cycle 2 or later in patients who tolerate 
selinexor well.  
9.1.1 Permitted Concomitant Medication  
Patients will receive concomitant medications to treat symptoms, adverse events and 
intercurrent illnesses that are medically necessary as standard care. Medications to treat 
concomitant diseases like diabetes, hypertension, etc. are allowed.
 
9.1.1.1 Prevention of
 pregnancy 
Female patients of child-bearing potential must agree to use dual methods of contraception 
and have a negative serum pregnancy test at screening
, and male patients must use an 
effective barrier method of contraception if sexually active with a female of child-bearing 
potential
. Acceptable methods of contraception are condoms with contraceptive foam, oral, 
implantable or injectable contraceptives
, contraceptive patch, intrauterine device
, 
diaphragm with spermicidal gel, or a sexual partner who is surgically sterilized or post-
menopausal. For both male and female patients
, effective methods of contraception must be 
used throughout the study and for three months following the last dose. 
9.1.1.2 Use of blood products 
During the administration of selinexor, patients may receive red blood cell (RBC) or platelet 
transfusions, if clinically indicated, per institutional guidelines.  

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 69 
Appropriate anti-coagulation is allowed during the study (eg: LMW heparin, direct factor Xa 
inhibitors, etc). Warfarin is allowed during the study provided that patients are monitored 
for INR twice a week during the first two cycles of therapy, then weekly to biweekly 
thereafter.  
Patients may receive supportive care with erythropoietin, darbepoetin, G-CSF or GM-CSF
,  
growth factors, and platelet stimulatory factors, in accordance with clinical practice or 
institutional guidelines prior to entry and throughout the study. 
9.1.1.3 Glucocorticoid therapy 
Patients must receive corticosteroid therapy as part of the treatment regimen. Additional 
corticosteroid are allowed for the treatment of non malignant conditions (inflammatory 
disorders or adrenal insufficiency) provided the dose does not exceed the equivalent of 20 
mg of prednisone daily 
9.1.1.4 Radiation Treatment 
The need for radiation therapy is generally considered to be a treatment failure
. However
, 
an exception (that is patients allowed to remain in the treatment phase of the study) is 
made for radiation therapy to a pathological fracture site to enhance bone healing or to 
treat post-fracture pain that is refractory to narcotic analgesics because pathologic bone 
fractures do not by themselves fulfill a criterion for disease progression  
9.1.1.5 Proton pump inhibitors 
The use of proton pump inhibitors (for example omeprazole) will be required for the 
prevention of dexamethasone toxicity as is clinical practice 
9.1.1.6 Bisphosphonate 
The use of bisphosphonate for the prevention of skeletal related events due to myeloma is 
allowed per routine clinical care
.  
9.1.1.7 IVIG 
The use of intravenous immunoglobulins for the prevention of recurrent infections in 
patients with hypogammaglobulinemia is allowed per routine clinical practice  
9.1.2 Prohibited Medication 
Patients should minimize the use of products containing acetaminophen. For combination 
painkillers containing acetaminophen it is recommended that single agent opiates (when 
clinically acceptable) be substituted, particularly on the days of selinexor dosing
. 
Concurrent therapy with an approved or investigative anticancer therapeutic
, other than 
glucocorticoids as specified herein, is not allowed.  
Use of any immunosuppressive agents during the study must be confirmed by the Medical 
Monitor
.   
Other investigational agents should not be used during the study. 
Inactivation of selinexor by glutathione conjugation is a significant metabolic pathway in 
vitro and in vivo, including in humans. This process can be mediated in the absence of 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 70 
proteins, indicating that it is thermodynamically favorable. In vitro studies using human 
liver microsomes confirm in vivo findings that selinexor undergoes minimal CYP450 
metabolism
. Therefore
, administration of selinexor with drugs which undergo substantial 
glutathione conjugation should be minimized or avoided
. These drugs include 
acetaminophen and ethyl alcohol. It should be noted that studies of selinexor in 
combination with acetaminophen are to begin in late 2013 and therefore that these 
recommendations are empirical. It should also be noted that recreational ethanol ingestion 
is associated with glutathione depletion; therefore
, the use of products containing ethanol 
should be minimized or avoided on selinexor dosing days. 
9.2 Supportive Care Guidelines 
Supportive measures for optimal medical care shall be provided during participation in this 
clinical trial
. Supportive care including anti-nausea / anti-emetic therapy, and other 
standard treatments may be administered as per institutional guidelines for symptomatic 
patients
. As needed and per individual study site institutional guidelines, prophylactic 
therapies
, including antivirals, antifungals, and antibiotics, may be administered to 
ameliorate risks associated with non-malignant disorders or of immune system 
compromise. 
9.2.1 Anorexia 
Based on clinical observations with over 90 patients treated with selinexor  across this and 
the companion protocol in advanced hematologic tumor patients (OZM-040), the dose 
limiting toxicities (DLTs) are primarily related to anorexia with poor caloric and fluid intake 
leading to weight loss, fatigue and nausea. Therefore, it is strongly recommended that 
patients at risk for anorexia, weight loss, and/or fatigue receive strong nutritional 
counseling
, high caloric beverages with adequate electrolyte levels (e.g
., Ensure®), 
prophylaxis with appetite-stimulating agent(s), and anti-emetic agents.  Patients with 
proper nutritional support and counseling have remained on selinexor  for  >11  months
.  
There is no correlation between initial BMI or weight and the development of anorexia. 
In patients with problematic food/liquid/caloric intake, a patient log of food and drink 
should be considered and monitored by the treatment team. 
Fresh juices, simple carbohydrates, as well as ginger can improve appetite before the meal; 
ginger may also improve dysgeusia. 
Supportive care for anorexia should be given promptly. The site can consider prophylactic 
treatment in case of cachexia or previous anorexia associated with anti-cancer therapies. 
Active treatment of anorexia should start with the first sign of decreasing appetite or loss of 
weight. Standard appetite stimulants are allowed and strongly recommended. In particular
, 
megesterol acetate (Megace®), olanzapine and glucocorticoids, have been most useful in 
improving appetite in many patients treated with selinexor .   
The recommended dose of megesterol acetate is 400mg – 800mg po/d.  Lower doses have 
also been effective
. Olanzapine may be given as 5.0mg po qhs (also improves sleep and 
reduces nausea); divided doses of olanzapine (e.g
.
, 2.5mg po qam and qpm) may also be 
used but can increase sedation. Combination of megesterol acetate at 400mg qd  + 
olanzepine 5.0mg qhs has been reported to be synergistic and most effective in a recent 
meta-analysis.  

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 71 
In cases of anorexia grade ≥ 3, combination treatment with daily megesterol acetate 400mg  
+ olanzepine 5.0mg is strongly recommended for long-term use. 
Dronabinol (Marinol) has shown some activity in both nausea/emesis and anorexia in 
patients treated with elinexor .  In patients who do not respond to, or are intolerant of
, the 
above agents, oxandrolone (Anavar®) should be considered.  The recommended dose of 
oxandrolone is 2.5-10mg given 2-4 times per day to maximum dose of 20mg per day. 
If constipation occurs
, then laxatives should be given as constipation can contribute to 
anorexia and loss of appetite. 
9.2.2 Fatigue 
Fatigue may be related to underlying malignancy, selinexor side effects
, side effects of other 
agents or concurrent morbidities.  Fatigue may also be related to anorexia and/or 
dehydration, so caloric and fluid intake should be optimized in all patients (please see above 
aggressive guidelines for maintenance of food and fluid intake).   
Glucocorticoids use may reduce fatigue. In patients with persistent fatigue, oxandrolone as 
described above should be considered.  Dose interruptions and/or reductions may also 
improve fatigue due to selinexor, but may lead to loss of disease control. 
9.2.3 Emesis 
Supportive care for nausea and vomiting should be given promptly.  Prophylactic treatment, 
 
in case of previous side effect of nausea and vomiting with prior anti-cancer therapy, can be 
considered. The treatment should start with the first sign of nausea
. Standard anti-emetics 
are allowed and strongly recommended
. 
9.2.3.1 Acute Emesis 
Acute emesis is not a major observation with selinexor but has been reported.  Selinexor  
associated nausea/emesis generally responds to D2-antagonists
, 5-HT3 antagonists, or 
combinations of agents. 
5-HT3 receptor antagonists (Zofran® 8 mg od on days of dosing) — First-generation 5-HT3 
receptor antagonists all appear equally effective at preventing nausea/emesis at the 
recommended doses. A single dose of a 5-HT3 receptor antagonist prior to therapy is 
equivalent to a multiple dose schedule. The efficacy of 5-HT3 receptor antagonists is 
significantly improved when they are combined with glucocorticoids. If first-generation 5-
HT3 receptor antagonists+dexamethasone do not adequately control emesis, second 
generation 5-HT3 receptor antagonists (e.g
., palonosetron) should be considered. Second 
generation 5-HT3 receptor antagonists also improve delayed nausea/emetic response. 
Neurokinin-1 receptor antagonists (e.g
., aprepitant or fosaprepitant, Emend®) – should be 
considered in case of uncontrolled emesis with standard treatments as described above
. 
Neurokinin-1 receptor antagonists should be given with combination of dexamethasone 
and first or second generation 5-HT3 receptor antagonists. 
Additional treatment: Metoclopramide Hydrochloride 10mg
, 30 min before meal (up to 4 
time a day) or prochlorperazine (standard doses) have been effective in many patients.  
Dronabinol (Marinol) has shown some activity in both nausea/emesis and anorexia in 
patients treated with selinexor .  Lorazapeam can be added to the combination treatment of 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 72 
5-HT3 receptor antagonists +dexamethasone
, e.g
., at night, but has been less effective in 
elinexor  associated nausea/emesis
.   
9.2.3.2 Delayed Emesis - > 24h after treatment. 
Management — selinexor  is infrequently associated with delayed, resistant emesis
. Many 
of the regimens associated with delayed emesis are classified as high-emetic risk, and 
professional guidelines recommend the use of an NK1 receptor antagonist (either NK-1 
blockers e.g
., aprepitant on days 1 to 3 or fosaprepitant on day 1 only), plus a 
glucocorticoids on days 1 to 4, along with a 5-HT3 receptor antagonist (particularly second 
generation agents) on day 1. This regimen is effective against both acute and delayed 
emesis. The data supporting the individual components of this regimen are reviewed below. 
Olanzapine — Conventional antiemetics are more successful at preventing emesis than in 
preventing nausea, particularly delayed nausea. Olanzapine 10 mg once daily (typically 
given at night to mitigate sedative effects) was proven effective in both anti emesis and 
nausea control. It may also be useful for management of breakthrough emesis, and to 
improve food intake in patients with anorexia. 
Granisetron transdermal patch — A transdermal preparation of granisetron should be 
consider in patients that have uncontrolled emesis/nausea >grade 2 under best supportive 
treatment 
Ginger —  Supplemental ginger added to foods or at doses of 0.5, 1.0gm powder daily total 
dose
, usually in divided doses.  Ginger may also improve dysgeusia. 
Additional agents can be added, including lorazepam or alprazolam, 
olanzapine, a 
dopaminergic D2-antagonist (e.g
., prochlorperazine, thiethylperazine, haloperidol), or 
substituting high-dose intravenous metoclopramide for the 5-HT3 antagonist. 
9.2.4 Diarrhea  
Diarrhea is common at up to 32% (mostly Grade 1), which responds to standard anti-
diarrheal agents
. Fluid replacement is important to prevent dehydration, fatigue and 
electrolyte abnormalities (e
.g
., hyponatremia). 
9.2.5 Thrombocytopenia 
The etiology of thrombocytopenia in patients treated with Selinexor is unclear.  Selinexor  
did not cause thrombocytopenia in preclinical toxicology studies (i.e., in animals without 
prior anticancer therapies), and closely related SINE compounds (i.e., KPT-335) has not 
caused thrombocytopenia in dogs with newly diagnosed or first relapsed Non-Hodgkin’s 
Lymphoma. 
Grade  ≥3  thrombocytopenia  can  be  treated  with  growth  factors  romiplostim  (N-plate®)
, 
eltrombopag (Promacta®), rIL-11 (Neumega®) may be used throughout the study.  
Dose reduction should then be considered.   
9.2.6 
Hyponatremia 
Hyponatremia (Grade 3) has been reported in 8 patients out of 50 as of May 31, 2013; one 
of these cases was pseudohyponatremia due to hyperglycemia (not associated with 
selinexor).  None of these cases have been symptomatic.  Most of the patients had anorexia
, 
nausea, vomiting and/or diarrhea.  Two of the patients with Grade 3 hyponatremia have 
third-space fluid accumulation or resolution (e.g
.
, ascites, edema).  Adequate fluid and 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 73 
caloric intake, including electrolyte rich beverages rather than free water, has lead to 
reversal of the hyponatremia
. 
9.2.7 
Liver Enzyme Increase 
Liver toxicities in rodents and monkeys were not observed in the GLP toxicology studies. To 
date, significant liver toxicity has not been reported in patients treated with selinexor.  
Patients should minimize their use of alcohol and acetaminophen as these drugs may 
deplete hepatic glutathione which could alter selinexor metabolism.  Glutathione (GSH) 
replacing agents such as N-acetylcysteine or S-adenosylmethionine may be considered if 
selinexor induced liver
 dysfunction
 is suspected. 
10 
CORRELATIVE STUDIES AND PHARMACOKINETICS 
10.1 Exploratory Correlative Studies (See Correlative Flowchart below) 
Bone Marrow Aspirates Summary: Bone Marrow aspirates will be collected from patients 
at the time of screening and at relapse. Mononuclear cells isolated from patient aspirates 
will be assayed for drug sensitivity (EC50). A portion of these aspirates will be aliquoted, 
CD138 selected and stored for subsequent molecular characterization by next generation 
sequencing
. A portion of the lymphocyte fraction will be incubated overnight in the 
presence of selinexor (100nm & 300nM) and cytospin slides made to assay the intracellular 
location (nucleus versus cytoplasm) of topoisomerase IIα, p53, XPO1, IkBα, histone control, 
and possibly other biomarkers of relevance with and without treatment with selinexor.  
Myeloma Patient Bone Marrow Biopsy Microarrays Summary:  The bone marrow 
biopsies collected at screening
, day-7 and at relapse will be used to construct a tumor 
microarray for biomarker analysis. Plasma cells in tumor microarrays will be identified by 
lambda or kappa light-chain staining and examined for the expression and intracellular 
location (nucleus versus cytoplasm) of topoisomerase IIα, p53, XPO1, IkBα, histone control, 
and possibly other biomarkers of relevance before and after in vivo treatment with 
selinexor.  
 
Myeloma Patient Bone Marrow Aspirates at Screening: Patient bone marrow aspirates 
collected during screening will be used to evaluate the predictive value of baseline ex vivo 
sensitivity with selinexor +/- doxorubicin and if adequate sample is available selinexor +/- 
dexamethasone and KPT-8602 +/- dexamethasone
. The lymphocyte fraction of patient bone 
marrow aspirates will be isolated by ficoll-gradient centrifugation and incubated overnight 
in the presence of selinexor (0, 0.156, 0.625, 2.5, 10, 40 µM) +/- doxorubicin (2 µM), and if 
adequate sample available selinexor (0, 0
.156
, 0.625, 2.5, 10, 40 µM) +/- dexamethasone 
and  (10 µM). KPT-8602 (0, 0.156
, 0.625, 2.5, 10, 40 µM) +/- dexamethasone (10 µM). Ex 
vivo sensitivity will be assayed in CD-138/light chain double positive myeloma cells by flow 
cytometry and activated caspase 3 apoptosis assay for EC50 analysis
. Assay order of 
importance based on cell numbers will be selinexor, selinexor+dexamethasone, 
selinexor+doxorubicin, KPT-8602 and KPT-8602+dexamethasone. 
 
A portion of the lymphocyte fraction will be incubated overnight in the presence of 
selinexor (100nm & 300nM) and cytospin slides made to assay the intracellular location 
(nucleus versus cytoplasm) of topoisomerase  IIα
,  p53,  XPO1
,  IkBα, histone control, and 
possibly other biomarkers of relevance with and without treatment with selinexor. The 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 74 
intracellular  location  of  topoisomerase  IIα,  p53,  XPO1,  IkBα  and  histone  control  seen  in 
plasma cells from the aspirates will be compared to that seen in the biopsy tissue arrays.  
 
Cells from the lymphocyte fraction of the bone marrow aspirate will be isolated using CD-
138 magnetic bead selection.  DNA from CD-138 positive myeloma cells will be isolated and 
interrogated for specific mutations by whole genomic DNA sequencing.  In addition, gene 
expression of RNA isolated from CD-138 positive myeloma cells will be assayed by 
microarray analysis. 
 
Myeloma Patient Bone Marrow biopsy at day-7: Bone marrow biopsies collected day-7 
will be used to construct a tumor microarray for biomarker analysis
. Plasma cells in tumor 
microarrays will be identified by lambda or kappa light-chain staining and examined for the 
expression and intracellular location (nucleus versus cytoplasm) of topoisomerase IIα
, p53
, 
XPO1, IkBα, histone control, and possibly other biomarkers of relevance. 
 
Myeloma Patient Bone Marrow Aspirates at Relapse: Patient bone marrow aspirates 
collected at relapse will be used to evaluate the predictive value of baseline ex vivo 
sensitivity with selinexor +/- doxorubicin and if adequate sample is available selinexor +/- 
dexamethasone and KPT-8602 +/- dexamethasone
. The lymphocyte fraction of patient bone 
marrow aspirates will be isolated by ficoll-gradient centrifugation and incubated overnight 
in the presence of selinexor (0, 0.156, 0.625, 2.5, 10, 40 µM) +/- doxorubicin (2 µM), and if 
adequate sample available selinexor (0, 0
.156
, 0.625, 2.5, 10, 40 µM) +/- dexamethasone 
and  (10 µM). KPT-8602 (0, 0.156
, 0.625, 2.5, 10, 40 µM) +/- dexamethasone (10 µM). Ex 
vivo sensitivity will be assayed in CD-138/light chain double positive myeloma cells by flow 
cytometry and activated caspase 3 apoptosis assay for EC50 analysis
. Assay order of 
importance based on cell numbers will be selinexor, selinexor+dexamethasone, 
selinexor+doxorubicin, KPT-8602 and KPT-8602+dexamethasone. 
 
A portion of the lymphocyte fraction will be incubated overnight in the presence of 
selinexor (100nm & 300nM) and cytospin slides made to assay the intracellular location 
(nucleus versus cytoplasm) of topoisomerase  IIα
,  p53,  XPO1
,  IkBα, histone control, and 
possibly other biomarkers of relevance with and without treatment with selinexor. The 
intracellular  location  of  topoisomerase  IIα,  p53,  XPO1,  IkBα  and  histone  control  seen  in 
plasma cells from the aspirates will be compared to that seen in the biopsy tissue arrays.  
 
Cells from the lymphocyte fraction of the bone marrow aspirate will be isolated using CD-
138 magnetic bead selection.  DNA from CD-138 positive myeloma cells will be isolated and 
interrogated for specific mutations by whole genomic DNA sequencing.  In addition, gene 
expression of RNA isolated from CD-138 positive myeloma cells will be assayed by 
microarray analysis. 
 
LD 
Plasma and blood leukocytes will be obtained from patients during the loading phase on 
day -7 (pre dose, post dose 4 hours and if possible 8 hours), Cycle 1 Day 1 (pre dose, post 
dose 4 hours and 8 hours), Cycle 1 Day 8 (pre dose
, post dose 4 hours), Cycle 1 Day 15 (pre 
dose
, and post dose 4 hours), and Cycle 2 Day 1 (pre dose, and post dose 4 hours) and XPO1 
inhibition (by qRT-PCR for XPO1) and levels of key cytokines will be assessed as a potential 
biomarker for response in an exploratory analysis (see appendix C for schedule of sample 
collection). These assays will be done at Karyopharm. 
 
 
 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 77 
10.2 Limited Pharmacokinetic Studies 
 
Patients enrolled on the phase I and phase II parts of this study will also have peripheral 
blood collected for limited PK analyses of selinexor and LD.  See appendix C for schedule of 
sample collection.  We will correlate blood levels of selinexor and LD with the expression 
and intracellular location of the proteins described above. 
11 
STATISTICAL CONSIDERATIONS   
11.1 Endpoints 
11.1.1 
Primary Endpoint  
Phase 1: determine the maximum tolerated dose (MTD) and recommended phase II dose 
(RP2D) of the combination of selinexor, Liposomal doxorubicin, and dexamethasone in 
patients with relapsed and refractory multiple myeloma 
Phase 2: determine the overall response rate per the modified uniform response criteria of 
the international myeloma working group (partial response and better) 
11.1.2 
Secondary Endpoints 
• Clinical benefit rate (minimal response and better) 
• Progression free survival 
• Duration of response 
• Overall survival 
• Safety – NCI CTC version 4.03. 
11.2 Sample Size Justification   
A standard 3+3 design will apply in the phase I part of the trial. Given 4 dose levels are 
planned, the number of patients enrolled would be between 12 and 24 patients.  
For the phase II study, a single-arm Simon Two stage design will be used[48]. 
 
Thirteen eligible patients will be enrolled in the first stage (including the 6 patients from the 
phase I treated at the RP2D). If 3 or more partial responses are noted
, another 16 patients 
will be enrolled. If 8 or more patients achieve a partial response or better, the combination 
is deemed active.  Under this two-stage optimum design, there would be a 90.7% chance of 
detecting a tumor response rate of at least 40% and a response rate of 15% or less would 
lead to the conclusion that the regimen lacks antitumor activity at a 0.05 significance level. 
The probability of early stopping (in stage I) is 0.058 if the true response rate of the 
combination is 40%
.  
11.3 Study Population Definition 
For both Phase I (MTD) and Phase II (Open Label Treatment):  
• Safety Population – all patients who take at least one dose of study medication.  

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 78 
For the determination of the MTD, if a patient does not complete 1 cycle of therapy for 
reasons other than toxicity and without having a DLT, he/she will be replaced as they would 
not be evaluable for the determination of the MTD.  
For Phase II:  
The Intent-to-Treat (ITT) population will be used for all analyses and is defined as all 
patients eligible for therapy. ITT patients who have inadequate data post
-baseline to assess 
efficacy according to the criteria for response will be considered treatment failures for 
analysis.  
In order to determine if any bias results from including untreated patients or patients lost 
to follow-up in the primary ITT analysis, an additional analysis will be conducted on 
patients who are protocol-compliant (per protocol population (PPP)). Patents with major 
protocol violations will be excluded from this population. Patients who have inadequate 
post baseline data will be excluded from this analysis 
11.4 Study Design 
The phase I portion of the trial will be a standard “3+3” design. The details of this design are 
listed as follows. 
Number of patients with DLT  
Escalation Decision Rules  
0/3  
Enter 3 patients at the next higher dose 
level.  
≥2  
Dose will be de-escalated to the prior lower 
dose level. Three additional patients will be 
enrolled to that lower dose cohort unless 6 
patients had been treated at that lower 
dose
. If ≤1 of 6 patients experience DLT, 
then this lower dose will be declared the 
MTD.  
1/3  
Enter 3 more patients at this dose level.  
If 0 of 3 patients experience DLT
, proceed 
to the next higher dose level. If ≥1 patient 
suffers DLT, then dose will be de-escalated 
to the previous lower level. Three 
additional patients will be enrolled to that 
lower dose cohort unless 6 patients had 
been treated at that lower dose. If ≤1 of 6 
patients experience DLT, this lower dose 
level will be declared the MTD.  
≤1 out of 6 at highest dose level  
This is the MTD/recommended phase II 
dose
. At least 6 patients must be entered at 
the MTD/recommended phase II dose.  
Four dose level escalations of oral selinexor / LD are planned. The number of patients 
needed for the determination of the MTD can thus vary from 6 to 24 patients. For Phase 1 
MTD Portion, dose limiting toxicities (DLTs) will be summarized at the conclusion of each 
dose level, and reviewed by the investigators and the Protocol Monitoring Committee and 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 79 
the decision to proceed to the next dose level will be made accordingly. The MTD is defined 
as the highest dose that causes one or less patients out of 6 to have a DLT. 
The phase II portion is a single-arm Simon optimum two stage design. 
11.5 Analysis of the Phase I 
For the phase I, the primary objective is to determine the maximum tolerated dose of 
selinexor in combination with  liposomal doxorubicin and dexamethasone. Patients’ 
demographic and clinical characteristics will be summarized using descriptive statistics. All 
toxicities and DLTs will be listed for each patient and summarized for each dose level. 
11.6 Analysis of the Phase II 
For the primary endpoint in Phase II trial, we are interested in comparing the overall 
response rate of this combination with historical efficacy data using  liposomal doxorubicin 
and dexamethasone in patients with relapsed and refractory myeloma. The overall response 
rate and its 95% confidence will be calculated using the method proposed by Atkinson and 
Brown[49]. This confidence interval takes into account the nature of the two-stage Simon 
design. 
The secondary endpoints include progression-free survival (PFS), overall survival (OS), 
safety, and duration of response. Patients will be followed for survival and progression until 
termination of the study. PFS is defined as the time from start of treatment to death of any 
cause, disease progression, or the date of last follow-up, whichever comes first. OS is 
defined as the time from start of treatment to death of any cause or the date of last follow-
up, whichever comes first. The time-to-event data will be estimated using the Kaplan-Meier 
method. The median of PFS and OS and 95% confidence intervals will be computed. The 
effect on time-to-event data adjusting for other factors (such as age and tumor stage) will be 
analyzed using the Cox proportional hazards regression models
. 
As the exploratory endpoints, the association between the change of each biomarker (e.g.
, 
nucleus to cytoplasm ratio, p53, CRM1, lκB and NFκB) from screening to day 1 of cycle 1 and 
the response to the therapy will be examined by the Satterthwaite t-test or the Wilcoxon 
rank sum test
.  The appropriate transformation such as log-transformation may be 
considered if necessary.  In addition, we will examine if the disease progression is 
associated with the change from screening to date of progression or from day 1 of cycle 1 to 
date of progression. No multiplicity adjustment is planned due to the nature of exploratory 
study. A two-sided p-value of < 0.05 will be considered significant. We expect that 12 or 
more of 29 patients in Phase II are responders.  With a two-sided significance level of 5%
, 
29 samples will provide 80.4% power to detect an effect size (mean difference divided by 
standard deviation) of 1
.2 when the numbers of responders and non-responders are 12 and 
17, respectively.  
The safety analyses will be performed using data from all subjects who receive any study 
drug
. The severity of the toxicities will be graded according to the NCI CTCAE v 4.0 
whenever possible. Adverse events leading to death or to discontinuation from treatment, 
events classified as NCI CTCAE v 4.0 Grade 3 or higher
, study-drug-related events, and 
serious adverse events will be listed separately. Cross tabulations will be provided to 
summarize frequencies of abnormalities. 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 80 
12 REGULATORY CONSIDERATIONS 
12.1 Institutional Review Board/Ethics Committee Approval  
The protocol for this study has been designed in accordance with the general ethical 
principles outlined in the Declaration of Helsinki. The review of this protocol by the IRB/EC 
and the performance of all aspects of the study, including the methods used for obtaining 
informed consent, must also be in accordance with principles enunciated in the declaration
, 
as well as ICH Guidelines, Title 21 of the Code of Federal Regulations (CFR), Part 50 
Protection of Human Subjects and Part 56 Institutional Review Boards. 
The Investigator will be responsible for preparing documents for submission to the relevant 
IRB/EC and obtaining written approval for this study. The approval will be obtained prior 
to the initiation of the study.  The approval for both the protocol and informed consent must 
specify the date of approval, protocol number and version, or amendment number.  
Any amendments to the protocol after receipt of IRB/EC approval must be submitted by the 
Investigator to the IRB/EC for approval. The Investigator is also responsible for notifying 
the IRB/EC of any serious deviations from the protocol
, or anything else that may involve 
added risk to subjects.  
Any advertisements used to recruit subjects for the study must be reviewed and approved 
by the IRB/EC prior to use. 
12.2 Informed Consent 
The Investigator must obtain informed consent of a subject or his/her designee prior to any 
study related procedures as per GCPs as set forth in the CFR and ICH guidelines.  
Documentation that informed consent occurred prior to the subject’s entry into the study 
and the informed consent process should be recorded in the subject’s source documents. 
The original consent form signed and dated by the subject and by the person consenting the 
subject prior to the subject’s entry into the study must be maintained in the Investigator’s 
study files. 
12.3 Subject Confidentiality 
In compliance with United States federal regulations, Karyopharm requires the Investigator 
to permit its representatives and, when necessary, representatives of the FDA or other 
regulatory authorities to review and/or copy any medical records relevant to the study in 
accordance with local laws.  
Should direct access to medical records require a waiver or authorization separate from the 
subject’s statement of informed consent, it is the responsibility of the Investigator to obtain 
such permission in writing from the appropriate individual. 
12.4 Study Record Requirements  
The Investigator must ensure that the records and documents pertaining to the conduct of 
the study and the distribution of the study drug
, that is copies of CRFs and source 
documents (original documents
, data, and records [e.g
., hospital records; clinical and office 
charts; laboratory notes; memoranda; subject’s diaries or evaluation checklists; SAE 
reports
, pharmacy dispensing records; recorded data from automated instruments; copies 
or transcriptions certified after verification as being accurate copies; microfiches 
photographic negatives, microfilm, or magnetic media; x-rays; subject files; and records 
kept at the pharmacy, at the laboratories, and at medico-technical departments involved in 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 81 
the clinical study; documents regarding subject treatment and study drug accountability; 
original signed informed consents, etc.]) be retained by the Investigator for as long as 
needed to comply with national and international regulations (generally 2 years after 
discontinuing clinical development or after the last marketing approval). The Investigator 
agrees to adhere to the document/records retention procedures by signing the protocol
. 
12.5 Premature Discontinuation of the Study 
The responsible local clinical Investigator as well as Karyopharm has the right to 
discontinue this study at any time for reasonable medical or administrative reasons. 
Possible reasons for termination of the study could be but are not limited to:  
• Unsatisfactory enrollment
 with respect to quantity or quality.  
• Inaccurate or incomplete data collection.  
• Falsification of records.  
• Failure to adhere to the study protocol.  
13 REGULATORY AND REPORTING REQUIREMENTS 
13.1 Adverse Events  
(All serious adverse events (SAE) must be reported to Karyopharm within 24 hours of 
the investigational staff’s knowledge; this includes any event that occurs during the 
participation of the trial regardless of associated therapy, severity or relationship)  
Adverse events which occur during screening and before the initiation of the 
treatment phase of the trial will not be captured / reported as they are not related to 
treatment.  
13.2 Serious Adverse Event (SAE) Definition  
 
A serious adverse event is one that at any dose (including overdose):  
• Results in death  
• Is life-threatening
1  
• Requires inpatient hospitalization or prolongation of existing hospitalization  
• Results in persistent or significant disability or incapacity2  
• Is a congenital anomaly or birth defect  
• Is an important medical event
3  
• Suspected positive pregnancy  
1“Life-threatening” means that the subject was at immediate risk of death at the time of the 
serious adverse event; it does not refer to a serious adverse event that hypothetically might 
have caused death if it were more severe.  
2“Persistent or significant disability or incapacity” means that there is a substantial 
disruption of a person’s ability to carry out normal life functions
.  
3Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in situations where none of the outcomes listed above occurred
. 
Important medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to prevent one 
of the other outcomes listed in the definition above should also usually be considered 
serious. Examples of such events include allergic bronchospasm requiring intensive 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 83 
All adverse experience reports must include the patient number
, age, sex
, weight, severity of 
reaction (mild
, moderate, severe)
, relationship to study drug (probably related, unknown 
relationship, definitely not related), date and time of administration of test medications and 
all concomitant medications, and medical treatment provided. The investigator is 
responsible for evaluating all adverse events to determine whether criteria for “serious” 
and as defined above are present. 
Adverse drug reactions that are Serious
, Unlisted/unexpected, and at least possibly 
associated to the drug
, and that have not previously been reported in the Investigators 
brochure, or reference safety information document should be reported promptly to the 
Food and Drug Administration (FDA) in writing by each investigator/physician engaged in 
clinical research. A clear description of the suspected reaction should be provided along 
with an assessment as to whether the event is drug
 or disease related.  
The investigator/physician shall notify the FDA by telephone or by fax of any unexpected 
fatal or life threatening experience associated with the use of the drug
. As soon as possible, 
but no later than 7 calendar days after the sponsors initial receipt of the information. Each 
phone call or fax shall be transmitted to the FDA new drug review division in the Center for 
Drug Evaluation and Research or the product review division in the Center for Biologics 
Evaluation and Research that has responsibility for review of the IND if applicable.  
Participating study sites should NOT report SAEs to the FDA.  Rather, participating sites 
should report SAEs to Karyopharm Therapeutics and H. Lee Moffitt Cancer center, and H. 
Lee Moffitt Cancer center will be responsible for reporting to FDA. 
 
13.5.2 Reporting to karyopharm 
In addition to reporting to the FDA, Sponsor-Investigator will forward completed SAE and 
pregnancy forms to representatives of karyopharm. Forms will be completed and emailed 
to  
 
 
Address and Phone Number of person/sponsor responsible for SAE management  
  
 
  
 
 
IN ADDITION, scanned form must be emailed to the following recipients:  
 
 
 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 84 
The Sponsor / investigator is responsible for providing 6-month Adverse Reaction 
Reports (all AEs assessed as causality related to Karyopharm investigational 
product) to Karyopharm   
 throughout the duration of the 
study. These reports are to contain listings of non-serious (expected or unexpected) 
adverse reactions and serious or non-serious expected adverse reactions which 
were collected during the 6-month report cycle 
The Sponsor is responsible for obtaining any additional follow-up information 
regarding safety reports
, upon request from Karyopharm
. 
Karyopharm will inform the Sponsor regarding any SUSAR detected in other clinical 
studies
, ISTs
, or Compassionate Use as promptly as possible upon becoming aware of 
same 
13.5.3 Reporting to the IRB 
The principal Investigator
 is required to notify his/her Institutional Review Board (IRB) of a 
serious adverse event according to institutional policy. The following SAE are reported to 
the IRB: Unexpected, related events which increase the risk of harm to subjects.  
13.6 Adverse Events Updates / IND Safety Reports 
Karyopharm Therapeutics shall notify the Investigator via an IND Safety Report of the 
following information:  
• Any AE associated with the use of study drug in this study or in other studies that is 
both serious and unexpected.  
• Any finding from tests in laboratory animals that suggests a significant risk for 
human
 subjects including
 reports of mutagenicity, teratogenicity, or
 carcinogenicity.  
 
The Investigator shall notify his/her IRB/EC promptly of these new serious and unexpected 
AE(s) or significant risks to subjects.  
14 DATA MANAGEMENT 
14.1 Data Collection  
The Clinical Research Coordinators and Investigators of each site will be responsible for the 
recording of the site’s data into the electronic data capture system
, ONCORE.  
To obtain access to Oncore, the site research staff must complete an Oncore Access Request 
Form and a Moffitt Information Systems Confidentiality Agreement (provided in the MCRN 
Handbook at the site initiation visit) and submit both to the Coordinating Center. Once the 
completed forms are received
, the site coordinator will receive VPN access
, 
logon/password
, and information on how to access Oncore using the VPN. The MCRN 
Coordinating Center will provide Oncore training to the site once initial access is granted 
and on an ongoing basis, as needed
.  
14.2 Protocol Monitoring Committee  
The Protocol monitoring committee (PMC) will be composed of medical and statistical 
independent reviewers and will meet to review the efficacy and safety data and determine a 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 85 
risk/benefit analysis in this subject population. The purpose of the PMC is to advise on 
serious safety considerations
, lack of efficacy and any other considerations within the 
charge to the Committee. The PMC may request additional meetings or safety reports as 
deemed necessary upon discussion with the principal investigator. The PMC may stop the 
study following review of results from each interim analysis.  
14.3 Study Monitoring and Auditing  
14.3.1 Investigator Responsibilities  
Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice (GCP) 
and in the US Code of Federal Regulations. The principal investigator is responsible for 
every aspect of the design, conduct and actions of all members of the research team as well 
as final analysis of the protocol
. 
Investigators, or a designated member, must enter study data onto CRFs or other data 
collection system. The Investigator will permit study-related monitoring visits and audits by 
Karyopharm Therapeutics or its representatives, IRB/EC review, and regulatory 
inspection(s) (e.g
., FDA, EMEA, TPP), providing direct access to the facilities where the 
study took place
, to source documents, to CRFs, and to all other study documents.  
The Investigator, or a designated member of the Investigator’s staff, must be available at 
some time during monitoring visits to review data and resolve any queries and to allow 
direct access to the subject’s records (e.g
., medical records, office charts, hospital charts
, and 
study related charts) for source data verification. The data collection must be completed 
prior to each visit and be made available to the Karyopharm Therapeutics representative so 
that the accuracy and completeness may be checked
. 
14.3.2 Site Responsibilities  
 
Before the study can be initiated at any site, the site will be required to provide regulatory 
documentation to the Moffitt Clinical Research Network (MCRN) at  Moffitt Cancer Center. 
Sites must provide a copy of their informed consent to the MCRN coordinating center for 
review and approval prior to submission of any documents to the site’s IRB. Any changes 
requested by the site’s IRB must be provided to the MCRN staff for review and approval 
prior to resubmission to the IRB. 
The MCRN Coordinating Center must receive the following trial specific documents either 
by hardcopy, fax
, or email before a site can be activated for any trial: 
1. IRB Approval Letter that includes the protocol version and date 
2. FDA Related Forms 1572/1571/310 as appropriate 
3. Signed Protocol Title Page 
4. IRB Approved Consent Form 
5. Site Delegation of Authority Log 
6. Signed Financial Interest Disclosure Forms (principal and sub investigators) 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 86 
7. Updated Investigator/Personnel documents (CVs, licenses, Conflict of Interest statements, 
etc.) as needed 
8. Updated Laboratory Documents (certifications, normal ranges, etc
.) as needed  
9. Signed protocol specific Task Order 
A study initiation teleconference will be held prior to the start of any study related activity 
at the site. Attendance is required for:  
• The site PI and appropriate research staff 
• Moffitt PI and MCRN research coordinator 
The requirements of the protocol and all associated procedures and processes will be 
reviewed and agreed upon prior to the activation of the study. The MCRN utilizes the EDC 
system, Oncore. Oncore training will be scheduled
, if indicated
, with the appropriate staff 
from the site.  
A conference call/study meeting will be held weekly for the phase I and monthly for the 
phase II to review patient enrollment and accrual, safety and toxicity data, and treatment 
results, as available.  
14.3.3 Monitoring  
Data will be captured in Oncore, Moffitt’s Clinical Trials Database. Regulatory documents 
and case report forms will be monitored internally according to Moffitt Cancer Center 
Monitoring Policies. Monitoring will be performed regularly to verify data is accurate
, 
complete
, and verifiable from source documents; and the conduct of the trial is in 
compliance with currently approved protocol / amendments
, good clinical practice (GCP) 
and applicable regulatory requirements.  Monitoring at external sites will be per Moffitt 
policy. 
15 PROTOCOL AMENDMENTS OR DEVIATIONS  
15.1 Protocol Amendments  
Any amendment to this protocol must be agreed to by the Principal Investigator and 
reviewed and approved by Karyopharm Therapeutics. Amendments should only be 
submitted to IRB/EC after consideration of Karyopharm Therapeutics review. Written 
verification of IRB/EC approval will be obtained before any amendment is implemented.  
15.2 Protocol Deviations  
When an emergency occurs that requires a deviation from the protocol for a subject, a 
deviation will be made only for that subject. A decision will be made as soon as possible to 
determine whether or not the subject (for whom the deviation from protocol was effected) 
is to continue in the study. The subject’s medical records will completely describe the 
deviation from the protocol and state the reasons for such deviation. In addition, the 
Investigator will notify the IRB/EC in writing of such deviation from protocol.  
 
 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 87 
16   REFERENCES  
 
1. 
Siegel
, R., et al.
, Cancer Statistics
, 2014. CA Cancer J Clin, 2014
. 
2. 
Orlowski, R.Z
., et al
., Randomized phase III study of pegylated liposomal doxorubicin 
plus bortezomib compared with bortezomib alone in relapsed or refractory multiple 
myeloma: combination therapy improves time to progression.
 J Clin Oncol
, 2007. 
25(25): p. 3892-901. 
3. 
Rajkumar, S.V., et al.
, Multicenter
, randomized
, double-blind
, placebo-controlled study 
of thalidomide plus dexamethasone compared with dexamethasone as initial therapy 
for newly diagnosed multiple myeloma
. J Clin Oncol
, 2008. 26(13): p. 2171-7. 
4. 
Richardson, P.G., et al., Phase 1 study of pomalidomide MTD
, safety
, and efficacy in 
patients with refractory multiple myeloma who have received lenalidomide and 
bortezomib
. Blood, 2013. 121(11): p. 1961-7. 
5. 
Richardson, P.G., et al., Bortezomib or high-dose dexamethasone for relapsed multiple 
myeloma
. N Engl J Med, 2005. 352(24): p. 2487-98. 
6. 
Siegel
, D.S., et al.
, A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in 
patients with relapsed and refractory multiple myeloma
. Blood, 2012. 120(14): p. 
2817-25. 
7. 
Weber, D
.M., et al
., Lenalidomide plus Dexamethasone for Relapsed Multiple Myeloma 
in North America 
10.1056/NEJMoa070596. N Engl J Med, 2007
. 357(21): p. 2133-2142. 
8. 
Rifkin, R.M., et al.
, Pegylated liposomal doxorubicin
, vincristine
, and dexamethasone 
provide significant reduction in toxicity compared with doxorubicin
, vincristine
, and 
dexamethasone in patients with newly diagnosed multiple myeloma: a Phase III 
multicenter randomized trial. Cancer, 2006
. 106(4): p. 848-58. 
9. 
Baz, R.C.
, et al., Phase II study of pegylated liposomal doxorubicin
, low-dose 
dexamethasone
, and lenalidomide in patients with newly diagnosed multiple myeloma
. 
Am J Hematol, 2013. 
10. 
Hussein
, M.A., et al.
, Phase 2 study of pegylated liposomal doxorubicin
, vincristine
, 
decreased-frequency dexamethasone
, and thalidomide in newly diagnosed and 
relapsed-refractory multiple myeloma
. Mayo Clin Proc, 2006. 81(7): p. 889-95. 
11. 
Lazaryan, A., et al.
, Mature results of MM-011: A phase I/II trial of liposomal 
doxorubicin
, Vincristine
, Dexamethasone
, and Lenalidomide combination therapy 
followed by lenalidomide maintenance for relapsed/refractory multiple myeloma
. Am 
J Hematol
, 2013
. 
12. 
Engel, R., et al., The cytoplasmic trafficking of DNA topoisomerase IIalpha correlates 
with etoposide resistance in human myeloma cells
. Exp Cell Res, 2004. 295(2): p. 421-
31. 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 88 
13. 
Turner
, J.G., et al., Human topoisomerase IIalpha nuclear export is mediated by two 
CRM-1-dependent nuclear export signals
. J Cell Sci, 2004. 117(Pt 14): p. 3061-71. 
14. 
Turner
, J.G., et al., Human multiple myeloma cells are sensitized to topoisomerase II 
inhibitors by CRM1 inhibition
. Cancer research, 2009
. 69(17): p. 6899-905. 
15. 
Turner
, J.G., et al., CRM1 Inhibition Sensitizes Drug Resistant Human Myeloma Cells to 
Topoisomerase II and Proteasome Inhibitors both In Vitro and Ex Vivo. J Cancer
, 2013. 
4(8): p. 614-25
. 
16. 
Dimopoulos, M., et al., Lenalidomide plus Dexamethasone for Relapsed or Refractory 
Multiple Myeloma 
10.1056/NEJMoa070594. N Engl J Med, 2007
. 357(21): p. 2123-2132. 
17. 
Rajkumar, S.V., et al.
, Phase III clinical trial of thalidomide plus dexamethasone 
compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical 
trial coordinated by the Eastern Cooperative Oncology Group
. J Clin Oncol, 2006. 
24(3): p. 431-6. 
18. 
Turner
, J.G. and D.M. Sullivan, CRM1-mediated nuclear export of proteins and drug 
resistance in cancer
. Curr Med Chem
, 2008
. 15(26): p. 2648-55. 
19. 
Turner
, J.G., J. Dawson, and D.M. Sullivan, Nuclear export of proteins and drug 
resistance in cancer
. Biochemical pharmacology, 2012. 83(8): p. 1021-32. 
20. 
Etchin, J., et al.
, Anti-leukemic activity of nuclear export inhibitors that spare normal 
hematopoietic cells
. Leukemia : official journal of the Leukemia Society of America
, 
Leukemia Research Fund, U.K, 2012. 
21. 
Ranganathan, P., et al.
, Pre-clinical activity of a novel CRM1 inhibitor in acute myeloid 
leukemia
. Blood
, 2012. 
22. 
Baz, R., et al.
, Lenalidomide and pegylated liposomal doxorubicin-based chemotherapy 
for relapsed or refractory multiple myeloma: safety and efficacy
. Ann Oncol, 2006. 
17(12): p. 1766-71. 
23. 
Valkov, N.I.
, et al., Cell density-dependent VP-16 sensitivity of leukaemic cells is 
accompanied by the translocation of topoisomerase IIalpha from the nucleus to the 
cytoplasm
. Br J Haematol, 2000. 108(2): p. 331-45. 
24. 
Ren, R., Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous 
leukaemia
. Nature reviews. Cancer, 2005. 5(3): p. 172-83. 
25. 
Jiao, W., et al.
, Nucleocytoplasmic shuttling of the retinoblastoma tumor suppressor 
protein via Cdk phosphorylation-dependent nuclear export. J Biol Chem, 2006. 
281(49): p. 38098-108. 
26. 
Rosin-Arbesfeld
, R., et al.
, Nuclear export of the APC tumour suppressor controls beta-
catenin function in transcription
. Embo J, 2003. 22(5): p. 1101-13. 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 89 
27. 
O'Brate, A. and P. Giannakakou, The importance of p53 location: nuclear or 
cytoplasmic zip code? Drug Resist Updat
, 2003
. 6(6): p. 313-22
. 
28. 
Keeshan, K.
, T.G
. Cotter
, and S.L. McKenna, Bcr-Abl upregulates cytosolic p21WAF-
1/CIP-1 by a phosphoinositide-3-kinase (PI3K)-independent pathway
. Br J Haematol
, 
2003. 123(1): p. 34-44
. 
29. 
Min, Y
.H., et al.
, Cytoplasmic mislocalization of p27Kip1 protein is associated with 
constitutive phosphorylation of Akt or protein kinase B and poor prognosis in acute 
myelogenous leukemia
. Cancer Res, 2004. 64(15): p. 5225-31. 
30. 
Burzlaff, A., et al.
, Multi parameter in vitro testing of ratjadone using flow cytometry.
 
Appl Microbiol Biotechnol
, 2003. 62(2-3): p. 174-9. 
31. 
Kalesse
, M., et al
., The chemistry and biology of ratjadone
. Chembiochem, 2001. 2(9): 
p. 709-14. 
32. 
Koster, M., et al
., Ratjadones inhibit nuclear export by blocking CRM1/exportin 1. Exp 
Cell Res, 2003. 286(2): p. 321-31. 
33. 
Meissner
, T.
, E. Krause, and U. Vinkemeier, Ratjadone and leptomycin B block CRM1-
dependent nuclear export by identical mechanisms
. FEBS Lett, 2004. 576(1-2): p. 27-
30. 
34. 
Mutka, S.C., et al., Identification of nuclear export inhibitors with potent anticancer 
activity in vivo. Cancer Res, 2009. 69(2): p. 510-7
. 
35. 
Kau, T.R., et al
., A chemical genetic screen identifies inhibitors of regulated nuclear 
export of a Forkhead transcription factor in PTEN-deficient tumor cells
. Cancer Cell, 
2003. 4(6): p. 463-76
. 
36. 
Murakami
, N., et al., New Rev-transport inhibitor with anti-HIV activity from 
Valerianae Radix
. Bioorganic & medicinal chemistry letters, 2002. 12(20): p. 2807-
10. 
37. 
Tamura
, S., et al
., New Rev-export inhibitor from Alpinia galanga and structure-
activity relationship
. Bioorganic & medicinal chemistry letters, 2009. 19(9): p. 2555-
7. 
38. 
Sakakibara, K., et al., CBS9106 is a novel reversible oral CRM1 inhibitor with CRM1 
degrading activity
. Blood, 2011. 118(14): p. 3922-31. 
39. 
Etchin, J., et al.
, KPT-330 inhibitor of CRM1 (XPO1)-mediated nuclear export has 
selective anti-leukaemic activity in preclinical models of T-cell acute lymphoblastic 
leukaemia and acute myeloid leukaemia
. British journal of haematology, 2013. 
161(1): p. 117-27. 
40. 
Tai
, Y
.T., et al., CRM1 inhibition induces tumor cell cytotoxicity and impairs 
osteoclastogenesis in multiple myeloma: molecular mechanisms and therapeutic 
implications
. Leukemia : official journal of the Leukemia Society of America, 
Leukemia Research Fund, U.K, 2013. 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 90 
41. 
Lapalombella, R.
, et al., Selective inhibitors of nuclear
 export show that CRM1/XPO1 is 
a target in chronic lymphocytic leukemia
. Blood, 2012. 120(23): p. 4621-34
. 
42. 
Inoue, H.
, et al., CRM1 Blockade by Selective Inhibitors of Nuclear Export Attenuates 
Kidney Cancer Growth. The Journal of urology, 2012
. 
43. 
Zhang
, K., et al., Novel selective inhibitors of nuclear export CRM1 antagonists for 
therapy in mantle cell lymphoma
. Experimental hematology, 2013. 41(1): p. 67-78 
e4. 
44. 
Salas Fragomeni, R.A.
, et al., CRM1 and BRAF inhibition synergize and induce tumor 
regression in BRAF mutant melanoma
. Molecular cancer therapeutics, 2013. 
45. 
Turner
, J.G., et al., Human multiple myeloma cells are sensitized to topoisomerase II 
inhibitors by CRM1 inhibition
. Cancer Res, 2009. 69(17): p. 6899-905
. 
46. 
Turner
, J.G., et al., CRM1 Inhibition Sensitizes Drug Resistant Human Myeloma Cells to 
Topoisomerase II and Proteasome Inhibitors both In Vitro and Ex Vivo. Journal of 
Cancer
, 2013
. 4(8): p. 614-25. 
47. 
Durie, B.G., et al
., International uniform response criteria for multiple myeloma
. 
Leukemia, 2006. 20(9): p. 1467-73. 
48. 
Simon, R., Optimal two-stage designs for phase II clinical trials
. Control Clin Trials, 
1989. 10(1): p. 1-10. 
49. 
Atkinson, E.N. and B.W. Brown, Confidence limits for probability of response in 
multistage phase II clinical trials
. Biometrics, 1985. 41(3): p. 741-4. 
 
 
 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 91 
APPENDIX A: Response Criteria 
 
a. All response categories require two consecutive assessments made at anytime before the 
institution of any new therapy; all categories also require no known evidence of progressive 
or new bone lesions if radiographic studies were performed. Radiographic studies are not 
required to satisfy these response criteria.  
b Confirmation with repeat biopsy not necessary.  
c Presence/absence of clonal cells is based upon the κ/λ ratio by immunohistochemistry 
and/or immunofluorescence requires a minimum of 100 plasma cells for analysis. An 
abnormal ration reflecting presence of an abnormal clone is κ/λ of > 4:1 or < 1:2.  
d Applicable only to patients who have ‘measurable’ disease defined by at least one of the 
following
 three measurements:
 Serum M-protein ≥ 0.5 g/dl, Urine M
-protein ≥ 200 
mg/24hour, Serum FLC assay involved FLC level ≥ 10 mg/dl provided serum FLC ration is 
abnormal
. e. Not recommended for use as an indicator of response; stability of disease is 
best described by providing the time to progression estimates).  
f All relapse categories require two consecutive assessments made at anytime before 
classification as relapse or disease progression and/or the institution of any new therapy.  
g For progressive disease
, serum M-component increases of ≥ 1 g/dL are sufficient to define 
relapse if starting M component is ≥ 5 g/dL. Progression can also be defined by a 25% 
increase in the serum M component or M spike provided that the increase is >0.5 g/dL. 
 
 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 92 
APPENDIX B: Performance Status Criteria  
 
 
 

MCC 17814  Phase I/II of Selinexor in combination with LD and dexamethasone for 
Myeloma  
 
Page 94 
2PDn sampling:  Plasma and blood leukocytes for XPO1 inhibition and select cytokine assays will be obtained on day -
7, Cycle 1 day 1, 8, and 15, and Cycle 2 day 1 and assayed by Karyopharm.