Clinical trial NCT04843579
Conditions: Myeloma Multiple Myeloma Refractory Multiple Myeloma
Sponsor: Weill Medical College of Cornell University
Start date: 2021-12-29; Completion date: 2022-12-30
Enrollment: 4 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine the efficacy and safety of investigational combination therapy of Selinexor, Clarithromycin, Pomalidomide and Dexamethasone (ClaSPd) for patients with relapsed/refractory multiple myeloma. The hypothesis is that the addition of Selinexor to Clarithromycin, Pomalidomide and Dexamethasone will increase the overall response rate of patients with relapsed/refractory multiple myeloma.

Detailed description:

Arms: arm 1: Selinexor

• Given orally at a dose of 60 mg on days 1, 8, and 15 of a 28-day cycle.

Dexamethasone

* Given orally at a dose of 40 mg on days 1, 8, 15 and 22 of a 28-day cycle.
* Subjects will receive a prescription for dexamethasone 4 mg tablets (generic).

Clarithromycin

* Given orally at a dose of 500 mg twice a day on days 1-28 of a 28-day cycle.
* Subjects will receive a prescription for clarithromycin 250 or 500 mg tablets (generic) for oral administration.

Pomalidomide

* Given orally at a dose of 4 mg daily on days 1-21 of a 28-day cycle.
* Subjects will receive a 21-day supply of pomalidomide 1, 2, 3, or 4 mg capsules for oral administration for each treatment cycle.
Interventions: intervention 1: Selinexor intervention 2: Clarithromycin intervention 3: Pomalidomide intervention 4: Dexamethasone
Intervention descriptions: intervention 1: Given as 60 mg oral capsule intervention 2: Given as 500 mg oral capsule intervention 3: Given as 4 mg oral capsule intervention 4: Given as 40 mg oral capsule

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Cover Page 
 
 
 
 
A Phase 2, Open-Label, Single-Arm Study of Selinexor in Combination with 
Clarithromycin, Pomalidomide and Dexamethasone in Patients with 
Relapsed/Refractory Multiple Myeloma (NCT04843579) 
 
 
IRB Protocol #: 20-12023093 
 
IND/IDE #: 154930 
 
Version Date: 07/08/2021 
 
Funding Source: Karyopharm Therapeutics, Inc. (IST-343) 
 
Principal Investigator: Jorge Monge, M.D. 
425 East 61st Street, 8th Floor 
New York, NY 10065 
T: 646.962.6500 
F: 212.746.8961 
E: jum9127@med.cornell.edu  


 
 
  
Page # i 
 
 
TITLE:  A Phase 2, Open-Label, Single-Arm Study of Selinexor in Combination with 
Clarithromycin, Pomalidomide and Dexamethasone in Patients with Relapsed/Refractory 
Multiple Myeloma 
 
IRB Protocol #: 20-12023093 
IND/IDE #: 154930  
Version Date: 07/08/2021 
Funding Source: Karyopharm Therapeutics, Inc. (IST-343) 
 
Principal Investigator: 
 
Jorge Monge, M.D. 
425 East 61st Street, 8th Floor 
New York, NY 10065 
T: 646.962.6500 
F: 212.746.8961 
 
E: jum9127@med.cornell.edu  
 
Co-Investigators: 
 
 
Ruben Niesvizky, M.D. 
425 East 61st Street, 8th Floor 
New York, NY 10065 
T: 646.962.6500 
F: 212.746.8961 
E: run9001@med.cornell.edu  
 
Roger Pearse, M.D., Ph.D. 
425 East 61st Street, 8th Floor 
New York, NY 10065 
T: 646.962.6500 
F: 212.746.8961 
E: rnp2001@med.cornell.edu  
 
Cara Rosenbaum, M.D. 
425 East 61st Street, 8th Floor 
New York, NY 10065 
T: 646.962.6500 
F: 212.746.8961 
E: car9156@med.cornell.edu  
 
Perry Cook, MD 
506 6th Street, Wesley House #3C 
Brooklyn, NY 11215 
T: 718.780.5541 
E: pec9040@nyp.org 
 
Andy Huang, MD 
506 6th St  
Brooklyn, NY 11215 
T: 718.780.5246 
E: anh9107@nyp.org 


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Page # ii 
 
 
 
 
 
Statistician: 
 
 
 
 
Paul Christos, Dr.PH, MS 
 
1300 York Ave, Box 65 
 
New York, NY 10065  
T: 212.746.6565 
 
F: 212.746.5981 
 
pac2001@med.cornell.edu 
 
 
 
Participating Network Site:  
NewYork Presbyterian-Brooklyn Methodist Hospital  
Perry Cook, MD and Andy Huang, MD 
515 6th Street, 6th floor  
Brooklyn, NY 11215  
pec9040@nyp.org and anh9107@nyp.org 
 
 
Participating Sites: 
 
TBD 
 
 
PROTOCOL VERSION AND DATE:  
Original, April 19th, 2021  
Amendment 1, July 8th, 2021  
 


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Page # iii 
 
TABLE OF CONTENTS 
1. PROTOCOL SUMMARY .................................................................................................. 1 
1.1 
Schema ...................................................................................................................... 4 
Figure 1. ClaSPd Study Design ....................................................................................... 4 
Table 1. ClaSPd Dosing Schedule .................................................................................. 4 
1.2 Study Objectives and End Points ............................................................................. 5 
1.2.1 Primary Objectives ............................................................................................... 5 
1.2.2 Secondary Objectives .......................................................................................... 5 
1.2.3 Exploratory Objectives ........................................................................................ 5 
1.2.4 Primary Endpoints ............................................................................................... 5 
1.2.5 Secondary Endpoints .......................................................................................... 5 
2. BACKGROUND ................................................................................................................ 6 
2.1 Disease .......................................................................................................................... 6 
2.2 Investigational Agent/Device, or Surgical Treatment/Method ............................. 6 
2.2.1 Selinexor ................................................................................................................ 6 
2.2.2 Clarithromycin ...................................................................................................... 7 
2.2.3 Pomalidomide ....................................................................................................... 8 
2.3 Rationale ....................................................................................................................... 9 
2.4 Risk/Benefit Assessment ........................................................................................... 9 
2.4.1 Known Potential Risks ........................................................................................ 9 
2.4.2 
Known Potential Benefits .............................................................................. 12 
2.4.3 
Assessment of Potential Risks and Benefits ............................................. 15 
2.5 Correlative Studies Background ............................................................................ 15 
3. STUDY DESIGN ............................................................................................................. 15 
3.1 Overall Design............................................................................................................ 15 
3.2 Scientific Rationale for Study Design .................................................................... 16 
3.3 Justification for Dose ............................................................................................... 16 
3.4 End of Study Definition ............................................................................................ 17 
4. SUBJECT SELECTION .................................................................................................. 17 
4.1 Study Population ....................................................................................................... 17 
4.2 Inclusion Criteria ....................................................................................................... 17 
4.3 Exclusion Criteria ...................................................................................................... 17 
4.4 
Lifestyle Considerations ...................................................................................... 19 
4.5 
Screen Failures ...................................................................................................... 19 
4.6 
Strategies for Recruitment and Retention ......................................................... 19 
5. REGISTRATION PROCEDURES .................................................................................. 19 
5.1 Subject Registration (WCM only) ........................................................................... 19 
5.2 Subject Registration (Sub-sites) ............................................................................. 20 


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6. STUDY PROCEDURES ................................................................................................. 20 
6.1 
Schedule of Assessments ................................................................................... 20 
6.1.1 
Screening Visit (-21 to -1 days before start of treatment) ........................ 23 
6.1.2 
Treatment Phase ............................................................................................. 23 
6.1.2.1 
Visit 1 (baseline; Cycle 1 Day 1) ............................................................... 23 
6.1.2.2 
Visit 2 (Cycle 1 Day 8 ± 1 day) ................................................................... 24 
6.1.2.3 
Visit 3 (Cycle 1 Day 15 ± 1 day) ................................................................. 24 
6.1.2.4 
Visit 4 (Cycle 2 Day 1 ± 2 days) ................................................................. 24 
6.1.2.5 
Visit 5 (Cycle 2 Day 15 ± 2 days) ............................................................... 25 
6.1.2.6 
Visit ≥ 6 (Cycle ≥ 3 Day 1 ± 2 days) ........................................................... 25 
6.1.2.7 
End of Treatment Visit (≤ 14 days after last dose) ................................. 25 
6.1.3 
Follow-up Phase ............................................................................................. 26 
6.1.3.1 
Follow Up Assessment (30 days after last dose ± 7 days) ................... 26 
6.1.3.2 
Duration of Response and Survival (every 3 months ± 14 days after 
last dose for 12 months) ............................................................................................. 26 
7. STUDY INTERVENTION ................................................................................................ 26 
7.1 
Study Intervention/Device Description .............................................................. 26 
7.2 
Availability .............................................................................................................. 27 
7.3 
Acquisition and Accountability ........................................................................... 27 
7.4 
Formulation, Appearance, Packaging, and Labeling ...................................... 27 
7.5 
Product Storage and Stability ............................................................................. 28 
7.6 
Preparation ............................................................................................................. 28 
7.7 
Dosing and Administration .................................................................................. 28 
7.7.1 
Dosing Delays/Dose Modifications .............................................................. 30 
7.8 
General Concomitant Therapy and Supportive Care Guidelines .................. 39 
7.9 
Duration of Therapy and Criteria for Removal from Study ............................ 44 
7.10 Duration of Follow Up ............................................................................................. 44 
7.11 Measures to Minimize Bias: Randomization and Blinding ............................... 45 
7.12 Study Intervention/Follow-up Compliance ......................................................... 45 
8. STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................... 45 
8.1 
Discontinuation of Study Intervention ............................................................... 45 
8.2 
Participant Discontinuation/Withdrawal from the Study ................................ 45 
8.3 
Lost to Follow Up ................................................................................................... 46 
9. CORRELATIVE/SPECIAL STUDIES ............................................................................ 46 
9.1 
Laboratory Correlative Studies ........................................................................... 47 
9.2 
Special Studies ...................................................................................................... 47 
10.  MEASUREMENT OF EFFECT ................................................................................... 47 
10.1 Response Criteria .................................................................................................... 47 
10.2 Duration of Response ............................................................................................. 47 


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10.3 Progression-Free Survival ..................................................................................... 47 
10.4 Other Response Parameters ................................................................................. 47 
11. DATA REPORTING / REGULATORY CONSIDERATIONS ..................................... 47 
11.1 Data Collection ........................................................................................................ 47 
11.1.1 REDCap .............................................................................................................. 48 
11.2 Regulatory Considerations .................................................................................... 48 
11.2.1 Institutional Review Board/Ethics Committee Approval ........................... 48 
11.2.2 Ethical Conduct of the Study ......................................................................... 49 
11.2.3 Informed Consent ............................................................................................. 49 
11.2.4 Compliance with Trial Registration and Results Posting Requirements 49 
11.2.5 Record Retention ............................................................................................. 49 
12. STATISTICAL CONSIDERATIONS ............................................................................ 49 
12.1 Study Design/Endpoints ........................................................................................ 49 
12.2 Sample Size/Accrual Rate ...................................................................................... 50 
12.3 Stratification Factors .............................................................................................. 50 
12.4 Analysis of Endpoints ............................................................................................ 50 
12.4.1 
Analysis of Primary Endpoints ................................................................. 50 
12.4.2 
Analysis of Secondary Endpoints ............................................................ 51 
12.4.3 
Analysis of Exploratory Endpoints .......................................................... 52 
12.5 Interim Analysis ....................................................................................................... 53 
12.6 ..................................................................................................................................... 53 
Reporting and Exclusions .............................................................................................. 53 
12.6.1 
Evaluation of Toxicity ................................................................................. 53 
12.6.2 
Evaluation of Response ............................................................................. 53 
13. ADVERSE EVENT REPORTING REQUIREMENTS ................................................. 53 
13.1 Adverse Event Definitions ..................................................................................... 53 
13.1.1 
Expected Adverse Events .......................................................................... 54 
13.1.2 
Adverse Event Characteristics and Related Attributions .................... 54 
13.1.3 
Recording of Adverse Events ................................................................... 55 
13.1.4 
Reporting of AE to WCM IRB .................................................................... 56 
13.1.5 
Reporting Events to Participants ............................................................. 56 
13.1.6 
Events of Special Interest .......................................................................... 56 
13.1.7 
Reporting of Pregnancy ............................................................................. 56 
13.2 Definition of SAE ..................................................................................................... 57 
13.2.1 
Reporting of SAE to IRB ............................................................................ 58 
13.2.2 
Reporting of SAE to FDA ........................................................................... 58 
13.2.3 
Reporting of SAE to Karyopharm Therapeutics, Inc. ............................ 59 
13.2.4 
Reporting of SAE to WCM by Sub-sites .................................................. 60 
13.3 AE/SAE Follow Up ................................................................................................... 60 
13.4 Time Period and Frequency for Event Assessment and Follow Up ............... 60 


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14. UNANTICIPATED PROBLEMS INVOLVING RISKS TO SUBJECTS OR OTHERS61 
14.1 Definition of Unanticipated Problems Involving Risks to Subjects or Others 
(UPIRTSO) ......................................................................................................................... 61 
14.1.2 
Unanticipated Problem Reporting ............................................................ 61 
15. DATA AND SAFETY MONITORING PLAN (DSMP) ................................................. 62 
16. REFERENCES .............................................................................................................. 64 
Appendix 1. Cytochrome P450 Drug Interactions ...................................................... 67 
Appendix 2. Glutathione (GSH)-, S-adenosylmethionine (SAM)-, or N-
acetylcysteine (NAC)-Containing Products ................................................................ 72 
Appendix 3. Eastern Cooperative Oncology Group (ECOG) Performance Status 
Scale .................................................................................................................................. 73 
Appendix 4. International Myeloma Working Group (IMWG) Response Criteria .. 73 
Appendix 5. Functional Assessment of Cancer Therapy - Multiple Myeloma 
(FACT-MM) ........................................................................................................................ 77 
Appendix 6. FDA Label (package insert) for Selinexor, Clarithromycin 
Pomalidomide and Dexamethasone ............................................................................. 77 
 
 
 


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Statement of Compliance 
 
The trial will be conducted in accordance with International Conference on Harmonization 
Good Clinical Practice (ICH GCP), applicable United States (US) Code of Federal 
Regulations (CFR), and the <specify NIH Institute or Center (IC) > Terms and Conditions 
of Award. The Principal Investigator will assure that no deviation from, or changes to the 
protocol will take place without prior agreement from the Investigational New Drug (IND) 
or Investigational Device Exemption (IDE) sponsor, funding agency and documented 
approval from the Institutional Review Board (IRB), except where necessary to eliminate 
an immediate hazard(s) to the trial participants. All personnel involved in the conduct of 
this study have completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials 
will be submitted to the IRB for review and approval.  Approval of both the protocol and 
the consent form must be obtained before any participant is enrolled.  Any amendment to 
the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  All changes to the consent form will be IRB approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
 


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Confidentiality Statement 
 
This document is confidential and is to be distributed for review only to investigators, potential 
investigators, consultants, study staff, and applicable independent ethics committees or 
institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from WCM, unless disclosure on ClinicalTrials.gov is federally required. 
 
 
 
 
_________________________________________________________________ 
Institution Name 
 
 
 
 
 
 
______________________________       _____________________________     ____________ 
Principal Investigator’s Name                 Principal Investigator’s Signature     Date 
 
 
 
 
 


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Page # ix 
 
List of Abbreviations 
 
AE 
Adverse Event 
C 
CFR 
ClaSPd 
CrCl 
Cycle 
Code of Federal Regulations 
Clarithromycin, selinexor, pomalidomide and dexamethasone 
Creatinine Clearance 
CRF 
Case Report Form 
CTSC 
CYP 
Clinical Translational Science Center  
Cytochrome 
D 
DSMC 
Day 
Data Safety Monitoring Committee 
DSMP 
ECOG PS 
Data Safety Monitoring Plan 
Eastern cooperative oncology group performance status 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HRBFA 
Human Research Billing Analysis Form 
HUD 
Humanitarian Use Device  
ICF 
Informed Consent Form 
IDE 
Investigational Device Exemption  
IND 
Investigational New Drug 
IRB 
MM 
N 
ORR 
OS 
PFS 
Institutional Review Board 
Multiple Myeloma 
Number of patients 
Overall response rate 
Overall survival 
Progression-free survival 
PHI 
Protected Health Information 
PI 
PO 
Pts 
QD 
QOL 
Principal Investigator 
Oral 
Patients 
Daily 
Quality of life 
REDCap 
RRMM 
Research Electronic Data Capture 
Relapsed/Refractory Multiple Myeloma 
SAE 
Serious Adverse Event 


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SINE 
Selective inhibitor of nuclear export 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
 UIRTSO 
 Unanticipated Problem Involving Risks to Subjects or Others 
 WCM 
 Weill Cornell Medicine 


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1. Protocol Summary 
 
Full Title:  
 
 
 
A Phase 2, Open-Label, Single-Arm Study of Selinexor in 
Combination with Clarithromycin, Pomalidomide and 
Dexamethasone in Patients with Relapsed/Refractory Multiple 
Myeloma 
 
Short Title: 
 
 
 
ClaSPd in patients with RRMM  
 
Clinical Phase: 
 
 
II 
 
Principal Investigator:  
Jorge Monge, MD 
 
Study Description:   
This study will assess the efficacy and safety of combination 
therapy with Selinexor, Clarithromycin, Pomalidomide and 
Dexamethasone (ClaSPd) for the treatment of patients with 
relapsed/refractory multiple myeloma (RRMM). 
 
Sample Size: 
 
N = 26 in a two-stage design; n1 = 18, n2 = 8. 
 
Enrollment: 
 
This study will enroll 26 subjects and screen up to 50 subjects.   
Study Population: 
 
Patients over 18 and under 75 years of age with RRMM previously 
treated with two to four prior lines of therapy. 
 
Enrollment Period:  
13 months  
 
Study Design: 
 
This is a phase 2, open-label, single-arm study to assess the 
efficacy and safety of ClaSPd in patients with RRMM previously 
treated with two to four prior lines of therapy.  
 
 
A Simon's two-stage design will be used. In the first stage, 18 
patients will be accrued. If there are 6 or fewer responses in these 
18 patients, the study will be stopped. Otherwise, 8 additional 
patients will be accrued for a total of 26. The null hypothesis will 
be rejected if 14 or more responses are observed in 26 patients. 
The study treatment is an all-oral regimen given in 28-day cycles 
until progression of disease, death, toxicity that cannot be 
managed by standard care or study withdrawal:  
 
 
 
Selinexor 60 mg PO on days 1, 8, and 15. 
 
 
Clarithromycin 500 mg PO twice a day on days 1-28. 
 
 
Pomalidomide 4 mg PO daily on days 1-21. 
 
 
Dexamethasone 40 mg PO on days 1, 8, 15 and 22. 
 
 
 


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Description of Sites/  
Facilities Enrolling 
Participants: 
 
Subjects will be screened and enrolled at Weill Cornell Medicine 
and NewYork Presbyterian-Brooklyn Methodist Hospital in New 
York, NY. There is no intention to include sites outside of the 
United States. 
 
Study Duration: 
 
The projected total study duration is 40 months (13 months to 
complete enrollment, 24 months of median study treatment 
duration for the last enrolled participant, and 3 months for data 
analysis). 
 
Participant Duration: 
Participants are estimated to receive study treatment for 
approximately 10 months, undergo a follow-up assessment 1 
month later, and four duration-of-response/survival follow-up 
assessments every 3 months, for approximately 24 months on 
study. 
 
Study Agent/Device Name  
Intervention Description: 
Selinexor 60 mg PO on days 1, 8, and 15, 
 
 
Clarithromycin 500 mg PO twice a day on days 1-28, 
 
 
Pomalidomide 4 mg PO daily on days 1-21, and 
 
 
Dexamethasone 40 mg PO on days 1, 8, 15 and 22 of a 28-day 
cycle, until progression of disease, death, toxicity that cannot be 
managed by standard care or study withdrawal. 
 
Primary Objective: 
To determine the efficacy of combination therapy with ClaSPd for 
the treatment of patients with RRMM. 
 
Secondary Objectives: 
To evaluate the safety of combination therapy with ClaSPd for the 
treatment of patients with RRMM. 
 
Exploratory Objectives: 
To determine the duration of response of combination therapy with 
ClaSPd for the treatment of patients with RRMM. 
 
 
To determine the clinical benefit rate of combination therapy with 
ClaSPd for the treatment of patients with RRMM. 
 
 
To determine the disease control rate of combination therapy with 
ClaSPd for the treatment of patients with RRMM. 
 
 
To determine the progression-free survival of combination therapy 
with ClaSPd for the treatment of patients with RRMM. 
 
 
To determine the overall survival of combination therapy with 
ClaSPd for the treatment of patients with RRMM. 
 
 
To determine the relative dose intensity of combination therapy 
with ClaSPd for the treatment of patients with RRMM. 


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To assess quality of life during combination therapy with ClaSPd 
for the treatment of patients with RRMM. 
 
Primary Endpoints: 
Overall response rate, which includes a partial response or better 
according to the International Myeloma Working Group response 
criteria, assessed at the completion of every cycle of study 
treatment. 
 
Secondary Endpoints: 
Frequency of participants with Adverse Events as assessed by the 
National Cancer Institute Common Terminology Criteria for 
Adverse Events version 5.0.   
 
 


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1.1 Schema 
 
 
Figure 1. ClaSPd Study Design 
 
 
 
Abbreviations: ClaSPd = selinexor + clarithromycin + pomalidomide + dexamethasone; CYP = 
cytochrome; ECOG PS = eastern cooperative oncology group performance status; N = number 
of patients; ORR = overall response rate; OS = overall survival; pts = patients; PFS = 
progression-free survival; PO = by mouth; QD = once daily; QOL = quality of life; RRMM = 
relapsed/refractory multiple myeloma; SINE = selective inhibitor of nuclear export. 
 
Table 1. ClaSPd Dosing Schedule 
 
 
Week 1 
Week 2 
Week 3 
Week 4 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D1
0
D1
1
D1
2
D1
3
D1
4
D1
5
D1
6
D1
7
D1
8
D1
9
D2
0
D2
1
D2
2
D2
3
D2
4
D2
5
D2
6
D2
7
D2
8
Sel 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cla 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Po
m 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Dex 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Abbreviations: Cla = clarithromycin; ClaSPd = selinexor + clarithromycin + pomalidomide + 
dexamethasone; D = day; Dex = dexamethasone; Pom = pomalidomide; Sel = selinexor; X = 
dosing day. 
 
 


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1.2 Study Objectives and End Points 
 
 
This study will explore the efficacy and safety of selinexor in combination with clarithromycin, 
pomalidomide and dexamethasone (ClaSPd) for the treatment of patients with 
relapsed/refractory multiple myeloma (RRMM) previously treated with two to four prior lines of 
therapy. 
 
1.2.1 Primary Objectives 
 
 
To determine the efficacy of combination therapy with ClaSPd for the treatment of 
patients with RRMM. 
 
1.2.2 Secondary Objectives  
 
To evaluate the safety of combination therapy with ClaSPd for the treatment of 
patients with RRMM. 
 
1.2.3 Exploratory Objectives 
 
 
 
- 
To determine the duration of response of combination therapy with ClaSPd 
for the treatment of patients with RRMM. 
- 
To determine the time to maximum response of combination therapy with 
ClaSPd for the treatment of patients with RRMM. 
- 
To determine the clinical benefit rate of combination therapy with ClaSPd for 
the treatment of patients with RRMM. 
- 
To determine the disease control rate of combination therapy with ClaSPd 
for the treatment of patients with RRMM. 
- 
To determine the progression-free survival of combination therapy with 
ClaSPd for the treatment of patients with RRMM. 
- 
To determine the overall survival of combination therapy with ClaSPd for the 
treatment of patients with RRMM. 
- 
To determine the relative dose intensity of combination therapy with ClaSPd 
for the treatment of patients with RRMM. 
- 
To assess quality of life during combination therapy with ClaSPd for the 
treatment of patients with RRMM. 
 
 
1.2.4 Primary Endpoints 
 
Overall response rate, which includes a partial response or better according to the 
International Myeloma Working Group response criteria, assessed at the completion 
of every cycle of study treatment. 
 
1.2.5 Secondary Endpoints 
 


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Frequency of participants with Adverse Events as assessed by the National Cancer 
Institute Common Terminology Criteria for Adverse Events version 5.0.   
 
2. Background 
 
2.1 Disease 
 
Multiple myeloma (MM) is the second most common hematological malignancy, representing 
1.8% of all cancers. In 2020, there are an estimated 140,779 people living with myeloma in the 
United States, and it is estimated that there will be 32,270 new cases of myeloma and an 
estimated 12,830 people will die of this disease.1 Although a rare disease, myeloma is more 
common in men than women and among individuals of African American descent, with a 
median age at diagnosis of 69. Despite the increased efficacy of new agents, nearly all patients 
will eventually relapse with their disease becoming drug resistant. There continues to be an 
unmet medical need for patients with relapsed and/or refractory MM (RRMM) that can provide a 
deep and durable response. 
 
2.2 Investigational Agent/Device, or Surgical Treatment/Method 
 
2.2.1 Selinexor 
Selective inhibitor of nuclear export (SINE) compounds, a new generation of exportin 1 (XPO1) 
inhibitors, were designed as drug-like small molecules that selectively inhibit XPO1 in order to 
increase efficacy and reduce toxicity secondary to non-specific binding and off-target effects. 
Mechanistic studies show that SINE compounds induce nuclear localization and activation of 
multiple tumor suppressor proteins (TSPs), along with reduction in oncoprotein levels (e.g., c-
Myc and the anti-apoptotic protein BCL-XL) leading to rapid apoptosis of MM cells. 
Selinexor is an orally bioavailable SINE compound that specifically blocks XPO1, with anti-MM 
activity demonstrated in preclinical studies. In a phase 1 clinical trial (NCT01607892) of 
selinexor in patients with advanced hematological malignancies, 25 patients with heavily 
pretreated MM (22) or Waldenstrom macroglobulinemia (3) were administered selinexor (3-60 
mg/m2) in 8 or 10 doses per 28-day cycle.11 In the dose-expansion phase, 59 patients with MM 
received selinexor at 45 or 60 mg/m2 with dexamethasone 20 mg, twice weekly in 28-day 
cycles, or selinexor (40 or 60 mg flat dose) without corticosteroids in 21-day cycles. The most 
common non-hematologic adverse events (AEs) were nausea (75%), fatigue (70%), anorexia 
(64%), vomiting (43%), weight loss (32%), and diarrhea (32%), which were primarily grade 1 or 
2. The most common grade 3 or 4 AEs were hematologic, particularly thrombocytopenia (45%). 
Single-agent selinexor showed modest efficacy with an objective response rate (ORR) of 4% 
and a clinical benefit rate of 21%. In contrast, the addition of dexamethasone increased the 
ORR with all responses of greater than partial response occurring in the 45 mg/m2 selinexor 
plus dexamethasone 20 mg twice weekly cohort (ORR = 50%). Furthermore, 46% of all patients 
showed a reduction in MM markers from baseline. These findings demonstrated the activity of 
selinexor in combination with dexamethasone in heavily pretreated MM.   
In a phase 2 clinical trial (NCT02336815), 122 patients with triple-class refractory MM received 
selinexor (80mg) and dexamethasone (20mg) twice weekly.9 A partial response or better was 
observed in 26% of patients, including two stringent complete responses; 39% of patients had a 
minimal response or better. The median duration of response was 4.4 months, median 
progression-free survival was 3.7 months, and median overall survival was 8.6 months. Fatigue, 
nausea, and decreased appetite were common and were typically grade 1 or 2 (grade 3 events 


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were noted in up to 25% of patients, and no grade 4 events were reported). Thrombocytopenia 
occurred in 73% of the patients (grade 3 in 25% and grade 4 in 33%). Thrombocytopenia led to 
bleeding events of grade 3 or higher in 6 patients. This trial showed that the combination of 
selinexor with dexamethasone resulted in objective treatment responses in patients with triple-
class refractory multiple myeloma.  
The phase 1/2 clinical trial of selinexor in combination with backbone treatments for 
relapsed/refractory multiple myeloma (STOMP; NCT02343042) is currently evaluating the 
efficacy and safety of multiple combinations. Preliminary results from the cohort of patients 
receiving selinexor, pomalidomide and dexamethasone were presented at the 61st American 
Society of Hematology Annual Meeting on December 7, 2019.10 Oral selinexor was evaluated in 
a once-weekly or twice-weekly schedule with low-dose dexamethasone and escalating doses of 
pomalidomide 2, 3 or 4 mg PO (days 1-21). Fifty-one patients with relapsed/refractory multiple 
myeloma had been enrolled. Common hematologic treatment-related adverse events (TRAEs) 
included neutropenia, thrombocytopenia, anemia, and leukopenia; while non-hematologic 
TRAEs included nausea, fatigue, decreased appetite, weight decreased, diarrhea, and vomiting. 
Lower rates of ≥grade 3 thrombocytopenia (27% vs 44%) were observed in the weekly vs twice-
weekly dosing. Among 46 evaluable patients for efficacy, the ORR was 50% (56% in patients 
who were pomalidomide-naïve), 15% achieved a VGPR, and the median PFS was 10.4 months 
(12.2 months in patients who were pomalidomide-naïve). Once-weekly selinexor can be safely 
combined with pomalidomide and low-dose dexamethasone in heavily pretreated patients with 
MM. The recommended phase 2 dose was defined as selinexor 60mg once-weekly, 
pomalidomide 4mg daily (days 1-21) and dexamethasone 40 mg once-weekly. 
On July 3, 2019, the Food and Drug Administration granted accelerated approval to selinexor in 
combination with dexamethasone for adult patients with relapsed/refractory multiple MM who 
have received at least four prior therapies and whose disease is refractory to at least two 
proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal 
antibody. 
 
2.2.2 Clarithromycin 
The semisynthetic macrolide antibiotic, clarithromycin, is indicated for the treatment of mild to 
moderate infections caused by susceptible bacteria. In the treatment of patients with multiple 
myeloma, clarithromycin has resulted in deep responses when added to dexamethasone in 
combination with thalidomide, lenalidomide or pomalidomide.3-8 It optimizes the pharmacologic 
effects of glucocorticoids by increasing the area under the curve and the maximum 
concentration levels of some steroids through inhibition of CYP3A4.12 It has an 
immunomodulatory effect and may have direct antineoplastic properties by synergistically 
decreasing the secretion of tumor necrosis factor-α and interleukin-6 through the inhibition of 
ERK1/2 and AKT in combination with other immunomodulatory drugs like thalidomide and 
lenalidomide.13 Other studies have suggested that clarithromycin inhibits autophagy, increasing 
the cytotoxic effect of immunomodulatory drugs on MM cells.14  
The phase 2 clinical trial (NCT00151203) evaluated the safety and efficacy of combination 
therapy with clarithromycin, lenalidomide and dexamethasone for the treatment of newly 
diagnosed MM.7  Of 72 patients enrolled, 90% achieved an objective response of which 39% 
were CR or better, and an actuarial 2-year event-free survival of 97%. The most common grade 
≥3 hematologic AEs were neutropenia (19.4%), anemia (13.8%), and thrombocytopenia 


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(22.2%); common non-hematologic grade ≥3 AEs were myopathy (11.1%), rash (5.6%), 
diverticular abscess (5.6%), and thromboembolic events (12.5%). 
A case–matched study compared the addition of clarithromycin to lenalidomide and 
dexamethasone vs lenalidomide and dexamethasone for the treatment of newly diagnosed 
myeloma.4 It retrospectively analyzed the data obtained for the 72 patients enrolled in the above 
study and 72 pair mates selected among patients seen at the Mayo Clinic who received 
lenalidomide and dexamethasone. On an intention-to-treat analysis, CR rates (45.8% vs 13.9%, 
p<0.001) and ≥VGPR rates (73.6% vs 33.3%, p<0.001) were significantly higher with the 
addition of clarithromycin. Time-to-progression (median 48.3 vs 27.5 months, p=0.071), and 
progression-free survival (median 48.3 vs 27.5 months, p=0.044) also favored the addition of 
clarithromycin, however, overall survival was similar between both groups (3-year OS: 89.7% vs 
73.0%, p=0.17). 
A phase 3 clinical trial (NCT02575144) randomized 286 patients with newly diagnosed MM, 
transplant ineligible, to receive lenalidomide (daily for 21 days every 28 days) and weekly 
dexamethasone with or without twice-daily clarithromycin.15 The preliminary results were 
presented at the 61st American Society of Hematology Annual Meeting on December 9, 2019. 
The addition of clarithromycin to lenalidomide and dexamethasone significantly increased the 
depth of response (≥CR 21% vs 11%; p = 0.037) but it was not associated with an improved 
PFS and OS due to a higher proportion of treatment-related deaths in the clarithromycin-
containing arm, mostly infectious, and affecting primarily patients ≥75 years of age. 
The addition of clarithromycin to pomalidomide and dexamethasone for the treatment of patients 
with relapsed/refractory multiple myeloma previously exposed to lenalidomide was evaluated in 
a phase 2 study (NCT01159574).6 The median number of prior therapies was 5 (range 3-15). 
The overall response rate (ORR) was 60% with 23% achieving at least a very good partial 
response. The median PFS was 7.7 months and the median overall survival was 19.2 
months. The most common grade ≥3 toxicities included neutropenia (58%), thrombocytopenia 
(31%), and anemia (28%). 
 
2.2.3 Pomalidomide 
Pomalidomide is an immunomodulatory drug approved for the treatment of patients with RRMM. 
In combination with dexamethasone, pomalidomide has been shown to be effective in patients 
with relapsed/refractory MM previously treated with bortezomib and/or lenalidomide, with ORR 
ranging from 31 to 47% (ORR pooled estimate 35%; 95% confidence interval: 30-42%).16-20 
Toxicity is mostly hematologic, with grade ≥3 neutropenia occurring in 40-48%, anemia in 22-
33%, and thrombocytopenia in 19-22%; while non-hematologic grade ≥3 toxicity included 
pneumonia (13-22%) and fatigue (5-14%).19,20  
More recently, multiple phase 2 and 3 clinical trials have demonstrated the efficacy of three-drug 
regimens including pomalidomide and dexamethasone in combination with clarithromycin (ORR 
60%), carfilzomib (ORR 62%), ixazomib (ORR 48%), cyclophosphamide (ORR 51-65%), 
elotuzumab (ORR 53%), daratumumab (ORR 60%), or isatuximab (ORR 60%) (ORR pooled 
estimate 58%; 95% confidence interval: 54-62%).6,21-27 These studies reported a median PFS of 
7.7 to 11.5 months (median 9.9 months). 
 


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2.3 Rationale 
 
Multiple myeloma (MM) is the second most common hematological malignancy.1 Despite the 
increased efficacy of new agents, nearly all patients will eventually relapse and require further 
therapy. The prognosis of patients with MM who have relapsed/refractory disease is poor, with 
decreased response rates and duration of response to each subsequent line of treatment. 
Achieving a deep response is associated with improvement in quality of life and longer duration 
of freedom from disease symptoms and overall survival.2 There continues to be an unmet 
medical need for effective treatment of patients with relapsed and/or refractory MM. 
The use of clarithromycin, a semisynthetic macrolide antibiotic, in the treatment of patient with 
multiple myeloma has resulted in deep responses when added to dexamethasone in 
combination with thalidomide, lenalidomide or pomalidomide.3-8 Recently, the combination of 
selinexor with dexamethasone, as well as with pomalidomide and dexamethasone, has shown 
to be a safe and effective treatment in patients with heavily pretreated MM.9,10 The rationale for 
combining selinexor with clarithromycin, pomalidomide and dexamethasone in the current study 
is based on the clinical synergistic activity observed when clarithromycin is combined with 
pomalidomide and dexamethasone,6 the clinical synergistic activity observed when selinexor is 
combined with pomalidomide and dexamethasone,10 the clinical appeal of an all oral regimen, 
and the urgent need to induce deeper and more durable responses in patients with 
relapsed/refractory MM. 
This study will explore the efficacy and safety of selinexor in combination with clarithromycin, 
pomalidomide and dexamethasone for the treatment of patients with relapsed/refractory multiple 
myeloma (RRMM) previously treated with at least one line of therapy. 
 
2.4 Risk/Benefit Assessment  
 
 
2.4.1 Known Potential Risks 
 
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. If toxicities are 
encountered, adjustments will be made to the study treatment as detailed in the sections below. 
All adverse events (AEs) and serious adverse events (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 
anticancer therapy, whichever occurs first. 
 
2.4.1.1 Selinexor 
The U.S. FDA granted approval for selinexor based on the STORM trial (KCP‐330‐012; 
NCT02336815), in which 122 patients with relapsed and refractory patients were treated with 
twice-weekly selinexor (80mg) in combination with dexamethasone (20mg). The most 
commonly reported hematological treatment emergent adverse events (TEAEs) were 
thrombocytopenia (74%), anemia (59%), leukopenia (28%), and neutropenia (34%). The most 
common non-hematological TEAEs were nausea (72%), fatigue (73%), decreased appetite 
(53%), diarrhea (44%) and vomiting (41%). Common (>10%) grade 3 or greater AEs included 
thrombocytopenia, fatigue, anemia, hyponatremia, neutropenia, leukopenia and lymphopenia. 
These results are generally consistent with the overall TEAE results reported for all selinexor 
studies in patients with hematological malignancies. 


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2.4.1.2 Clarithromycin 
Based on pooled data across all indications, the most frequent adverse reactions for both adult 
and pediatric populations observed in clinical trials of clarithromycin are abdominal pain (5%), 
diarrhea (8%), nausea (11%), vomiting (6%) and dysgeusia (8%). Also reported were 
dyspepsia, liver function test abnormalities, anaphylactic reaction, candidiasis, headache, 
insomnia, and rash.  
In a trial of clarithromycin use in immunocompromised adult patients, 8% who received 
clarithromycin 500 mg twice a day and 12% of the patients who received 1000 mg twice a day 
discontinued therapy due to drug related adverse reactions during the first 12 weeks of therapy. 
Adverse reactions leading to discontinuation in at least two patients included nausea, vomiting, 
abdominal pain, diarrhea, rash, and asthenia. In the first 12 weeks of starting on clarithromycin 
500 mg twice a day, 5% of patients had an increase > 5 times the upper limit of normal in liver 
function tests. This includes only patients with baseline values within the normal range or 
borderline low. 
In one clinical trial evaluating treatment with clarithromycin on outcomes in patients with 
coronary artery disease, an increase in risk of all-cause mortality was observed in patients 
randomized to clarithromycin. Clarithromycin for treatment of coronary artery disease is not an 
approved indication. Patients were treated with clarithromycin or placebo for 14 days and 
observed for primary outcome events (e.g., all-cause mortality or non-fatal cardiac events) for 
several years. A numerically higher number of primary outcome events in patients randomized 
to receive clarithromycin was observed with a hazard ratio of 1.06 (95% confidence interval 0.98 
to 1.14). However, at follow-up 10 years post-treatment, there were 866 (40%) deaths in the 
clarithromycin group and 815 (37%) deaths in the placebo group that represented a hazard ratio 
for all-cause mortality of 1.10 (95% confidence interval 1.00 to 1.21). The difference in the 
number of deaths emerged after one year or more after the end of treatment. The cause of the 
difference in all-cause mortality has not been established. Other epidemiologic studies 
evaluating this risk have shown variable results. 
 
2.4.1.3 Pomalidomide and Dexamethasone 
The U.S. FDA granted accelerated approval for pomalidomide on the basis of the Phase 2 study 
(MM-002), comparing pomalidomide alone or in combination with dexamethasone for the 
treatment of relapsed and refractory MM. The most common hematologic Grade 3/4 AEs were 
neutropenia (41% vs. 48%), anemia (22% vs. 24%), and thrombocytopenia (19% vs. 22%). The 
most common nonhematologic AE was pneumonia (22% versus 15%) and fatigue (14% versus 
11%) in the pomalidomide and dexamethasone arm compared to the pomalidomide alone arm, 
respectively. The frequency of febrile neutropenia was low (3% versus 5%), as was the 
incidence of DVT (2% versus 3%). There were no grade 3 or 4 events of peripheral neuropathy 
reported. The EMA granted approval for pomalidomide in Europe based on the phase 3 study 
(MM-003/NIMBUS trial) which evaluated the combination of pomalidomide with low-dose 
dexamethasone vs. high-dose dexamethasone in refractory or relapsed and refractory MM 
subjects. In the pomalidomide plus low-dose dexamethasone and high-dose dexamethasone 
arms, respectively, the most common grade 3–4 hematological adverse events were 
neutropenia (48% vs 16%), anemia (33% vs 37%), and thrombocytopenia (22% vs 26%). The 
most common grade 3–4 non-hematological adverse events were pneumonia (13% vs 8%), 
bone pain (7% vs 5%), and fatigue (5% vs 6%). 


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2.4.1.4 Selinexor in combination with pomalidomide and dexamethasone  
The preliminary results of a phase 1b/2 clinical trial reported the most common AEs 
(≥20%) suspected to be related to once-weekly selinexor in combination with pomalidomide and 
dexamethasone to be neutropenia (67%), thrombocytopenia (52%), nausea (52%), fatigue 
(52%), anemia (45%), weight loss (39%), anorexia (36%), leukopenia (36%), vomiting (27%), 
diarrhea (24%), hyponatremia (21%) and dizziness (18%). Most of these effects can be 
managed effectively with dose modification and/or supportive care initiated prior to first dosing. 
There were three grade 5 adverse events: one intracranial hemorrhage in cycle 2; one febrile 
neutropenia in cycle 1 and one pneumonia in cycle 5.  
 
2.4.1.5 Clarithromycin in combination with other immunomodulatory agents 
Results from a case-matched study comparing the addition of clarithromycin to lenalidomide 
and dexamethasone to lenalidomide and dexamethasone for the treatment of newly diagnosed 
MM showed 76.4% vs 58.3% of patients at least one grade 3 or higher AE. The frequency of 
neutropenia was similar between the two groups while thrombocytopenia was significantly more 
frequent with the addition of clarithromycin (23.6% vs 8.3%, p = 0.01). One of the most common 
non-hematological toxicities reported with clarithromycin was steroid related myopathy (9.7% vs 
0%, p = 0.01), while there was no difference in the rate of infections (9.7% vs 16.7%, p = 0.22) 
or dermatological toxicities (4.2% vs 12.5%, p = 0.13). The rate of thromboembolic events (VTE) 
was similar in the two groups (9.7% vs 12.5%, p = 0.6). There were two treatment-related 
deaths in the clarithromycin group, one due to pulmonary embolism and one due to myocardial 
infarction. 
The preliminary results of a phase 3 clinical trial of lenalidomide and dexamethasone with or 
without clarithromycin showed a significantly higher incidence of treatment-related deaths in the 
clarithromycin-containing arm, mostly due to infections and affecting primarily patients 75 years 
of age or older. 
2.4.1.6 Reproductive Risks 
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 that patients understand the need to use birth control while on this study. Female 
patients of childbearing potential must agree to use a highly effective method of contraception 
(see “Prevention of pregnancy”) and have a negative serum pregnancy test at screening and a 
negative urine pregnancy test prior to receiving the first dose of study treatment. Male patients 
must use an effective barrier method of contraception if sexually active with a female of 
childbearing potential, as per the requirements of the Risk Evaluation and Mitigation Strategy 
(REMS) program. 
2.4.1.6.1 Selinexor 
Macroscopic and microscopic changes in reproductive organs were noted during rat and 
monkey toxicology studies, most of which partially or fully resolved during the recovery period. 
The long-term effects of these changes on reproductive potential are unknown. Secondary 
developmental effects due to reduced maternal body weights were also noted during a study on 
rat embryo/fetal development. It is unknown whether similar effect may occur in humans. As it is 


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unknown whether selinexor might have reproductive toxicity in humans, patients must agree to 
use effective contraception during the study and for 3 months after the end of treatment. 
2.4.1.6.2 Clarithromycin 
Based on findings from animal studies, clarithromycin is not recommended for use in pregnant 
women except in clinical circumstances where no alternative therapy is appropriate. If 
pregnancy occurs while taking clarithromycin, the patient should be apprised of the potential 
hazard to the fetus. Clarithromycin demonstrated adverse effects on pregnancy outcome and/or 
embryo fetal development, including fetal malformations, in pregnant animals administered oral 
clarithromycin. Administration of clarithromycin resulted in testicular atrophy in rats, dogs and 
monkeys. Limited data from a small number of published human studies with clarithromycin use 
during pregnancy are insufficient to inform drug-associated risks of major birth defects, 
miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, 
administration of oral clarithromycin to pregnant mice, rats, rabbits, and monkeys during the 
period of organogenesis produced malformations in rats (cardiovascular anomalies) and mice 
(cleft palate) at clinically relevant doses based on body surface area comparison. Fetal effects 
in mice, rats, and monkeys (e.g., reduced fetal survival, body weight, body weight gain) and 
implantation losses in rabbits were generally considered to be secondary to maternal toxicity. 
The estimated background risk of major birth defects and miscarriage for the indicated 
population is unknown. All pregnancies have a background risk of birth defect, loss, or other 
adverse outcomes. In the U.S. general population, the estimated background risk of major birth 
defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, 
respectively. 
2.4.1.6.3 Pomalidomide 
Pomalidomide is structurally and pharmacologically related to thalidomide, a known teratogen, 
and is contraindicated in pregnant women and women who are at risk of becoming pregnant. 
The pomalidomide product monographs/labeling contain the following boxed-text warning: 
EMBRYO-FETAL TOXICITY and VENOUS AND ARTERIAL THROMBOEMBOLISM (See full 
prescribing information for complete boxed warning EMBRYO-FETAL TOXICITY)· POMALYST 
(pomalidomide) is contraindicated in pregnancy. POMALYST is a thalidomide analogue. 
Thalidomide is a known human teratogen that causes severe life-threatening birth defects.  For 
females of reproductive potential: Exclude pregnancy before start of treatment. Prevent 
pregnancy during treatment by the use of 2 reliable methods of contraception. POMALYST is 
available only through a restricted program called POMALYST REMS®. 
In order to prevent pregnant women from being exposed to pomalidomide, a Risk Evaluation 
and Mitigation Strategy (REMS) called POMALYST REMS, has been established by the 
manufacturer of pomalidomide. In order to participate in this study, investigators and patients 
must agree to comply with the requirements of the plans. 
2.4.1.6.4 Dexamethasone 
Animal studies have shown evidence of teratogenicity due to systemic corticosteroids. There 
are no controlled data in human pregnancy. Dexamethasone is only recommended for use 
during pregnancy when there are no alternatives and benefit outweighs risk.  
 
2.4.2 Known Potential Benefits  
 


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2.4.2.1 Selinexor 
Selective inhibitor of nuclear export (SINE) compounds, a new generation of exportin 1 (XPO1) 
inhibitors, were designed as drug-like small molecules that selectively inhibit XPO1 in order to 
increase efficacy and reduce toxicity secondary to non-specific binding and off-target effects. 
Mechanistic studies show that SINE compounds induce nuclear localization and activation of 
multiple tumor suppressor proteins (TSPs), along with reduction in oncoprotein levels (e.g., c-
Myc and the anti-apoptotic protein BCL-XL) leading to rapid apoptosis of MM cells. 
Selinexor is an orally bioavailable SINE compound that specifically blocks XPO1, with anti-MM 
activity demonstrated in preclinical studies. In a phase 1 clinical trial (NCT01607892) of 
selinexor in patients with advanced hematological malignancies, 25 patients with heavily 
pretreated MM (22) or Waldenstrom macroglobulinemia (3) were administered selinexor (3-60 
mg/m2) in 8 or 10 doses per 28-day cycle.11 In the dose-expansion phase, 59 patients with MM 
received selinexor at 45 or 60 mg/m2 with dexamethasone 20 mg, twice weekly in 28-day 
cycles, or selinexor (40 or 60 mg flat dose) without corticosteroids in 21-day cycles. The most 
common non-hematologic adverse events (AEs) were nausea (75%), fatigue (70%), anorexia 
(64%), vomiting (43%), weight loss (32%), and diarrhea (32%), which were primarily grade 1 or 
2. The most common grade 3 or 4 AEs were hematologic, particularly thrombocytopenia (45%). 
Single-agent selinexor showed modest efficacy with an objective response rate (ORR) of 4% 
and a clinical benefit rate of 21%. In contrast, the addition of dexamethasone increased the 
ORR with all responses of greater than partial response occurring in the 45 mg/m2 selinexor 
plus dexamethasone 20 mg twice weekly cohort (ORR = 50%). Furthermore, 46% of all patients 
showed a reduction in MM markers from baseline. These findings demonstrated the activity of 
selinexor in combination with dexamethasone in heavily pretreated MM.   
In a phase 2 clinical trial (NCT02336815), 122 patients with triple-class refractory MM received 
selinexor (80mg) and dexamethasone (20mg) twice weekly.9 A partial response or better was 
observed in 26% of patients, including two stringent complete responses; 39% of patients had a 
minimal response or better. The median duration of response was 4.4 months, median 
progression-free survival was 3.7 months, and median overall survival was 8.6 months. Fatigue, 
nausea, and decreased appetite were common and were typically grade 1 or 2 (grade 3 events 
were noted in up to 25% of patients, and no grade 4 events were reported). Thrombocytopenia 
occurred in 73% of the patients (grade 3 in 25% and grade 4 in 33%). Thrombocytopenia led to 
bleeding events of grade 3 or higher in 6 patients. This trial showed that the combination of 
selinexor with dexamethasone resulted in objective treatment responses in patients with triple-
class refractory multiple myeloma.  
The phase 1/2 clinical trial of selinexor in combination with backbone treatments for 
relapsed/refractory multiple myeloma (STOMP; NCT02343042) is currently evaluating the 
efficacy and safety of multiple combinations. Preliminary results from the cohort of patients 
receiving selinexor, pomalidomide and dexamethasone were presented at the 61st American 
Society of Hematology Annual Meeting on December 7, 2019.10 Oral selinexor was evaluated in 
a once-weekly or twice-weekly schedule with low-dose dexamethasone and escalating doses of 
pomalidomide 2, 3 or 4 mg PO (days 1-21). Fifty-one patients with relapsed/refractory multiple 
myeloma had been enrolled. Common hematologic treatment-related adverse events (TRAEs) 
included neutropenia, thrombocytopenia, anemia, and leukopenia; while non-hematologic 
TRAEs included nausea, fatigue, decreased appetite, weight decreased, diarrhea, and vomiting. 
Lower rates of ≥grade 3 thrombocytopenia (27% vs 44%) were observed in the weekly vs twice-
weekly dosing. Among 46 evaluable patients for efficacy, the ORR was 50% (56% in patients 


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who were pomalidomide-naïve), 15% achieved a VGPR, and the median PFS was 10.4 months 
(12.2 months in patients who were pomalidomide-naïve). Once-weekly selinexor can be safely 
combined with pomalidomide and low-dose dexamethasone in heavily pretreated patients with 
MM. The recommended phase 2 dose was defined as selinexor 60mg once-weekly, 
pomalidomide 4mg daily (days 1-21) and dexamethasone 40 mg once-weekly. 
On July 3, 2019, the Food and Drug Administration granted accelerated approval to selinexor in 
combination with dexamethasone for adult patients with relapsed/refractory multiple MM who 
have received at least four prior therapies and whose disease is refractory to at least two 
proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal 
antibody. 
 
2.4.2.2 Clarithromycin 
The semisynthetic macrolide antibiotic, clarithromycin, is indicated for the treatment of mild to 
moderate infections caused by susceptible bacteria. In the treatment of patients with multiple 
myeloma, clarithromycin has resulted in deep responses when added to dexamethasone in 
combination with thalidomide, lenalidomide or pomalidomide.3-8 It optimizes the pharmacologic 
effects of glucocorticoids by increasing the area under the curve and the maximum 
concentration levels of some steroids through inhibition of CYP3A4.12 It has an 
immunomodulatory effect and may have direct antineoplastic properties by synergistically 
decreasing the secretion of tumor necrosis factor-α and interleukin-6 through the inhibition of 
ERK1/2 and AKT in combination with other immunomodulatory drugs like thalidomide and 
lenalidomide.13 Other studies have suggested that clarithromycin inhibits autophagy, increasing 
the cytotoxic effect of immunomodulatory drugs on MM cells.14  
The phase 2 clinical trial (NCT00151203) evaluated the safety and efficacy of combination 
therapy with clarithromycin, lenalidomide and dexamethasone for the treatment of newly 
diagnosed MM.7  Of 72 patients enrolled, 90% achieved an objective response of which 39% 
were CR or better, and an actuarial 2-year event-free survival of 97%. The most common grade 
≥3 hematologic AEs were neutropenia (19.4%), anemia (13.8%), and thrombocytopenia 
(22.2%); common non-hematologic grade ≥3 AEs were myopathy (11.1%), rash (5.6%), 
diverticular abscess (5.6%), and thromboembolic events (12.5%). 
A case–matched study compared the addition of clarithromycin to lenalidomide and 
dexamethasone vs lenalidomide and dexamethasone for the treatment of newly diagnosed 
myeloma.4 It retrospectively analyzed the data obtained for the 72 patients enrolled in the above 
study and 72 pair mates selected among patients seen at the Mayo Clinic who received 
lenalidomide and dexamethasone. On an intention-to-treat analysis, CR rates (45.8% vs 13.9%, 
p<0.001) and ≥VGPR rates (73.6% vs 33.3%, p<0.001) were significantly higher with the 
addition of clarithromycin. Time-to-progression (median 48.3 vs 27.5 months, p=0.071), and 
progression-free survival (median 48.3 vs 27.5 months, p=0.044) also favored the addition of 
clarithromycin, however, overall survival was similar between both groups (3-year OS: 89.7% vs 
73.0%, p=0.17). 
A phase 3 clinical trial (NCT02575144) randomized 286 patients with newly diagnosed MM, 
transplant ineligible, to receive lenalidomide (daily for 21 days every 28 days) and weekly 
dexamethasone with or without twice-daily clarithromycin.15 The preliminary results were 
presented at the 61st American Society of Hematology Annual Meeting on December 9, 2019. 
The addition of clarithromycin to lenalidomide and dexamethasone significantly increased the 
depth of response (≥CR 21% vs 11%; p = 0.037) but it was not associated with an improved 


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PFS and OS due to a higher proportion of treatment-related deaths in the clarithromycin-
containing arm, mostly infectious, and affecting primarily patients ≥75 years of age. 
The addition of clarithromycin to pomalidomide and dexamethasone for the treatment of patients 
with relapsed/refractory multiple myeloma previously exposed to lenalidomide was evaluated in 
a phase 2 study (NCT01159574).6 The median number of prior therapies was 5 (range 3-15). 
The overall response rate (ORR) was 60% with 23% achieving at least a very good partial 
response. The median PFS was 7.7 months and the median overall survival was 19.2 
months. The most common grade ≥3 toxicities included neutropenia (58%), thrombocytopenia 
(31%), and anemia (28%). 
 
2.4.2.3 Pomalidomide 
Pomalidomide is an immunomodulatory drug approved for the treatment of patients with RRMM. 
In combination with dexamethasone, pomalidomide has been shown to be effective in patients 
with relapsed/refractory MM previously treated with bortezomib and/or lenalidomide, with ORR 
ranging from 31 to 47% (ORR pooled estimate 35%; 95% confidence interval: 30-42%).16-20 
Toxicity is mostly hematologic, with grade ≥3 neutropenia occurring in 40-48%, anemia in 22-
33%, and thrombocytopenia in 19-22%; while non-hematologic grade ≥3 toxicity included 
pneumonia (13-22%) and fatigue (5-14%).19,20  
More recently, multiple phase 2 and 3 clinical trials have demonstrated the efficacy of three-drug 
regimens including pomalidomide and dexamethasone in combination with clarithromycin (ORR 
60%), carfilzomib (ORR 62%), ixazomib (ORR 48%), cyclophosphamide (ORR 51-65%), 
elotuzumab (ORR 53%), daratumumab (ORR 60%), or isatuximab (ORR 60%) (ORR pooled 
estimate 58%; 95% confidence interval: 54-62%).6,21-27 These studies reported a median PFS of 
7.7 to 11.5 months (median 9.9 months). 
 
2.4.3 Assessment of Potential Risks and Benefits 
 
Effective therapies for patients with relapsed/refractory MM remain a current and growing unmet 
medical need. Based on the previously described results of combination therapy with 
clarithromycin, pomalidomide and dexamethasone in patients with RRMM and the preliminary 
results of selinexor in combination with pomalidomide and dexamethasone, we propose the 
addition of selinexor to clarithromycin, pomalidomide and dexamethasone for the treatment of 
patients with RRMM. The risks associated with participation in this trial are commensurate with 
the expected risks of other potential therapies in the same setting and are reasonable given the 
potential benefit to patients. If the addition of selinexor to clarithromycin, pomalidomide and 
dexamethasone is as effective in patients with RRMM as anticipated, the achievement of 
deeper and more durable responses with an all-oral regimen could lead to improved survival 
and quality of life. 
 
2.5 Correlative Studies Background 
 
Not applicable. 
 
3. Study Design 
 
3.1 Overall Design 
 


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This is a phase 2, open-label, single-arm study to assess the efficacy and safety of selinexor 
in combination with clarithromycin, pomalidomide and dexamethasone (ClaSPd) in patients 
with RRMM previously treated with at least one line of therapy.  
 
We hypothesize the addition of selinexor to clarithromycin, pomalidomide and 
dexamethasone will increase the overall response rate of patients with RRMM. Patients who 
sign informed consent and fulfill all eligibility criteria will be enrolled. A Simon's two-stage 
design will be used. In the first stage, 18 patients will be accrued. If there are 6 or fewer 
responses in these 18 patients, the study will be stopped. Otherwise, 8 additional patients 
will be accrued for a total of 26. The null hypothesis that the true ORR is ≤ 35% will be 
tested against a one-sided alternative that the true ORR ≥ 60% (see Background section for 
further details regarding a pooled estimate of the ORR in studies of pomalidomide-
containing two- and three-drug regimens). The null hypothesis will be rejected if 14 or more 
responses are observed in 26 patients. 
 
Study treatment – selinexor, clarithromycin, pomalidomide and dexamethasone (ClaSPd): 
 
Selinexor 60 mg PO on days 1, 8, and 15 of a 28-day cycle. 
Clarithromycin 500 mg PO twice a day on days 1-28 of a 28-day cycle. 
Pomalidomide 4 mg PO daily on days 1-21 of a 28-day cycle. 
Dexamethasone 40 mg PO on days 1, 8, 15 and 22 of a 28-day cycle. 
 
At the end of every cycle (which may coincide with day 1 of the next cycle), response and 
toxicity will be evaluated. Patients will receive the study treatment until disease progression, 
death, or toxicity that cannot be managed with medical care. Safety analyses will be 
performed on patients who received at least one dose of the study treatment. 
 
Subjects will be screened and enrolled at Weill Cornell Medicine in New York, NY. There is 
no intention to include sites outside of the United States. 
 
3.2 Scientific Rationale for Study Design 
A two-stage design has been selected to in order to allow for the early termination of the trial 
when the treatment seems to be inactive, minimizing the number of subjects exposed to the 
therapy. This is an open-label, single-arm study without a control group, designed to explore 
the efficacy and safety of ClaSPd for the treatment of patients with RRMM previously treated 
with two to four prior lines of therapy. ClaSPd allows for the addition of the recently 
approved agent, selinexor, to the combination of clarithromycin, pomalidomide and 
dexamethasone, an effective regiment for the treatment of RRMM.   
 
3.3 Justification for Dose  
 
The selected dose of selinexor, pomalidomide and dexamethasone was derived from 
preliminary efficacy and safety data of the expansion phase of arm 1 of STORM 
(NCT02343042), as noted above. The dose of clarithromycin is in accordance to prior 
studies, including phase 3 randomized clinical trial (NCT02575144) evaluating lenalidomide 
and weekly dexamethasone with or without twice-daily clarithromycin, as well as the addition 
of clarithromycin to pomalidomide and dexamethasone (NCT01159574); further details of 
these studies have been noted above.  
 


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3.4 End of Study Definition 
 
A participant is considered to have completed the study after completing all phases of the 
study including the last duration of response/survival follow-up assessment as stated in the 
Schedule of Activities (SoA). The end of the study is defined as completion of the last visit or 
procedure shown in the SoA in the trial globally. 
 
4. Subject Selection 
 
4.1 Study Population 
 
Adult subjects (18 to 74 years of age) with a diagnosis of RRMM who meet the inclusion and 
exclusion criteria will be eligible for participation in this study.   
 
4.2 Inclusion Criteria 
 
1. Written informed consent in accordance with federal, local, and institutional guidelines. 
2. Age ≥18 and <75 years at the time of informed consent. 
3. Histologically confirmed diagnosis of MM. 
4. Symptomatic MM as per IMWG guidelines.  
5. Measurable disease as defined by at least one of the following: 
a. Serum M-protein ≥ 0.5 g/dL by serum protein electrophoresis (SPEP) or, for IgA 
myeloma, by quantitative IgA, and/or 
b. Urinary M-protein excretion at least 200 mg/24 hours, and/or 
c. Serum FLC ≥ 100 mg/L, provided that FLC ratio is abnormal, and/or 
d. If serum protein electrophoresis is felt to be unreliable for routine M-protein 
measurement (e.g., for IgA MM), then quantitative Ig levels by nephelometry or 
turbidometry are acceptable. 
6. Relapsed and refractory MM with: 
a. Documented evidence of PD after achieving at least SD for ≥ 1 cycle during a 
previous MM regimen (i.e., relapsed MM), and 
b. ≤ 25% response (i.e., patients never achieved ≥ MR) or PD during or within 60 
days from the end of the most recent MM regimen (i.e., refractory MM). 
7. Previously received two to four prior lines of therapy and be pomalidomide-naïve.  
 
4.3 Exclusion Criteria  
 
1. Documented active systemic light chain amyloidosis. 
2. Active plasma cell leukemia. 
3. Eastern Cooperative Oncology Group (ECOG) Performance Status greater than 2. 
4. Persistent non-hematological toxicity (except for peripheral neuropathy) from a prior 
treatment which has not resolved to at least Grade 2 or better by Cycle 1 Day 1 (C1D1).  
5. Severe hepatic dysfunction with either:  
a. Total bilirubin > 1.5x ULN (> 3x ULN in subjects with Gilbert’s syndrome 
[hereditary indirect hyperbilirubinemia]), and/or 
b. AST and/or ALT > 2.5x ULN 
6. Severe renal dysfunction with an estimated creatinine clearance (CrCl) of < 15 mL/min 
calculated using the Cockcroft and Gault formula. 
7. Impaired hematopoietic function with either:  
a. White blood cell count < 1,500/mm3, and/or 


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b. Absolute neutrophil count < 1000/mm3, and/or 
c. Hemoglobin < 8.0 g/dL, and/or 
d. Platelet count < 100,000/mm3 (for patients in whom ≥ 50% of bone marrow 
nucleated cells are plasma cells, platelets ≥ 75,000/mm3 are acceptable).  
8. Blood (or blood product) transfusions or blood growth factors within 7 days of C1D1.  
a. Use of hematopoietic growth factor support is acceptable, including 
erythropoietin (EPO), darbepoetin, granulocyte-colony stimulating factor (G-
CSF), granulocyte macrophage colony stimulating factor (GM-CSF), and platelet 
stimulators (e.g., eltrombopag or romiplostim). However, patients must be 
platelet transfusion independent for > 1 week in order to be enrolled in the study. 
9. Radiation, chemotherapy or immunotherapy, or any other anticancer therapy within 2 
weeks prior to C1D1, or radio-immunotherapy within 6 weeks prior to C1D1. Patients on 
long-term glucocorticoids during Screening do not require a washout period. Prior 
radiation is permitted for treatment of fractures or to prevent fractures, as well as for pain 
management. 
10. Patients with history of spinal cord compression with residual paraplegia. 
11. Treatment with an investigational anti-cancer therapy within 3 weeks prior to C1D1. 
12. Prior autologous stem cell transplantation < 1 month, or allogeneic stem cell 
transplantation < 3 months prior to C1D1. 
13. Active graft versus host disease after allogeneic stem cell transplantation. 
14. Life expectancy < 3 months. 
15. Major surgery within 4 weeks prior to C1D1. 
16. Active, unstable cardiovascular function with either: 
a. Symptomatic ischemia 
b. Uncontrolled clinically significant conduction abnormalities (e.g., patients with 
ventricular tachycardia on antiarrhythmics are excluded; patients with 1st degree 
atrioventricular (AV) block or asymptomatic left anterior fascicular block/right 
bundle branch block (LAFB/RBBB) will not be excluded) 
c. Congestive heart failure (CHF) of New York Heart Association (NYHA) Class ≥ 3 
d. Myocardial infarction (MI) within 6 months prior to C1D1 
e. Screening 12-lead ECG showing a baseline QT interval as corrected by Bazett’s 
formula (QTc) > 470 msec 
17. Uncontrolled active hypertension 
18. Venous thromboembolism within 6 months prior to C1D1 or a known inherited 
thrombophilia 
19. Inability to receive either prophylactic or therapeutic anticoagulation as determined 
appropriate by the Investigator 
20. Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals 
within one week prior to C1D1 
21. Any active gastrointestinal dysfunction that prevents the patient from swallowing tablets 
or interferes with absorption of study treatment 
22. Currently pregnant or breastfeeding. Lactating females must agree not to breast feed 
while receiving selinexor, pomalidomide and/or clarithromycin 
23. A serious psychiatric or medical condition which, in the opinion of the Investigator, could 
interfere with treatment 
24. Hypersensitivity or contraindication to selinexor, pomalidomide, dexamethasone and/or 
clarithromycin 
25. Prior exposure to a SINE compound, including selinexor 
26. Concomitant use of any strong CYP3A4 and/or CYP1A2 inhibitors (see Appendix 1) or 
other restricted drugs (see section 7.8.11) 


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27. Unable to obtain commercial clarithromycin, pomalidomide and dexamethasone through 
a regular and/or specialty pharmacy. 
28. Unable or unwilling to register into the mandatory POMALYST REMSTM program and 
comply with its requirements. 
29. Male and female patients unwilling or unable to use effective methods of contraception 
throughout the study and for three months following the last dose. 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. 
a. Female patients of childbearing potential must agree to use dual methods of 
contraception and have a negative serum pregnancy test at Screening. 
b. Male patients must use an effective barrier method of contraception if sexually 
active with a female of child-bearing potential.  
 
4.4 Lifestyle Considerations 
 
Not applicable.  
 
4.5 Screen Failures  
 
Screen failures are defined as participants who consent to participate in the clinical trial but 
are not subsequently assigned to the study intervention or entered in the study. A minimal 
set of screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse 
event. 
 
Individuals who do not meet the criteria for participation in this trial (screen failure) because 
of impaired liver, renal or hematopoietic function may be rescreened. Rescreened 
participants should be assigned the same participant number as for the initial screening. 
 
4.6 Strategies for Recruitment and Retention 
 
 
Participants will be recruited by their primary oncologist at Weill Cornell Medicine and 
NewYork Presbyterian-Brooklyn Methodist Hospital. We estimate a study sample size of 26 
participants without gender, race, ethnicity or age targets, and an anticipated accrual rate of 
2 subjects per month. 
 
Potential participants will be identified by their primary oncologist and approached by a co-
investigator; the study coordinators will keep records of monthly screening and enrollment 
logs at each site. No other recruitment strategies are planned. Vulnerable participants are 
not eligible for this study. Participants will receive a $50 stipend for each completed study 
visit at Weill Cornell Medicine and NewYork Presbyterian-Brooklyn Methodist Hospital. The 
stipend will be provided via Clincard.  
 
5. Registration Procedures 
 
5.1 Subject Registration (WCM only) 
 


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Subjects will be registered within the WRG-CT as per the standard operating procedure 
for Subject Registration.  
 
 
 
5.2 Subject Registration (Sub-sites) 
 
Study participants will be centrally registered with the Weill Cornell Medicine Joint 
Clinical Trials Office (JCTO).  To register a new study subject, email the following 
documents to JCTOIIT@med.cornell.edu : 
 
• 
Completed WCM subject registration form 
• 
First and last page of the fully executed informed consent form, plus additional pages 
if checkboxes for correlative studies are required 
• 
Fully executed HIPAA research authorization form 
• 
Eligibility checklist signed and dated by investigator and research nurse 
• 
Documentation of any eligibility waivers granted  
• 
Source documentation to verify eligibility  
 
Note that attachments larger than 4.5 MB are not accepted, so larger attachments 
should be split into more than one email. Central registration information is reviewed and 
entered into the REDCap database.   
 
6. Study Procedures 
 
6.1 Schedule of Assessments 
 
Table 2. Schedule of Activities (SOA) 
 
Activity/ 
Assessment 
Screening 
C 1 
C 2 
C ≥ 3 
EoT Visit 
FU 
Assessment 
DOR and 
Survival FU 
D-21 to D-1 
D1 
D8 ± 1d 
D15 ± 1d 
D1 ± 2d 
D15 ± 2d 
D1 ± 2d 
≤14d after 
LD 
30d after 
LD ± 7d 
every 3m 
after LD for 
12m ± 14d 
Informed consent  
X 
  
  
  
  
  
  
  
  
  
Medication dispensation (1) 
  
X 
  
  
X 
  
X 
  
  
  
Patient History 
 
  
  
  
  
          
Inclusion and exclusion criteria 
X 
  
  
  
  
  
  
  
  
  
Demographics 
X 
  
  
  
  
  
  
  
  
  
Medical history (2) 
X 
  
  
  
  
  
  
  
  
  
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Concomitant medications  
X 
X 
  
  
X 
  
X 
X 
  
  
Dose intensity (3) 
  
X 
  
  
X 
  
X 
X 
  
  


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QOL assessment (4) 
X 
X 
  
  
X 
  
X 
X 
X 
  
Telephone contact (5) 
  
  
  
  
  
  
  
  
X 
X 
Physical Examination 
 
  
  
  
  
          
Patient height 
X 
  
  
  
  
  
  
  
  
  
Patient weight 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
Vital signs (BP, pulse, 
temperature) 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
Complete physical examination 
X 
  
  
  
  
  
  
X 
  
  
Symptom-directed physical 
examination 
  
X 
X 
X 
X 
X 
X 
  
  
  
12-lead ECG 
X 
  
  
  
  
  
  
  
  
ECOG Performance Status 
X 
  
  
X 
  
X 
X 
  
  
Clinical Labs 
  
 
 
  
  
  
    
      
CBC with differential 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
TSH 
X 
  
  
  
  
  
  
  
  
Complete serum chemistry (6) 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
Pregnancy test (7) 
X 
X 
  
  
X 
  
X 
X 
  
  
Multiple Myeloma Disease 
Assessments  
 
 
 
SPEP and serum immunofixation 
(8) 
X 
X 
  
  
X 
  
X 
X 
  
X* 
UPEP (24-hr urine) and urine 
immunofixation (8) 
X 
X* 
  
  
X 
  
X 
X 
  
X* 
Quantitative Ig levels (8) 
X 
X 
  
  
X 
  
X 
X 
  
X* 
Serum FLC (8) 
X 
X 
  
  
X 
  
X 
X 
  
X* 
β2-microglobulin 
X 
  
  
  
  
  
  
  
  
  
Skeletal survey (9) 
X 
  
  
  
X* 
  
X* 
X* 
  
X* 
Plasmacytoma assessment (10) 
X 
X* 
  
  
X* 
  
X* 
X* 
  
X* 
Bone marrow biopsy and aspirate 
(11) 
X 
  
  
  
X* 
  
X* 
X* 
  
  
 
* indicates that additional schedule information is provided in the footnotes. Merged cells 
indicate that the procedure may be performed during either Screening or the C1D1 visit. 
Abbreviations: BP = blood pressure; BSA = body surface area; CBC = complete blood count; D 
= day; DOR = duration of response; ECG = electrocardiogram; ECOG = Eastern Cooperative 
Oncology Group; EoT = End of Treatment; FLC = free light chain; FU = follow-up; Ig = 
immunoglobulin; LD = last dose; M = month; MM = multiple myeloma; QOL = quality of life; 
SPEP = serum protein electrophoresis; UPEP = urine protein electrophoresis; Y = year. 
 
Footnotes: 
1. Only enough selinexor for 1 cycle will be provided to the patient at the beginning of each 
cycle. 


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2. Includes baseline symptoms as well as a detailed history of prior cancer therapies, 
especially MM therapies, including start and stop dates, disease progression during or 
after therapy, as well as discontinuations due to intolerability or any other serious illness. 
Collect data on cigarette smoking status and, if current smoker, counsel regarding 
smoking cessation per institutional guidelines. 
3. Dose intensity assessments involve the use of subject medication diaries, provided on 
C1D1 and assessed on day 1 of every cycle beginning at cycle 2.  
4. QOL assessment as measured by the Functional Assessment of Cancer Therapy - MM 
(FACT-MM). See Appendix 6. 
5. Telephone call (or visit) for:  
a. Follow-up assessment to evaluate adverse events. 
b. Durability of Response and Survival Follow-up: After treatment discontinuation, if 
possible and feasible for patients whose disease is not progressing, a telephone 
call will be made to the patient (or the patient’s family) every 3 months for 18 
months to inquire about the patient’s survival, MM status, and information on any 
antineoplastic therapies utilized since discontinuation of study treatment, as well 
as available SPEP with serum immunofixation, UPEP with urine immunofixation, 
serum FLC, quantitative Ig levels, and plasmacytoma assessment when clinically 
appropriate. 
6. Complete serum chemistry must include serum potassium and magnesium levels. 
7. For women of childbearing potential, a serum hCG pregnancy test must be performed 
during Screening and at EoT Visit. After an initial negative serum hCG pregnancy test 
during Screening, urine pregnancy tests may be performed instead of serum testing. 
Women of childbearing potential require two negative pregnancy tests prior to receiving 
the first dose of study treatment (at Screening and at C1D1). 
8. Response criteria include SPEP, serum immunofixation, quantitative Ig levels, and 
serum FLC assay on C1D1 and measurements must be taken either on Day -1 or pre-
dose on C1D1. These are in addition to the disease assessments performed during 
Screening for enrollment. UPEP (24-hr urine) and urine immunofixation may be omitted 
on C1D1 if performed adequately during screening within ≤ 7 days. 
9. Skeletal survey to be performed using X-rays, MRI, CT or PET/CT per institutional 
guidelines. Bone lesions seen at Screening should be re-assessed during the study 
using the same imaging modality that was used at Screening. Repeat scans should be 
done at a clinically appropriate frequency, as determined by the Investigator. 
10. If plasmacytomas are detected at baseline by physical examination, they should be re-
assessed during the physical exam on D1 of each cycle and at the EoT visit. 
11. Bone marrow samples:  
a. At Screening, aspirate and biopsy for:  
i. Morphology, flow cytometry and FISH analysis to confirm diagnosis and 
classification 
ii. Clonotype identification for subsequent MRD analysis 
b. At suspicion of CR (negative serum and urine immunofixation), aspirate and 
biopsy for:  
i. Morphology, flow cytometry and FISH analysis to confirm CR and/or sCR 
ii. Aspirate for MRD analysis  
c. At suspicion of progressive disease, if clinically appropriate, aspirate and biopsy 
for:  
i. Morphology, flow cytometry and FISH analysis to confirm progressive 
disease 


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6.1.1 Screening Visit (-21 to -1 days before start of treatment) 
 
• 
Informed consent 
• 
Inclusion and exclusion criteria 
• 
Demographics 
• 
Medical history 
• 
Adverse events 
• 
Concomitant medications  
• 
QOL assessment 
• 
Height 
• 
Weight 
• 
Vital signs 
• 
Complete physical exam 
• 
12-lead ECG (may be performed on C1D1) 
• 
ECOG PS (may be performed on C1D1) 
• 
CBC with differential 
• 
TSH (may be performed on C1D1) 
• 
Complete serum chemistry 
• 
Pregnancy test 
• 
SPEP and serum immunofixation 
• 
UPEP (24-hr urine) and urine immunofixation 
• 
Quantitative Ig levels 
• 
Serum FLC 
• 
LDH and β2-microglobulin 
• 
Skeletal survey 
• 
Plasmacytoma assessment 
• 
Bone marrow biopsy and aspirate 
 
6.1.2 Treatment Phase 
 
 
 
 
 
 
 
 
 
 
 
 
6.1.2.1 Visit 1 (baseline; Cycle 1 Day 1) 
 
• 
Medication dispensation 
• 
Adverse events 
• 
Concomitant medications  
• 
Dose intensity 
• 
QOL assessment 
• 
Weight 
• 
Vital signs 
• 
Symptom-directed physical exam 
• 
12-lead ECG (may be performed on Screening visit) 
• 
ECOG PS (may be performed on Screening visit) 
• 
CBC with differential 
• 
TSH (may be performed on Screening visit) 
• 
Complete serum chemistry 
• 
Pregnancy test 


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• 
SPEP and serum immunofixation 
• 
UPEP (24-hr urine) and urine immunofixation 
• 
Quantitative Ig levels 
• 
Serum FLC 
• 
Skeletal survey 
• 
Plasmacytoma assessment 
 
 
 
 
6.1.2.2 Visit 2 (Cycle 1 Day 8 ± 1 day) 
 
• 
Adverse events 
• 
Weight 
• 
Vital signs 
• 
Symptom-directed physical exam 
• 
CBC with differential 
• 
Complete serum chemistry 
 
 
6.1.2.3 Visit 3 (Cycle 1 Day 15 ± 1 day) 
 
• 
Adverse events 
• 
Weight 
• 
Vital signs 
• 
Symptom-directed physical exam 
• 
CBC with differential 
• 
Complete serum chemistry 
 
 
6.1.2.4 Visit 4 (Cycle 2 Day 1 ± 2 days) 
 
• 
Medication dispensation 
• 
Adverse events 
• 
Concomitant medications  
• 
Dose intensity 
• 
QOL assessment 
• 
Weight 
• 
Vital signs 
• 
Symptom-directed physical exam 
• 
ECOG PS 
• 
CBC with differential 
• 
Complete serum chemistry 
• 
Pregnancy test 
• 
SPEP and serum immunofixation 
• 
UPEP (24-hr urine) and urine immunofixation 
• 
Quantitative Ig levels 
• 
Serum FLC 
• 
Skeletal survey* 
• 
Plasmacytoma assessment* 
• 
Bone marrow biopsy and aspirate* 
 


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6.1.2.5 Visit 5 (Cycle 2 Day 15 ± 2 days) 
 
• 
Adverse events 
• 
Weight 
• 
Vital signs 
• 
Symptom-directed physical exam 
• 
CBC with differential 
• 
Complete serum chemistry 
 
 
6.1.2.6 Visit ≥ 6 (Cycle ≥ 3 Day 1 ± 2 days) 
 
• 
Medication dispensation 
• 
Adverse events 
• 
Concomitant medications  
• 
Dose intensity 
• 
QOL assessment 
• 
Weight 
• 
Vital signs 
• 
Symptom-directed physical exam 
• 
ECOG PS 
• 
CBC with differential 
• 
Complete serum chemistry 
• 
Pregnancy test 
• 
SPEP and serum immunofixation 
• 
UPEP (24-hr urine) and urine immunofixation 
• 
Quantitative Ig levels 
• 
Serum FLC 
• 
Skeletal survey* 
• 
Plasmacytoma assessment* 
• 
Bone marrow biopsy and aspirate* 
 
 
6.1.2.7 End of Treatment Visit (≤ 14 days after last dose) 
 
• 
Adverse events 
• 
Concomitant medications  
• 
Dose intensity 
• 
QOL assessment 
• 
Weight 
• 
Vital signs 
• 
Complete physical exam 
• 
ECOG PS 
• 
CBC with differential 
• 
Complete serum chemistry 
• 
Pregnancy test 
• 
SPEP and serum immunofixation 
• 
UPEP (24-hr urine) and urine immunofixation 
• 
Quantitative Ig levels 


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• 
Serum FLC 
• 
Skeletal survey* 
• 
Plasmacytoma assessment* 
• 
Bone marrow biopsy and aspirate* 
 
6.1.3 Follow-up Phase 
 
 
6.1.3.1 Follow Up Assessment (30 days after last dose ± 7 days) 
 
• 
Adverse events 
• 
QOL assessment 
• 
Telephone contact 
 
 
6.1.3.2 Duration of Response and Survival (every 3 months ± 14 days after 
last dose for 12 months) 
 
• 
Telephone contact 
• 
SPEP and serum immunofixation 
• 
UPEP (24-hr urine) and urine immunofixation 
• 
Quantitative Ig levels 
• 
Serum FLC 
• 
Skeletal survey* 
• 
Plasmacytoma assessment* 
• 
Bone marrow biopsy and aspirate* 
 
7. Study Intervention 
 
7.1 
Study Intervention/Device Description   
 
The following drugs will be used in this study: 
 
7.1.1 Selinexor 
 
Provided as coated, immediate-release 20 mg tablets for oral administration in wallet-
sized blister packs. Karyopharm Therapeutics Inc. will supply selinexor at no charge and 
ship it to each site. Selinexor will be dispensed from the investigational pharmacy at 
each site and participants will be provided with only enough tablets for one cycle on the 
first day of each cycle. For information regarding storage, handling, precautions and 
contraindications, please refer to the package insert. 
 
7.1.2 Clarithromycin 
 
Patients will receive a prescription for clarithromycin 250 or 500 mg tablets (generic) for 
oral administration. Study participants will obtain this drug at their local pharmacy. For 
information regarding storage, handling, precautions and contraindications, please refer 
to the package insert. 
 
7.1.3 Pomalidomide 
 


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Patients will receive a 21-day supply of pomalidomide 1, 2, 3, or 4 mg capsules for oral 
administration, as appropriate, for each 28-day treatment cycle. The investigator will 
enter an electronic prescription for pomalidomide after the study participant enrolls in the 
POMALYST REMS program. A specialty pharmacy will ship pomalidomide to the study 
participant’s home. For information regarding storage, handling, precautions and 
contraindications, please refer to the package insert. 
 
7.1.4 Dexamethasone 
 
Patients will receive a prescription for dexamethasone 4 mg tablets (generic) for oral 
administration. Study participants will obtain this drug at their local pharmacy. For 
information regarding storage, handling, precautions and contraindications, please refer 
to the package insert. 
 
7.2 Availability 
 
Selinexor is an FDA approved drug which will be supplied to investigators by 
Karyopharm Therapeutics Inc. Commercial co-therapies will be obtained by the study 
participant through retail and/or specialty pharmacies. 
 
7.3 Acquisition and Accountability  
 
 
 
Selinexor will be provided by Karyopharm Therapeutics Inc. Commercial co-therapies 
will be obtained by the study participant. All co-therapies should be reimbursed by 
insurance or designated healthcare systems. Study drug accountability records will be 
maintained at the site pharmacy and will be available for review. Drug accountability is to 
be performed on selinexor only. “All-selinexor” accountability must be reviewed by the 
study monitor prior to destruction or return shipment.  
 
The Investigator, or a responsible party designated by the Investigator, must maintain a 
careful record of the inventory and disposition of selinexor using the NCI Drug 
Accountability Record or another comparable drug accountability form. Available at the 
Cancer Therapy Evaluation Program website at http://ctep.cancer.gov/ protocol 
development for the “Policy and Guidelines for Accountability and Storage of 
Investigational Agents”. 
 
Selinexor will be ordered through DRIVE, Endpoint’s supply management engine. Drug 
ordering instructions have been provided by Karyopharm Therapeutics, along with 
recommended initial and resupply stock orders. Orders submitted via DRIVE will be filled 
by Karyopharm Therapeutics within 5 business days of receipt. 
At the end of the study, unused supplies of selinexor should be destroyed according to 
institutional policies. Destruction will be documented in the Drug Accountability Record 
Form. 
 
7.4 Formulation, Appearance, Packaging, and Labeling  
 
Selinexor is a Selective Inhibitor of Nuclear Export (SINE) compound. Selinexor 
specifically blocks nuclear export by binding to the nuclear export protein XPO1. 
 


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The chemical name is: (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N'-
(pyrazin-2-yl)acrylohydrazide 
 
The molecular formula is: C17H11F6N7O. 
 
The molecular weight is: 443.31. 
 
Each Selinexor drug container will be labeled in accordance with current International 
Conference on Harmonization (ICH), Good Clinical Practice (GCP), and specific 
regulatory requirements, e.g., FDA, Health Canada (HC), European Medicines Agency 
(EMA), etc. Containers for take-home use may require additional in-pharmacy labeling 
with take-home and patient-specific instructions (such as exact dose) depending on 
country-specific regulations or laws. All treatments will be labeled in accordance with 
current ICH, GCP, FDA, HC, and EMA regulations and guidelines. Labels will include the 
medication name, storage conditions, and batch number, and will comply with language 
and legal requirements of Canada, EU, and the US.  
 
Selinexor will be supplied and administered as coated, immediate-release 20 mg oral 
tablets in wallet-sized blister packs. 
 
Further information for Selinexor, as well as clarithromycin, pomalidomide and 
dexamethasone can be found on their respective package insert. 
 
7.5 Product Storage and Stability 
 
Selinexor tablets should be stored in a locked and secured area with access restricted to 
the site staff pharmacist or designee(s) at or below 30˚C (86˚F). Room temperature 
storage is recommended, refrigerated is acceptable. Tablets should not be stored 
frozen. 
 
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the chemotherapeutic agent in a self-contained and protective environment. 
 
Selinexor tablets are coated for ease of use and handling. Tablets should not be broken 
or crushed due to increased risk of dermal exposure and/or toxicities. 
All other study medications should be stored as described on their respective package 
insert. 
 
7.6 Preparation 
 
No special preparation required. Tablets of selinexor should not be crushed because of 
increased risk of dermatologic toxicity if powder comes in contact with skin. 
 
7.7 Dosing and Administration 
 


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For doses of study medication that are to be taken on non-clinic days, the patient will be 
provided with selinexor by the investigational pharmacy, and clarithromycin, 
pomalidomide and dexamethasone by their local and/or specialty pharmacy.  
 
The doses of study treatments for individual patients should remain constant throughout 
the study, except for allowed dose modifications. 
 
Study medications will be dosed according to the schedule provided below. For doses of 
oral medications to be taken on non-clinic days, patients will either be provided with 
medication to take home or with a prescription to obtain the medication from their local 
and/or specialty pharmacy. 
 
Selinexor should be given with at least 120 mL (4 ounces) of fluids (water, milk, etc.). 
 
Dexamethasone should be administered at least one hour before selinexor. In general, 
where possible, each drug should be given at least 1-2 hours apart, however the 
sequence and times of administration are per the Investigator’s discretion. 
 
Clarithromycin, pomalidomide, and dexamethasone should be administered in a manner 
consistent with each product’s approved labeling. 
 
Selinexor tablets should be swallowed whole (not crushed) to prevent an increased risk 
of dermatologic toxicity if the powder comes in contact with skin. 
 
Missed doses of Selinexor should be managed as follows: 
• 
If a dose was missed, the schedule of that week should be altered to 
accommodate one dose in that week with at least 36 hours between two 
consecutive doses. 
• 
If a dose must be skipped (e.g., due to recommendation of treating physician), 
the next dose will be taken as per schedule. Doses should not be administered 
less than 36 hours apart and all missed and delayed doses should be 
documented. 
If a patient missed a full one-week period of dosing for non-study drug-related events 
(e.g., a required medical procedure or an unanticipated personal emergency), the days 
missed will be replaced.  
 
If a dose is vomited within 1 hour of ingestion, it will be replaced. If vomiting occurs more 
than 1 hour after dosing, it will be considered a complete dose. 
 
All patients will receive selinexor, clarithromycin, pomalidomide and dexamethasone in 
28-day cycles according to the following schedule: 
 
Selinexor will be given orally at a dose of 60 mg on days 1, 8, and 15 of a 28-day cycle. 
Clarithromycin will be given orally at a dose of 500 mg twice a day on days 1-28 of a 28-
day cycle. 
Pomalidomide will be given orally at a dose of 4 mg daily on days 1-21 of a 28-day 
cycle. 


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Dexamethasone will be given orally at a dose of 40 mg on days 1, 8, 15 and 22 of a 28-
day cycle. 
 
7.7.1 Dosing Delays/Dose Modifications 
 
In order to optimize specific anti-tumor activity and tolerability, dose reductions and/or 
schedule modifications will be allowed. Patients should also be treated aggressively with 
supportive care to reduce toxicities. Doses must be adjusted for adverse events deemed 
related to study drug by the Investigator. Doses may be adjusted for adverse events 
related to study medications not listed below at the discretion of the Investigator. 
 
Toxicity will be graded according to CTCAE v.5.0; the therapy modifications described 
below are to be applied according to severity grading. If more than one type of AE 
occurs concurrently, the most severe grade will determine the modification. Each dose 
modification or treatment delay must be documented, including the respective reason. 
Re-escalation of selinexor is allowed as outlined in Table 3. If drug-related toxicity 
requires a treatment delay of more than 28 days, the patient will be taken off study 
treatment. For all ≥ Grade 3 hematological or non-hematological AEs that are NOT 
selinexor related, after consultation with the Medical Monitor and at the discretion of the 
Investigator, selinexor dosing may be maintained. 
 
Table 3 summarizes the study treatment dose levels; Table 4 describes supportive care 
and dose adjustment guidelines. General supportive care recommendations are 
provided below. Deviations from the guidelines are permitted after discussion between 
the PI and the treating physician. 
 
In patients with renal impairment, start each drug at the following dose level: 
1) Selinexor: 
(a) CrCl ≥15 mL/min: There are no dosage adjustments provided in the 
manufacturer's labeling. 
(b) CrCl <15 mL/min: Patients with severe renal impairment are excluded from 
this study. 
2) Clarithromycin: 
(a) CrCl ≥30 mL/minute: No dosage adjustment necessary. 
(b) CrCl 15-29 mL/minute: Decrease clarithromycin dose by 50% by starting at 
dose level -1. 
(c) CrCl <15: Patients with severe renal impairment are excluded from this study.  
3) Pomalidomide: 
(a) CrCl ≥15 to <60 mL/minute: There are no dosage adjustments provided in the 
manufacturer's labeling. Compared to patients with normal renal function, 
pomalidomide pharmacokinetics were not significantly altered in patients with 
CrCl between 15 to 60 mL/minute. 
(b) CrCl <15 mL/min: Patients with severe renal impairment are excluded from 
this study. 
4) Dexamethasone: 


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(a) There are no dosage adjustments provided in the manufacturer’s labeling. 
The International Myeloma Working Group (IMWG) recommendations 
suggest that dexamethasone may be administered without dosage 
adjustment in multiple myeloma patients with renal impairment. 
 
In patients with hepatic impairment, start each drug at the following dose level: 
1) Selinexor: 
(a) Mild impairment: There are no dosage adjustments provided in the 
manufacturer's labeling; however, there are no clinically significant effects on 
selinexor pharmacokinetics. 
(b) Moderate impairment: There are no dosage adjustments provided in the 
manufacturer's labeling (has not been studied). 
(c) Patients with severe hepatic impairment are excluded from this study. 
2) Clarithromycin: 
(a) No dosage adjustment necessary if renal function is normal; however, in 
patients with hepatic impairment and concomitant severe renal impairment, a 
dosage reduction or prolonged dosing intervals may be appropriate, and 
patients should be started at dose level -1. 
3) Pomalidomide: 
(a) Mild or moderate impairment (Child-Pugh class A or B): Start at dose level -1 
(3 mg once daily). 
(b) Severe impairment (Child-Pugh class C): Patients with severe hepatic 
impairment are excluded from this study. 
4) Dexamethasone: 
(a) There are no dosage adjustments provided in the manufacturer’s labeling. 
 
Table 3. Study Drug Dose Modification Guidance 
 
Dose Level 
Selinexor 
Clarithromycin 
Pomalidomide 
Dexamethasone 
0 
60 mg on days 
1, 8 and 15 
500 mg twice 
daily 
4 mg daily on 
days 1-21 
40 mg on days 
1, 8, 15 and 22 
-1 
40 mg on days 
1, 8 and 15 
500 mg once 
daily 
3 mg daily on 
days 1-21 
20 mg on days 
1, 8, 15 and 22 
-2 
20 mg on days 
1, 8 and 15 
250 mg once 
daily 
2 mg daily on 
days 1-21 
20 mg on days 1 
and 15 
 
Table 4. Supportive Care and Dose Adjustment Guidelines 
 
Toxicity 
Grade 
Dose Modification 
 
Selinexor 
 


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Fatigue 
Grade 1 or 
Grade 2 
lasting ≤ 7 
days 
Maintain dose. Rule out other causes of fatigue, 
particularly dehydration and anemia. If found to be 
anemic, consider transfusing for Hb < 8 g/dL. 
Institute supportive care medications per institutional 
guidelines. Consistent with the National Comprehensive 
Cancer Network (NCCN) Clinical Practice Guidelines in 
Oncology (CPGO), the use of methylphenidate should be 
considered. Additional options are provided in the NCCN 
CPGO. 
Patients with significant fatigue after several doses of 
selinexor may have an ongoing anti-tumor response. If 
fatigue is significant, consider assessment of tumor 
response as part of the patient’s evaluation. 
Grade 2 
lasting > 7 
days or 
Grade 3 
Interrupt selinexor dosing. Monitor until fatigue resolves to 
Grade 1 or baseline and restart selinexor at 1 dose level 
lower. 
Institute supportive care medications as described above 
for Grade 1 or 2. 
Patients with significant fatigue after several doses of 
selinexor may have an ongoing anti-tumor response. If 
fatigue is significant, consider assessment of tumor 
response as part of the patient’s evaluation. 
Anorexia or 
Weight Loss 
Grade 1 
Maintain dose. Rule out other causes of anorexia. 
Nutritional consultation can be helpful. 
Consider instituting supportive care medications per 
institutional guidelines. 
Consistent with the NCCN CPGO, megesterol acetate 
200-400 mg twice daily should be considered. Other 
options are provided in the NCCN CPGO. 
Grade 2 
Rule out other causes of anorexia and order a nutritional 
consultation. 
Institute supportive care medications as described for 
Grade 1 anorexia or weight loss above. For additional 
options, see NCCN CPGO. 
Interrupt dosing with selinexor until improves to Grade 1 
or baseline and weight stabilizes, then restart selinexor at 
1 dose level lower.  
Grade 3 
Nutritional consultation and supportive care medications 
for anorexia per institutional guidelines should already be 
instituted. For additional options, see NCCN CPGO. 
Interrupt dosing with selinexor until improves to Grade 1 
or baseline and the weight stabilizes. Restart selinexor at 
1 dose level reduction. 
Nausea and/or 
Vomiting 
Grade 1 or 
2 
Maintain dose. Rule out other causes of nausea. 
Patients should be receiving 5HT3 antagonists unless 
contra-indicated. For those patients who cannot receive 
5HT3 antagonists, consider olanzapine per NCCN 
CPGO. For additional options, see NCCN CPGO. 


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If intolerable or persistent Grade 2, follow guidelines for 
Grade 3. 
Grade 3 
Supportive care medications per institutional guidelines 
should already be instituted. For additional options, see 
NCCN CPGO. 
Interrupt selinexor dosing until resolved to Grade ≤ 2 or 
baseline. Restart selinexor at 1 dose level lower. 
If nausea stabilizes for at least 4 weeks at Grade ≤ 1, 
may re-escalate to the original dose after consulting 
Medical Monitor. 
Hyponatremia 
Grade 1 
Maintain dose. Rule out other causes including drug (e.g., 
diuretic) effects. Be certain that reported sodium level is 
corrected for concurrent hyperglycemia (serum glucose > 
150 mmol/L). 
Treat hyponatremia per institutional guidelines including 
dietary review. Consider addition of salt tablets to 
patient’s diet. 
Grade 2 
Correct for hyperglycemia as outlined under Grade 1. 
Treat hyponatremia per institutional guidelines. If 
(corrected) sodium is Grade ≤ 3 and continues to be 
asymptomatic, then patient may continue current dosing 
provided that intravenous saline and/or salt tablets (1-3 
times daily) are provided. 
If Grade 2 is persistent or worsens or does not respond to 
treatment, dose interruptions may be considered after 
consulting with the Medical Monitor. 
Grade 3 or 
4 
Treat per institutional guidelines. Delay selinexor until 
sodium resolved to Grade ≤ 1 (≥ 130 mmol/L) then 
reduce selinexor dose by 1 level. If serum sodium 
stabilizes to Grade ≤ 1 for at least 4 weeks, may re-
escalate to previous dose of selinexor. 
Diarrhea 
Grade 1 or 
2 
Initiate treatment for any Grade 1 diarrhea. Treat per 
institutional guidelines with antidiarrheals and maintain 
dosing. 
For persistent Grade 2 only that does not respond to anti-
diarrheals within 3 days, interrupt selinexor dosing until 
resolved to Grade 1, then restart at the current dose level. 
Grade 3 or 
4 
Delay selinexor until resolved to Grade 1, then reduce 
selinexor dose by 1 dose level. 
If diarrhea stabilizes for at least 4 weeks at Grade ≤ 1, 
may re-escalate to previous dose of selinexor after 
consulting with the Medical Monitor. 
Thrombocytopeni
a 
Grade 1 
Maintain dose. 
Grade 2 or 
3 without 
bleeding 
Consider platelet growth factors, e.g., romiplostim, which 
may take up to four weeks for an effect. 
Reduce selinexor at 1 dose level lower. 
Patients with stable platelet counts for ≥ 4 weeks 
following dose reduction may have their dose of selinexor 
increased by one dose level. 


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Grade 4 
without 
bleeding 
Strongly consider platelet growth factors and transfuse 
per clinical practice/institutional guidelines. 
Delay dosing until recovery to ≤ Grade 2 or baseline and 
resume selinexor at 1 dose level lower. 
Grade 2 or 
3 with 
bleeding 
Delay dosing until the bleeding has stopped and the 
patient is clinically stable. 
Reduce selinexor at 1 dose level lower. 
Neutropenia 
Grade 3 or 
4 
Neutropeni
a without 
fever 
Institute colony stimulating factors, and delay dosing with 
selinexor until ANC returns to Grade ≤ 2. Reduce 
selinexor by 1 dose level. After stabilization for at least 4 
weeks, a re-escalation may be considered after 
discussing with the Medical Monitor. 
Grade 3 or 
4 
Neutropeni
a with fever 
Institute colony stimulating factors, and delay dosing with 
selinexor until the patient’s ANC returns to Grade ≤ 2 or 
baseline, fever has resolved, and patient’s condition is 
stable. Reduce selinexor by 1 dose level.  
Anemia 
Grade 3 
Treat per institutional guidelines including blood 
transfusions and/or erythropoietins. Consider transfusing 
for Hb < 8 g/dL. Reduce selinexor by 1 dose level. 
Grade 4 
Treat per institutional guidelines including blood 
transfusions and/or erythropoietins. Consider transfusing 
for Hb < 8 g/dL. Delay dosing of selinexor until Hb is 8 
g/dL or higher. Reduce selinexor by 1 dose level. 
Ocular Toxicity 
Grade 2, 
excluding 
cataract 
Perform ophthalmologic evaluation. Interrupt selinexor 
and provide supportive care. Monitor until ocular 
symptoms resolve to Grade 1 or baseline. Restart 
selinexor at 1 dose level lower. 
Grade 3 or 
4, excluding 
cataract 
Permanently discontinue selinexor. Perform 
ophthalmologic evaluation. 
Other Selinexor-
related AEs 
Grade 1 or 
2 
Maintain dose. Initiate standard supportive care per 
institutional guidelines. 
Grade 3 
Delay dosing with selinexor until recovery to Grade ≤ 2 or 
baseline and resume selinexor at 1 dose level lower. Re-
escalation can be considered after ≥ 4 weeks at the lower 
dose with reduction of the AE to Grade 1 or baseline. 
Grade 4 
Delay dosing until resolved to Grade ≤ 2 or baseline, then 
resume at 1 dose level lower. If further dose 
reduction/interruption is desired, consultation with the 
Medical Monitor is required. 
 
Clarithromycin 
 
Nausea and/or 
Vomiting 
Grade 1 or 
2 
Maintain dose. Rule out other causes of nausea. 
Patients should be receiving 5HT3 antagonists unless 
contra-indicated. For those patients who cannot receive 
5HT3 antagonists, consider olanzapine per NCCN 
CPGO. For additional options, see NCCN CPGO. 


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If intolerable or persistent Grade 2, follow guidelines for 
Grade 3. 
Grade ≥ 3 
Supportive care medications per institutional guidelines 
should already be instituted. For additional options see 
NCCN CPGO. 
If AE is thought to be due to clarithromycin, interrupt 
clarithromycin dosing until resolved to Grade ≤ 2 or 
baseline. For first occurrence of Grade 3, if adequate 
supportive care resulted in an improvement to Grade 1 or 
baseline within 3 days, restart clarithromycin at current 
dose. 
Otherwise (i.e., the recovery took longer than 3 days), 
restart clarithromycin at 1 dose level lower. 
If nausea stabilizes for at least 4 weeks at Grade ≤ 1, 
may re-escalate to the original dose after consulting 
Medical Monitor. 
Other 
Clarithromycin-
related Non-
hematologic AEs 
Grade ≥ 3 
Hold (interrupt) clarithromycin and follow weekly. If 
toxicity has resolved to Grade ≤ 1, restart clarithromycin 
at next lower dose level. 
 
Dexamethasone 
 
Dyspepsia, 
Gastritis, Gastric 
or Duodenal Ulcer 
Grade ≥ 3 
Hold (interrupt) dexamethasone and follow weekly. If 
toxicity has resolved to Grade ≤ 1, restart dexamethasone 
at next lower dose level. 
Edema 
Grade ≥ 3 
Reduce the dose of dexamethasone by 1 dose level. Use 
diuretics as needed. 
Agitation, 
Confusion, and/or 
other Psychiatric 
Disorder 
Grade ≥ 2 
Hold (interrupt) dexamethasone and follow weekly. If 
toxicity has resolved to Grade ≤ 1, restart 
dexamethasone at next lower dose level. 
Generalized Muscle 
Weakness 
Grade ≥ 3 
Reduce the dose of dexamethasone by 1 dose level, if 
symptoms persist, continue to reduce the dose of 
dexamethasone by 1 dose level as needed until toxicity 
has resolved to Grade ≤ 2. 
Hyperglycemia 
Grade ≥ 3 
Reduce the dose of dexamethasone by 1 dose level. 
Start insulin or other hypoglycemic therapy as needed. 
Acute Pancreatitis 
Grade ≥ 3 
Discontinue dexamethasone. Remove patient from study. 
Other 
Dexamethasone-
related Non-
hematologic AEs 
Grade ≥ 3 
Hold (interrupt) dexamethasone and follow weekly. If 
toxicity has resolved to Grade ≤ 1, restart 
dexamethasone at next lower dose level. 
 
Pomalidomide 
 
 
Onset day 1-14 of cycle 
Onset ≥ day 15 of cycle 


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Neutropenia 
Grade 3 
without 
fever 
Maintain dose. 
Maintain dose. 
Grade 3 
with fever 
or Grade 4 
Hold (interrupt) 
pomalidomide and follow 
CBC weekly. If neutropenia 
has resolved to Grade ≤ 2 
prior to day 21, restart 
pomalidomide at next lower 
dose level and continue the 
cycle through day 21. If 
neutropenia is the only 
toxicity for which a dose 
reduction is required, G-
CSF may be used and the 
pomalidomide dose 
maintained. 
Omit pomalidomide for the 
remainder of cycle. See 
instructions for initiation of 
a new cycle and reduce the 
dose of pomalidomide by 1 
dose level. If neutropenia is 
the only toxicity for which a 
dose reduction is required, 
G-CSF may be used and 
the pomalidomide dose 
maintained for the next 
cycle at the Investigators 
discretion. 
Thrombocytopeni
a 
Grade 1 or 
2 
Maintain dose. 
Maintain dose. 
Grade 3 or 
4 
Hold (interrupt) 
pomalidomide and follow 
CBC weekly. If 
thrombocytopenia has 
resolved to Grade ≤ 2 prior 
to day 21, restart 
pomalidomide at next lower 
dose level and continue the 
cycle through day 21. 
Omit pomalidomide for the 
remainder of cycle. See 
instructions for initiation of 
a new cycle and reduce the 
dose of pomalidomide by 1 
dose level. 
Non-blistering 
rash 
Grade 3 
Hold (interrupt) 
pomalidomide and follow 
weekly. If toxicity has 
resolved to Grade ≤ 1 prior 
to day 21, restart 
pomalidomide at next lower 
dose level and continue the 
cycle through day 21. 
Omit pomalidomide for the 
remainder of cycle. See 
instructions for initiation of 
a new cycle and reduce the 
dose of pomalidomide by 1 
dose level. 
 
Grade 4 
Discontinue pomalidomide. 
Remove patient from 
study. 
Discontinue pomalidomide. 
Remove patient from study. 
Desquamating 
(blistering) rash 
Any grade 
Discontinue pomalidomide. 
Remove patient from 
study. 
Discontinue pomalidomide. 
Remove patient from study. 
Neuropathy 
Grade 3 
Hold (interrupt) 
pomalidomide and follow 
weekly. If toxicity has 
resolved to Grade ≤ 1 prior 
to day 21, restart 
pomalidomide at next lower 
Omit pomalidomide for the 
remainder of cycle. See 
instructions for initiation of 
a new cycle and reduce the 
dose of pomalidomide by 1 
dose level. 


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dose level and continue the 
cycle through day 21. 
Grade 4 
Discontinue pomalidomide. 
Remove patient from 
study. 
Discontinue pomalidomide. 
Remove patient from study. 
Thromboembolic 
event 
Grade 3 or 
4 
Hold (interrupt) 
pomalidomide and start 
therapeutic dose 
anticoagulation. Restart 
pomalidomide at the 
Investigator's discretion 
mainatining dose level. 
Omit pomalidomide for the 
remainder of cycle and 
start therapeutic dose 
anticoagulation. 
Hyperthyroidism 
Grade 3 or 
4 
Omit pomalidomide for the 
remainder of the cycle, 
evaluate etiology and 
initiate appropriate therapy. 
See instructions for 
initiation of a new cycle 
and reduce the dose of 
pomalidomide by 1 dose 
level. 
Omit pomalidomide for the 
remainder of the cycle, 
evaluate etiology and 
initiate appropriate therapy. 
See instructions for 
initiation of a new cycle and 
reduce the dose of 
pomalidomide by 1 dose 
level. 
Hypothyroidism 
Grade 3 or 
4 
Omit pomalidomide for the 
remainder of the cycle, 
evaluate etiology and 
initiate appropriate therapy. 
See instructions for 
initiation of a new cycle 
and reduce the dose of 
pomalidomide by 1 dose 
level. 
Omit pomalidomide for the 
remainder of the cycle, 
evaluate etiology and 
initiate appropriate therapy. 
See instructions for 
initiation of a new cycle and 
reduce the dose of 
pomalidomide by 1 dose 
level. 
Other 
Pomalidomide-
related non-
hematologic AEs 
Grade 1 or 
2 
Maintain dose. Initiate 
standard supportive care 
per institutional guidelines. 
Maintain dose. Initiate 
standard supportive care 
per institutional guidelines. 
Grade 3 or 
4 
Hold (interrupt) 
pomalidomide and follow 
weekly. If toxicity has 
resolved to Grade ≤ 2 prior 
to day 21, restart 
pomalidomide at next lower 
dose level and continue the 
cycle through day 21. 
Omit pomalidomide for the 
remainder of the cycle. See 
instructions for initiation of 
a new cycle and reduce the 
dose of pomalidomide by 1 
dose level. 
 
All dose modifications should be based on the worst preceding toxicity. 
 
Note: For combinations of Grade 1 or 2 AEs (e.g., nausea, fatigue, anorexia) that 
significantly impair the patient’s quality of life, 1-2 doses of selinexor may be skipped and 
aggressive supportive care implemented. Selinexor may then be restarted at the original 
dose. 
 


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National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in 
Oncology (NCCN Guidelines): Fatigue, Palliative Care, and Antiemesis. Available at 
http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.  
 
Isolated values of ≥ Grade 3 alkaline phosphatase do NOT require dose interruption. 
Determination of liver versus bone etiology should be made, and evaluation of gamma-
glutamyl transferase, 5’-nucleotidase, or other liver enzymes should be performed. 
 
The possibility of overlapping toxicities with selinexor, pomalidomide, and 
dexamethasone should be considered. 
 
7.7.1.1 Dose Modifications for Overlapping Toxicities 
 
Thrombocytopenia and neutropenia are potential overlapping toxicities for selinexor with 
pomalidomide. If a patient experiences drug-induced thrombocytopenia or neutropenia 
while receiving the combination under investigation in this study, the Investigator should 
attempt to determine which drug may be responsible and treat appropriately, including 
dose modifications, as necessary. If the cause cannot be attributed to a single drug, 
suggested management strategies for possibly drug-induced thrombocytopenia and 
neutropenia Grade 3/4 events are provided below. 
 
7.7.1.2 Thrombocytopenia 
 
1. Grade ≥ 2: Hold/adjust selinexor dose as described in Table 4, under 
Thrombocytopenia. 
2. Grade ≥ 3: Hold/adjust pomalidomide dose as described in Table 4, under 
Thrombocytopenia. 
 
7.7.1.3 Neutropenia 
 
1. Grade 3 without fever: Reduce selinexor by 1 dose level and consider supportive 
care as described in Table 4, under Neutropenia. 
2. Grade 4 without fever: Hold selinexor until ANC returns to Grade ≤ 2. Reduce 
selinexor by 1 dose level. See additional supportive care in Table 4, under 
Neutropenia. 
3. Grade ≥ 3 with fever: Hold selinexor until ANC returns to Grade ≤ 2, fever 
resolves, and patient is clinically stable. Reduce selinexor by 1 dose level. See 
additional supportive care in Table 4, under Neutropenia. 
4. Grade ≥ 3: If holding selinexor does not resolve the neutropenia, consider 
holding/adjusting pomalidomide dose as described in Table 4, under 
Neutropenia. 
 
The manufacturer of pomalidomide has provided dose adjustment guidelines for 
managing Grade ≥ 3 thrombocytopenia and neutropenia that occur during treatment in 
the package insert. These guidelines, together with the recommended dose adjustments 
provided in Table 4, should be consulted by the Investigator to manage 
thrombocytopenia and neutropenia associated with study treatments, as needed. 
 
7.7.2 Conditions Not Requiring Selinexor Dose Reduction 
 


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The following conditions are exceptions to the dose-modification guidelines. Selinexor 
does not need to be held in the following cases: 
 
• 
Alopecia of any grade 
• 
Electrolyte or serum analyte (e.g., urate) abnormalities that are reversible with 
standard interventions. Treat hypokalemia and hypomagnesemia per institutional 
guidelines and repeat a 12-lead ECG to monitor the QTc as clinically indicated. 
 
7.7.3 Selinexor Dose Reduction for Decreased Glomerular Filtration Rate 
 
Selinexor is not significantly eliminated by the kidney; therefore, no dose alteration of 
selinexor is required with renal dysfunction. 
 
7.8 General Concomitant Therapy and Supportive Care Guidelines 
 
All concomitant medications will be recorded and/or updated on subject medication log 
throughout the course of the study and saved in subject binder, if applicable. 
 
7.8.1 Required Anti-emetics: 5-HT3 Antagonists and Olanzapine 
 
In order to minimize nausea, anorexia and fatigue, unless contraindicated, all patients 
should receive serotonin receptor subtype (5-HT3) antagonists (ondansetron 8 mg or 
equivalent), starting Q8 hours before each dosing and continue 2-3 times daily for a few 
days (2-4 days) after dosing for the first 2 cycles, after which it may be tapered of 
discontinued as tolerated. Alternative antiemetic agents may be used if the patient does 
not tolerate or has inadequate antiemetic effect with 5-HT3 antagonists.  
 
In addition, patients should receive olanzapine 2.5 mg PO daily starting on the evening 
prior to Day 1 and continuing for at least the first 2 months of the study. The dose of 
olanzapine can be increased as deemed necessary. The olanzapine dose may be dose 
reduced or stopped after 2 months of combination therapy period if nausea is well 
controlled. Please note that olanzapine can induce fatigue and should be discontinued in 
the case for fatigue grade >2. 
 
Alternatives to olanzapine include: 
• 
Megesterol Acetate - patients may receive megesterol acetate 80-400 mg daily, 
starting 1-3 days before the first dosing day of selinexor. In addition, megesterol 
acetate 80-400 mg daily may be added for any patients as part of general 
supportive care for anorexia.  
• 
Mirtazapine 7.5-15 mg daily (QHS), starting 0-3 days in the evening before the 
first dosing day of selinexor. Please note that mirtazapine can induce fatigue and 
should be discontinued in the case for fatigue grade >2. 
Avoid the use of strong CYP3A4 and/or CYP1A2 inhibitors (Appendix 1). 
 
7.8.2 Supportive Care 
 
Supportive care guidelines for managing adverse events (AEs) are provided in Table 4. 


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Patients may receive other supportive care, including hydration prophylaxis, antibiotics, 
as appropriate. 
 
Supportive care including additional anti-nausea/anti-emetic therapy, acid suppression 
(proton-pump inhibitors [PPI] and/or H2-blockers) and other treatments may be 
administered as follows: 
• 
Appetite stimulants: megestrol acetate at a dose of 400-800 mg daily. Mirtazapine 
15mg PO qPM can also be given  
• 
Centrally acting agents: per National Comprehensive Cancer Network® [NCCN] 
Clinical Practice Guidelines®. 
 
7.8.3 Infection Prophylaxis 
 
Patients will receive sulfamethoxazole/trimethoprim (800 mg/160 mg) PO three times 
weekly (i.e., Monday, Wednesday and Friday), or equivalent in case of allergy or 
intolerance. Patients considered by the Investigator to be at high risk for a bacterial 
infection should receive levofloxacin prophylaxis. 
 
7.8.4 Glucocorticoid Side Effects 
 
The management of common glucocorticoid side effects is well documented. Aggressive 
use of PPIs, anti-hypertensives, glucose-lowering drugs and other agents is strongly 
encouraged in order to maintain the use of dexamethasone in combination with 
selinexor, clarithromycin and pomalidomide in this study. 
 
Patients with documented osteopenia or osteoporosis should continue to take 
dexamethasone with selinexor as indicated in the study. Standard precautions such as 
use of antiresorptive therapy should be instituted unless contraindicated. 
 
7.8.5 Non-study Related Concomitant Medication and Treatment 
 
Concomitant medications include any prescription or over-the-counter preparation, 
including vitamins, dietary supplements, over-the-counter medications, and oral herbal 
preparations taken during the study. Patients may continue their baseline medication(s), 
unless listed below under Restrictions or Prohibited Medications, as noted below. All 
concomitant medication(s) must be reported in the eCRF. Any diagnostic, therapeutic, or 
surgical procedure performed during the study period should be recorded, including the 
dates, description of the procedure(s), and any clinical findings, if applicable. 
 
7.8.6 Prevention of pregnancy 
 
Patients should not become pregnant or father a child while on this study because the 
study treatments in this study can affect an unborn baby. Women should not breastfeed 
a baby while on this study. It is important that patients understand the need to use birth 
control while on this study. Female patients of childbearing potential must agree to use 
two methods of contraception (one highly effective and one effective) and have a 
negative serum pregnancy test at Screening and a negative urine test prior to receiving 
the first dose of study treatment, and male patients must use an effective barrier method 
of contraception if sexually active with a female of childbearing potential. 


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Highly effective methods include: 
• 
Hormonal contraceptives (e.g., combined oral contraceptives, patch, vaginal ring, 
injectables, and implants) 
• 
Intrauterine device or intrauterine system 
• 
Vasectomy or tubal ligation 
 
Effective methods include: 
• 
Barrier methods of contraception (e.g., male condom, female condom, cervical 
cap, diaphragm, contraceptive sponge). Notes: No barrier method by itself 
achieves a highly effective standard of contraception. The proper use of 
diaphragm or cervical cap includes use of spermicide and is considered one 
barrier method. The cervical cap and contraceptive sponge are less effective in 
parous women. The use of spermicide alone is not considered a suitable barrier 
method for contraception. When used consistently and correctly, “double barrier” 
methods of contraception (e.g., male condom with diaphragm, male condom with 
cervical cap) can be used as an effective alternative to the highly effective 
contraception methods described above. Male and female condoms should not 
be used together as they can tear or become damaged. 
 
Alternatively, the following fulfill the contraception requirements: 
• 
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. NOTE: 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 3 months following the last dose of study treatment. Please 
refer to the “Reproductive Risks” section above for additional safety information. 
 
7.8.7 Thrombosis Prophylaxis 
 
Study participants should receive adequate prophylaxis for venous thromboembolism 
(VTE) depending on the thrombotic risk as assessed by the Investigator. Low VTE risk 
patients should receive aspirin 81 mg PO daily while receiving pomalidomide. Patients 
with multiple VTE risk factors (eg, previous VTE, known inherited thrombophilia, central 
venous catheter or pacemaker, severe cardiac disease, uncontrolled diabetes mellitus, 
prolonged immobilization, use of erythropoietin, obesity, chronic kidney disease [eGFR 
<30 mL/min], elevated D-dimer levels) should receive prophylactic or therapeutic dose 
low molecular weight heparin, warfarin or a non-vitamin K oral anticoagulant, rather than 
low-dose aspirin, while receiving pomalidomide. 
 
7.8.8 Radiation Treatment 
 
If clinically indicated, palliative radiation therapy to non-target lesions is permitted but 
study drug should be held for ≥ 1 day before the start of palliative radiation therapy and ≥ 
1 day following each dose of palliative radiation therapy. Treatment with selinexor shall 
not be discontinued solely due to palliative radiation. 


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7.8.9 Hematopoietic support 
 
Thrombocytopenia should be treated conservatively. In the absence of bleeding, platelet 
transfusions should only be given for a platelet count below 10,000/mm3. If the patient 
develops bleeding, platelet transfusions should be administered in accordance with 
standard of practice, usually maintaining a platelet count ≥ 50,000/mm3. Platelet growth 
factors may be used according to Table 4.  
 
Treat anemia per institutional guidelines including blood transfusions and/or 
erythropoietin stimulating agents with concurrent anticoagulation as described above. 
Consider transfusing for hemoglobin < 8 g/dL.  
 
Granulocyte colony stimulating factors may be used for the management of neutropenia 
according to Table 4. 
 
7.8.10 Prevention of skeletal related events 
 
Patients should receive osteoclast inhibitor therapy as deemed appropriate by the 
Investigator. Routine dental care is recommended. 
 
7.8.11 Restrictions 
 
There are no restrictions on the use of acetaminophen or acetaminophen-containing 
products in combination with selinexor, except on days of selinexor dosing, when 
acetaminophen use must not exceed a total daily dose of 1 g.  
 
Patients should not take any strong CYP3A4 and/or CYP1A2 inhibitors; please see 
Appendix 1 for a list of representative products. Patients should not take glutathione 
(GSH)-, S-adenosylmethionine (SAM)-, or N-acetylcysteine (NAC)-containing products 
during their participation in this study as these products may enhance the metabolism of 
selinexor. However, they are permitted if the patient has elevated liver function tests; 
please see Appendix 2 for a list of representative products.  
 
Patients should not take drugs that are contraindicated with clarithromycin: colchicine, 
cisapride, pimozide, ergot alkaloids (e.g., ergotamine, dihydroergotamine), lomitapide, 
HMG-CoA reductase inhibitors extensively metabolized by CYP3A4 (e.g., lovastatin, 
simvastatin), saquinavir, midazolam (oral), ticagrelor, astemizole, domperidone, 
terfenadine, or ranolazine.  
 
Prescribing Information for pomalidomide and dexamethasone should serve as a 
reference for potential restrictions and/or prohibitions.  
 
There are no dietary restrictions in this study. Patients on selinexor should maintain 
adequate caloric and fluid intake. 
 
7.8.12 Prohibited Medications 
 
Concurrent therapy with any approved or investigative anticancer therapeutic outside of 
those included in this study is not allowed. Use of any immunosuppressive agents during 


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the study must be confirmed by the Medical Monitor. The package insert should serve as 
a reference for potential restrictions and/or prohibitions. Avoid the use of strong CYP3A4 
and/or CYP1A2 inhibitors (Appendix 1). 
 
7.8.13 Day one dosing guidelines 
 
On day one of study treatment, the patient will take: 
• 
Selinexor 60 mg by mouth 
• 
Clarithromycin 500 mg by mouth twice a day 
• 
Pomalidomide 4 mg by mouth 
• 
Dexamethasone 40 mg by mouth 
 
Unless dose reduction is warranted due to renal and/or hepatic impairment, see section 
7.7.1. 
 
The patient will also be directed to take the following prophylactic medications:  
• 
Aspirin 81 mg by mouth daily 
• 
Omeprazole 20 mg by mouth (or equivalent) daily 
• 
Ondansetron 8 mg by mouth (or equivalent) starting 8 hours before Selinexor 
dosing and continue 2-3 times daily for 2-4 days after dosing for at least the first 
2 cycles. 
• 
Olanzapine 2.5 mg by mouth every evening, starting on the evening before day 1 
and continuing for at least the first 2 cycles. 
• 
Trimethoprim-sulfamethoxazole 1 DS tablet by mouth three times per week 
(Monday, Wednesday, Friday). 
 
Documentation of two negative pregnancy tests (serum hCG at Screening visit, and a 
urine pregnancy test on C1D1) is required prior to first dose in all female patients of 
childbearing potential. 
 
7.8.14 Instructions for initiation of a subsequent cycle 
 
A new course of treatment may begin on the scheduled day 1 of a new cycle if: 
• 
Absolute neutrophil count (ANC) ≥ 1,000 cells/mm³ 
• 
Platelets count ≥ 75,000/mm³ 
• 
Any drug-related somnolence, rash, peripheral neuropathy, sinus 
bradycardia/other cardiac arrhythmia, allergic reaction/hypersensitivity, 
dyspepsia, gastritis, gastric or duodenal ulcer or confusion or mood alterations 
that may have occurred has resolved to ≤ grade 1 severity. 
• 
Any other drug-related non-hematologic 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 the toxicity does not resolve within four weeks, the patient will be taken off the study. If 
the dosing of selinexor, clarithromycin, pomalidomide or dexamethasone was halted 
during the previous cycle and was restarted with a one-level dose reduction without 


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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 the dosing of selinexor, clarithromycin, pomalidomide or dexamethasone 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 dose 
modifications as described in Tables 3 and 4.  
 
If the start of a new cycle is delayed more than 4 weeks, the patient will be taken off 
study. 
 
7.9 Duration of Therapy and Criteria for Removal from Study 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until 
one of the following criteria applies: 
 
• 
Disease progression, 
• 
Intercurrent illness that prevents further administration of treatment, 
• 
Unacceptable adverse event(s), 
• 
Subject decides to withdraw from the study, or 
• 
General or specific changes in the subject’s condition render the subject 
unacceptable for further treatment in the judgment of the investigator. 
 
Patients may discontinue study treatment for any reason. Patients who elect to 
discontinue study treatment should be encouraged to continue in the study so that 
follow-up information on disease progression and survival status may be obtained. 
However, patients may elect to withdraw consent and decline further participation in the 
trial. All patients will be followed until disease progression, withdrawal of consent, death 
or loss to follow up. 
 
7.10 Duration of Follow Up 
 
Subjects will be followed for 12 months after end of treatment (EoT) visit or until death, 
whichever occurs first.  Subjects removed from study for unacceptable adverse events 
will be followed until resolution or stabilization of the adverse event.  
 
End of study will occur after the last patient to be enrolled has completed the one year 
follow up period, died, withdrawn consent, or been lost to follow up, whichever comes 
first. 
 
7.10.1 Safety Follow Up 
 
Study procedures will be performed 30 days (+ 7 days) after the last dose of study 
medication. Patients will be contacted by telephone or visit to obtain the following 
information: 
 
• 
Follow-up on any AEs that had not resolved by the EoT visit 
• 
Information on any antineoplastic therapies utilized since discontinuation of 
ClaSPd treatment 


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7.10.2 Duration of Response and Survival Follow Up 
 
Every three months (± 14 days) for 12 months after the EoT visit, if feasible and clinically 
appropriate, the following assessments should be obtained for patients who have not 
progressed to assess durability of response: 
 
• 
SPEP and serum protein immunofixation 
• 
UPEP (24-hour urine) and urine protein immunofixation 
• 
Serum FLC 
• 
Quantitative Ig levels 
• 
Bone marrow aspirate, as clinically indicated, to assess progression 
• 
Re-assessment of plasmacytomas by physical examination (if detected by 
physical examination at Screening) 
• 
Skeletal survey (imaging) for bone lesions, including tumor measurements as 
clinically indicated to document response, at frequency determined by the 
Investigator 
 
If these procedures cannot be obtained, at a minimum, a telephone call will be made to 
the patient (or the patient’s family) every 3 months to inquire about the patient’s MM 
status, general health, and information on any antineoplastic therapies utilized since 
discontinuation of study treatment. 
 
7.11 Measures to Minimize Bias: Randomization and Blinding  
 
Not applicable. 
 
7.12 Study Intervention/Follow-up Compliance 
 
Not  Applicable. 
 
8. Study Intervention Discontinuation and Participant Discontinuation/Withdrawal 
 
8.1 Discontinuation of Study Intervention 
 
Discontinuation from study treatment does not mean discontinuation from the study, and 
remaining study procedures should be completed as indicated by the study protocol. If a 
clinically significant finding is identified (including, but not limited to changes from 
baseline) after enrollment, the investigator or qualified designee will determine if any 
change in participant management is needed. Any new clinically relevant finding will be 
reported as an adverse event (AE). 
 
The data to be collected at the time of study intervention discontinuation will include the 
those outlined in the EoT visit as well as the Follow Up Phase. 
 
8.2 Participant Discontinuation/Withdrawal from the Study 
 
Participants are free to withdraw from participation in the study at any time upon request. 
Patients who elect to discontinue study treatment should be encouraged to continue in 


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the study so that follow-up information on disease progression and survival status may 
be obtained. However, patients may elect to withdraw consent and decline further 
participation in the trial. All patients will be followed until disease progression, withdrawal 
of consent, death or loss to follow up. 
 
An investigator may discontinue or withdraw a participant from the study for the following 
reasons: 
 
• 
Pregnancy 
• 
Significant study intervention non-compliance  
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition 
or situation occurs such that continued participation in the study would not be in the 
best interest of the participant 
• 
Disease progression 
• 
If the participant meets an exclusion criterion (either newly developed or not 
previously recognized) that precludes further study participation 
• 
Participant lost to follow-up after three attempts to contact subject to schedule study 
visit. 
The reason for participant discontinuation or withdrawal from the study will be recorded 
on the eCRF. Subjects who sign the informed consent form but do not receive the study 
intervention may be replaced.  Subjects who sign the informed consent form, and 
receive the study intervention, and subsequently withdraw, or are withdrawn or 
discontinued from the study, will not be replaced. 
8.3 Lost to Follow Up 
A participant will be considered lost to follow-up if he or she fails to return for two or 
more visits for the beginning of a cycle and is unable to be contacted by the study site 
staff.  
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit within 
one week and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain if the participant wishes to and/or should continue in the 
study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up.  
 
9. Correlative/Special Studies  
 
Not Applicable. 
 


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9.1 Laboratory Correlative Studies 
 
Not Applicable. 
 
9.2 Special Studies 
 
Not Applicable. 
 
10.  Measurement of Effect 
 
10.1 Response Criteria 
 
 
Overall response rate (ORR): the sum of partial response (PR), very good partial 
response (VGPR), complete response (CR) and stringent complete response (sCR), 
based on the IMWG response criteria (Appendix 4). Response will be assessed on day 1 
of every cycle starting on cycle 2. 
 
10.2 Duration of Response  
 
Duration of response:  The duration of response is measured from the time 
measurement criteria for PR, VGPR, CR or sCR (whichever is first recorded) is first met 
until the date of progressive disease (PD) or death, whichever comes first. 
 
10.3 Progression-Free Survival  
 
Progression-Free Survival: defined as the length of time measured from start of study 
treatment to PD or death, whichever comes first. 
 
10.4 Other Response Parameters 
 
 
Clinical benefit rate (CBR), defined as overall response rate (ORR) plus minimal 
response (MR), as defined by the IMWG criteria (Appendix 4) 
 
Disease control rate (DCR), defined as CBR plus stable disease (SD) for a minimum 
of 12 weeks 
 
Overall survival (OS), defined as the length of time measured from start of study 
treatment to death 
 
Minimal residual disease (MRD), as defined by the IMWG criteria (Appendix 4) 
 
Relative dose intensity, defined as the ratio of delivered to the planned dose intensity 
expressed as a percentage 
 
Quality of life (QOL) score, as measured by the Functional Assessment of Cancer 
Therapy - MM (FACT-MM) (Appendix 5) 
 
11. Data Reporting / Regulatory Considerations 
 
11.1 Data Collection 
 
 
The data collection plan for this study is to utilize REDCap to capture all treatment, 
toxicity, efficacy, and adverse event data for all enrolled subjects.  
 


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11.1.1 REDCap 
 
REDCap (Research Electronic Data Capture) is a free data management 
software system that is fully supported by the Weill-Cornell Medical Center 
CTSC.  It is a tool for the creation of customized, secure data management 
systems that include Web-based data-entry forms, reporting tools, and a full 
array of security features including user and group based privileges, 
authentication using institution LDAP system, with a full audit trail of data 
manipulation and export procedures.  REDCap is maintained on CTSC-owned 
servers that are backed up nightly and support encrypted (SSL-based) 
connections.  Nationally, the software is developed, enhanced and supported 
through a multi-institutional consortium led by the Vanderbilt University CTSA. 
 
11.2 Regulatory Considerations 
 
11.2.1 Institutional Review Board/Ethics Committee Approval  
 
As required by local regulations, the Investigator will ensure all legal aspects are covered, 
and approval of the appropriate regulatory bodies obtained, before study initiation.  
Before initiation of the study at each study center, the protocol, the ICF, other written 
material given to the patients, and any other relevant study documentation will be 
submitted to the appropriate Ethics Committee. Written approval of the study and all 
relevant study information must be obtained before the study center can be initiated or the 
IP is released to the Investigator. Any necessary extensions or renewals of IRB approval 
must be obtained for changes to the study, such as amendments to the protocol, the ICF, 
or other study documentation. The written approval of the IRB together with the approved 
ICF must be filed in the study files.  
The Investigator will report promptly to the IRB any new information that may adversely 
affect the safety of the patients or the conduct of the study. The Investigator will submit 
written summaries of the study status to the IRB as required. On completion of the study, 
the IRB will be notified that the study has ended.  
 
All agreed protocol amendments will be clearly recorded on a protocol amendment form 
and will be signed and dated by the original protocol approving signatories. All protocol 
amendments will be submitted to the relevant institutional IRB for approval before 
implementation, as required by local regulations. The only exception will be when the 
amendment is necessary to eliminate an immediate hazard to the trial participants. In this 
case, the necessary action will be taken first, with the relevant protocol amendment 
following shortly thereafter.  
Once protocol amendments or consent form modifications are implemented at the lead 
site, Weill Cornell Medicine, updated documents will be provided to participating sites, as 
applicable. Weill Cornell Medicine must approve all consent form changes prior to local 
IRB submission.  
Relevant study documentation will be submitted to the regulatory authorities of the 
participating countries, according to local/national requirements, for review and approval 


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before the beginning of the study. On completion of the study, the regulatory authorities 
will be notified that the study has ended.  
 
11.2.2 Ethical Conduct of the Study  
The Investigators and all parties involved should conduct this study in adherence to the 
ethical principles based on the Declaration of Helsinki, GCP, ICH guidelines and the 
applicable national and local laws and regulatory requirements.  
 
This study will be conducted under a protocol reviewed and approved by the applicable 
ethics committees and investigations will be undertaken by scientifically and medically 
qualified persons, where the benefits of the study are in proportion to the risks. 
 
11.2.3 Informed Consent 
 
The investigator or qualified designee must obtain documented consent according to ICH-
GCP and local regulations, as applicable, from each potential subject or each subject’s 
legally authorized representative prior to participating in the research study. Subjects who 
agree to participate will sign the approved informed consent form and will be provided a 
copy of the signed document.   
 
The initial ICF, any subsequent revised written ICF and any written information provided 
to the subject must approved by IRB prior to use. The ICF will adhere to IRB requirements, 
applicable laws and regulations. 
 
11.2.4 Compliance with Trial Registration and Results Posting Requirements  
 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor-Investigator of the 
trial is solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to http://www.clinicaltrials.gov. Information posted will allow 
subjects to identify potentially appropriate trials for their disease conditions and pursue 
participation by calling a central contact number for further information on appropriate trial 
locations and trial site contact information. 
 
11.2.5 Record Retention 
 
Essential documents are those documents that individually and collectively permit 
evaluation of the study and quality of the data produced.  After completion of the study, all 
documents and data relating to the study will be kept in an orderly manner by the 
Investigator in a secure study file.  Essential documents should be retained for 2 years 
after the final marketing approval in an ICH region or for at least 2 years since the 
discontinuation of clinical development of the IP. In addition, all subjects medical records 
and other source documentation will be kept for the maximum time permitted by the 
hospital, institution, or medical practice.   
 
12. Statistical Considerations 
 
12.1 Study Design/Endpoints 
 


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A Simon's two-stage design (Simon, 1989) will be used. The null hypothesis that the true 
ORR is ≤ 35% will be tested against a one-sided alternative that the true ORR ≥ 60% (see 
Background section for further details regarding a pooled estimate of the ORR in studies of 
pomalidomide-containing two- and three-drug regimens).  
 
Tabulations will be produced for appropriate disposition, demographic, baseline, efficacy 
and safety parameters. For categorical variables, summary tabulations of the number and 
percentage of patients within each category (with a category for missing data) of the 
parameter will be presented, as well as 95% confidence intervals (CI), unless otherwise 
stated. For continuous variables, the number of patients, mean, median, standard deviation 
(SD), minimum, and maximum values will be presented. Time-to-event data will be 
summarized using Kaplan-Meier methodology using 25th, 50th (median), and 75th percentiles 
with associated 95% CI, as well as percentage of censored observations. 
 
The analysis will be performed on an intent-to-treat population, consisting of all patients who 
receive at least one dose of the study treatment. This population will include patients who 
have discontinued therapy due to toxicity or disease progression and patients who have 
died from any cause, including those related to study drug or disease. This population will 
be used for the analyses of both efficacy and safety.  
 
Demographic characteristics will include gender, race, ethnicity (Hispanic/non-Hispanic 
origin), and age at time of consent. For gender, race, and ethnicity, the summary statistics 
will be the number and percentage of patients within each category. For age at time of 
consent, the mean, median, minimum, maximum, and standard deviation will be provided for 
each group and the total sample. Baseline characteristics include ECOG Performance 
Status, duration from initial diagnosis, response to previous therapy, types of prior therapy, 
and height/weight. Baseline data will be tabulated for the same categories as used for 
demographics, using summary statistics. Medical history and physical examination results at 
baseline will be tabulated by cohort. 
 
12.2 Sample Size/Accrual Rate 
 
In the first stage, 18 patients will be accrued. If there are 6 or fewer responses in these 18 
patients, the study will be stopped. Otherwise, 8 additional patients will be accrued for a total 
of 26. The null hypothesis will be rejected if 14 or more responses are observed in 26 
patients. This design yields a one-sided type I error rate of 0.05 and power of 0.8 when the 
true ORR is 60%.  
 
12.3 Stratification Factors  
 
Not applicable. 
 
12.4 Analysis of Endpoints 
 
12.4.1 Analysis of Primary Endpoints 
 
The analysis of Overall Response Rate (ORR) will be performed by calculating the point 
estimate of the percentage of patients who have a response of sCR, CR, VGPR or PR, 
as assessed by IMWG criteria. A 95% CI for the ORR will be calculated using exact 
methods and presented for descriptive purposes. 


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12.4.2 Analysis of Secondary Endpoints 
 
Safety analyses will be performed using data available from all patients who receive ≥ 1 
dose of the study treatment. Adverse Events (AEs) will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) dictionary and displayed in tables and 
listings using System/Organ/Class (SOC) and Preferred Term. Analyses of AEs will be 
performed for those events that are considered to be treatment emergent AEs (TEAEs), 
defined as any AE with onset or worsening of a pre-existing condition on or after the first 
administration of study medication through 30 days following last dose or any event 
considered drug-related by the Investigator through the end of the study. AEs with partial 
dates will be assessed using the available date information to determine if treatment-
emergent; AEs with completely missing dates will be assumed to be treatment-
emergent. 
 
AEs will be summarized by patient incidence rates. In all tabulations, a patient may 
contribute only once to the count for a given AE preferred term. The number and 
percentage of patients with TEAEs will be summarized, as well as the number and 
percentage of patients with TEAEs assessed by the Investigator as at least possibly 
related to treatment. The number and percentage of patients with any Grade ≥ 3 TEAE 
will be tabulated in the same manner. In the event that a patient experiences repeated 
episodes of the same TEAE, the event with the highest severity and/or strongest causal 
relationship to study treatment will be used for purposes of tabulations. Serious AEs 
(SAEs) will also be tabulated. No formal hypothesis-testing analysis of AE incidence 
rates will be performed. 
 
All AEs (treatment emergent and post-treatment) will be listed in patient data listings. 
Separate by-patient listings will be provided for the following: patient deaths, SAEs, and 
AEs leading to withdrawal. 
 
The actual value and change from baseline for each on study evaluation will be 
summarized for each clinical laboratory parameter, including hematology and clinical 
chemistry, and for all study patients combined. In the event of repeat values, the last 
non-missing value per study day/time will be used. Severity of select clinical lab 
measures will be determined using CTCAE criteria (i.e., those measures that have a 
corresponding CTCAE grade classification). Labs with CTCAE Grades ≥ 3 will be 
presented in a data listing. Shift tables that present changes from baseline to worst on-
study values relative to CTCAE classification ranges will be produced. 
 
The actual value and change from baseline to each on-study evaluation will be 
summarized for vital signs for all study patients combined. By-patient listings of vital sign 
measurements will be presented in data listings.  
 
Physical examination results at screening will be summarized; all other abnormal 
physical examination data were to be recorded on the AE eCRF. All examination 
findings will be presented in a data listing. 
 
The use of concomitant medications will be included in by-patient data listings. 
 


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12.4.3 Analysis of Exploratory Endpoints 
 
Duration of Response (DOR) will be analyzed by Kaplan-Meier descriptive statistics for 
patients who have a response of sCR, CR, VGPR or PR, as assessed by IMWG criteria. 
DOR will be calculated as the number of days from the date of the first evidence of 
response until progression or death. Patients who have not progressed at the time of 
analysis will be censored at the last available assessment date at which no evidence of 
disease was observed. Estimates will include the 25th, 50th (median), and 75th 
percentiles and associated 95% CIs, as well as the number and percentage of censored 
patients. 
 
The clinical benefit rate (CBR) will be performed by calculating the point estimate of the 
percentage of patients who have a response of sCR, CR, VGPR, PR or MR, as 
assessed by IMWG criteria. Analysis will be performed by calculation of the point 
estimate of CBR, as well as a two-sided 95% CI, using exact methods. 
 
The disease control rate (DCR) will be performed by calculating the point estimate of the 
percentage of patients who have a response of sCR, CR, VGPR, PR, MR or SD, as 
assessed by IMWG criteria. Analysis will be performed by calculation of the point 
estimate of DCR, as well as a two-sided 95% CI, using exact methods. 
 
Progression-free Survival (PFS) will be calculated from the date of start of study therapy 
to the date of progression based on IMWG criteria, or date of death due to any cause 
should progression not have occurred. Patients who drop out prior to study end will be 
censored at the last available assessment date at which no evidence of disease was 
observed. The analysis of PFS will be based on the Kaplan-Meier method for estimation 
of summary statistics, and include the 25th, 50th (median), and 75th percentiles and 
associated 95% CIs. 
 
Overall Survival (OS) will be calculated from the date of start of study therapy to the date 
of death due to any cause. This analysis will be performed in the same manner as the 
analysis of PFS. 
 
Patients will be provided medication diaries at the beginning of each cycle. Delivered 
dose intensity will be assessed on day 1 of each cycle starting on cycle 2; defined as the 
total amount of study drug taken in one cycle.  
 
The standard dose intensity is defined as the cumulative planned dose for cycle 1.  
 
The relative dose intensity (RDI) is calculated by dividing the average delivered dose 
intensity over the standard dose intensity, expressed as a percentage. 
 
Quality of life (QOL) will be assessed by completing the Functional Assessment of 
Cancer Therapy - MM (FACT-MM) (Appendix 5) questionnaire as outlined in Table 2. 
The FACT-MM questionnaire consists of the four core FACT HRQoL subscales 
measuring physical, functional, social, and emotional well-being (FACT-G; 27 items) and 
an additional subscale (MM subscale) measuring MM-specific concerns (14 items). 
Items are rated using a 0- to 4-point scale based on the past 7 days, with higher scores 
indicating better HRQoL and fewer MM-related symptoms. The actual value and change 
from baseline of each subscale and total score will be summarized for all study patients 


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combined. By-patient listings of each subscale and total score will be presented in data 
listings.  
 
 
12.5 Interim Analysis 
 
As stated above, the study design is a two-stage design. In the first stage, 18 patients will be 
accrued. If there are 6 or fewer responses in these 18 patients, the study will be stopped. 
Otherwise, 8 additional patients will be accrued for a total of 26. 
 
12.6 Reporting and Exclusions 
 
12.6.1 Evaluation of Toxicity 
 
All subjects will be evaluable for toxicity from the time of their first treatment with 
ClaSPD. 
 
12.6.2 Evaluation of Response 
 
All subjects included in the study will be assessed for response to treatment if they have 
received at least one treatment dose. 
 
13. Adverse Event Reporting Requirements  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
investigator will be required to provide appropriate information concerning any findings that 
suggest significant hazards, contraindications, side effects, or precautions pertinent to the safe 
use of the drug or device under investigation.  Safety will be monitored by evaluation of adverse 
events reported by subjects or observed by investigators or research staff, as well as by other 
investigations such as clinical laboratory tests, x-rays, electrocardiographs, etc. 
 
13.1 Adverse Event Definitions 
 
• 
Adverse event (AE): Any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of 
study treatment, whether or not considered related to the study treatment.  
• 
Life-threatening adverse event or life-threatening suspected adverse reaction: An 
adverse event or suspected adverse reaction is considered "life-threatening" if, in the 
view of either the investigator or sponsor, its occurrence places the patient or subject 
at immediate risk of death. It does not include an adverse event or suspected 
adverse reaction that, had it occurred in a more severe form, might have caused 
death. 
• 
Treatment-emergent adverse event (TEAE): Any event that was not present prior to 
the initiation of study treatment or any event already present that worsens in either 
intensity or frequency following exposure to study treatment.  
• 
Serious adverse event (SAE): Any untoward medical occurrence that, at any dose, 


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results in death; is life threatening (ie, an event in which the patient was at risk of 
death at the time of the event; it does not refer to an event that hypothetically might 
have caused death if it were more severe); requires inpatient hospitalization or 
prolongation of existing hospitalization; results in persistent or significant 
disability/incapacity; or is a congenital anomaly/birth defect. Important medical 
events that may not result in death, be life-threatening, or require hospitalization may 
be considered serious when, based upon appropriate medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse.  
• 
Suspected adverse reaction: Any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety 
reporting, "reasonable possibility" means there is evidence to suggest a causal 
relationship between the drug and the adverse event. Suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction, which 
means any adverse event caused by a drug. 
• 
Unexpected adverse event or unexpected suspected adverse reaction: An adverse 
event or suspected adverse reaction is considered "unexpected" if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been 
observed; or, if an investigator brochure is not required or available, is not consistent 
with the risk information described in the general investigational plan or elsewhere in 
the current application, as amended. For example, under this definition, hepatic 
necrosis would be unexpected (by virtue of greater severity) if the investigator 
brochure referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater 
specificity) if the investigator brochure listed only cerebral vascular accidents. 
"Unexpected," as used in this definition, also refers to adverse events or suspected 
adverse reactions that are mentioned in the investigator brochure as occurring with a 
class of drugs or as anticipated from the pharmacological properties of the drug, but 
are not but are not specifically mentioned as occurring with the particular drug under 
investigation. 
 
 
13.1.1 Expected Adverse Events 
 
Please refer to the package insert included in the Appendix for each of the components 
of the study treatment (ClaSPd). 
 
13.1.2 Adverse Event Characteristics and Related Attributions 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting.  A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site (http://ctep.cancer.gov). 
 
The severity of the AE will be graded by the Investigator according to the CTCAE 
Grading Scale, version 5.0. If NCI CTCAE grading does not exist for an AE, the severity 


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will be characterized as “mild,” “moderate,” “severe,” or “life-threatening (corresponding 
to Grades 1 to 4) according to the following definitions: 
 
• 
Grade 1 (Mild) events are usually transient and do not interfere with the patient’s 
daily activities. 
• 
Grade 2 (Moderate) events introduce a low level of inconvenience or concern to 
the patient and may interfere with daily activities. 
• 
Grade 3 (Severe) events interrupt the patient’s usual daily activities. 
• 
Grade 4 events are Life-threatening. 
 
The term “severe” is used to describe the intensity of an AE; the event itself could be of 
relatively minor clinical significance (e.g., ‘severe’ headache). This is not the same as a 
“serious” AE. 
 
 
Causality of the AE: 
• 
Not related: The lack of a strong temporal relationship of the event to the study 
treatment makes a causal relationship not reasonably possible, or other drugs, 
therapeutic interventions, or underlying conditions provide a sufficient 
explanation. 
• 
Related: The temporal relationship of the event to the study treatment makes a 
definitive relationship, and the event is more likely explained by exposure to the 
study treatment than by any other drugs, therapeutic interventions, or underlying 
conditions. 
 
 
 
13.1.3 Recording of Adverse Events 
 
All AEs that begin or worsen after the patient has provided informed consent will be 
recorded on the AE eCRF, regardless of whether dosing with study drug has 
commenced. AE monitoring should be continued for at least 30 days following the last 
dose of study treatment (i.e., through 30 days following last dose or until resolution or 
through the end of the study for events considered related to study treatment by the 
Investigator). AEs (including laboratory abnormalities that constitute AEs) should be 
described using a diagnosis whenever possible, rather than individual underlying signs 
and symptoms. When a clear diagnosis cannot be identified, each sign or symptom 
should be recorded as a separate AE. 
 
The Investigator should ask the patient non-leading questions to determine if AEs occur 
during the study. AEs may also be recorded when they are volunteered by the patient, or 
through physical examination, laboratory tests, or other clinical assessments.  
 
An AE should be followed until its resolution or until it is judged to be permanent, and 
assessment should be made at each visit (or more frequently, if necessary) of any 
changes in severity of the event, the suspected relationship to the study treatment, the 
interventions required to treat the event, and the outcome. 
 
Laboratory abnormalities that constitute an AE in their own right (i.e., are considered to 
be clinically significant, induce clinical signs or symptoms, require concomitant therapy, 
or require changes in study treatment), should be recorded on the Adverse Events 
eCRF. 


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Whenever possible, a diagnosis, rather than a symptom should be provided (e.g., 
anemia instead of low hemoglobin). Laboratory abnormalities that meet the criteria for an 
AE should be followed until they have returned to baseline (at screening) or an adequate 
explanation of the abnormality is identified. When an abnormal laboratory or test result 
corresponds to a sign/symptom of an already reported AE, it is not necessary to 
separately record the laboratory/test result as an additional event. 
 
A laboratory abnormality that does not meet the definition of an AE should not be 
reported as an AE. A Grade 3 or 4 event (severe per NCI CTCAE version 5.0) does not 
automatically indicate an SAE unless it meets the definition of serious, as defined above, 
and/or as per Investigator’s discretion. A laboratory abnormality that results in a dose 
being held or modified would, by definition, be an AE and must be recorded as such in 
the eCRFs. 
 
13.1.4 Reporting of AE to WCM IRB 
 
All AEs occurring on this study will be reported to the IRB according to the IRB policy, 
which can be accessed via the following link:  
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immediate_Reporting
_Policy.pdf.  
 
13.1.5 Reporting Events to Participants 
 
The investigator or co-investigator will inform each participant about AEs and SAEs, and 
study-related results on an individual level. In addition, incidental findings associated 
with study procedures will be disclosed at the earliest opportunity to the participant.    
 
13.1.6 Events of Special Interest 
All secondary primary malignancies will be captured and reported as an AE. 
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are 
unexpected and judged by the Investigator or Karyopharm to be related to the study 
treatment administered. SUSARs will be collected and reported to the competent 
authorities and relevant ethics committees in accordance with the FDA’s “Safety 
Reporting Requirements for Investigational New Drugs and Bioanalytical/Bioequivalence 
Studies” or as per national regulatory requirements in participating countries. 
In the event that an overdose is associated with an SAE, the SAE report form must be 
submitted to the IRB and Karyopharm Pharmacovigilance within 24 hours of awareness. 
 
13.1.7 Reporting of Pregnancy 
 
Pregnancy per se is not considered to be an AE; however, it is discussed here because 
of the importance of reporting pregnancies that occur during studies and because a 
medical occurrence observed in the mother or fetus/newborn would be classified as an 
AE. To ensure patient safety, a pregnancy occurring while the patient is on study 
treatment must be reported to Karyopharm Pharmacovigilance by email or fax within 24 
hours of first knowledge of its occurrence as well as to the Pomalidomide REMS 


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program. 
 
The pregnancy should be followed up to determine outcome, including spontaneous or 
voluntary termination, details of the birth, and the presence or absence of any birth 
defects, congenital abnormalities, or maternal and/or newborn complications. 
Pregnancies must be reported to Karyopharm, regardless of whether the patient 
received selinexor or other study drugs, regardless of whether the patient withdraws 
from the study or the study is completed, for 3 months after the patient receives his/her 
last dose of study treatment. Patients should be instructed to inform the Investigator 
regarding any 
pregnancies. 
 
Any SAE that occurs during pregnancy must be recorded on the SAE report form (e.g., 
maternal serious complications, therapeutic abortion, ectopic pregnancy, stillbirth, 
neonatal death, congenital anomaly, birth defect) and reported within 24 hours in 
accordance with the procedure for reporting SAEs. 
 
A pregnancy in a female partner of a male patient must be reported to Karyopharm and 
the Pomalyst REMS program within 24 hours of learning of its occurrence.  
 
13.2 Definition of SAE 
 
Any untoward medical occurrence that, at any dose, results in death; is life threatening 
(ie, an event in which the patient was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were more severe); 
requires inpatient hospitalization or prolongation of existing hospitalization; results in 
persistent or significant disability/incapacity; or is a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse.  
 
Please note that SAEs that occur at any time between the signing of the ICF up to the 
first dose of study treatment, must be reported (in addition to SAEs that occur after the 
first dose of study treatment). 
 
Hospitalizations for elective surgery or other medical procedures that are not due to an 
AE are not considered SAEs. A hospitalization meeting the regulatory definition for 
‘serious’ is any inpatient hospital admission that includes a minimum of an overnight stay 
in a health care facility greater than 24 hours or results in a prolongation of a current 
hospitalization. An emergency room visit is not considered a hospitalization unless it 
results in an official admission to the hospital. 
 
Progression of the malignancy (including fatal outcomes) should not be reported as an 
SAE during the study or within the safety reporting period. Sudden and unexplained 
death should be reported as an SAE. If there is any uncertainty about a finding being 
due solely to progression of malignancy, the finding should be reported as an AE or 


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SAE, as appropriate. 
 
Progression of the malignancy (including fatal outcomes) if documented per IMWG 
criteria for progression of MM (see Appendix 4), should not be reported as an SAE 
during the study or within the safety reporting period (see below). 
 
The Investigator will record and document all SAEs occurring from the signing of the ICF 
until at least 30 days after the patient has stopped study treatment. All SAEs must be 
reported on the SAE Report Form in addition to being recorded in the eCRF. The original 
SAE report form must be retained in the Investigator’s site file. 
 
All applicable sections of the form must be completed in order to provide a clinically 
thorough report. The Investigator must assess and record the relationship of each SAE 
to study treatment and complete the SAE Report Form. Key data elements required for 
expedited reporting will follow ICH E2A standards (Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting). 
 
13.2.1 Reporting of SAE to IRB 
 
All SAEs occurring on this study will be reported to the IRB according to the IRB policy, 
which can be accessed via the following link: 
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immediate_Reporting
_Policy.pdf.  
 
13.2.2 Reporting of SAE to FDA 
 
The Investigator must report any suspected adverse reaction or adverse reaction 
to study treatment that is both serious and unexpected. Unexpected fatal or life-
threatening suspected adverse reactions represent especially important safety 
information and must be reported to FDA as soon as possible but no later than 7 
calendar days following the sponsor’s initial receipt of the information. 
i. death, 
ii. a life-threatening adverse event,   
iii. in-patient hospitalization or prolongation of existing hospitalization, 
iv. a persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions, or   
v. a congenital anomaly or birth defect 
 
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient or research subject and may 
require medical or surgical intervention to prevent one of the outcomes listed as 
serious 
 
CDER INDs:  
Food and Drug Administration 
Center for Drug Evaluation and Research 
Division of Hematologic Malignancies  


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5901-B Ammendale Road  
Beltsville, MD 20705-1266  
 
13.2.3 Reporting of SAE to Karyopharm Therapeutics, Inc. 
 
Every SAE, regardless of the causal relationship to the study treatment, occurring after the 
patient has signed informed consent, until at least 30 days after the patient has stopped 
study treatment, must be reported to the Karyopharm Pharmacovigilance Department within 
24 hours of learning of its occurrence. The investigational site personnel must use the SAE 
Report Form provided by Karyopharm for reporting any SAE to the Karyopharm 
Pharmacovigilance Department, including: 
 
• 
Protocol number 
• 
Site and/or Investigator’s number 
• 
Patient’s number 
• 
Brief description of the event 
• 
Resolution date and time, if the event resolved 
• 
Any medication administered to treat the event 
• 
Investigator’s assessment of the SAE’s relationship to investigational 
product 
• 
Outcome of the event on the date of report 
 
Upon completion, the SAE Report Form must be immediately emailed or faxed to: 
 
Pharmacovigilance Department 
Karyopharm Therapeutics Inc. 
Email: pharmacovigilance@karyopharm.com 
Fax: +1-617-334-7617 (USA) 
+49-89-9218-5650 (Germany) 
 
Any SAE observed after the 30-day follow-up period should only be reported to Karyopharm 
if the Investigator suspects that the SAE has a causal relationship to study treatment. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode within 24 hours of the Investigator receiving the follow-up 
information. 
 


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An SAE should be followed until its resolution or until it is judged to be permanent, and 
assessment should be made at each visit (or more frequently, if necessary) of any changes 
in severity of the event, the suspected relationship to the study treatment, the interventions 
required to treat the event, and the outcome. 
 
13.2.4 Reporting of SAE to WCM by Sub-sites 
 
Within 24 of the Investigator’s knowledge of the event, participating sites must report SAE to 
WCM by sending the following forms via email to jctoiit@med.cornell.edu: 
 
WCM SAE Cover Sheet 
• 
Karyopharm SAE form 
• 
Form FDA 3500A for Mandatory Reporting (MedWatch) 
https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM0
48334.pdf 
 
The SAE should be reported to the participating site’s institutional regulatory board (IRB), as 
per institutional guidelines.  Proof of submission and IRB acknowledgment should be sent 
via email to jctoiit@med.cornell.edu when received. 
WCM (Sponsor-investigator) is responsible for reporting the SAE to the Karyopharm 
Therapeutics, the FDA, and any other applicable regulatory agencies. 
 
13.3 AE/SAE Follow Up 
 
All SAEs and AEs reported during this study will be followed until resolution or until the 
investigator confirms that the AE/SAE has stabilized, and no more follow-up is required. 
This requirement indicates that follow-up may be required for some events after the 
subject discontinues participation from the study, as outlined in the Follow Up Phase 
above.  
 
13.4 Time Period and Frequency for Event Assessment and Follow Up 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to 
the attention of study personnel during study visits and interviews of a study participant 
presenting for medical care, or upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be 
captured on the appropriate case report form (CRF). Information to be collected includes 
event description, time of onset, clinician’s assessment of severity, relationship to study 
treatment (assessed only by those with the training and authority to make a diagnosis), 
and time of resolution/stabilization of the event. All AEs occurring while on study must be 


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documented appropriately regardless of relationship. All AEs will be followed to 
adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s 
condition deteriorates at any time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the 
duration of the event at each level of severity to be performed. AEs characterized as 
intermittent require documentation of onset and duration of each episode. 
 
 
The investigator or research nurse will record all reportable events with start dates 
occurring any time after informed consent is obtained until 7 (for non-serious AEs) or 30 
days (for SAEs) after the last day of study participation.  At each study visit, the 
investigator will inquire about the occurrence of AE/SAEs since the last visit.  Events will 
be followed for outcome information until resolution or stabilization. 
 
14. Unanticipated Problems Involving Risks to Subjects or Others 
 
14.1 Definition of Unanticipated Problems Involving Risks to Subjects or Others 
(UPIRTSO) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems 
involving risks to participants or others to include, in general, any incident, experience, or 
outcome that meets all of the following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 
Board (IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously known 
or recognized. 
 
14.1.2 Unanticipated Problem Reporting 
 
The investigator will report unanticipated problems (UPIRTSOs) to the reviewing 
Institutional Review Board (IRB) and to the Data Coordinating Center (DCC)/lead 
principal investigator (PI). The UPIRTSO report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the 
IRB project number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, 
or outcome represents an UPIRTSO;  
• 
A description of any changes to the protocol or other corrective actions that have 
been taken or are proposed in response to the UPIRTSO. 


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To satisfy the requirement for prompt reporting, UPIRTSOs will be reported using the 
following timeline:   
 
• 
UPIRTSOs that are serious adverse events (SAEs) will be reported to the IRB 
and to the DCC/study sponsor within <insert timeline in accordance with policy> 
of the investigator becoming aware of the event.  
• 
Any other UPIRTSO will be reported to the IRB and to the DCC/study sponsor 
within <insert timeline in accordance with policy> of the investigator becoming 
aware of the problem.  
• 
All UPs should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or 
designee), Food and Drug Administration (FDA), and the Office for Human 
Research Protections (OHRP) within <insert timeline in accordance with policy> 
of the IRB’s receipt of the report of the problem from the investigator. 
 
15. Data and Safety Monitoring Plan (DSMP) 
 
Weill Cornell Medicine Data and Safety Monitoring Committee (WCM DSMC) will be 
composed of medical and statistical independent reviewers and will meet to review the 
efficacy and safety data and determine a risk/benefit analysis in this subject population. The 
purpose of the WCM DSMC is to advise on serious safety considerations, lack of efficacy and 
any other considerations within the charge to the Committee. The WCM DSMC may request 
additional meetings or safety reports as deemed necessary upon discussion with Karyopharm 
Therapeutics and its representatives. The PI, Dr. Jorge Monge, will be the safety contact for 
all WCM DSMC related analysis outcomes and can be contacted at:  
 
Weill Cornell Medicine Myeloma Center 
425 E 61st St, 8th Floor 
New York, NY 10065 
Phone: +1-646-962-6500 
Fax: +1-212-746-8961 
Email: jum9127@med.cornell.edu 
 
The WCM DSMC may stop the study following review of results from each interim analysis. 
The first interim analysis will take place 3 months after the study begins subject accrual or 
after 6 patients have been enrolled, whichever occurs first, and will examine the safety and 
tolerability of minimum one cycle of study treatment prior to enrolling additional subjects. A 
subsequent interim analysis will take place 6 months after the study begins subject accrual or 
after 12 patients have been enrolled, whichever occurs first, and every six months thereafter, 
and will examine both safety and efficacy. The WCM DSMC will also review the study at the 
end of the first stage of accrual (18 patients) including toxicity data, protocol adherence, and 
protocol deviations. Efficacy and safety data summaries will be provided to the WCM DSMC 
after each interim analysis.  
 
Early discontinuation of the study may result from the following study-terminating events: 
 
1. Any abrupt or unexpected patient death that appears to be related to study medication. 
2. Early death (defined by death within 30 days of beginning therapy) of more than 50% 
of subjects at any interim analysis. 


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3. Early need for hospitalization (defined by hospitalization within 30 days of beginning 
therapy) of more than 50% of subjects at any interim analysis. 
4. Unacceptable toxicity (defined by a Grade 4 or higher drug-related adverse event) in 
more than 50% of subjects at any interim analysis. 
5. The interim stopping rule for the study is defined by statistical futility of the ClaSPD 
regimen, as outlined in the two-stage study design. 
 
The WCM DSMC will submit their comments/review to the IRB at the time of continuing review 
and to participating sites upon receipt of review comments.  
 
Written documentation will be provided to investigators and regulatory agencies if the protocol 
is stopped or paused for toxicity concerns. 
 
 
 


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16. References 
 
1. 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7-30. 
2. 
Munshi NC, Avet-Loiseau H, Rawstron AC, et al. Association of Minimal Residual Disease 
With Superior Survival Outcomes in Patients With Multiple Myeloma: A Meta-analysis. JAMA 
Oncol. 2017;3(1):28-35. 
3. 
Coleman M, Leonard J, Lyons L, et al. BLT-D (clarithromycin [Biaxin], low-dose thalidomide, 
and dexamethasone) for the treatment of myeloma and Waldenström's macroglobulinemia. 
Leuk Lymphoma. 2002;43(9):1777-1782. 
4. 
Gay F, Rajkumar SV, Coleman M, et al. Clarithromycin (Biaxin)-lenalidomide-low-dose 
dexamethasone (BiRd) versus lenalidomide-low-dose dexamethasone (Rd) for newly 
diagnosed myeloma. Am J Hematol. 2010;85(9):664-669. 
5. 
Mark TM, Bowman IA, Rossi AC, et al. Thalidomide, clarithromycin, lenalidomide and 
dexamethasone therapy in newly diagnosed, symptomatic multiple myeloma. Leuk 
Lymphoma. 2014;55(12):2842-2849. 
6. 
Mark TM, Forsberg PA, Rossi AC, et al. Phase 2 study of clarithromycin, pomalidomide, and 
dexamethasone in relapsed or refractory multiple myeloma. Blood Adv. 2019;3(4):603-611. 
7. 
Niesvizky R, Jayabalan DS, Christos PJ, et al. BiRD (Biaxin [clarithromycin]/Revlimid 
[lenalidomide]/dexamethasone) combination therapy results in high complete- and overall-
response rates in treatment-naive symptomatic multiple myeloma. Blood. 2008;111(3):1101-
1109. 
8. 
Rossi A, Mark T, Jayabalan D, et al. BiRd (clarithromycin, lenalidomide, dexamethasone): 
an update on long-term lenalidomide therapy in previously untreated patients with multiple 
myeloma. Blood. 2013;121(11):1982-1985. 
9. 
Chari A, Vogl DT, Gavriatopoulou M, et al. Oral Selinexor-Dexamethasone for Triple-Class 
Refractory Multiple Myeloma. N Engl J Med. 2019;381(8):727-738. 
10. 
Chen CI, Bahlis N, Gasparetto C, et al. Selinexor plus pomalidomide and low dose 
dexamethasone (SPd) in patients with relapsed or refractory multiple myeloma. Blood. 
2019;134(Supplement 1):141. 
11. 
Chen C, Siegel D, Gutierrez M, et al. Safety and efficacy of selinexor in relapsed or 
refractory multiple myeloma and Waldenstrom macroglobulinemia. Blood. 2018;131(8):855-
863. 
12. 
Fost DA, Leung DY, Martin RJ, Brown EE, Szefler SJ, Spahn JD. Inhibition of 
methylprednisolone elimination in the presence of clarithromycin therapy. J Allergy Clin 
Immunol. 1999;103(6):1031-1035. 
13. 
Qiu XH, Shao JJ, Mei JG, Li HQ, Cao HQ. Clarithromycin Synergistically Enhances 
Thalidomide Cytotoxicity in Myeloma Cells. Acta Haematol. 2016;135(2):103-109. 


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14. 
Nakamura M, Kikukawa Y, Takeya M, Mitsuya H, Hata H. Clarithromycin attenuates 
autophagy in myeloma cells. Int J Oncol. 2010;37(4):815-820. 
15. 
Puig N, Hernández MT, Rosinol Dachs L, et al. Randomized Trial of Lenalidomide and 
Dexamethasone Versus Clarythromycin, Lenalidomide and Dexamethasone As First Line 
Treatment in Patients with Multiple Myeloma Not Candidates for Autologous Stem Cell 
Transplantation: Results of the GEM-Claridex Clinical Trial. Blood. 
2019;134(Supplement_1):694. 
16. 
Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low dose 
dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple 
myeloma (MM). Leukemia. 2010;24(11):1934-1939. 
17. 
Lacy MQ, Allred JB, Gertz MA, et al. Pomalidomide plus low-dose dexamethasone in 
myeloma refractory to both bortezomib and lenalidomide: comparison of 2 dosing strategies 
in dual-refractory disease. Blood. 2011;118(11):2970-2975. 
18. 
Leleu X, Attal M, Arnulf B, et al. Pomalidomide plus low-dose dexamethasone is active and 
well tolerated in bortezomib and lenalidomide-refractory multiple myeloma: Intergroupe 
Francophone du Myélome 2009-02. Blood. 2013;121(11):1968-1975. 
19. 
Miguel JS, Weisel K, Moreau P, et al. Pomalidomide plus low-dose dexamethasone versus 
high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma 
(MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14(11):1055-1066. 
20. 
Richardson PG, Siegel DS, Vij R, et al. Pomalidomide alone or in combination with low-dose 
dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. 
Blood. 2014;123(12):1826-1832. 
21. 
Attal M, Richardson PG, Rajkumar SV, et al. Isatuximab plus pomalidomide and low-dose 
dexamethasone versus pomalidomide and low-dose dexamethasone in patients with 
relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-
label, phase 3 study. Lancet. 2019;394(10214):2096-2107. 
22. 
Baz RC, Martin TG, Lin HY, et al. Randomized multicenter phase 2 study of pomalidomide, 
cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood. 
2016;127(21):2561-2568. 
23. 
Chari A, Suvannasankha A, Fay JW, et al. Daratumumab plus pomalidomide and 
dexamethasone in relapsed and/or refractory multiple myeloma. Blood. 2017;130(8):974-
981. 
24. 
Dimopoulos MA, Dytfeld D, Grosicki S, et al. Elotuzumab plus Pomalidomide and 
Dexamethasone for Multiple Myeloma. N Engl J Med. 2018;379(19):1811-1822. 
25. 
Bringhen S, Mina R, Cafro AM, et al. Once-weekly carfilzomib, pomalidomide, and low-dose 
dexamethasone for relapsed/refractory myeloma: a phase I/II study. Leukemia. 
2018;32(8):1803-1807. 


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26. 
Krishnan A, Kapoor P, Palmer JM, et al. Phase I/II trial of the oral regimen ixazomib, 
pomalidomide, and dexamethasone in relapsed/refractory multiple myeloma. Leukemia. 
2018;32(7):1567-1574. 
27. 
Larocca A, Montefusco V, Bringhen S, et al. Pomalidomide, cyclophosphamide, and 
prednisone for relapsed/refractory multiple myeloma: a multicenter phase 1/2 open-label 
study. Blood. 2013;122(16):2799-2806. 


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17. Appendices 
 
Appendix 1. Cytochrome P450 Drug Interactions 
 
 
 


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Source: Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana 
University School of Medicine (2007). "https://drug-interactions.medicine.iu.edu" Accessed 
01/20/2020. 
 
 
Appendix 2. Glutathione (GSH)-, S-adenosylmethionine (SAM)-, or N-acetylcysteine 
(NAC)-Containing Products 
  
Glutathione (GSH) 
S-adenosylmethionine (SAM) 
N-acetylcysteine 
(NAC) 
Product Name 
Ingredient 
Product Name 
Ingredient 
Product 
Name 
Ingredient 
Glutathione  
glutathione 
Acetadote for 
acetaminophen 
overdose 
acetylcysteine 
SAM-e 
Complete 
S-
adenosyl-
methionine 
L-Glutathione 
L-
glutathione 
Cerefolin NAC: 
medical food for 
age-related 
memory loss 
L-methylfolate, 
vitamin B12, 
N-acetyl 
cysteine 
SAMe 
S-
adenosyl-
L-
methionine 
Glutathione 
reduced 
glutathione 
NAC 
N-acetyl 
cysteine 
Double 
Strength 
SAMe 
400 
S-
adenosyl-
methionine 
Reduced 
glutathione with 
alpha lipoic 
acid 
Setria L-
glutathione 
N-A-C Sustain 
N-acetyl L-
cysteine 
 
 
Glutathione, 
Cysteine & C 
Glutathione, 
L-cysteine, 
vitamin C 
Best NAC Detox 
Regulators 
N-acetyl 
cysteine 
 
 


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(Mega-) 
Liposomal 
Glutathione 
glutathione 
 
 
 
 
Lypospheric 
GSH 
glutathione 
 
 
 
 
Ivory Caps 
Skin 
Enhancement 
Formula 
glutathione 
 
 
 
 
 
 
Appendix 3. Eastern Cooperative Oncology Group (ECOG) Performance Status Scale 
 
ECOG Performance Status Scale 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work). 
2 
In bed < 50% of the time. Ambulatory and capable of all self-care, but unable to 
carry out any work activities. Up and about more than 50% of waking hours. 
3 
In bed > 50% of the time. Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair. 
5 
Dead. 
 
Source: Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655. 
 
 
Appendix 4. International Myeloma Working Group (IMWG) Response Criteria 
 
Category 
Response Criteria 
IMWG MRD criteria (requires a complete response as defined below) 
Sustained 
MRD-negative 
MRD negativity in the marrow (NGF or NGS, or both) and by imaging as 
defined below, confirmed minimum of 1 year apart. Subsequent evaluations 
can be used to further specify the duration of negativity (eg, MRD-negative 
at 5 years)† 
Flow MRD-
negative 
Absence of phenotypically aberrant clonal plasma cells by NGF‡ on bone 
marrow aspirates using the EuroFlow standard operation procedure for 
MRD detection in multiple myeloma (or validated equivalent method) with a 
minimum sensitivity of 1 in 105 nucleated cells or higher 
Sequencing 
MRD-negative 
Absence of clonal plasma cells by NGS on bone marrow aspirate in which 
presence of a clone is defined as less than two identical sequencing reads 
obtained after DNA sequencing of bone marrow aspirates using a validated 
method with a minimum sensitivity of 1 in 105 nucleated cells§ or higher 


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Imaging plus 
MRD-negative 
MRD negativity as defined by NGF or NGS plus disappearance of every 
area of increased tracer uptake found at baseline or a preceding PET/CT or 
decrease to less mediastinal blood pool SUV or decrease to less than that 
of surrounding normal tissue¶ 
Standard IMWG response criteria‖ 
Stringent 
complete 
response 
Complete response as defined below plus normal FLC ratio** and absence 
of clonal cells in bone marrow biopsy by immunohistochemistry (κ/λ ratio 
≤4:1 or ≥1:2 for κ and λ patients, respectively, after counting ≥100 plasma 
cells)†† 
Complete 
response 
Negative immunofixation on the serum and urine and disappearance of any 
soft tissue plasmacytomas and <5% plasma cells in bone marrow aspirates 
Very good 
partial 
response 
Serum and urine M-protein detectable by immunofixation but not on 
electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein 
level <100 mg per 24 h 
Partial 
response 
≥50% reduction of serum M-protein plus reduction in 24 h urinary M-protein 
by ≥90% or to <200 mg per 24 h; 
If the serum and urine M-protein are unmeasurable, a ≥50% decrease in the 
difference between involved and uninvolved FLC levels is required in place 
of the M-protein criteria; 
If serum and urine M-protein are unmeasurable, and serum-free light assay 
is also unmeasurable, ≥50% reduction in plasma cells is required in place of 
M-protein, provided baseline bone marrow plasma-cell percentage was 
≥30%. In addition to these criteria, if present at baseline, a ≥50% reduction in 
the size (SPD)§§ of soft tissue plasmacytomas is also required 
Minimal 
response 
≥25% but ≤49% reduction of serum M-protein and reduction in 24-h urine M-
protein by 50–89%. In addition to the above listed criteria, if present at 
baseline, a ≥50% reduction in the size (SPD)§§ of soft tissue 
plasmacytomas is also required 
Stable disease 
Not recommended for use as an indicator of response; stability of disease is 
best described by providing the time-to-progression estimates. Not meeting 
criteria for complete response, very good partial response, partial response, 
minimal response, or progressive disease 
Progressive 
disease ¶¶,‖‖ 
Any one or more of the following criteria: 
Increase of 25% from lowest confirmed response value in one or more of 
the following criteria: 
Serum M-protein (absolute increase must be ≥0·5 g/dL); 
Serum M-protein increase ≥1 g/dL, if the lowest M component was ≥5 g/dL; 
Urine M-protein (absolute increase must be ≥200 mg/24 h); 
In patients without measurable serum and urine M-protein levels, the 
difference between involved and uninvolved FLC levels (absolute increase 
must be >10 mg/dL); In patients without measurable serum and urine M-
protein levels and without measurable involved FLC levels, bone marrow 
plasma-cell percentage irrespective of baseline status (absolute increase 
must be ≥10%); 
Appearance of a new lesion(s), ≥50% increase from nadir in SPD§§ of >1 
lesion, or ≥50% increase in the longest diameter of a previous lesion >1 cm 
in short axis; 
≥50% increase in circulating plasma cells (minimum of 200 cells per μL) if 
this is the only measure of disease 


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Clinical 
relapse 
Clinical relapse requires one or more of the following criteria: 
Direct indicators of increasing disease and/or end organ dysfunction (CRAB 
features) related to the underlying clonal plasma-cell proliferative disorder. It 
is not used in calculation of time to progression or progression-free survival 
but is listed as something that can be reported optionally or for use in clinical 
practice; 
Development of new soft tissue plasmacytomas or bone lesions 
(osteoporotic fractures do not constitute progression); 
Definite increase in the size of existing plasmacytomas or bone lesions. A 
definite increase is defined as a 50% (and ≥1 cm) increase as measured 
serially by the SPD§§ of the measurable lesion; 
Hypercalcemia (>11 mg/dL); 
Decrease in hemoglobin of ≥2 g/dL not related to therapy or other non-
myeloma-related conditions; 
Rise in serum creatinine by 2 mg/dL or more from the start of the therapy 
and attributable to myeloma; 
Hyperviscosity related to serum paraprotein 
Relapse from 
complete 
response (to 
be used only if 
the end point 
is disease-free 
survival) 
Any one or more of the following criteria: 
Reappearance of serum or urine M-protein by immunofixation or 
electrophoresis; 
Development of ≥5% plasma cells in the bone marrow; 
Appearance of any other sign of progression (ie, new plasmacytoma, lytic 
bone lesion, or hypercalcemia see above) 
Relapse from 
MRD negative 
(to be used 
only if the end 
point is 
disease-free 
survival) 
Any one or more of the following criteria: 
Loss of MRD negative state (evidence of clonal plasma cells on NGF or 
NGS, or positive imaging study for recurrence of myeloma); 
Reappearance of serum or urine M-protein by immunofixation or 
electrophoresis; 
Development of ≥5% clonal plasma cells in the bone marrow; 
Appearance of any other sign of progression (ie, new plasmacytoma, lytic 
bone lesion, or hypercalcemia) 
 
For MRD assessment, the first bone marrow aspirate should be sent to MRD (not for 
morphology) and this sample should be taken in one draw with a volume of minimally 2 mL (to 
obtain sufficient cells), but maximally 4–5 mL to avoid hemodilution. IMWG=International 
Myeloma Working Group. MRD=minimal residual disease. NGF=next-generation flow. 
NGS=next-generation sequencing. FLC=free light chain. M-protein=myeloma protein. SPD=sum 
of the products of the maximal perpendicular diameters of measured lesions. CRAB 
features=calcium elevation, renal failure, anemia, lytic bone lesions. FCM=flow cytometry. 
SUVmax=maximum standardized uptake value. MFC=multiparameter flow cytometry. 18F-FDG 
PET=18F-fluorodeoxyglucose PET. ASCT=autologous stem cell transplantation. 
 
* All response categories require two consecutive assessments made any time before starting 
any new therapy; for MRD there is no need for two consecutive assessments, but information 
on MRD after each treatment stage is recommended (e.g., after induction, high-dose 
therapy/ASCT, consolidation, maintenance). MRD tests should be initiated only at the time of 
suspected complete response. All categories of response and MRD require no known evidence 
of progressive or new bone lesions if radiographic studies were performed. However, 


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radiographic studies are not required to satisfy these response requirements except for the 
requirement of FDG PET if imaging MRD-negative status is reported. 
 
† Sustained MRD negativity when reported should also annotate the method used (e.g., 
sustained flow MRD-negative, sustained sequencing MRD-negative). 
 
‡ Bone marrow MFC should follow NGF guidelines. The reference NGF method is an eight-
color two-tube approach, which has been extensively validated. The two-tube approach 
improves reliability, consistency, and sensitivity because of the acquisition of a greater number 
of cells. The eight-color technology is widely available globally and the NGF method has already 
been adopted in many flow laboratories worldwide. The complete eight-color method is most 
efficient using a lyophilized mixture of antibodies which reduces errors, time, and costs. 5 million 
cells should be assessed. The FCM method employed should have a sensitivity of detection of 
at least 1 in 105 plasma cells. 
 
§ DNA sequencing assay on bone marrow aspirate should use a validated assay such as 
LymphoSIGHT (Sequenta), now ClonoSEQ (Adaptive). 
 
¶ Criteria used by Zamagni and colleagues, and expert panel (IMPetUs; Italian Myeloma criteria 
for PET Use). Baseline positive lesions were identified by presence of focal areas of increased 
uptake within bones, with or without any underlying lesion identified by CT and present on at 
least two consecutive slices. Alternatively, an SUVmax=2·5 within osteolytic CT areas >1 cm in 
size, or SUVmax=1·5 within osteolytic CT areas ≤1 cm in size were considered positive. 
Imaging should be performed once MRD negativity is determined by MFC or NGS. 
 
‖ When the only method to measure disease is by serum FLC levels: complete response can be 
defined as a normal FLC ratio of 0·26 to 1·65 in addition to the complete response criteria listed 
previously. Very good partial response in such patients requires a ≥90% decrease in the 
difference between involved and uninvolved FLC levels. All response categories require two 
consecutive assessments made at any time before the institution of any new therapy; all 
categories also require no known evidence of progressive or new bone lesions or 
extramedullary plasmacytomas if radiographic studies were performed. Radiographic studies 
are not required to satisfy these response requirements. Bone marrow assessments do not 
need to be confirmed. Each category, except for stable disease, will be considered unconfirmed 
until the confirmatory test is performed. The date of the initial test is considered as the date of 
response for evaluation of time dependent outcomes such as duration of response. 
 
** All recommendations regarding clinical uses relating to serum FLC levels or FLC ratio are 
based on results obtained with the validated Freelite test (Binding Site, Birmingham, UK). 
 
†† Presence/absence of clonal cells on immunohistochemistry is based upon the κ/λ/L ratio. An 
abnormal κ/λ ratio by immunohistochemistry requires a minimum of 100 plasma cells for 
analysis. An abnormal ratio reflecting presence of an abnormal clone is κ/λ of >4:1 or <1:2. 
 
‡‡ Special attention should be given to the emergence of a different monoclonal protein 
following treatment, especially in the setting of patients having achieved a conventional 
complete response, often related to oligoclonal reconstitution of the immune system. These 
bands typically disappear over time and in some studies have been associated with a better 
outcome. Also, appearance of monoclonal IgG κ in patients receiving monoclonal antibodies 
should be differentiated from the therapeutic antibody. 


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§§ Plasmacytoma measurements should be taken from the CT portion of the PET/CT, or MRI 
scans, or dedicated CT scans where applicable. For patients with only skin involvement, skin 
lesions should be measured with a ruler. Measurement of tumor size will be determined by the 
SPD. 
 
¶¶ Positive immunofixation alone in a patient previously classified as achieving a complete 
response will not be considered progression. For purposes of calculating time to progression 
and progression-free survival, patients who have achieved a complete response and are MRD-
negative should be evaluated using criteria listed for progressive disease. Criteria for relapse 
from a complete response or relapse from MRD should be used only when calculating disease-
free survival. 
 
‖‖ In the case where a value is felt to be a spurious result per physician discretion (eg, a 
possible laboratory error), that value will not be considered when determining the lowest value. 
 
Source: Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P, et al. International 
Myeloma Working Group consensus criteria for response and minimal residual disease 
assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328-e346. 
 
Appendix 5. Functional Assessment of Cancer Therapy - Multiple Myeloma (FACT-MM) 
 
Appended as a PDF file at the end of this document. Also available at:  
https://tinyurl.com/yb5rexhe 
 
Appendix 6. FDA Label (package insert) for Selinexor, Clarithromycin Pomalidomide and 
Dexamethasone 
 
Appended as 4 PDF files at the end of this document. Also available at:  
https://tinyurl.com/y7wl3gqf 
https://tinyurl.com/ybynjh4d 
https://tinyurl.com/y7bjfde9  
https://tinyurl.com/y83wmadx