A Multicenter, Randomized, Open-label Phase 2 Study Evaluating the Safety and Efficacy of Three Different Regimens of Oral Panobinostat in Combination With Subcutaneous Bortezomib and Oral Dexamethasone in Patients With Relapsed or Relapsed/Refractory Multiple Myeloma Who Have Been Previously Exposed to Immunomodulatory Agents
Phase: PHASE2
Conditions: Multiple Myeloma
Sponsor: pharmaand GmbH

Clinical Development 
LBH589 / Panobinostat / Farydak® 
Protocol CLBH589D2222 
A multicenter, randomized, open-label Phase 2 study 
evaluating the safety and efficacy of three different 
regimens of oral panobinostat in combination with 
subcutaneous bortezomib and oral dexamethasone in 
patients with relapsed or relapsed/refractory multiple 
myeloma who have been previously exposed to 
immunomodulatory agents 
Document type 
Amended Protocol Version 
EUDRACT number 
2015-001564-19 
Version number 
02 
Development phase 
II 
Document status 
Final 
Release date 
30-Oct-2019
Property of Secura Bio Inc. 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Secura Bio Inc. 
NCT #: NCT02654990

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Table of contents 
Table of contents ................................................................................................................. 2 
List of figures ...................................................................................................................... 6 
List of tables ........................................................................................................................ 7 
List of abbreviations ............................................................................................................ 9 
Glossary of terms ............................................................................................................... 13 
Protocol summary .............................................................................................................. 14 
Amendment History .......................................................................................................... 19 
1 
Background ........................................................................................................................ 25 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment .............. 25 
1.2 
Introduction to investigational treatment(s) and other study treatment(s) ............. 26 
1.2.1 
Overview of panobinostat ..................................................................... 26 
2 
Rationale ............................................................................................................................ 28 
2.1 
Study rationale and purpose ................................................................................... 28 
2.2 
Rationale for the study design ............................................................................... 30 
2.2.1 
Rationale for biomarker assessment ...................................................... 32 
2.3 
Rationale for dose and regimen selection .............................................................. 32 
2.4 
Rationale for choice of combination drugs ............................................................ 35 
2.5 
Rationale for choice of comparators drugs ............................................................ 35 
2.6 
Risks and benefits .................................................................................................. 35 
3 
Objectives and endpoints ................................................................................................... 37 
4 
Study design ...................................................................................................................... 39 
4.1 
Description of study design ................................................................................... 39 
4.2 
Timing of interim analyses and design adaptations ............................................... 41 
4.3 
Definition of end of the study ................................................................................ 41 
4.4 
Early study termination .......................................................................................... 42 
5 
Population .......................................................................................................................... 42 
5.1 
Patient population .................................................................................................. 42 
5.2 
Inclusion criteria .................................................................................................... 42 
5.3 
Exclusion criteria ................................................................................................... 44 
6 
Treatment ........................................................................................................................... 47 
6.1 
Study treatment ...................................................................................................... 47 
6.1.1 
Dosing regimen ..................................................................................... 47 
6.1.2 
Ancillary treatments .............................................................................. 51 
6.1.3 
Rescue medication ................................................................................ 52 
6.1.4 
Guidelines for continuation of treatment .............................................. 52 

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6.1.5 
Treatment duration ................................................................................ 52 
6.2 
Dose escalation guidelines ..................................................................................... 52 
6.3 
Dose modifications ................................................................................................ 53 
6.3.1 
Dose modification and dose delay ........................................................ 53 
6.3.2 
Follow-up for toxicities ......................................................................... 68 
6.3.3 
Anticipated risks and safety concerns of the study treatment ............... 69 
6.4 
Concomitant medications ...................................................................................... 70 
6.4.1 
Permitted concomitant therapy ............................................................. 70 
6.4.2 
Permitted concomitant therapy requiring caution and/or action ........... 70 
6.4.3 
Prohibited concomitant therapy ............................................................ 71 
6.4.4 
Use of bisphosphonates (or other concomitant medications) ............... 73 
6.5 
Patient numbering, treatment assignment or randomization ................................. 73 
6.5.1 
Patient numbering ................................................................................. 73 
6.5.2 
Treatment assignment or randomization ............................................... 73 
6.5.3 
Treatment blinding ................................................................................ 74 
6.6 
Study drug preparation and dispensation ............................................................... 74 
6.6.1 
Study drug packaging and labeling ....................................................... 75 
6.6.2 
Drug supply and storage ........................................................................ 76 
6.6.3 
Study drug compliance and accountability ........................................... 76 
6.6.4 
Disposal and destruction ....................................................................... 77 
7 
Visit schedule and assessments ......................................................................................... 77 
7.1 
Study flow and visit schedule ................................................................................ 77 
7.1.1 
Molecular pre-screening ........................................................................ 86 
7.1.2 
Screening ............................................................................................... 86 
7.1.3 
Run-in period ........................................................................................ 89 
7.1.4 
Treatment period ................................................................................... 89 
7.1.5 
Discontinuation of study treatment ....................................................... 89 
7.1.6 
Withdrawal of consent .......................................................................... 90 
7.1.7 
Follow up for safety evaluations ........................................................... 91 
7.1.8 
Post-treatment follow-up ....................................................................... 91 
7.1.9 
Survival follow-up ................................................................................ 91 
7.1.10 
Lost to follow-up ................................................................................... 92 
7.2 
Assessment types ................................................................................................... 92 
7.2.1 
Efficacy assessments ............................................................................. 92 
7.2.2 
Safety and tolerability assessments ....................................................... 98 
7.2.3 
Pharmacokinetics ................................................................................ 104 

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7.2.4 
Biomarkers .......................................................................................... 109 
7.2.5 
Resource utilization ............................................................................. 111 
7.2.6 
Patient reported outcomes ................................................................... 111 
8 
Safety monitoring and reporting ...................................................................................... 113 
8.1 
Adverse events ..................................................................................................... 113 
8.1.1 
Definitions and reporting .................................................................... 113 
8.1.2 
Laboratory test abnormalities .............................................................. 114 
8.1.3 
Adverse events of special interest ....................................................... 115 
8.2 
Serious adverse events ......................................................................................... 115 
8.2.1 
Definitions ........................................................................................... 115 
8.2.2 
Reporting ............................................................................................. 116 
8.3 
Emergency unblinding of treatment assignment ................................................. 116 
8.4 
Pregnancies .......................................................................................................... 116 
8.5 
Warnings and precautions .................................................................................... 117 
8.6 
Data Monitoring Committee ................................................................................ 117 
8.7 
Steering Committee ............................................................................................. 117 
8.8 
Independent Review Committee .......................................................................... 117 
9 
Data collection and management ..................................................................................... 118 
9.1 
Data confidentiality ............................................................................................. 118 
9.2 
Site monitoring .................................................................................................... 119 
9.3 
Data collection ..................................................................................................... 119 
9.4 
Database management and quality control .......................................................... 120 
10 Statistical methods and data analysis .............................................................................. 121 
10.1 
Analysis sets ........................................................................................................ 121 
10.1.1 
Full Analysis Set ................................................................................. 121 
10.1.2 
Safety Set ............................................................................................ 121 
10.1.3 
Per-Protocol Set .................................................................................. 121 
10.1.4 
Dose-determining analysis set............................................................. 122 
10.1.5 
Pharmacokinetic analysis sets ............................................................. 122 
10.1.6 
Other analysis sets ............................................................................... 122 
10.2 
Patient demographics/other baseline characteristics ........................................... 122 
10.3 
Treatments (study treatment, concomitant therapies, compliance) ..................... 123 
10.3.1 
Study treatment ................................................................................... 123 
10.3.2 
Concomitant therapies ......................................................................... 123 
10.4 
Primary objective ................................................................................................. 123 
10.4.1 
Variable ............................................................................................... 123 

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10.4.2 
Statistical hypothesis, model, and method of analysis ........................ 124 
10.4.3 
Handling of missing values/censoring/discontinuations ..................... 124 
10.4.4 
Supportive analyses ............................................................................. 124 
10.5 
Secondary objectives ........................................................................................... 124 
10.5.1 
Secondary objective(s) ........................................................................ 125 
10.5.2 
Other secondary efficacy objectives ................................................... 125 
10.5.3 
Safety objectives ................................................................................. 125 
10.5.4 
Pharmacokinetics and dose response .................................................. 127 
10.5.5 
Biomarkers .......................................................................................... 129 
10.5.6 
Patient-reported outcomes ................................................................... 130 
10.6 
Exploratory objectives ......................................................................................... 130 
10.7 
Interim analysis .................................................................................................... 130 
10.7.1 
Interim efficacy analysis ..................................................................... 131 
10.7.2 
Interim safety analysis ......................................................................... 132 
10.7.3 
Interim PK analysis ............................................................................. 132 
10.8 
Sample size calculation ........................................................................................ 133 
10.9 
Power for analysis of key secondary variables .................................................... 133 
11 Ethical considerations and administrative procedures .................................................... 133 
11.1 
Regulatory and ethical compliance ...................................................................... 133 
11.2 
Responsibilities of the investigator and IRB/IEC/REB ....................................... 133 
11.3 
Informed consent procedures ............................................................................... 134 
11.4 
Discontinuation of the study ................................................................................ 134 
11.5 
Publication of study protocol and results............................................................. 134 
11.6 
Study documentation, record keeping and retention of documents ..................... 134 
11.7 
Confidentiality of study documents and patient records ..................................... 135 
11.8 
Audits and inspections ......................................................................................... 135 
11.9 
Financial disclosures ............................................................................................ 136 
12 Protocol adherence .......................................................................................................... 136 
12.1 
Amendments to the protocol ................................................................................ 136 
13 References (available upon request) ................................................................................ 137 
14 Appendices ...................................................................................................................... 140 
14.1 
Appendix 1: Co-medications which are known to prolong the QT interval 
and/or induce Torsades de Pointes, are strong CYP3A4/5 inhibitors/inducers 
or sensitive CYP2D6 substrates ........................................................................... 140 
14.1.1 
Medications which are known to prolong the QT interval and/or 
induce Torsades de Pointes ventricular arrhythmia should be 
avoided ................................................................................................ 140 

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14.1.2 
Dose reduce panobinostat when combined with medications which 
are known strong CYP3A inhibitors ................................................... 142 
14.1.3 
Medications which are known strong CYP3A inducers are to be 
avoided ................................................................................................ 143 
14.1.4 
Medications which are known sensitive CYP2D6 substrates or 
substrates with narrow therapeutic index are to be avoided ............... 143 
14.1.5 
References (available upon request) ................................................... 144 
14.2 
Appendix 2: Guidelines for response assessment in multiple myeloma ............. 145 
14.2.1 
Introduction and scope ........................................................................ 145 
14.2.2 
Efficacy assessments ........................................................................... 145 
14.2.3 
Derivation rules ................................................................................... 157 
14.2.4 
Medical review of response assessment .............................................. 162 
14.2.5 
References (available upon request) ................................................... 163 
14.3 
Appendix 3: ECOG performance status scale ..................................................... 164 
14.4 
Appendix 4: New York Heart Association (NYHA) functional classification ... 165 
14.5 
Appendix 5: The Bristol Stool Form Scale .......................................................... 166 
 
List of figures 
Figure 4-1 
Study design .......................................................................................... 40 
Figure 6-1 
Recommended dosing schedule for Arm A and Arm C of 
PAN/BTZ/Dex for patients less than or equal to 75 years of age (on 
1st day of screening) from Cycle 1 to 4 (TP1) ....................................... 48 
Figure 6-2 
Recommended dosing schedule for Arm A and Arm C of 
PAN/BTZ/Dex for patients greater than 75 years of age (on 1st day 
of screening) from Cycle 1 to 4 (TP1), and all patients (in Arm A 
and Arm C) starting from Cycle 5 (TP2) .............................................. 48 
Figure 6-3 
Recommended dosing schedule for Arm B of PAN/BTZ/Dex for 
patients less than or equal to 75 years of age (on 1st day of 
screening) from Cycle 1 to 4 (TP1) ....................................................... 48 
Figure 6-4 
Recommended dosing schedule for Arm B  of PAN/BTZ/Dex for 
patients greater than 75 years of age (on 1st day of screening) from 
Cycle 1 to 4 (TP1), and all patients (in Arm B) starting from Cycle 
5 (TP2) .................................................................................................. 48 
Figure 6-5 
Sequence of dosing of PAN/BTZ/Dex on days when PK samples 
are collected .......................................................................................... 51 
Figure 14-1 
International Staging System .............................................................. 149 
Figure 14-2 
The Bristol Stool Form Scale .............................................................. 166 
 

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List of tables 
Table 2-1 
Simulated grade-3/4 thrombocytopenia risk over six weeks for 
single-agent panobinostat by regimen ................................................... 33 
Table 2-2 
Summary of panobinostat dose reduction to 10 mg TIW in D2308 ..... 34 
Table 3-1 
Objectives and related endpoints .......................................................... 38 
Table 6-1 
Dose and study treatment schedule ....................................................... 47 
Table 6-2 
Criteria for PAN/BTZ dose modifications for common toxicities ........ 54 
Table 6-3 
Dose reductions for PAN ...................................................................... 56 
Table 6-4 
Criteria for interruption, modification and re-initiation of PAN due 
to PAN-related toxicity ......................................................................... 57 
Table 6-5 
Dose reduction steps for BTZ for all Treatment Arms ......................... 61 
Table 6-6 
Dose reduction steps for Dex for all Treatment Arms .......................... 61 
Table 6-7 
Drug related adverse events dose modification guidelines for BTZ ..... 62 
Table 6-8 
Recommended dose modification for BTZ-related neuropathic pain 
and/or peripheral sensory neuropathy ................................................... 62 
Table 6-9 
Dex dose modifications ......................................................................... 63 
Table 6-10 
Proposed anti-diarrheal medication ....................................................... 65 
Table 6-11 
Diarrhea management and PAN/BTZ dose modifications .................... 66 
Table 6-12 
Follow-up evaluations for selected toxicities ........................................ 68 
Table 6-13 
Preparation and dispensing ................................................................... 75 
Table 6-14 
Packaging and labeling ......................................................................... 75 
Table 6-15 
Supply and storage of study treatments ................................................ 76 
Table 7-1 
Visit evaluation schedule ...................................................................... 78 
Table 7-2 
Disease assessment collection plan ....................................................... 93 
Table 7-3 
Additional assessments to confirm disease progression or response .... 95 
Table 7-4 
Local clinical laboratory parameters collection plan ............................ 99 
Table 7-5 
Central and local ECG collection plan ................................................ 103 
Table 7-6 
Pharmacokinetic blood collection log for panobinostat (PAN) TIW 
Treatment Arm A & C and bortezomib (BTZ) ................................... 105 
Table 7-7 
Pharmacokinetic blood collection log for panobinostat (PAN) BIW 
Treatment Arm B and bortezomib (BTZ) ........................................... 106 
Table 7-8 
Biomarker sample collection plan ....................................................... 110 
Table 7-9 
Patient reported outcomes collection plan .......................................... 112 
Table 10-1 
Noncompartmental pharmacokinetic parameters ................................ 128 
Table 10-2 
Predictive probability of observing ORR at least 55% at the 
primary analysis (n=80) in the FAS under different interim results 
(n=40 patients) .................................................................................... 132 

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Table 10-3 
Operating characteristics for an individual treatment group – 
Interim analysis (40 patients) .............................................................. 133 
Table 14-1 
Medications which are known to prolong the QT interval and/or 
induce Torsades de pointes to be avoided ........................................... 140 
Table 14-2 
Medications which are known strong CYP3A inhibitors ................... 142 
Table 14-3 
Medications which are known strong CYP3A inducers are to be 
avoided ................................................................................................ 143 
Table 14-4 
Medications which are known sensitive CYP2D6 substrates or 
substrates with a narrow therapeutic index are to be avoided ............. 144 
Table 14-5 
Recommended use of a central or local laboratory ............................. 148 
Table 14-6 
Durie-Salmon staging system ............................................................. 149 
Table 14-7 
Response classification in MM according to IMWG criteria ............. 154 
Table 14-8 
Additional response categories in MM according to IMWG criteria . 156 
Table 14-9 
Best overall response ........................................................................... 157 
Table 14-10 
Censoring rules for time to response ................................................... 159 
Table 14-11 
Options for event dates used in PFS and TTP ..................................... 161 
Table 14-12 
ECOG performance status scale .......................................................... 164 
Table 14-13 
NYHA functional classification .......................................................... 165 
 

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List of abbreviations 
AE(s) 
Adverse Event(s) 
AESI 
Adverse events of special interest 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
ANC 
Absolute neutrophil count 
APTT 
Activated partial thromboplastin time 
ASO-PCR 
Allele-specific oligonucleotide polymerase chain reaction 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
ATC 
Anatomical Therapeutic Chemical Class 
AUC 
Area under the curve 
BCR 
B-cell receptor 
b.i.d. 
bis in diem/twice a day 
BIW 
Twice a week 
BL 
Baseline 
BM 
Bone marrow 
BSA 
Body surface area 
BTZ 
Bortezomib (Velcade®) 
C 
Cycle of study treatment 
CCL 
Creatinine clearance 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CL 
Confidence limit 
Cmax 
Maximum observed plasma concentration 
CMO&PS 
Chief Medical Office & Patient Safety 
Cmin 
Minimum observed plasma concentration 
CR 
Complete Response 
CRAB 
Commonly noted signs and symptoms of MM (Calcium elevation, Renal dysfunction, 
Anemia, Bone destruction) 
CRF 
Case Report/Record Form; the term CRF can be applied to either EDC or Paper 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CSR addendum 
An addendum to Clinical Study Report (CSR) that captures all the additional information 
that is not included in the CSR 
CT 
Computer tomography 
CTCAE 
Common Terminology Criteria for adverse events 
CTEP 
Cancer Therapy Evaluation Program 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
D 
Day of cycle 
D 
Captured in database 
DACi 
Pan-deacetylase inhibitor 
DAR 
Dose administration record 
DBP 
Diastolic blood pressure 
decr. 
Decrease 
Dex  
Dexamethasone 
DFS 
Disease-free survival 
Dia 
Diarrhea 

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diff 
Difference 
DILI 
Drug induced liver injury 
DLT 
Dose limiting toxicity 
DMC 
Data Monitoring Committee 
DOR 
Duration of response 
 
 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ECHO 
Echocardiogram 
eGFR 
Estimated glomerular filtration rate 
EDC 
Electronic data capture 
EORTC 
European Organization for Research and Treatment of Cancer 
EOT 
End-of-treatment 
EU 
European Union 
FACT 
Functional assessment of cancer therapy 
FAS 
Full analysis set 
FBSS 
Full body skeletal survey 
FDA 
Food and Drug Administration 
FISH 
Fluorescence in situ hybridization 
FLC 
Free light chain 
FT4 
Free thyroxine 
G-CSF 
Granulocyte colony stimulating factor 
GCP 
Good clinical practice 
GI 
Gastrointestinal 
GOG 
Gynecologic Oncology Group 
H3/4 
Histone 3 or 4 
HDAC 
Histone deacytelase 
Hgb 
Hemoglobin 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
HRQoL 
Health-related quality of life 
HSP90 
Heat shock protein 90 
IA 
Interim analysis 
IC 
Informed consent 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
iCR 
Immunophenotypic CR 
IEC 
Independent Ethics Committee 
IF 
Immunofixation 
IHC 
Immunohistochemistry 
IMiD(s) 
Immunomodulatory agent(s) 
IMWG 
International Myeloma Working Group 
incr. 
increase 
INR 
International standardized ratio 
INV 
Investigator (assessment) 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 

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IRT 
Interactive Response Technology that includes Interactive Voice Response System and 
Interactive Web Response System 
ISS 
International Staging System 
ITT 
Intent to treat 
IWRS 
Interactive web response system 
i.v. or iv 
Intravenous(ly) 
LBBB 
Left bundle branch block 
Len 
lenalidomide 
LLN 
Lower limit of normal 
LVEF 
Left ventricular ejection fraction 
MAP 
Master Analysis Plan documents project standards in the statistical methods which will be 
used within the individual clinical trial RAP documentation 
MDRD 
Modification of Diet in Renal Disease (study) 
MedDRA 
Medical dictionary for regulatory activities 
MM 
Multiple Myeloma 
MR 
Minimal response 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum tolerated dose 
MUGA 
Multigated acquisition scan 
NC 
No change 
NCA 
Non-compartmental PK analysis 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
nCR 
Near complete response 
NDA 
New Drug Application 
NTI 
Narrow therapeutic index 
Ntx 
Neurotoxicity 
o.d. 
omnia die/once a day 
ORR 
Overall response rate 
OS 
Overall survival 
OW 
Once a week 
p.o. 
per os/by mouth/orally 
PAN 
Panobinostat / LBH589 / Farydak® 
PAS 
Pharmacokinetic analysis set 
PBO 
Placebo 
PC 
Plasma cells 
PCC 
Plasma cell count 
PD 
Progressive disease 
PEP 
Protein electrophoresis 
PFS 
Progression free survival 
PHI 
Protected Health Information 
PK 
Pharmacokinetics 
PK/PD 
Pharmacokinetic/Pharmacodynamic 
PLT 
Platelet count 
Pop PK 
Population PK 
POS 
Probability of success 
PPS 
Per-protocol-set 

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PR 
Partial response 
PRO 
Patient reported outcomes 
PS 
Performance score 
PT 
Prothrombin time 
PT-FU 
Post Treatment Follow-up 
QLQ 
Quality of life questionnaire 
QOL 
Quality of Life 
QTcF 
Corrected QT interval using Fridericia’s correction 
RAP 
The Report and Analysis Plan (RAP) is a regulatory document which provides evidence of 
preplanned analyses 
REB 
Research Ethics Board 
RVDP 
Revlimid, velcade and dexamethasone and panobinostat 
s 
In serum, e.g. sPEP, sIF 
S 
Source data 
SAE 
Serious Adverse Event 
SBP 
Systolic blood pressure 
s.c. or sc 
sub-cutaneous(ly) 
SC 
Steering Committee 
Scr 
Serum creatinine 
sCR 
Stringent CR 
SD 
Stable disease 
S-FU 
Survival follow-up 
SOP 
Standard Operating Procedure 
SPD 
Sum of the products of the diameters 
STP 
Soft tissue plasmacytoma 
TBIL 
Total bilirubin 
TCP 
Thrombocytopenia 
TIW 
Three times a week 
T½ 
Half life 
Tmax 
Maximum plasma concentration time 
TNT 
Time to next treatment 
TP1 
Treatment period 1: first four cycles of study treatment, when patients ≤ 75 years receive 
bortezomib (BTZ) twice a week (BIW), and patients > 75 years receive BTZ once a week 
(OW) 
TP2 
Treatment period 2: Cycle 5 until disease progression (Cycle 5+) of study treatment, when 
all patients independent of their age receive BTZ OW 
TTP 
Time to progression 
TTR 
Time to response 
u 
In urine; e.g. uPEP, uIF 
UK 
United Kingdom 
ULN 
Upper limit of normal 
UNK 
Unknown 
US 
United States of America 
VGPR 
Very good partial response 
WOCBP 
Women of child-bearing potential 

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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, tissue, 
urine, stool, etc. taken from a study subject or study patient 
Control drug 
A study treatment used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or evaluate 
comparative effects of the investigational drug 
Cycles 
Number and timing or recommended repetitions of therapy are usually expressed as 
number of days (e.g.: q21 days) 
Dose level 
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment 
Point/time of patient entry into the study; the point at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol) 
Investigational drug 
The study treatment whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with “investigational 
new drug.” 
Investigational 
treatment 
Drug whose properties are being tested in the study as well as their associated 
placebo and active treatment controls (when applicable). This also includes approved 
drugs used outside of their indication/approved dosage, or that are tested in a fixed 
combination. Investigational treatment generally does not include other study 
treatments administered as concomitant background therapy required or allowed by 
the protocol when used in within approved indication/dosage 
Medication number 
A unique identifier on the label of each study treatment package which is linked to 
one of the treatment groups of a study 
Other study treatment 
Any drug administered to the patient as part of the required study procedures that 
was not included in the investigational treatment 
Subject Number 
(Subject No.) 
A unique identifying number assigned to each patient/subject/healthy volunteer who 
enrolls in the study 
Period 
A subdivision of the study timeline; divides stages into smaller functional segments 
such as screening, baseline, titration, washout, etc. 
Randomization 
number 
A unique treatment identification code assigned to each randomized patient, 
corresponding to a specific treatment arm assignment 
Stage related to study 
timeline 
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc. 
Stop study 
participation 
Point/time at which the patient came in for a final evaluation visit or when study 
treatment was discontinued whichever is later 
Study treatment 
Includes any drug or combination of drugs in any study arm administered to the 
patient (subject) as part of the required study procedures, including placebo and 
active drug run-ins. 
In specific examples, it is important to judge investigational treatment component 
relationship relative to a study treatment combination; study treatment in this case 
refers to the investigational and non-investigational treatments in combination. 
Study treatment 
discontinuation 
Point/time when patient permanently stops taking study treatment for any reason 
Supportive treatment 
Refers to any treatment required by the exposure to a study treatment, e.g. 
premedication of vitamin supplementation and corticosteroid for pemetrexed 
disodium. 
Variable 
Identifier used in the data analysis; derived directly or indirectly from data collected 
using specified assessments at specified time-points 
Withdrawal of Consent 
Withdrawal of consent occurs only when a patient does not want to participate in the 
study any longer, and does not want any further visits or assessments, and does not 
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Protocol summary 
Title 
A multicenter, randomized, open-label Phase 2 study evaluating the safety and 
efficacy of three different regimens of oral panobinostat in combination with 
subcutaneous bortezomib and oral dexamethasone in patients with relapsed or 
relapsed/refractory multiple myeloma who have been previously exposed to 
immunomodulatory agents 
Brief title 
Study of safety and efficacy of panobinostat in combination with bortezomib and 
dexamethasone in relapsed or relapsed/refractory multiple myeloma 
Sponsor and Clinical 
Phase 
Secura Bio 
II 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
Results of pivotal Study D2308 demonstrated superiority of the panobinostat (PAN) + 
i.v. bortezomib (BTZ) + dexamethasone (Dex) combination compared to placebo 
(PBO) + iv BTZ + Dex in patients with MM who progressed on at least one line of 
prior therapy. Despite observing efficacy benefit in D2308, safety concerns were 
noted as the most frequent AEs included thrombocytopenia and neutropenia, GI 
toxicities (primarily diarrhea, nausea and vomiting), and fatigue/asthenia, which were 
more frequent in the PAN + i.v. BTZ + Dex arm compared to the PBO + i.v. BTZ + 
Dex arm. Therefore, further evaluation to improve the safety and tolerability of this 
combination is needed. 
At the time of conduct, the D2308 study used the intravenous formulation of BTZ but 
today, the subcutaneous formulation of BTZ has become standard of care as this 
formulation has been shown to be associated with less GI toxicity and peripheral 
neuropathy compared to the i.v. formulation, albeit without compromising efficacy. 
The purpose of this study is to investigate the safety and efficacy of three different 
regimens of PAN (20 mg TIW, 20 mg BIW, and 10 mg TIW) in combination with s.c. 
BTZ and Dex and to provide exposure, safety and efficacy data to identify the optimal 
regimen of PAN in a randomized, 3-arm parallel design. This study will also assess 
the impact of administering s.c. BTZ (in combination with PAN and Dex) twice weekly 
for 4 cycles, and then weekly starting from Cycle 5 until disease progression in 
patients ≤ 75 years of age. Patients > 75 years of age will receive for the entire 
treatment period s.c. BTZ weekly (in combination with PAN and Dex) until disease 
progression. 
Primary Objective 
To assess overall response rate (ORR) up to 8 cycles (by IRC assessment). 
Secondary Objectives 
To assess overall response rate (ORR) 
To assess the individual iCR, sCR, CR, VGPR rates 
To assess progression-free survival (PFS) 
To assess overall survival (OS) 
To evaluate overall safety of the combination of PAN, BTZ and Dex 
To assess pharmacokinetics 
To assess exposure-response (efficacy and safety) relationship 
To assess time to progression (TTP), time to response (TTR), duration of response 
(DOR) 
To assess Health-related quality of life (HRQoL) 
Exploratory Objectives 
To assess the pharmacodynamic effect of PAN 
To evaluate novel predictive markers of response in bone marrow aspirate and blood 

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Study design 
Global, randomized, open-label, multicenter, three-arm phase II study evaluating 
three different regimens of oral panobinostat in combination with subcutaneous 
bortezomib and oral dexamethasone to assess safety and efficacy in patients with 
relapsed or relapsed/refractory multiple myeloma who have been previously exposed 
to immunomodulatory agents. 
Up to 240 patients will be randomized in a 1:1:1 ratio into one of the 3 treatment 
arms, distinguished by different regimens of PAN (20 mg TIW, 20 mg BIW and 10 mg 
TIW) according to the following strata: 
1 - Number of prior lines of anti-myeloma treatment: 1 vs. 2 vs. 3 or 4  
2 - Age of patient on 1st day of screening (which is equivalent to the day when the 
main ICF is signed): ≤ 75 years vs. > 75 years of age 
Patients will receive study treatment of PAN (20 mg TIW, 20 mg BIW and 10 mg TIW) 
in combination with s.c. BTZ and Dex in 21-day cycle duration: 
Treatment Period 1 (TP1) of 4 cycles (Cycle 1 to 4): Patients who are ≤ 75 years of 
age on 1st day of screening, will receive BTZ twice a week independent from the 
treatment arm to which they were randomized. Patients who are > 75 years of age 
will receive BTZ once a week in this treatment period. 
Treatment Period 2 (TP2) starting from Cycle 5: all patients (independent of age and 
treatment arm) will receive BTZ once a week until documented disease progression, 
unless they discontinue earlier due to unacceptable toxicity or for other reasons. 
Patients who discontinued study treatment for reasons other than documented 
disease progression, death, lost to follow-up or withdrawal of consent will be entered 
in the Post Treatment follow-up (PT-FU), to assess efficacy every 6 weeks until 
documented disease progression, death, lost to follow up or withdrawal of consent. 
All patients will eventually enter the Survival Follow-up (after completion of study 
treatment or the PT-FU, whichever occurs last) and be followed for survival every 12 
weeks until last patient entering long-term follow up has completed a 3 year survival 
follow-up or discontinued earlier. 
Population 
The study will include adult patients with measurable relapsed or relapsed/refractory 
multiple myeloma who have received 1 to 4 prior lines of therapy and require re-
treatment based on IMWG 2011 criteria; patients who have been exposed to an IMiD 
and whose disease is not bortezomib-refractory. 
Inclusion criteria 
Patient has a previous diagnosis of multiple myeloma, based on following IMWG 
2014 definition: Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or 
extramedullary plasmacytoma and any one or more of the following myeloma defining 
events: 
Evidence of end organ damage that can be attributed to the underlying plasma cell 
proliferative disorder (at initial diagnosis by local assessment), specifically: 
● Hypercalcaemia 
● Renal insufficiency 
● Anaemia 
● Bone lesions: one or more osteolytic lesions 
Any one or more of the following biomarkers of malignancy: 
● Clonal bone marrow plasma cell percentage ≥60% 
● Involved: uninvolved serum free light chain ratio ≥100 
● >1 focal lesion(s) on MRI studies 
Patient must have measurable disease defined by at least 1 of the following 
conditions present at screening by central assessment: 
● Serum M-protein by PEP ≥ 0.5 g/dL ( ≥ 5 g/L) 
● Urine M-protein by PEP ≥ 200 mg/24 hours 
● Involved serum free light chain level ≥ 10 mg/dL (≥ 100 mg/L) provided that the 
serum free light chain ratio is abnormal 
Patient with 1 to 4 prior lines of therapy who requires re-treatment of myeloma for one 
of the 2 conditions below as per IMWG 2011: 
Relapsed myeloma: defined as previously treated myeloma that progresses and 
requires the initiation of salvage therapy but does not meet criteria for either “primary 
refractory myeloma” or “relapsed-and-refractory myeloma” categories 
Relapsed-and-refractory myeloma: defined as nonresponsive while on salvage 
therapy (except BTZ), or progresses within 60 days of last therapy in patients having 

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achieved minimal response (MR) or better at some point before progressing in their 
disease course 
Patients with prior IMiD exposure (e.g. thalidomide, lenalidomide and/or 
pomalidomide) 
Patient has an ECOG performance status (PS) ≤ 2 
Patient has the following laboratory values (performed at local laboratory) within 4 
weeks before starting study drug (lab tests may be repeated, as clinically indicated, to 
obtain acceptable values before failure at screening is concluded but supportive 
therapies are not to be administered in the week prior to the screening tests for ANC 
or platelet count) 
● Absolute neutrophil count (ANC) ≥ 1.0 x 109/L 
● Platelet count ≥ 75 x 109/L 
● AST and ALT ≤ ULN 
● Serum total bilirubin ≤ ULN 
● Creatinine clearance (CCL) assessed by estimated Glomerular Filtration Rate 
(eGFR) ≥ 30 mL/min/1.73 m2 (using Modification of Diet in Renal Disease (MDRD) 
study equation)  
● Serum calcium greater or equal to lower normal limits (≥ LLN), and not higher than 
CTCAE Grade 2 in case of elevated value. 
Patient age ≥ 18 years at time of signing the informed consent 
Written informed consent prior to any screening assessments 
Exclusion criteria 
Patients with primary refractory myeloma defined as disease nonresponsive in 
patients who have never achieved a minimal response or better with any therapy 
Patients refractory to BTZ 
Any concomitant anti-cancer therapy (other than BTZ/Dex) 
Unresolved diarrhea ≥ CTCAE Grade 2 or presence of medical condition associated 
with chronic diarrhea (such as irritable bowel syndrome, inflammatory bowel disease) 
Patient has grade ≥ 2 peripheral neuropathy or Grade 1 peripheral neuropathy with 
pain on clinical examination at screening 
Patient received prior treatment with DAC inhibitors including Panobinostat 
Patient who received: 
● prior anti-myeloma chemotherapy or medication including IMiDs and Dex ≤ 2 
weeks prior to start of study. Dex as supportive treatment (e.g. for pain relief) is 
allowed. 
● experimental therapy or biologic immunotherapy including monoclonal antibodies 
≤ 4 weeks prior to start of study 
● prior radiation therapy ≤ 4 weeks or limited field radiotherapy ≤ 2 weeks prior start 
of study 
Patient taking medications with relative risk of prolonging the QT interval or inducing 
Torsade de pointes, if such treatment cannot be discontinued or switched to a 
different medication prior to starting study drug 
Pregnant or nursing (lactating) women 
Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and 3 months after having stopped all study medication 
Sexually active males unless they use a condom during intercourse while taking drug 
and for 6 months after having stopped all study medication and should not father a 
child in this period 
Investigational and 
Study Treatment 
“Investigational study drug(s)” or “study drug(s)” will refer to oral panobinostat (also 
known as LBH589 or Farydak® or PAN) capsules, to subcutaneous bortezomib (also 
known as BTZ or Velcade®) and to oral dexamethasone (also known as Dex) tablets. 
“Study treatment” refers to the combination of PAN, BTZ and Dex 

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Efficacy assessments 
Central Serum M-protein by electrophoresis (sPEP) 
Central Urine M-protein by electrophoresis (uPEP) 
Central Serum immunofixation (sIF) 
Central Urine immunofixation (uIF) 
Central Serum free light chain (FLC) ratio 
Clinical evaluation of soft tissue plasmacytoma (STP) 
Central ionized calcium level (in serum) 
Local bone marrow plasma cell count 
Local assessment of aberrant cells from bone marrow for component of sCR 
Lytic bone lesion by skeletal survey (X-ray, CT/MRI by local radiologist review) on 
suspected region is only to be performed to assess PD (compared to full skeletal 
survey at baseline), or relapse (for patients in CR). Only required if clinically indicated 
(e.g. bone pain)  
Imaging by CT or MRI (by local radiologist review) is only to be performed at baseline 
(screening or C1D1) if STP is suspected by clinical assessment; and every 6 weeks, 
thereafter, for STP present at study entry; If STP is not present at screening or C1D1, 
imaging by CT or MRI (by local radiologist review) is only performed during study if 
clinically indicated.  
Additional response assessments (by central lab) to determine residual disease as 
component of iCR (multiparametric flow cytometry). 
Safety assessments 
Physical examination 
ECOG performance status 
Weight and vital signs 
12 lead ECGs 
Laboratory assessments including hematology, chemistry, electrolytes, thyroid 
function, coagulation, Troponin I (locally or centrally or Troponin T locally), CCL 
(assessed by eGFR), pregnancy tests for WOCBP. 
Adverse events 
Other assessments 
Central cytogenetics by FISH within 28 days of planned first dose 
European Organization for Research and Treatment of Cancer’s core quality of life 
questionnaire C30 (EORTC QLQ-C30) 
Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-
Neurotoxicity (FACT/GOG-Ntx) 
Diary for diarrhea management 
Pharmacokinetic: Pharmacokinetic blood samples will be obtained on all patients for 
the analysis of PAN and BTZ plasma concentrations. 
Biomarkers:  
● Blood samples will be collected prior and post PAN treatment to assess the 
pharmacodynamic effect of PAN by treatment arm. 
● Blood samples for free cell DNA assessment will be collected at Cycle 1 Day 1, at 
end of treatment and during PT-FU at time of disease progression 
● Bone marrow aspirate sample should be collected prior study treatment, at end of 
treatment and during PT-FU at time of progression to explore predictive markers of 
response 

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Data analysis 
The primary analysis will be performed when all randomized patients have been 
treated for up to 8 cycles. An interim analysis (IA) will be performed when 
approximately 120 randomized patients (40 in each arm) have been treated up to 8 
cycles. 
A final analysis will be performed when all patients have completed a 3-year Survival 
follow-up or discontinued follow-up prematurely. 
The primary objective of the study is to assess efficacy of study treatment by 
treatment arm as measured by overall response rate (ORR: iCR, sCR, CR, VGPR 
and PR) after all randomized patients have received up to 8 cycles of study 
treatment, assessed by IRC, according to IMWG criteria. 
All secondary efficacy assessments (iCR/sCR/CR/VGPR rate, PFS, OS, TTR, DOR, 
TTP, and ORR) will be analyzed as per IRC assessment. 
No comparison of the treatment arms is planned in this study. 
The point estimate of ORR along with corresponding exact 95% two-sided confidence 
intervals will be presented by treatment arm. 
Survivorship functions will be estimated by using the Kaplan-Meier product-limit 
method and displayed as graphs. The estimations are performed by treatment arm. 
Median PFS, Median OS time and its two-sided 95% confidence intervals will be 
reported for each treatment arm. 
Median TTR, DOR and TTP along with corresponding 95% confidence intervals will 
be reported for each treatment arm. 
For efficacy analyses, the full analysis set (FAS) will be used. All listings and 
summary tables will be presented by treatment arm. 
All safety data will be analyzed and reported overall and by treatment arm. 
PK parameters will be summarized by treatment arm using descriptive statistics. 
Frequency tables for compliance to complete all patient-reported questionnaires will 
be provided by treatment arm and visit for EORTC-QLQ-C30 and FACT/GOG-Ntx.  
Overall QOL scores and subscales will be summarized over time using mean, 
median, standard deviation, and range by treatment arm. QOL scale means and 
standard errors will be plotted over time by treatment arm. 
All biomarker analysis will be performed on the full analysis set. 
Key words 
 
Multiple myeloma, DACi-Pan-deacetylase inhibitor, PAN-panobinostat, BTZ-
bortezomib, Dex-dexamethasone, IMIDs-immunomodulatory agents, ORR-Overall 
response rate, IRC-Independent review committee, IMWG-International Myeloma 
Working Group, PK-pharmacokinetics. 

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Amendment History 
Amendment 02 (30-Oct-2019) 
Amendment Rationale 
The Investigational Medicinal Product (IMP), panobinostat (also referred to as LBH589 or 
Farydak®), was acquired by Secura Bio Inc. from Novartis. Updates were made in this 
document in all sections, as applicable, to reflect that Secura Bio is now the Sponsor for this 
study. This is an administrative change that does not affect the planned study. 
In addition, minor language and format corrections were also done throughout the document. 
 
Amendment 01 (17-Nov-2017) 
Amendment rationale 
The first patient for this study was randomized in May 2016, and as of end of October 2017 one 
hundred-twenty two patients have been enrolled and approximately 90% of the planned study 
sites have been initiated.  
This amendment is written to facilitate the study conduct and improve the enrollment rate based 
on feedback from investigators (via direct contact or surveys).  
The major changes to the selection criteria are as follows: 
• Based on recent availability of new drugs and combinations in the treatment of multiple 
myeloma in this patient population, there is a very limited number of patients available, 
who have 1, 2 or 3 prior lines of therapy. Therefore, the protocol is amended to allow 
patients with up to 4 prior lines of therapy to be included in this protocol with no 
limitation on how many patients can be treated with 3 or 4 prior lines of therapy.  
• As patients with 3 or 4 prior lines of therapy will have lower platelet counts at study entry, 
and also as it was found in study CLBH589D2308 that platelets return to baseline counts 
by Day 1 of the subsequent cycle after an initial decrease, it is considered acceptable to 
change the platelet limit for inclusion to ≥75 x 109/L. Similar expectations apply for 
absolute neutrophil count (ANC), and the ANC inclusion criterion was changed to ≥1.0 x 
109/L. Both, thrombocytopenia and neutropenia were found to be reversible and not 
cumulative and to be manageable through close monitoring and dose modification. 
To facilitate the study conduct, the following major changes to the study procedures were 
implemented: 
• In case a patient has to be re-screened, the protocol required that the bone marrow 
collection together with all other assessments have to be repeated. As the bone marrow 
collection is an invasive procedure, and in general results would not change within the 
anticipated time frame, with implementation of amendment 1, the bone marrow collection 
does not have to be repeated, unless patients received alternative anti-myeloma therapy 
between initial screening and re-screening. 
• This amendment also removes the mandatory CT/MRI scan at screening if the clinical 
assessment of soft tissue plasmacytoma (STP) does not suggest the presence of a STP. 

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This would be in line with the post baseline assessments of STP when a CT/MRI is only 
mandatory in case STP is suspected by clinical assessment. 
• It was determined that the daily collection/completion of the diary for diarrhea 
management and PAN/Dex dosing is time intensive and complex, leading to incorrect 
and/or incomplete entries. In addition, some patients were not able to complete the eDiary 
due to special circumstances (e.g., peripheral neuropathy) and had to be excluded. This 
amendment simplifies the diary for diarrhea management by removing the anti-diarrheal 
medication entries and fluid intake entries, and allows the patient’s caregiver or a member 
of the patient’s family to make the entries for the patient in case the patient is not able to 
make the entries her/himself. In addition, the amendment removes the eDiary to document 
PAN/Dex dose administration and allows for this feature to be replaced by a paper diary 
as per local requirements. 
The following additional minor changes were implemented: 
 
Description of the change 
Rationale 
Screening period changed from 21 days to 28 days 
To allow additional time for availability of 
central results (lab and ECG) and bone 
marrow and imaging results. 
PK objectives – will also include Cmin of PAN (not 
only Cmin of BTZ) 
Oversight of original protocol 
PD objectives – revised to include only H3 and H4 
acetylation status (alpha tubulin acetylation status 
removed) 
During the assay validation it was found 
that alpha tubulin could not be measured 
due to its limitations in assay 
Enrollment period extended to 30 months and overall 
study duration to 6.6 years (12 months added) 
Slow recruitment observed in 2016 and 
expected enrollment of 9-10 patients per 
month. 
Inclusion criterion 1: - clarified that the defined clinico-
pathological manifestation of the disease will be 
required to have occurred from the date of initial 
diagnosis, not within screening 
To verify the diagnosis of myeloma, the 
occurrence of the disease defined changes 
is sufficient, given the patient has 
documented measurable disease by PEP 
and/or FLC 
Exclusion criterion 11a: use of prior anti-myeloma 
chemotherapy or medication including IMiDs and Dex 
within 2 weeks (instead of 3 weeks) prior to start of 
study treatment. Supportive Dex treatment for 
analgesic purposes at lower doses (up to 10mg/day) 
allowed within 2 weeks prior to start of study 
treatment 
To allow progressing patients to be treated 
with anti-myeloma chemotherapy or 
medication including IMiDs and Dex 1 
week sooner (or stay on prior 
chemotherapy 1 week longer) and to allow 
supportive treatment with Dex as needed 
in the screening period. 
Exclusion criterion 15 c: added additional examples of 
history and presence of any cardiac arrhythmias that 
are not clinically significant and would not meet 
exclusion criterion 
To allow patients with asymptomatic 
Grade 1 first degree AV block and second 
degree AV block type 1 to be included in 
the study. 

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Description of the change 
Rationale 
Exclusion criterion 15d and e: unstable atrial 
fibrillation and resting bradycardia also requires mean 
value of triplicate ECGs by central review at screening 
to be below exclusion criterion 
Clarification and conformity with procedure 
for QTcF eligibility check. 
Exclusion criterion 23: The requirement to use 
additionally a barrier method will be added for 
WOCBP patients using only hormonal contraceptives  
Due to risk of PK interaction between 
PAN/Dex and the hormonal contraceptives 
as known CYP3A4 inducers 
Dosing regimen: In case of a dose delay, an 
additional efficacy assessment is requested at the 
time when the new cycle should have started 
To ensure close monitoring and detect 
progression, as early as possible  
Assessments: The frequency of mandatory local 
assessment of beta 2 microglobulin is reduced to 
screening, and as clinically indicated  
Beta 2 microglobulin is already analyzed at 
screening and on Day 1 of every cycle by 
the central lab 
Re-screening: if STP imaging, lytic bone lesions 
assessment, bone marrow collection were adequate 
at time of first screening – these assessments do not 
have to be repeated in case a patient is rescreened 
for other reasons (except for bone marrow collection if 
patient received alternative anti-myeloma therapy 
between initial screening and re-screening) 
To avoid a repetition of a painful bone 
marrow aspirate or biopsy with limited 
additional information and/or to avoid 
repeated exposure to radiation with limited 
additional information. 
Assessments: If inadequate or uninterpretable, a 
repetition of the bone marrow baseline assessment is 
requested within 28 days only if the Plasma cell count 
was inadequate or uninterpretable 
FISH and biomarker assessment are not 
part of the primary endpoint; If these 
results are missed a repetition of a painful 
bone marrow aspirate or biopsy does not 
seem to be warranted. 
Assessments: Troponin I; if this cannot be evaluated 
by local laboratory; Troponin I can be determined by 
Covance instead, or Troponin T can be determined by 
local laboratory 
Local laboratories have recently changed 
to only assessing Troponin T and not 
Troponin I results. Both Troponin I or T are 
adequately assessing cardiac status. 
Steering committee fulfills role of DMC 
Steering committee will fulfill DMC role for 
this study.  
 
In this protocol amendment, additional clarifications will be implemented, and typos will be 
corrected as observed during the ongoing review and discussion of the protocol with the 
investigative sites. 
Changes to the protocol 
Section 2.2: Changed to allow up to 4 prior lines of therapy, and to remove alpha tubulin as one 
of the biomarkers to be measured.  
Section 3: Added Cmin PAN to assess pharmacokinetics and removed alpha tubulin as one of 
the biomarkers to be measured for assessment of pharmacodynamics effect of PAN.  

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Section 4.1: Extended screening period duration to 28 days and changed stratification regarding 
number of prior lines of anti-myeloma treatment to 1 vs. 2 vs 3 or 4 without limitation in number 
of patients that can be assigned to each stratum. 
Section 4.3: Extended enrollment period to 30 months, and total study duration to 6.6 years. 
Section 5.1: Changed study population by allowing four prior lines of therapy. 
Section 5.2: Clarified Inclusion criterion 1 to refer to events at time of initial diagnosis; 
Inclusion criterion 3 – allowed up to 4 prior lines of therapy; Inclusion criterion 6 – decreased 
ANC limit to ≥1.0 x 109/L and platelet count limit to ≥75 x 109/L; Inclusion criterion 8 – aligned 
with exclusion criterion 11c. 
Section 5.3: Clarified exclusion criterion 2; modified exclusion criterion 11a to exclude prior 
anti-myeloma chemotherapy or medication including IMiDs and Dex within 2 weeks prior to 
start of study treatment. Clarified that Dex as supportive treatment (e.g., for pain relief) is 
allowed in the screening period; Exclusion criterion 15c: was updated to clarify which 
conduction abnormalities would not be considered an exclusion criterion; Exclusion criterion 
15 d and e: updated to indicate that mean value of triplicate ECGs by central review at screening 
also must meet this criterion; Exclusion criterion 21: it was clarified that WOCBP using only 
hormonal contraceptives should also use a barrier method. 
Section 6.1.1: Added clarification that Dex should not be administered if BTZ is held; removed 
reference to electronic dosing diary; added additional clarifications that a new cycle only can 
start if PAN and BTZ are administered together; added additional clarifications that BTZ doses 
should be administered at least 72 hours apart;  
Sections 6.1.2 and 6.4.1.2: Removed statement regarding preferred use of granisetron for the 
group of 5HT3 antagonists and replaced by a general statement that if use of anti-emetic 
medication with a known risk of QT prolongation cannot be avoided frequent ECG monitoring 
should be performed. 
Section 6.3.1: Added clarification that ideally a new cycle should only start when BTZ, PAN 
and Dex can be administered or at least BTZ and PAN can be administered together. 
Section 6.3.1.2: Added clarification that if BTZ dose/schedule is reduced to once a week, Dex 
doses should only be administered on Days 1, 2, 8 and 9 of a cycle. 
Section 6.3.1.4: Clarified diarrhea management and PAN/BTZ dose modifications – in case of 
Grade 2 toxicity with improvement to Grade 1 or 0 after > 48 hours or Grade 3 toxicity with 
improvement to Grade 1 or 0 – both BTZ and PAN should be reduced if PAN dose is > 10 mg; 
and only BTZ should be reduced if PAN dose is 10 mg. 
Section 6.5.2: clarified that the stratification for prior lines of anti-myeloma treatment will be 1 
vs. 2 vs. 3 or 4, allowing patients with 4 prior lines of therapy to be enrolled.  
Section 6.6.3.1: removed the use of an electronic dosing diary and replaced with potential use 
of a paper diary, as per local requirements, if applicable. 
Section 7.1: Removed eDiary for PAN/Dex dosing; extended screening period from 21 to 28 
days; added clarification on baseline definition; clarification on Troponin I assessment, STP 
imaging assessment at screening; correction of PD biomarkers in blood to be assessed on Day 

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8 of Cycles 5 to 8; clarification for bone marrow collection and X-ray/CT/MRI for bone lesions 
or STP at re-screening; added clarification that beta 2 microglobulin assessment by local labs 
is only performed at screening and unscheduled, as clinically indicated. 
Section 7.1.8: clarified when the first PTFU visit will occur and that additional unscheduled 
PTFU visits could occur as clinically indicated. 
Section 7.2.1: clarified that beta 2 microglobulin is also part of the central laboratory assessment 
on the days when serum for M-protein PEP is collected. Clarified that STP at screening or C1D1 
would only be assessed by CT/MRI if STP is suspected by clinical assessment, and that if 
imaging was performed at screening, imaging does not have to be repeated on C1D1. In 
addition, if STP is present at screening clarified that the first of the CT/MRI after start of study 
treatment should take place on C3D1 and every 6 weeks thereafter. Further clarified that if 
central ionized calcium could not be assessed or collected, the local corrected calcium may be 
used on days when local albumin and local calcium results are available. Added unscheduled 
response assessments by investigator or by IRC that can be performed, as clinically indicated. 
Section 7.2.2: Reduced mandatory local assessment of beta 2 microglobulin; Allowed option 
for site to perform Troponin I (performed locally, or by central lab if the local assessment is not 
possible) or Troponin T performed locally. Additional information on how the results should 
be entered on the eCRF is provided. For eGFR calculation according to original or IDMS 
traceable MDRD study equation clarified that the factor of 1.212 should be applied if the 
patient’s race is ‘black’ and not only if the patient is of African American origin. Also clarified 
that the serum creatinine result used in both formulas should be provided in mg/dL. Allowed 
for body temperature to be assessed as per standard practice at the institution (e.g. orally , via 
ear, as well as using other methods). Added additional guidance that ECG abnormalities at 
screening should be presented in medical history, and new or worsened clinical findings after 
informed consent was obtained must be recorded on the AE CRF page. 
Section 7.2.3: Widened the allowed window for pre-dose PAN PK collections and provided 
additional scheduled time point information regarding the last PAN dose prior to the PK 
collection. 
Section 7.2.4: Aligned the pre-dose biomarker sample collections in blood/plasma window with 
the pre-dose PAN PK sample collection. 
Section 7.2.6: Clarified that anti-diarrheal medication and fluid intake will be removed from the 
ediary for diarrhea management. 
Section 8.1.1: Added clarification about how to report worsening and improving of AEs. 
Section 8.1.3: Added additional section to define adverse events of special interest 
Section 8.2.2: Updated reporting of AEs and introduced new name for what was formerly 
known as Drug Safety & Epidemiology.  
Section 8.6: Added that the Steering Committee will fulfill the role of the Data Monitoring 
Committee for this study. 
Section 9.3: Removed dosing eDiary for PAN/Dex. 

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Section 10.2: removed presentation of ‘25th and 75th percentiles’ for continuous demographic 
data. 
Section 10.3.1: removed ‘Time to first transfusion’ as part of the analysis due to limited number 
of subjects. 
Section 10.5.3.3: removed ‘urinary’ laboratory tests. 
Section 10.5.3.4: removed ‘shift table baseline to worst on-treatment result for overall 
assessments’ of ECGs and ‘shift table baseline to worst on-treatment result’ for vital signs. 
Section 10.5.4.1: Added Cmin (PAN) 
 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 

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1 
Background 
1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
Multiple myeloma (MM) is a malignant proliferation of plasma cells which accounts for 10% 
to 15% of all hematologic malignancies and 20% of deaths related to cancers of the blood and 
bone marrow in adults. Approximately 24,000 people in the US will receive a new diagnosis of 
MM in 2014 (Howlader et al 2014). Despite a survival that improved from 45 to 60 months 
after the introduction of newer therapies (particularly proteasome inhibitors and 
immunomodulatory drugs, commonly called “IMiDs”, often used in combination with 
dexamethasone), all patients ultimately progress and there is still today no evidence of cure. 
Multiple myeloma is characterized by excessive proliferation of plasma cells resulting in 
production of monoclonal proteins, which can lead to end-organ damage. The hallmarks of MM 
are bone marrow failure, renal failure, and bone disease. Symptoms related to bone marrow 
dysfunction include anemia, decreased white blood cells leading to increased susceptibility to 
infection, and decreased platelet counts leading to increased susceptibility to bleeding. Patients 
with MM suffer from bone pain and fractures as a result of osteolytic lesions. They also suffer 
from the symptoms and complications of renal failure which further contribute to worsening 
anemia. These signs and symptoms are commonly denoted as CRAB (Calcium elevation, Renal 
dysfunction, Anemia, Bone destruction). 
The management of patients with relapsed and refractory disease represents a clinical challenge, 
as these patients suffer from continuing symptoms, complications of the disease (including renal 
failure, blood cytopenia or recurrent infections) and decreased quality of life. 
By expert consensus (Rajkumar et al 2011), relapsed MM is defined as previously treated 
myeloma that progresses and requires the initiation of salvage therapy but does not meet the 
criteria for either “primary refractory myeloma” or “relapsed-and refractory myeloma”, 
whereas a relapsed and refractory MM refers to a clinical scenario that is nonresponsive while 
on primary or salvage therapy, or progresses within 60 days of last therapy in patients who have 
achieved minimal response (MR) or better at some point previously before then progressing in 
their disease course. 
Relapsed or relapsed/refractory patients typically receive salvage therapy until relapse or 
toxicity and then go onto the next salvage option (Richardson et al 2014). However, with each 
treatment failure and subsequent line of treatment, the clinical benefit typically decreases. 
In current clinical practice, the established agents, thalidomide, lenalidomide and bortezomib 
are widely used in treating patients with relapsed or relapsed/refractory MM. However, despite 
marked improvements in patients’ outcomes, the prognosis of patients with relapsed or 
relapsed/refractory disease is generally still poor. 
In patients who had progressive MM after at least one previous treatment – the patient 
population studied in the Phase III [Study LBH589D2308] (thereafter named Study D2308) – 
the median OS is about 30 months for patients who had received lenalidomide+dexamethasone 
(Len+Dex) (Weber et al 2007) or bortezomib (Richardson et al 2007). In this population the 
median time to progression (TTP)/ PFS is in the range of 6 to 9 months with iv bortezomib ± 

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dexamethasone (Richardson et al 2007, Moreau et al 2011), 10.4 months for sc bortezomib ± 
dexamethasone (Moreau et al 2011) and 11.1 to 11.3 months for Len+Dex (Weber et al 2007, 
Dimopoulos et al 2007). 
Recently, carfilzomib and pomalidomide were approved in the US as third-line treatment. 
Pomalidomide was also approved in the EU in August 2013 for the third-line treatment of 
patients with relapsed and refractory MM. However, both these drugs have similar mechanisms 
of action compared with the established agents thalidomide, lenalidomide and bortezomib 
acting either as a new generation proteasome inhibitor (carfilzomib, Kuhn et al 2007) or as a 
new IMiD (pomalidomide, Richardson et al 2002). 
In summary, despite the introduction of two new classes of compounds in the past decade, the 
use of multiple lines of therapy is limited by the overlapping mechanisms of action of the 
available agents. Based on these considerations, there is a need for new agents with different 
mechanisms of action for patients with relapsed or relapsed and refractory MM. 
Panobinostat (Farydak®) has received approval from the FDA in Feb 2015 and in the EU in 
Aug 2015 for the treatment of patients with multiple myeloma who have received at least 2 
prior regimens, including bortezomib and an immunomodulatory agent.  
1.2 
Introduction to investigational treatment(s) and other study 
treatment(s) 
1.2.1 
Overview of panobinostat 
Panobinostat (LBH589) belongs to a structurally novel cinnamic hydroxamic acid class of 
compounds and is a pan-inhibitor of Class I, II, and IV histone (and non-histone) DACs 
(HDAC) which are epigenetic modulators and important cancer targets due to the dysregulation 
of these enzymes in many types of tumors. DAC enzymes also target lysine groups on various 
non-histone proteins such as p53, α-tubulin, Hsp90, and HIF1-α; thus panobinostat is also 
referred to as a pan-DAC inhibitor. 
Through its effects on histone acetylation and gene expression, as well as on the oncogenic 
function of non-histone proteins such as Hsp90, panobinostat offers a multifaceted approach 
for the inhibition of cancer cell proliferation and survival. Panobinostat is highly effective at 
inhibiting the HDAC activity of the majority of class I, IIa, IIb, and IV isoforms at low 
nanomolar concentrations, and is the most potent pan-HDAC inhibitor developed to date, 
including those which already received regulatory approval in indications other than MM in 
select countries, including the US. 
Panobinostat (Farydak®) has received approval from the FDA in Feb 2015 and in the EU in 
Aug 2015 for the treatment of patients with multiple myeloma who have received at least 2 
prior regimens, including bortezomib and an immunomodulatory agent. 
1.2.1.1 
Non-clinical experience 
In multiple models, panobinostat has been shown to impact several pathways that are critical to 
the biology of MM. These include the up-regulation of cyclin-dependent kinase inhibitor p21 
leading to cell-cycle arrest and apoptosis, the disruption of the signaling pathway between MM 

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cells and bone marrow stromal cells, and the inhibition of the aggresome protein degradation 
pathway by hyperacetylation of α-tubulin. 
It has been demonstrated that panobinostat is effective as a single agent in multiple in-vitro and 
ex-vivo experiments, including in cells known to be resistant to standard of care agents. The 
combination of bortezomib and panobinostat has been shown to be synergistic in in-vitro and 
in-vivo models of MM (Ocio et al 2010). The combination of these two agents results in a 
synergistic inhibition of the unfolded protein response pathways (aggresome, proteasome) 
which are particularly relevant to MM. 
1.2.1.2 
Clinical experience 
The FDA and EU approval of panobinostat for the treatment of patients with multiple myeloma 
who have received at least 2 prior regimens, including bortezomib and an immunomodulatory 
agent was primarily based on data from a large, double-blind, placebo-controlled Phase III study 
[CLBH589D2308] of panobinostat in combination with bortezomib and dexamethasone (PAN 
arm) compared to placebo in combination with bortezomib and dexamethasone (PBO arm) in 
768 relapsed or relapsed and refractory MM patients (excluding bortezomib-refractory patients) 
with a primary endpoint of progression free survival (PFS). 
Additional data included results from a supportive Phase II study [CLBH589DUS71] in 
55 relapsed and bortezomib-refractory MM patients who received at least 2 prior lines of 
therapy including an IMiD, as well as safety and efficacy data from Phase Ib study 
[CLBH589B2207]. 
Studies B2201, B2202, B2203, B2211, B2101 and B2102 evaluated panobinostat as a single 
agent in patients with other hematological malignancies and solid tumors and provide additional 
information on the general safety profile at the relevant dose of 20 mg. 
The pharmacokinetic profile of panobinostat has been characterized in a total of 14 single-agent 
clinical studies conducted in patients with various hematologic malignancies and solid tumors. 
The registration Study D2308 met its primary objective, demonstrating a statistically significant 
and clinically important reduction in the risk of progression or death of 37% with 
PAN+BTZ+Dex over the standard regimen of PBO+BTZ+Dex (hazard ratio [HR] 0.63; 95% 
Confidence Interval [CI]: 0.52, 0.76; p <0.0001). Median progression free survival was 
significantly longer in the panobinostat group than in the placebo group (11·99 months [95% 
CI 10.32–12.94] vs 8.08 months [7.56–9.23]; hazard ratio [HR] 0.63, 95% CI 0.52–0.76; 
p<0.0001). The proportion of patients achieving an overall response did not differ between 
treatment groups (235 [60.7%, 95% CI 55.7–65.6] for panobinostat vs 208 [54.6%, 49.4–59.7] 
for placebo; p=0.09); however, the proportion of patients with a complete or near complete 
response was significantly higher in the panobinostat group than in the placebo group (107 
[27.6%, 95% CI 23.2–32.4] vs 60 [15.7%, 12.2–19.8]; p=0.00006). Final overall survival data 
are not yet available, although at the time of second OS interim analysis, median overall survival 
was 38.24 months (95% CI 34.63-45.37) for the panobinostat group and 35.38 months (95% CI 
29.37-39.92) for the placebo group (HR 0.87, 95% CI 0.70 – 1.07; p=0.1783) 
(Richardson et al Lymphoma & Myeloma Congress 2014). 
Consistent benefit was also shown in the Phase II study DUS71 in a more advanced and heavily 
pre-treated patient population with an ORR of 34.5% (1 near-complete response and 18 partial 

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responses). An additional 10 patients achieved minimal response, for a clinical benefit rate of 
52.7%. Progression-free survival was 5.4 months (Richardson et al 2013). 
In study D2308, patients who received PAN+BTZ+Dex generally experienced more adverse 
events (AEs) than patients receiving PBO+BTZ+Dex. This increase in AEs was not unexpected 
given the overlapping safety profiles of panobinostat and bortezomib, including 
myelosuppression, fatigue and gastrointestinal (GI) toxicity. 
The 3 most frequent severe categories of events were blood disorders, GI toxicities, metabolism 
disorders and infections and infestations. 
• The rate of Grade 3/4 thrombocytopenia laboratory abnormalities was higher in the PAN 
arm (67.4% vs. 31.4%). In this context, the rate of Grade 3/4 hemorrhage (mostly GI) was 
low in both arms (4.2% vs. 2.4%). Thrombocytopenia AEs led to discontinuation in 1.6% 
and 0.5% of patients in the PAN and PBO arms, respectively. 
• GI toxicities were more common in the PAN arm than in the PBO arm, mostly due to 
diarrhea (Grade 3/4: 25.5% vs. 8%), nausea (Grade 3/4: 5.5% vs. 0.5%), and vomiting 
(Grade 3/4: 7.3% vs. 1.3%). Diarrhea was a reason for treatment discontinuation in 4.5% 
and 1.6% of patients in the PAN and PBO arms, respectively. 
• The rate of Grade 3/4 infections was higher in the PAN arm (31.2% vs. 23.9%). These 
Grade 3/4 infections were primarily pneumonia and sepsis. These severe infections were 
preceded by a severe neutropenia in only 20% of patients. Patients in the PAN arm 
experienced more severe neutropenia, but few were Grade 4 (6.6% vs. 2.4%). Febrile 
neutropenia was infrequent (1.0% vs. 0.5%). 
• Elderly patients (≥ 65 years) generally had a higher level of toxicity compared to younger 
patients, in particular for severe (Grade 3/4) thrombocytopenia (72.5% vs. 56.6%), 
diarrhea (31.3% vs. 21.3%) and asthenia/fatigue (48.1% vs. 18.1%). 
Thirty patients (7.9%) in the PAN arm died on treatment compared to 18 (4.8%) in the PBO 
arm. The primary causes of death were disease progression (1.0% vs. 1.6%) and AEs (6.8% vs. 
3.2%) in the PAN vs. PBO arms. The main causes of these deaths included infections and 
hemorrhages. The cases were complex and confounded by the natural history of the disease and 
concurrent comorbidities. 
The approved indication of PAN in combination with BTZ and Dex is based on MM patients 
with 2 or more prior lines including BTZ and an IMiD. This is a subpopulation of the Study 
D2308 population for which results are presented above. 
In a more advanced and heavily pretreated population, the safety data from studies DUS71 and 
B2207 were consistent with the Phase III Study D2308. In study DUS71, 18% patients 
discontinued therapy because of an AE suspected to be study treatment related, and there was 
only one (1.8%) on-treatment death due to AE (a multi-organ failure). 
2 
Rationale 
2.1 
Study rationale and purpose 
The registration Study D2308 met its primary objective, demonstrating a statistically significant 
and clinically relevant reduction in the risk of progression or death of 37% with PAN+iv BTZ 

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+Dex over the standard regimen of PBO+iv BTZ +Dex (hazard ratio [HR] 0.63; 95% 
Confidence Interval [CI]: 0.52, 0.76; p <0.0001). 
This improvement in PFS translated into a prolongation of median PFS of 3.9 months (from a 
median of 8.1 to 12.0 months) over the standard regimen of intravenous (iv) bortezomib and 
dexamethasone. 
Despite the efficacy benefit observed in D2308, there were some safety concerns. The most 
frequent AEs included thrombocytopenia and neutropenia, GI toxicities (primarily diarrhea, 
nausea and vomiting), and fatigue/asthenia, which all were more frequent in the 
PAN+BTZ+Dex arm than in the PBO+BTZ+Dex arm. There were more on-treatment deaths in 
the PAN+BTZ+Dex arm. Dose reductions were more frequent among patients treated with 
PAN+BTZ+Dex (50.9% with at least one dose reduction) compared to those treated with 
PBO+BTZ+Dex (22.8%). 
In summary, in patients with MM who progressed on at least one line of prior therapy, the 
results of Study D2308 demonstrate superiority of the PAN+iv BTZ+Dex combination 
compared to PBO+iv BTZ+Dex, however, further evaluation to improve the safety and 
tolerability of this combination is needed. 
D2308 study used the intravenous formulation of bortezomib as it was the standard of care for 
the time. Since then, the subcutaneous formulation of BTZ has become standard of care as this 
formulation has been shown to be associated with less GI toxicity and peripheral neuropathy 
compared to the i.v. formulation, without compromising efficacy (Moreau et al 2011). A safety 
analysis of patients enrolled in D2308 comparing treatment phase 1 (in which bortezomib was 
administered twice weekly) compared to treatment phase 2 (in which bortezomib was 
administered once weekly) demonstrated a higher incidence of AEs in the initial 8 cycles of 
therapy for both treatment regimens (PAN+BTZ+Dex and PBO+BTZ+Dex). Of note, for 
patients in the PAN+BTZ+Dex arm, the rates of Grade 3/4 events for the most common AEs 
were markedly reduced in treatment phase 2: thrombocytopenia – 56.7% reduced to 6.0%; 
diarrhea – 24.1% to 7.1%; fatigue – 16.3% to 1.8%. This was also the case in the 
PBO+BTZ+Dex arm, in which the frequency of Grade 3/4 thrombocytopenia, diarrhea and 
peripheral neuropathy decreased (Richardson et al ASH 2014). Although these observations 
should be interpreted with caution due to potential patient selection bias, they are particularly 
interesting in the context of published Phase III data showing that weekly bortezomib is 
associated with an improved tolerability profile particularly with regards to thrombocytopenia, 
gastro-intestinal AE and neuropathy in comparison with twice a week regimen (Bringhen et al 
2010). Therefore, once weekly bortezomib is frequently used in the elderly > 75 years of age 
and frail patients. Elderly patients have generally a higher frequency of AEs including severe 
AEs, and require closer patient selection and monitoring as recommended in international MM 
practice guidelines (Palumbo et al 2011 and Palumbo et al 2014a). 
This study is investigating the safety and efficacy of three different regimens of panobinostat 
(20 mg TIW as evaluated in D2308; 20 mg BIW, and 10 mg TIW) in combination with s.c. 
BTZ and Dex and will provide exposure - safety and exposure - efficacy data to identify the 
optimal dose of panobinostat. This study will also assess the impact of administering 
bortezomib (in combination with PAN and Dex) subcutaneously twice weekly for 4 cycles, and 
then weekly starting from Cycle 5 until disease progression, unless discontinued earlier due to 

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unacceptable toxicity or for other reasons in patients ≤ 75 years of age. Patients > 75 years of 
age will receive for the entire treatment period s.c. BTZ weekly (in combination with PAN and 
Dex) until disease progression, unless discontinued earlier due to unacceptable toxicity or for 
other reasons. 
2.2 
Rationale for the study design 
This is a multicenter, randomized, open-label, three arm, phase II study to characterize the 
safety and efficacy of three different regimens of oral panobinostat in combination with s.c. 
bortezomib and oral dexamethasone in adult patients with measurable relapsed or 
relapsed/refractory multiple myeloma having received 1 to 4 prior lines of therapy and requiring 
re-treatment based on IMWG 2011 criteria. Only patients having been previously exposed to 
an immunomodulatory agent (IMiD) will be enrolled in this study. 
As the objective of this study is to characterize the safety and efficacy of three different 
regimens of panobinostat and to identify the optimal regimen of panobinostat in combination 
with s.c. bortezomib and dexamethasone, a randomized, three-arm parallel design has been 
chosen. 
This study is randomized to avoid selection bias and is open-label since effective blinding would 
be difficult as three different regimens of panobinostat will be administered. If blinding occurs, 
the dose adjustment would be difficult to perform. In addition, the capsules of different strengths 
are of different color and size. 
The following stratification factors have been selected: the number of prior lines 1 vs. 2 vs. 3 
or 4 prior lines of myeloma treatment and age ≤ 75 vs. > 75 years of age. With increasing 
numbers of prior lines of therapy, the disease status is advancing, which makes stratification by 
prior lines of therapy necessary.  
Patients ≤ 75 years of age will receive BTZ s.c. twice a week over 4 cycles and then weekly 
BTZ s.c. starting from Cycle 5 until disease progression unless they discontinue earlier for 
unacceptable toxicity or for other reasons in combination with PAN/Dex. Patients > 75 years 
of age will receive weekly BTZ and a reduced dose of dexamethasone for the entire study 
treatment until disease progression, unless they discontinue earlier for unacceptable toxicity or 
for other reasons, in consideration of the higher susceptibility for treatment toxicity in this 
elderly population (Palumbo et al 2011 and Palumbo et al 2014a). 
Patients being enrolled in this study are required to have been exposed to an immunomodulatory 
agent (IMiD). Study D2308 met its primary endpoint (PAN+BTZ+Dex demonstrated a median 
PFS benefit of 3.9 months in MM patients with 1-3 prior lines of therapy, over the PBO 
combination). Of interest, patients having received a prior treatment line containing an IMiD 
(e.g. thalidomide, pomalidomide and/or lenalidomide), which was a pre-specified subgroup in 
this study, derived a significant benefit from the addition of panobinostat, showing a median 
PFS of 12.3 months, vs 7.4 months in the PBO arm (HR 0.55, 95% CI: 0.44, 0.70) with a safety 
profile similar to the overall patients’ population. 
Patients will be treated with study treatment until disease progression, unless they discontinue 
earlier due to unacceptable toxicity, or for other reasons. Recent Phase 3 studies with BTZ in 
different combinations (Phase 3 of carfilzomib + Dex vs bortezomib + Dex; Phase 3 of 
pomalidomid + bortezomib + Dex vs bortezomib + Dex) have been conducted using BTZ 

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treatment until disease progression. The longer administration of BTZ in this study as compared 
to a maximum 16 cycles used in D2308 is based on the following rationale. The subcutaneous 
formulation of BTZ has become standard of care as this formulation has been shown to be 
associated with less GI toxicity and peripheral neuropathy compared to the i.v. formulation, 
without compromising efficacy (Moreau et al 2011). A safety analysis of patients enrolled in 
D2308 comparing treatment phase 1 (in which bortezomib was administered twice weekly) 
compared to treatment phase 2 (in which bortezomib was administered once weekly) 
demonstrated a higher incidence of AEs in the initial 8 cycles of therapy for both treatment 
regimens (PAN+BTZ+Dex and PBO+BTZ+Dex). Of note, for patients in the PAN+BTZ+Dex 
arm, the rates of Grade 3/4 events for the most common AEs were markedly reduced in 
treatment phase 2: thrombocytopenia – 56.7% reduced to 6.0%; diarrhea – 24.1% to 7.1%; 
fatigue – 16.3% to 1.8%. This was also the case in the PBO+BTZ+Dex arm, in which the 
frequency of Grade 3/4 thrombocytopenia, diarrhea and peripheral neuropathy decreased 
(Richardson et al ASH 2014). Although these observations should be interpreted with caution 
due to potential patient selection bias, they are particularly interesting in the context of 
published Phase III data showing that weekly bortezomib is associated with an improved 
tolerability profile particularly with regards to thrombocytopenia, gastro-intestinal AE and 
neuropathy in comparison with twice a week regimen (Bringhen et al 2010). Therefore, the use 
of BTZ s.c. and an early switch from twice a week to weekly BTZ administration in this study 
is expected to further improve tolerability of PAN+BTZ+Dex combination over a longer 
treatment duration. 
Patients who discontinued study treatment for reasons other than documented disease 
progression, death, lost to follow-up or withdrawal of consent will be followed every 6 weeks 
in the Post-Treatment follow-up (PT-FU) for efficacy until documented disease progression, 
death, lost to follow-up or withdrawal of consent. All patients will be followed for survival 
every 12 weeks. Randomized patients who have not received any dose of study treatment will 
also be included in the Post-treatment follow-up for efficacy until documented disease 
progression, death lost to follow-up or withdrawal of consent and, thereafter, in the Survival 
follow-up, as applicable. 
The study will end when the last patient who entered the long-term follow-up (Post-Treatment 
follow-up or Survival follow-up, whichever occurs first) will have completed 3 years of 
Survival follow-up, which is approximately equivalent to the median overall survival observed 
for the panobinostat group in D2308. 
An interim analysis will be performed when approximately 120 patients (40 in each arm) have 
completed up to 8 cycles of study treatment. The results of this interim analysis will provide 
information on the optimal regimen of panobinostat used in combination with BTZ s.c. and Dex 
for an improved benefit/ risk assessment. The interim analysis will also have a futility rule for 
stopping the PAN 10 mg TIW and 20 mg BIW arms since they have not yet been extensively 
tested in patients. The primary endpoint (ORR by IRC assessment) will be analyzed at the time 
when the last randomized patient has completed up to 8 cycles of treatment. 

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2.2.1 
Rationale for biomarker assessment 
The search for biomarkers that may identify which patients will benefit the most from 
panobinostat will be investigated in the context of this panobinostat regimen optimization study 
through cytogenetic, targeted and molecular profiling:  
To enable this strategy, various biological specimens (e.g. blood, bone marrow aspirate) are 
being collected in this study to conduct targeted and molecular profiling such as: 
• Determine if the baseline cytogenetic profile (number of acquired abnormalities well 
known in MM cells including t(4;14), t(14;16), del(17p) etc.) is associated to the response 
to treatment 
• Determine the acetylation pattern of H3 and H4 in response to treatment as a 
pharmacodynamic marker and through PK-PD understand the correlation between 
acetylation of lysine residues of histone 3 and histone 4 and disease progression to explore 
optimal drug schedule 
• Use cell free DNA profile to characterize patients achieving minimal residual disease 
(MRD). Circulating DNA carries tumour-related genetic and epigenetic alterations that are 
relevant to cancer development, progression and resistance to therapy. These alterations 
may include but are not limited to loss of heterozygosity (LOH) and mutations of tumour 
suppressor genes (such as TP53) and oncogenes (such as KRAS and BRAF). 
2.3 
Rationale for dose and regimen selection 
This study will assess the safety, efficacy and pharmacokinetics of 20 mg TIW, 20 mg BIW and 
10 mg TIW of panobinostat administered 2 weeks on / 1 week off in combination with BTZ s.c. 
and Dexamethasone. 
The cumulative doses for those three PAN regimens are 120 mg, 80 mg and 60 mg of PAN per 
cycle, respectively. 
The 20 mg panobinostat TIW was the starting dose in study D2308, which demonstrated 
clinically relevant PFS advantage over iv BTZ and oral Dex combination. The dose and 
schedule of panobinostat (20 mg panobinostat, 2 weeks on / 1 week off) used in Study D2308 
was selected based on the clinical experience in the Phase I/II program. The Phase Ib dose-
finding Study B2207 evaluating the combination of panobinostat with bortezomib in patients 
with relapsed or relapsed and refractory MM, following at least one prior line of therapy 
determined a Maximum Tolerated Dose (MTD) of 20 mg panobinostat TIW in combination 
with 1.3 mg/m2 bortezomib. The dosing schedule of 2 weeks on/ 1 week off was introduced 
into the dose expansion phase of Study B2207 to facilitate platelet recovery and thus minimize 
dose interruptions and dose reductions due to thrombocytopenia (Lin et al 2009) and was 
subsequently used in the DUS71 and D2308 studies with demonstrated efficacy. 
It is also the approved dose and regimen for panobinostat (Farydak®) in combination with 
bortezomib and dexamethasone in the US and in EU. Therefore, the same dose and schedule 
(20 mg Panobinostat, 2 weeks on/ 1 week off) has been chosen to be further investigated in this 
study. It is expected that the safety and tolerability of panobinostat in combination with 
bortezomib and dexamethasone may be improved by the use of BTZ sc and the early switch to 
the weekly schedule of BTZ sc. 

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A simulation based on exposure-platelet model developed with single-agent panobinostat data 
(Table 2-1) suggested that 20 mg single-agent panobinostat administered twice weekly 2 weeks 
on 1 week off (BIW) is expected to reduce G3/4 thrombocytopenia rate from 28.6% (20 mg 
TIW 2 weeks on 1 week off) to 20.6%. Similar reduction is anticipated when panobinostat is 
combined with bortezomib and dexamethasone. 
Table 2-1 
Simulated grade-3/4 thrombocytopenia risk over six weeks for single-
agent panobinostat by regimen 
Regimen 
Dose (mg) 
Thrombocytopenia Rate (%) 
TIW_2Weeks On, 1Week Off 
20 
28.6 
BIW_2Weeks On, 1Week Off 
20 
20.6 
TIW_2Weeks On, 1Week Off 
10 
15.6 
Based on simulation of 500 patients 
Source: /vob/CLBH589/pool/pkpd_002/nonmem/Platelets/FDA2015/SimSumm3.R -> SimSumm3.txt 
In addition, the BIW schedule had been tested in 2 single-agent panobinostat studies and was   
found to be well-tolerated (B2111 and B2101). PAN doses of 20/45 mg BIW were tested in the 
food effect study B2111 (Shapiro 2012). Panobinostat was generally well tolerated in this study. 
Most common AEs were fatigue, nausea and vomiting. These were as well the most common 
Grade 3 or 4 AEs.  
In study B2101 (A phase IA, multicenter, dose-escalation study of LBH589 administered orally 
on two dose schedules in adult patients with advanced solid tumors or non-Hodgkin’s 
lymphoma), 22 patients were treated with panobinostat on Monday and Thursday (MTh) every 
week (BIW) at doses from 30 to 60 mg/day. The most frequently reported AEs (reported 
in >50% of patients) in patients treated with the BIW regimen were fatigue, nausea, anorexia 
and thrombocytopenia. 
The above data suggest that this 20 mg BIW regimen in combination with BTZ and 
dexamethasone may show an improved tolerability and should therefore be further investigated. 
The 10 mg panobinostat TIW dose has been selected as plasma exposure of single agent PAN 
10 mg does not overlap with 20 mg based on simulation (data on file). Therefore, this lower 
dose of panobinostat can be considered as an adequate low dose to characterize the dose-
response relationship of panobinostat. 
Recent literature suggests that thrombocytopenia (TCP) may be an on-target biomarker for 
histone acetylase inhibition in the bone marrow (Lancu-Rubin et al 2012). Study B2207 data 
suggest that target inhibition as reflected by G3/4 TCP in the 10 mg TIW cohort was similar to 
that of 20 mg PAN TIW in combination with 1.3 mg/m2 BTZ [CLBH589B2207]. Of note, 
severe AEs including diarrhea were reduced with 10 mg PAN. However, since TCP was one of 
the overlapping toxicities between PAN and BTZ, single-agent PAN-induced TCP was 
simulated and compared between 10 and 20 mg TIW. Even though histone acetylase inhibition 
associated with 10 mg TIW as reflected in the typical longitudinal platelet count-time profile 
from 10 mg TIW was not as severe as that of 20 mg TIW, individual profiles may overlap due 
to the variability associated with platelet counts. PAN 10 mg TIW may offer a better balance 
between efficacy and toxicity associated with HDAC inhibition. 

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In study D2308, 10 mg panobinostat TIW was the second dose reduction option, and 17% of 
patients had their dose reduced to 10 mg TIW and stayed on 10 mg TIW. Although no 
conclusion on exposure data at RDI of 50% of PAN (equivalent to 10 mg dose level) can be 
made due to very small sample size, a subgroup analysis of 65 patients (17%) who were dose 
reduced to 10 mg panobinostat dose (median time to reduction of 85 days) and stayed on 10 mg 
panobinostat dose without any further dose modifications suggests similar efficacy as compared 
to patients who stayed on 20 mg panobinostat; with similar median PFS (PAN 10 mg: 10.9 vs 
PAN 20 mg: 10.6 months) and ORR (PAN 10 mg: 61.5% vs PAN 20 mg: 56.8%), and improved 
tolerability (see Table 2-2, data on file). 
Table 2-2 
Summary of panobinostat dose reduction to 10 mg TIW in D2308 
Dose reduction 
to 10 mg TIW* 
Patients staying 
at 20 mg TIW 
PAN+BTZ+Dex 
N=65 
PAN+BTZ+Dex 
N=191 
Time to reduction(days), median 
85 
NA 
PFS (Inv), medians 
10.91 
10.58 
ORR % 
61.5 
56.8 
CR/nCR % 
36.9 
20.3 
On treatment deaths, % 
7.7 
6.8 
Over study period 
(%) 
After reduction to 10 
mg  
(%) 
Over study period  
(%) 
Grade 3-4 
100 
67.7 
92.7 
 
Thrombocytopenia 
80.0 
33.8 
60.5 
 
Infections (pneumonia) 
13.8 
3.1 
19.9 
 
Infections (sepsis) 
4.6 
1.5 
7.3 
 
Diarrhea 
44.6 
18.5 
17.3 
 
Fatigue 
38.5 
13.8 
12.0 
 
Hemorrhage 
3.1 
0.0 
3.1 
*: without further dose adjustment 
Inv: by investigator 
In addition, 10 mg panobinostat administered TIW in combination with Revlimid, Velcade and 
dexamethasone (RVDP) suggested activity (Shah et al 2014). 
Finally, it should be emphasized, that in this study CLBH589D2222, 10 mg panobinostat TIW 
will be added to a full dose of the BTZ s.c. and Dex backbone therapy (in contrast to study 
D2308 where patients who were dose reduced to 10 mg panobinostat TIW also had a reduction 
of the BTZ dose). 
In summary, these data suggest that the 10 mg panobinostat TIW dose may still be sufficient 
for histone acetylase inhibition in the bone marrow (based on TCP data from study B2207), and 
to maintain efficacy when combined with full standard dose of BTZ while improving safety and 
tolerability as compared to the 20 mg panobinostat TIW dose. 

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2.4 
Rationale for choice of combination drugs 
Panobinostat (Farydak®) in combination with bortezomib and dexamethasone has received 
approval from the FDA in Feb 2015 for the treatment of patients with multiple myeloma who 
have received at least 2 prior regimens, including bortezomib and an immunomodulatory agent. 
The backbone regimen of intravenous bortezomib with a dose of 1.3 mg/m2 administered on 
days 1, 4, 8, 11 of 21-days treatment cycles was the standard approved regimen used in 2009 
when the study D2308 was initiated. Since the initiation of this study, BTZ s.c. has been shown 
to be associated with less GI toxicity and peripheral neuropathy compared to the i.v. 
formulation, without compromising efficacy (Moreau et al 2011) and has become an approved 
standard of care for bortezomib containing regimens. A safety analysis of patients enrolled in 
D2308 comparing treatment phase 1 (in which bortezomib was administered twice weekly) with 
treatment phase 2 (in which bortezomib was administered once weekly) demonstrated a higher 
incidence of AEs in the initial 8 cycles of therapy for both treatment regimens (PAN+BTZ+Dex 
and PBO+BTZ+Dex). 
In addition, once weekly BTZ administration has been reported to have similar efficacy and a 
better safety profile than the twice weekly regimen (Bringhen et al 2010). Therefore, the 
treatment with BTZ s.c. and the use of weekly BTZ is expected to further improve the safety 
profile of the combination. 
2.5 
Rationale for choice of comparators drugs 
Not Applicable. 
2.6 
Risks and benefits  
The risk to subjects in this study may be minimized by compliance with the eligibility criteria 
and study procedures, close clinical monitoring, and stopping rules for patients in treatment 
Arm B and C. 
There may be unforeseen risks with the study treatment which could be serious. 
In study D2308, the addition of panobinostat to the standard of care regimen of BTZ+Dex to 
treat patients with relapsed or relapsed and refractory multiple myeloma prolonged the median 
PFS by 3.9 months over patients treated with standard of care BTZ+Dex (HR=0.63, [95% CI: 
0.52, 0.76], p<0.0001) corresponding to a 37% reduction in the risk of progression or death. 
At the time of second OS interim analysis, median overall survival was 38.24 months (95% CI 
34.63-45.37) for the panobinostat group and 35.38 months (95% CI 29.37-39.92) for the 
placebo group (HR 0.87, 95% CI 0.70 – 1.07; p=0.1783) (Richardson et al Lymphoma & 
Myeloma Congress 2014). 
The most frequent AEs included thrombocytopenia and neutropenia, GI toxicities (primarily 
diarrhea, nausea and vomiting), and fatigue/asthenia, which all were more frequent in the 
PAN+BTZ+Dex arm than in the PBO+BTZ+Dex arm. There were more on-treatment deaths in 
the PAN+BTZ+Dex arm. Dose reductions were more frequent among patients treated with 
PAN+BTZ+Dex (50.9% with at least one dose reduction) compared to those treated with 
PBO+BTZ+Dex (22.8%). This study will help to further characterize the safety profile of this 
combination using different regimens of panobinostat. 

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Acknowledging the need to further optimize the dose and schedule of the PAN+BTZ+Dex 
regimen and improve the safety and tolerability of this triple combination, Secura Bio will 
conduct Study D2222 outlined below: 
The study will be a multicenter, randomized, open-label, phase II study to characterize the 
safety and efficacy of three different regimens of oral PAN in combination with subcutaneous 
(sc) BTZ and oral Dex in approximately 240 adult patients with measurable relapsed or 
relapsed/refractory multiple myeloma. Patients previously exposed to an IMiD will be enrolled 
in this study. In D2308, patients having received a prior treatment line containing an IMiD 
(thalidomide, pomalidomide and/or lenalidomide), which was a pre-specified subgroup in this 
study, derived a significant benefit from the addition of PAN, showing a median PFS of 
12.3 months, vs 7.4 months in the BTZ+Dex arm (HR 0.56, 95% CI: 0.39, 0.80) with a safety 
profile similar to the overall patients’ population. For patients with relapsed or 
relapsed/refractory multiple myeloma the clinical benefit typically decreases with each 
treatment failure and subsequent line of treatment. Therefore there is still an unmet medical 
need in this patient population. 
This study will also assess the impact of sc BTZ in combination with PAN and Dex. 
The backbone regimen of intravenous (iv) BTZ with a dose of 1.3 mg/m2 administered on days 
1, 4, 8, 11 of 21-days treatment cycles was the standard approved regimen used in 2009 when 
the Study D2308 was initiated. Since the initiation of this study, sc BTZ has been shown to be 
associated with less gastrointestinal (GI) toxicity and peripheral neuropathy compared to the iv 
formulation, without compromising efficacy (Moreau et al 2011) and has become an approved 
standard of care for BTZ containing regimens. 
In addition, once weekly BTZ administration has been reported to have similar efficacy and a 
better safety profile than the twice weekly regimen (Bringhen et al 2010). Therefore, once 
weekly BTZ is frequently used in the elderly > 75 years of age and frail patients. Overall, the 
treatment with sc BTZ and the use of weekly BTZ is expected to further improve the safety 
profile of the combination. 
In this study s.c. BTZ will be used and patients ≤ 75 years of age will switch BTZ administration 
from twice a week to weekly BTZ early (after having completed 4 cycles). Patients > 75 years 
of age will receive BTZ s.c. weekly over the whole study duration. 
This study will assess the safety, efficacy and pharmacokinetics of 20 mg TIW, 20 mg BIW and 
10 mg TIW of PAN administered 2 weeks on / 1 week off in combination with BTZ s.c. and 
Dex. 
PAN 20 mg TIW, 2 weeks on/ 1 week off is the approved starting dose and regimen for 
panobinostat (Farydak®) in combination with BTZ and Dex in the US. Data from the PK 
simulation suggests that the 20 mg PAN BIW regimen is expected to improve safety and 
tolerability (see Section 2.3). Data on PAN 10 mg TIW suggests that this dose may still be 
sufficient for histone acetylase inhibition, therefore potentially maintaining efficacy when 
combined with full standard dose of BTZ while also improving safety and tolerability as 
compared to the 20 mg PAN TIW regimen. 
An interim analysis, including a futility rule for stopping the PAN 10 mg TIW and 20 mg BIW 
arms in case of insufficient efficacy, will be performed when approximately 120 patients (40 in 

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each arm) have completed up to 8 cycles of study treatment. The Steering Committee (SC) will 
review efficacy and safety in the conduct of the interim analysis. The SC’s role includes 
providing recommendations to Secura Bio to continue, modify or stop a treatment arm or the 
study early. Secura Bio will share the recommendations with the FDA and the final decision 
will be implemented in agreement with the FDA. 
For this study, early monitoring and proactive dose modification and toxicity management 
guidelines have been implemented, especially for hematologic toxicities such as 
thrombocytopenia, neutropenia; cardiac toxicity and diarrhea. In addition, for diarrhea a 
specific diary has been implemented for adequate surveillance. 
In conclusion, the modification to s.c. BTZ and an early switch from twice a week to weekly 
administration, the monitoring and adequate management of the expected toxicities of the 
PAN+BTZ+Dex combination is expected to further improve tolerability of PAN+BTZ+Dex 
combination over a longer treatment duration. Therefore, the overall risk benefit profile is 
considered favorable for initiating this clinical study in a subset of patients with high unmet 
medical need. 
3 
Objectives and endpoints 
Objectives and related endpoints are described in Table 3-1 below. 

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Table 3-1 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary 
 
Refer to Section 10.4. 
To assess overall response rate (ORR) up to 8 cycles 
ORR (according to IMWG criteria by IRC assessment) comprised of 
immunophenotypic CR (iCR), stringent Complete Response (sCR), Complete 
Response (CR), Very Good Partial Response (VGPR) and Partial Response 
(PR) after all randomized patients completed up to 8 cycles of study treatment 
 
Secondary 
 
Refer to Section 10.5. 
To assess overall response rate (ORR) 
ORR (according to IMWG criteria by IRC assessment) 
Refer to Section 10.5.1. 
To assess the individual iCR, sCR, CR, VGPR rates 
iCR, sCR, CR, VGPR rates (according to IMWG criteria by IRC assessment) 
 
To assess progression free survival (PFS) 
PFS (according to IMWG criteria by IRC assessment) 
 
To assess overall survival (OS) 
OS 
 
To evaluate overall safety of the combination of PAN, 
BTZ and Dex 
AEs (graded by CTCAE v4.03), SAEs Abnormalities in vital signs, ECG 
parameters, and laboratory test values. 
This will include events up to 30 days after discontinuation of study treatment. 
Refer to Section 10.5.3. 
To assess pharmacokinetics 
To assess exposure-response (efficacy and safety) 
relationship 
Cmax (PAN, BTZ), C24h (PAN), Cmin (PAN, BTZ) and AUC0-8h (PAN, BTZ) 
ORR, Grade 3/4 Thrombocytopenia, Grade 3/4 Diarrhea (relationship with PAN, 
BTZ PK parameters derived from NCA or Pop PK analysis) 
Refer to Section 10.5.4. 
To assess Time to Progression (TTP), Time to 
Response (TTR), Duration of Response (DOR) 
TTP, TTR, DOR (according to IMWG criteria by IRC assessment) 
Refer to Section 10.5.1. 
To assess health-related quality of life (HRQoL) 
HRQoL as measured by EORTC QLQ-C30 and FACT/GOG-Ntx 
Refer to Section 10.5.6. 
Exploratory  
 
Refer to Section 10.5.5. 
To assess the pharmacodynamic effect of PAN 
H3 and H4 acetylation status 
 
To evaluate novel predictive markers of response in 
bone marrow aspirate and in blood  
Molecular status of exploratory markers 
 

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4 
Study design 
4.1 
Description of study design 
This is a global, randomized, open-label, multicenter, three-arm phase II study evaluating three 
different regimens of oral panobinostat in combination with subcutaneous bortezomib and oral 
dexamethasone to assess efficacy and safety in patients with relapsed or relapsed/refractory 
multiple myeloma who have been previously exposed to immunomodulatory agents. 
After a screening period of up to 28 days, up to 240 patients will be randomized into one of the 
3 treatment arms in a 1:1:1 ratio, distinguished by different regimens (20 mg TIW, 20 mg BIW 
and 10 mg TIW) of panobinostat (PAN), according to the following strata: 
• Number of prior lines of anti-myeloma treatment: 1 vs. 2 vs. 3 or 4  
• Age of patient on 1st day of screening (which is equivalent to the day when the main ICF 
is signed): ≤ 75 years vs. > 75 years of age 
Once randomized, patients will be included in the Post-Treatment follow-up (PT-FU) for 
efficacy until disease progression, death, lost to follow-up or withdrawal of consent, and, 
thereafter, in the Survival follow-up (S-FU) even if they did not receive a dose of study 
treatment, as applicable. 
After randomization, patients will receive study treatment (the combination of PAN/BTZ 
s.c./Dex) in 21-day cycles as described below: 
• Treatment Period 1 (TP1) of 4 cycles (Cycle 1 to 4): Patients who are ≤ 75 years of age 
at time of first screening, will receive subcutaneous bortezomib (BTZ) twice a week 
independent from the treatment arm to which they were randomized. Patients who are > 
75 years of age will receive BTZ once a week in this treatment period. 
• Treatment Period 2 (TP2) starting from Cycle 5: all patients (independent of age) will 
receive BTZ once a week until disease progression, unless they discontinue earlier due to 
unacceptable toxicity or for other reasons (see Section 7.1.5). 
Patients who discontinued study treatment for reasons other than documented disease 
progression, death, lost to follow-up, or withdrawal of consent will be entered in the PT-FU, to 
assess efficacy every 6 weeks until documented disease progression, death, lost to follow-up or 
withdrawal of consent. 
All patients will eventually enter the S-FU (after completion of study treatment or the PT-FU, 
whichever occurs last) and be followed for survival every 12 weeks until death, lost to follow-
up, or patient decision to discontinue S-FU. During this S-FU, data on new anti-neoplastic 
therapy administered during this follow-up will also be collected. S-FU for all patients will end 
when the last patient entering the long-term follow-up (PT-FU or S-FU whichever occurs first) 
has completed a 3-year S-FU or discontinued earlier. 

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Figure 4-1 
Study design 
Screening 
Randomization 
Stratification 
Treatment 
arm 
Study Treatment * 
PAN/sc BTZ/Dex 
(21-day cycles, 14d on / 7d off) 
30d 
Safety FU 
Long-term FU 
(last patient entering will be followed for 
3 years) 
Post-Treatment FU (PT-
FU) 
Survival 
FU (S-FU) 
within  
28 days 
1:1:1 
n=80/arm 
TP-1 
C 1 - C4 
TP-2 
C 5 + 
≥30d post 
trt 
every  
6 weeks 
every  
12 weeks 
Adult female or male 
patients with 
measurable 
relapsed or 
relapsed/refractory 
MM 
1-4 prior lines of 
therapy (PLT) with 
prior exposure to 
IMiDs, but not BTZ 
refractory 
PLT: 
1 vs 2 vs 3 or 4 
 
Age: 
≤ 75 vs >75 
A: PAN 
20 mg TIW 
D 1, 3, 5, 8, 
10, 12 
 
B: PAN 
20 mg BIW 
D 1, 4, 8, 11 
 
C: PAN 
10 mg TIW 
D 1, 3, 5, 8, 
10, 12 
≤ 75 years: 
BTZ:1.3 mg/m2  
D1, 4, 8 & 11 
 
+ Dex: 20 mg 
D1,2,4,5, 
8,9,11 &12 
 
>75 years: 
BTZ:1.3 mg/m2  
D1 & 8 
+ Dex: 10 mg 
D1,2,8 & 9 
≤ 75 years: 
BTZ: 1.3mg/m2  
D1 & 8 
 
+ Dex: 20 mg 
D1,2, 
8 & 9 
 
>75 years: 
BTZ: 1.3 mg/m2 
D1 & 8 
+ Dex: 10 mg 
D1,2,8 & 9 
All patients 
30 days 
after last 
dose of 
study 
treatment 
Criteria to enter PT-FU: 
 
  
randomized but never 
started study treatment 
 
 
completed / discontinued 
study treatment for 
reasons other than 
documented disease 
progression, death, lost to 
follow-up, or withdrawal of 
consent 
Criteria to enter S-
FU: 
 
 
completed / 
discontinued study 
treatment and/or PT-
FU 
 
 
had documented 
disease progression  
 
 
decided not to be 
followed for efficacy 
*: study treatment will be administered until disease progression, unless study treatment is discontinued earlier due to unacceptable toxicity, or for other reasons (see 
Section 7.1.5) 
C: Cycle; D: Day; TP1: treatment period 1; TP2: treatment period 2; FU: follow-up; PLT: prior lines of therapy; PT-FU: Post treatment follow-up; S-FU: Survival follow-
up; MM: multiple myeloma 

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4.2 
Timing of interim analyses and design adaptations 
An interim analysis (IA) will be performed using data collected on or before the cut-off date, 
which corresponds to the time when approximately 120 patients (40 per treatment arm) have 
completed up to 8 cycles of study treatment or have discontinued earlier. 
Patient enrollment will not be stopped during the interim analysis. Results will be used to 
determine the optimal panobinostat regimen used in combination with BTZ s.c. and Dex for an 
improved benefit/risk assessment. 
Given that the PAN 10 mg TIW arm is the lowest dose level of the dose range, and that PAN 
20 mg BIW was never extensively investigated in patients, and in order to avoid exposing 
patients unnecessarily to an insufficiently efficacious dose, the interim analysis will include a 
futility rule for stopping the PAN 10 mg TIW and the PAN 20 mg BIW arms in case of 
insufficient efficacy based on SC recommendations (see Section 10.7). 
If the PAN 20 mg BIW and/or 10 mg TIW arm(s) is/are stopped for futility at interim analysis: 
• Patients who are on study treatment in the PAN 20 mg BIW and/or 10 mg TIW arms at 
the time this decision is made, will be given the option to discontinue treatment or to 
continue their study treatment.  The decision to continue treatment will be taken by the 
investigator on an individual basis dependent on the benefit patient is deriving from study 
treatment. 
• If not all 80 patients are enrolled to the PAN 20 mg BIW and/or 10 mg TIW arms at the 
time of this decision, further enrollment to the PAN 20 mg BIW and/or 10 mg TIW arm 
will be stopped. 
4.3 
Definition of end of the study 
The total study enrollment period is expected to be approximately 30 months. Patients will be 
treated with the study treatment until disease progression unless they discontinue earlier for 
other reasons. Patients who discontinue the study treatment for reasons other than documented 
disease progression, death, lost to follow-up, or withdrawal of consent, will be followed for 
efficacy every 6 weeks until disease progression, death, lost-to follow-up or withdrawal of 
consent. All patients will eventually (after completion of study treatment and/or the PT-FU, 
whichever ends last) be followed for a maximum of 3 years for survival every 12 weeks until 
death, lost to follow-up, or patient decision to discontinue S-FU. 
The end of the study is reached when the last patient entering the long-term follow-up (PT-FU 
or S-FU whichever occurs first) has completed a 3-year S-FU or discontinued earlier. 
The primary analysis will be conducted 24 weeks (8 cycles of treatment) after the last patient 
enrolled received the first study treatment.  The primary analysis data will be summarized in 
the primary clinical study report (CSR). 
Following the cut-off date for the analysis reported in the primary CSR, patients will continue 
to be followed according to the visit schedule.  
The final analysis will occur at the end of the study. All available data from all patients up to 
this cut-off date will be analyzed and summarized in a final CSR.  

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Assuming that the last patient receives study treatment close to the median time to progression 
of 12.7 months observed in D2308, and enters a long-term follow-up of 3 years, the total study 
duration including long-term follow-up will be approximately 6.6 years. 
4.4 
Early study termination 
The study can be terminated at any time for any reason by Secura Bio. Should this be necessary, 
the patients who are on study treatment at the time of termination should be seen as soon as 
possible for a final End-of-treatment (EOT) visit and the 30-day safety follow-up after the last 
dose. The patients who are in the PT-FU should be seen for a last PT-FU visit, and the patients 
in the S-FU at the time of termination – should be contacted by the investigator by phone or in 
writing (see Table 7-1 for the respective assessments to be done). The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate consideration 
is given to the protection of the patient’s interests. The investigator will be responsible for 
informing IRBs and/or ECs of the early termination of the study.  
5 
Population 
5.1 
Patient population 
Adult female or male patients with measurable relapsed or relapsed/refractory multiple 
myeloma who have received 1 to 4 prior lines of therapy and require re-treatment based on 
IMWG 2011 (Rajkumar et al 2011) criteria; patients who have been exposed to an IMiD and 
whose disease is not bortezomib-refractory will participate in this study.  
Patients enrolled in this study are not permitted to participate in additional parallel 
investigational drug or device studies. Patients who have completed the study may not be 
enrolled for a second course of treatment. 
The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are randomized into the study. For guidelines on re-screening 
of patients after they failed the initial screening please refer to Section 7.1.2. 
5.2 
Inclusion criteria 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
Written informed consent must be obtained prior to any screening procedures. 
1. Patient has a previous diagnosis of multiple myeloma, based on following IMWG 2014 
definition (Rajkumar et al 2014): 
• Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary 
plasmacytoma and any one or more of the following myeloma defining events at 
initial diagnosis (by local assessment). 
 
 

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Myeloma defining events: 
• Evidence of end organ damage that can be attributed to the underlying plasma cell 
proliferative disorder, specifically: 
a. Hypercalcaemia 
b. Renal insufficiency 
c. Anaemia 
d. Bone lesions: one or more osteolytic lesions 
• Any one or more of the following biomarkers of malignancy: 
a. Clonal bone marrow plasma cell percentage ≥60% 
b. Involved: uninvolved serum free light chain ratio ≥100 
c. >1 focal lesion on MRI studies 
2. Patient must have measurable disease based on protein assessment defined by at least 1 of 
the following conditions present at screening by central assessment: 
a. Serum M-protein by PEP ≥ 0.5 g/dL ( ≥ 5 g/L). 
b. Urine M-protein by PEP ≥ 200 mg/24 hours. 
c. Involved serum free light chain level ≥ 10 mg/dL (≥ 100 mg/L), provided the serum 
free light chain ratio is abnormal. 
3. Patient with 1 to 4 prior lines of therapy who requires re-treatment of myeloma for one of 
the 2 conditions below as per IMWG 2011: 
a. Relapsed myeloma: defined as previously treated myeloma that progresses and 
requires the initiation of salvage therapy but does not meet criteria for either “primary 
refractory myeloma” or “relapsed-and-refractory myeloma” categories. 
b. Relapsed-and-refractory myeloma: defined as nonresponsive while on salvage therapy 
or progresses within 60 days of last therapy in patients having achieved minimal 
response (MR) or better at some point previously before then progressing in their 
disease course. Note: Patients refractory to BTZ are excluded. 
4. Patients with prior IMiD exposure (thalidomide, lenalidomide and/or pomalidomide) 
5. Patient has an ECOG performance status (PS) ≤ 2 
6. Patient has the following laboratory values (performed at local laboratory) within 4 weeks 
before randomization (lab tests may be repeated, as clinically indicated, to obtain 
acceptable values before failure at screening is concluded but supportive therapies are not 
to be administered in the week prior to screening tests for ANC or platelet count) 
a. Absolute neutrophil count (ANC) ≥ 1.0 x 109 /L 
b. Platelet count ≥ 75 x 109/L 
c. AST and ALT ≤ Grade 1 
d. Serum total bilirubin ≤ ULN 
e. Creatinine clearance  as assessed by eGFR  ≥ 30 mL/min/1.73m2 (applying MDRD 
study equation (Section 7.2.2.5.7; Dimopoulos et al 2010) 
f. Serum calcium greater or equal to lower normal limits (> LLN), and not higher than 
CTCAE Grade 2 in case of elevated value. 

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7. Patient must have the following laboratory values (performed at local laboratory) within 
normal limits or corrected to within normal limits with supplements before randomization: 
serum sodium, potassium, magnesium, phosphorus. 
8. Patient treated with local radiotherapy with or without concomitant exposure to steroids 
for pain control or management of cord/nerve root compression, is eligible. Patients who 
require concurrent radiotherapy should have entry to the protocol deferred until the 
radiotherapy is completed and 2 weeks have passed since the last date of therapy. See also 
exclusion criterion 11c. 
9. Patients must avoid consumption of grapefruit, pomegranates, starfruit, Seville oranges or 
products containing the juice of each during the entire study and preferably 7 days before 
the first dose of study treatment, due to potential CYP3A4 interaction with the study 
treatment. Orange juice is allowed. 
10. Patient’s age is ≥ 18 years at time of signing the informed consent 
11. Patient has provided written informed consent prior to any screening procedures 
12. Patient is able to swallow capsules 
13. Patient must be able to adhere to the study visit schedule and other protocol requirements 
14. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at 
screening and a negative urine pregnancy test at baseline 
5.3 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. Patients with primary refractory myeloma defined as disease nonresponsive in patients 
who have never achieved a minimal response or better with any therapy. 
2. Patients refractory to bortezomib, i.e. patients who progressed while receiving salvage 
therapy with BTZ, or patients who progressed within 60 days of their most recent BTZ 
containing treatment. 
3. Any concomitant anti-cancer therapy (other than bortezomib/dexamethasone; 
bisphosphonates are permitted only if commenced prior to the start of screening period) 
4. Unresolved diarrhea ≥ CTCAE Grade 2 or presence of medical condition associated with 
chronic diarrhea (such as irritable bowel syndrome, inflammatory bowel disease). 
5. Allogeneic stem cell transplant recipient presenting with graft versus host disease either 
active or requiring immunosuppression 
6. Patient has shown intolerance to bortezomib or to dexamethasone or components of these 
drugs or has any contraindication to one or the other drug, following locally applicable 
prescribing information 
7. Patient has grade ≥ 2 peripheral neuropathy or Grade 1 peripheral neuropathy with pain on 
clinical examination at screening 
8. Patient received prior treatment with DAC inhibitors including Panobinostat 
9. Patient needing valproic acid for any medical condition during the study or within 5 days 
prior to first administration of panobinostat/study treatment. 
10. Patient has a second primary malignancy < 3 years of first dose of study treatment (except 
for treated basal or squamous cell carcinoma, or in situ cancer of the cervix). 
11. Patient who received: 

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a. prior anti-myeloma chemotherapy or medication including IMiDs and Dex ≤ 2 weeks 
prior to start of study treatment. Use of Dex as supportive treatment (e.g. for pain 
relief) is allowed. 
b. experimental therapy or biologic immunotherapy including monoclonal antibodies ≤ 
4 weeks prior to start of study treatment. 
c. prior radiation therapy ≤ 4 weeks or limited field radiotherapy ≤ 2 weeks priorstart of 
study treatment. 
d. Stem cell transplant ≤ 3 weeks prior to start of study treatment 
12. Patient has not recovered from all therapy-related toxicities associated with above listed 
treatments to < Grade 2 CTCAE. 
13. Patient has undergone major surgery ≤ 2 weeks prior to starting study drug or who have 
not recovered from side effects of such therapy to < Grade 2 CTCAE 
14. Patients with evidence of mucosal or internal bleeding 
15. Clinically significant, uncontrolled heart disease and/or recent cardiac event (within 6 
months prior to randomization), such as: 
a. History of angina pectoris, symptomatic pericarditis, or myocardial infarction 
b. Left Ventricular Ejection Fraction (LVEF) < 40%, as determined by echocardiogram 
(ECHO) or Multiple Gated acquisition (MUGA) 
c. History or presence of any cardiac arrhythmias, e.g. ventricular, supraventricular, 
nodal arrhythmias, or conduction abnormality other than asymptomatic Grade 1 first 
degree AV block (asymptomatic long PR interval) or asymptomatic second degree 
AV block type 1 (asymptomatic Mobitz 1)  
d. Presence of unstable atrial fibrillation (ventricular response rate >100 bpm; mean 
value of triplicate ECGs by central review at screening). Patients with stable atrial 
fibrillation can be enrolled provided they do not meet other cardiac exclusion criteria. 
e. Resting bradycardia defined as < 50 beats per minute (mean value of triplicate ECGs 
by central review at screening) 
f. Complete left bundle branch block (LBBB), bifascicular block 
g. Congenital long QT syndrome 
h. Any clinically significant ST segment and/or T-wave abnormalities 
i. Corrected QT (QTcF) > 450 ms for males and females using Fridericia’s correction 
on screening ECG (mean value of triplicate ECGs by central review at screening) 
j. History of documented congestive heart failure (New York Heart Association 
functional classification III-IV) 
k. Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥160 mm Hg 
and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without anti-
hypertensive medication. Initiation or adjustment of antihypertensive medication (s) is 
allowed prior to screening. 
l. Other clinically significant heart disease and vascular disease 
16. Patient taking medications with relative risk of prolonging the QT interval or inducing 
Torsade de pointes, if such treatment cannot be discontinued or switched to a different 
medication prior to starting study drug 

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17. Patient has impairment of gastrointestinal (GI) function or GI disease that may 
significantly alter the absorption of panobinostat (e.g. ulcerative disease, uncontrolled 
nausea, vomiting, malabsorption syndrome, obstruction, or stomach and/or small bowel 
resection) 
18. Patient has any other concurrent severe and/or uncontrolled medical conditions (e.g., 
uncontrolled diabetes, active or uncontrolled infection, chronic obstructive or chronic 
restrictive pulmonary disease including dyspnea at rest from any cause, uncontrolled 
thyroid dysfunction) that could cause unacceptable safety risks or compromise compliance 
with the protocol 
19. Patient has a known history of HIV seropositivity or history of active/treated hepatitis B or 
C (a test for screening is not required). 
20. Pregnant or nursing (lactating) women. 
21. Women of child-bearing potential (WOCBP), defined as all women physiologically 
capable of becoming pregnant, unless they are using highly effective methods of 
contraception during dosing and 3 months after stopping all study medication. Highly 
effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment 
• Male sterilization (at least 6 months prior to screening). The vasectomized male 
partner should be the sole partner for that subject 
• Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception. 
In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking study treatment. 
In women of child-bearing potential using only hormonal contraceptives, a barrier 
method should be additionally used due to the unknown risk of PK interaction 
between hormonal contraceptives and panobinostat and dexamethasone 
(weak/moderate CYP3A4 inducer) that might result in reduced efficacy of hormonal 
contraceptives. 
 
Women are considered post-menopausal and not of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six 
weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment is she 
considered not of child bearing potential. 

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22. Sexually active males unless they use a condom during intercourse while taking drug and 
for 6 months after having stopped all study medication and should not father a child in this 
period. A condom is required to be used also by vasectomized men as well as during 
intercourse with a male partner in order to prevent delivery of the drug via seminal fluid. 
6 
Treatment 
6.1 
Study treatment 
The terms “investigational study drug(s)” or “study drug(s)” will refer to oral panobinostat (also 
known as LBH589 or Farydak® or PAN) capsules, to subcutaneous bortezomib (also known as 
BTZ or Velcade®) and to oral dexamethasone (also known as Dex) tablets. “Study treatment” 
refers to the combination of PAN, BTZ and Dex. 
6.1.1 
Dosing regimen 
Table 6-1 
Dose and study treatment schedule 
Study 
treatments 
Pharmaceutical 
form and route 
of 
administration 
Initial dose* 
Frequency and/or Regimen 
PAN –  
Arm A 
Capsule for oral 
use 
 
20 mg/d 
Three times a week (TIW) 14 days on / 7 
days off (21-day cycles); 
Day 1, 3, 5, & 8, 10, 12 (e.g. Mon, Wed, 
Fri) 
PAN – 
Arm B 
20 mg/d 
Two times a week (BIW) 14 days on/7 days 
off ( 21-day cycles);  
Day 1, 4, 8, 11 (e.g. Mon, Thur) 
PAN – 
Arm C 
10 mg/d 
Three times a week (TIW) 14 days on / 7 
days off (21-day cycles); 
Day 1, 3, 5, & 8, 10, 12 (e.g. Mon, Wed, 
Fri) 
BTZ – all 
treatment 
arms 
Sub-cutaneous 
injection 
1.3 mg/m2  
In TP1 (Cycle 1 – 4): 
Patients ≤ 75 yrs of age: Twice a week 
(BIW); 14 days on / 7 days off (in 21-day 
cycles) 
Day 1, 4, 8, 11 (e.g. Mon, Thur) 
Patients > 75 yrs of age: Once a week 
(OW); 14 days on / 7 days off (in 21-day 
cycles) 
Day 1, 8 (e.g. Mon) 
same as BTZ dose 
administered at the 
completion of TP1 
In TP2 (Cycles 5+): 
All patients independent of age: 
Once a week (OW); 14 days on / 7 days off 
(21-day cycles); 
Day 1, 8 (e.g. Mon) 
Dex – all 
treatment 
arms 
Tablets for oral 
use 
20 mg/day for patients ≤ 75 
years of age on 1st day of 
screening; 
10 mg/d for patients > 75 
years of age on 1st day of 
screening 
On the day of BTZ treatment (about 15 – 
30 minutes prior to BTZ s.c. injection) and 
the day after BTZ treatment. 
Dexamethasone should not be 
administered if BTZ treatment is on hold.  
* initial doses only, for dose reductions please see Table 6-3 for PAN, Table 6-5 for BTZ and Table 6-6 for Dex. 

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Figure 6-1 
Recommended dosing schedule for Arm A and Arm C of PAN/BTZ/Dex 
for patients less than or equal to 75 years of age (on 1st day of 
screening) from Cycle 1 to 4 (TP1) 
(3-week cycles) 
Week 1 
 
Days 1-7 
Week 2 
 
Days 8-14 
Week 3 
 
Days 15-21 
Panobinostat (PAN) 
1 
 
3 
 
5 
 
 
8 
 
10 
 
12 
 
 
Rest Period 
Bortezomib (BTZ) 
1 
 
 
4 
 
 
 
8 
 
 
11 
 
 
 
Rest Period 
Dexamethasone (Dex) 
1 
2 
 
4 
5 
 
 
8 
9 
 
11 
12 
 
 
Rest Period 
Figure 6-2 
Recommended dosing schedule for Arm A and Arm C of PAN/BTZ/Dex 
for patients greater than 75 years of age (on 1st day of screening) from 
Cycle 1 to 4 (TP1), and all patients (in Arm A and Arm C) starting from 
Cycle 5 (TP2) 
(3-week cycles) 
Week 1 
 
Days 1-7 
Week 2 
 
Days 8-14 
Week 3 
 
Days 15-21 
Panobinostat (PAN) 
1 
 
3 
 
5 
 
 
8 
 
10 
 
12 
 
 
Rest Period 
Bortezomib (BTZ) 
1 
 
 
 
 
 
 
8 
 
 
 
 
 
 
Rest Period 
Dexamethasone (Dex) 
1 
2 
 
 
 
 
 
8 
9 
 
 
 
 
 
Rest Period 
Figure 6-3 
Recommended dosing schedule for Arm B of PAN/BTZ/Dex for 
patients less than or equal to 75 years of age (on 1st day of screening) 
from Cycle 1 to 4 (TP1) 
(3-week cycles)  
Week 1 
 
Days 1-7 
Week 2 
 
Days 8-14 
Week 3 
 
Days 15-21 
Panobinostat (PAN) 
1 
 
 
4 
 
 
 
8 
 
 
11 
 
 
 
Rest Period 
Bortezomib (BTZ) 
1 
 
 
4 
 
 
 
8 
 
 
11 
 
 
 
Rest Period 
Dexamethasone (Dex) 
1 
2 
 
4 
5 
 
 
8 
9 
 
11 
12 
 
 
Rest Period 
Figure 6-4 
Recommended dosing schedule for Arm B  of PAN/BTZ/Dex for 
patients greater than 75 years of age (on 1st day of screening) from 
Cycle 1 to 4 (TP1), and all patients (in Arm B) starting from Cycle 5 
(TP2) 
(3-week cycles) 
Week 1 
 
Days 1-7 
Week 2 
 
Days 8-14 
Week 3 
 
Days 15-21 
Panobinostat (PAN) 
1 
 
 
4 
 
 
 
8 
 
 
11 
 
 
 
Rest Period 
Bortezomib (BTZ) 
1 
 
 
 
 
 
 
8 
 
 
 
 
 
 
Rest Period 
Dexamethasone (Dex) 
1 
2 
 
 
 
 
 
8 
9 
 
 
 
 
 
Rest Period 
Study treatment in general will be administered in 21-day cycles. It is recommended that a new 
cycle should only start if when BTZ, PAN and Dex or at a minimum PAN and BTZ can be 
administered together. A delay of a cycle of up to 3 weeks is allowed (please refer to 
Section 6.3).  

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Patients will self-administer panobinostat as follows: 
• Every effort must be made for the patient to take PAN at approximately the same time on 
each day of administration in the morning and consistently on the same days of the week 
throughout the study  
• For patients randomized to Treatment Arm A or C, e.g. if Cycle 1 day 1, 3, 5 is a 
Monday, Wednesday, Friday; for subsequent cycles/weeks PAN dosing should again 
be on Monday, Wednesday, Friday. 
• For patients randomized to Treatment Arm B, e.g. if Cycle 1 day 1 & 4 is a Monday 
and Thursday; for subsequent cycles/weeks PAN dosing should again be on a 
Monday and Thursday. 
• For patients randomized to Treatment Arm A or C, doses should be separated by a 
minimum of 30 hours within the week of dosing. For patients enrolled to Treatment Arm 
B, doses should be separated by a minimum of 60 hours. 
• On the days of PK sampling: 
• For patients randomized to Treatment Arm A or C:  
• Patients should bring PAN to the clinical site to be administered upon 
instructions from study personnel on Days 1 and 8 of Cycle 1 and on Day 8 of 
Cycles 2 to 8. The dose administration time of PAN will be recorded by the study 
personnel to determine the actual PK collection time.  
• Patients should document the time when panobinostat was taken at home on 
Days 3, 5 and 10 of Cycle 1 and Day 5 of Cycles 2 to 8 and provide this 
information to the study personnel the next visit/day when PK samples are 
collected. 
• For patients randomized to Treatment Arm B:  
• Patients should bring PAN to the clinical site to be administered upon 
instructions from study personnel on Days 1, 4, 8 and 11 of Cycle 1 and on Day 8 
of Cycles 2 to 8. The dose administration time of PAN will be recorded by the 
study personnel to determine the actual PK collection time.  
• Study personnel should also record the time when panobinostat was taken on Day 
4 of Cycles 2 to 8 after BTZ administration at the site to determine the actual PK 
collection time. 
• The panobinostat dose may be taken with or without food. 
• Each dose of panobinostat should be taken with a glass of water (approximately 8 ounces / 
240 mL). Patients should be instructed to swallow the capsules whole and not chew or 
open them. 
• Patients must avoid consumption of grapefruits, pomegranates, starfruit, Seville oranges or 
products containing the juice of each (e.g. also in form of bitter orange marmalade) during 
the entire study treatment period and preferably 7 days before the first dose of study 
treatment, due to potential CYP3A4 interaction with the study treatment. Orange juice is 
allowed. 
• Patients should be instructed not to make up missed doses. A missed dose is defined as a 
case when the full dose is not taken within 12 hours after the approximate time of the 

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usual daily dosing. If more than 12 hours have passed, then that missed dose should be 
omitted and the patient should continue treatment with the next scheduled dose. 
• If vomiting occurs after intake of study drug, then no re-dosing of the patient is allowed 
before the next scheduled dose. 
Patients will self-administer dexamethasone as per the package insert and/or the site personnel’s 
instructions: 
• On the days when BTZ s.c. is administered, the patient should bring in their 
dexamethasone tablets, so that they can take them at the site within 15 – 30 minutes prior 
to the BTZ s.c. injection. 
• On the day after the BTZ s.c. injection the patient will take dexamethasone at home as 
instructed, about 24 hours after the Dex dose on the day of the BTZ injection. 
At the start of the study, patients, depending on local requirements, will be given a paper diary 
to document the self-administered doses of PAN/Dex starting on Cycle 1 Day 1. The PAN/Dex 
dosing data will be reviewed by the study personnel at the beginning of each cycle (starting 
with Cycle 2) and at EOT for drug accountability and consideration when entering the dosing 
information in the respective Dose Administration Record page CRF. 
Site personnel will administer BTZ s.c. as per package insert: 
• BTZ doses must be administered at least 72 hours apart. 
• The actual BTZ dose will be defined based on the BSA of the patient which is calculated 
from the patient’s weight determined on Day 1 of every cycle. 
To calculate the BSA one of the following is recommended: 
• BSA calculated using Gehan and George Equation: BSA (m2) = 0.0235 x 
Height(cm)0.42246 x Weight(kg)0.51456 
• The BSA can be calculated as per standard practice at site. However, the same 
formula/method should be consistently used for all BSA calculations of a patient. 
• On PK sampling days, when BTZ is administered on Cycle 1 Days 1, 4, 8 and Day 11 & 
on Day 8, Cycle 2 to 8, the site personnel must document the time of BTZ s.c. injection, as 
well as the time of PAN administration. When BTZ and PAN are given on the same day, 
the BTZ s.c. injection must be shortly followed by PAN ingestion (within 1-5 minutes of 
end of BTZ s.c. injection). Please note that the BTZ dose on Day 4 and 11 will only be 
administered in Cycles 1 to 4 to patients who are ≤ 75 years of age at time of signing the 
initial main informed consent. 

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Figure 6-5 
Sequence of dosing of PAN/BTZ/Dex on days when PK samples are 
collected 
All Treatment Arms (A, B & C): Cycles 1: Day 1 and 8; Cycles 2 – 8: Day 8 – all patients: 
-35 to -16 minutes prior 0h 
-5 to -1 minute(s) prior 0h 
0h = time when or just prior to when PAN 
was taken on day 1 or 8 
e.g. 08:25 to 08:44 
e.g. 08:55 to 08:59 
e.g. 09:00 
take Dex tablets 
s.c. BTZ injection 
take PAN capsule(s) 
Treatment Arm A & C: Cycle 1 Day 4 and 11 – for patients ≤ 75 years of age: 
-35 to -16 minutes prior 0h 
-5 to -1 minute(s) prior 0h 
0h = 24h after time when PAN was taken on 
day 3 or 10 
e.g. 08:25 to 08:44 
e.g. 08:55 to 08:59 
e.g. 09:00 
take Dex tablets 
s.c. BTZ injection 
no PAN capsule(s) 
Treatment Arm A & C: Cycle 1 Day 4 and 11 – for patients > 75 years of age: 
-35 to -16 minutes prior 0h 
-5 to -1 minute(s) prior 0h 
0h = 24h after time when PAN  was taken 
on day 3 or 10 
e.g. 08:25 to 08:44 
e.g. 08:55 to 08:59 
e.g. 09:00 
no Dex tablets 
no s.c. BTZ injection 
no PAN capsule(s) 
Treatment Arm B: Cycle 1 Day 4 and 11 – for patients ≤ 75 years of age: 
-35 to -16 minutes prior 0h 
-5 to -1 minute(s) prior 0h 
0h = 72h after time when PAN was taken on 
day 1 or 8 
e.g. 08:25 to 08:44 
e.g. 08:55 to 08:59 
e.g. 09:00 
take Dex tablets 
s.c. BTZ injection 
take PAN capsule(s) 
Treatment Arm B: Cycle 1 Day 4 and 11 – for patients > 75 years of age: 
-35 to -16 minutes prior 0h 
-5 to -1 minute(s) prior 0h 
0h = 72h after time when PAN  was taken 
on day 1 or 8 
e.g. 08:25 to 08:44 
e.g. 08:55 to 08:59 
e.g. 09:00 
no Dex tablets 
no s.c. BTZ injection 
take PAN capsule(s) 
6.1.2 
Ancillary treatments 
The following ancillary treatments are required while on study treatment: 
• Antiviral prophylaxis (e.g. valacyclovir or equivalent) 
• Proton pump inhibitors (e.g. lansoprazole) while taking dexamethasone 
The following ancillary treatments can be administered while on study treatment at the 
investigator’s discretion: 
• Antibiotic prophylaxis (e.g. in first one or two cycles of study treatment) 
• Growth factor prophylaxis after Cycle 1 (no growth factors should be given 
prophylactically in Cycle 1) 
• Prophylactic anti-emetics  
In case use of anti-emetic medicinal products with a known risk of QT prolongation such 
as for example 5HT3 antagonists like granisetron, ondansetron and tropisetron cannot be 
avoided, more frequent ECG monitoring should be performed.  
For details please also refer to Section 6.4 for permitted concomitant medication and permitted 
concomitant medication to be used with caution or concomitant medication that is prohibited 
during the study. 

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6.1.3 
Rescue medication 
Not applicable 
6.1.4 
Guidelines for continuation of treatment 
Please refer to Section 6.3 Dose Modifications. 
6.1.5 
Treatment duration 
Patients will be treated with the study treatment until disease progression unless they 
discontinue earlier for other reasons (Section 7.1.5). 
6.2 
Dose escalation guidelines 
Patients receiving a reduced dose level due to toxicity of PAN/BTZ/Dex during treatment 
period may be considered for dose re-escalation if: 
• either the study treatment-related adverse event has reverted in severity to grade ≤ 1 or 
baseline level, and: 
a. at least 9 scheduled doses of PAN for Treatment Arm A, and at least 6 scheduled 
doses of PAN for Treatment Arm B.  
Note: Treatment Arm C cannot be re-escalated unless dose was previously increased 
after futility decision.  
b. at least 3 scheduled doses of BTZ 
c. at least 6 scheduled doses of Dex 
at the reduced level have been administered and tolerated. 
Note: For common toxicities of PAN and BTZ (see Table 6-2) the minimum required 
number of doses for PAN and BTZ should have been administered and tolerated before 
escalation of either or both study drugs.  
or 
• the adverse event due to which the dose was omitted/reduced is determined to be not 
related to PAN/BTZ/Dex (whichever drug is considered for re-escalation). 
Should this guidance be met, then the patient may be dose escalated back to the previous dose 
(dose that was given prior to the onset of the event(s) for which the dose was modified). 
However, dose escalations cannot go beyond the initial PAN/BTZ/Dex dose that was assigned 
to the patient at time of randomization. And for patients ≤ 75 years of age in case dose escalation 
is proposed after the first 4 cycles, dose escalations cannot go beyond the doses given on Day 
1 of Cycle 5. 
Prior to consideration for dose re-escalation, the clinical condition of the patient (based on 
performance status and laboratory data) must be determined to be such that the re-escalated 
dose will be tolerated.  

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6.3 
Dose modifications 
6.3.1 
Dose modification and dose delay 
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment. The following guidelines 
need to be applied: 
• Patients unable to tolerate the minimum dose level of Dex may continue treatment with 
PAN and BTZ alone. 
• It is recommended that a new cycle should only start when BTZ, PAN and Dex or at least 
BTZ and PAN can be administered together 
• Patients requiring permanent discontinuation of PAN must discontinue study treatment. 
• Patients requiring permanent discontinuation of BTZ must discontinue study treatment. 
• If a patient requires a PAN and/or BTZ dose delay of more than 3 weeks from the 
intended day of the next scheduled dose, the patient should be discontinued from study 
treatment. If, however, the patient was clearly benefitting from study treatment and the 
cause of the delay has resolved, the patient may be able to restart study treatment based on 
investigator decision. This option should be used with the highest amount of caution 
keeping the safety of the patient in mind and evaluating whether or not the benefit 
outweighs the risk. 
These changes must be recorded on the Dosage Administration Record CRF. 
The following table (Table 6-2) provides information on dose modifications of both, PAN and 
BTZ, for common toxicities. 

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Table 6-2 
Criteria for PAN/BTZ dose modifications for common toxicities 
Worst Toxicity 
CTCAE Grade* unless otherwise specified (Value) 
HEMATOLOGICAL TOXICITIES 
PAN dose 
BTZ dose 
Platelet count 
(PLT) decreased 
Grade 3 (PLT < 50 x 109/L – 25 x 
109/L) uncomplicated 
No change 
No change 
Grade 4 (PLT < 25 x 109/L) 
or Grade 3 (PLT < 50 x 109/L – 25 x 
109/L) with bleeding 
Interrupt** 
until resolved to ≤ Grade 2, or baseline, 
then, restart at reduced dose level if current 
PAN dose is > 10 mg, and at same dose if 
current PAN dose is 10 mg (see Table 6-3) 
Interrupt** 
until resolved to ≤ Grade 2; 
if only one dose was omitted prior to correction to these 
levels, BTZ should be restarted at same dose; 
if two or more doses were omitted - consecutively, or 
within the same cycle - then BTZ should be restarted at a 
reduced dose by one dose level (see Table 6-5). 
Neutrophil count 
(ANC) decreased 
Grade 3 uncomplicated 
ANC < 1.0 - 0.75 x 109/L 
No change 
No change 
Grade 3 
ANC < 0.75 - 0.5 x 109/L 
Single occurrence within cycle, no change 
in dosing. 
Two or more occurrences within cycle, hold 
until return to ≥ Grade 2 (ANC ≥ 1.0 x 
109/L), and restart at same dose. 
No change 
Grade 4 (ANC < 0.5 x 109/L) 
Interrupt** 
until resolved to ≤ Grade 2, or baseline, 
then, restart at reduced dose level if current 
PAN dose is > 10 mg, and at same dose if 
current PAN dose is 10 mg (see Table 6-3) 
Interrupt** 
until neutropenia resolved to ≤ Grade 2; 
if only one dose was omitted prior to correction to these 
levels, BTZ should be restarted at same dose; 
if two or more doses were omitted - consecutively, or 
within the same cycle - then BTZ should be restarted at a 
reduced dose by one dose level (see Table 6-5). 
Grade 3 febrile neutropenia 
(ANC < 1.0 x 109/L, with a single 
temperature of >38.3°C (101°F) or a 
sustained temperature of ≥38°C 
(100.4°F) for > 1 hour) 
Interrupt** 
until fever resolved and ANC ≤ Grade 2, 
then, restart at reduced dose level if current 
PAN dose is > 10 mg, and at same dose if 
current PAN dose is 10 mg (see Table 6-3) 
Interrupt** 
until neutropenia resolved to ≤ Grade 2; 
if only one dose was omitted prior to correction to these 
levels, BTZ should be restarted at same dose; 
if two or more doses were omitted - consecutively, or 
within the same cycle - then BTZ should be restarted at a 
reduced dose by one dose level (see Table 6-5). 
For other hematological toxicities (i.e. anemia) that are not common to PAN/BTZ see Table 6-4 

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Worst Toxicity 
CTCAE Grade* unless otherwise specified (Value) 
For other hematological toxicities (i.e. anemia) that are not common to PAN/BTZ see Table 6-4 and Table 6-7, respectively. 
NON-HEMATOLOGICAL TOXICITIES 
Diarrhea 
Please refer to Section 6.3.1.4 (see Table 6-11) 
For other non-hematological toxicities that are not common to both PAN/BTZ see Table 6-4 and Table 6-7, respectively 
* Common Terminology Criteria for Adverse Events (CTCAE Version 4.03) 
**: Both, PAN and BTZ dosing should be interrupted at occurence of this event. 

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6.3.1.1 
Dose modifications of PAN 
Panobinostat dosing may be modified based on Table 6-3 below. An investigator can use his/her 
discretion when making dose-reduction decisions unless otherwise specified in the guidelines 
below. 
Table 6-3 
Dose reductions for PAN 
Drug/Arm 
Starting dose 
1st dose reduction 
2nd dose reduction 
3rd dose reduction 
Pan p.o. /A 
20 mg/d TIW 
D 1, 3, 5 & 
D 8, 10, 12 
15 mg/d TIW 
D 1, 3, 5 & 
D 8, 10, 12 
10 mg/d TIW 
D 1, 3, 5 & 
D 8, 10, 12 
Discontinue* 
Pan p.o. /B 
20 mg/d BIW 
D 1, 4 & D 8, 11 
15 mg/d BIW 
D 1, 4 & D 8, 11 
10 mg/d BIW  
D 1, 4 & D 8 & 11 
Discontinue* 
Pan p.o. /C 
10 mg/d TIW 
D 1, 3, 5 & 
D 8, 10, 12 
Discontinue* 
 
 
*: PAN 10 mg dosing can be interrupted and restarted at the same dose level after resolution within 22 days of 
next intended dose (see Table 6-2, Table 6-4, Section 6.3.1.1.3 and Table 6-11) 
General guidelines for panobinostat dose modifications due to adverse events related to PAN 
are provided below. If such adverse event(s) are considered possibly related to bortezomib or 
dexamethasone, the relevant dose-modification guidelines for each should be followed. 
PAN 20 mg will also need to be dose reduced to 10 mg in case of co-administration with a 
strong CYP3A inhibitor, see Section 6.4.2.2 and Section 14.1.2 for details. 

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Table 6-4 
Criteria for interruption, modification and re-initiation of PAN due to PAN-related toxicity 
Worst Toxicity 
CTCAE Grade* unless otherwise specified (Value) 
Dose Modification Guidelines 
At any time during a cycle of therapy (including intended day of 
PAN dosing) 
HEMATOLOGICAL TOXICITIES 
Please also refer to Table 6-2. 
Anemia 
Grade 2 (Hgb < 10.0 g/dL – 8.0 g/L) 
No change in PAN dosing - Consider supportive measures 
Grade 3 (Hgb < 8.0 g/dL; transfusion indicated) 
or Grade 4 (life threatening consequences, 
urgent intervention indicated) 
Temporarily interrupt PAN dosing and use supportive measures until 
resolved to ≤ Grade 1, or baseline, then, restart at reduced dose level 
if current PAN dose is > 10 mg, and at same dose if current PAN dose 
is 10 mg (see Table 6-3) 
NON-HEMATOLOGICAL TOXICITIES 
CARDIAC 
Cardiac - Prolonged QTcF interval** 
Please refer to Section 6.3.1.1.3 
GASTROINTESTINAL 
Diarrhea** 
Please refer to Section 6.3.1.4 (see Table 6-11) 
Vomiting**/Nausea*** 
Grade 1 & 2 
No change in PAN dosing 
Grade 3 or 4 vomiting 
or Grade 3 nausea that cannot be controlled 
despite the use of standard anti-emetics 
Temporarily interrupt PAN dosing until resolved to ≤ Grade 1, or 
baseline, then, restart PAN at reduced dose level if current PAN dose 
is > 10 mg, and at same dose if current PAN dose is 10 mg (see 
Table 6-3) 
FATIGUE 
Fatigue 
Grade 3 
Temporarily interrupt PAN dosing until resolved to ≤ Grade 2, or 
baseline, then: 
● If resolved within 7 days, then restart PAN at the same dose level 
● If resolved in more than 7 days, then, restart PAN at reduced dose 
level if current PAN dose is > 10 mg, and at same dose if current PAN 
dose is 10 mg (see Table 6-3) 
INVESTIGATIONS 
Blood bilirubin Increased 
Grade 3 (>3.0 – 10.0 x ULN) or 4 (> 10.0 x 
ULN) 
Temporarily interrupt PAN dosing until resolved to ≤ Grade 2, or 
baseline, then, restart PAN at reduced dose level if current PAN dose 
is > 10 mg, and at same dose if current PAN dose is 10 mg (see 
Table  6-3) 

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Worst Toxicity 
CTCAE Grade* unless otherwise specified (Value) 
Dose Modification Guidelines 
At any time during a cycle of therapy (including intended day of 
PAN dosing) 
Note: If Grade 3 or Grade 4 hyperbilirubinemia is due to the indirect component only, and hemolysis as the etiology has been ruled out as per institutional guidelines 
(e.g., review of peripheral blood smear and haptoglobin determination), then reduction of one PAN dose level and continuation of treatment is at the discretion of the 
Investigator. 
Aspartate Aminotransferase (AST) 
increased 
Alanine Aminotransferase (ALT) 
increased 
> 5.0-20.0 x ULN 
Temporarily interrupt PAN dosing until resolved to ≤ Grade 1, or 
baseline, then: 
● If resolved within 7 days restart PAN at the same dose level 
● If resolved in more than 7 days, then, restart PAN at reduced dose 
level if previous PAN dose is > 10 mg, and at same dose if current 
PAN dose is 10 mg (see Table 6-3) 
> 20.0 x ULN 
Temporarily interrupt PAN dosing until resolved to ≤ Grade 1, or 
baseline, then, restart PAN at reduced dose level if current PAN dose 
is > 10 mg, and at same dose if current PAN dose is 10 mg (see 
Table 6-3) 
All dose modifications should be based on the worst preceding toxicity. 
* Common Terminology Criteria for Adverse Events (CTCAE Version 4.03) 
** It is critical that electrolyte abnormalities be followed closely and corrected prior to PAN dosing 
*** See also concomitant medication  

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6.3.1.1.1 Grade 2 non-hematologic toxicity 
Patients experiencing CTCAE Grade 2 non-hematologic adverse event(s) not listed in 
Table 6-4, which the patient believes is/are tolerable and in the Investigator’s judgment is/are 
acceptable, may continue treatment at the current dose and schedule. More frequent patient 
monitoring may be required, and patients must be informed to call the Investigator immediately 
if there is any worsening of symptoms. 
If a patient experiences new (or treatment emergent) Grade 2 non-hematologic adverse event(s) 
considered at least possibly related to PAN, and which the patient finds intolerable or in the 
Investigator’s judgment is/are not acceptable, treatment must be held until the adverse event(s) 
resolves to ≤ CTCAE Grade 1. PAN treatment may then be restarted at the same dose and 
schedule. If the same intolerable Grade 2 adverse event(s) occurs again, PAN treatment must 
again be temporarily interrupted until the toxicity resolves to ≤ CTCAE grade 1 and can be 
restarted at reduced dose level if current PAN dose was > 10 mg, and at same dose level if 
current PAN dose was 10 mg (see Table 6-3). At the discretion of the Investigator, patients with 
grade ≥ 2 adverse events of major organs (e.g. heart, lungs, CNS) may be discontinued from 
further study therapy without being retreated with a dose reduction. 
6.3.1.1.2 Grade 3 or 4 non-hematologic toxicity 
Patients experiencing new (or treatment emergent) CTCAE Grade 3 or 4 non-hematologic AEs 
not listed in Table 6-4, must have their PAN treatment temporarily interrupted until the adverse 
event resolves to ≤ CTCAE Grade 1 or baseline unless otherwise specified in Table 6-4. If the 
AE was considered related to PAN, PAN should then be restarted at reduced dose level if 
current PAN dose was > 10 mg, and at same dose level if current PAN dose was 10 mg (see 
Table 6-3). If the AE was considered not related to PAN then PAN may be restarted (when the 
AE resolves to ≤ Grade 1 or baseline) at the current dose. 
6.3.1.1.3 Dose modification of panobinostat for prolonged QTcF interval 
All cardiac events should be treated as per the local standard of care and referred to a 
cardiologist if clinically indicated. The central and/or local readings of ECGs will use the 
Fridericia’s correction for QTc interval assessment: QTcF. Any final decisions concerning PAN 
dose modifications or permanently discontinuing the patient from study treatment due to QTcF 
prolongation will be based on the assessment performed by the Investigator. 
In case of average QTcF > 450 ms pre-dose (Dex/BTZ/PAN) on Cycle 1 Day 1: 
• Assess the quality of the ECG recording and the QT value and repeat if needed 
• Do not initiate study treatment 
• Determine the serum electrolyte levels (in particular hypokalemia, hypomagnesemia). If 
abnormal, correct abnormalities before initiating study treatment 
• Review concomitant medication use for other causes for QT prolongation (refer to 
Section 6.4.3.1 and qtdrugs.org for known QT prolonging drugs), and for drugs with the 
potential to increase the risk of drug exposure related QT prolongation (e.g., concomitant 
use of strong CYP3A4 inhibitors, see Section 6.4.2.2) 
• Within 7 days, repeat triplicate pre-dose ECG  

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• If average QTcF >450 ms, do not initiate study treatment 
• If patient was not yet randomized, consider patient a screen failure and complete 
end of screening disposition form 
• If patient was randomized, complete end of treatment disposition form, and start 
patient in long-term follow-up. 
• If average QTcF ≤ 450 ms, initiate study treatment  
In case of average QTcF >480 ms, (or average QTcF prolongation >60 ms from baseline) 
any time after 1st dose of PAN until end of PAN treatment: 
• Assess the quality of the ECG recording and the QT value and repeat if needed 
• Interrupt PAN treatment 
• Determine the serum electrolyte levels (in particular hypokalemia, hypomagnesemia). If 
abnormal, correct abnormalities before resuming study drug treatment.  
• Review concomitant medication use for other causes for QT prolongation, and for drugs 
with the potential to increase the risk of drug exposure related QT prolongation  
• Check study drug dosing schedule and treatment compliance 
• Consider more frequent ECG monitoring (e.g. approximately every 2-3 hours between 2 
hours post PAN and 6 hours post PAN) until average QTcF is ≤ 480 ms) 
After confirming ECG reading at site (and/or receiving central vendor results in case 
ECGs are performed between 1st PAN dose and end of Cycle 16), if average QTcF  
> 480 ms:  
• Interrupt PAN treatment  
• Repeat ECG and confirm ECG diagnosis by a cardiologist or central ECG lab  
• If average QTcF confirmed > 480 ms: 
• Correct electrolytes, eliminate culprit concomitant treatments, and identify clinical 
conditions that could potentially prolong the QT  
• Consult with a cardiologist (or qualified specialist)  
• Increase cardiac monitoring as indicated (e.g., perform approximately hourly ECGs at 
between 2 h post PAN and 6 h post PAN on the same day an average QTcF > 480 ms 
is reported and pre-dose and at 2 h post PAN and the next PAN dosing days) until the 
average QTcF returns to ≤ 480 ms 
• After resolution within 7 days to ≤ 480 ms, consider re-introducing PAN treatment at the 
same or reduced dose, and increase ECG monitoring (e.g., pre-dose PAN and 2 h post 
PAN) for the next PAN treatment(s):  
• If average QTcF remains ≤ 480 ms, continue planned ECG monitoring during 
subsequent PAN treatment  
• If average QTcF recurs > 480 ms after re-introduction PAN treatment or remains  
> 480 ms for more than 7 days prior to re-introduction, discontinue patient from study 
treatment.  

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Please note that for unscheduled ECGs at any time during PAN treatment including all 
ECGs performed after Cycle 16 (i.e. when ECG will only be performed and assessed 
locally, as clinically indicated):  
If a single QTcF is > 480 ms, two additional ECGs should be performed. The three ECGs should 
be separated by 5-10 minutes. The average QTcF of those three ECGs should be calculated and 
used for determination of PAN dose modifications. 
6.3.1.2 
Dose modifications for BTZ/Dex 
Dose modifications for bortezomib and dexamethasone may be performed based on Table 6-5 
and Table 6-6 below. For criteria for dose modifications for toxicities that are common to PAN 
and BTZ, see Table 6-2. 
Table 6-5 
Dose reduction steps for BTZ for all Treatment Arms 
Drug 
Patient age 
on 1st day of 
screening 
Starting Dose 
1st Dose 
Reduction 
2nd Dose 
Reduction 
3nd Dose 
Reduction 
4th Dose 
Reduction 
BTZ 
s.c. 
≤ 75 years 
1.3 mg/m2 twice 
a week (BIW) 
D 1, 4, 8 & 11 
1.3 mg/m2 OW 
D 1 & 8* 
1.0 mg/m2 OW 
D 1 & 8* 
0.7 mg/m2 OW 
D 1 & 8* 
Discontinue 
> 75 years 
1.3 mg/m2 once 
a week (OW) 
D 1 & 8 
1.0 mg/m2 OW 
D 1 & 8 
0.7 mg/m2 OW 
D 1 & 8 
Discontinue 
 
Total BTZ dose to be administered is calculated using weight determined on Day 1 of each cycle 
* Please note the Dex dose remains unchanged but Dex is administered on D1, 2, 8 and 9 only once BTZ 
schedule is changed to once a week. 
Table 6-6 
Dose reduction steps for Dex for all Treatment Arms 
Drug 
Patient age 
on 1st day of 
screening 
Starting Dose  
1st Dose 
Reduction 
2nd Dose 
Reduction 
3rd Dose 
Reduction 
Dex 
p.o. 
≤ 75 years 
20 mg/d the day of 
and 1 day after 
BTZ s.c. injection 
10 mg/d the day of 
and 1 day after 
BTZ s.c. injection 
6 mg/d the day of 
and 1 day after 
BTZ s.c. injection 
Discontinue Dex 
Continue with 
PAN/BTZ alone 
> 75 years 
10 mg/d the day of 
and 1 day after 
BTZ s.c. injection 
6 mg/d the day of 
and 1 day after 
BTZ s.c. injection 
Discontinue Dex 
Continue with 
PAN/BTZ alone 
 
Dexamethasone tablets should be taken approximately 15-30 minutes prior to BTZ s.c. injection; and 
approximately at the same time the following day. 

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Table 6-7 
Drug related adverse events dose modification guidelines for BTZ 
CTCAE Category 
Dose Modification Guideline - 
At any time during a cycle of BTZ (including intended 
day of dosing) 
HEMATOLOGICAL TOXICITIES 
(ANC, PLT) 
See Table 6-2. 
NON-HEMATOLOGICAL TOXICITIES 
 
Peripheral Neuropathy 
See Table 6-8. 
Herpes Zoster reactivation any grade 
Hold BTZ until lesions are dry. 
Other BTZ related non-hematologic toxicity ≥ Gr 3 
Determine attribution of toxicity and hold BTZ. 
If toxicity resolves to ≤ Gr 2, resume BTZ with one level 
dose reduction (see Table 6-5). 
6.3.1.3 
Management of patients with BTZ-related neuropathic pain and/or 
peripheral sensory neuropathy 
The neurotoxicity-directed questionnaire (FACT/GOG-Ntx) is a useful tool for determining the 
presence and intensity of neuropathic pain and/or peripheral neuropathy from the patient’s 
perspective. Neuropathic symptoms are more prominent than abnormalities on the clinical 
examination. After the patient completes the neurotoxicity-directed questionnaire, the 
questionnaire should be reviewed to assist with the evaluation of the onset and intensity of 
peripheral neuropathy and other neurotoxicities that may possibly require intervention or BTZ 
dose modification. 
Table 6-8 
Recommended dose modification for BTZ-related neuropathic pain 
and/or peripheral sensory neuropathy 
Severity of Peripheral Neuropathy 
Signs and Symptoms 
Modification of Dose and Regimen 
Gr 1 (Asymptomatic; loss of deep 
tendon reflexes or paresthesia) 
No action 
Gr 1 with pain or Gr 2 (Moderate symptoms; 
limiting instrumental ADL) 
Reduce BTZ by one dose level (see Table 6-5) 
Gr 2 with pain or Gr 3 (Severe symptoms; limiting 
self-care ADL) 
Hold BTZ until toxicity resolves to < Gr 2 
When toxicity resolves, reinitiate BTZ with a reduction by 
one dose level (see Table 6-5) 
If no more dose reductions are possible, discontinue 
study treatment 
Gr 4 (Life-threatening consequences; urgent 
intervention indicated) 
Discontinue study treatment 
Grading based on NCI Common Terminology Criteria CTCAE v4.03 
NCI Common Toxicity Criteria website - http://ctep.info.nih.gov/reporting/ctc.html. 

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Table 6-9 
Dex dose modifications 
Dexamethasone dose modifications 
Gastrointestinal 
Dyspepsia, gastric or duodenal 
ulcer, gastritis Gr 1-2 (requiring 
medical management) 
Treat with H2 blockers, sucralfate, or omeprazole. If 
symptoms persist despite above measures, reduce 
Dex by one dose level (see Table 6-6) 
> Gr 3 (requiring hospitalization 
or surgery) 
Hold Dex until symptoms adequately controlled. 
Restart and reduce one dose level (see Table 6-6) 
along with concurrent therapy with H2 blockers, 
sucralfate, or omeprazole. If symptoms persist 
despite above measures, discontinue Dex and do 
not resume. 
Acute pancreatitis 
Discontinue Dex and do not resume. 
Cardiovascular 
Edema 
> Gr 3 (limiting function and 
unresponsive to therapy or 
anasarca) 
Diuretics as needed, and reduce Dex by one dose 
level (see Table 6-6); if edema persists despite 
above measures, reduce another dose level. 
Discontinue Dex and do not resume if symptoms 
persist despite second reduction. 
Neurology 
Confusion or Mood alteration > 
Gr 2 (interfering with function +/- 
interfering with activities of daily 
living) 
Hold Dex until symptoms resolve. Restart with one 
dose level reduction (see Table 6-6). If symptoms 
persist despite above measures, discontinue Dex 
and do not resume. 
Musculoskeletal 
Muscle weakness 
> Gr 2 (symptomatic and 
interfering with function +/- 
interfering with activities of daily 
living) 
Reduce Dex by one dose level (see Table 6-6). If 
weakness persists despite above measures reduce 
by another dose level. Discontinue Dex and do not 
resume if symptoms persist. 
Metabolic 
Hyperglycemia 
> Gr 3 or higher 
Treatment with insulin or oral hypoglycemics as 
needed. If uncontrolled despite above measures, 
reduce Dex by one dose level (see Table 6-6) until 
levels are satisfactory. 
6.3.1.4 
Management of diarrhea (including PAN and BTZ dose modifications) 
The electronic diary for diarrhea management will be provided to patients to track the 
frequency, onset, duration, stool consistency. Patients should be instructed on the daily 
completion of the electronic diary on a hand-held device between first day of screening and last 
day of Cycle 8, unless study treatment is discontinued earlier. In addition, the patient should be 
instructed to contact the physician/other study personnel at the first sign of diarrhea (increase 
of bowel movements/day from baseline and/or increased stool fluidity). The patient should also 
be instructed on the use of loperamide or other anti-diarrheal medication as per investigator’s 
discretion at home (see Table 6-10). 
At the beginning of every cycle, each patient should be asked if he/she experienced any diarrhea 
and if any self-care measures were taken for this event. Additionally, on Day 1 of Cycles 1 
through 9, the patients’ diary entries should be reviewed by the study personnel (see 
Section 7.2.6). The study personnel should ensure that adverse event(s) of diarrhea and use of 
concomitant anti-diarrheal medication are documented on the relevant pages of the CRF as 
needed. 
If the regimen described below is inadequate or at the investigator’s discretion, additional 
evaluation and treatment should be pursued including hospitalization as needed. Replacement 

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i.v. fluids and electrolytes may be used as appropriate. Additional treatment should be provided 
in accordance with institutional standard of care and/or local guidelines. 
At the time of the first screening visit: 
History and physical are documented and patient is counseled on diet, use of laxatives, as 
follows: 
• Take thorough history of diarrhea (Definition as per CTCAE: A disorder characterized by 
frequent and watery bowel movements)  
• Determine average number of bowel movements/day and record in electronic diary 
• Determine average stool type according to the Bristol Stool Form Scale (see 
Appendix 5) and record in electronic diary 
• Assess the patient for fever, abdominal pain, cramps, distension, bloating, nausea, 
vomiting, dizziness, weakness (i.e., rule out sepsis, clostridium difficile, bowel 
obstruction, or dehydration) 
• Obtain patient’s medication profile (i.e., to identify and limit the use of any diarrhea 
causing agents) 
• Obtain dietary profile and counsel patient on dietary modifications: 
• Instruct the patient to stop all lactose-containing products 
• Instruct the patient to stop taking laxatives, bulk fiber (i.e. Metamucil®), and stool 
softeners (docusate sodium; Colace®) 
• Instruct the patient to drink 8 to 10 large glasses of clear liquids per day (i.e. water, 
Pedialyte®, Gatorade®, broth) 
• Instruct the patient to eat frequent small meals (bananas, rice, applesauce, Ensure®, 
toast) 
• Instruct the patient to stop consuming high-osmolar food supplements such as Ensure 
Plus® and Jevity Plus® (with fiber) 
In the screening period, patients will complete a daily diary for diarrhea management from the 
first day of screening until the first day of study treatment. The diary will be in the form of an 
electronic device that the patients will take home with them. They will be instructed how to turn 
it on, complete the diary and submit their results after they complete the diary every day for at 
least one week. The study personnel should review the patient entries, prior to the start of study 
treatment on Cycle 1 Day 1 and depending on the outcome of the review the following actions 
should be taken: 
• If the patient has normal stools prior to study entry, no anti-diarrheal treatment is needed. 
• If the patient has Grade 1 diarrhea that is NOT attributable to infectious or other 
conditions where anti-diarrheal therapy may be contraindicated, it is recommended that 
the patient starts standard dose loperamide (Table 6-10). Study treatment may be started. 
• If the patient has ≥ Grade 2 diarrhea prior to dosing, study treatment can be delayed for up 
to 48 hours until diarrhea is ≤ Grade 1. 
• Site personnel to determine the baseline of average bowel movements/day and baseline 
average stool type according to Bristol Stool Form Scale on Cycle 1 Day 1 prior to first 

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study treatment, move the patient to the treatment phase and record results in electronic 
diary.  
The patient should take loperamide and/or other anti-diarrheal medication as per investigator’s 
discretion/instructions at home.  
Proposed diarrhea management after 1st screening visit and during study treatment 
Table 6-10 and Table 6-11 describe the anti-diarrheal medications and other diarrhea 
management steps (including dose modifications) proposed after the first screening visit, 
respectively. 
Table 6-10 
Proposed anti-diarrheal medication 
 
Medication 
Dose 
Step 1 
standard dose loperamide 
(Imodium) 
4 mg followed by 2 mg every 4 hours OR after each loose 
stool (maximum 16 mg/day). 
Step 2 
high dose loperamide (Imodium) 
4 mg followed by 2 mg every 2 hours OR 4 mg every 4 hours 
(maximum of 16 mg/day) 
Step 3 
other anti-diarrheal medication as 
per investigator’s discretion 
as per investigator’s discretion and standard of care/package 
insert ( e.g. diphenoxylate/atropine 5 mg every 6 hours) 

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Table 6-11 
Diarrhea management and PAN/BTZ dose modifications 
Diarrhea CTCAE grade 
Diarrhea management 
PAN and BTZ dosing 
Prior to first planned dose 
Grade 1 
Increase of < 4 stools / day over baseline*; mild increase 
in ostomy output compared to baseline* 
*as captured on first day of screening 
Standard dose loperamide 
Give full dose of both PAN and BTZ 
On study treatment 
Grade 1 
Increase of < 4 stools / day over baseline**; mild increase 
in ostomy output compared to baseline** 
Standard dose loperamide 
Give full dose of PAN and BTZ 
Grade 2 
increase of 4-6 stools / day 
over baseline**; moderate 
increase in ostomy output 
compared to baseline** 
Grade 2 
High dose loperamide 
Interrupt both, PAN and BTZ 
when improved to 
≤ Grade 1 w/i 24h 
Modify anti-diarrheal medication as 
appropriate 
Restart both, PAN and BTZ, at current doses 
Grade 2 for > 24h 
Start other anti-diarrheal medication, 
continue high dose loperamide 
Interrupt both, PAN and BTZ 
when improved to 
≤ Grade 1 w/i 48 h 
Modify anti-diarrheal medication as 
appropriate 
Restart both, PAN and BTZ, at current doses 
Grade 2 for > 48h 
Continue other anti-diarrheal medication 
and high dose loperamide 
Interrupt both PAN and BTZ 
when improved to 
≤ Grade 1 after >48 h 
Modify anti-diarrheal medication as 
appropriate 
Dose reduction of BTZ and PAN if current PAN dose is > 10 
mg. Dose reduction of BTZ and no dose reduction if current 
PAN dose is 10 mg (see Table 6-3). 
Grade 3 
increase of ≥7 stools / 
day over baseline**; 
incontinence; hospitalization 
indicated; severe increase in 
ostomy output compared to 
baseline**; self-limiting care 
ADL 
Grade 3 
High dose loperamide and other anti-
diarrheal medication 
Consider hospitalization for monitoring / 
volume management 
Interrupt both, PAN and BTZ 
until diarrhea improves 
to ≤ Grade 1 
Continue high dose loperamide and other 
anti-diarrheal medication and supportive 
care unit ≤ Grade 1 
Interrupt both, PAN and BTZ 
when improved to 
≤ Grade 1 
Modify anti-diarrheal medication as 
appropriate 
Dose reduction of BTZ and PAN if current PAN dose is > 10 
mg. Dose reduction of BTZ and no dose reduction in PAN if 
current PAN dose is 10 mg (see Table 6-3). 

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Diarrhea CTCAE grade 
Diarrhea management 
PAN and BTZ dosing 
for further episodes of 
Grade 3 
Start/Continue high dose loperamide and 
diphenoxylate/atropine as necessary until 
improved to ≤ Grade1 
Dose reduction of BTZ and PAN if current PAN dose is > 10 
mg. Dose reduction of BZT and no dose reduction if current 
PAN dose is 10 mg (see Table 6-3). 
Grade 4 
Life threatening 
consequences; urgent 
intervention indicated 
Grade 4 
Hospitalize and provide intensive 
supportive care and anti-diarrheals 
Discontinue study treatment 
**: determined on Cycle 1 Day 1 prior to first dose of study treatment 
Note: Diarrhea definition as per CTCAE: A disorder characterized by frequent and watery bowel movements 
Anti-diarrheal medication and IV fluids given as supportive care, should be documented on the anti-diarrheal medication CRF page.

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6.3.2 
Follow-up for toxicities 
Patients whose study treatment is interrupted or permanently discontinued due to an adverse 
event or clinically significant laboratory value, must be followed up at least once a week (or 
more frequently if required by institutional practices, or if clinically indicated) for 4 weeks, and 
subsequently at approximately 4-week intervals, until resolution or stabilization of the event, 
whichever comes first. Appropriate clinical experts such as ophthalmologist, endocrinologist, 
dermatologist, psychiatrists etc. should be consulted as deemed necessary. 
Table 6-12 outlines the follow-up evaluation recommended for toxicities of specific types and 
CTCAE grades after study treatment is permanently discontinued. For follow-up for toxicities 
while study treatment is temporarily interrupted see dose modifications in Table 6-2, Table 6-4, 
Section 6.3.1.1.3, Table 6-7 and/or Table 6-8, respectively.  
Table 6-12 
Follow-up evaluations for selected toxicities 
TOXICITY 
FOLLOW-UP EVALUATION 
Blood and lymphatic system 
disorders 
Continue to test weekly until resolution to baseline or stabilization. 
Investigations (hematologic) 
Neutropenia ≥ CTCAE Grade 3 
Thrombocytopenia ≥ CTCAE 
Grade 3 
Continue to test weekly until resolution to baseline or stabilization. 
Perform physical exam for check on bruising in case of major 
thrombocytopenia. 
Investigations (hepatic) 
Liver enzymes ≥ CTCAE Grade 3 
Continue to test weekly until resolution to ≤ CTCAE Grade 1 or 
stabilization. 
Cardiac disorders 
QT and ECG  
ECG changes indicative of ischemic 
event 
Perform twice weekly ECGs until normalization or stabilization of ECG 
findings. 
● Central ECGs, if disorder is observed prior to start of Cycle 17 
● Local ECGs, if disorder is observed after start of Cycle 17 
Further guidelines and recommendations for the management of specific study treatment related 
toxicities (diarrhea and cardiac toxicities) are provided in Section 6.3.1.4 and Section 6.3.1.1.3. 
All patients must be followed up for adverse events and serious adverse events for 30 days 
following the last dose of study treatment. 
Follow up on potential drug-induced liver injury (DILI) cases 
Patients with transaminase increase combined with total bilirubin (TBIL) increase may be 
indicative of potential DILI and should be considered as clinically important events.  
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below: 
For patients with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x ULN 
combined with TBIL > 2.0 x ULN  
For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x baseline 
AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], whichever is lower, combined with 
[TBIL > 2 x baseline AND > 2.0 x ULN] 

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Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as: ALP elevation > 2.0 x ULN with R value < 2 in patients without bone metastasis, or elevation 
of ALP liver fraction in patients with bone metastasis. 
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes the relative pattern of ALT and/or ALP elevation is due to cholestatic 
or hepatocellular liver injury. 
In the absence of cholestasis, these patients should be immediately discontinued from study 
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours 
from the awareness of the abnormal results. The evaluation should include laboratory tests, 
detailed history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc.  
Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct and 
indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase.  
A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected.  
Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary tract) 
may be warranted.  
Obtain an additional unscheduled PK sample, as close as possible to last dose of PAN, if PK 
analysis is performed in the study.  
Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), autoimmune 
hepatitis or liver biopsy may be considered as clinically indicated or after consultation with 
specialist/hepatologist.  
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus, met the definition of SAE (Section 8.2.1) and reported as SAE using the term 
“potential drug-induced liver injury”. All events should be followed up with the outcome clearly 
documented. 
6.3.3 
Anticipated risks and safety concerns of the study treatment 
Appropriate eligibility criteria, as well as specific dose modification and stopping rules are 
included in this protocol. Recommended guidelines for prophylactic or supportive treatment for 
expected toxicities, including management of study-treatment induced adverse events, i.e., 
diarrhea are provided in Section 6.3.1.4 and Section 6.4. Refer to preclinical toxicity and/or 
clinical data found in the PAN Investigator’s Brochure and BTZ and Dex package insert. 

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6.4 
Concomitant medications 
6.4.1 
Permitted concomitant therapy 
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications (other than study drug) and significant 
non-drug therapies (including physical therapy, herbal/natural medications and blood 
transfusions) administered during the study must be listed on the Concomitant Medications or 
the Procedures and Significant Non-Drug Therapies CRF. 
6.4.1.1 
Growth factors 
Granulocyte colony stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating 
factor (GM-CSF) should not be used prophylactically in the first cycle. G-CSF may be initiated 
for an individual patient in accordance with American Society of Clinical Oncology’s 
guidelines (Smith et al 2006), if the patient experiences febrile neutropenia and/or Grade 4 
neutropenia for > 7 days. Growth factors may then be administered prophylactically in all 
subsequent cycles for that patient. 
Patients who were receiving available recombinant erythropoiesis stimulating agents such as 
epoetin and darbepoetin prior to starting study treatment may continue to receive it throughout 
the study. Likewise, these can be introduced during the study. Investigators should follow 
available guidelines on criteria for initiation, target and doses provided in ASCO/ASH 
guidelines (Rizzo et al 2010). 
6.4.1.2 
Anti-emetic medication 
Prophylactic anti-emetics: may be considered at the discretion of the physician and in 
accordance with local medical practice. In case use of anti-emetic medicinal products with a 
known risk of QT prolongation such as for example 5HT3 antagonists like granisetron, 
ondansetron and tropisetron cannot be avoided, more frequent ECG monitoring should be 
performed.  
Anti-diarrhea medication: Please refer to Section 6.3.1.4 for details on management of 
diarrhea. 
6.4.1.3 
Prophylaxis treatment 
Please refer to Section 6.1.2 for ancillary treatment. 
6.4.2 
Permitted concomitant therapy requiring caution and/or action 
6.4.2.1 
Anti-coagulant therapy/ anti-platelet therapy 
Panobinostat therapy, especially in combination with bortezomib, is commonly associated with 
moderate to severe degree of thrombocytopenia. This may lead to an increase in the risk of 
bleeding especially if co-administered with long acting anticoagulation, such as sodium 
warfarin (Coumadin®). It is recommended that patients who require anticoagulation therapy 

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while on panobinostat therapy use low molecular weight heparin (LMWH). However, if the use 
of LMWH is not feasible or indicated, patients on vitamin K inhibitors such as sodium warfarin 
may continue such therapy while on panobinostat but for such patients, a close and frequent 
monitoring of the coagulation parameters, especially PT/INR should be followed and 
maintained within a therapeutic range (suggested INR 2-3). Warfarin should be used with 
caution and the dose of sodium warfarin may be adjusted as needed while on study treatment. 
It is recommended that if the platelet count falls below 50 x 109/L, withholding of 
thromboprophylaxis be considered to minimize the risk of bleeding. Newer direct Factor Xa 
and thrombin inhibitors should not be used as there is no effective antidote available and fresh 
frozen plasma is not effective in reversing their effects. 
For patients requiring anti-platelet therapy while on panobinostat, Aspirin ≤325 mg or 
Plavix ≤75 mg daily are allowed. It is recommended that anti-platelet therapy be held if platelet 
counts fall below 50 x 109/L. 
6.4.2.2 
Medications that are known to be strong CYP3A inhibitors 
See Section 14.1.2. 
Panobinostat is a substrate of CYP3A with minor involvement of CYP2D6, and CYP2C19 in 
in vitro evaluation of its metabolism. Thus, a clinical drug-drug interaction study was conducted 
using ketoconazole, a strong CYP3A inhibitor, in combination with panobinostat in study 
[CLBH589B2110]. 
Multiple ketoconazole doses at 400 mg increased Cmax and AUC of panobinostat by 1.6- and 
1.7-fold, respectively, but with no change in Tmax or half-lives in 14 cancers patients. The less 
than 2-fold increase in panobinostat AUC upon co-administration of a strong CYP3A inhibitor 
is considered a weak drug inhibition. However, panobinostat dose should be reduced from 20 
mg to 10 mg when combined with medications which are known strong CYP3A inhibitors. If 
patients are already at reduced doses of panobinostat 15 mg or 10 mg, combination with strong 
CYP3A inhibitors should be avoided. If this is not avoidable, patients should be monitored 
closely for toxicity. 
Patients with impaired liver function (as defined by NCI CTEP criteria, Synold et al 2007) are 
recommended not to receive panobinostat concomitantly with strong CYP3A inhibitors due to 
lack of safety data in this population. 
6.4.3 
Prohibited concomitant therapy 
See Section 14.1. 
The following medications are prohibited during this study: 
• Systemic anticoagulation or drugs that inhibit platelet function, WITH THE EXCEPTION 
OF (see Section 6.4.2.1): 
• Aspirin ≤ 325 mg/day 
• Plavix ≤ 75 mg/day 
• Low molecular weight heparin (LMWH). 

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• Titrated dose warfarin may be used in patients requiring chronic anticoagulation 
• Any investigational medication (other than PAN) 
• Chemo-, biologic or immunologic therapy is not allowed while the patient is on study 
treatment. Palliative radiation therapy may be permitted, but the need for radiation therapy 
is usually indicative of disease progression. 
• DAC inhibitors, including valproic acid, for any clinical indication while on PAN 
treatment. 
6.4.3.1 
Drugs that are known to prolong the QT interval and/or induce 
Torsade de Pointes ventricular arrhythmia 
Patients who are currently receiving treatment with any of the medications in Section 14.1.1 
which have a known risk of prolonging the QT interval or inducing Torsades de pointes and 
cannot either discontinue this treatment or switch to a different medication prior to study 
enrollment, will be excluded from the study. Patients may not begin treatment with any of the 
medications listed in Section 14.1.1. 
Ensure that patient is off panobinostat treatment for at least 72 hours prior to starting treatment 
with a medication listed in Section 14.1.1. 
It is of importance to avoid combining drugs listed in Table 14-1 (QT prolonging drugs) and 
Table 14-2 (CYP3A inhibitors) in the presence of electrolyte abnormalities notably decreased 
potassium or magnesium levels commonly associated with diuretic usage. 
The current panobinostat guidance (as specified in Section 14.1) includes an updated list of 
medications which was developed in collaboration with an external cardiologist consultant and 
is based on the ARIZONA CERT (CredibleMeds.org) website on drugs that prolong the QT 
interval and/or induce Torsades de Pointes or ventricular arrhythmia. 
6.4.3.2 
Medications which are known strong CYP3A inducers are to be 
avoided 
Panobinostat plasma exposure was reduced by 20% or more when combined with bortezomib 
and dexamethasone (B2207 and D2308). Co-administration of panobinostat with strong 
CYP3A inducers was not evaluated in a clinical study however, an approximately 70% decrease 
in the systemic exposure of panobinostat in the presence of strong inducers of CYP3A was 
observed in simulations using mechanistic models. Therefore, the concomitant use of strong 
CYP3A inducers should be avoided. 
6.4.3.3 
Medications which are known sensitive CYP2D6 substrates or 
substrates with narrow therapeutic index 
Panobinostat was also shown to be a CYP2D6 inhibitor (Ki 0.17 µM) in vitro. Thus, clinical 
drug-drug interaction study with panobinostat as CYP2D6 inhibitor and dextromethorphan as 
CYP2D6 substrate was recently conducted in study [CLBH589B2109]. 

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Panobinostat increased the median Cmax and AUC of a sensitive substrate of CYP2D6 by 
approximately 80% and 60%, respectively; however, these increases were highly variable 
(increased the Cmax and AUC0-∞ of dextromethorphan by 20% to 200% and 20% to 130% 
(interquartile ranges), respectively). 
Avoid co-administrating panobinostat with sensitive CYP2D6 substrates (Table 14-4) or 
CYP2D6 substrates that have a narrow therapeutic index (i.e., thioridazine, pimozide). If 
concomitant use of CYP2D6 substrates is unavoidable, monitor patients frequently for adverse 
reactions. 
6.4.4 
Use of bisphosphonates (or other concomitant medications) 
Bisphosphonate therapy is permitted only if commenced prior to the start of screening period. 
Mouth care is recommended in these patients. 
Bisphosphonates may be given according to their product license and routine clinical practice, 
at the investigator’s discretion 
Patients taking bisphosphonates prior to entering the study should continue with the same 
bisphosphonate treatment, given as per local medical practice.  
6.4.4.1 
Other concomitant medications 
Please refer to Section 6.1.2 Ancillary treatments. 
6.5 
Patient numbering, treatment assignment or randomization 
6.5.1 
Patient numbering 
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the patient 
throughout his/her entire participation in the study. The Subject No. consists of the Center 
Number (Center No.) assigned to the investigative site, with a sequential patient number 
suffixed to it, so that each subject is numbered uniquely across the entire database. Upon signing 
the informed consent form, the patient is assigned to the next sequential Subject No. available 
to the investigator through the Oracle Clinical RDC interface. 
The investigator or designated staff will contact the IRT and provide the requested identifying 
information for the patient to register them into the IRT. Once assigned, the Subject No. must 
not be reused for any other subject and the Subject No. for that individual must not be changed, 
even if the patient is re-screened. If the patient fails to be randomized for any reason, the reason 
will be entered into the Screening Disposition page.  
IRT must be notified within 2 days that the patient was not randomized. 
6.5.2 
Treatment assignment or randomization 
Patients will be assigned to one of the three treatment arms (Section 4.1 and Section 6.1) in a 
ratio of 1:1:1. 

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Randomization will be stratified by: 
• Number of prior lines of anti-myeloma treatment: 1 vs. 2 vs. 3 or 4  
• Age of patient on 1st day of screening (which is equivalent to the day when the main ICF 
is signed): ≤ 75 years vs. > 75 years of age 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the Interactive Response Technology (IRT) provider 
using a validated system that automates the random assignment of patient numbers to 
randomization numbers. These randomization numbers are linked to the different treatment 
arms, which in turn are linked to medication numbers. A separate medication randomization list 
will be produced by or under the responsibility of the Sponsor (previously Novartis, now Secura 
Bio) Drug Supply Management using a validated system that automates the random assignment 
of medication numbers to medication packs containing each of the study treatments. 
Prior to dosing, all patients who fulfill all inclusion/exclusion criteria will be randomized via 
IRT to one of the treatment arms. The investigator or his/her delegate will call or log on to the 
IRT and confirm that the patient fulfills all the inclusion/exclusion criteria. The IRT will assign 
a randomization number to the patient, which will be used to link the patient to a treatment arm 
and will specify a unique medication number for the first package of study treatment to be 
dispensed to the patient. The randomization number will not be communicated to the caller. 
6.5.3 
Treatment blinding 
This is an open-label study. 
6.6 
Study drug preparation and dispensation 
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
PAN capsules and Dex tablets as per protocol. Study drug(s) will be dispensed to the patient by 
authorized site personnel only. 
BTZ will be reconstituted and handled as per the manufacturer’s instructions by the responsible 
site personnel and administered as subcutaneous injection at the site. 
All dosages prescribed to the patient and all dose changes during the study must be recorded on 
the individual Dosage Administration Record CRFs 

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Table 6-13 
Preparation and dispensing 
Study 
drugs 
Dispensing 
Preparation 
PAN 
PAN capsules are given to the patient on the 1st day of a 
cycle by study personnel. Additional capsules including 
instructions for administration are dispensed by study 
personnel on an outpatient basis. 
Patients will be provided with adequate supply of study 
treatment for self-administration at home until at least the 
first day of the subsequent cycle. 
Not applicable 
BTZ s.c. 
Not applicable 
Refer to local product information 
Dex 
Dex tablets are given to the patient on the day of BTZ s.c. 
injection by study personnel. Additional tablets including 
instructions for administration are dispensed by study 
personnel on an outpatient basis. 
Patients will be provided with adequate supply of study 
treatment for self-administration at home until at least the 
first day of the subsequent cycle. 
Not applicable 
6.6.1 
Study drug packaging and labeling 
Each study site will be supplied by Secura Bio with PAN (LBH589 10 mg, 20 mg and 15 mg 
[for dose reductions only]) capsules. The study medication packaging has a 2-part label. 
Responsible site personnel will identify the panobinostat bottles/strength to dispense to the 
patient by using the IRT and obtaining the medication kit number(s) which correspond(s) to 
treatment arm and/or dose reduction information. Site personnel will add the patient number on 
the label. Immediately before dispensing the bottle to the patient, site personnel will detach the 
outer part of the label from the bottle and affix it to the source document (Drug Label Form) for 
that patient’s unique patient number. 
Medication labels will be used, and medication labels will be in the local language and comply 
with the legal requirements of each country. They will include storage conditions for the drug 
and the medication kit number but no information about the patient. 
Bortezomib and dexamethasone will be supplied locally (by investigational site or Secura Bio), 
unless not commercially available. 
Table 6-14 
Packaging and labeling 
Study drugs 
Packaging 
Labeling (and dosing frequency) 
PAN  
Capsules in bottles 
Labeled as ‘LBH589’  
For Treatment Arm A or C’ dosing will be TIW 14 
days on / 7 days off every 21 days & For Treatment 
Arm B dosing will be BIW 14 days on / 7 days off 
every 21 days. 
Study drug packaging has a 2-part label. 
BTZ s.c. 
Refer to local product information 
(unless not approved in the country) 
Refer to local product information or study treatment 
label in countries where not approved (please see 
Table 6.1). 
Dex 
Refer to local product information 
(unless not approved in the country) 
Refer to local product information or study treatment 
label in countries where not approved in required 
strengths and/or formulations 

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6.6.2 
Drug supply and storage 
Study treatments must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, the panobinostat should be stored according to the 
instructions specified on the drug labels and in the Investigator’s Brochure. 
Bortezomib and dexamethasone should be stored according to the local product information (or 
label if not approved in a country). 
Table 6-15 
Supply and storage of study treatments 
Study drugs 
Supply 
Storage 
PAN (LBH589) 
Centrally supplied by Secura Bio 
Refer to medication label 
BTZ s.c. 
Locally (unless not approved in a 
country) 
Refer to local product information or study treatment 
label in countries where not approved. 
Dex 
Locally (unless not approved in a 
country in an adequate strength) 
Refer to local product information or study treatment 
label in countries where not approved. 
6.6.3 
Study drug compliance and accountability 
6.6.3.1 
Study drug compliance 
The total daily doses of study treatment (PAN/BTZ and Dex) taken, the date of dose, 
information regarding dose change, dose interruption, permanent discontinuation and reason(s), 
as well as information whether the study drug was dispensed in error, will be recorded on the 
respective Dose Administration Record (DAR) of the CRF. For BTZ the dose prescribed in 
mg/m2 will also be captured. 
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each patient 
visit. 
On days where blood samples for PK are collected (on Cycle 1 Day 1, 4, 8 & 11, and Day 8 of 
Cycles 2 to 8), compliance will be assured by administrations of the study treatment under the 
supervision of investigator or his/her designee and will be verified by determinations of 
PAN/BTZ concentrations in plasma. On these days, in addition to dose administered and date 
of dose, time of PAN/BTZ dose taken/administered, and occurrence of vomiting within 2 hours 
of PAN dosing will be recorded in the CRF on the respective PK Dosing page(s). 
Patients will be asked to record self-administered PAN/Dex doses in a paper diary, as per local 
requirements, if applicable, and to bring in any unused study medication or empty study 
medication bottles, as applicable on Day 1 of every cycle starting with Cycle 2, as well as at the 
EOT visit. The dosing information will be reviewed by site personnel at the beginning of each 
cycle and information will be used to support/record information on PAN/Dex dosing on the 
respective DAR CRF page. 

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6.6.3.2 
Study drug accountability 
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return all 
unused study treatment and packaging on a regular basis, at the end of the study or at the time 
of study treatment discontinuation. 
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Secura Bio monitor or to the Secura Bio address provided in the 
investigator folder at each site. 
6.6.3.3 
Handling of other study treatment 
The following non-investigational treatment has to be monitored specifically: 
• loperamide 
• other anti-diarrheal medication at the discretion of the investigator 
• anti-viral prophylaxis 
• use of proton pump inhibitor with Dex treatment 
Details are described in the monitoring plan. 
Loperamide and other anti-diarrheal medication for diarrhea management will be 
supplied/purchased locally (by the investigational site or the patient), as needed. 
6.6.4 
Disposal and destruction 
The study drug supply can be destroyed at the local Secura Bio facility, Drug Supply group or 
third party, as appropriate. 
7 
Visit schedule and assessments 
7.1 
Study flow and visit schedule 
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. The entry in the ‘Category’ column indicates which data will be captured in the 
database (D) or which data will be part of the source documentation (S) only. 
No CRF will be used as a source document. 
The patient entries into the electronic devices for Patient Reported Outcome questionnaires 
(EORT-QLQ-C30 and FACT/GOG-Ntx) and into the electronic diary for diarrhea management. 

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Table 7-1 
Visit evaluation schedule 
Day of cycle 
Category 
Protocol Section 
Screening 
Study Treatment 
30d Safety 
FU 
Long-term FU 
Treatment Period 1 (TP1) 
TP2 
EOT 
Post-
Treatment 
Efficacy 
FU 
Survival 
FU 
Cycle (C) 1 
21 days/cycle 
Cycle 2 – 4 
21 days/cycle 
Cycles 
5 + 
21 days/ cycle 
Day 28 to 
Day 1 
1 
4 
8 
11 
1 
4 
8 
11 
1 
8 
EOT 
30 days 
post dose 
Every 6 
weeks 
Every 12 
weeks 
Obtain informed consent (IC) 
D 
7.1.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Registration / Randomization with IRT/IWRS 
Registration after signing of 
IC 
S 
7.1.2.1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization if eligible 
D 
7.1.2.1 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient history 
Demography 
D 
7.1.2.3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
D 
5.2/5.3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
D 
7.1.2.3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MM Diagnosis/history and 
extent of cancer 
D 
7.1.2.3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cytogenetic status at 
diagnosis 
D 
7.1.2.3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central cytogenetics (FISH) at 
study entry  
D 
7.1.2.3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior anti-neoplastic therapy 
D 
7.1.2.3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
and non-drug therapy 
D 
7.1.2.3 & 
6.4 
Continuously from 14 days prior to first dose until 30 days after last dose of study treatment 
 
 

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Day of cycle 
Category 
Protocol Section 
Screening 
Study Treatment 
30d Safety 
FU 
Long-term FU 
Treatment Period 1 (TP1) 
TP2 
EOT 
Post-
Treatment 
Efficacy 
FU 
Survival 
FU 
Cycle (C) 1 
21 days/cycle 
Cycle 2 – 4 
21 days/cycle 
Cycles 
5 + 
21 days/ cycle 
Day 28 to 
Day 1 
1 
4 
8 
11 
1 
4 
8 
11 
1 
8 
EOT 
30 days 
post dose 
Every 6 
weeks 
Every 12 
weeks 
- Anti-diarrheal medication 
D 
7.1.2.3 & 
6.4 
Continuously from 28 days prior to first dose until 30 days after last dose of study treatment 
 
 
Transfusions of blood 
products 
D 
7.1.2.3 & 
6.4 
Continuously from 14 days prior to first dose until 30 days after last dose of study treatment 
 
 
Efficacy / Disease Assessment  (additional unscheduled M-protein, FLC or ionized calcium assessments required to confirm response or disease 
progression should be performed as soon as possible after response or disease progression is suspected – see Section 7.2.1 for details)  
Central M-Protein by Protein Electrophoresis (PEP) 
- in serum (sPEP) 
D 
7.2.1.1 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
- in urine (uPEP) 
D 
7.2.1.1. 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
Central M-Protein by Immunofixation (IF) 
- in serum (sIF) 
D 
7.2.1.1 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
- in urine (uIF) 
D 
7.2.1.1 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
Central free light chain protein assessment (FLC) 
- in serum (sFLC) 
D 
7.2.1.2 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
Local plasma cell count in bone marrow (PCC)  
- PCC  
D 
7.2.1.3 
X 
 
During the study as clinically indicated to qualify for CR, sCR, and iCR; and PD for 
patients with non-measurable disease by M protein in serum and urine as well as by FLC 
 

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Day of cycle 
Category 
Protocol Section 
Screening 
Study Treatment 
30d Safety 
FU 
Long-term FU 
Treatment Period 1 (TP1) 
TP2 
EOT 
Post-
Treatment 
Efficacy 
FU 
Survival 
FU 
Cycle (C) 1 
21 days/cycle 
Cycle 2 – 4 
21 days/cycle 
Cycles 
5 + 
21 days/ cycle 
Day 28 to 
Day 1 
1 
4 
8 
11 
1 
4 
8 
11 
1 
8 
EOT 
30 days 
post dose 
Every 6 
weeks 
Every 12 
weeks 
Local assessment of soft tissue plasmacytoma (STP) 
- Clinical assessment 
D 
7.2.1.4 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
-by CT/MRI  
 
D 
7.2.1.4 
 
CT/MRI at screening or C1D1 is only performed if STP is suspected by clinical assessment. (If at 
screening STP is suspected by clinical assessment and CT/MRI is performed, CT/MRI does not have to be 
repeated on C1D1.) 
 
During the study every 6 weeks starting from C3D1 in case of presence at screening or C1D1 until disease 
progression; and as clinically indicated in case not present at screening or C1D1. 
 
Local full body skeletal survey (FBSS) to assess lytic bone lesions 
- by Xray and/or CT/MRI 
D 
7.2.1.5 
X 
 
During the study as clinically indicated; In case of newly symptomatic areas with no 
finding by X-ray a targeted CT/MRI assessment should be performed.  
 
Central ionized calcium  
D 
7.2.1.6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Assessment of aberrant plasma cells from bone marrow for component of stringent CR: Choose one of the two methods below 
- Local standard flow 
cytometry (2-4 colors) 
D 
7.2.1.7 
 
 
During the study as clinically indicated for component of stringent CR (sCR) 
Method chosen should be used consistently throughout the study 
 
- Local standard 
Immunohistochemistry 
D 
7.2.1.7 
 
 
 
Additional response assessments in bone marrow for component of iCR 
- Central multiparametric flow 
cytometry 
D 
7.2.1.8 
 
 
During the study as clinically indicated for component of immunophenotypic CR (iCR) 
 

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Day of cycle 
Category 
Protocol Section 
Screening 
Study Treatment 
30d Safety 
FU 
Long-term FU 
Treatment Period 1 (TP1) 
TP2 
EOT 
Post-
Treatment 
Efficacy 
FU 
Survival 
FU 
Cycle (C) 1 
21 days/cycle 
Cycle 2 – 4 
21 days/cycle 
Cycles 
5 + 
21 days/ cycle 
Day 28 to 
Day 1 
1 
4 
8 
11 
1 
4 
8 
11 
1 
8 
EOT 
30 days 
post dose 
Every 6 
weeks 
Every 12 
weeks 
Response assessment by 
investigator 
D 
7.2.1.9 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
Response assessment by 
IRC 
D 
7.2.1.10 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
Clinical examination 
Physical exam (including brief 
neurological exam) 
S 
7.2.2.1 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
 
Vital signs 
D 
7.2.2.2 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
 
Height 
D 
7.2.2.3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight / BSA calculated by 
site 
D 
7.2.2.3 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
 
ECOG Performance status 
D 
7.2.2.4 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
 
Local laboratory assessments 
7.2.2.5 
Hematology 
D 
7.2.2.5.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Chemistry 
D 
7.2.2.5.2 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
 
 
Electrolytes 
D 
7.2.2.5.3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Thyroid 
D 
7.2.2.5.4 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Coagulation 
D 
7.2.2.5.5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Troponin I (locally or centrally 
if it cannot be determined 
locally, or local Troponin T) 
D 
7.2.2.5.6 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
 

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Day of cycle 
Category 
Protocol Section 
Screening 
Study Treatment 
30d Safety 
FU 
Long-term FU 
Treatment Period 1 (TP1) 
TP2 
EOT 
Post-
Treatment 
Efficacy 
FU 
Survival 
FU 
Cycle (C) 1 
21 days/cycle 
Cycle 2 – 4 
21 days/cycle 
Cycles 
5 + 
21 days/ cycle 
Day 28 to 
Day 1 
1 
4 
8 
11 
1 
4 
8 
11 
1 
8 
EOT 
30 days 
post dose 
Every 6 
weeks 
Every 12 
weeks 
CCL assessed by eGFR 
using MDRD study equation 
D 
7.2.2.5.7 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
 
 
Pregnancy tests for women of childbearing potential 
- In serum (w/i 7 days prior to 
1st planned dose) 
D 
7.2.2.5.8 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
- In urine 
D 
7.2.2.5.8 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Follow-up on potential drug 
induced liver injury (DILI) 
cases 
D 
6.3.2 
In case of potential DILI, a detailed history; additional lab tests to include creatinine 
kinase, GGT, and alkaline phosphatase; testing for acute hepatitis infection or other 
hepatotropic viral infection or autoimmune hepatitis should be considered at screening 
and in case of DILI as clinically indicated. An additional unscheduled PK sample as 
close as possible to last dose of PAN, should also be obtained. This will be 
documented in an unscheduled visit. 
 
 
 
Cardiac Assessments 
7.2.2.6 
Central 12-lead ECG up to C 
16 
(triplicate ECGs, and 
unscheduled as clinically 
indicated) 
D 
7.2.2.6.1 
X 
X 
 
 
 
X 
 
 
 
C5 to 
C16 
 
X 
 
 
 
Local 12-lead ECG from 
C17+ 
D 
7.2.2.6.1 
 
 
Single or triplicate as clinically indicated, starting from Cycle 
17 
(locally performed and read) 
X 
 
 
 
Cardiac Imaging 
(MUGA/ECHO) 
D 
7.2.2.6.2 
X 
As clinically indicated 
X 
 
 
 

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Day of cycle 
Category 
Protocol Section 
Screening 
Study Treatment 
30d Safety 
FU 
Long-term FU 
Treatment Period 1 (TP1) 
TP2 
EOT 
Post-
Treatment 
Efficacy 
FU 
Survival 
FU 
Cycle (C) 1 
21 days/cycle 
Cycle 2 – 4 
21 days/cycle 
Cycles 
5 + 
21 days/ cycle 
Day 28 to 
Day 1 
1 
4 
8 
11 
1 
4 
8 
11 
1 
8 
EOT 
30 days 
post dose 
Every 6 
weeks 
Every 12 
weeks 
Pharmacokinetics 
7.2.3. 
PK sampling in serum (time of 
PAN/BTZ dose as applicable) 
(see Table 7-6 and Table 7-7 
for exact visit sampling 
timepoints) 
D 
7.2.3 
 
X 
X 
X 
X 
 
 
X 
 
 
C5 to 
C8 
 
 
 
 
Biomarkers  
Pharmacodynamic 
biomarkers in blood 
D 
7.2.4 
 
pre 
PAN 
4h 
post 
8h 
post 
 
pre 
 
 
 
pre 
 
 
pre C5 
to C8 
X 
 
at PD 
 
Whole blood for cell free DNA 
(cf DNA) 
D 
7.2.4 
 
pre 
PAN 
 
 
 
 
 
 
 
 
 
X  
 
at PD 
 
BMA to explore novel 
predictive markers 
D 
7.1.2.3 
X 
 
 
 
 
 
 
 
 
 
 
X (PD 
only) 
 
at PD 
 
Patient-reported Outcomes 
7.2.6 
EORTC-QLQ-C30 
D 
7.2.6 
 
X 
 
 
 
C3D1, C5D1, C7D1 and every 4 cycles 
(12 weeks) thereafter 
X 
 
Every 12 
weeks 
 
FACT/GOG-Ntx 
D 
7.2.6 
 
X 
 
 
 
C3D1, C5D1, C7D1 and every 4 cycles 
(12 weeks) thereafter 
X 
 
 
 

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Day of cycle 
Category 
Protocol Section 
Screening 
Study Treatment 
30d Safety 
FU 
Long-term FU 
Treatment Period 1 (TP1) 
TP2 
EOT 
Post-
Treatment 
Efficacy 
FU 
Survival 
FU 
Cycle (C) 1 
21 days/cycle 
Cycle 2 – 4 
21 days/cycle 
Cycles 
5 + 
21 days/ cycle 
Day 28 to 
Day 1 
1 
4 
8 
11 
1 
4 
8 
11 
1 
8 
EOT 
30 days 
post dose 
Every 6 
weeks 
Every 12 
weeks 
Electronic diary for diarrhea 
management 
D 
7.2.6 
The diary should be completed by the patient (or a family member or 
caregiver) on a daily basis from the first day of screening until the last day of 
Cycle 8 
 
 
 
 
- Instructions on diarrhea 
management and use of 
electronic diary by study 
personnel 
S 
7.2.6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- Review of diary for diarrhea 
management by study 
personnel 
S 
7.2.6 
 
X 
 
 
 
On Day 1 of every cycle from Cycle 2 to 9 
 
 
 
 
Adverse events 
Adverse events 
D 
8. 
Continuously after signed ICF until 30 days after last study treatment 
 
 
Study treatment administration and new anti-neoplastic therapies after discontinuation of study treatment 
Panobinostat (PAN) p.o.  
D 
6.1 & 6.3 
 
Treatment Arm A & C: Day (D) 1, 3, 5, 8, 10, 12 q 21 days 
Treatment Arm B:   Day (D) 1, 4, 8, 11 q 21 days 
(for dose reductions please refer to Section 6.3) 
 
 
 
 
Bortezomib (BTZ) s.c. 
D 
6.1 & 6.3 
 
For patients ≤ 75 yrs: D1, 4, 8, 11 q 21 days 
For patients > 75 yrs: D1 and 8 q 21 days 
All patients: 
D 1 & 8 
 
 
 
 
Dexamethasone (Dex) p.o. 
D 
6.1 & 6.3 
 
For patients ≤ 75 yrs: D1, 2, 4, 5, 8, 9, 11, 12 q 21 
days 
For patients > 75 yrs: D1, 2, 8, 9 q 21 days 
All patients: D1, 
2 & 8, 9 
 
 
 
 

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Day of cycle 
Category 
Protocol Section 
Screening 
Study Treatment 
30d Safety 
FU 
Long-term FU 
Treatment Period 1 (TP1) 
TP2 
EOT 
Post-
Treatment 
Efficacy 
FU 
Survival 
FU 
Cycle (C) 1 
21 days/cycle 
Cycle 2 – 4 
21 days/cycle 
Cycles 
5 + 
21 days/ cycle 
Day 28 to 
Day 1 
1 
4 
8 
11 
1 
4 
8 
11 
1 
8 
EOT 
30 days 
post dose 
Every 6 
weeks 
Every 12 
weeks 
Dosing diary, if applicable as 
per local regulations 
S 
6.6.3.1 
 
The dosing diary should be completed by the patient for all PAN and Dex doses 
taken during the study as per local requirements, if applicable.  
Patients enrolled to treatment arms A or C should at a minimum document the 
time when panobinostat was taken at home on Days 3, 5 and 10 of Cycle 1 and 
Day 5 of Cycles 2 to 8 and share this information with the study personnel. 
 
 
 
Instructions on dosing and 
review of dosing information 
by study personnel 
S 
6.1 & 6.6 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
 
Anti-neoplastic therapies 
since discontinuation of 
study treatment 
D 
6.4 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Survival Follow-up (until last patient entering long-term follow-up has completed 3 year Survival follow-up or discontinued follow-up prematurely 
Survival Follow-up 
D 
7.1.9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 

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7.1.1 
Molecular pre-screening  
Not applicable. 
7.1.2 
Screening 
Following signature of the main study Informed Consent (ICF), the majority of screening 
assessments will be performed within 28 days prior to first dose on Cycle 1 Day 1. The serum 
pregnancy test for WOCBP that will need to be performed within 7 days prior to first planned 
dose of study treatment (see Table 7-1 for detailed list of assessments to be performed). 
Note: Any screening assessment that is done outside the screening window (Day -28 to Day 1 
or Day -7 to Day 1 as applicable) must be repeated prior to randomization. Please perform 
central lab and central ECG assessments and start eDiary entries within the first week of 
screening.  
A patient who has (a) laboratory test result(s) and/or (an) ECG finding(s) that do(es) not satisfy 
the selection criteria may have the test(s) repeated. These test(s) may be repeated as soon as the 
investigator believes the re-test result(s) is/are likely to be within the acceptable range to satisfy 
the entrance criteria but should be completed within approximately 4 weeks of the original 
screening visit date. In this case, the subject will not be required to sign another ICF, and the 
original patient Subject ID number assigned by the investigator will be used. In the event that 
the laboratory test(s)/ECG(s) cannot be performed within 4 weeks of the original screening 
visit, or the re-test(s) do not meet the entrance criteria, or the patient’s medical condition has 
changed significantly during the screening phase so that the inclusion/exclusion criteria are no 
longer met, the patient is considered a screen failure, and must be discontinued from the study. 
If the bone marrow sample collected at screening was inadequate/uninterpretable for assessment 
of PCC, it should be repeated within 28 days of the original screening start date prior to 
randomization.  
A new ICF will need to be signed if the investigator chooses to re-screen the patient after a 
patient has screen failed. The same Subject ID number will be used, and all required screening 
activities must be performed when the patient is re-screened for participation in the study. An 
individual patient may only be re-screened once for the study. If the PCC assessment and the 
whole body scan for lytic bone lesions was performed as part of the first screening, results are 
interpretable and patient has not received any new alternative anti-myeloma therapy between 
initial screening and re-screening, these results can be used for the re-screening and bone 
marrow collection and imaging do not have to be repeated.  
Once the number of patients screened and enrolled is likely to ensure target enrollment, the 
Sponsor may close the study to further screening. In this case, the patients who screen failed 
will not be permitted to re-screen. 
Informed Consent CRF should be completed as appropriate. 

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7.1.2.1 
Eligibility screening 
Following registering in the IRT for screening, patient eligibility will be checked once all 
screening procedures are completed. The eligibility check will be embedded in the IRT system. 
Please refer and comply with detailed guidelines in the IRT manual. 
If patient meets all eligibility criteria, the site personnel can proceed with the 
randomization/stratification of the patient in the IRT. In addition, the Randomization page in 
the CRF will be completed. 
At the end of the screening phase, the End of Screening Phase Disposition Page will be 
completed for both, randomized patients and screening failures. 
7.1.2.2 
Information to be collected on screening failures 
Patients who sign an informed consent but fail to be started on treatment for any reason will be 
considered a screen failure. The reason for not being started on treatment will be entered on the 
Screening Phase Disposition Page. The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for Screen Failure patients. No other data 
will be entered into the clinical database for patients who are screen failures, unless the patient 
experienced a Serious Adverse Event during the Screening Phase (see Section 8 for SAE 
reporting details). If the patient fails to be randomized, the IRT must be notified within 2 days 
of the screen fail that the patient was not randomized. 
If the patient is randomized but then does not start study treatment, the patient will be part of 
the full analysis set, and will be followed for efficacy and survival in the long-term follow-up. 
The IRT must be notified within 2 days of the fact, that the randomized patient will not receive 
study treatment and moved to the long-term follow-up. 
7.1.2.3 
Patient demographics and other baseline characteristics 
During the screening period, the following data must be collected/evaluated and recorded for 
all randomized patients on the appropriate CRFs: 
• After the main study ICF is signed the patient will be registered with IRT. 
• Instruction of patient on use of electronic diary for diarrhea management (on first day of 
screening after main study ICF is signed); discussion of patient diarrhea history, diet, use 
of laxatives and anti-diarrheals (see Section 6.3.1.4) 
• Demography (date of birth and initials (where permitted), sex, information on child-
bearing status of female patients, race, ethnicity). 
• Medical history (e.g., important medical, surgical, and allergic conditions from the 
patient’s medical history which could have an impact on the patient’s evaluation) / current 
medical conditions (e.g., all relevant current medical conditions which are present at the 
time of signing informed consent). Ongoing medical conditions, symptoms and disease 
which are recorded on the Medical History CRF should include the toxicity grade. 
• Diagnosis of Multiple Myeloma and extent of cancer (including staging at study entry and 
cytogenetic status at diagnosis). 
• BM aspirate/biopsy for central cytogenetics (FISH)  

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• All prior anti-neoplastic therapies including surgical interventions and chemo-, biologic-, 
immunologic- and radiation-therapies and stem cell transplants provided as treatment for 
Multiple Myeloma prior to the administration of study drug. 
• All other medications and significant non-drug therapies including ancillary medication 
(except for anti-diarrheal medication and transfusions of blood products) taken within 14 
days before first dose is administered must be recorded on the Prior and Concomitant 
Medication CRF and updated on a continual basis if there are any new changes to the 
medication. Medications include prescription medications, over-the-counter medications, 
vitamins, and herbal and alternative therapy. 
• Anti-diarrheal medication taken within 28 days before first dose is administered, will be 
recorded on the Prior and Concomitant Anti-diarrheal Medication CRF. Besides what is 
being recorded on the Prior and Concomitant Medication CRF above, the dose unit, 
dosing frequency pre interval and route of administration will be captured. 
• Transfusions of blood products administered within 14 days prior to first dose must be 
recorded on the Blood Transfusion CRF. 
In addition, the following assessments must be performed and recorded for all randomized 
patients on the appropriate CRFs: 
• Complete physical examination (including brief neurological exam, see Section 7.2.2.1 for 
details, results will not be recorded on CRF, but as appropriate on medical history or 
adverse event CRF page) 
• Eastern Cooperative Oncology Group (ECOG) performance status 
• Height, Weight, BSA (although the Gehan and George equation is recommended (see 
Section 6.1.1), the BSA can be calculated as per standard practice at the site. However, the 
same formula/method should be consistently used for the BSA calculation for a patient 
throughout the study) 
• Vital signs (sitting blood pressure, sitting pulse, respiratory rate and body temperature) 
• Serum pregnancy test performed in WOCBP (within 7 days prior to first planned dose) 
• Cardiac imaging (MUGA/ECHO) 
• Central 12-Lead ECG (triplicate, 5-10 minutes apart) 
• The screening ECG must be reviewed by the central lab to determine eligibility prior 
to dosing. Therefore, it is advisable to perform the screening at least 3 days prior to 
planned first dose. 
• Local laboratory evaluations (hematology, chemistry, electrolytes, thyroid, coagulation, 
Troponin I [if Troponin I cannot be determined locally, it can be determined by the central 
lab or Troponin T can be determined locally],  other hepatic assessments, as necessary, 
creatinine clearance assessed by eGFR based on serum creatinine, age, race and gender 
using the MDRD study equation (see Section 7.2.2.5.7). 
• Disease assessments 
• Central laboratory evaluations: 
• In serum: 
a. M-protein by PEP and IF 

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b. FLC protein assessment 
c. Ionized calcium 
• In urine (24-h urine collection required): 
M-protein by PEP and IF; 
• Local plasma cell count in bone marrow  
• Clinical assessment of soft tissue plasmacytomas (STP) 
• Local assessment of STP by CT/MRI, if STP is suspected by clinical assessment 
• Local full body skeletal survey by Xray (or CT/MRI) for assessment of lytic bone 
lesions 
• Additional BMA sample will be collected for exploratory novel predictive biomarkers  
7.1.3 
Run-in period 
Not applicable. 
7.1.4 
Treatment period 
After randomization using the IRT, up to 240 patients will receive study treatment in 21-day 
cycles until disease progression, unacceptable toxicity, death, or discontinuation from the study 
treatment due to any other reason (see Section 7.1.5), as described below. 
• Treatment Period 1 (TP1) of 4 cycles (Cycle 1 to 4): Patients who are ≤ 75 years of age at 
time of first screening, will receive subcutaneous bortezomib (BTZ) twice a week 
independent from the treatment arm to which they were randomized. Patients who are > 
75 years of age will receive BTZ once a week in this treatment period. 
• Treatment Period 2 (TP2) starting from Cycle 5: all patients (independent of age) will 
receive BTZ once a week. 
See Table 7-1 for details of assessments during the treatment period. The general visit window 
during the treatment period is +/- 3 days, unless otherwise specified for specific assessments in 
Section 7.2. 
7.1.5 
Discontinuation of study treatment 
Patients may voluntarily discontinue from the study treatment for any reason at any time. If a 
patient decides to discontinue from the study treatment, the investigator should make a 
reasonable effort (e.g. telephone, e-mail, letter) to determine the primary reason for this decision 
and record this information in the patient’s chart and on the appropriate CRF pages. They may 
be considered withdrawn if they state an intention to withdraw, fail to return for visits, or 
become lost to follow-up for any other reason. 
The investigator should discontinue study treatment for a given patient if, he/she believes that 
continuation would be detrimental to the patient’s well-being. 
Study treatment must be discontinued under the following circumstances: 
• Emergence of the following adverse events (including lab abnormalities, as applicable): 
• Adverse events that require discontinuation of study treatment as per Table 6-5, 
Table 6-8 or Table 6-12. 

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• Adverse events that require dose reductions beyond the permitted dose reductions of 
PAN/BTZ outlined in Table 6-3 and Table 6-6, respectively 
• Adverse events that lead to a PAN and/or BTZ dose delay of more than 3 weeks from 
the intended day of the next scheduled dose, unless the patient was clearly benefitting 
from study treatment and the cause of the delay has been resolved. 
• Pregnancy 
• The following deviations from the prescribed dose regimen for study treatment: 
• Dose interruption of PAN and/or BTZ of more than 3 weeks from the intended day of 
the next scheduled dose for any reasons, unless the patient was clearly benefitting 
from study treatment and the cause of the delay has been resolved. 
• Dose reduction of BTZ below lowest dose reduction step indicated in Table 6-6. 
• Dose reduction of PAN below lowest dose reduction step indicated in Table 6-3. 
• Start of new anti-neoplastic therapy 
• Documented disease progression (by investigator) 
• Death 
• For use of prohibited treatment refer to Section 6.4.3 and Section 14.1. 
• Any other protocol deviation that results in a significant risk to the patient’s safety 
Patients who discontinue study treatment should undergo an end of treatment visit within 7 days 
of last dose (whichever, study drug (PAN/BTZ/Dex) was given last) and enter the long-term 
follow-up period (either post-treatment follow-up for efficacy (see Section 7.1.8) or survival 
follow-up (see Section 7.1.9) based on the reason for discontinuation). For assessments 
performed at the end of treatment visit please refer to Table 7-1. 
If the decision to discontinue study treatment is made on the day of a regular visit, this visit may 
become the EOT visit rather than having the patient return for an additional visit. 
The reason for discontinuation of study treatment should be recorded on the End of Treatment 
Disposition CRF page. 
For patients who discontinue treatment for reasons other than documented disease progression, 
death, lost to follow-up, or withdrawal of consent, tumor assessments must continue to be 
performed every 6 weeks until documented disease progression (per investigator), death, lost 
to follow-up, or withdrawal of consent. 
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment. 
7.1.5.1 
Replacement policy 
All randomized patients are part of the full analysis set. There is no plan to replace patients who 
have stopped the study prematurely. 
7.1.6 
Withdrawal of consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a patient does not want to participate in the study any 

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longer, and does not want any further visits or assessments, and does not want any further study 
related contact. 
Secura Bio will continue to retain and use all research results that have already been collected 
for the study evaluation. All biological samples that have already been collected may be retained 
and analyzed at a later date (or as required by local regulations). 
If a patient withdraws consent, the investigator should make a reasonable effort (e.g. telephone, 
e-mail, letter) to understand the primary reason for this decision and record this information in 
the patient’s chart and on the appropriate CRF pages. 
Study treatment must be discontinued and no further assessments conducted. 
Further attempts to contact the patient are not allowed unless safety findings require 
communication or follow up. 
Withdrawal from ICF should be recorded on the Withdrawal of Informed Consent/Withdrawal 
of Optional Informed Consent CRF(s). 
7.1.7 
Follow up for safety evaluations 
All patients must have safety evaluations for 30 days after the last dose of study treatment. 
If the patient refuses to return for a 30-day safety follow-up visit, the site should at a minimum 
contact the patient for the 30-day safety follow-up by telephone, email, or letter. 
Data collected should be added to the Adverse Events CRF and the Concomitant Medications 
CRF. 
7.1.8 
Post-treatment follow-up 
Patients who discontinue treatment for reasons other than documented disease progression, 
death, lost to follow-up, or withdrawal of consent must continue to be followed for response 
assessments every 6 weeks +/- 3 days until documented disease progression (by investigator), 
death, lost to follow-up, or withdrawn consent to efficacy follow-up occurs. The first PT-FU 
visit will be approximately 6 weeks +/- 3 days from the EOT visit date. Additional unscheduled 
PT-FU visits could be completed, as clinically indicated. 
At that time, the reason for completion/discontinuation of this PT-FU should be recorded on the 
End of Post treatment Phase Disposition CRF page. 
If a patient starts new anti-neoplastic therapy prior to disease progression, every attempt should 
be made to perform tumor evaluations until documented disease progression. In addition, all 
new anti-neoplastic therapy administered starting from the last dose of the study treatment until 
death, lost to follow-up, or withdrawal of consent to survival follow-up will be recorded in the 
CRFs. 
7.1.9 
Survival follow-up 
All patients will be followed for survival once they discontinued study treatment and/or 
completed PT-FU for efficacy until the last patient entering long-term follow-up has completed 
at least 3-years of Survival follow-up or discontinued follow-up prematurely. All patients will 
be followed for survival status every 12 weeks +/- 14 days (see Table 7-1) until death, lost to 

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follow-up, or withdrawal of consent to survival follow-up or planned end of the survival follow-
up period. In addition, all anti-neoplastic therapy administered during survival follow-up, until 
disease progression, death, lost to follow-up, or withdrawal of consent will be recorded in the 
CRFs. The first Survival follow-up visit will occur approximately 12 weeks +/- 14 days from 
the EOT visit date or from the last PT-FU visit date, whichever comes last. 
Survival follow-up visits will be recorded on the Survival Information CRF page and in case of 
death of the patient on the Death CRF page. 
Survival information can be obtained via phone, and information will be documented in the 
source documents and relevant CRFs. 
7.1.10 
Lost to follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow up should be recorded as such on the appropriate 
Disposition CRF (if the patient is lost to follow-up during screening, study treatment, or post 
treatment follow-up) or on the Survival Information CRF page (if patient is lost to follow-up 
during survival follow-up). 
7.2 
Assessment types 
7.2.1 
Efficacy assessments 
Overall response rate (comprised of iCR, sCR, CR, VGPR and PR) after all randomized patients 
have completed up to 8 cycles of this study, assessed by IRC is the primary endpoint for this 
study. For the response classification in MM and additional response categories in MM 
according to IMWG criteria please refer to Section 14.2, Table 14-7 and Table 14-8, 
respectively.  
Response will be assessed by the investigator and by the Independent Review Committee (IRC) 
according to the Guidelines for Response Assessment in Multiple Myeloma that are described 
in Section 14.2 and are based on the IMWG guidance (Rajkumar et al 2011). The response 
assessment by the investigator and by the IRC will be based on the same CRF efficacy data. 
The IRC will periodically review all efficacy data that were used by investigators to determine 
response. Details of the central IRC review process will be described in the independent review 
committee charter. The results of the central IRC review will be used for primary and secondary 
analyses (including interim analysis) purposes. The investigator’s response assessment will be 
used for sensitivity analysis and treatment decision making. Confirmation of response or disease 
progression should occur as soon as possible after the response/disease progression was 
determined by the investigator (e.g. on the same day or on Day 8 of the same cycle). 
Investigators are asked to hold off on discontinuation of study treatment due to presumed 
disease progression until all central laboratory data are available to confirm progression.  

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The disease assessment collection plan is presented in Table 7-2. The assessments that are 
required to confirm response or disease progression are presented in Table 7-3. 
These additional assessments and any other assessments that may be performed more frequently 
if clinically indicated at the investigator’s discretion should be recorded on the Unscheduled 
Visit CRF pages. 
Blood and urine samples will be analyzed at a designated central laboratory for the following 
assessments: 
• Serum and urine M-protein measurements by PEP and IF. 
• Serum free light chain protein assessment 
• Ionized serum calcium 
• Beta 2 microglobulin (assessed on days when serum M-protein measurements by PEP are 
performed) 
Bone marrow samples for multi-parametric flow cytometry (iCR component) will be also be 
analyzed at a designated central laboratory. 
For central laboratory data (from serum, urine and BM collections) for disease assessment, the 
site personnel designated by the Investigator will enter the information required by the protocol 
onto the appropriate Assessment Sample Collection Cover pages, as well as the designated 
laboratory’s requisition forms that will be printed on 2- part paper. 
Details on the collection of samples and reporting of results can be found in the respective 
laboratory manuals. 
Imaging data (CT/MRI for STP, and X-ray and/or CT/MRI for full skeletal survey) will be 
locally assessed.  
Table 7-2 
Disease assessment collection plan 
Procedure 
Screening/Baseline 
During Treatment/Follow-up 
Central M-Protein by Protein Electrophoresis (PEP) 
In serum (sPEP) 
Screening and 
Baseline (C1D1) 
Day 1 of every subsequent cycle (Cycles 2+); 
End of treatment; 
Post-treatment-Follow-up: every 6 weeks  
Unscheduled: as needed (e.g. to confirm disease 
progression) 
In urine (uPEP) 
Central M-Protein by Immunofixation (IF) 
In serum (sIF) 
Screening and 
Baseline (C1D1)  
Day 1 of every subsequent cycle (Cycles 2+); 
End of treatment; 
Post-treatment-Follow-up: every 6 weeks  
Unscheduled: as needed (e.g. to confirm disease 
progression) 
In urine (uIF) 
Central Serum Free Light Chain assessment 
FLC in serum 
Screening and 
Baseline (C1D1) 
Day 1 of every subsequent cycle (Cycles 2+); 
End of treatment; 
Post-treatment-Follow-up: every 6 weeks 
Unscheduled: as needed (e.g. to confirm disease 
progression) 
Local plasma cell count in bone marrow 

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Procedure 
Screening/Baseline 
During Treatment/Follow-up 
Local plasma cell count in 
bone marrow 
Screening  
During the study as clinically indicated to qualify for 
CR, stringent CR, and immuno-phenotypic CR and 
PD in case of patients with non-measurable disease 
by M protein in serum and urine as well as by FLC. 
Local assessment of soft tissue plasmacytoma (STP) 
Clinical Assessment of STP 
Screening and 
Baseline (C1D1) 
Day 1 of every subsequent cycle (Cycles 2+); 
End of treatment; 
Post-treatment-Follow-up: every 6 weeks 
Unscheduled: as needed 
Assessment of STP by 
CT/MRI 
Screening or C1D1 is 
only performed if 
STP is suspected by 
clinical assessment. 
(If at screening STP 
is suspected by 
clinical assessment 
and CT/MRI is 
performed, CT/MRI 
does not have to be 
repeated on C1D1.) 
During the study every 6 weeks starting from C3D1 in 
case of presence at screening or C1D1 until disease 
progression and if not present at screening or C1D1, 
as clinically indicated 
Local full body skeletal survey 
Assessment of lytic bone 
lesions by X-ray film and/or 
CT/MRI scan  
Screening 
During the study as clinically indicated 
In case of newly symptomatic areas with no finding by 
X-ray a targeted CT/MRI assessment should be 
performed. 
Central ionized calcium in serum  
Ionized calcium 
Screening and 
Baseline (Cycle 1 
Day 1) 
Cycle 1 Days 4, 8, 11; Cycles 2-4: Days 1, 4, 8, 11; 
Cycles 5 +: Day 1 & 8; 
End of treatment; 
Post-treatment-Follow-up: every 6 weeks  
Unscheduled: as needed (e.g. to confirm disease 
progression) 
Note: In case central ionized calcium could not be assessed or was not collected, the corrected calcium result 
from the local lab assessments may be used on days when local albumin and local calcium results are 
available. 
Assessment of aberrant plasma cells from bone marrow for component of stringent CR 
Site can choose one of the two methods below 
Local standard flow 
cytometry (2-4 colors) 
n/a 
During the study as clinically indicated for component 
of sCR; The method chosen should be used 
consistently throughout the study 
Local immunohistochemistry 
n/a 
Additional Response Assessments in bone marrow for component of iCR 
Central multiparametric flow 
cytometry (≥4 colors) 
n/a 
During the study as clinically indicated for component 
of iCR 
Response assessment by investigator and IRC 
Response assessment by 
investigator 
n/a 
Day 1 of every subsequent cycle (Cycles 2+) 
End of Treatment 
Post-treatment-Follow-up: every 6 weeks 
Unscheduled: as clinically indicated 
Response assessment by 
IRC 
n/a 
Day 1 of every subsequent cycle (Cycles 2+)  
End of Treatment 
Post-treatment-Follow-up: every 6 weeks 
Unscheduled: as clinically indicated 

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Table 7-3 
Additional assessments to confirm disease progression or response 
Confirmation of disease progression (PD):  
If PD* is suspected by: 
● rising serum or urine M protein (PEP): 
Requires confirmation: Perform an additional 
assessment from central lab  
● hypercalcaemia attributed to solely plasma cell 
proliferative disorder and as detected by central 
ionized calcium 
Requires confirmation: Perform an additional 
assessment from central lab (ionized serum calcium 
values should be > 6.0 mg/dL) 
If central lab ionized calcium is not assessable, the 
local corrected calcium result can be used as long as 
a local albumin and local calcium results are 
available. 
● rising serum FLC (only in patients with non-
measurable disease in serum and urine M protein) 
Requires confirmation: Perform an additional 
assessment from central lab 
● definite development of new bone lesions or STP 
or increase in size of bone lesions or STP(s) as 
identified by local imaging 
No confirmation is required. 
*For the definition of PD, please refer to Table 14-7. 
Investigators should discontinue patients due to PD* only after confirmatory central lab results are available. 
Confirmation of response: 
All response categories require confirmation (except for stable disease).  
There is no minimum time interval but confirmation of increase in M-protein or FLC should be done as soon as 
possible and PD assessment has to be entered in the CRF. Response and PD assessments have to be 
entered in the CRF per time point without considering confirmation. Confirmation of response will be derived by 
statistical analysis. 
Confirmatory assessments can be performed at any time. With the exception of PD, this is performed along the 
scheduled assessments as defined in Table 7-1. For CR or better, no repetition of bone marrow assessments 
is required 
7.2.1.1 
Serum and urine sample collection for central M-protein assessment 
by PEP, and IF 
Blood (serum) and 24-h urine for M-protein assessment will be collected as indicated in 
Table 7-2. Samples will be processed and shipped as per instructions in the respective 
laboratory manual. 
The central lab will analyze all samples collected by PEP. Beta 2 microglobulin will be 
determined for all blood samples received for serum M-protein analysis. Analysis by IF will be 
done for all patients at screening and baseline, and thereafter only in patients/at time-points in 
case of disappearance of M-protein by PEP. 
IgD and IgE immunoglobulin testing will only be performed for patients who are reported as 
IgD/IgE positive at time of diagnosis/relapse prior to starting study treatment. 
7.2.1.2 
Serum sample collection for central FLC assessment 
Blood (serum) for FLC assessment will be collected as indicated in Table 7-2. Samples will be 
processed and shipped as per instructions in the respective laboratory manual. 
The central lab will analyze FLC only when serum M-protein or urine M-protein or both 
assessed by PEP is/are non-measurable and to identify sCR in case CR criteria are met. 

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7.2.1.3 
Plasma cell count in bone marrow by local assessment 
A bone marrow aspirate/biopsy for plasma cell quantification will be collected as indicated in 
Table 7-2. The PCC will be evaluated locally only. Either BM aspirate or biopsy can be used 
for this assessment. However, the same method (aspirate versus biopsy) should be used 
throughout the study, if possible. In case both, BM aspirate and BM biopsy were performed, 
the response criteria need to be satisfied by both assessments and the highest of both percent 
values should be used for the assessment. In case of inadequate/uninterpretable BM sample, the 
sampling must be repeated in a timely manner but no later than within 28 days. The screening 
BM sample needs to be repeated and be evaluable prior to randomization. In case a patient is 
re-screened and has an evaluable BM sample from the first screening, this assessment does not 
have to be repeated as long as no new anti-myeloma therapy was received between initial 
screening and re-screening. 
7.2.1.4 
Assessment of soft tissue plasmacytoma 
7.2.1.4.1 Clinical assessment by investigator 
The investigator should perform a clinical exam to assess presence of soft tissue plasmacytoma 
as per Table 7-2. 
In case no STP is present at screening, but during the clinical exam there is a suspicion of STP 
post baseline, CT or MRI must be performed immediately to confirm or disconfirm this 
suspicion. 
7.2.1.4.2 Local Imaging assessment by CT/MRI 
Baseline imaging assessment: A CT/MRI to assess presence of soft tissue plasmacytoma will 
only be performed at screening within 28 days prior to start of study treatment (Day -28 to Day 
-1 prior to Cycle 1 Day 1,) CT/MRI at screening or C1D1 is only performed if STP is suspected 
by clinical assessment. (If at screening STP is suspected by clinical assessment and CT/MRI is 
performed, CT/MRI does not have to be repeated on C1D1). 
Any imaging assessments already completed during the regular work-up of the patient within 
28 days prior to start of treatment, including before signing the main study ICF, can be 
considered as the baseline images for this study as long as they can be made available for central 
storage and review. Any imaging assessments obtained after randomization cannot be 
considered baseline images. 
Post-baseline imaging assessments: 
Imaging assessments as described in Table 7-2 should be performed using the same imaging 
modality used at baseline, irrespective of study treatment interruption or actual dosing (see 
Table 7-1). 
• If STP is present at baseline, a CT/MRI should be performed every 6 weeks (+/- 7 days) 
until disease progression starting with Cycle 3 Day 1. 
• If STP is not present at baseline, but there is a suspicion of STP and/or disease progression 
(based on clinical exam or symptoms) during study treatment or in the PT-FU, a CT/MRI 
should be promptly performed to confirm/disconfirm this suspicion. 

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7.2.1.5 
Full body skeletal survey 
A skeletal survey using X-ray and/or CT/MRI in case of newly symptomatic areas with no 
finding by X-ray a targeted MRI should be performed at Screening within 28 days prior to first 
dose of study treatment (Cycle 1 Day 1). 
Any X-ray and/or CT/MRI already completed during the regular work-up of the patient within 
28 days prior to start of treatment, including before signing the main study ICF, can be 
considered as the baseline X-ray and/or CT/MRI images for this study as long as they can be 
made available for central storage and review. Any X-ray and/or CT/MRI imaging assessments 
obtained after randomization cannot be considered baseline images. 
Post-baseline, a full body skeletal survey will only be completed as clinically indicated, e.g. to 
document a response of PR or better, or to evaluate disease progression. 
7.2.1.6 
Central ionized calcium  
Ionized calcium in serum for determination of hypercalcemia as part of the response assessment 
will be evaluated by a central laboratory as per Table 7-2 and Table 7-3. 
7.2.1.7 
Local assessment of aberrant plasma cells in bone marrow 
A local assessment of aberrant plasma cells in bone marrow for the component of sCR, as 
clinically indicated, can be performed using one of the two methods described below as 
described in Table 7-2: 
• Standard flow cytometry (2-4 colors) 
• Immunohistochemistry (IHC) 
The method selected should be consistently used for all patients at a specific site throughout the 
study conduct. 
In case of inadequate/uninterpretable BM sample, the procedure must be repeated in a timely 
manner but no later than within 28 days. 
7.2.1.8 
Additional central response assessments in bone marrow 
Additional response assessments will be performed in a central laboratory and will include the 
determination of immunophenotypic CR (iCR). For additional response categories in MM 
according to IMWG criteria see Table 14-6 of Section 14.2. 
Absence of aberrant plasma cells in bone marrow for the component of iCR (minimum of 
1 million total BM cells analyzed) will be assessed by multiparametric flow cytometry 
(>4 colors), as clinically indicated (at CR). 
For this assessment, 8 mL of bone marrow aspirate will be collected in a 10 cc EDTA tube. 
In case of inadequate/uninterpretable BM sample, the procedure must be repeated in a timely 
manner but no later than within 28 days. 

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7.2.1.9 
Response assessment by Investigator 
The response assessment by Investigator should be based on all efficacy data (including central 
vendor data) as per IMWG guidelines (see Table 14-7 and Table 14-8), as per Table 7-2. 
7.2.1.10 Response assessment by IRC 
The response assessment by the IRC will be based on all efficacy data as per IMWG guidelines 
(including central vendor data; see Table 14-7 and Table 14-8). These data are detailed in 
Table 7-2 and do not include the investigator’s response assessment. 
7.2.2 
Safety and tolerability assessments 
Safety will be monitored by assessing physical examinations, ECOG performance status, height 
and weight, vital signs, ECG, laboratory assessments including hematology, chemistry, 
electrolytes, thyroid function, coagulation, Troponin I (or Troponin T), and calculated 
creatinine clearance, as well as collection of the adverse events at every visit. For details on AE 
collection and reporting, refer to Section 8. 
7.2.2.1 
Physical examination 
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed. Physical examination is 
to be performed according to the visit schedule as outlined in Table 7-1. 
Significant findings that were present prior to the signing of informed consent must be included 
in the Medical History CRF page. Significant new findings that begin or worsen after informed 
consent must be recorded on the Adverse Event page of the patient’s CRF. 
7.2.2.2 
Vital signs 
Vital signs include blood pressure and pulse measurements, body temperature and respiratory 
rate will be monitored as per the visit schedule (see Table 7-1). After the patient has been sitting 
for five minutes, with back supported and both feet placed on the floor, systolic and diastolic 
blood pressure and pulse will be measured. In case the cuff sizes available are not large enough 
for the patient's arm circumference, a sphygmomanometer with an appropriately sized cuff may 
be used. Body temperature may be measured as per standard practice at the institution (e.g. 
orally, via ear, etc.). 
7.2.2.3 
Height, weight and calculated BSA 
Height in centimeters and body weight (in indoor clothing, but without shoes) will be measured 
as per visit schedule (see Table 7-1). (Note: CRFs are designed to collect the data in the units 
they are measured in; e.g., height in cm or in and weight in kg or lb). Height will only be 
measured at the screening visit, whereas weight will be measured on Day 1 of every cycle and 
at the EOT visit. The weight measured on Day 1 of a cycle will be used by the study personnel 
to calculate the BSA of the patient for a specific cycle. Although the use of the Gehan and 
George equation (see Section 6.1.1) is recommended, the BSA can be calculated as per standard 

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practice at the site. However, the same formula/method should be used consistently throughout 
the study. The BSA calculated at the beginning of every cycle will be used to calculate the total 
BTZ s.c. dose/day to be administered during a specific cycle. 
7.2.2.4 
Performance status 
The performance status for a patient will be assessed according to the ECOG performance status 
scale (Section 14.3) following the visit evaluation schedule given in Table 7-1. 
7.2.2.5 
Laboratory evaluations 
All lab parameters outlined in Table 7-4, will be evaluated locally as per the visit evaluation 
schedule (see also Table 7-1). Secura Bio must be provided with a copy of the lab certification 
and tabulation of the normal ranges for all lab parameters of all local labs used. 
The local lab results will be entered on the respective Local Laboratory CRF pages. 
During the study treatment, all lab results should be available prior to administration of 
PAN/BTZ, in order for the investigator to implement dose modifications based on the lab results 
as necessary (e.g. interrupt dosing, see Section 6.3, and Table 6-2, Table 6-4, Table 6-5, and 
Table 6-7 for details). 
Abnormal laboratory values or test results constitute an AE only, if they induce clinical signs 
or symptoms, and are considered clinically significant (i.e. require dose modification and/or 
interruption of study treatment, lead to clinical symptoms, cause study treatment 
discontinuation or constitute in and of itself an SAE) or require therapy. These events should 
be recorded on the AE CRF as well as the appropriate laboratory CRF and/or comments CRF 
page. If the administration of study treatment is delayed/modified due to unacceptable lab 
toxicities (see Section 6.3), re-evaluation should at a minimum be performed prior to the next 
scheduled study treatment. 
Additional labs parameters or the same lab parameters as outlined in Table 7-4 should be 
additionally evaluated as clinically indicated. These evaluations can be done at the site or at the 
patient’s local doctor’s office. These results will be recorded on the Unscheduled Visit CRF. 
Table 7-4 
Local clinical laboratory parameters collection plan 
Hematology 
Complete blood cell count (RBC and WBC) with differential (neutrophils, basophils, 
eosinophils, lymphocytes, monocytes, blast cells, other – absolute results preferred), 
hemoglobin, platelet count 
To be performed at: 
Screening 
Cycles 1-4: Days 1, 4, 8, 11; Cycles 5+: Day 1 & 8; 
End of treatment 
Unscheduled: as clinically indicated 

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Chemistry 
BUN/Urea, creatinine, serum albumin, glucose, total bilirubin, AST/SGOT and 
ALT/SGPT, Beta 2 microglobulin*, total protein, direct and indirect bilirubin only if total 
bilirubin is abnormal, LDH. 
Biochemistry tests should be performed after the patient has fasted, if possible. 
To be performed at: 
Screening 
Cycle 1: Days 1, 4, 8, 11; Cycles 2+: Day 1 & 8; 
End of treatment 
Unscheduled: as clinically indicated 
*To be performed by the local laboratory only at screening, and, thereafter, as clinically 
indicated. Please note that in addition, beta 2 microglobulin is analyzed by the central 
laboratory every time serum M-protein by PEP is determined. 
 
Electrolytes 
serum calcium, sodium, potassium, phosphorus, magnesium 
To be performed at: 
Screening 
Cycles 1-4: Days 1, 4, 8, 11; Cycles 5+: Day 1 & 8; 
End of treatment 
Unscheduled: as clinically indicated 
Thyroid 
Thyroid Stimulating Hormone (TSH) and free T4 (thyroxine). 
To be performed at: 
Screening 
Cycle 1 Day 1; 
End of treatment 
Unscheduled: as clinically indicated 
Coagulation 
Prothrombin time (PT) or International normalized ratio [INR]), activated partial 
thromboplastin time (APTT) and fibrinogen; 
To be performed at: 
Screening 
Unscheduled: as clinically indicated 
Cardiac Enzyme 
Troponin I 
Troponin I* 
To be performed at: 
Screening 
Cycles 1+: Day 1; 
End of treatment 
Unscheduled: as clinically indicated (e.g. on days when unscheduled 12-Lead ECGs) 
*Note if Troponin I cannot be performed by the local lab, it can be analyzed centrally, or 
Troponin T can be analyzed locally instead. The same test should be performed 
throughout the study. The central Troponin I results, or local Troponin T results still 
would be entered on the local cardiac enzyme eCRF page by the site. 
CCL assessed by 
eGFR 
CCL is assessed by eGFR which is calculated by the site using the MDRD study 
equation (Dimopoulos et al 2010) based on serum creatinine results (Scr), age, gender 
and race of a patient and depending on the analytics used to determine Scr (Isotope 
dilution mass spectrometry (IDMS) traceable technique or other technique used) (See 
Section 7.2.2.5.7 for details).  
To be calculated at: 
Screening 
Cycle 1: Days 1, 4, 8, 11; Cycles 2 +: Day 1 & 8; 
End of treatment 
Unscheduled: as clinically indicated (if serum creatinine was determined) 
Pregnancy Test 
for all women 
(female patients) of 
childbearing 
potential 
(WOCP) 
Pregnancy test in serum: 
Screening (within 7 days prior to the first planned dose of study treatment) 
End of treatment 
Pregnancy test in urine: 
Cycles 1 +: Day 1 

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7.2.2.5.1 Hematology 
Hematology tests are performed as indicated in Table 7-4. 
7.2.2.5.2 Chemistry 
Clinical chemistry tests are performed as indicated in Table 7-4. 
7.2.2.5.3 Electrolytes 
Electrolytes are performed as indicated in Table 7-4. 
7.2.2.5.4 Thyroid 
Thyroid function tests are performed as indicated in Table 7-4. 
7.2.2.5.5 Coagulation 
The coagulation tests are performed at screening (Table 7-4). The coagulation profile should be 
repeated as clinically indicated and the results should be recorded on the Unscheduled Visit 
CRF. If the patient is receiving Coumadin or other anti-coagulant therapy, then the coagulation 
parameters should be monitored more frequently at the discretion of the investigator (please 
also see Section 6.4.2.1). 
7.2.2.5.6 Cardiac Enzyme: Troponin I 
Troponin I should be evaluated on all visits when ECGs (scheduled or unscheduled) are 
performed (see Table 7-4). On days when an unscheduled ECG is performed, the Troponin I 
result is also recorded on the Unscheduled Visit CRF. If Troponin I cannot be performed by the 
local laboratory, it can be determined by the central laboratory, or Troponin T can be performed 
locally. The same parameter test should be used consistently for a patient throughout the study. 
The central Troponin I results or local Troponin T results would also be entered on the local 
cardiac enzyme eCRF page with the central lab ID. 
7.2.2.5.7 Creatinine Clearance (assessed by eGFR) 
CCL is assessed by eGFR which is calculated as indicated in Table 7-4 using the MDRD study 
equation based on serum creatinine in mg/dL (Scr), age, gender and race. Dependent on the 
method used to determine serum creatinine (IDMS or not), the original or IDMS traceable 
MDRD study equation should be used: 
Original MDRD study equation: 
eGFR (ml/min/1.73m2) = 186 x (Scr) -1.154 x age -0.203 x (0.742 if female) x 1.212 (if patient’s 
race is black) 
IDMS traceable MDRD study equation: 
eGFR (ml/min/1.73m2) = 175 x (Scr) -1.154 x age -0.203 x (0.742 if female) x 1.212 (if patient’s 
race is black) 

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7.2.2.5.8 Pregnancy and assessments of fertility 
Since highly effective contraception is required pregnancy testing should be done as indicated 
in Table 7-4. In case of a positive test, the patient will need to discontinue the study treatment 
unless the test result is proven to be false positive. 
Post-menopausal women must have been amenorrheic for ≥ 12 months in order to be considered 
‘of no-childbearing potential’. 
7.2.2.6 
Cardiac assessments 
7.2.2.6.1 Electrocardiogram (ECG) 
Standard 12-lead ECGs will be performed according to Table 7-5 on ECG units provided by 
the CRO from Cycle 1 through 16 or on local ECG units starting from Cycle 17. All scheduled 
12-lead ECGs will be done in triplicates to obtain the mean and should be separated by 5 to 
10 minutes each. On days when ECGs are to be performed, the patient should take their study 
medication at this site, after the pre-dose ECGs have been performed. 
The last of the pre-dose triplicate ECGs should be performed prior to the planned dose of PAN 
and BTZ. The first of the 2h post-dose triplicate ECGs should be performed around the 2 h post-
dose time point, the last of triplicates should be within 30 minutes of the 2 h post-dose time 
point. 
Central 12-Lead ECGs performed up to Cycle 16: 
All ECGs (scheduled or unscheduled) performed up to Cycle 16, and end of treatment ECGs if 
last dose was before start of Cycle 17, will be submitted by the site for central review. Central 
ECG results are uploaded to the portal and will be available for review by the investigator within 
approximately 1-2 working days. The centralized reading of ECGs will use the Fridericia’s 
correction: QTcF will be the formal data entered into the clinical study database. Local ECG 
and central review results will not be reconciled. 
Information on the performance of the ECG will be documented on the Central ECG CRF page, 
or on the Unscheduled Visit CRF page, as applicable. 
Local 12-Lead ECGs performed starting from Cycle 17: 
From Cycle 17 onwards, local single or triplicate ECGs will only be performed as clinically 
indicated during study treatment and results will be reviewed locally at the site. 
If study treatment discontinues after start of Cycle 17, three local triplicate ECGs will be 
performed and locally reviewed at the EOT visit. 
Results will be entered on the Unscheduled Local CRF Page and on the Local Analysis ECG 
CRF page for triplicates performed at the EOT, as applicable. 
Review of all ECGs at site: 
The mean QTcF of the 3 ECGs obtained pre-dose on Cycle 1 Day 1 by central review will be 
used as the baseline value to compare to other QTcF results throughout the study. If a prolonged 
QTcF interval is noted at any time, additional days of QT monitoring may be required (see 
Table 6-5). 

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Treatment decisions should be based on the real-time assessment of QTcF values at the site, as 
determined by the automated machine reading or as measured and calculated by trained 
personnel at the site. All cardiac events should be treated as per the local standard of care and 
referred to a specialist, if clinically indicated (see Section 6.3.1 for required dose modifications 
for prolonged QTcF). Any final decisions concerning dose modifications or permanently 
discontinuing the patient from study drug due to QTcF prolongation will be based on the 
assessment performed by central review in Cycles 1 through 16 and based on the local 
assessment performed at the site starting from Cycle 17. 
The screening ECGs must be reviewed by the central lab to determine eligibility prior to dosing. 
Therefore, it is advisable to perform and transmit the screening ECGs in the first week of 
screening and at least 10 days prior to planned first dose. 
Clinically significant ECG abnormalities present at screening should be reported on the Medical 
History CRF page. New or worsened clinically significant findings occurring after informed 
consent must be recorded on the Adverse Events CRF page. 
Table 7-5 
Central and local ECG collection plan 
Cycle 
Day of cycle 
ECG monitoringa 
Central 12-Lead ECGs performed on units provided by central vendor and centrally reviewed up to 
Cycle 16 
Screening b 
n/a 
Triplicate 12 Lead ECG to assess eligibility 
Cycle 1 
1 
Pre-dose and 2h post PAN dose: 
Triplicate 12 lead ECG 
Cycle 2 to Cycle 4 
1 
Pre-dose: 
Triplicate 12 lead ECG 
Cycles 5 to Cycle 16 
1 
Pre-dose: 
Triplicate 12 lead ECG 
End of Treatment if last dose was 
administered within first 16 cycles 
n/a 
Triplicate 12-Lead ECG 
Cycle 1 to 16 Unscheduled 
Unscheduled 
Any time single or triplicate 12 lead ECG, as clinically 
indicated 
Local 12-Lead ECGs performed on local units starting from Cycle 17 
Cycle 17+ Unscheduled 
Unscheduled 
Any time single or triplicate 12-lead ECG, as clinically 
indicated 
End of Treatment if last dose was 
administered after 16 cycles (in 
Cycles 17+) 
n/a 
Triplicate 12-Lead ECG 
a Refer to Table 6-5 for the recommended dose modifications due to QTcF prolongation 
b Central vendor (for eligibility mean of central triplicate QTcF results will be used) 
Note: Triplicate ECGs should be performed approximately 5-10 minutes apart 
7.2.2.6.2 Cardiac imaging - MUGA (multiple gated acquisition) scan or 
echocardiogram 
A MUGA scan or ECHO to assess left ventricular ejection fraction (LVEF) will be performed 
within the screening period (see exclusion criterion 16b) prior to the first administration of study 
treatment and at the EOT visit within 7 days of last dose of study treatment. 

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Additional, unscheduled assessments may be performed at the Investigator’s discretion if there 
are signs or symptoms of cardiotoxicity and will be recorded on the Unscheduled Visit CRF 
page. 
The LVEF result and a general comment on the interpretation of the assessment will be recorded 
on the Cardiac Imaging CRF page. 
7.2.3 
Pharmacokinetics 
Serial PK blood samples for both BTZ and PAN will be collected from all patients at the same 
time points (6 mL of whole blood at collection time points as specified in Table 7-6 for 
Treatment Arms A & C, and Table 7-7 for treatment Arm B). Non-compartmental PK 
parameters will be estimated from each individual plasma concentration-time profile using 
appropriate methods and software. Refer to Section 10.5.4 for a table of PK parameters that will 
be estimated. 
The sequence of administration of study treatment on days where all three study drugs are 
administered (i.e. Day 1 and Day 8 of Cycle 1 and Day 8 of Cycles 2 through 8): should be as 
follows: 
Dex taken within 15 to 30 minutes prior to BTZ, BTZ s.c. injection within 1-5 minutes prior to 
PAN. The time when PAN was taken or just prior to when PAN was taken will be considered 
0h. On days were PAN is not taken (i.e. Day 4 and Day 11 for Treatment Arms A & C), the 
sample should be taken approximately 24 hours after the last PAN dose. See Figure 6-5 for 
details. 
Date/time of blood samples must be recorded relative to the PAN dose, actual time of dosing 
for PAN and for BTZ, as applicable and actual times of blood collection have to be recorded on 
the corresponding PK blood collection CRF pages. 

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Table 7-6 
Pharmacokinetic blood collection log for panobinostat (PAN) TIW Treatment Arm A & C and bortezomib (BTZ) 
Cycle 
Day 
Scheduled Time Point 
Allowed 
window 
PAN 
BTZ 
Sample 
Volume 
In mL 
Dose 
Reference ID 
PK Sample 
No 
Dose Reference ID 
PK Sample 
No 
Patients ≤ 75 
years of age* 
Patients > 75 
years of age* 
1 
1 
Pre-dose PAN / 0h 
-60 min 
101 
101 
201 
201 
201 
6 
1 
1 
0.5h post PAN 
+/- 5 min 
101 
102 
201 
201 
202 
6 
1 
1 
1h post PAN 
+/- 10 min 
101 
103 
201 
201 
203 
6 
1 
1 
2h post PAN 
+/- 20 min 
101 
104 
201 
201 
204 
6 
1 
1 
4h post PAN 
+/- 40 min 
101 
105 
201 
201 
205 
6 
1 
1 
8h post PAN 
+/- 60 min 
101 
106 
201 
201 
206 
6 
1 
4 
24h post PAN dose on D3** 
+/- 60 min 
102 
107 
201 
201 
207 
6 
1 
4 
26h post PAN dose on D3 
+/- 20 min 
102 
108 
202 
201 
208 
6 
1 
4 
28 – 32h post PAN dose on D3 
n/a 
102 
109 
202 
201 
209 
6 
1 
8 
Pre-dose PAN/0h 
72h post PAN on D5 
-60 min 
103 
110 
202 
201 
210 
6 
1 
11 
24h post PAN on D10** 
+/- 60 min 
104 
111 
203 
202 
211 
6 
2 
8 
Pre-dose PAN/0h 
72h post PAN on D5 
-60 min 
105 
112 
204 
204 
212 
6 
2 
8 
2h post PAN 
+/- 20 min 
106 
113 
205 
205 
213 
6 
3 
8 
Pre-dose PAN/0h 
72h post PAN on D5 
-60min 
107 
114 
206 
206 
214 
6 
3 
8 
2h post PAN 
+/- 20 min 
108 
115 
207 
207 
215 
6 
4 
8 
Pre-dose PAN/0h 
72h post PAN on D5 
-60 min 
109 
116 
208 
208 
216 
6 
4 
8 
2h post PAN 
+/- 20 min 
110 
117  
209 
209 
217 
6 
5 
8 
Pre-dose PAN/0h 
72h post PAN on D5 
-60 min 
111 
118 
210 
210 
218 
6 
5 
8 
2h post PAN 
+/- 20 min 
112 
119 
211 
211 
219 
6 

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Cycle 
Day 
Scheduled Time Point 
Allowed 
window 
PAN 
BTZ 
Sample 
Volume 
In mL 
Dose 
Reference ID 
PK Sample 
No 
Dose Reference ID 
PK Sample 
No 
Patients ≤ 75 
years of age* 
Patients > 75 
years of age* 
6 
8 
Pre-dose PAN/0h 
72h post PAN on D5 
-60 min 
113 
120 
212 
212 
220 
6 
6 
8 
2h post PAN 
+/- 20 min 
114 
121 
213 
213 
221 
6 
7 
8 
Pre-dose PAN/0h 
72h post PAN on D5 
-60 min 
115 
122 
214 
214 
222 
6 
7 
8 
2h post PAN 
+/- 20 min 
116 
123 
215 
215 
223 
6 
8 
8 
Pre-dose PAN/0h 
72h post PAN on D5 
-60 min 
117 
124 
216 
216 
224 
6 
8 
8 
2h post PAN 
+/- 20 min 
118 
125 
217 
217 
225 
6 
Total 
150 
Pre-dose PAN/0h: samples should be drawn pre-dose PAN and BTZ 
*: age on first day of screening (date of signing of initial informed consent);  
**: sample should be drawn prior to BTZ dosing on this day for patients who are ≤ 75 years of age on first day of screening 
Table 7-7 
Pharmacokinetic blood collection log for panobinostat (PAN) BIW Treatment Arm B and bortezomib (BTZ) 
Cycle 
Day 
Scheduled Time Point 
Allowed 
window 
PAN 
BTZ 
Sample 
Volume 
in mL 
Dose 
Reference ID 
PK Sample 
No 
Dose Reference ID 
PK Sample 
No 
Patients ≤ 75 
years of 
age* 
Patients > 75 
years of 
age* 
1 
1 
Pre-dose PAN / 0h 
-60 min 
101 
301 
201 
201 
401 
6 
1 
1 
0.5h post PAN 
+/- 5 min 
101 
302 
201 
201 
402 
6 
1 
1 
1h post PAN 
+/- 10 min 
101 
303 
201 
201 
403 
6 
1 
1 
2h post PAN 
+/- 20 min 
101 
304 
201 
201 
404 
6 
1 
1 
4h post PAN 
+/- 40 min 
101 
305 
201 
201 
405 
6 
1 
1 
8h post PAN 
+/- 60 min 
101 
306 
201 
201 
406 
6 

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Cycle 
Day 
Scheduled Time Point 
Allowed 
window 
PAN 
BTZ 
Sample 
Volume 
in mL 
Dose 
Reference ID 
PK Sample 
No 
Dose Reference ID 
PK Sample 
No 
Patients ≤ 75 
years of 
age* 
Patients > 75 
years of 
age* 
1 
4 
Pre-dose PAN/0h 
72h post PAN on D1 
- 60 min 
101 
307 
201 
201 
407 
6 
1 
4 
2h post PAN dose on D4 
+/- 20 min 
102 
308 
202 
201 
408 
6 
1 
4 
4-8h post PAN dose on D4 
n/a 
102 
309 
202 
201 
409 
6 
1 
8 
Pre-dose PAN/0h 
96h post PAN dose on D4 
-60 min 
102 
310 
202 
201 
410 
6 
1 
11 
Pre-dose PAN/0h 
72h post PAN dose on D8 
- 60 min 
103 
311 
203 
202 
411 
6 
2 
8 
Pre-dose PAN/0h  
96h post PAN dose on D4 
-60 min 
104 
312 
204 
204 
412 
6 
2 
8 
2h post PAN 
+/- 20 min 
105 
313 
205 
205 
413 
6 
3 
8 
Pre-dose PAN/0h  
96h post PAN dose on D4 
-60 min 
106 
314 
206 
206 
414 
6 
3 
8 
2h post PAN 
+/- 20 min 
107 
315 
207 
207 
415 
6 
4 
8 
Pre-dose PAN/0h  
96h post PAN dose on D4 
-60 min 
108 
316 
208 
208 
416 
6 
4 
8 
2h post PAN 
+/- 20 min 
109 
317 
209 
209 
417 
6 
5 
8 
Pre-dose PAN/0h  
96h post PAN dose on D4 
-60 min 
110 
318 
210 
210 
418 
6 
5 
8 
2h post PAN 
+/- 20 min 
111 
319 
211 
211 
419 
6 
6 
8 
Pre-dose PAN/0h  
96h post PAN dose on D4 
-60 min 
112 
320 
212 
212 
420 
6 
6 
8 
2h post PAN 
+/- 20 min 
113 
321 
213 
213 
421 
6 
7 
8 
Pre-dose PAN/0h 
96h post PAN dose on D4 
-60 min 
114 
322 
214 
214 
422 
6 
7 
8 
2h post PAN 
+/- 20 min 
115 
323 
215 
215 
423 
6 

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Cycle 
Day 
Scheduled Time Point 
Allowed 
window 
PAN 
BTZ 
Sample 
Volume 
in mL 
Dose 
Reference ID 
PK Sample 
No 
Dose Reference ID 
PK Sample 
No 
Patients ≤ 75 
years of 
age* 
Patients > 75 
years of 
age* 
8 
8 
Pre-dose PAN/0h 
96h post PAN dose on D4 
-60 min 
116 
324 
216 
216 
424 
6 
8 
8 
2h post PAN 
+/- 20 min 
117 
325 
217 
217 
425 
6 
Total 
150 
Pre-dose PAN/0h: samples should be drawn pre-dose PAN and BTZ (on days on which BTZ is administered) 
*: age on first day of screening (date of signing of initial informed consent) 

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7.2.3.1 
Pharmacokinetic blood collection and handling 
At specified time points (Table 7-6 for Treatment Arms A & C and Table 7-7 for Treatment 
Arm B), blood will be collected in tubes containing sodium heparin. All blood samples will be 
taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein. If 
indwelling catheters are used and flushed with saline or heparin, at least 2 mL of blood should 
be discarded before collecting the blood samples. 
Immediately after collection of blood samples for PAN (2 mL) and BTZ (4 mL), the tube should 
be inverted several times to prevent clotting. Blood samples for PAN and BTZ should be kept 
in an ice water bath at approximately 4ºC until centrifugation. The tubes should be centrifuged 
as soon as possible but within no more than 60 minutes after collection at approximately 800 x 
g at 4ºC for 15 minutes to separate plasma. 
PAN plasma (~ 1 mL) will be transferred to a 2-mL polypropylene screw-cap tube (no skirt), 
the tube capped, and the sample mixed briefly and then immediately placed in a freezer set at ≤ 
-60ºC until shipment with sufficient dry ice to the central laboratory. 
For BTZ, the harvested plasma samples (~2 mL) will be mixed with 20 µL of 20% formic acid 
(v/v) into a 3-mL polypropylene screw-cap tube (no skirt) with a final formic acid concentration 
of ~0.2% (v/v). This was followed by capping and thorough mixing prior to being stored at ≤ -
60ºC until shipment with sufficient dry ice to the central laboratory. 
Refer to the [LBH589D2222 PK Laboratory Manual] for detailed instructions for the collection, 
handling, and shipping of samples. 
Residual plasma used for PK analysis may also be used for exploratory PK analysis. This could 
include using leftover plasma for protein binding analysis, metabolite profiling, or exploratory 
biomarker analysis, if there is sufficient sample remaining. 
7.2.3.2 
Analytical method 
7.2.3.2.1 Panobinostat 
The plasma samples from all patients who received panobinostat will be assayed for 
panobinostat concentrations using a validated liquid chromatography-tandem mass 
spectrometry assay (LC-MS/MS). Values below the lower limit of quantification (LLOQ) of 
approximately 0.1 ng/mL will be reported as zero. Missing values will be labeled accordingly. 
7.2.3.2.2 Bortezomib 
The plasma samples from all patients will be assayed for bortezomib. This assay will be 
validated with a LLOQ of 0.1 ng/mL or lower. Values below LLOQ will be reported as zero. 
Missing values will be labeled accordingly. 
7.2.4 
Biomarkers  
Biomarker assessments will be performed in blood to measure the molecular pharmacodynamic 
effects of panobinostat treatment when used in combination with bortezomib and 
dexamethasone.  

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Since panobinostat is a pan-HDAC inhibitor, two different assays will be used to measure the 
acetylation status of histone proteins. These assessments will be performed on peripheral blood 
samples which are collected at multiple time-points. The data from these studies will be 
compared with the dose level and pharmacokinetic data to determine whether there is an 
association of these parameters, and any further association with clinical outcome. These 
analyses are exploratory. 
In addition, blood samples will be collected to assess the molecular status of cell free DNA 
(cfDNA) at baseline, at the end of treatment visit and for patients who entered the PT-FU at 
time of disease progression.  If the reason for end of treatment is disease progression only the 
end of treatment sample needs to be collected.  
Lastly, biomarker assessments will be performed in bone marrow aspirate (BMA) samples at 
screening, at the end of treatment and for patients who entered the PT-FU at time of disease 
progression. The end of treatment sample is only collected if the reason for end of treatment is 
disease progression, or if the patient who discontinued study treatment for reasons other than 
disease progression does not wish to continue to the PT-FU. 
These samples will be used to explore whether the status of molecular markers might correlate 
with clinical outcome parameters. The analyses in cfDNA and BMA are for purposes of 
discovery.  
7.2.4.1 
 Biomarker sample collection 
Table 7-8 
Biomarker sample collection plan 
Sample Type 
Volume 
Visit 
Time point 
Allowed window 
Blood for 
pharmacodynamic 
analysis 
8 mL 
Cycle 1 Day 1 (C1D1) 
Pre-dose/0h 
-60 min 
8 mL 
Cycle 1 Day 1 
4h post PAN 
+/- 40 min 
8 mL 
Cycle 1 Day 1 
8h post PAN 
+/- 60 min 
8 mL 
Cycle 1 Day 8 
Pre-dose/0h 
-60 min 
8 mL x 7 = 56mL 
Cycle 2-8 Day 8 
Pre-dose/0h 
-60 min 
8mL 
End of treatment 
n/a 
n/a 
8mL 
During PT-FU: At time of 
disease progression 
n/a 
n/a 
Blood plasma for 
cfDNA analysis 
6mL 
Cycle 1 Day 1 
Pre-dose/0h 
-60min 
6mL 
End of treatment 
n/a 
n/a 
6mL 
During PT-FU: At time of 
disease progression  
n/a 
n/a 
Total 
122 mL 
Note: If the reason for end of treatment is disease progression 
only the end of treatment sample needs to be collected. 
BMA to explore 
novel predictive 
markers  
2mL 
Screening 
n/a 
n/a 
2mL 
End of treatment* 
n/a 
n/a 
2mL 
During PT-FU: at time of 
disease progression 
n/a 
n/a 
*at end of treatment if reason for EOT is a PD or if a patient who discontinued study treatment for other 
reasons than PD does not wish to continue in PT-FU; i.e. bone marrow is only collected at 2 time points for 
each patient at screening and at EOT/PD 

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Detailed instructions for the collection, handling, and shipping of samples are outlined in the 
[CLBH589D2222 Laboratory Manual]. Sample collection dates/information will be entered on 
the appropriate CRF page(s) and/or central laboratory paper requisition forms. 
7.2.4.2 
Optional additional exploratory biomarker assessments using 
remaining biomarker samples 
If the patient agrees, the remaining biomarker samples (bone marrow, blood) may be stored for 
up to 15 years and further analyzed to address scientific questions related to the study treatment 
or cancer. A decision to perform such additional exploratory biomarker research studies beyond 
what is described in Section 7.2.4 would be based on outcome data from this study or from new 
scientific findings related to the drug class or disease, as well as reagent and assay availability. 
Other assessments 
No additional tests will be performed on patients entered into this study. 
7.2.5 
Resource utilization 
Not applicable. 
7.2.6 
Patient reported outcomes 
Quality of life (QOL) will be assessed by the European Organization for Research and 
Treatment (EORTC) core 30-item questionnaire (EORTC-QLQ-C30) and by the Functional 
Assessment of Cancer Therapy / Gynecology Oncology Group Neurotoxicity scale 
(FACT/GOG-Ntx).  
The EORTC-QLQ-C30 will be used to provide patient-reported outcome measures of health-
related quality of life. The EORTC-QLQ-C30 is frequently employed in clinical studies of 
patients with multiple myeloma and is recognized as reliable and valid measures (Aaronson et 
al 1993; Osoba et al 1994, Benboubker et al 2015, Stewart et al 2014). The EORTC-QLQ-C30 
measures functional dimensions (physical, role, emotional, cognitive, and social), three 
symptom items (fatigue, nausea/vomiting, and pain), six single items (dyspnea, sleep 
disturbance, appetite loss, constipation, diarrhea and financial impact) and a global health and 
quality-of-life scale (Aaronson et al 1993). Higher score values for a functional/QoL scale 
indicate higher functioning and health-related quality of life. Higher score values for symptom 
scales indicate greater symptomatology or problems. 
The FACT/GOG-Ntx, Version 4 is a 38-item questionnaire designed to assess general quality 
of life and the severity and impact of neurotoxicity from systemic chemotherapy. The 
FACT/GOG-Ntx has been used in previous bortezomib clinical studies of patients with MM 
and is recognized as reliable and valid measure to assess symptoms associated with 
neurotoxicity (Sonneveld et al 2013; Calhoun et al 2003). The FACT/GOG-Ntx was developed 
from the Functional Assessment of Chronic Illness Therapy Measurement System and focuses 
on four general quality of life domains for physical well-being, functional well-being, 
social/family well-being, and emotional well-being, and includes additional items to 
characterize treatment-related neurotoxicity. Higher subscales/total scores represent higher 
QOL. In the case of the neurotoxicity subscale, lower scores correspond to higher neurotoxicity. 

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Patient questionnaires should be completed before any study drug administrations at the visits 
as indicated in Table 7-9. The measures will be administered sequentially at the beginning of 
the study visit prior to any interaction with the study physician or other study personnel 
including any tests, treatments or receipt of results from any tests to avoid biasing the patient. 
The questionnaires will be completed by the patient in the patient’s local language on an 
electronic device at the site. In case the patient has difficulties completing these questionnaires 
by her-/himself, a family member or a caregiver can assist with the completion. Completed 
questionnaires should be reviewed by the investigator/study personnel before the clinical 
examination for responses which may indicate potential AEs or SAEs. If an AE or SAE is 
confirmed, then the physician should record the event as instructed in Section 8 of this protocol. 
Investigators/study personnel should not encourage the patients to change responses reported 
in the questionnaires or diary. 
In addition, to the above-mentioned PRO measures, a daily diary will be used to measure 
concepts related to diarrhea to help patients manage their diarrhea symptoms, anti-diarrheal 
medications and fluid intake. The diary will include a diarrhea event log that records every 
bowel movement in the last 24 hours, along with stool consistency (as per Bristol Stool Form 
Scale) and time of day when bowel movement occurred.  The diary will be in the form of an 
electronic hand-held device, which the patient will be provided to fill out daily from the first 
day of screening until the end of Cycle 8. Log in and usage instructions will be provided by the 
study personnel at the beginning of the study. Alarms will be set up in the electronic hand-held 
device to remind the patient to fill out their diaries. 
Table 7-9 
Patient reported outcomes collection plan 
Patient 
Questionnaires 
Treatment 
Period 
Visit / Cycle 
Time 
EORTC QLQ-
C30 
Baseline 
Cycle 1 Day 1 
The EORTC QLQ-C30 will be administered at 
the beginning of the study visit prior to any 
interaction with the study physician including 
any tests, treatments or receipt of results from 
any tests to avoid biasing the patient. 
 
On Day 1 of a cycle the measures should be 
administered prior to the patient taking any 
study treatment for this day. 
Study Treatment 
(in cycles of 21 
days) 
Cycle 3 Day 1 
Cycle 5 Day 1 
Cycle 7 Day 1 
and every 4 cycles 
(12 wks), thereafter 
End of treatment 
Post Treatment 
FU 
Every 12 weeks 
FACT/GOG-Ntx 
Baseline 
Cycle 1 Day 1 
The FACT/GOG-Ntx will be administered after 
the EORTC-QLQ-C30 at the beginning of the 
study visit prior to any interaction with the 
study physician including any tests, treatments 
or receipt of results from any tests to avoid 
biasing the patient. 
On Day 1 of a cycle, the measures should be 
administered prior to the patient taking any 
study treatment for this day. 
Study Treatment 
(in cycles of 21 
days) 
Cycle 3 Day 1 
Cycle 5 Day 1 
Cycle 7 Day 1 
and every 4 cycles 
(12 wks), thereafter 
End of treatment 

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Patient 
Questionnaires 
Treatment 
Period 
Visit / Cycle 
Time 
Diary for diarrhea 
management 
Screening 
Screening (1st day 
of screening until 
pre-dose Cycle 1 
Day 1) 
The diary should be completed by the patient 
(or a family member or caregiver, if patient is 
unable to complete it her-/himself) on a daily 
basis from the first day of screening until the 
last day of Cycle 8. The study personnel 
should review the diary entries with the patient 
on Day 1 of Cycles 1 through 9. 
Study Treatment 
Cycle 1 Day 1 to 
Cycle 8 Day 21 (last 
day of Cycle 8) 
8 
Safety monitoring and reporting 
8.1 
Adverse events 
8.1.1 
Definitions and reporting 
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent 
has been obtained. 
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s). 
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s CRF. Adverse event monitoring should 
be continued for at least 30 days following the last dose of study treatment. Adverse events 
(including lab 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 reported as a separate Adverse 
Event. 
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. 
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, corresponding to Grades 1 - 4, will be used. CTCAE Grade 5 (death) is not 
used in this study; but is collected as a seriousness criteria in the Adverse Event CRF and also 
in other CRFs (e.g. Study Completion, Death etc.). 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be evaluated 
to determine: 
• The toxicity grade (CTCAE Grade 1-4) 
• Its duration (Start and end dates) 

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• Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes) 
• Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable) 
• Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
• Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown) 
• Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1 
and which seriousness criteria have been met. 
If the event worsens, the event should be reported a second time in the CRF noting the start date 
when the event worsens in toxicity. For Grade 3 and 4 adverse events only, if improvement to 
a lower grade is determined a new entry for this event should be reported in the CRF noting the 
start date when the event improved from having been Grade 3 or Grade 4. 
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF. 
Once an adverse event is detected, it 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, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (as per IMWG Guidelines for response assessment in MM, see Section 14.2), should 
not be reported as a serious adverse event. 
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the study treatment. 
8.1.2 
Laboratory test abnormalities 
8.1.2.1 
Definitions and reporting 
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events CRF. 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 Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 

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investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 
the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such. 
8.1.3 
Adverse events of special interest 
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the investigator to the sponsor may be 
appropriate. Such events may require further investigation in order to characterize and 
understand them. 
Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data. AESIs are discussed in detail in the Investigator Brochure. 
8.2 
Serious adverse events 
8.2.1 
Definitions 
Serious adverse event (SAE) is defined as one of the following: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Note that hospitalizations for the following reasons should not be reported as serious 
adverse events: 
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (e.g. hospitalization to receive blood transfusions) 
• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event 
• Protocol exempt SAEs: 
a. Progression of disease (including fatal outcomes), if documented by use of 
appropriate method, should not be reported as serious adverse event. 
b. Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements. Despite the clinical description of “life-threatening or 
disabling” provided as general guidance for severity of Grade 4 events in the 
introduction to CTCAE v. 4.03, this does not automatically indicate that all Grade 4 

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adverse events or lab abnormalities are SAEs unless they meet the definition of 
serious as indicated above and as per investigator discretion. 
8.2.2 
Reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided main informed consent and until at least 30 days after the patient has 
stopped study treatment must be reported to Secura Bio or its designee within 24 hours of 
learning of its occurrence. 
Any additional information for the SAE including, complications, or progression of the initial 
SAE, and recurrent episodes must be reported as follow-up to the original episode within 24 
hours of the investigator receiving the follow-up information. An SAE occurring at a different 
time interval or otherwise considered completely unrelated to a previously reported one should 
be reported separately as a new event. 
Any SAEs experienced after this 30-day period should only be reported to Secura Bio if the 
investigator suspects a causal relationship to the study treatment.  
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; 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 each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and submit the completed form within 24 hours to Secura Bio.  Detailed 
instructions regarding the submission process and requirements for signatures are to be found 
in the investigator folder provided to each site. 
Follow-up information is submitted in the same way as the original SAE Report.  Each re-
occurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the patient continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Secura Bio study treatment, a Secura Bio 
representative may urgently require further information from the investigator for Health 
Authority reporting. Secura Bio may need to issue an Investigator Notification (IN), to inform 
all investigators involved in any study with the same drug that this SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with Directive 
2001/20/EC or as per national regulatory requirements in participating countries. 
8.3 
Emergency unblinding of treatment assignment 
Not applicable. 
8.4 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Secura Bio within 24 hours of learning of its occurrence. The pregnancy should 

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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. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the Secura Bio representative or Secura bio designee. Pregnancy follow-up 
should be recorded on the same form and should include an assessment of the possible 
relationship to the study treatment any pregnancy outcome. Any SAE experienced during 
pregnancy must be reported on the SAE Report Form. 
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
8.5 
Warnings and precautions 
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. 
8.6 
Data Monitoring Committee 
The Steering Committee (SC) will be fulfilling the role of the Data Monitoring Committee. The 
details of the role of the Steering Committee will be defined in a SC Charter. 
8.7 
Steering Committee 
The Steering Committee (SC) will be established comprising investigators participating in the 
study, i.e. not being members of the IRC and Secura Bio representatives from the Study team. 
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. The SC will also review safety data approximately every 
6 months (after first randomized patient started study treatment). A consultant cardiologist may 
assist the SC in this safety review, as necessary. The SC should also review the results of the 
interim, the primary and the final analyses. At time of the interim analysis, the SC will provide 
recommendations to Secura Bio to continue, modify or stop the study early. These 
recommendations will be shared with FDA and will only be implemented once FDA 
concurrence has been obtained. Together with the clinical study team, the SC will also develop 
recommendations for publications of study results including authorship rules. The details of the 
role of the Steering Committee will be defined in a SC charter. 
8.8 
Independent Review Committee 
An Independent Review Committee (IRC) will also be established prior to the randomization 
of the first patient. IRC will perform an independent review of disease response data at all 
analysis time points for all patients randomized in the study and provide response assessments 
based on the IMWG criteria, as well as dates of response assessments in a blinded manner. For 

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PD, the IRC will document the reason for progression. Response and PD assessments will be 
entered in the CRF per time point without considering confirmation. Confirmation of response 
will be derived by statistical analysis. 
The results of the IRC review will be part of the clinical database. 
Responses assessed by the IRC will be used for the primary endpoint of ORR (when all 
randomized patients have been treated for up to 8 cycles) and all other efficacy related endpoints 
(for the interim and primary analysis and at time of final data cut-off). It is expected that the 
IRC will at a minimum consist of three hematologists. There will be a kick-off meeting with 
the IRC describing their roles and responsibilities, to agree on potential format for data listings 
and process logistics prior to the finalization of the IRC charter and the IRC statistical analysis 
plan.  
9 
Data collection and management 
9.1 
Data confidentiality 
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following: 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI. 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the subject 
experienced any new or worsened AEs) at the end of their scheduled study period. 
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training. 
Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the subject satisfies protocol age requirements and 
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9.2 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, Sponsor personnel 
(or designated CRO) reviewed the protocol and CRFs with the investigators and their staff. 
During the study, the field monitor will visit the site regularly to check the completeness of 
patient records, the accuracy of entries on the CRFs, the adherence to the protocol to Good 
Clinical Practice, the progress of enrollment, and to ensure that study treatment is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be available 
to assist the field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Secura Bio monitoring standards require full verification for 
the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the CRFs 
are performed according to the study-specific monitoring plan. 
9.3 
Data collection 
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (CRF). The CRFs have 
been built using fully validated secure web-enabled software that conforms to 21 CFR Part 11 
requirements, Investigator site staff will not be given access to the EDC system until they have 
been trained. Automatic validation programs check for data discrepancies in the CRFs and, 
allow modification or verification of the entered data by the investigator staff. 
The Principal Investigator is responsible for assuring that the data entered into CRF is complete, 
accurate, and that entry and updates are performed in a timely manner. 
The following third party vendor data will be acquired for this study and will be transferred 
directly from the respective CRO to the Secura Bio database: 
• Central ECG data will be transmitted by the sites to the designated CRO to undergo 
quality checks and central review. 
• PRO questionnaires (EORTC-QLQ-C30 and FACT/GOG-Ntx) will be recorded by 
patients on an electronic device at the site and transmitted by the sites to a designated 
CRO. 
• The diary for diarrhea management will be recorded by patients on an electronic hand-
held device and transmitted by patient to a designated CRO.  
• PK (blood) samples for PAN and BTZ drawn during the course of the study will be 
collected from the Investigator sites and analyzed by a Secura Bio assigned laboratory or 
contracted central laboratory. 

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• Biomarker (blood and BMA) samples drawn during the course of the study will be 
collected from the Investigator sites and analyzed by a Secura Bio assigned laboratory or 
contracted central laboratories. 
• An additional bone marrow aspirate sample for cytogenetics (FISH) assessment will 
be collected during screening and will be sent to a central laboratory for assessment. 
• Bone marrow samples for additional response assessments to determine 
immunophenotypic CR by multi-parametric flow cytometry, will be sent to a central lab 
for analysis, as needed. 
• Serum for disease assessment by PEP, IF and FLC; and ionized serum calcium will be 
collected by the site and sent to a central lab for analysis. 
• Urine samples for disease assessment by PEP and IF will be collected by the site and 
sent to a central lab for analysis. 
Details regarding all CRO procedures including collection and shipment of data will be 
described in the manual provided by the respective CRO. 
Enrollment will be tracked using an IRT. The system will be supplied by a vendor, who will 
also manage the database. The data will be sent electronically to Secura Bio personnel (or 
designated CRO). 
9.4 
Database management and quality control 
For studies using electronic CRFs, Secura Bio personnel (or designated CRO) will review the 
data entered by investigational staff for completeness and accuracy. Electronic data queries 
stating the nature of the problem and requesting clarification will be created for discrepancies 
and missing values and sent to the investigational site via the EDC system. Designated 
investigator site staff are required to respond promptly to queries and to make any necessary 
changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
Samples and/or data will be processed centrally and the results will be sent electronically to 
Secura Bio (or a designated CRO). 
Electronic PRO questionnaires will be entered into an electronic device by the patient at the 
site. The system will be supplied by a vendor(s), who will also manage the database. The data 
will be sent electronically to Secura Bio personnel (or designated CRO). 
Diary for diarrhea management data will be entered into an electronic hand-held device by the 
patient from screening until end of Cycle 8. The system will be supplied by a vendor(s), who 
will also manage the database. The database will be sent electronically to Secura Bio personnel 
(or designated CRO). 
Randomization codes and data about all study treatments dispensed to the patient and all IRT 
assigned dosage changes will be tracked using an Interactive Response Technology. The system 

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will be supplied by a vendor(s), who will also manage the database. The data will be sent 
electronically to Secura Bio personnel (or designated CRO). 
At the conclusion of the study, after return of all unused drug supplies to Secura Bio personnel 
(or designated CRO), the occurrence of any protocol violations will be determined. After these 
actions have been completed and the data has been verified to be complete and accurate, the 
database will be declared locked. Authorization is required prior to making any database 
changes to locked data, by joint written agreement between the Global Head of Biostatistics 
and Data Management and the Global Head of Clinical Development. 
For EDC studies, after database lock, the investigator will receive a CD-ROM for archiving at 
the investigational site. 
10 
Statistical methods and data analysis 
The primary analysis will be performed when all randomized patients have been treated for up 
to 8 cycles. 
Interim analysis (IA) will be performed when approximately 120 randomized patients (40 in 
each arm) have been treated up to 8 cycles. 
The final analysis will be performed when all patients have completed a 3-year Survival follow-
up or discontinued follow-up prematurely. 
10.1 
Analysis sets 
10.1.1 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been assigned 
by randomization. According to the intent to treat principle, patients will be analyzed according 
to the treatment and strata they have been assigned to during the randomization procedure. 
The randomized treatment information is taken from the IWRS patient randomization listing. 
10.1.2 
Safety Set 
The safety set consists of all patients who received at least one dose of any component of the 
study treatment. 
Patients who have been randomized but did not take at least one dose of any component of study 
treatment will not be included in the safety set. Patients will be analyzed according to the study 
treatment (regimen) they actually received. 
A precise definition of “actually received” will be added in the RAP. 
10.1.3 
Per-Protocol Set 
The Per-Protocol Set (PPS) consists of a subset of patients in the FAS who received at least one 
dose of the randomized study drug and had no major protocol deviation. 
Protocol deviations leading to exclusion from the PPS are: 

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• If it is in direct conflict with the population definition given in the title of the study (i.e., 
patient diagnosis, stage of disease, measurability of disease, or use of prior treatment does 
not correspond to the intended patient population to be studied). 
• Study treatment received different from treatment assigned by randomization 
• If the protocol deviation is very likely to confound the scientific analysis of the primary 
efficacy endpoint(s) or if it precludes any meaningful efficacy assessment. 
• Primary refractory multiple myeloma or Bortezomib refractory. 
• If the ECOG performance status (PS) is worse than 2 
10.1.4 
Dose-determining analysis set 
Not applicable 
10.1.5 
Pharmacokinetic analysis sets 
The pharmacokinetic analysis set (PAS) for PAN consists of all patients with at least one 
evaluable PK concentration of PAN after dosing on Day 1. A PK concentration is considered 
evaluable in a respective cycle if: 
• The patient took the full scheduled dose as randomized in a respective cycle 
• The patient did not vomit within 4 hours after dosing in a respective cycle 
The pharmacokinetic analysis set (PAS) for BTZ consists of all patients with at least one 
evaluable PK concentration of BTZ after dosing on Day 1. A PK concentration is considered 
evaluable in a respective cycle if: 
• The patient took the full scheduled dose in a respective cycle 
Individual samples or PK parameters may additionally be flagged by CP expert for exclusion 
from analysis. This does not exclude the patient from the analysis set unless they also meet the 
criteria listed above. 
10.1.6 
Other analysis sets 
Not applicable. 
10.1.6.1 Efficacy/evaluable set 
Not applicable 
10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline data (including disease characteristics) will be summarized 
descriptively by treatment arm for the FAS. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. 

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10.3 
Treatments (study treatment, concomitant therapies, 
compliance) 
10.3.1 
Study treatment 
Duration of study treatment, cumulative dose, average daily dose, actual dose intensity and 
relative dose intensity of each of the components of study treatment will be summarized by 
treatment arm and by every 21-day cycle. The number of patients with dose 
changes/interruptions will be presented by treatment arm, along with reasons for the dose 
change/interruptions. Safety set will be used for the analyses. 
10.3.2 
Concomitant therapies 
Concomitant medications or procedures and significant non-drug therapies taken concurrently 
with the study treatment will be listed and summarized by Anatomical Therapeutic Chemical 
(ATC) Class, preferred term and treatment arm by means of frequency counts and percentages. 
These summaries will include medications starting on or after the start of study treatment 
(defined as cycle 1 day 1) or medications starting prior to the start of study treatment and 
continuing after the start of study treatment. 
Any prior concomitant medications or significant non-drug therapies starting and ending prior 
to the start of study treatment will be listed. 
For the analyses of transfusions, only transfusions received after start of study treatment and up 
to 30 days after last dose will be considered. Number of patients with transfusions, Number of 
transfusions per patient, Number of transfusion days normalized to study treatment duration 
will be analyzed by treatment arm. 
Safety set will be used for all above mentioned concomitant medication tables and listings. 
10.4 
Primary objective 
The primary objective of the study is to assess efficacy of study treatment by treatment arm as 
measured by overall response rate (ORR: iCR, CR, sCR, VGPR and PR) after all randomized 
patients have been treated for up to 8 cycles of study treatment, assessed by IRC, according to 
IMWG criteria in patients with relapsed or relapsed/refractory multiple myeloma who have 
been previously exposed to immunomodulatory agents. 
10.4.1 
Variable 
The primary endpoint, overall response rate (ORR), is defined as the proportion of patients with 
a confirmed partial response (PR) or better as their best overall response. Best overall response 
is the best post baseline confirmed overall response observed in a given patient, among the 
confirmed response categories, excluding “unknown” and “not assessed”. Best overall response 
is determined based on overall responses observed at all post-baseline response assessments, 
recorded from the randomization until PD, death, start of new therapy, withdrawal of consent 
or end of study, whatever comes first.  For the primary endpoint of ORR, all the data collected 
up to end of cycle 8 + 3 days for patients still being on treatment and collected up to 168 + 3 
days from randomization for patients who discontinued study treatment earlier will be included. 
The ORR will be reported as per IRC according to IMWG criteria (see Section 14.2) in patients 

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with relapsed or relapsed/refractory multiple myeloma who have been previously exposed to 
immunomodulatory agents. 
10.4.2 
Statistical hypothesis, model, and method of analysis 
The assessment of efficacy of study treatment will be based on ORR per IMWG criteria in 
patients with relapsed or relapsed/refractory multiple myeloma who have been previously 
exposed to immunomodulatory agents as determined by IRC. FAS will be used as the primary 
analysis; PPS will be used as a supportive analysis. 
No comparison of the treatment arms is planned in this study. 
The point estimate of ORR along with corresponding exact 95% two-sided confidence intervals 
according to Clopper-Pearson will be presented by treatment arm. 
The assessment of efficacy will be based on the IA data and based on the calculated Bayesian 
predictive probabilities of occurrence of ORR>=55% (i.e. 44 out of 80 patients per treatment 
arm) and lower bound of 95% exact CI ≥ 35% at the primary analysis. In addition, the PAN 10 
mg TIW and PAN 20 mg BIW arms will have an option to be stopped for futility at interim 
analysis. For the details of interim analysis refer to Section 10.7. 
The primary analysis will be performed when all randomized patients have been treated for up 
to 8 cycles. For the primary endpoint (ORR), the cut-off for the primary analysis will be 
determined when all randomized patients have been treated for up to 8 cycles.  
The final analysis of study data will be when the last patient entering the long-term follow-up 
(post treatment follow-up or survival follow-up whichever occurs first) has completed a 3-year 
Survival follow-up or discontinued earlier. 
A sensitivity analysis will be performed using investigator assessment at interim, primary and 
final analysis. 
10.4.3 
Handling of missing values/censoring/discontinuations 
For the purposes of the interim, primary and final analyses, patients with a best overall response 
of ‘Unknown’ (UNK) will be treated as non-responders in estimating the ORR in the FAS (per 
the ITT principle). PFS for patients who are free of disease progression or are lost-to-follow-up 
will be right-censored at their last adequate response assessment date. 
OS time for patients who are alive at the end of the study or are lost to follow-up will be right-
censored at the date of last contact. 
10.4.4 
Supportive analyses 
Subgroup analyses based on number of prior lines of anti-MM therapy (1 vs. 2 vs. 3 or 4), age 
(≤75 vs. >75 years), gender, race, etc. will be performed as appropriate. 
10.5 
Secondary objectives 
All secondary efficacy assessments (iCR/sCR/CR/VGPR rate, PFS, OS, TTR, DOR, TTP, and 
ORR) will be analyzed as per IRC assessment. All secondary analyses will be performed based 
on the FAS, unless otherwise specified. 

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10.5.1 
Secondary objective(s) 
The individual iCR, sCR, CR, VGPR rates will be assessed based on IMWG criteria (see 
Section 14.2) as per IRC assessment. 
The ORR will be assessed based on the IMWG criteria as per IRC assessment. 
Progression-free survival (PFS) will be assessed based on IMWG criteria (see Section 14.2) as 
per IRC assessment, and is defined as the time from date of randomization to date of first 
documented disease progression or death (regardless of cause of death). 
Overall survival (OS) is defined as the time from date of randomization to the date of death due 
to any cause. If a patient is not known to have died, survival will be censored at the date of last 
contact. 
Time to response (TTR) is the time between date of randomization to the date of first onset of 
PR or better response (iCR or sCR or CR or VGPR or PR) and will be based on IMWG criteria 
as per IRC assessment. 
Duration of response (DOR) is defined as the duration from the first documented onset of PR 
or better response (iCR or sCR or CR or VGPR or PR) to the date of first documented disease 
progression or death due to multiple myeloma and will be based on IMWG criteria (see 
Section 14.2) as per IRC assessment. 
Time to progression (TTP) is defined as the time from the date of randomization to the date of 
the first documented disease progression or death due to multiple myeloma and will be based 
on IMWG criteria (see Section 14.2) as per IRC assessment. 
Survivorship functions will be estimated by using the Kaplan-Meier product-limit method and 
displayed as graphs. The estimations are performed by treatment arm. Median PFS, Median OS 
time and its two-sided 95% confidence intervals will be reported for three treatment arms. 
Median TTR, DOR and TTP along with corresponding 95% confidence intervals will be 
reported for three treatment arms. 
A sensitivity analysis will be performed using investigator assessment at, primary and final 
analysis for the secondary endpoints (PFS, TTP, TTR, DoR, ORR). 
10.5.2 
Other secondary efficacy objectives 
Not applicable. 
10.5.3 
Safety objectives 
All safety data will be by analyzed and reported overall and by treatment arm. 
10.5.3.1 Analysis set and grouping for the analyses 
For all safety analyses, the safety set will be used. The overall observation period will be divided 
into three mutually exclusive segments: 
1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication 

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2. on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication 
3. post-treatment period: starting at day 31 after last dose of study medication 
The safety summary tables will include only assessments collected within 30 days after study 
treatment discontinuation and assessments prior to the data cut-off date for ongoing patients, 
unless otherwise specified. 
All data, regardless of observation period, will be listed and assessments collected in the pre-
treatment and post-treatment period will be flagged in all the listings. 
10.5.3.2 Adverse events (AEs) 
AEs will be assessed according to the Common Terminology Criteria for AEs (CTCAE version 
4.03). AEs are coded using the MedDRA terminology version 17.1 or later. 
The following summaries will be provided by treatment arm. 
• Incidence of treatment-emergent adverse events (new or worsening from baseline) during 
on-treatment period 
• Non-fatal serious adverse events during on-treatment period 
• All deaths (on-treatment and post-treatment) will be tabulated. 
However, all AEs, deaths and non-fatal serious adverse events (including those from the pre 
and post-treatment periods) will be listed and those collected during the pre-treatment and post-
treatment period will be flagged. 
Adverse Events of Special Interest (AESI) will be analysed. Such categories consist of one or 
more well-defined safety events which are similar in nature and for which there is a specific 
clinical interest in connection with the investigational treatment(s). 
Adverse events of special interest are defined at the project level and are regularly updated 
based on emergent data. For each specified AESI, number and percentage of patients with at 
least one event part of the AESI will be reported. 
10.5.3.3 Laboratory abnormalities 
Categorization of lab values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 or according to normal ranges 
for those parameters without available CTCAE grading. The calculation of CTCAE grades will 
be purely based on the observed lab values, clinical assessments will not be taken into account. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used. 
For laboratory tests where grades are not defined by CTCAE v4.03, results will be graded by 
the low/normal/high (low and high) classifications based on laboratory normal ranges. 
The following by-treatment summaries will be generated separately for hematology and 
biochemistry laboratory tests 
• Worst post-baseline CTCAE grade (regardless of the baseline status). Each patient will be 
counted only once for the worst grade observed post-baseline. 

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• Shift tables using CTCAE grades to compare baseline to the worst on-treatment value 
• For laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-
treatment value. 
Listings of all laboratory data with values flagged to show the corresponding CTCAE grades 
and the classifications relative to the laboratory normal ranges will also be generated. 
In addition to the above-mentioned tables and listings, other exploratory analyses, for example 
figures plotting time course of raw or change in laboratory tests over time or box plots may be 
specified in the RAP. 
10.5.3.4 Other safety data 
ECGs, Vital signs and ECOG PS will be summarized by treatment arm. 
ECG 
• listing of ECG evaluations for all patients with at least one abnormality. 
• Change from baseline QTcF (mean QtcF value of triplicate ECGs performed pre-dose on 
C1D1) 
Vital signs 
• table with descriptive statistics at baseline, one or several post-baseline time points and 
change from baseline to this/these post-baseline time points. 
ECOG PS 
• shift tables comparing the baseline PS with the worst result during post-baseline will be 
summarized for each treatment arm. 
10.5.3.5 Supportive analyses for secondary objectives 
Subgroup analyses will be provided for specific secondary variables based on number of prior 
lines of anti-MM therapy (1 vs. 2 vs. 3 or 4), age (≤75 vs. >75 years), gender, race, etc. will be 
performed as appropriate, more details will be provided in the SAP. 
10.5.3.6 Tolerability 
Not applicable 
10.5.4 
Pharmacokinetics and dose response 
10.5.4.1 Pharmacokinetics 
PK parameters listed in Table 10-1 will be calculated from concentration-time data for 
panobinostat and bortezomib on Cycle 1 Day 1 using WinNonLin (Pharsight, Mountain View, 
CA). 

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Table 10-1 
Noncompartmental pharmacokinetic parameters 
AUC0-8h (PAN, 
BTZ) 
The AUC from time zero to 8 hours (tlast) (ng*h/mL) 
Cmax (PAN, BTZ) 
The maximum (peak) observed plasma, blood, serum, or other body fluid drug 
concentration after single and multiple dose administration (ng/mL) 
Tmax (PAN, BTZ) 
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single and multiple dose administration (h) 
Cmin (PAN, BTZ) 
The minimum (trough) observed plasma, blood, serum, or other body fluid drug 
concentration after single and multiple dose administration (ng/mL) 
C24h (PAN) 
The observed plasma, blood, serum, or other body fluid drug concentration 24 hours 
after single and multiple dose administration (ng/mL) 
PAS will be used in all pharmacokinetic data analysis except where otherwise stated and PK 
summary statistics. The full analysis set will be used for pharmacokinetic data listings. 
Descriptive statistics by dose and, where applicable, scheduled time-point of AUC0-8h, Cmax, 
C24h and Cmin will include arithmetic and geometric mean, median, SD, and CV, geometric 
CV, minimum and maximum for panobinostat and bortezomib where applicable. Similar 
descriptive statistics will be provided by dose and time for concentrations observed after Day 
1. Zero concentrations will not be included in the geometric mean calculation. For Tmax 
median, minimum and maximum will be provided. 
The PK data may be analyzed using a population approach with linear or nonlinear mixed-
effects models. If so, such analyses will be reported separately. 
10.5.4.2 Exposure response 
Overall response, incidence of Grade 3/4 thrombocytopenia (based on group term), Grade 3/4 
diarrhea and other key adverse events as appropriate will be modeled by separate binary logistic 
regression models including Cycle 1 Day 1 AUC0-8 (or cumulative AUC up to onsets of AEs), 
average Cmax and other plasma concentration summaries as appropriate. Bortezomib exposure 
as well as other baseline covariates may be included in the model if appropriate. In addition cox 
regression models will be fitted to time to first Grade 3/4 thrombocytopenia, Grade 3/4 diarrhea, 
other key adverse events and PFS with similar covariate considerations as for the logistic 
regression models. Analyses of adverse events will be based on patients in the safety set who 
also have PK data whereas analysis of overall response and PFS will be based on patients in the 
full analysis set who also have PK data. Full details of the analysis will be provided in the 
statistical analysis plan. 
PK/PD relationships may also be explored using a population approach with linear or nonlinear 
mixed-effects models. Any such population-model-based analyses will be reported separately. 
10.5.4.3 Data handling principles 
Plasma concentrations will be expressed in ng/mL All concentrations below the limit of 
quantitation or missing data will be reported as such in the concentration data listings and will 
be treated as zero in calculations of noncompartmental pharmacokinetic parameters. 

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10.5.5 
Biomarkers  
This clinical study was not designed to address specific biomarkers-related hypotheses, and the 
analysis of this data should be viewed as exploratory and hypotheses generating. Additional 
data from subsequent clinical studies will be required to further investigate and confirm any 
preliminary findings. 
Additional exploratory analyses may be performed after the completion of the end-of-study 
CSR and all such analyses will be outlined in stand-alone biomarker analysis plans and results 
will be documented in separate biomarker reports. 
10.5.5.1 Outline of the data analysis 
The proposed data analysis will be aligned with the exploratory biomarker objectives of the 
protocol. For biomarker collected only at baseline, the distribution of baseline level will be 
presented (summary and frequency tables as appropriate). For biomarker collected over the 
course of the study, eg. Pharmacodynamic biomarker, the changes from baseline will be 
summarized. 
The relationship between Pharmacodynamic biomarkers and dose/PK parameters may be 
explored via suitable graphical aids. Associations between biomarkers of molecular status and 
selected efficacy endpoints may also be explored. 
In situations where the numbers of samples are inadequate to perform any analysis, the available 
biomarker data will only be listed. 
10.5.5.2 Data handling principles 
Relevant aspects of data handling will be addressed in the RAP. 
10.5.5.3 Data analysis principles 
10.5.5.3.1 
Analysis sets 
All biomarker analysis will be performed on the full analysis set unless otherwise specified. 
This includes patients from the FAS with valid biomarker assessments. If associations between 
biomarkers and safety endpoints are being explored then the safety/per-protocol set will be used. 
10.5.5.3.2 
Basic tables, figures and listings 
Levels and changes from baseline will be summarized at each visit for each continuous 
biomarker. Both absolute change and relative change will be tabulated. Summary statistics such 
a number of samples, mean, median etc. will be presented. In addition, a longitudinal plot of 
the mean/median change over time may be produced for each biomarker, by dose group if 
sufficient data are available. 
Frequency tables for categorical biomarker may also be produced to summarize the number and 
percentage in each category/group. 
Associations between biomarkers at efficacy endpoints of interest may be explored via suitable 
figures. 

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All biomarker data will be listed. 
10.5.5.3.3 
Advanced analysis methods 
Advanced analysis methods may be used for exploration and hypothesis generation. These 
could be to perform meta-analysis or exploration of the relationship between biomarker 
endpoints and efficacy and safety endpoints and such methods will be described in a stand-
alone analysis plan document. 
10.5.6 
Patient-reported outcomes 
10.5.6.1 EORTC-QLQ-C30, FACT/GOG-Ntx 
The EORTC QLQ30 will be scored according to the guidelines provided by the EORTC 
administration and scoring manual (EORTC Scoring Manual 2001). For each domain and item, 
a linear transformation is applied to standardize the score between 0 and 100. Higher values 
indicate higher functioning and health-related quality of life. 
The FACT GOG/Ntx will be scored in accordance with their specific scoring guidelines (Cella 
et al 1997). For these scores, lower values denote higher fatigue and neurotoxicity. FACT/GOG-
NTX scores range from 0 - 44. 
EORTC QLQ-C30 and FACT GOG/Ntx scores will be evaluated among patients who had a 
valid baseline HRQoL assessment and at least one post-baseline assessment. 
Frequency tables for compliance to completing all patient-reported questionnaires will be 
provided by treatment arm and visit for EORTC-QLQ-C30 and FACT/GOG-Ntx. 
Cycle 1, Day 1 QOL measures will be used as baseline. Overall QOL scores and subscales will 
be summarized over time using mean, median, standard deviation, and range by treatment arm. 
QOL scale means and standard errors will be plotted over time by treatment arm. Additional 
exploratory analysis will be pre-specified in the RAP as appropriate. 
10.5.6.2 Diary for diarrhea management 
The electronic diary for diarrhea management will be provided to patients and will be completed 
on a daily basis from the first day of screening until the last day of Cycle 8, unless study 
treatment was discontinued earlier. 
The frequency and intensity of bowel movements will be summarized descriptively by cycle, 
type of bowel movement and by treatment arm. Additional exploratory analysis will be 
specified in the RAP as appropriate. 
10.6 
Exploratory objectives 
Please refer to Section 10.5.5 - Biomarkers. 
10.7 
Interim analysis 
The preliminary determination of the optimal panobinostat dose in combination with BTZ s.c. 
and Dex with an improved benefit/risk assessment, will be based on probability of success 
(POS) and overall safety data at interim analysis. None of the treatment arms will be stopped at 

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the interim analysis due to efficacy. Only the PAN 10 mg TIW arm and the PAN 20 mg BIW 
arm will have an option to be stopped for futility as a result of the interim analysis. 
10.7.1 
Interim efficacy analysis 
One interim analysis (IA) is planned and will be based on the data collected on or before the 
cut-off date, which corresponds to the time after approximately 120 randomized patients (40 in 
each arm) have completed up to 8 cycles of study treatment. Patient enrollment will not be 
suspended for the interim analysis (IA). Assuming an accrual rate of 7 patients every month it 
is expected that approximately 17 months will be needed to accrue approximately 120 patients 
for IA, and the IA will occur at approximately 26 months from randomization of the first patient. 
The Steering Committee (SC) will monitor safety on a regular basis, The SC will also review 
interim results and provide recommendation(s) to Secura Bio to stop/continue the “PAN 10 mg 
TIW and 20 mg BIW” treatment arms based on futility criteria and safety data (see Section 8.7). 
The recommendation to terminate or continue enrollment to any treatment arm will be shared 
with the FDA and a decision will be made in agreement with the FDA. 
The assessment of efficacy at the interim analysis will be based on ORR according to IMWG 
criteria as determined by IRC assessment. The decision to stop/continue enrollment for futility 
in the “PAN 10 mg TIW and 20 mg BIW” treatment arms will be based on probability of 
success: 
Based on the predictive probability (PP) that the observed ORR at the primary analysis reaches 
the target of 55% or more and the lower bound of 95% exact CI ≥ 35% (i.e., the probability of 
a positive conclusion of the study), given at the interim observed data (x) among patients. Thus, 
POS = Prob [ Observed ORR at primary analysis >=55% and lower bound of 95% exact CI ≥ 
35% | x,n] 
 
= Prob [Observed number of responders>= 44 out of 80 patients and lower bound of 
95% exact CI ≥ 35% | x,n] 
The efficacy outcome (overall response rate) is binary, namely, response (iCR, sCR, CR, VGPR 
or PR) vs. non-response (MR, SD, PD or UNK), and the number of responders on each arm is 
assumed to follow a binomial distribution. Suppose the prior belief regarding the probability of 
response (π) is that it has a beta distribution with parameters a0 and b0. If there are x responders 
out of n patients at the interim analysis, then the posterior distribution for π is beta with 
parameters a1=a0+x and b1=b0+n-x. Now let Y represent the number of successes (i.e. 
responders) from m future observations at the primary analysis, then the (posterior) predictive 
distribution of Y conditioned on the observed data at the interim analysis (x responders out of 
n patients) is a betabinomial distribution described by 
 
where B (a, b) is the beta function. 
A weakly informative Beta (0.82, 1) prior distribution for ORR is used for each treatment arm. 
This prior distribution has mean 45% and 95% probability interval from 1.1% to 97.0%. 
Assuming exactly 120 (40 in each arm) patients have been included in the interim: 

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• The PAN 10 mg TIW and/or PAN 20 mg BIW arm will be stopped, if observed ORR <= 
42.5% (number of observed responders <=17 out of 40 in the respective arm) which 
corresponds to predictive probability (ORR of PAN 10 mg >= 55% at FA) <4%  
• Predictive probability of 4.4% corresponds to observed number of responders of 18 out of 
40 patients which is equivalent to a 45% ORR. Given that the observed ORR up to 8 
cycles in the Placebo arm from D2308 is 46%, the POS cut-off of 4% seems a reasonable 
assumption. 
In addition to the criteria based on predictive probability, the decision to choose an appropriate 
regimen at IA will also be based on overall safety.  
The decision rules at interim analysis based on ORR are presented below in Table 10-2. 
However, the cut-off for the number of responders needed in each of the 2 arms will be 
determined at the time of interim analysis based on the actual number of patients who completed 
up to 8 cycles of study treatment. 
Table 10-2 
Predictive probability of observing ORR at least 55% at the primary 
analysis (n=80) in the FAS under different interim results (n=40 
patients) 
Observed response rate at IA 
Predictive probability of 
observing ORR ≥ 55% at the 
primary analysis (%) 
Decision at IA if predictive 
probability is <4% 
# of responses 
% 
17 
42.5 
1.5 
Not recommended to continue 
18 
45.0 
4.4 
Recommended to continue 
19 
47.5 
10.4 
Recommended to continue 
20 
50.0 
20.9 
Recommended to continue 
21 
52.5 
35.8 
Recommended to continue 
22 
55.0 
53.3 
Recommended to continue 
23 
57.5 
70.2 
Recommended to continue 
24 
60.0 
83.6 
Recommended to continue 
25 
62.5 
92.3 
Recommended to continue 
26 
65.0 
96.9 
Recommended to continue 
10.7.2 
Interim safety analysis 
Review of safety data will include, but is not limited to, assessment of the nature and frequency 
of deaths during treatment, serious adverse events, Grade 3 or 4 adverse events, key laboratory 
abnormalities, abnormal results from electrocardiogram (ECG) assessments and distribution of 
safety-related reasons for treatment discontinuation. 
10.7.3 
Interim PK analysis 
Review of pharmacokinetic data will include, but is not limited to, assessment of the PK 
parameters (AUC0-8h, Cmax, Tmax, C24h and Cmin) for PAN and/or BTZ, as applicable and 
also assessment of exposure response (efficacy and safety) relationship. 

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10.8 
Sample size calculation 
The study design allows randomization of up to 240 patients in order to obtain up to 80 patients 
in each arm. 
The operating characteristics of the design based on the primary endpoint (ORR per IMWG 
criteria as determined by IRC assessment) under different true ORR is provided in Table 10-3. 
This assessment is based on 80 patients per arm in the FAS at the primary analysis. The 
proposed study design has reasonable operating characteristics. At the time of interim analysis, 
probability of success at the primary analysis is 54.2% if the true ORR is 55% and the risk of 
recommending an arm is 4.6% if the true ORR is 45%. 
Table 10-3 
Operating characteristics for an individual treatment group – Interim 
analysis (40 patients) 
True 
ORR 
(%) 
Operating characteristics 
Probability of 
not 
recommending 
the arm at IA (%) 
Probability of recommending the 
arm at IA and positive conclusion at 
primary analysis (80 patients/arm) 
(%) 
Probability of recommending the arm 
at IA and negative conclusion at 
primary analysis (80 patients/arm) 
(%) 
40.0 
68.9 
0.5 
30.7 
45.0 
43.9 
4.6 
51.5 
50.0 
21.5 
21.5 
57.0 
55.0 
7.7 
54.2 
38.1 
60.0 
1.9 
84.5 
13.6 
10.9 
Power for analysis of key secondary variables 
Not applicable. 
11 
Ethical considerations and administrative procedures 
11.1 
Regulatory and ethical compliance 
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki. 
11.2 
Responsibilities of the investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is required 
to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Secura Bio monitors, auditors, 
Secura Bio Clinical Quality Assurance representatives, designated agents of Secura Bio, 
IRBs/IECs/REBs and regulatory authorities as required. 

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11.3 
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent. 
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the patient source documents. The date when a subject’s Informed Consent was 
actually obtained will be captured in their CRFs. 
Secura Bio will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Secura Bio before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Secura Bio monitor after IRB/IEC/REB approval. 
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study, they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study. 
Additional consent form 
Sub-studies and studies with an optional Exploratory Biomarker component will have a separate 
consent form covering those studies. This form will be adapted for each Study based on a 
standard template used globally for all Studies. These informed consent forms will be submitted 
for ethical approval together with the Study Protocol and the main informed consent form of 
the Study. If a subject opts not to participate in the optional assessments, this in no way affects 
the subject’s ability to participate in the main research study. 
11.4 
Discontinuation of the study 
Secura Bio reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are outlined in 
Section 4.4. 
11.5 
Publication of study protocol and results 
Secura Bio assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results. 
11.6 
Study documentation, record keeping and retention of 
documents 
Each participating site will maintain appropriate medical and research records for this study, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of subjects. As part of participating in a Secura Bio-

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sponsored study, each site will permit authorized representatives of the sponsor(s) and 
regulatory agencies to examine (and when required by applicable law, to copy) clinical records 
for the purposes of quality assurance reviews, audits and evaluation of the study safety and 
progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical study necessary for the reconstruction and evaluation of the study. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
study. 
Data collection is the responsibility of the clinical study staff at the site under the supervision 
of the site Principal Investigator. The study case report form (CRF) is the primary data 
collection instrument for the study. The investigator should ensure the accuracy, completeness, 
legibility, and timeliness of the data reported in the CRFs and all other required reports. Data 
reported on the CRF, that are derived from source documents, should be consistent with the 
source documents or the discrepancies should be explained. All data requested on the CRF must 
be recorded. Any missing data must be explained. Any change or correction to a paper CRF 
should be dated, initialed, and explained (if necessary) and should not obscure the original entry. 
For electronic CRFs an audit trail will be maintained by the system. The investigator should 
retain records of the changes and corrections to paper CRFs. 
The investigator/institution should maintain the study documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines. 
11.7 
Confidentiality of study documents and patient records 
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Novartis previously or to Secura Bio. Signed informed consent 
forms and patient enrollment log must be kept strictly confidential to enable patient 
identification at the site. 
11.8 
Audits and inspections 
Source data/documents must be available to inspections by Secura Bio or designee or Health 
Authorities. 

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11.9 
Financial disclosures 
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start. 
12 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Secura Bio or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are permitted. If 
the investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Secura Bio 
and approved by the IRB/IEC/REB it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR. 
12.1 
Amendments to the protocol 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Secura Bio, Health Authorities where required, and the IRB/IEC/REB. 
Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the safety 
of any patient included in this study, even if this action represents a deviation from the protocol. 
In such cases, Secura Bio should be notified of this action and the IRB/IEC at the study site 
should be informed according to local regulations (e.g. UK requires the notification of urgent 
safety measures within 3 days) but not later than 10 working days. 

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13 
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14 
Appendices 
14.1 
Appendix 1: Co-medications which are known to prolong the QT 
interval and/or induce Torsades de Pointes, are strong CYP3A4/5 
inhibitors/inducers or sensitive CYP2D6 substrates 
14.1.1 
Medications which are known to prolong the QT interval and/or induce 
Torsades de Pointes ventricular arrhythmia should be avoided 
Patients who are currently receiving treatment with any of the medications in Table 14-1, and 
cannot either discontinue from this treatment or switch to an alternative medication prior to 
enrollment in a panobinostat clinical study, will be excluded from the study. Patients enrolled 
in a panobinostat clinical study may not begin treatment with any of the medications listed in 
Table 14-1 unless discussed with the Sponsor and approval is granted by the Sponsor. The 
Sponsor may agree to temporarily discontinue panobinostat treatment (e.g., for 72 hours) during 
administration with these drugs or withhold medications in Table 14-1 for at least 72 hours 
when panobinostat is to be administered. 
NOTE: It is of great importance to avoid combining drugs listed below in Table 14-1 and Table 
14-2 (CYP3A inhibitors) in combination with panobinostat especially in the presence of 
electrolyte abnormalities, notably decreased potassium or magnesium levels commonly 
associated with diuretic usage. 
In general, medications listed in Table 14-1, Table 14-3 and Table 14-4 should be avoided. 
Medications listed in Table 14-2 and Table 14-3 are to be used with caution when co-
administered with panobinostat. The use of any of the drugs in Table 14-1, Table 14-2, and 
Table 14-3, and Table 14-4 in combination with panobinostat must be discussed with the 
Sponsor. 
Table 14-1 
Medications which are known to prolong the QT interval and/or induce 
Torsades de pointes to be avoided 
Antiarrhythmics 
amiodarone 
disopyramide 
dofetilide 
flecainide 
ibutilide 
procainamide 
quinidine 
sotalol 
Anticancer 
arsenic trioxide 
vavdetanib 
Antihistamines 
astemizole 
terfenadine 

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Antibiotics 
azithromycin 
clarithromycin 
erythromycin 
moxifloxacin 
sparfloxacin 
Antianginal 
bepridil 
Antimalarial 
chloroquine 
halofantrine 
Antipsychotics 
chlorpromazine 
haloperidol 
mesoridazine 
pimozide 
thioridazine 
Antinausea 
domperidone 
droperidol 
dolasetron (intravenous and oral)^ 
Anti-infective 
pentamidine 
Antilipemic 
probucol 
Antidpressants 
citalopram 
Opiate agonists 
levomethadyl 
methadone 
GI stimulant 
cisapride 
^Intravenous dolasetron is contraindicated for preventing nausea and vomiting associated with chemotherapy 
based on FDA drug safety communication dated December 17, 2010. Based on this finding, both intravenous 
and oral dolasetron are prohibited to be taken with panobinostat. 
This is not a comprehensive list of medications which may prolong the QT interval and/or 
induce Torsades de pointes. This list of medications was developed in collaboration with an 
external cardiology consultant and represents those medications which are deemed to have an 
unacceptable risk of co-administration with panobinostat. 
The following website may be referenced as a supplemental guide for drugs which have been 
associated with Torsades de pointes or prolonging the QT interval but at this point lack 
substantial evidence for causing Torsades de pointes: https://CredibleMeds.org/. 
Medications listed on the website which do not appear in Table 14-1 above may be used with 
caution at the discretion of the investigators. 
Ondansetron (a known CYP2D6 substrate, Table 14-4) has been associated with Torsades de 
pointes and QT prolongation but has not been shown to cause Torsades de pointes. Therefore, 
if use of ondansetron cannot be avoided, more frequent ECG monitoring should be performed. 

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14.1.2 
Dose reduce panobinostat when combined with medications which 
are known strong CYP3A inhibitors 
Panobinostat is a substrate of CYP3A4/5 with minor involvement of CYP2D6, and CYP2C19 
in in vitro evaluation of its metabolism. Thus, a clinical drug-drug interaction study was 
conducted using ketoconazole, a strong CYP3A inhibitor, in combination with panobinostat in 
study [CLBH589B2110]. 
Multiple ketoconazole doses at 400 mg increased Cmax and AUC of panobinostat by 1.6- and 
1.7-fold, respectively, but with no change in Tmax or half-lives in 14 cancers patients. The less 
than 2-fold increase in panobinostat AUC upon co-administration of a strong CYP3A inhibitor 
is considered a weak drug inhibition. However, panobinostat dose should be reduced from 20 
mg to 10 mg when combined with medications which are known strong CYP3A inhibitors. If 
patients are already at reduced doses of panobinostat 15 mg or 10 mg, combination with strong 
CYP3A inhibitors should be avoided. If this is not avoidable, patients should be monitored 
closely for toxicity. 
Table 14-2 
Medications which are known strong CYP3A inhibitors 
Antibiotics 
telithromycin 
troleandomycin 
Protease inhibitors 
Indinavir 
lopinavir 
nelfinavir 
ritonavir 
saquinavir 
tipranavir 
Antifungals 
itraconazole 
ketoconazole 
posaconazole 
voriconazole 
Antivirals 
boceprevir 
telaprevir 
Others 
cobicistat 
conivaptan 
elvitegravir 
mibefradil 
nefazodone 
Miscellaneous drugs or products 
Star fruit and pomegranate product and juice 
* regular orange juice is allowed. 
Although clarithromycin is a known strong CYP3A inhibitor, it is also known to prolong QT intervals which is 
listed in Table 14-1 and is prohibited to be taken with panobinostat. This drug is thus not listed again in Table 
14-3. 
This is not a comprehensive list of medications which may inhibit CYP3A4/5. The above list 
was compiled by using information listed under “draft guidance for industry, drug interaction 
studies, CDER 2006”, Indiana University School of Medicine drug interaction tables at 

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http//medicine.iupui.edu/clinpharm/DDIs/ClinicalTable.asp and “drug interaction database” 
from University of Washington. 
Additional updated versions with moderate and weak CYP3A inhibitors, which are meant to be 
used 
as 
a 
guide, 
may 
be 
found 
at 
the 
following 
website: 
http://medicine.iupui.edu/clinpharm/DDIs/ClinicalTable.asp. 
14.1.3 
Medications which are known strong CYP3A inducers are to be 
avoided 
Panobinostat plasma exposure was reduced by 20% or more when combined with bortezomib 
and dexamethasone (B2207 and D2308). Co-administration of panobinostat with strong 
CYP3A inducers was not evaluated in vitro or in a clinical study however, a reduction in 
panobinostat exposure is likely. An approximately 70% decrease in the systemic exposure of 
panobinostat in the presence of strong inducers of CYP3A was observed in simulations using 
mechanistic models. Therefore, the concomitant use of strong CYP3A inducers should be 
avoided. 
Table 14-3 
Medications which are known strong CYP3A inducers are to be 
avoided 
Strong Inducers (AUC decreased by ≥ 80%) 
avasimibe, carbamazepine, mitotane, phenobarbital, phenytoin, rifabutin, rifampin (rifampicin), St. John's wort 
(hypericum perforatum) 
14.1.4 
Medications which are known sensitive CYP2D6 substrates or 
substrates with narrow therapeutic index are to be avoided 
Panobinostat was also shown to be a CYP2D6 inhibitor (Ki 0.17 µM) in vitro. Thus, clinical 
drug-drug interaction study with panobinostat as CYP2D6 inhibitor and dextromethorphan as 
CYP2D6 substrate was conducted in study [CLBH589B2109]. 
Panobinostat increased the median Cmax and AUC of a sensitive substrate of CYP2D6 by 
approximately 80% and 60%, respectively; however these increase were highly variable 
(increased the Cmax and AUC0-∞ of dextromethorphan by 20% to 200% and 20% to 130% 
(interquartile ranges), respectively). 
Avoid co-administrating panobinostat with sensitive CYP2D6 substrates or CYP2D6 substrates 
that have a narrow therapeutic index (i.e., thioridazine, pimozide). If concomitant use of 
CYP2D6 substrates is unavoidable, patients should be frequently monitored for adverse 
reactions. 

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Table 14-4 
Medications which are known sensitive CYP2D6 substrates or 
substrates with a narrow therapeutic index are to be avoided 
Antipsychotics 
Tricyclics/tetracyclics 
perphenazine 
desipramine 
thioridazine1 
 
pimozide1 
 
 
Others 
Beta blockers 
atomoxetine 
metoprolol 
dextromethorphan 
nebivolol 
tolterodine 
 
 
Antidepressants 
Antiemetics 
venlafaxine 
ondansetron 
1 substrate with narrow therapeutic index (NTI): drug whose exposure-response indicates that increases in its 
exposure levels by the concomitant use of potent inhibitors may lead to serious safety concerns. 
 
This is not a comprehensive list of CYP2D6 substrates. Additional updated versions of this list, 
which are meant to be used as a guide, may be found at the following website 
http://medicine.iupui.edu/clinpharm/DDIs/ClinTable.asp. 
14.1.5 
References (available upon request) 
Hidaka M, Fujita K, Ogikubo T, et al. (2004). Potent inhibition by star fruit of human 
cytochrome P450 3A (CYP3A) activity, Drug Metab Dispos 2004; 32: 581. 
Synold TW, Takimoto CH, Doroshow JH, et al. (2007). Escalating and Pharmacological 
Study of Oxaliplatin in Adult Cancer Patients with Impaired Hepatic Function: A National 
Cancer Institute Organ Dysfunction Working Group Study, Clin Cancer Res. 2007 13; 3660. 
Woosley RL, Heise CW and Romero KA, www.CredibleMeds.org QTdrugs list, AZCERT, 
Inc. 1822 Innovation Park Dr. Oro Valley, AZ 85755. 

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14.2 
Appendix 2: Guidelines for response assessment in multiple 
myeloma 
14.2.1 
Introduction and scope 
This document provides working definitions and specifications for consistent and efficient 
analyses of efficacy for Secura Bio clinical studies assessing anti-neoplastic activity in multiple 
myeloma (MM). 
This document is based on the uniform response criteria as proposed by the International 
Myeloma Working Group (IMWG; International Myeloma Workshop Consensus Panel I, 
Rajkumar et al 2011). These response criteria will be referred to as IMWG criteria. Other 
references were used to add recommendations. With the release of this document, newly 
developed study protocols in MM should use the IMWG criteria as described in this document. 
The objectives of this document are: 
• to ensure that the definitions of responses in a clinical study protocol correctly reflect the 
IMWG criteria in the target patient population 
• to provide guidance for the response assessment and clinical monitoring to ensure 
consistency with the IMWG’s criteria for response in multiple myeloma 
The assessment and analysis of MM-specific patient reported outcomes will be covered in a 
subsequent version of this guideline or in an attachment. 
14.2.2 
Efficacy assessments 
14.2.2.1 Assessments – general 
The following should be addressed/considered while designing a study: 
1. frequency of response assessments should be adapted to the type and schedule of 
treatment, phase of the study (e.g. treatment phase, post-treatment follow-up phase)  
2. schedule and time window for response assessments should be included in the protocol  
3. guideline on following-up patients for PD or survival after completion or discontinuation 
of study treatment should be provided in the protocol 
All data associated with response assessments should be captured in the CRF (i.e. not merged 
from several sources), if possible. 
14.2.2.1.1 
Measurable disease 
For the IMWG criteria, measurable disease based on protein assessment is defined as at least 
one of the following conditions present at baseline (Durie et al 2006, Dimopoulos et al 2015): 
• Serum M-protein by PEP ≥ 1.0 g/dL (for protocols including relapsed and refractory 
patients a threshold of ≥ 0.5 g/dL can be considered) 
• 24h-urine M-protein by PEP ≥ 200 mg/24h 
• Involved serum FLC level ≥ 10 mg/dL provided the FLC ratio is abnormal 
(Section 14.2.2.2.2) 
In case of none of the criteria applies, the patient is considered to have non-measurable disease. 

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14.2.2.1.2 
Eligibility 
In general, patients with measurable disease according to Section 14.2.2.1.1 should be included 
in a study. In case a patient with non-measurable disease was enrolled, disease assessment 
should be continued with bone marrow aspiration / biopsy and a protocol deviation should be 
documented if measurability is mandated by the protocol. 
14.2.2.1.3 
Definition of lines of therapy 
A line of therapy is defined as one or more planned cycles of either single agent or combined 
therapy, as well as a sequence of treatments administered in a planned manner (e.g. a autologous 
stem cell transplant, followed by maintenance, is considered only one line of therapy).  
A line of therapy ends at the planned treatment completion, disease progression, relapse, 
discontinuation of treatment due to toxicity, start of an unplanned anti-MM therapy or death 
(Rajkumar et al 2011). 
14.2.2.1.4 
Baseline assessments 
The following baseline assessments are mandatory: 
• M-protein in serum and urine by PEP (Section 14.2.2.2.1) 
• M-protein in serum and urine by immunofixation (IF) (Section 14.2.2.2.1) 
• Serum FLC ratio (Section 14.2.2.2.2) 
• Plasma cell count in bone marrow (Section 14.2.2.2.3) 
• Clinical assessment for soft tissue plasmacytomas. In case of known or detectable soft 
tissue plasmacytoma at baseline, further confirmation and measurements are required at 
baseline by imaging techniques (CT/MRI) (Section 14.2.2.2.5) 
• Full body skeletal survey by X-ray: full body CT scan and full body MRI are also 
accepted if X-rays cannot be performed (Section 14.2.2.2.6) 
• Routine biochemistry including ionized calcium or total serum calcium and albumin 
(Section 14.2.2.2.7) 
For baseline assessments, no confirmation measurement is required. 
14.2.2.1.5 
Time frame of response assessments 
For the baseline assessment, the last available measurement for a variable prior to first intake 
of study treatment/randomization has to be used. Baseline assessments should be done prior to 
the first intake of study treatment/randomization and within a time window defined by the 
protocol. 
All measurements required for a response assessment post-baseline should be performed within 
a predefined time window. It is recommended to align this time window with the treatment 
cycle length for the treatment period. The time window(s) should be specified in the study 
protocol. 
In case there is more than one measurement of any variable in the predefined time window, the 
latest non-missing measurement of this variable will be used. Exception: In case of one 

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measurement qualifying for PD, this will be used for the response assessment irrespective of 
subsequent measurements of the same variable. 
14.2.2.1.6 
Response assessment by time point 
Response is to be assessed based on the response assessment criteria (Table 14-5) and on data 
collected for scheduled response assessment. Confirmation of response should be obtained in 
all instances by M-protein assessments (tests may include part or all of tests PEP/ sFLC 
depending on measurability and response level). For confirmation of response see 
Section 14.2.2.4.1 and Section 14.2.2.4.2. 
14.2.2.1.7 
Response assessment date 
The response assessment date is defined as the last of all dates of measurements which are 
required to qualify for a response category (excluding PD). In case of PD, the first of all 
measurement dates associated with a disease assessment will be used as assessment date. The 
assessment date will be used for the derivation of the time-to-event endpoints. 
14.2.2.1.8 
Mandatory assessments 
For every patient the following assessments have to be performed at every scheduled post 
baseline visits for response assessment: 
1. M-protein in serum and urine by PEP (Section 14.2.2.2.1) 
2. M-protein in serum and urine by IF (Section 14.2.2.2.1) 
3. Serum FLC assessment if patient has non-measurable disease in serum and urine M-
protein at baseline (Section 14.2.2.2.2) 
4. Soft tissue plasmacytomas (Section 14.2.2.2.5) 
5. Lytic bone lesion assessment if clinically indicated (Section 14.2.2.2.6) 
6. Serum calcium and albumin or ionized calcium (Section 14.2.2.2.7) 
7. Plasma cell count in bone marrow by aspirate or biopsy in patients who met all criteria for 
CR by serum and urine M-protein with no indication of disease progression by STP, lytic 
bone lesions and hypercalcemia or in case of non-measurable disease by M-protein in 
serum and urine by PEP and by FLC (Section 14.2.2.2.3)  
8. Residual disease by flow cytometry / immunohistochemistry in bone marrow plasma cells 
in case CR criteria are met (Section 14.2.2.2.4) 
14.2.2.1.9 
Nadir 
The nadir is defined as the lowest value of a variable including baseline measurements 
excluding the measurement of the respective visit. This rule implies that the time point of 
determination of the lowest value of a patient may be different for each variable. 
14.2.2.1.10 Use of a central laboratory 
Laboratory to laboratory variability could potentially be high. So, the use of a central laboratory 
is recommended for the assessments defined in Table 14-5. 

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Table 14-5 
Recommended use of a central or local laboratory 
Assessment 
Recommendation 
Serum and urine M protein by PEP 
Central laboratory 
FLC  
Central laboratory 
Bone marrow assessments plasma cell counts 
Local laboratory; keep archival slides for subsequent 
potential central review of BM pathology 
Bone marrow flow cytometry and 
immunohistochemistry 
Central laboratory 
Bone marrow for ASO-PCR or equivalent  
Central laboratory 
Serum calcium variables  
Local laboratory 
For pivotal efficacy studies phase II and III, central laboratories for measurement of M-protein 
by PEP are strongly recommended. If local laboratories are used for M protein measurement by 
PEP in such studies, this choice should be justified in the study protocol. Any use of a local 
laboratory should be addressed during the site selection process, and ability of the local 
laboratories to perform and report the protocol required measurements needs to be verified. 
Adequate measures for local laboratory selection and monitoring should be taken and 
specifically described in the study monitoring plan. The same laboratory should be used 
throughout the study. 
14.2.2.1.11 Staging of Multiple Myeloma 
Staging of MM should be done according the International Staging System (ISS, Greipp et al 
2005, Figure 14-1). To compare patient staging across studies, the Durie-Salmon staging system 
(Durie, Salmon 1975; Kyle et al 2009) can be used additionally (Table 14-6). 

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Figure 14-1 
International Staging System 
 
 
Table 14-6 
Durie-Salmon staging system 
Stage 
Criteria 
Stage I 
All of the following: 
Hemoglobin value >10 g/dL 
Serum calcium value normal or <10.5 mg/dL 
Bone x-ray, normal bone structure (scale 0), or solitary bone plasmacytoma only 
Low M-component production rates (IgG value <5 g/dL; IgA value <3 g/dL) 
Urine light chain M-component on electrophoresis <4 g/24h 
Stage II 
Fitting neither stage I nor stage III 
Stage III 
One or more of the following: 
Hemoglobin value <8.5 g/dL 
Serum calcium value >12 mg/dL 
Advanced lytic bone lesions (scale 3) 
High M-component production rates (IgG value >7 g/dL IgA value >5 g/dL) 
Bence Jones protein >12 g/24h 
Sub-
classification 
A: relatively normal renal function (serum creatinine value) <2.0 mg/dL 
B: abnormal renal function (serum creatinine value) >2.0 mg/dL 

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14.2.2.2 Tests required for response assessment 
14.2.2.2.1 
Assessment of M-protein in serum and urine 
The assessment of the M-protein levels in serum and urine is the basis for the response 
assessments for multiple myeloma. The following two methods are used to assess M-protein in 
serum as well as in urine 
1. Protein electrophoresis (PEP): Provides quantitative measurements. Techniques other than 
electrophoresis are not acceptable unless specifically mentioned in this document. 
2. Immunofixation (IF): Provides qualitative measurements (Present/absent). This is a more 
sensitive method than PEP and is used to confirm the absence of M-protein by PEP. 
For M-protein in urine by PEP, a 24h urine collection is required. 
The PEP has to be performed to assess serum and urine M-protein levels at baseline and post 
baseline. Even if the disease is non-measurable, both, serum and urine M-protein should be 
measured by PEP routinely at post. 
In case no M-protein is found by protein electrophoresis, this should be confirmed by 
serum/urine immunofixation. 
In case urine/serum M-protein was not assessed by PEP and the corresponding urine/serum 
immunofixation indicates absence of M-protein, it can be concluded that there is no M-protein 
identifiable by PEP in serum/urine. 
14.2.2.2.2 
Assessment of free light chain proteins (FLC) 
The free light chain (FLC) assessment was introduced by the IMWG using serum FLC assay 
(FREELITE, The Binding Site Ltd., Birmingham, UK), which is performed by 
immunonephelometry (Dispenzieri et al 2009). 
The serum FLC assay measures: 
1. Free kappa light chain (also known as kappa serum level) (reference interval, 0.33-1.94 
mg/dL) and 
2. Free lambda light chain (also known as lambda serum level) (reference interval, 0.57-2.63 
mg/dL) 
The FLC ratio is defined as the kappa serum level divided by the lambda serum level. 
Involved light chain is determined based on the following criteria (Snozek et al 2008): 
1. Lambda is the involved light chain if FLC ratio < 0.26 
2. Kappa is the involved light chain if FLC ratio of > 1.65 
The FLC ratio is considered to be 
• Normal if FLC ratio is within [0.26-1.65] 
• Abnormal if FLC ratio is <0.26 or >1.65 
The FLC serves as monitoring indicator of disease status when serum M-protein or urine M-
protein or both assessed by PEP is/are non-measurable and to identify sCR in case CR criteria 
are met (Table 14-7). 

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14.2.2.2.3 
Assessment of bone marrow for percentage of plasma cells 
Bone marrow should be assessed for percentage of plasma cells. Either bone marrow aspirate 
or biopsy can be used for this assessment. The same method (aspirate versus biopsy) should be 
used throughout the study, if possible. In case both aspirate and biopsy were done, the response 
criteria need to be satisfied by both assessments. In case both aspirate and biopsy are performed, 
the highest of both percent values should be used for the assessment. 
Bone marrow samples are usually drawn from either sternum or iliac crest. Percentage of 
plasma cells will be determined by using cytological/histological examination. 
In case of inadequate/uninterpretable bone marrow sample, the sampling must be repeated in a 
timely manner but no later than within the protocol-defined time window (Section 14.2.2.1.5). 
Bone marrow aspirate and/or biopsy should be performed for every patient at baseline. 
Bone marrow aspirate and biopsy are invasive procedures. Standard practice is to perform post-
baseline bone marrow assessment only when it is essential. Therefore, recommendation is for 
performing bone marrow assessments under the following conditions: 
1. to confirm complete response  
2. in case of non-measurable disease by M-protein in serum and urine as well as by FLC, 
bone marrow plasma cell count is used to assess response  
14.2.2.2.4 
Assessment of aberrant plasma cells 
The two most widely used methods for assessing residual neoplastic plasma cells (PCs) in the 
bone marrow are 1) flow cytometry and 2) immunohistochemistry. 
1) 
Flow cytometry 
IMWG criteria require assessment of clonal plasma cells for assessment of sCR, by standard 
flow cytometry (using 2 to 4 colors). If the protocol requires determining iCR, which is a more 
strict criterion, PCs should only be assessed by multiparametric flow cytometry (using  >4 
colors), counting a minimum of 1x106 PCs. 
If there are no bone marrow elements and no plasma cells in the sample, this will be considered 
not to be suitable for analysis and will need to be repeated. 
2) 
Immunohistochemistry 
Immunohistochemistry is used to differentiate normal from clonal PCs in the bone marrow for 
assessment of sCR. Presence/absence of clonal cells is based upon the kappa/lambda (k/l) ratio. 
An abnormal k/l ratio by immunohistochemistry requires a minimum of 100 plasma cells for 
analysis. An abnormal ratio reflecting presence of an abnormal clone is a k/l ratio of > 4:1 or < 
1:2 (Durie et al 2006). 
3) 
Molecular assessment 
Assessment of mCR in the bone marrow will be done by quantitative nested polymerase chain 
reaction (PCR) with a minimal sensitivity of 10-5 using patient-specific primers to identify 
rearrangements of immunoglobulin-heavy-chain sequences (ASO-primers), or equivalent 
methods. 

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IMWG refers to the ASO-PCR method only to identify mCR. However, the rapidly developing 
area of sequencing-based methods with high concordance to ASO-PCR justifies the use of 
equivalent methods, such as B-cell receptor (BCR) sequencing (Lopez et al 2014). However, 
the same method should be used and detailed in the study protocol. 
14.2.2.2.5 
Assessment of soft tissue plasmacytomas 
General definitions: 
• The size of the soft tissue plasmacytoma (STP) is defined as the sum of the products of the 
cross-diameters (SPD) of each STP using the longest perpendicular diameters. 
• A definite increase in the size is defined as a ≥ 50% increase (and at least 10mm2) of this 
sum from the nadir. 
Assessment of STPs: 
1. Each patient should be clinically assessed for STP(s) at each visit for response 
assessments. 
2. For STP(s) present at baseline (per clinical assessment): 
• imaging by CT or MRI must be performed at baseline (screening or C1D1) for 
suspected STP to confirm and to determine size and location of the soft tissue 
plasmacytoma. 
• size and location of the STP(s) will be monitored by imaging at regular intervals 
according to the requirements of the individual study protocol. 
3. In case of clinical suspicion of (re-)appearance of STP(s) post-baseline, imaging by CT or 
MRI must be performed as soon as possible to confirm and to determine size and location 
of the STP(s). 
4. Size and location of identified STP(s) should be captured on the CRF. 
a. The size should be captured in terms of longest perpendicular diameters 
b. If any of the perpendicular diameters cannot be reliably measured because of its small 
size, the minimum limit of detection as the diameter size (e.g. 7.5 mm for CT) should 
be entered. 
c. A value of 0 mm x 0 mm should be entered in case of disappearance of a STP 
The same imaging technique must be used throughout the course of the study to monitor an 
existing soft tissue plasmacytoma. 
CT and MRI should be performed with slice thickness ≤ 7.5 mm. 
If soft tissue plasmacytomas become confluent over time, then these should be measured as one 
soft tissue plasmacytoma. The overall diameters should be recorded for one of the soft tissue 
plasmacytomas, and 0 mm x 0 mm should be recorded for the rest of the soft tissue 
plasmacytomas. 
If a soft tissue plasmacytoma splits during the study, each part of the soft tissue plasmacytoma 
should be measured separately for all subsequent assessments and all parts of the soft tissue 
plasmacytoma should contribute to the SPD. 

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14.2.2.2.6 
Assessment of lytic bone lesions 
Full body skeletal survey using conventional X-rays (preferred method) or CT or MRI should 
be performed on every patient prior to study treatment start/randomization. Based on the 
currently available evidence, PET is not recommended to be used for the assessment of lytic 
bone lesions (Dimopoulos et al 2009, Rajkumar et al 2014). 
Interpretation of full body skeletal survey (in terms of presence or absence of lytic bone lesion, 
number and location of lesions) will be captured on the CRF. 
Targeted post baseline assessments using bone X-ray/CT/MRI on location(s) should be 
performed if there is any medical indication (e.g. bone pain) as determined by the investigator. 
The following information will be captured on the CRF: absence/ presence, lesion location, 
unchanged, new lesion(s) or increase in size of existing lesion(s). 
The same imaging technique at baseline and post-baseline should be used for comparison of 
lytic bone lesion assessments. In case of newly symptomatic areas with no finding by X-ray a 
targeted MRI or CT assessment(s) should be performed. 
14.2.2.2.7 
Assessment of hypercalcemia 
For each response classification, the assessment of hypercalcemia by determination of corrected 
or ionized serum calcium is required. 
In case total serum calcium is measured, the value needs to be corrected for serum albumin 
according to the following formula (Ladenson et al 1978): 
Corrected serum calcium [mg/dL] = measured total serum calcium [mg/dL] + (3.5 - serum 
albumin [g/dL]) x 0.8. 
It is not acceptable to use uncorrected total calcium to assess hypercalcemia. 
Corrected serum calcium values > 11.5 mg/dL indicate hypercalcemia. 
In case ionized serum calcium is measured, no correction for serum albumin is required and 
values > 6.0 mg/dL indicate hypercalcemia. 
In case corrected serum calcium and ionized calcium are measured at the same visit, the ionized 
calcium value will be used for response assessment. It is recommended to use the same method 
throughout the study. 
14.2.2.3 Capturing response classification 
Response classification can be obtained/determined from different sources: 
1. Investigator assessment 
2. Assessment by independent review committee (IRC) 
3. Response derived from data collected in the CRF 
The source of response classification to be used in the protocol, defined efficacy analyses 
associated with protocol objectives needs to be pre-specified in the protocol (investigator, IRC, 
derived response). 

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For assessment of disease progression it is recommended to collect the variable(s) on which 
progression is documented on the CRF (investigator and IRC, if applicable). 
It is recommended to use IRC assessments for registration studies with an efficacy endpoint. 
14.2.2.4 Response assessment per IMWG criteria 
Response assessment according to IMWG criteria is described in Table 14-7 and Table 14-8. 
For assessing response, criteria for PD should be assessed first. When PD can be ruled out, 
criteria for positive response should be checked. 
For patients with non-measurable disease at baseline or missing baseline assessments of M- 
protein in urine and serum and FLC, only PD criteria will be checked. In case PD is not met, 
“unknown” should be assigned. 
The response categories sCR, CR, VGPR, PR and PD need to be confirmed. The criteria are 
defined in Section 14.2.2.4.1 and Section 14.2.2.4.2. 
For patients with measurable disease at baseline by one component only (serum M-protein or 
urine M-protein), the measurable component will be used to derive MR or PR. However, VGPR 
and CR categories require serum and urine studies regardless of whether disease at baseline was 
measurable on serum, urine, both, or neither. Irrespective of the measurability (M-protein 
measurable by PEP in serum, urine, or both), M-protein should be investigated regularly in both 
serum and urine and needs to be considered for response assessment. 
Assessments to determine PD are dependent on change from nadir. 
Table 14-7 
Response classification in MM according to IMWG criteria 
Response category 
Definition* 
Stringent complete 
response (sCR) 
● CR criteria as defined below AND 
● normal FLC ratio AND 
● Absence of clonal PCs in bone marrow analyzed by immunohistochemistry or 2- 
to 4-color flow cytometry#. 
Complete response 
(CR) 
● Negative immunofixation of serum and urine AND 
● In case of presence of soft tissue plasmacytoma(s) at baseline, disappearance of 
any soft tissue plasmacytoma(s), AND 
● < 5% plasma cells in bone marrow. 
● In case the only measurable disease at baseline is the serum FLC assessment, a 
normal FLC ratio of 0.26 to 1.65 is required additionally to qualify for CR. 
Very good partial 
response (VGPR) 
● Serum and/or urine M-protein detectable by immunofixation but not on PEP OR 
((≥ 90% reduction from baseline in serum) AND (urine M-protein < 100 mg/24h)) 
AND 
● In case of presence of soft tissue plasmacytoma(s) at baseline, a reduction in the 
SDP by ≥ 50% from baseline (see Section 14.2.2.2.5) is required 
In case the only measurable disease in a patient at baseline is the serum FLC level 
(i.e. no measurable disease in serum and urine PEP), a decrease of > 90% in the 
difference between involved and uninvolved FLC levels from baseline is required. 

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Response category 
Definition* 
Partial response (PR) 
● (≥ 50% reduction from baseline in serum M-protein) AND 
(≥ 90% reduction from baseline in 24h urine M-protein OR urine M-protein < 
200 mg/24h) 
 
If the serum and urine M-protein are not measurable at baseline a ≥ 50% reduction 
from baseline 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 not measurable, and serum FLC assay is also not 
measurable, ≥ 50% reduction from baseline in percent plasma cells in bone marrow 
is required instead of M-protein measurement, provided baseline percentage in 
plasma cells in bone marrow was ≥ 30%. 
AND 
● In case of presence of soft tissue plasmacytoma(s) at baseline, a reduction in the 
SPD by ≥ 50% from baseline (see Section 14.2.2.2.5) is required. 
Stable disease (SD) 
Not meeting the criteria for mCR, sCR, CR, VGPR, PR, PD 
Progressive disease 
(PD)& 
● Increase of at least 25% from the nadir in at least one of the following criteria: 
 
● serum M-protein (absolute increase must be ≥ 0.5 g/dL) 
 
● urine M-protein (absolute increase must be ≥ 200 mg/24h) 
 
● only in patients with non-measurable serum and urine M-protein levels: 
difference in involved and uninvolved FLC levels (absolute increase must be > 10 
mg/dL) 
 
● Only in patients with non-measurable disease in serum and urine M protein 
and by FLC: Bone marrow plasma cell percentage (absolute % must be ≥ 10%) 
OR 
● definite development of new lytic bone lesions or definite increase from baseline 
in size of lytic bone lesion(s) 
OR 
● definite development of new soft tissue plasmacytoma(s) or definite increase from 
nadir in existing soft tissue plasmacytomas 
OR 
● development of hypercalcemia (corrected serum calcium > 11.5 mg/dL or ionized 
calcium > 6 mg/dL) for patients without hypercalcemia at baseline. In case of 
preexisting hypercalcemia at baseline, PD will be assessed in case the corrected 
serum calcium level was ≤ 11.5 mg/dL (ionized serum calcium ≤ 6 mg/dL) at an 
earlier assessment (including baseline/post-baseline) and increased beyond 11.5 
mg/dL (> 6 mg/dL). 
“25% increase” refers to M-protein, FLC, and bone marrow results, and does not 
refer to bone lesions, soft tissue plasmacytomas, or hypercalcemia and the “lowest 
response value” does not need to be a confirmed value. 
* If not defined otherwise, all of the criteria apply. 
# Presence/absence of clonal cells is based upon the k/l ratio. An abnormal k/l ratio by immunohistochemistry 
and/or immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting 
presence of an abnormal clone is a k/l ratio of > 4:1 or < 1:2 
& Biological relapse or significant paraprotein release (Section 14.2.3.2.7) does not constitute PD unless ≥ 1 
criterion for PD is met 
In case response assessment is incomplete, e.g. one or more mandatory assessments are missing, 
at a time point then the category “unknown” will be assigned to the response assessment of that 
time point unless a criterion for PD is met. 
In addition to the criteria above, further response categories are endorsed by the IMWG as 
defined in Table 14-8. 

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Table 14-8 
Additional response categories in MM according to IMWG criteria 
Response category 
Definition* 
Molecular complete 
response (mCR) 
● All criteria of a CR 
AND 
● negative by ASO-PCR (minimal sensitivity 10-5) or equivalent methods such 
as BCR sequencing 
Immunophenotypic CR 
(iCR) 
● All criteria of sCR 
AND 
● Absence of phenotypically aberrant PCs (clonal) in BM with a minimum of 1 
million total BM cells analyzed by multiparametric flow cytometry (>4 colors) 
Minimal response (MR) 
● (Reduction from baseline in serum M-protein by ≥25%) and 
(reduction from baseline in 24h urine M-protein by ≥50%) 
AND 
● In case of soft tissue plasmacytomas at baseline, a reduction in the size of 
≥25% is required 
AND 
● No increase in size or number of lytic bone lesions (development of 
compression fracture does not exclude response) 
Minimal response should only be assessed in patients with relapsed or 
refractory myeloma. 
For VGPR, PR and MR: In case disease is measurable in serum or urine only, criteria for serum 
and urine M-protein are to be checked for the measurable samples only (i.e. serum or urine). 
14.2.2.4.1 
Confirmation of response 
According to IMWG criteria, confirmation of response is required for all response categories 
other than SD. The intention of this confirmation is to rule out laboratory or other errors 
(Durie et al 2006). For response confirmation, a consecutive assessment at any time is 
sufficient; no time window is specified by IMWG. Therefore, confirmation assessment can be 
performed on the same day of the initial assessment. It is recommended to do the confirmation 
assessment as soon as possible. This confirmation should be obtained in all instances by M-
protein assessments (tests may include part or all of tests PEP/sFLC depending on measurability 
and response level). Details need to be specified in the study protocol. 
Response assessments should be captured in the CRF per time point without considering 
confirmation. This applies to response assessments by investigator as well as by IRC. 
For confirmation of response, the following rules apply which will be implemented for 
statistical analyses: 
• It is not required to repeat assessments on bone marrow. However, at least one bone 
marrow assessment is required to qualify for CR or better (sCR, iCR or mCR).  
• In case imaging studies were done, it is necessary that they exclude evidence of PD with 
regard to new lytic bone lesions for mCR, iCR, sCR, CR, VGPR, PR, MR and SD. 
Imaging is indicated in case of clinical suspicion of new or worsened lytic bone lesions 
e.g. bone pain. 
• In case the confirmation assessment revealed a better category compared to the previous 
assessment (e.g. VGPR after PR), the response category of the previous assessment will 
be considered as confirmed (PR). 

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• In case the confirmation assessment revealed a worse category compared to the previous 
assessment (e.g. VGPR after CR), the response category of the subsequent assessment will 
be considered as confirmed (VGPR). 
• In case of repeated measurements of a variable at a given response assessment resulting in 
more values than required for an assessment and confirmation, the worst assessment has to 
be considered for response assessment by applying the rules given above. 
14.2.2.4.2 
Confirmation of PD 
Declaration of PD requires confirmation in case the PD was determined based on M-protein 
measurement. There is no minimum time interval but confirmation of increase in M-protein or 
FLC should be done as soon as possible. 
PD has to be assessed and entered in the CRF per time point without considering confirmation. 
Confirmed PD will be determined by statistical analyses. 
This applies to PD assessments by investigator as well as by IRC. 
14.2.3 
Derivation rules 
14.2.3.1 Best overall response and overall response 
Best overall response is the best post baseline confirmed overall response observed in a given 
patient, among the confirmed response categories, excluding “unknown” and “not assessed”. 
Best overall response is determined based on overall responses observed at all post-baseline 
response assessments, recorded from the start of the study treatment/randomization until PD, 
death, start of new therapy, withdrawal of consent or end of study, whichever comes first. 
If the first complete post-baseline response assessment indicates, for example, PR or better 
(VGPR, CR, sCR or mCR) and no confirmation response assessment available then SD will be 
considered as best overall response. 
Best overall response will be assigned according to the following ascending order (Table 14-9). 
Table 14-9 
Best overall response 
Rank 
Best overall response category 
1 
Molecular complete response (mCR) 
2 
Immunophenotypic complete response (iCR) 
3 
Stringent complete response (sCR) 
4 
Complete response (CR) 
5 
Very good partial response (VGPR) 
6 
Partial response (PR) 
7 
Minimal response (MR) 
8 
Stable disease (SD) 
9 
Unknown 
10 
Progressive disease (PD) 
In case no post-baseline assessment is available or assessments with only unknown response 
status are available, the category “unknown” will be assigned as best overall response. 

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Based on the patients’ best overall response during the study, the following rate is calculated: 
Overall response rate (ORR) is the proportion of patients with best overall response of PR or 
better. For the calculation of the ORR, the denominator should include all patients in the 
targeted patient population. Additional analysis sets can be defined in the study protocol. 
MR can be an indicator of drug activity in certain patient populations, and in particular for 
patients with relapsed, as well as, relapsed and refractory MM. In case MR is used, the rate of 
patients with MR should be reported separately from the ORR (Rajkumar et al 2011). 
The clinical benefit rate (CBR) is defined as the proportion of patients with best overall response 
of MR, PR, VGPR, CR, sCR, iCR or mCR (Anderson et al 2008). 
14.2.3.2 Calculation of time-to-event variables 
General rule for the calculation of the time to event interval is: 
Time to event = end date - start date + 1 (in days) 
When no post-baseline response assessment is available, the date of randomization/ start of 
study treatment will be used as end date (duration = 1 day), i.e. time to event variables will 
never be negative. 
14.2.3.2.1 
Adequate response assessment 
Often censoring time is determined based on date of adequate response assessment. Any 
response assessment is considered to be adequate if the assessment was performed and the 
outcome of the assessment was other than “unknown” or PD. 
14.2.3.2.2 
Overall survival 
Overall survival (OS) is defined as the time from date of randomization/start of study treatment 
to the date of death due to any cause. 
If a patient is alive or his/her survival status is unknown, OS will be censored at the date of last 
contact. 
14.2.3.2.3 
Progression-free survival 
Progression-free survival (PFS) is defined as time from date of randomization/start of study 
treatment to date of (1) death due to any cause or (2) PD. 
If a patient has not had an event, PFS is censored at the last adequate response assessment date. 
14.2.3.2.4 
Time to progression 
Time to progression (TTP) is defined as time from date of randomization/start of study 
treatment to date of (1) death due to multiple myeloma or (2) PD. 
If a patient has not had an event, TTP is censored at the last adequate response assessment date. 

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14.2.3.2.5 
Duration of response 
Duration of response (DOR) is defined as the duration from the first documented onset of PR 
or better response to the date of PD or death due to multiple myeloma. 
In case a patient does not have PD or death due to multiple myeloma, DOR will be censored at 
the date of the last adequate assessment. 
In general patients without PR or better response are excluded from this analysis. However, 
there are several ways to address this issue. Clear instruction on this should be included in 
protocol. 
14.2.3.2.6 
Time to response 
Time to response (TTR) is defined as the time between date of randomization/start of study 
treatment to the date of first onset of PR or better response. 
Patients without experiencing any PR or better response will be censored according to the 
following events: 
• Patients experiencing a PD will be censored at maximum follow-up (i.e. FPFV to LPLV 
used for the analysis) for patients (i.e. either progressed or died due to any cause). 
• Patients not experiencing PD will be censored at their last adequate response assessment 
date which is different from “unknown” or “not done”. 
Table 14-10 
Censoring rules for time to response 
Situation 
Start-date 
End-date 
Outcome 
A 
PR or better 
Date of randomization/ 
start of study treatment 
Date of first onset of confirmed PR or 
better (before cut-off date and before 
start of new anti-neoplastic therapy) 
Event 
B 
PD/Death 
Date of randomization/ 
start of study treatment 
Date of maximum follow-up of all 
patients in study 
Censor 
C 
No PR or better 
and no PD/death 
Date of randomization/ 
start of study treatment 
Date of last adequate response 
assessment before cut-off date and 
before start of new anti-neoplastic 
therapy 
Censor 
14.2.3.2.7 
Time to next treatment 
Time to next treatment (TNT) is defined as the time from the date of randomization/start of 
study treatment to the date of next treatment for multiple myeloma or death due to any cause. 
The need to start the next treatment should be defined clearly in the protocol. According to the 
IMWG criteria, this should be in case of either clinical relapse or significant paraprotein relapse. 
Start of new treatment without meeting the relapse criteria is also considered as a relapse. 
In case a patient does not experience a relapse event and does not start new anti-neoplastic 
therapy, time to next treatment will be censored at the last adequate response assessment.  
Clinical relapse is defined as one or more of the following indicators that are related to the 
underlying MM: 
• Development of new soft tissue plasmacytomas or lytic bone lesions on skeletal survey, 
MRI, or other imaging. 

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• Definite increase in size of existing plasmacytomas or lytic bone lesions.  
• Hypercalcemia (ionized serum calcium > 6 mg/dL and if missing corrected serum 
calcium >11.5 mg/dL) 
• Decrease in hemoglobin of ≥ 2 g/dL (1.25 mmol/L) or to less than 10 g/dL (6.2 mmol/L) 
• Rise in serum creatinine by ≥ 2 mg/dL from nadir 
• Hyperviscosity (as reported as Adverse Event) 
A significant paraprotein relapse is defined as one or more of the following indicators: 
• Doubling of the M-component in two consecutive measurements separated by ≤ 2 months. 
• Increase in the absolute level of serum M protein by ≥ 1 g/dL in two consecutive 
measurements separated by ≤ 2 months 
• Increase in the absolute level of urine M protein by ≥ 500 mg/24h in two consecutive 
measurements separated by ≤ 2 months 
• Increase in involved FLC level by ≥ 20 mg/dL (plus an abnormal FLC ratio) in two 
consecutive measurements separated by ≤ 2 months. 
As it is difficult to compare across studies, TNT is preferably to be used in randomized studies. 
14.2.3.3 Event and censoring date, sensitivity analysis 
This section outlines the possible event and censoring dates for PD (Table 14-11), as well as 
addressing the issues of missing response assessments during the study. It is important that the 
protocol and analysis plan specify the primary analysis in detail with respect to the definition 
of event and censoring dates and also include a description of one or more sensitivity analyses 
to be performed. Using the draft FDA guideline on endpoints (Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics, April 2005) as a reference, the following analyses 
can be considered: 

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Table 14-11 
Options for event dates used in PFS and TTP 
Situation 
Options for end-date1 
(1) = default unless specified differently in 
the protocol or analysis plan 
Outcome 
A 
No baseline assessment 
(1) Date of randomization/start of treatment 
Censor 
B 
PD at scheduled assessment date or 
before next scheduled assessment 
(1) Date of PD 
(2) Date of next scheduled assessment 
Event 
Event 
C1 
PD or death after exactly one missing 
assessment 
(1) Date of PD (or death) 
(2) Date of next scheduled assessment1 
Event 
Event 
C2 
PD or death after two or more missing 
assessments 
(1) Date of last adequate assessment1 
(2) Date of next scheduled assessment1 
(3) Date of PD/ (or death) 
Censor 
Event 
Event 
D 
No PD and no death 
(1) Date of last adequate assessment 
Censor 
E 
Treatment discontinuation due to 
‘Disease PD’ without documented PD, 
i.e. clinical PD based on investigator 
claim 
(1) N/A 
(2) Date of discontinuation (visit date at which 
clinical PD was determined) 
Ignored 
Event 
F 
New anticancer therapy given 
(1) Date of last adequate assessment prior to 
start of new anti-cancer therapy 
(2) Date of new anti-cancer therapy 
(3) Date of new anti-cancer therapy 
(4) N/A 
Censor 
 
Censor 
Event 
Not 
considered 
as event 
G 
Deaths due to reason other than 
multiple myeloma 
(1) Date of last adequate assessment 
Censor 
(only TTP 
and TNT) 
1 PFS: death due to any reason; TTP: death due to MM 
In case a patient does not have an adequate assessment, the date of randomization/start of study 
treatment is used as end date. 
Situations C (C1 and C2): PD or death after one or more missing assessments: The primary 
analysis is usually using options (1) for situations C1 and C2, i.e. 
- (C1) taking the actual PD or death date, in the case of only one missing assessment. 
- (C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments. 
In the case of two or more missing assessments (situation C2), option (3) may be considered 
jointly with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2. 
Situation E: Treatment discontinuation due to ‘PD’ without documented PD: By default, 
option (1) is used for situation E as patients without documented PD should be followed for PD 
after discontinuation of treatment. However, option (2) may be used as sensitivity analysis. If 
PD is claimed based on clinical deterioration instead of response assessment by e.g. sPEP, 
option (2) may be used for indications with high early PD rate or difficulties to assess response 
due to clinical deterioration. 

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Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1), i.e. censoring at last adequate assessment may be 
used as a default in this case. 
Additional suggestions for sensitivity analyses 
Other suggestions for additional sensitivity analyses may include analyses to check for potential 
bias in follow-up schedules for response assessments, e.g.: 
• By assigning the dates for censoring and events only at scheduled visit dates. The latter 
could be handled by replacing in Table 14-11 the “Date of last adequate assessment” by 
the “Date of previous scheduled assessment (from baseline)”, with the following 
definition: Date of previous scheduled assessment (from baseline) is the date when a 
response assessment would have taken place, if the protocol assessment scheme was 
strictly followed from baseline, immediately before or on the date of the last adequate 
assessment. 
• By considering any appearance or recurrence of clinical indicators not part of the criteria 
list but mentioned in the IMWG criteria, in particular “bone pain”. 
The need for these types of sensitivity analyses will depend on the individual requirements for 
the specific study and disease area and have to be specified in the Study Protocol or RAP 
documentation. 
14.2.4 
Medical review of response assessment 
In case the investigator assesses response in the CRF, this assessment needs to be checked in 
terms of calculated response according to the rules provided in this document. Discrepancies 
between investigator’s assessment and calculated response will be clarified via a query. 
For any discontinuation due to disease progression, the respective patients’ response needs to 
qualify the criteria for this category as defined in this document. 
In case IRC data are checked, the detailed process needs to be planned in advance to avoid a 
time lag between the independent review and the check. 

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14.2.5 
References (available upon request) 
Anderson KC, Kyle RA, Rajkumar SV, et al. (2008). Clinically relevant end points and new 
drug approvals for myeloma. Leukemia 22:231-239. 
Dimopoulos M, Terpos E, Comenzo RL, et al. (2009). International myeloma working group 
consensus statement and guidelines regarding the current role of imaging techniques in the 
diagnosis and monitoring of multiple Myeloma. Leukemia online publication: 1-12. 
Dimopoulos MA, Moreau P, Palumbo A, et al (2015) Carfilzomib and dexamethasone vs 
bortezomib and dexamethasone in patients with relapsed multiple myeloma: Results from the 
phase III study ENDEAVOR. J Clin Oncol 33, 2015 (suppl; abstr 8509). 
Dispenzieri A, Kyle R, Merlini G (2009). International myeloma working group guidelines 
for serum-free light chain analysis in multiple myeloma and related disorders. Leukemia 23: 
215-224. 
Durie BGM, Harousseau J-L, Miguel JS, et al. (2006). International uniform response criteria 
for multiple myeloma. Leukemia 20:1467-1473. 
Durie BGM, Harousseau J-L, Miguel JS, et al. (2007). Corrigenda/Erratum: International 
uniform response criteria for multiple myeloma. Leukemia 21:1134-1135. 
EMA (2012) Answers from the CHMP Scientific Advisory Group (SAG) for Oncology for 
Revision of the anticancer guideline. 
FDA Guideline: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, 
April 2005. 
Greipp PR, San Miguel J, Durie BGM et al (2005) International staging system for multiple 
myeloma. J Clin Onc 23(15):3412-3420. 
Kyle RA, Rajkumar SV (2009). Criteria for diagnosis, staging, risk stratification and response 
assessment of multiple myeloma. Leukemia 23:3-9. 
Ladenson JH, Lewis JW, McDonald JM, et al. (1978). Relationship of free and total calcium 
in hypercalcemic conditions. J Clin Endocrinol Metab 48:393-397. 
Martinez-Lopez J, Lahuerta JJ, et al. (2014). Prognostic value of deep sequencing method for 
minimal residual disease detection in multiple myeloma. Blood 123: 3073-3079. 
Rajkumar SC, Dimopoulos MA, Palumbo A (2014). International Myeloma Working Group 
updated criteria for the diagnosis of multiple myeloma. Lancet Onc 15:e538-548. 
Rajkumar SC, Harousseau JL, Durie B, et al. (2011). Consensus recommendations for the 
uniform reporting of clinical trials: Report of the International Myeloma Workshop 
Consensus Panel I. Blood 117(18):4691-4695. 
Rajkumar SC, Dimopoulos MA, Palumbo A (2014) International Myeloma Working Group 
updated criteria for the diagnosis of multiple myeloma. Lancet Onc 15:e538-548. 
Snozek CLH, Katzmann JA, Kyle RA, et al. (2008). Prognostic value of the serum free light 
chain ratio in newly diagnosed myeloma: proposed incorporation into the international staging 
system. Leukemia 22:1933-1937. 

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14.3 
Appendix 3: ECOG performance status scale 
This scale is used by doctors and researchers to assess how a patient's disease is progressing, 
assess how the disease affects the daily living abilities of the patient, and determine appropriate 
treatment and prognosis. 
Table 14-12 
ECOG performance status scale 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, 
P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin 
Oncol 5:649-655, 1982. 
Credit to: the Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair. 

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14.4 
Appendix 4: New York Heart Association (NYHA) functional 
classification 
The NYHA function classification provides a simple way classifying the extent of heart failure. 
Table 14-13 
NYHA functional classification 
NYHA 
Class 
Symptoms 
I 
Cardiac disease, but no symptoms and no limitation in ordinary physical activity, e.g. no 
shortness of breath when walking, climbing stairs etc. 
II 
Mild symptoms (mild shortness of breath and/or angina) and slight limitation during ordinary 
activity. 
III 
Marked limitation in activity due to symptoms, even during less-than-ordinary activity, e.g. 
walking short distances (20–100 m). 
Comfortable only at rest. 
IV 
Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients. 
As published in: The Criteria Committee of the New York Heart Association. (1994). Nomenclature and 
Criteria for Diagnosis of Diseases of the Heart and Great Vessels. (9th ed.). Boston: Little, Brown & 
Co. pp. 253–256. 

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14.5 
Appendix 5: The Bristol Stool Form Scale  
The Bristol Stool Form Scale provides a simple method of monitoring intestinal function and 
will be used in the electronic diary for diarrhea management. 
Figure 14-2 
The Bristol Stool Form Scale 
 
Lewis SJ, Heaton KW. Stool form as a useful guide to intestinal transit time. Scand J 
Gastroenterol 1997;32:920-924.