Clinical trial NCT02290431
Conditions: Relapse/Refractory Multiple Myeloma
Keywords: LBH589 panobinostat bortezomib dexamethasone Phase II bortezomib and dexamethasone Japanese patients relapsed/refractory multiple myeloma Panobinostat (PAN)
Sponsor: Novartis Pharmaceuticals
Start date: 2014-12-16; Completion date: 2018-12-25
Enrollment: 31 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study was to evaluate the efficacy and safety of panobinostat in combination with bortezomib and dexamethasone in Japanese patients with relapsed/refractory multiple myeloma.

Detailed description:

Arms: arm 1: Participants were administered LBH589 (panobinostat)in combination with bortezomib and dexamethasone 2 weeks on/1 week off.
Interventions: intervention 1: LBH589 (panobinostat) intervention 2: bortezomib intervention 3: dexamethasone
Intervention descriptions: intervention 1: Panobinostat (PAN) capsules were supplied at dose strengths of 10 mg and 15 mg. and dosed at 20mg during treatment phase 1 (21 days) and treatment phase 2 (42 days) intervention 2: Bortezomib (BTZ) s.c: 1.3 mg/m2 was administered during both treatment phase 1 (21 days) \& treatment phase 2 (42 days). intervention 3: Dexamethasone (Dex): 20mg tablets taken during both treatment phase 1 (21 days \& treatment phase 2 (42 days)

Protocol documents:
Prot_001.pdf: 
Clinical Development
Panobinostat (LBH589)
Clinical Trial Protocol CLBH589D1201 / NCT02290431
A phase II, multi-center, single arm, open label study to 
evaluate the efficacy and safety of panobinostat in 
combination with bortezomib and dexamethasone in 
Japanese patients with relapsed/refractory multiple 
myeloma
Document type
Amended Protocol Version
EUDRACT number
Not applicable
Version number
03 (Clean)
Development phase
II
Document status
Final
Release date
27-Feb-2018
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Table of contents
Table of contents .................................................................................................................2
List of appendices................................................................................................................6
List of figures ......................................................................................................................6
List of tables ........................................................................................................................7
List of abbreviations............................................................................................................9
Glossary of terms...............................................................................................................11
Amendment 3 (27-Feb-2018)............................................................................................12
Protocol summary:.............................................................................................................18
1
Background........................................................................................................................23
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............23
1.2
Introduction to investigational treatment(s) and other study treatment.................24
1.2.1
Overview of panobinostat (LBH589)....................................................24
2
Rationale............................................................................................................................33
2.1
Study rationale and purpose...................................................................................33
2.2
Rationale for the study design ...............................................................................34
2.3
Rationale for dose and regimen selection..............................................................35
2.4
Rationale for choice of combination drugs............................................................35
2.5
Rationale for choice of comparators drugs............................................................35
3
Objectives and endpoints...................................................................................................35
4
Study design ......................................................................................................................38
4.1
Description of study design ...................................................................................38
4.1.1
Screening period....................................................................................38
4.1.2
Treatment period...................................................................................38
4.1.3
Follow-up period...................................................................................39
4.2
Timing of interim analyses and design adaptations...............................................39
4.3
Definition of end of the study................................................................................39
4.4
Early study termination..........................................................................................39
5
Population..........................................................................................................................39
5.1
Patient population..................................................................................................39
5.2
Inclusion criteria ....................................................................................................40
5.3
Exclusion criteria...................................................................................................41
6
Treatment...........................................................................................................................44
6.1
Study treatment......................................................................................................44
6.1.1
Dosing regimen.....................................................................................44
6.1.2
Ancillary treatments..............................................................................46
6.1.3
Rescue medication ................................................................................46


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6.1.4
Guidelines for continuation of treatment ..............................................46
6.1.5
Treatment duration................................................................................46
6.2
Dose escalation guidelines.....................................................................................46
6.2.1
Study drug compliance and accountability ...........................................46
6.2.2
Disposal and destruction .......................................................................47
6.3
Dose modifications................................................................................................47
6.3.1
Dose modification and dose delay ........................................................47
6.3.2
Panobinostat - dosing modifications and delay.....................................47
6.3.3
Combination Therapy - dosing modifications and delay......................53
6.3.4
Follow-up for toxicities.........................................................................56
6.4
Concomitant medications ......................................................................................57
6.4.1
Permitted concomitant therapy .............................................................57
6.4.2
Permitted concomitant therapy requiring caution and/or action...........57
6.4.3
Prohibited concomitant therapy ............................................................59
6.5
Patient numbering..................................................................................................59
6.6
Study drug preparation and dispensation...............................................................59
6.6.1
Study drug panobinostat........................................................................59
6.6.2
Bortezomib s.c.......................................................................................60
6.6.3
Dexamethasone oral..............................................................................60
7
Visit schedule and assessments .........................................................................................60
7.1
Study flow and visit schedule................................................................................60
7.1.1
Screening...............................................................................................65
7.1.2
Treatment period...................................................................................66
7.1.3
Discontinuation of study treatment .......................................................66
7.1.4
Withdrawal of Consent .........................................................................67
7.1.5
Follow up period ...................................................................................68
7.2
Assessment types...................................................................................................69
7.2.1
Efficacy assessments.............................................................................69
7.2.2
Safety assessments ................................................................................70
7.2.3
Tolerability............................................................................................73
7.2.4
Resource utilization...............................................................................73
7.2.5
Patient reported outcomes.....................................................................73
7.2.6
Pharmacokinetics ..................................................................................73
7.2.7
PK sample labelling ..............................................................................75
7.2.8
Analytical method.................................................................................75
7.2.9
PK analysis............................................................................................76
8
Safety monitoring and reporting........................................................................................76


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8.1
Adverse events (AEs) ............................................................................................76
8.1.1
Definitions and reporting ......................................................................76
8.1.2
Laboratory test abnormalities................................................................78
8.2
Serious adverse events...........................................................................................78
8.2.1
Definitions.............................................................................................78
8.2.2
Reporting...............................................................................................79
8.3
Pregnancies............................................................................................................79
8.4
Warnings and precautions......................................................................................80
8.5
Data Monitoring Committee..................................................................................80
8.6
Steering Committee ...............................................................................................80
9
Data collection and management.......................................................................................80
9.1
Data confidentiality ...............................................................................................80
9.2
Site monitoring ......................................................................................................81
9.3
Data collection.......................................................................................................81
9.4
Database management and quality control............................................................81
10 Statistical methods and data analysis ................................................................................82
10.1
Analysis sets ..........................................................................................................82
10.1.1
Full Analysis Set ...................................................................................82
10.1.2
Safety Set ..............................................................................................82
10.1.3
Pharmacokinetic analysis set.................................................................82
10.2
Patient demographics/other baseline characteristics .............................................82
10.3
Treatments (study treatment, concomitant therapies, compliance) .......................83
10.4
Primary objective...................................................................................................83
10.4.1
Variable.................................................................................................83
10.4.2
Statistical hypothesis, model, and method of analysis..........................83
10.4.3
Handling of missing values/censoring/discontinuations.......................83
10.5
Secondary objectives .............................................................................................83
10.5.1
Key secondary objective(s)...................................................................84
10.5.2
Other secondary efficacy objectives .....................................................84
10.5.3
Safety objectives ...................................................................................85
10.5.4
Pharmacokinetics ..................................................................................86
10.5.5
Biomarkers............................................................................................86
10.5.6
Patient-reported outcomes.....................................................................86
86
10.7
Interim analysis......................................................................................................86
10.8
Sample size calculation..........................................................................................86
11 Ethical considerations and administrative procedures ......................................................87


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11.1
Regulatory and ethical compliance........................................................................87
11.2
Responsibilities of the investigator and IRB/IEC/REB.........................................87
11.3
Informed consent procedures.................................................................................87
11.4
Discontinuation of the study..................................................................................88
11.5
Publication of study protocol and results...............................................................88
11.6
Study documentation, record keeping and retention of documents.......................88
11.7
Confidentiality of study documents and patient records .......................................89
11.8
Audits and inspections...........................................................................................89
11.9
Financial disclosures..............................................................................................89
12 Protocol adherence ............................................................................................................89
12.1
Amendments to the protocol..................................................................................89
13 References (available upon request)..................................................................................90
14 Appendices ........................................................................................................................95
14.1
Appendix 1: Co-medications which prohibited for use, are known to prolong 
the QT interval and/or induce Torsades de Pointes, are strong CYP3A4/5 
inhibitors, are CYP2D6 substrates, or are moderate CYP3A4 inducers ...............95
14.1.1
Medication prohibited during the treatment period ..............................95
14.1.2
Medications which are known to prolong the QT interval and/or 
induce Torsades de pointes ventricular arrhythmia should be 
avoided..................................................................................................95
14.1.3
Medications which are known strong CYP3A4/5 inhibitors to be 
used with caution...................................................................................97
14.1.4
Medications which are known CYP2D6 substrates to be used with 
caution...................................................................................................98
14.1.5
Medications which are known to be moderate inducers of CYP3A4 
are to be used with caution....................................................................99
100
101
14.4
Appendix 4: Protocol Post-text Supplement - Guidelines for response 
assessment in Multiple Myeloma ........................................................................102
14.4.1
Introduction and scope ........................................................................105
14.4.2
Efficacy Assessments..........................................................................106
14.4.3
Capturing response classification........................................................118
14.4.4
Data sources ........................................................................................118
14.4.5
Derivation rules...................................................................................119
14.4.6
Medical review of investigator’s response assessment.......................125
14.4.7
References (available upon request) ...................................................126


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14.4.8
Appendices..........................................................................................127
Appendix A Modified EBMT - Flowchart of response assessment................................127
132
List of appendices
Appendix 1: Co-medications which prohibited for use, are known to prolong the QT interval 
and/or induce Torsades de Pointes, are strong CYP3A4/5 inhibitors, are CYP2D6 substrates, or 
are moderate CYP3A4 inducers
Appendix 4: Protocol Post-text Supplement - Guidelines for response assessment in Multiple 
Myeloma
List of figures
Figure 1-1
Inhibition of the proteasome by bortezombib and aggresome 
pathways by panobinostat and deacetylase inhibitors (DACi) .............26
Figure 4-1
Study design..........................................................................................38
Figure 6-1
Dosing schedules in the treatment period 1 and treatment period 2 .....45
Figure 14-1
Flowchart for response in patients with MM at 1st post-baseline 
assessment or previous NC according to modified EBMT criteria.....128
Figure 14-2
Flowchart for response in patients with MM at 1st post-baseline 
assessment or previous NC according to modified EBMT criteria.....129
Figure 14-3
Flowchart for response in patients with MM at 1st post-baseline 
assessment or previous NC according to modified EBMT criteria.....130
Figure 14-4
Flowchart for relapse in patients with MM after CR according to 
modified EBMT criteria......................................................................131
133
.134
135
135
136
136


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137
137
 
138
 
138
 
139
List of tables
Table 1-1
AEs by PT and severity, irrespective of causality (with an 
incidence greater than 10% in either group) .........................................32
Table 3-1
Objectives and related endpoints ..........................................................36
Table 6-1
Dose and treatment schedule.................................................................44
Table 6-2
Dosing level reductions for re-initiation of panobinostat .....................48
Table 6-3
Criteria for panobinostat dosing delays, dose-reductions, and re-
initiation of treatment due to study drug-related toxicity (excluding 
QT prolongation)...................................................................................48
Table 6-4
Dosing re-escalation for panobinostat treatment...................................52
Table 6-5
Dose reductions for QTc prolongation..................................................53
Table 6-6
Dose reduction steps for BTZ s.c..........................................................53
Table 6-7
Dose reduction steps for Dex................................................................53
Table 6-8
Drug related adverse events dose modification guidelines for BTZ 
s.c ..........................................................................................................54
Table 6-9
Recommended dose modification for BTZ-related neuropathic pain 
and/or peripheral sensory neuropathy...................................................55
Table 6-10
Dex dose modifications.........................................................................55
Table 7-1
Visit evaluation schedule ......................................................................61
Table 7-2
ECOG performance status scale............................................................71
Table 7-3
Clinical laboratory parameters collection plan .....................................72
Table 7-4
ECG assessment monitoring schedule ..................................................72
Table 7-5
Pharmacokinetic blood collection log for panobinostat........................74
Table 7-6
Pharmacokinetic blood collection log for bortezomib..........................75
Table 7-7
PK sample labelling ..............................................................................75
Table 7-8
Noncompartmental pharmacokinetic parameters of panobinostat 
and bortezomib......................................................................................76


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Table 14-1
Medications which are known to prolong the QT interval and/or 
induce Torsades de pointes to be avoided.............................................96
Table 14-2
Medications which are known strong CYP3A4/5 inhibitors to be 
used with caution...................................................................................98
Table 14-3
Medications which are known CYP2D6 substrates to be used with 
caution...................................................................................................99
Table 14-4
Response classification in MM according to modified EBMT 
criteria .................................................................................................111
115
.117
Table 14-7
Data sources ........................................................................................118
Table 14-8
Best overall response by classification system ...................................120
Table 14-9
Options for event dates used in PFS and TTP.....................................123
Table 14-10
Overview: Flowcharts for response assessment according to EBMT.127
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List of abbreviations
AE
Adverse Event
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
AML
Acute Myeloid Leukemia
aPTT
activated partial thromboplastin time
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
AUC
Area under the curve
BSA
Body surface area
BTZ
bortezomib
BUN
Bllod urea nitrogen 
CR
complete response
CRF
Case Report/Record Form
CRO
Contract Research Organization
CSR
Clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
CYP450
cytochrome p450
DAC
deacetylase
DACi
Deacetylase inhibitor
DDI
Drug-drug interaction
Dex
dexamethasone
DLT
Dose Limiting Toxicity
DOR
Duration of response
DS&E
Drug Safety and Epidemiology
EBMT
European Bone Marrow Transplant organization
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EOT
End of treatment
FAS
Full analysis set
FISH
fluorescence in situ hybridization
GCP
Good clinical practice 
G-CSF
Granulocyte colony stimulating factor
GI
gastrointestinal
GM-CSF
granulocyte-macrophage colony stimulating factor
Gr 3,Gr 4
Grade 3, grade 4
i.v.
intravenous(ly)
ICF
Informed consent form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IMiD
Immuno-modulatory Drug(s)
IMWG
International Myeloma Working Group
IRB
Institutional Review Board
ISS
International Scoring System
LDH
Lactate dehydrogenase
LEN
lenalidomide
LLN
Lower limit of normal values
LVEF
Left ventricular ejection fraction
MedDRA
Medical dictionary for regulatory activities


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MM
Multiple myeloma
MR
Minimal response
MRR
Minimal response rate
msec
milliseconds
MTD
Maximum Tolerated Dose
MUGA
Multiple uptake gated acquisition scan
NC
No change
NCI-CTC
National Cancer Institute – common toxicity criteria
nCR
Near Complete Response
ORR
Objective response rate
OS
Overall survival
PAN
Panobinostat
PD
Progressive disease
PEP
Protein electrophoresis
PFS
Progression free survival
PK
Pharmacokinetics
PLT
Platelets
PR
Partial Response 
PRO
Patient-reported outcome
PT
Prothrombin time
QoL
Quality of life
RAP
The Report and Analysis Plan (RAP) is a regulatory document which provides evidence of 
preplanned analyses
REB
Research Ethics Board
SAE
Serious Adverse Event
SCT
Stem Cell Transplant
T4
thyroxine
TIW
three times in/per week
TP1, TP2 
Treatment phase 1, treatment phase 2
TSH
Thyroid stimulation hormone
TTP
Time to progression
TTR
Time to response
ULN
Upper limit of normal values
WBC
White Blood Cells
WBC/HPF
White Blood Cells per High Power Field
WOCBP
Woman 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
Cycles
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g.: q28 days)
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
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
Variable
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints
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 study 
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Amendment 3 (27-Feb-2018) 
Amendment rationale
As of Jan 15 2018, 31 patients have been enrolled to receive treatment in this trial.
This amendment is written to improve the enrollment rate based on feedback from investigators 
(via direct contact or surveys).
The major changes to the selection criteria are as follows:
1. 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 5 prior lines of therapy to be included in this protocol.
2. 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 and CLBH589D1201 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.
Changes to the protocol

Table of contents: current page numbers and changes to section headings. 

Protocol Summary: changes in the main body of the protocol (see bullet points below) are 
also implemented in the relevant sections of the protocol synopsis.

Section 1.2.1.2: Update the number of studies and total number of patient as of 22 
February 2017.

Section 3.1: Clarify the primary endpoint

Section 4.1: Update Figure 4-1 to change prior lines of therapy from "1 to 3" to "1 to 5".

Section 5.1: 

Patient population: Changed prior lines of therapy from “1 to 3” to “1 to 5”.
Changed bortezomib (BTZ) to proteasome inhibitors to correct throughout the 
protocol.

Section 5.2:

Inclusion criteria 3: Changed prior lines of therapy from “1 to 3” to “1 to 5”.
Changed BTZ to proteasome inhibitors to correct throughout the protocol.

Inclusion criteria 7: Changed Absolute neutrophil count from “≥ 1.5 x 109 /L” to “1.0 
x 109 /L” and Platelet count from “≥ 100 x 109 /L” to “≥ 75 x 109 /L”.

Section 5.3:

Exclusion criteria 10 a: Added “Use of Dex as supportive treatment (e.g. for pain 
relief) is allowed”.

Exclusion criteria 15 a: Changed LVEF from “LLN of institutional norm” to “40%, as 
determined by echocardiogram (ECHO) or Multiple Gated acquisition (MUGA)”.


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
Section 7.1.1: Added the following sentence 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.
“If the plasma cell count 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”

Section 10.4: Clarify the primary objective

Section 14.1.2: Updated table 14-1 to consist with the latest LBH589 study.
IRBs/IECs
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.
Summary of previous amendments
Amendment 2 (15-Nov-2015) 
Amendment rationale
As of Sep 30 2015, 14 patients have been enrolled to receive treatment in this trial.
This amendment will introduce the following changes to the study protocol:
1. Update combination therapy – dosing modifications.
2. Introduce follow up on potential Drug-Induced Liver Injury cases.
3. Update inclusion and exclusion criteria.
1. Update combination therapy – dosing modifications
As of Sep 30 2015, 8/14 patients have discontinued study treatment due to adverse events, 
mainly fatigue, anorexia and nausea. Most patients discontinued study treatment at Cycle 4 or 
Cycle 5 (6/8 patients) and have experienced dose reductions of panobinostat before treatment 
discontinuations. 2/8 patients have changed bortezomib schedule from a twice-weekly to a 
once-weekly. 6/8 patients have had dose reduction of PAN and/or BTZ. On the other hand, 4/14 
patients have continued study treatment more than Cycle 5. 3/4 patients have dose reduction of 
PAN and changed to once-weekly BTZ or have skipped BTZ on D11 at every cycle. 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). In addition, a safety analysis of patients 
enrolled in PANORAMA-1 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 


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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). This amendment will implement 
a dose modification approach; the early change of BTZ from twice a week to weekly BTZ 
administration to improve tolerability of PAN+BTZ+Dex combination over a longer treatment 
duration.
2. Introduce follow up on potential Drug-Induced Liver Injury cases
This amendment provides follow up evaluations for hepatic toxicities and work-up guidelines 
for potential Drug-Induces Liver Injury cases in order to optimize patient safety.
3. Update inclusion and exclusion creitera
Different degree of renal impairment (mid, moderate and severe) did not alter panobinostat 
plasma exposure based on results from the renal impairment study [CLBH589X2106]. 
Therefore, criteria of renal functions were updated.
Contraception duration was updated as following reasons.

Terminal half-life of panobinostat is 15-18 hours

Genotoxic potential was shown in bacterial and eukaryotic systems

Oral administration of panobinostat to rats and rabbits is associated with embryo-fetal 
toxicity (increased resorptions/decreased live litters). Although no major malformations 
were observed, the incidence of fetal skeletal variations and anomalies was increased.

Male reproductive effects were observed in the testes, epididymides and prostate in 4- and 
13-week repeated dose oral toxicity studies in the dog.
These changes do not impact efficacy and safety assessment for patients who have been enrolled.
Changes to the protocol

Table of contents: current page numbers and changes to section headings.

Protocol Summary: changes in the main body of the protocol (see bullet points below) are 
also implemented in the relevant sections of the protocol synopsis.

Section 5.2:

Inclusion criteria 7: deleted criterion of serum creatinine levels and changed 
calculated creatinine clearance criterion from ≥ 60 to ≥30 with alliance of 
CLBH589D2222 study protocol which is the latest protocol for MM.

Inclusion criteria 13: added criterion related to CYP3A4 interaction to introduce new 
protocol template.

Section 5.3:

Exclusion criteria 10: added criterion of Stem cell therapy with alliance of 
CLBH589D2222 study protocol which is the latest protocol for MM.

Exclusion criteria 20: updated criterion of contraception methods and period for 
female subjects with alliance of CLBH589D2222 study protocol which is the latest 
protocol for MM.


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
Exclusion criteria 21: updated criterion of contraception period for male subjects.

Section 6.3.1 and 6.3.2: update this section for safety management with dose 
modifications.

Section 6.3.2.1: Updated management of grade 2 non-hematologic toxicity to allow dose 
reduction of study treatment (PAN/BTZ/Dex) at treatment restarting.

Section 6.3.3: updated Table 6-6, Table 6-7, Table 6-8 and Table 6-9 to early switch from 
twice a week to weekly BTZ administration.

Section 6.3.4: added this section to introduce follow up on potential drug-induced liver 
injury cases.

Table 7-1: added 3rd annotation in a footnote.

Section 7.1.1: updated this section to introduce new protocol template.

Section 7.1.3: updated this section to introduce new protocol template.

Section 7.1.5.2: added visit allowance for disease assessment.

Section 7.1.5.3: added visit allowance for survival information.

Section 8.2.2: updated this section to introduce new protocol template.
IRB/IEC
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.
Amendment 1 (23-Jun-2015)
Amendment rationale
As of May 20 2015, 12 patients have been enrolled to receive treatment in this trial.
This amendment will introduce the following changes to the study protocol:
1. Interim report.
2. Extension of study treatment period as an optional extension of the study.
3. Discontinuation of Clinical Trial Protocol Elements guideline
4. Update exclusion criteria.
The rationale for these changes is presented below:
1. Introduce interim report
In the review process of panobinostat submission for indication of relapsed or refractory MM
in Japan, 
requested sponsor to conduct 
additional interim report to present the key efficacy and safety information in public per 
approximately 6 months basis.


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2. Study treatment period
Based on the expected favorable tolerability under longer treatment of PAN + BTZ (weekly 
administration) + Dex in treatment phase 2 in PANORAMA1 study (San-Miguel JF et al ASH 
2014), the amendment will implement longer treatment beyond 12 cycles until disease 
progression under the careful risk/benefit assessment of the treating physicians.
3. Introduce Discontinuation of Clinical Trial Protocol Elements guideline
Discontinuation of Clinical Trial Protocol Elements provides guidance on how to effectively 
manage patients who discontinue Clinical Trial Protocol element(s) to maximize data captured.
Discontinuation of Clinical Trial Protocol Elements guidance helps to differentiate between 
patients who:

Discontinue certain CTP elements (e.g., discontinue study treatment, or some or all visits 
etc.)

Withdraw consent

Are lost to follow-up
4. Update exclusion criteria

Extend the exclusion criterion of ‘’patients who have been refractory to prior BTZ’’to 
‘’patents who have been refractory to prior BTZ and other proteasome inhibitors”. 
Recently, additional proteasome inhibitors have been developed and may gain marketing 
authorization. Given the identical mode of action of these newer drugs as BTZ, patients 
failing treatment with any representative of this class of drugs (proteasome inhibitors) 
shall be excluded from participation in this protocol.

Exclude patients have a known history of HIV seropositivity or history of active/treated 
hepatitis B or C.
Clarification/Inconsistencies:
Clarification was provided through edited text and inconsistent language was corrected 
throughout the protocol.

Sample size calculation was corrected to clarify the test statistics value-based p-value is 
used to reject or accept null hypothesis, the sentences regarding 90% confidence interval 
were deleted.

Exclusion criterion 21 was added to clarify the excludable condition of sexually active 
males.

Chemo-, biologic or immunologic therapy and/or other investigational agents are added as 
prohibited medications to be consistent with Appendix 1
Changes to the protocol

Table of contents: current page numbers and changes to section headings.

Protocol Summary: changes in the main body of the protocol (see bullet points below) are 
also implemented in the relevant sections of the protocol synopsis.


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
Section 2.2: updated rationale for study design to introduce optional extension of study 
treatment period as an option.

Section 4.1: update Figure 4-1 to extend treatment period.

Section 4.1.2: changed 2nd and 3rd bullets to allow extension of treatment period until
disease progression.

Section 5.3:

Exclusion criteria 2: changed BTZ to Proteasome inhibitors.

Exclusion criteria 18: added criterion that exclude patients have a known history of 
HIV seropositivity or history of active/treated hepatitis B or C.

Exclusion criteria 20: changed contraception period from during doing and for 28 
days to during and for 1 month.

Exclusion criteria 21: added criterion of contraception for sexually active males.

Section 6.1.1: corrected to change orange to Seville orange

Section 6.4.3: corrected for consistency with Appendix 1

Table 7-1: remove thyroid function test on day 1 between Cycle 2 to 8

Section 7.1: changed Section 7.1.3 and added Section 7.1.4 and 7.1.5 to introduce DOCE 
guideline

Section 7.2.2.6: specified urinary pregnancy test during study treatment period and at EOT 
visit

Section 10: added background pertaining to newly introduced interim analysis

Section 10.4.2: deleted a sentence regarding 90% confidence interval

Section 10.7: added information regarding interim analysis

Section 10.8: deleted a sentence regarding 90% confidence interval

Section 11.5: added a sentence regarding interim reports

Section 14.4: corrected Figure 14-1, 14-2, 14-3, 14-5, 14-6, 14-7, 14-8, 14-9 and 14-10


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Protocol summary:
Protocol number
CLBH589D1201
Title
A phase II, multi-center, single arm, open label study to evaluate the efficacy and 
safety of panobinostat in combination with bortezomib and dexamethasone in 
Japanese patients with relapsed/refractory multiple myeloma
Brief title
Study of efficacy and safety LBH589 in combination with bortezomib and 
dexamethasone in Japanese patients with relapsed/refractory multiple myeloma 
Sponsor and
Clinical Phase
Novartis,
Phase II
Investigation type
Drug
Study type
Interventional 
Purpose and rationale
[CLBH589D2308] (PANORAMA-1) study demonstrated panobinostat (PAN, 
LBH589) in combination with bortezomib (BTZ) and dexamethasone (Dex) was 
superior to BTZ, Dex and placebo (PBO) in patients with relapsed or relapsed 
and refractory multiple myeloma. The safety profile was generally manageable 
with dose reduction and supportive care. In PANORAMA-1 study, 34 Japanese 
patients were enrolled and the median PFS in Japanese population was longer in 
PAN+BTZ+Dex arm as compared to PBO+BTZ+Dex as well as in overall 
population. The near complete response (nCR)/complete response (CR) rate 
was higher in the PAN arm than the placebo arm. Also, the safety profile in 
Japanese population was not much different to the one of overall population and 
was generally manageable and predictable. As for detail, please refer to Section 
1.2
The purpose of this study is to collect additional efficacy and safety of oral PAN 
treatment in combination with BTZ and Dex in Japanese patients with 
relapsed/refractory multiple myeloma.
Primary Objective(s) and 
Key Secondary Objective
Primary objective: Evaluate nCR/CR rate after all patients have been treated for 
8 cycles or discontinued treatment ( as per investigator on modified EMBT 1998 
criteria)
Key secondary objective: Evaluate progression free survival 
Secondary Objectives
Evaluate overall response rate (ORR) comprising CR, nCR and PR
Evaluate minimal response rate (MRR)
Evaluate time to response (TTR)
Evaluate time to progression/relapse (TTP)
Evaluate duration of response (DOR)
Assess safety of the combination therapy
HRQoL as measured by: FACTGOG-NTX
Assess the Pharmacokinetics (PK) of PAN and BTZ in patients who agree to 
blood samplings for the PK assessments
Study design
A total of 33 eligible patients will be enrolled. PAN will be administered in 
combination with BTZ and Dex 2 weeks on/1 week off. Total duration of 
treatment will be 48 weeks, divided into two phases. Treatment Phase 1 will 
consist of 8 three-week (21 days) cycles for a total of 24 weeks. Patients with 
clinical benefit at the end of cycle 8 as per investigator assessment may continue 
to receive study treatment in treatment Phase 2 for 4 additional six-week (42 
day) cycles of therapy. After 4 additional six-week cycles of therapy, patients who 
investigators will judge continuous treatment provide benefit based on 
risk/benefit assessment may continue in the study until disease progression or 
the End of study whichever comes first as an optional extension. Post-treatment 
efficacy evaluations will continue up to progression, relapse, death or withdrawal 
of consent.
Population
Adult (at least 18 years of age) male and female, with relapsed multiple myeloma 
or relapsed and refractory multiple myeloma. 33 patients will be enrolled.


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Inclusion criteria
1. Age 18 years or older at time of consent
2. Patient has a previous diagnosis of multiple myeloma,
 
 
 
 
 
3. Patient with 1 to 5 prior lines of therapy who requires retreatment of myeloma 
for one of the 2 conditions below:
a.
Relapsed, defined by disease that recurred in a patient that responded 
under a prior therapy, by reaching a MR or better, and had not progressed 
under this therapy for up to 60 days of last dose of this therapy. Patients 
previously treated with BTZ are eligible
For regimen that are administered until progression, for example 
maintenance therapies, the documentation of a minimal duration of 60 days 
of MR or better is considered sufficient for a patient to qualify for the study.
b.
Relapsed-and-refractory defined as therapy that meets both of the 
following:
●
patient has relapsed to at least one prior line;
●
and patient was refractory to another line (except proteasome 
inhibitors), by either not reaching a MR, or progressed while under this 
therapy, or within 60 days of its last dose;
4. Patient has measurable disease at study screening
 
5. Patient treated with local radiotherapy with or without concomitant exposure 
to steroids for pain control or management of cord/nerve root compression, is 
eligible. Two weeks must have elapsed since last date of radiotherapy, which is 
recommended to be a limited field. Patient who requires 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
6. Patient has an Eastern Cooperative Oncology Group (ECOG) performance 
status (PS) ≤ 2
7. Patient has the following laboratory values within 3 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 within 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.
Serum potassium, magnesium, phosphorus , within normal limits (WNL) 
for Institution
d.
Total calcium (corrected for serum albumin) or ionized calcium greater 
or equal to lower normal limits (> LLN) for institution, and not higher than 
CTCAE grade 1 in case of elevated value
Note: Potassium, calcium, magnesium, and/or phosphorus supplements may be 
given to correct values that are < LLN
e.
AST/SGOT and ALT/SGPT ≤ 2.5 x ULN
f.
Serum total bilirubin ≤ 1.5 ULN (or ≤ 3.0 x ULN if patient has Gilbert 
syndrome)
g.
Calculated creatinine clearance ≥ 30 ml/min


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8. Patient has provided written informed consent prior to any screening 
procedures
9. Patient is able to swallow capsules
10. Patient must be able to adhere to the study visit schedule and other protocol 
requirements
11. Women of childbearing potential (WOCBP) must have a negative serum 
pregnancy test at baseline
12. Written informed consent for the main study must be obtained prior to any 
screening procedures. If consent cannot be expressed in writing, it must be 
formally documented and witnessed, ideally via an independent trusted witness
13. Patients must avoid consumption of grapefruit, 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. 
Exclusion criteria
1. Patients who have progressed under all prior lines of anti-multiple myeloma 
therapy (primary refractory)
2. Patients who have been refractory to prior Proteasome inhibitors (i.e. did not 
achieve at least a MR, or have progressed under it or within 60 days of last dose)
3. Allogeneic stem cell transplant recipient presenting with graft versus host 
disease either active or requiring immunosuppression
4. Patient has shown intolerance to BTZ or to dexamethasone (Dex) or 
components of these drugs or has any contraindication to one or the other drug, 
following locally applicable prescribing information
5. Patient has grade ≥ 2 peripheral neuropathy or grade 1 peripheral 
neuropathy with pain on clinical examination within 14 days before enrollment
6. Patient needing valproic acid for any medical condition during the study or 
within 5 days prior study treatment
7. Patient received prior treatment with DAC inhibitors including PAN
8. Patient taking any anti-cancer therapy concomitantly (bisphosphonates are 
permitted. Anti-RANKL antibody (Denosumab) can be also maintained if 
commenced prior to screening period.)
9. Patient has secondary 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).
10. Patient who received at least one of the following:
a.
prior anti-myeloma chemotherapy or medication including IMiDs and 
Dex ≤ 3 weeks prior to first dose 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 first dose of study treatment
c.
prior radiation therapy ≤ 4 weeks or limited field radiotherapy ≤ 2 weeks 
prior first dose of study treatment
d.
Stem cell transplant ≤ 3 weeks prior to start of study treatment
11. Patient has ≥ grade 2 CTCAE from all therapy-related toxicities associated 
with above listed treatments
12. Patients who have not recovered from side effect of prior surgery to < grade 2 
CTCAE
13. Patients with evidence of mucosal or internal bleeding
14. Patient has unresolved diarrhea ≥ grade 2 CTCAE
15. Patient has impaired cardiac function, including any one of the following:
a.
Known LVEF < 40%, as determined by echocardiogram (ECHO) or 
Multiple Gated acquisition (MUGA)
b.
obligate use of a permanent cardiac pacemaker
c.
congenital or acquired long QT syndrome
d.
presence of uncontrolled ventricular tachyarrhythmia


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e.
resting bradycardia defined as < 50 beats per minute
f.
QTcF > 450 msec on screening ECG
g.
complete left bundle branch block (LBBB), bifascicular block
h.
any clinically significant ST segment and/or T-wave abnormalities
i.
presence of unstable atrial fibrillation (ventricular response rate > 100 
bpm). Patients with stable atrial fibrillation can be enrolled provided they do 
not meet other cardiac exclusion criteria
j.
myocardial infarction or unstable angina pectoris ≤ 12months prior to 
starting study drug
k.
symptomatic congestive heart failure (New York Heart Association class 
III-IV)
l.
other clinically significant heart disease and vascular disease (e.g. 
uncontrolled hypertension
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
17. Patient has impairment of gastrointestinal (GI) function or GI disease that 
may significantly alter the absorption of PAN (e.g. ulcerative disease, 
uncontrolled nausea, vomiting, malabsorption syndrome, obstruction, or stomach 
and/or small bowel resection)
18. Patient has a known history of HIV seropositivity or history of active/treated 
hepatitis B or C.
19. Pregnant or nursing (lactating) women, where pregnancy is defined as the 
state of a female after conception and until the termination of gestation, 
confirmed by a positive hCG laboratory test.
20. 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 for 3 months after stopping all study treatment. 
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). For female 
subjects on the study 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.
21. 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 in order to prevent delivery of the drug via seminal fluid.
Investigational and 
reference therapy
Panobinostat is the investigational drug in this study. Investigational treatment 
refers to combination treatment with PAN, BTZ and Dex.


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Efficacy assessments
Efficacy will be evaluated based on modified EBMT 1998 criteria.
Throughout the trial, efficacy will be evaluated by the following parameters:
Serum M-protein (M-spike by PEP, by central laboratory assessment), urine M-
protein (M-spike by PEP, M-spike is measured at a central laboratory), serum 
immunofixation, urine immunofixation, serum calcium level, evaluation of soft 
tissue plasmacytoma (by CT scans or MRI), skeletal surveys and plasma cell 
count in bone marrow (by bone marrow aspiration/biopsy).
Efficacy parameters will be measured at screening and at every 3 weeks during 
treatment phases and at every 6 weeks during follow-up phase for response 
assessment.
Safety assessments
Safety will be evaluated by monitoring the frequency, duration and severity of 
adverse events and laboratory abnormalities, and assessing the physical 
examinations, vital signs and electrocardiograms. Severity of adverse events and 
laboratory abnormalities will be assessed using CTCAE 4.03. Concomitant 
medications and significant non-drug therapies will be assessed during the study.
Other assessments
Pharmacokinetic
Plasma samples from patients who agree to blood samplings for 
pharmacokinetic assessment of PAN and BTZ will be collected on Cycle 1 Day1 
and Day 8. Plasma concentrations of PAN (and its metabolite BJB432, if 
feasible) and BTZ will be measured, and the pharmacokinetic parameters 
(Cmax, Tmax, AUC, T1/2, etc) will be assessed.
Data analysis
Sample size assumptions in this trial are based on the data from the 
PANORAMA-1 study, which enrolled a similar patient population; i.e. patients 
with relapsed multiple myeloma or relapsed-and-refractory myeloma. 
Considering BTZ is currently widely used in newly diagnosed MM and 
relapsed/refractory MM in Japan, it is expected that most patients in this study 
have BTZ containing regimen.
Based on the data from the PANORAMA-1 study, for patients previously treated 
with BTZ, the nCR+CR rate for PAN is expected to be around 25 %. nCR+CR 
rate of 10 % or less is considered as an insufficient level of activity for the 
proposed patient population. Based on the normal distribution, approximately 33 
patients are required to reject a null hypothesis of the nCR+CR rate ≤ 10% vs. a 
target the nCR+CR rate of 25% or more, with a one-sided alpha of 0.05 and at 
least 80% power.
Key words
Panobinostat, Phase II, relapsed/refractory multiple myeloma


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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 and plasmacytoid cells. It 
is the second most common hematological malignancy and is invariably fatal (Raab et al 2009; 
Kyle et al 2008). The median age at diagnosis is 61 years for females and 62 years for males. 
The most common presenting symptoms are fatigue and bone pain (Kyle et al 2003). Osteolytic 
bone lesions and/or compression fractures are the hallmark of the disease and cause significant 
morbidity. Anemia occurs in 66% of patients at diagnosis and is the primary cause of fatigue. 
Renal dysfunction occurs in 20% and hypercalcemia in 15-20% of patients. The annual 
incidence of MM is approximately 2.0 per 100,000 in Japan (MHLW database 2011).
Myeloma cells are highly dependent upon the bone marrow microenvironment, including the 
presence of certain cytokines such as interleukin-6 (IL-6), macromolecules in the extracellular 
matrix, and supportive cells (stromal cells), for their growth and survival (Klein et al 1989; 
Vidriales et al 1996). Processes that change the bone marrow microenvironment either retard 
the growth of the tumor or cause myeloma cells to undergo apoptosis.
Although outcomes for patients with multiple myeloma (MM) have improved over the past 
decade, the disease remains incurable and even patients who respond well to induction therapy 
ultimately relapse and require additional treatment. Conventional chemotherapy and high-dose 
therapy with stem cell transplantation (SCT) have historically been utilized in the management 
of relapsed MM, but in recent years the immunomodulatory drugs (IMiDs) thalidomide and 
lenalidomide (LEN), as well as the proteasome inhibitor bortezomib (BTZ), have assumed a 
primary role in this setting. These agents have not only improved overall response, but emerging 
data suggest that these agents also have doubled patient survival from 3-4 years to 7-8 years as 
a direct result (Kumar et al 2008). The use of these targeted therapies to treat relapsed and 
refractory MM and relapsed MM has transformed MM therapy and patient outcome. However, 
there is still a high unmet need for patients with relapsed and refractory disease who have 
received prior targeted therapies. Patients who are refractory to BTZ and have failed LEN have 
a very poor progression free survival (PFS) of 5 months and overall survival (OS) of 9 months 
(Kumar et al 2011).
Relapsed and/or refractory MM represents an important focus of ongoing research efforts. 
Characterization of the molecular events underlying this disease at the level of the MM cell and 
the bone marrow microenvironment has provided the platform for development of the novel 
agents as well as various emerging compounds in MM, including new IMiD and proteasome 
inhibitors, as well as DAC inhibitors. It is anticipated that drug combinations that target 
different oncogenic pathways will deliver greater anti-MM activity and add to progress made 
in the treatment of patients with relapsed and/or refractory disease, for which there remains a 
clear medical need to improve outcomes.


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1.2
Introduction to investigational treatment(s) and other study 
treatment
1.2.1
Overview of panobinostat (LBH589)
Panobinostat (LBH589, PAN) belongs to a structurally novel cinnamic hydroxamic acid class 
of compounds and is a pan-inhibitor of Class I, II and IV histone deacetylases (DACs). DACs 
are involved in the deacetylation of histone and non-histone cellular proteins, targeting lysine 
groups on chromatin and transcription factors and various non-histone proteins such a p53, 
tubulin, heat shock protein 90 (Hsp90), and retinoblastoma protein (Rb). PAN has shown 
antitumor activity in preclinical models and in cancer patients and has been formulated as an 
oral capsule and as a solution for intravenous (i.v.) injection. Both the i.v. and oral formulations 
have been investigated in Phase IB/II studies in advanced solid tumors and hematological 
malignancies.
1.2.1.1
Non-clinical experience
PAN has been developed as an anticancer agent based on its potential to act:

by exhibiting differential antiproliferative activity against a broad range of solid tumor cell 
lines and high sensitivity in lymphomas and hematologic malignancy cell lines, including 
acute myeloid leukemia (AML) and multiple myeloma (MM).

by inducing consistent tumor growth control in various tumor-bearing xenografted mice 
and by increasing histone-H3 and H4 acetylation in excised tumors.

by showing synergistic or additive anti-tumor effect in combination with other anti-cancer 
agents such as trastuzumab, docetaxel, BTZ or standard cytotoxic agents e.g., doxorubicin, 
fludarabine, Ara-C.
The potent anticancer effects of PAN seen in experimental models may result from two distinct 
mechanisms of action, both related to pan-DAC inhibition. PAN was shown to affect epigenetic 
mechanism of gene expression via inhibition of Class I HDACs, as shown by induction of 
histone acetylation and consequent induction of cell cycle control genes (i.e. p21) and to inhibit 
HDAC6 through abrogation of Hsp90-mediated stabilization of client oncoproteins, resulting 
in their depletion and in reduced downstream oncogenic signaling (Atadja 2011).
Proteasome and DAC inhibition in multiple myeloma
BTZ is a reversible inhibitor of the chymotrypsin-like activity of the 20S proteasome in 
mammalian cells. The 20S proteasome is a large protein complex that degrades ubiquinated 
proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the 
intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. 
Inhibition of the 20S proteasome prevents this targeted proteolysis, which can affect multiple 
signaling cascades within the cell. This disruption of normal homeostatic mechanisms can lead 
to cell death. BTZ is cytotoxic to a variety of cancer cell types in vitro and causes a delay in 
tumor growth in vivo in non-clinical tumor models, most notably MM.
The microtubule-associated histone deacetylase HDAC6 is a component of aggresomes and 
recruits misfolded proteins for transport to aggresomes. Unfolded or misfolded proteins 
exceeding proteasomal degradation form aggregates and are transported to the microtubule 


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organizing center (MTOC) for degradation. This transport requires HDAC6 which deacetylates 
alfa-tubulin and binds both polyubiquitinated proteins and dynein. Inhibiting HDAC6 with 
tubacin, whether or not combined with the proteasome inhibitor BTZ, accumulates misfolded 
or unfolded proteins and leads to apoptosis.
Pei et al (2004) were the first to demonstrate in vitro that DACi in combination with BTZ 
resulted in an improved cytotoxic effect compared to their effects as single agents. Sequential 
exposure of U266 and MM1S cells to BTZ and suberoylanilide hydroxamide acid (SAHA) 
potently induced caspase-3, -8 and -9 activation and release of the pro-apoptotic mitochondrial 
proteins cyto-c and Smac, resulting in a synergistic induction of apoptosis indicating that several 
molecular mechanisms may contribute to the synergy between BTZ and DACi. (Feng et al 
2007)
The well-characterized model of synergy between proteasome inhibitors and DACi are the dual 
inhibition of the proteasome and aggresome pathways (Figure 1-1, Hideshima et al 2011). 
Targeting both the proteasome with BTZ and the aggresome with HDAC6 inhibitors in tumor 
cells induces greater accumulation of polyubiquitinated proteins, resulting in increased cellular 
stress and apoptosis (Catley 2006, Hideshima 2005). More specifically, proteasome inhibition 
drives the formation of aggresomes, which are dependent on the interaction of HDAC6 with 
tubulin and dynein complex (Catley et al 2006). Moreover, the proteasome inhibitor (BTZ) and 
HDAC6 inhibitors (tubacin or PAN) lead to increased hyperacetylation of tubulin and 
generation of polyubiquitinated proteins, thus increasing cellular stress response (i.e., c-Jun N-
terminal protein kinase activation) and leading to apoptosis, which is, in part, dependent on 
caspase activity (Catley 2006, Hideshima 2005). Therefore the combined use of BTZ and of 
PAN could lead to the blockage of known pathways of cytotoxic protein clearance from MM 
cells.


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Figure 1-1
Inhibition of the proteasome by bortezombib and aggresome 
pathways by panobinostat and deacetylase inhibitors (DACi)
Atadja et al (2007) demonstrated PAN to induce growth inhibition and apoptosis in MM cells, 
and to potentiate the activity of other drugs, such as BTZ, in vitro. Furthermore, PAN produced 
significant anti-tumor activity with protection from bone damage in an in vivo mouse model of 
MM. In this model PAN inhibited growth of MM cells sensitive or resistant to standard steroid 
or chemotherapeutic treatment as well as plasma cells isolated from MM patients. In particular, 
significant synergistic cytotoxicity was observed with PAN in combination with BTZ without 
additional toxicity to normal bone marrow stromal cells. Comparable single-agent anti-tumor 
activity, evidenced by reduced tumor burden was observed with PAN, BTZ, and melphalan in 
vivo. Importantly, PAN alone appeared to demonstrate preservation of bone integrity in this 
model. Enhanced anti-MM activity of the PAN/BTZ combination could not only be observed 
in primary human MM cells but also in co-culture conditions and conditions with exogenous 
growth factors IL-6 or IGF-1 (Atadja et al 2007). Moreover, a combination of PAN and BTZ
and with the addition of dexamethasone, resulted in strong synergistic effects seen on growth 
inhibition and apoptosis in both in vitro and in vivo models (Ocio et al 2010).
For the latest information on the pre-clinical pharmacology and toxicity of PAN, please refer to 
the current [Investigator Brochure].


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1.2.1.2
Clinical experience
As of 22 February 2017, 40 clinical studies, including clinical pharmacology (CP), Phase I and 
Phase II trials, as well as two randomized Phase III studies have either been completed or are 
ongoing. A total of 2592 patients were enrolled; of which 2202, 235 for i.v. and 1967 for oral, 
received at least one dose of PAN either as a single agent or in combination with other agents.
The most frequent non-hematologic toxicities included GI events (diarrhea, nausea, vomiting) 
and fatigue, which were mild to moderate in severity and generally reversible.
The most common ECG findings were sinus tachycardia, T-wave abnormalities and depressed 
ST segment. QTcF above 500 msec is uncommon and noted only with the weekly oral dosing 
regimen. No torsade de pointes have been reported in clinical trials with oral PAN.
1.2.1.2.1 Overview on human pharmacokinetics
Following oral administration, PAN was rapidly absorbed with a rate of absorption (Ka) of 0.3 
hour-1, peak plasma concentration was reached within 1 hour; systemic clearance was 33 L/hour 
and central volume of distribution was 25 liters. Half-life associated with the distribution, initial 
elimination and terminal elimination phases were 0.14, 2.3 and 37 hours, respectively. Observed 
drug accumulation was approximately 1.14 fold with TIW schedule. This is consistent with an 
effective half-life of 15 hours. Absolute oral bioavailability estimated for the Final Market 
Image (FMI) formulation was 21%.The compound can be administered regardless of food 
intake as the variability and overall systemic exposure remained unchanged in patients taking 
PAN with or without food (Lewis et al 2009). AUC increased linearly and proportionally with 
doses up to 50 mg. The inter-individual variability (CV%) in systemic exposure is 60%. The 
plasma protein binding of PAN (mainly to albumin) is moderate (89.6% at 37°C) and 
independent of concentration. Elimination half-lives averaged 15 hours. Steady state is achieved 
by the third dose following days 1, 3, and 5 (TIW) weekly (QW) dosing. On day 5, PAN has an 
observed AUC accumulation ratio (RA) of ~1.4 fold over a single dose AUC which is consistent 
with the estimated RA based on linear pharmacokinetic processes.
PAN was extensively metabolized in patients, with the parent compound accounting for 6-9% 
of the drug-related exposure in plasma with the remainder accounted for by approximately 40 
metabolites. Metabolites formed via the primary metabolic pathways were all inactive for DAC 
inhibitory activity in vitro.
CYP3A4 is the main oxidative metabolizing enzyme of PAN (70-98%) with minor involvement 
of CYP2D6 and CYP2C19. PAN is a competitive CYP2D6 inhibitor with a Ki value of 0.17µM 
in human liver microsomes. It is also a weak time-dependent inhibitor of CYP3A4 with Ki value 
of 12.0 µM and kinact value of 0.0228 min-1. PAN is not an inducer of CYP enzymes, UGT1A1, 
Pgp or MRP2 and does not inhibit Pgp efflux activity in vitro.
A strong CYP3A inhibitor, ketoconazole, increased PAN systemic exposure by 80% in cancer 
patients. This clinical drug interaction is deemed weak, and consistent with in vitro findings. 
Co-administration of a strong CYP3A inhibitor with PAN is feasible when medically necessary 
with close monitoring.
Population PK analysis was performed using plasma concentrations obtained from intravenous 
and oral administration of PAN. Among the covariates investigated, body surface area, age at 
baseline and race were statistically significant covariates on clearance and volume of 


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distribution in the central compartment. However, the extent of these covariate effects were 
small as compared to the large inter-individual variability and were not deemed clinically 
relevant.
For further details, please refer to the current [PAN Investigator Brochure].
1.2.1.2.2 Interactions with other drugs
Based on in vitro data, PAN is a CYP3A4 and CYP2D6 substrate and a CYP2D6 inhibitor (IC50
0.17 µM). Thus, two clinical DDI studies were conducted using ketoconazole as a potent 
CYP3A inhibitor [CLBH589B2110] and PAN as CYP2D6 inhibitor with dextromethorphan as 
CYP2D6 substrate [CLBH589B2109].
Study [CLBH589B2110] was conducted in 14 patients with advanced cancer. Multiple 
ketoconazole doses at 400 mg increased Cmax and AUC of PAN by 1.6- and 1.7-fold, 
respectively, but with no change in Tmax (de Jonge et al 2009). The less than 2-fold increase 
in PAN AUC upon co-administration suggests that CYP3A contribution to the total clearance 
is low (Ohno et al 2008). The observed effect of ketoconazole on PAN CYP3A mediated 
metabolic pathways is considered weak and not clinically relevant, as doses at least 2-fold 
greater than 20 mg (i.e., 40 mg and 60 mg) have been safely administered in patients. Clinical 
monitoring of signs of possibly PAN related adverse events is recommended when long-term 
(≥ 1 week) concomitant administration of potent CYP3A inhibitors and PAN at doses > 20 mg 
is medically indicated.
Study [CLBH589B2109] was conducted in 17 patients with advance cancer. Multiple PAN 
doses at 20 mg (TIW) increased Cmax and AUC of dextromethorphan by a mean of 1.8- and 
1.6-fold, respectively, but with no change in Tmax. An approximately 2-fold increase in 
Dextromethorphan AUC upon co-administration with PAN indicated that in vivo CYP2D6 
inhibition of PAN is weak. As the study was conducted using a sensitive CYP2D6 substrate 
resulting in a weak inhibition, drugs with a large therapeutic index such as anti-emetics, anti-
hypertensives, and anti-depressants are generally considered safe to be co-administered with 
PAN. Caution is to be exercised when PAN is co-administered with medications that are
exclusively metabolized by CYP2D6 and have a narrow therapeutic window (e.g., tamoxifen, 
anti-arrhythmics). Please refer to //druginteractioninfo.org for a more detailed reference list.
Study PANORAMA-1- Phase III placebo-controlled study in combination with 
bortezomib and dexamethasone in MM
The Study [PANORAMA-1] was a multi-center, randomized, double-blind, placebo-controlled 
Phase III study of PAN in combination with BTZ and Dexamethasone (Dex) in 768 patients 
with relapsed or relapsed and refractory MM Study.
In the treatment phase 1, patients received 20 mg PAN or placebo (PBO) TIW with a 2 weeks 
on/1 week off schedule, and 1.3 mg/m2 iv BTZ on Days 1, 4, 8 and 11, and 20 mg Dex on each 
day of and after BTZ dosing in a 21 day cycle. PK samplings were conducted in only Japanese 
population in this study. Serial dense blood samples to characterize the PK of PAN (Day 1 and 
Day 8 of Cycle 1) and BTZ (Day 8 of Cycle 1) were collected in a subset of 13 Japanese patients.
Geometric mean PAN plasma exposure, AUC0-48h (CV%) was 76.01 (45.6%) and 118.9 
(29.5%) ng*hr/mL, respectively on Cycle 1 Day 1 and Cycle 1 Day 8. Peak plasma 


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concentration of PAN (Cmax) showed similar increase from Cycle 1 Day 1 to Cycle 1 Day 8, 
and was 9.16 (74.8%) ng/mL on Cycle 1 Day 1 and 15.33 (39%) ng/mL on Cycle 1 Day 8. The 
apparent increase in plasma exposure of PAN on Cycle 1 Day 8 is most likely a reflection of 
not only drug accumulation based on the effective half-life of approximately 15 hours, but also 
the large variability.
PAN exposure was moderately variable, and was considerably lower than that from single-
agent trials likely due to induction of CYP3A4 by Dex.
1.2.1.2.3 Clinical experience in multiple myeloma with PAN combination therapy
The safety and efficacy data of oral PAN treatment in combination with BTZ (iv) and Dex in 
adult patients with relapsed or relapsed/refractory (RR) multiple myeloma is based on the 
results of three independent studies. These studies are summarized below and include the 
following: 1). LBH589B2207 a phase 1b dose escalation (n=47) and expansion (n=15) study 
establishing the MTD/DLTs and the RP2D; 2). LBH589DUS71 a phase 2 exploratory study 
(n=55) demonstrating efficacy in the relapsed and BTZ refractory myeloma patient population; 
and 3). PANORAMA-1, a phase 3 international randomized study (n=768) conducted in 34 
countries including Japan demonstrating superiority of the addition of PAN to the combination 
of BTZ and Dex.
Study LBH589B2207
Study [LBH589B2207] is an open-label Phase Ib dose-escalation/dose-expansion trial of oral 
PAN and IV BTZ that enrolled patients with relapsed or relapsed-and-refractory MM, following 
at least one prior line of therapy and who were suitable for treatment (or re-treatment) with BTZ 
(not mandatory for inclusion into the study). A total of 62 patients were enrolled: 47 patients in 
the dose escalation phase at five different dose levels in six consecutive dose-cohorts and 15 
patients in the dose-expansion phase.
The dose-escalation component of the trial consisted of a single treatment arm where escalating 
doses of oral PAN (3 times weekly) were administered in combination with escalating doses of 
intravenous BTZ. An adaptive Bayesian logistic regression model was used to guide the dose 
escalation. The observed safety profile and the Bayesian model based on DLTs from cycle one 
as defined in the protocol declared the PAN 20 mg (3 times weekly) + BTZ 1.3 mg/m2 dose 
level to be the maximal tolerated dose (MTD) on the continuous dosing schedule. Review of 
the long term safety and tolerability of the dose-escalation phase dose-level cohorts, resulted in 
modifying the dosing schedule of PAN to introduce a treatment rest week, to proceed 
simultaneously with that for BTZ (2-weeks on and 1-week off). To optimize clinical responses 
in the dose-expansion phase and conform to current standard-of-care (Jagannath et al 2006; 
Mikhael et al 2009), oral Dex (20 mg daily) was given to all dose-expansion patients starting at 
Cycle 2.
Promising results from the analysis of the dose-expansion phase (n=15) are reported here (data 
cut-off date of 10-Aug-2011) (San-Miguel et al 2013). Patients had received a median of 2 prior 
lines of anti-myeloma therapy (range: 1-7) and 46.6% of patients had received 3 or more prior 
lines of treatment. The majority of patients (53.3%) were relapsed-and-refractory at study entry.
In the Full Analysis Set (n=15, defined as all patients who received at least one dose of study 
treatment), the overall response rate 
 


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 was 73.3% (95% CI, 44.9-92.2), 
 
 in 3 patients (20.0%). In addition, half of patients (53.3%) achieved a partial response 
(PR), 2 patients (13.3%) achieved a minimal response (MR), and one patient (6.7%) had a best 
response of stable disease. The median time to response (≥PR) was 44.0 days (range: 22-1393). 
Median exposure to study treatment was 159 days (range: 45-353). Most patients (86.7%) 
received treatment for ≥3 months with one-third (33.3%) having received ≥6 months of 
treatment by the data cut-off date.
AEs ≥grade 3 were experienced by most patients (86.7%) in the dose-expansion cohort with; 
thrombocytopenia 
(66.7%), 
neutropenia 
(46.7%), 
lymphopenia 
(33.3%), 
and 
hypophosphatemia (26.7%) the most commonly observed grade 3-4 events. One patient (6.7%) 
experienced ≥grade 3 PN. There were two (13.3%) on-treatment deaths, attributed to ‘injury’ 
and ‘ischemic stroke’; none of the deaths were assessed as related to study treatment. Six 
patients (40.0%) had at least one serious AE (SAE); the most common SAEs were 
thrombocytopenia (26.7%) and dehydration (13.3%). Five patients (33.3%) had at least one AE 
that led to study drug discontinuation, and the most common AE in this category was peripheral 
neuropathy (13.3%). A hemorrhagic event was reported in one patient, a grade 4 cerebral 
hemorrhage (6.7%). No major changes in vital signs and ECG parameters were observed.
The promising efficacy (an ORR of 73.3%) and manageable safety of Study [LBH589B2207]
allowed the PAN clinical development program to move the triple combination regimen into a 
pivotal Phase III trial for relapsed or relapsed-and-/refractory MM.
Study LBH589DUS71
Study [LBH589DUS71] illustrates the efficacy of PAN in combination with BTZ and Dex in 
patients with relapsed or relapsed-and-refractory MM, including BTZ-refractory patients. 
Given that BTZ is a current standard-of-care for relapsed/refractory MM, either as a single agent 
or in combination, the possibility of rescuing a response in patients who have become refractory 
to BTZ is of high clinical relevance.
Patients that had received ≥2 prior lines of therapy including an IMiD and who had progressed 
on or within 60 days of their last BTZ-based therapy were treated in a single-arm, Phase II trial 
with PAN/BTZ/Dex (Richardson et al 2013). The main purpose of this study was to assess 
whether patients refractory to BTZ would regain responsiveness to the drug if given in 
combination with PAN.
Treatment phase 1 (TP1) consisted of eight 3-week cycles of oral PAN (20 mg three times 
weekly, 2-weeks on and 1-week off) + IV BTZ (1.3 mg/m2 on Days 1, 4, 8, and 11) + oral Dex
(20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12). Patients demonstrating clinical benefit (≥no change 
in disease status) could proceed to treatment phase 2 (TP2), which consisted of 6-week cycles 
until disease progression. The primary endpoint was ORR (≥PR) in TP1, as defined by 1998 
modified European Society for Blood and Marrow Transplant (mEBMT) criteria.
Patients (n=55) with BTZ-refractory MM were enrolled (median age: 61 years, range: 
41-88 years). This was a heavily pretreated population; patients had received a median of four 
prior lines of anti-myeloma therapy (range: 2-11). Most patients (67.3%) had received more 
than three prior lines of previous therapy. In the most recent prior line, almost half of patients 
(49.1%) had received BTZ. All patients were previously treated with BTZ, Dex, and at least 


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one IMiD (BTZ: 100%, lenalidomide: 98.2%, thalidomide: 69.1%). The majority of patients 
had received prior stem cell transplantation (63.6%).
The median duration of exposure to study treatment was 139.0 days (range: 2-735 days). 
Nineteen of the 55 patients completed TP1 and all 19 entered TP2.
The primary endpoint, ORR based on investigator’s assessment, was observed in 19 patients 
(34.5%) (95% CI: 22.2%, 46.7%). One patient (1.8%) achieved near Complete Response (nCR), 
18 patients (32.7%) achieved a PR. In addition, 10 patients (18.2%) had a MR, and 20 patients 
(36.4%) had no change as best response. For all patients, median PFS and OS were 5.4 months
and 17 months, respectively. Thus, the PAN/BTZ/Dex regimen recaptured clinical responses in 
heavily pretreated BTZ-refractory patients.
Most patients (89.1%) experienced ≥grade 3 AEs; thrombocytopenia (63.6%), diarrhea 
(20.0%), and fatigue (20.0%) were the most commonly observed ≥grade 3 events. One patient 
(1.8%) experienced grade 3 PN. Thirty-nine patients (70.9%) had at least one SAE; the most 
common SAEs were thrombocytopenia (29.1%), pneumonia (14.5%) and pyrexia (9.1%). Four 
(7.3%) on-treatment deaths occurred; of these four deaths, three (5.5%) were due to study 
indication and the remaining patient died of multi-organ failure in the context of pneumonia 
and disease progression. Ten patients (18.2%) had at least one AE that led to study drug 
discontinuation, and the most common AE in this category was fatigue (7.3%).
Study PANORAMA-1
PANORAMA-1 study is a Phase III randomized, double blind, placebo controlled, multicenter 
global registration study to evaluate LBH589 in combination with BTZ and Dex vs BTZ, Dex
and placebo in patients with relapsed or relapsed and refractory multiple myeloma having 
received 1 to 3 prior line of therapy. Treatment phase 1 (TP1) consisted of eight 3-week cycles 
of oral PAN (20 mg three times weekly, 2-weeks on and 1-week off) + IV BTZ (1.3 mg/m2 on 
Days 1, 4, 8, and 11) + oral Dex (20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12). Patients 
demonstrating clinical benefit (≥no change in disease status) could proceed to treatment 
phase 2 (TP2), which consisted of 6-week cycles until 48 weeks. The primary endpoint of the 
trial was progression-free survival (PFS) and the key secondary endpoint is overall survival 
(OS). Other secondary endpoints include overall response rate, nCR+CR rate, time to 
progression, time to response, duration of response and safety.
A total of 768 patients with relapsed or relapsed and refractory MM were enrolled in 
Study PANORAMA-1, and randomized to receive either PAN arm (n=387 patients) or PBO 
arm (n=381 patients). Treatment arms were well-balanced by baseline treatment history. In this 
trial, 51.4% of all patients had received one prior line of anti-MM therapy and 48.3% of all 
patients had received 2-3 prior lines. The proportion of patients receiving BTZ as prior 
antineoplastic therapy was similar between the two treatment arms (PAN arm, 43.7%; PBO arm, 
42.3%). The proportion of patients in both arms receiving thalidomide for prior antineoplastic 
therapy (PAN arm, 53.0%; PBO arm, 49.3%) was higher than in patients who received 
lenalidomide for prior antineoplastic therapy (PAN arm, 18.6%; PBO arm, 22.3%).
The primary endpoint of the study was met with median PFS of 12.0 months vs. 8.1 months 
(HR, 0.63; 95% CI: 0.52 to 0.76, p<0.0001) for patients treated on the PAN arm vs. PBO arm.
The PFS benefit of PAN+BTZ+Dex per investigator assessment was consistent across a series 


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of preplanned analyses in clinically relevant subgroups. Hazard ratios within all major 
subgroups are in favor of the PAN arm, demonstrating patient benefit independent of: sex, race, 
prior therapies (i.e BTZ, IMiDs, stem cell transplantation), renal impairment, clinical staging 
by International Scoring System (ISS), relapsed or relapsed and refractory disease, age, and 
cytogenetic risk. Overall response rate (ORR) was higher in the PAN arm (60.7%) compared 
to the PBO arm (54.6%) arm with a higher rate of complete and nCRs. The nCR+CR rate was 
almost two-fold higher in the PAN arm (27.6%) vs. the PBO arm (15.7%) indicating higher 
quality responses in the PAN arm. Of note, this tendency was observed in patients with having 
BTZ-containing therapy as a prior line of therapy (PAN arm: 24.9%, PBO arm: 10.2%). In the 
PANORAMA-1 study, 34 Japanese patients were enrolled. The median PFS in Japanese 
population was also longer in PAN arm (10.6 months vs. 9.0 months) as well as in overall 
population. In Japanese population, although the ORR was higher in PBO arm (75.0%) than 
PAN arm (61.1%), nCR+CR rate was also higher in the PAN arm (33.3%) vs. the PBO arm
(12.5%).
The most frequently reported AEs in Study PANORAMA-1 are presented in Table 1-1. Patients 
in the PAN arm generally had higher frequencies of common AEs. The most notable AEs with 
a frequency ≥30% for the PAN arm include diarrhea, thrombocytopenia, anemia, fatigue, 
nausea and peripheral neuropathy. Similarly the most notable grade 3/4 AEs with a frequency 
≥10% for the PAN arm include thrombocytopenia, diarrhea, neutropenia, hypokalemia, fatigue, 
anemia, pneumonia and lymphopenia.
Table 1-1
AEs by PT and severity, irrespective of causality (with an incidence 
greater than 10% in either group)
PAN+BTZ+Dex
N=381
PBO+BTZ+Dex
N=377
AEs by preferred term
All grades
n(%)
Grade 3/4
n(%)
All grades
n(%)
Grade 3/4
n(%)
Diarrhoea
260 (68.2)
97 (25.5)
157 (41.6)
30 (8.0)
Thrombocytopenia
246 (64.6)
217 (57.0)
154 (40.8)
94 (24.9)
Anaemia
158 (41.5)
63 (16.5)
126 (33.4)
60 (15.9)
Fatigue
157 (41.2)
65 (17.1)
110 (29.2)
33 (8.8)
Nausea
138 (36.2)
21 (5.5)
78 (20.7)
2 (0.5)
Neuropathy peripheral
117 (30.7)
26 (6.8)
133 (35.3)
21 (5.6)
Neutropenia
114 (29.9)
92 (24.1)
40 (10.6)
30 (8.0)
Oedema peripheral
109 (28.6)
8 (2.1)
72 (19.1)
1 (0.3)
Decreased appetite
107 (28.1)
12 (3.1)
47 (12.5)
4 (1.1)
Hypokalaemia
104 (27.3)
73 (19.2)
53 (14.1)
24 (6.4)
Constipation
102 (26.8)
4 (1.0)
123 (32.6)
4 (1.1)
Pyrexia
99 (26.0)
5 (1.3)
56 (14.9)
7 (1.9)
Vomiting
98 (25.7)
28 (7.3)
49 (13.0)
5 (1.3)
Asthenia
84 (22.0)
36 (9.4)
55 (14.6)
14 (3.7)
Cough
81 (21.3)
4 (1.0)
70 (18.6)
0
Insomnia
73 (19.2)
0
61 (16.2)
1 (0.3)
Dizziness
71 (18.6)
11 (2.9)
62 (16.4)
9 (2.4)
Upper respiratory tract infection
68 (17.8)
9 (2.4)
55 (14.6)
6 (1.6)
Pneumonia
65 (17.1)
48 (12.6)
48 (12.7)
39 (10.3)
Leukopenia
62 (16.3)
35 (9.2)
31 (8.2)
12 (3.2)


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PAN+BTZ+Dex
N=381
PBO+BTZ+Dex
N=377
AEs by preferred term
All grades
n(%)
Grade 3/4
n(%)
All grades
n(%)
Grade 3/4
n(%)
Dyspnoea
56 (14.7)
9 (2.4)
44 (11.7)
9 (2.4)
Hypotension
53 (13.9)
11 (2.9)
35 (9.3)
5 (1.3)
Headache
52 (13.6)
3 (0.8)
40 (10.6)
1 (0.3)
Lymphopenia
52 (13.6)
47 (12.3)
35 (9.3)
28 (7.4)
Abdominal pain
51 (13.4)
9 (2.4)
40 (10.6)
3 (0.8)
Hyponatraemia
49 (12.9)
37 (9.7)
19 (5.0)
13 (3.4)
Nasopharyngitis
49 (12.9)
0
47 (12.5)
2 (0.5)
Back pain
48 (12.6)
3 (0.8)
47 (12.5)
5 (1.3)
Dyspepsia
47 (12.3)
1 (0.3)
43 (11.4)
1 (0.3)
Abdominal pain upper
44 (11.5)
3 (0.8)
36 (9.5)
1 (0.3)
Weight decreased
44 (11.5)
7 (1.8)
17 (4.5)
2 (0.5)
Hypophosphataemia
43 (11.3)
33 (8.7)
32 (8.5)
24 (6.4)
Platelet count decreased
43 (11.3)
35 (9.2)
17 (4.5)
13 (3.4)
Peripheral sensory neuropathy
42 (11.0)
9 (2.4)
46 (12.2)
7 (1.9)
Pain in extremity
40 (10.5)
1 (0.3)
54 (14.3)
3 (0.8)
Blood creatinine increased
38 (10.0)
4 (1.0)
22 (5.8)
6 (1.6)
Neuralgia
38 (10.0)
5 (1.3)
44 (11.7)
3 (0.8)
Herpes zoster
18 (4.7)
4 (1.0)
40 (10.6)
7 (1.9)
Preferred terms are sorted in descending frequency of all grades, as reported in PAN treatment group.
A patient with multiple occurrences of an AE is counted only once in the AE category.
Adverse events occurring more than 28 days after the discontinuation of study treatment are not summarized.
The incidence of AEs leading to discontinuation of study treatment was 36.2% in the PAN arm
and 20.4% in the PBO arm. Grade 3/4 AEs leading to discontinuation were reported in 25.5% 
of patients in the PAN arm and 13.3% in the PBO arm. The single most frequent AEs leading 
to treatment discontinuations were diarrhea (4.5% and 1.6%, respectively), fatigue (2.9% both 
arms), asthenia (2.9% and 0, respectively), and peripheral neuropathy (3.7% and 1.9%, 
respectively). While the overall frequency of treatment discontinuation in the combination 
studies appears to be high, AEs leading to discontinuation of study treatment were relatively 
low in frequencies with no more than 5% of patients who discontinued due to one single AE. 
This indicates that AEs have been effectively managed with dose interruption, dose 
modification, and/or supportive medical intervention. In Japanese population, the safety profile
was not much different to the one of overall population and was generally manageable similar 
to overall population.
2
Rationale
2.1
Study rationale and purpose
The purpose of this study is to assess efficacy and safety of oral PAN treatment in combination 
with BTZ and Dex in Japanese patients with relapsed/refractory multiple myeloma to collect 
additional efficacy and safety data in Japanese patients.
In PANORAMA-1 study, a clinically meaningful and statistically significant median PFS 
prolongation was observed with higher nCR/CR rate in the PAN arm. This is particularly 


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relevant given that higher quality responses have been shown to be associated with longer PFS 
and OS in patients with relapsed or refractory MM (Lonial and Anderson 2014). Based on these 
data, the primary objective was set as nCR plus CR rate after 8 cycles, when most of patients 
reached confirmed nCR or CR in PANORAMA-1, to assess efficacy 
 in this single-
arm phase II study.
2.2
Rationale for the study design
This study is open-label, single arm, multi-center phase II evaluating efficacy PAN in 
combination with BTZ and Dex in Japanese patients with relapsed/refractory multiple myeloma. 
PAN will be administered in combination with BTZ and Dex 2 weeks on/1 week off. Total 
duration of treatment will be 48 weeks, divided into two phases. Treatment Phase 1 will consist 
of 8 three-week (21days) cycles for a total of 24 weeks. Patients with clinical benefit at the end 
of cycle 8 as per investigator assessment may continue to receive study treatment in Treatment 
Phase 2 for additional six-week (42 day) cycles of therapy. The treatment periods were set with 
reference to PANORAMA-1, which demonstrated that PAN in combination with BTZ/Dex
provides a meaningful and robust clinical benefit in relapsed or relapsed-and-refractory multiple 
myeloma with the safety profile that was generally predictable and manageable with dose 
reduction/interruption and supportive care.
After amendment 1, it is allowed that patients will be treated with study treatment as treatment 
phase 2 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 Pomalidomide + Bortezomib + Dex vs 
Bortezomib + Dex) have been conducted using BTZ treatment until progression. The longer 
administration of BTZ in this study as compared to a maximum 12 cycles used in 
PANORAMA-1 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 PANORAMA-1 
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 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 weekly BTZ administration 
after cycle 8 is expected to further improve tolerability of PAN+BTZ+Dex combination over 
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2.3
Rationale for dose and regimen selection
The selection of the dose levels of PAN 20 mg TIW and BTZ 1.3 mg/m2 on days 1, 4, 8 and 11 
is supported by the results of the Phase Ib study [CLBH589B2207] where 15 evaluable patients 
in the dose escalation phase receiving this dose remained longest on therapy and exhibited the 
best overall tolerability when compared to the other cohorts.
In addition, the review of efficacy, safety, and tolerability of this MTD dose, resulted in 
modifying the dosing schedule of PAN to introduce an on/off treatment strategy similar to that 
already used for BTZ (2 weeks on and 1 week off) in an effort to further improve tolerability.
This dose level and intermittent regimen investigated in the dose expansion phase (N=15) of 
[CLBH589B2207], was the one adopted in studies [PANORAMA-1] and [CLBH589DUS71]. 
Based on the results of these studies which demonstrated the safety profile that was generally 
predictable and manageable with dose reduction/interruption and supportive care, it has been 
determined to be the safest and most efficacious dosing regimen, and therefore will be utilized 
for this trial.
2.4
Rationale for choice of combination drugs
To collect additional efficacy and safety data in Japanese patients, same combination drug (BTZ 
and Dex) used in the trial will be used. In this study, BTZ will be administered by 
subcutaneously (sc). BTZ sc injection was approved and is widely used as an alternative to iv 
therapy based on the results of the phase III study to compare the use of sc vs. iv BTZ in patients 
with relapsed MM, which demonstrated similar efficacy with improved tolerability (Moreau et 
al 2011). Intravenous BTZ administration was not found to alter panobinostat PK in B2207 
study dose escalation phase. Comparing intravenous BTZ administration, subcutaneous BTZ 
administration will have little impact on AUC of BTZ, but will decrease Cmax of BTZ. 
Therefore, in terms of PK drug-drug interaction, subcutaneous BTZ will not alter panobinostat 
PK as well. Based on these data, it is reasonable to expect that the use of BTZ sc in this 
combination may demonstrate similar efficacy results with potential benefit in tolerability
compared to the combination with BTZ iv.
2.5
Rationale for choice of comparators drugs
Not applicable.
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 evaluate nCR/CR rate after all patients have 
been treated for 8 cycles or discontinued treatment
nCR plus CR rate after all patients have been treated for 8 cycles or discontinued 
treatment is based on modified EBMT criteria per investigator assessment 
Key secondary
Refer to Section 10.5.1
To evaluate progression free survival (PFS)
PFS, defined as time from first dose of study treatment to progression or death due 
to any cause, as assessed by investigator
Other secondary
Refer to Section 10.5.2
To evaluate overall response rate (ORR) comprising 
CR, nCR and PR
ORR is defined as the proportion of patients with CR or nCR or PR based on 
modified EBMT criteria per investigator assessment
To evaluate overall survival (OS)
OS, defined as time from first dose of study treatment to death
To evaluate minimal response rate (MRR)
MRR is based on modified EBMT criteria per investigator assessment
To evaluate time to response (TTR)
TTR is defined as the time from the date of first dose of study treatment to first 
documented response (PR or nCR or CR) per modified EBMT criteria as assessed 
by investigator
To evaluate time to progression/relapse (TTP)
TTP is defined as the time from the date of the first dose of study treatment to the 
date of the first documented disease progression or relapse
To evaluate duration of response (DOR)
DOR is defined as the time from date of the first documented CR/nCR or PR to the 
date of the first documented progression or relapse or death due to MM
To assess safety of the combination therapy
Toxicity will be assessed using the National Cancer Institute-Common Toxicology 
Criteria (NCI-CTC) grading scale for Adverse Events and for laboratory assessments 
(v4.03) that include biochemistry, hematology, urinalysis; special safety assessments 
that include LVEF, Thyroid function Creatinine clearance and ECGs.
To assess QoL as measured by FACT/GOG-NTX
Calculated scores and changes from baseline will be summarized by visit.
To assess the PK of Panobinostat and bortezomib in 
patients who agree to blood samplings for the PK 
assessments
Cmax, Tmax, AUC, T1/2, etc


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Objective
Endpoint
Analysis


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4
Study design
4.1
Description of study design
This study is an open-label, single arm, multi-center phase II evaluating efficacy panobinostat 
(PAN) in combination with bortezomib (BTZ) sc and dexamethasone (Dex) in Japanese patients 
with relapsed/refractory multiple myeloma. A total of 33 eligible patients will be enrolled. The 
primary objective is to evaluate nCR plus CR after 8 cycles of study treatment.
The study design is shown on Figure 4-1.
Figure 4-1
Study design
4.1.1
Screening period
Patient’s screening evaluation will commence after the patient signs informed consent and will 
be concluded within 21 days prior to first day of dosing.
4.1.2
Treatment period
PAN will be administered in combination with BTZ and Dex 2 weeks on/1 week off. Treatment 
period will be divided into two phases:

Treatment phase 1: 24 weeks of combined treatment with PAN + BTZ s.c / Dex (8 
cycles of 3 weeks duration each)


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
Treatment phase 2: 24 weeks of combined treatment with PAN + BTZ s.c / Dex (4 
cycles of 6 weeks duration each) After 24 weeks treatment, patients who investigators will 
judge continuous treatment provide benefit based on risk/benefit assessment may continue 
in the study as an optional extension. They will follow the same assessments with the 
same frequency until disease progression or the End of study whichever comes first.

All patients will receive study treatment until completion of week 24 (eight 21-day 
cycles). Patients with clinical benefit (achieving ≥ No Change at cycle 8 day 1, as assessed 
per modified EBMT criteria) will continue study treatment in Treatment phase2.
4.1.3
Follow-up period
All patients enrolled into the study will be followed through the treatment period and until 
relapse/progression after treatment discontinuation, and thereafter every 3 months for survival, 
except those who are lost to follow-up or withdraw consent.
Patients who discontinue study treatment due to reasons other than relapse or progression of 
disease will be followed for relapse/progression until 1 year after the last patient completed 24 
weeks of treatment, except those who are lost to follow-up or withdraw consent.
4.2
Timing of interim analyses and design adaptations
Not applicable.
4.3
Definition of end of the study
The End of study is defined as 1 year after the last patient completed 24 weeks of treatment.
4.4
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and the same assessments should be performed 
as described in Section 7.1.3.1 for a discontinued or withdrawn patient. 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 trial.
5
Population
5.1
Patient population
The eligible patient population will consist of adult patients with relapsed multiple myeloma or 
relapsed and refractory multiple myeloma. The target population includes patients with all of 
the following:

relapsed multiple myeloma having received 1 to 5 prior lines of therapy, or relapsed-and-
refractory multiple myeloma, but who are not refractory to prior proteasome inhibitors

A line of therapy is defined as one or more cycles of a planned treatment program. 
This may consist of one or more planned cycles of single-agent therapy or 
combination therapy, as well as a sequence of treatments administered in a planned 
manner. For example, a planned treatment approach of induction therapy followed by 


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autologous stem cell transplantation, followed by maintenance is considered one line 
of therapy. A new line of therapy starts when a planned course of therapy is modified 
to include other treatment agents (alone or in combination) as a result of disease 
progression, relapse, or toxicity. A new line of therapy also starts when a planned 
period of observation off therapy is interrupted by a need for additional treatment for 
the disease (Rajkumar et al 2011).
The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study.
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. Age 18 years or older at time of consent
2. Patient has a previous diagnosis of multiple myeloma, 
 
3. Patient with 1 to 5 prior lines of therapy who requires retreatment of myeloma 
 
 for one of the 2 conditions below:
a. Relapsed, defined by disease that recurred in a patient that responded under a prior 
therapy, by reaching a MR or better, and had not progressed under this therapy for up 
to 60 days of last dose of this therapy. Patients previously treated with BTZ are
eligible
For regimen that are administered until progression, for example maintenance
therapies, the documentation of a minimal duration of 60 days of MR or better is 
considered sufficient for a patient to qualify for the study.
b. Relapsed-and-refractory defined as therapy that meets both of the following:

patient has relapsed to at least one prior line;

and patient was refractory to another line (except proteasome inhibitors), by 
either not reaching a MR, or progressed while under this therapy, or within 60 
days of its last dose;
4. Patient has measurable disease at study screening 
 
5. Patient treated with local radiotherapy with or without concomitant exposure to steroids 
for pain control or management of cord/nerve root compression, is eligible. Two weeks 


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must have lapsed since last date of radiotherapy, which is recommended to be a limited 
field. Patient 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
6. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2
7. Patient has the following laboratory values within 3 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 within 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. Serum potassium, magnesium, phosphorus , within normal limits (WNL) for 
Institution
d. Total calcium (corrected for serum albumin) or ionized calcium greater or equal to 
lower normal limits (> LLN) for institution, and not higher than CTCAE grade 1 in 
case of elevated value
Note: Potassium, calcium, magnesium, and/or phosphorus supplements may be given to correct 
values that are < LLN
e. AST/SGOT and ALT/SGPT ≤ 2.5 x ULN
f.
Serum total bilirubin ≤ 1.5 ULN (or ≤ 3.0 x ULN if patient has Gilbert syndrome)
g. Calculated creatinine clearance ≥ 30 ml/min
8. Patient has provided written informed consent prior to any screening procedures
9. Patient is able to swallow capsules
10. Patient must be able to adhere to the study visit schedule and other protocol requirements
11. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at 
baseline
12. Written informed consent for the main study must be obtained prior to any screening 
procedures. If consent cannot be expressed in writing, it must be formally documented and 
witnessed, ideally via an independent trusted witness
13. Patients must avoid consumption of grapefruit, 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.
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Patients who have progressed under all prior lines of anti-multiple myeloma therapy 
(primary refractory)
2. Patients who have been refractory to prior Proteasome inhibitors (i.e. did not achieve at 
least a MR, or have progressed under it or within 60 days of last dose)
3. Allogeneic stem cell transplant recipient presenting with graft versus host disease either 
active or requiring immunosuppression


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4. Patient has shown intolerance to BTZ or to dexamethasone (Dex) or components of these 
drugs or has any contraindication to one or the other drug, following locally applicable 
prescribing information
5. Patient has grade ≥ 2 peripheral neuropathy or grade 1 peripheral neuropathy with pain on 
clinical examination within 14 days before enrollment
6. Patient needing valproic acid for any medical condition during the study or within 5 days 
prior to study treatment
7. Patient received prior treatment with DAC inhibitors including PAN
8. Patient taking any anti-cancer therapy concomitantly (bisphosphonates are permitted. 
Anti-RANKL antibody (Denosumab) can be also maintained if commenced prior to 
screening period.)
9. Patient has secondary 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).
10. Patient who received at least one of the following
a. prior anti-myeloma chemotherapy or medication including IMiDs and Dex ≤ 3 weeks 
prior to first dose 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 first dose of study treatment
c. prior radiation therapy ≤ 4 weeks or limited field radiotherapy ≤ 2 weeks prior first 
dose of study treatment
d. Stem cell transplant ≤ 3 weeks prior to start of study treatment
11. Patient has ≥ grade 2 CTCAE from all therapy-related toxicities associated with above 
listed treatments
12. Patients who have not recovered from side effect of prior surgery to < grade 2 CTCAE
13. Patients with evidence of mucosal or internal bleeding
14. Patient has unresolved diarrhea ≥ grade 2 CTCAE
15. Patient has impaired cardiac function, including any one of the following:
a. Known LVEF < 40%, as determined by echocardiogram (ECHO) or Multiple Gated 
acquisition (MUGA)
b. obligate use of a permanent cardiac pacemaker
c. congenital or acquired long QT syndrome
d. presence of uncontrolled ventricular tachyarrhythmia
e. resting bradycardia defined as < 50 beats per minute
f.
QTcF > 450 msec on screening ECG
g. complete left bundle branch block (LBBB), bifascicular block
h. any clinically significant ST segment and/or T-wave abnormalities
i.
presence of unstable atrial fibrillation (ventricular response rate > 100 bpm). Patients 
with stable atrial fibrillation can be enrolled provided they do not meet other cardiac 
exclusion criteria
j.
myocardial infarction or unstable angina pectoris ≤ 12months prior to starting study
drug


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k. symptomatic congestive heart failure (New York Heart Association class III-IV)
l.
other clinically significant heart disease and vascular disease (e.g. uncontrolled 
hypertension
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
17. Patient has impairment of gastrointestinal (GI) function or GI disease that may 
significantly alter the absorption of PAN (e.g. ulcerative disease, uncontrolled nausea, 
vomiting, malabsorption syndrome, obstruction, or stomach and/or small bowel resection)
18. Patient has a known history of HIV seropositivity or history of active/treated hepatitis B or 
C (a test for screening is not required)
19. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test.
20. 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 for 3 months after stopping all study treatment. 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). For female subjects on the 
study 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.
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.
21. 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 in order to prevent 
delivery of the drug via seminal fluid.


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6
Treatment
6.1
Study treatment
Panobinostat (PAN) is the study drug in this trial. Study treatment refers to combination 
treatment with PAN, Bortezomib (BTZ) sc and dexamethasone (Dex).
6.1.1
Dosing regimen
Table 6-1
Dose and treatment schedule
Treatment Phase 1: Cycles 1- 8, 3 week cycle (21 days)
Drug
PAN
BTZ s.c
Dex
Dose
20 mg
1.3 mg/m2
20mg 
Regimen
Days:
1, 3, 5
8, 10, 12
Days:
1, 4
8, 11
Days:
1, 2, 4, 5
8, 9,11, 12
Treatment Cycle duration
21 Days 
21 Days
21 Days
Treatment Phase 2: Cycles 9 -
Drug
PAN
BTZ s.c
Dex
Dose
20 mg
1.3 mg/m2
20mg 
Regimen
Days:
1, 3, 5
8, 10, 12
22, 24, 26
29, 31, 33
Days:
1
8
22
29
Days:
1, 2
8, 9
22, 23
29, 30
Treatment Cycle duration
42 Days 
42 Days
42 Days
Note: For PAN / BTZ/Dex dose modifications due to toxicity during a treatment cycle, please refer to Section 
6.3


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Figure 6-1
Dosing schedules in the treatment period 1 and treatment period 2
In both, TP 1 and TP2, every effort must be made to dose the patient with PAN on the same 3 
days of the week consistently throughout the study (e.g. if Cycle 1 day 1, 3, 5 is a Monday, 
Wednesday, Friday; for subsequent cycles/weeks dosing must again be on Monday, Wednesday, 
Friday). To allow for some flexibility (e.g. scheduled dose day is a Monday which happens to 
be a holiday or patient forgets to take the dose), it is permitted to change the original weekly 
schedule if necessary on any given week throughout the study, and to then return to the original 
schedule once appropriate as long as there is no dosing on consecutive days.
Treatment delays due to toxicities and/or scheduling issues are allowed but consecutive doses 
of PAN must be separated by a minimum of 30 hours. Continuous day dosing (e.g. Day 1 and 
Day 2 or Day 8 and Day 9 etc.) is not permitted. If a patient experiences an adverse event that 
leads to a dose delay, in order to ensure adequate exposure to panobinostat for restarting the 
drug, patients should be monitored at least weekly for resolution of adverse events that have led 
to dose delays.
Dose of PAN may be taken with or without food except for on Day 1 and Day 8 of Cycle 1 in 
case PK sampling will be conducted.
In the event that the patient does not take the daily dose at the specified routine time, unrelated 
to toxicity (for example, the patient forgets), but the dose can be taken within 12 hours of the 
specified time, then s/he may take the daily dose at that time. If more than 12 hours have passed, 
that day’s dose must be withheld, and the patient must wait to take the dose until the next 
scheduled treatment day. The patient will then continue treatment with the original dosing 
schedule.
Each dose of PAN should be taken with a large glass (approximately 240 mL) of non-
carbonated water. Patients should be instructed to swallow the capsules whole and not chew 
them.


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If vomiting occurs during the course of treatment, then no re-dosing of the patient is allowed 
before the next scheduled dose.
Patients must avoid grapefruits, grapefruit juice, Seville oranges and Seville orange juice during 
the entire study period.
6.1.2
Ancillary treatments
Not Applicable
6.1.3
Rescue medication
Not Applicable
6.1.4
Guidelines for continuation of treatment
Patients may continue treatment provided no tolerability issues are present (See Section 6.3) 
and criteria for discontinuation are not met (see Section 7.1.3)
6.1.5
Treatment duration
All patients will receive study treatment until completion of Treatment Phase 1 at week 24 
(eight three-week cycles). Patients may be discontinued from study treatment earlier due to
disease progression, unacceptable toxicity and/or study treatment discontinued at discretion of 
the investigator. Patients with clinical benefit at the end of Cycle 8 as per investigator 
assessment (achieving ≥ NC at the end of Cycle 8) may continue study treatment for up to week
48 (four additional six-week cycles) as Treatment Phase 2. After week 48, patients who 
investigators will judge continuous treatment provide benefit based on risk/benefit assessment 
may continue in Treatment Phase 2 as an optional extension. They will follow the same 
assessments with the same frequency until disease progression or the End of study whichever 
comes first.
6.2
Dose escalation guidelines
Not applicable.
6.2.1
Study drug compliance and accountability
6.2.1.1
Study drug compliance
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.
6.2.1.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of PAN 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 


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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 Novartis monitor or to the Novartis address provided in the investigator 
folder at each site.
6.2.1.3
Handling of other study treatment
Not applicable.
6.2.2
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate.
6.3
Dose modifications
6.3.1
Dose modification and dose delay
For patients who are unable to tolerate the protocol-specified dosing schedule, dose adjustments 
are permitted in order to keep the patient on study treatment. These dose adjustments may 
consist of withholding dosing and/or reductions in the dose being administered. Dosing should 
be withheld if the physician determines it is in the best interest of the patient. 
All dose modifications must be recorded on the Dosage Administration Record form.
Patients unable to tolerate the minimum dose level of Dex may continue on rest of therapy 
without Dex.
Patients requiring discontinuation of BTZ s.c due to peripheral neuropathy may continue on 
PAN and Dex (or without Dex) BTZ s.c may be restarted at any time during treatment phases 
1 and 2 if clinically indicated and in accordance with the local prescribing instructions for BTZ.
Patients requiring permanent discontinuation of BTZ s.c due to any other reason or permanent 
discontinuation of PAN must discontinue study treatment and be followed for PD/relapse and 
survival.
Before starting a next cycle, patient monitoring should be performed and dose delay may be 
considered by investigator in case patients experience AEs which are not recovered. If a patient 
requires a dose delay > 21 days from the intended day of the next scheduled dose, the patient 
should be discontinued from the study treatment. If, however, the patient was clearly benefiting 
from study treatment and the cause of delay has resolved, the patient may be able to restart 
study treatment upon agreement of the Investigator and the Sponsor. This option should be used 
with highest amount of caution keeping the safety of the patient in mind and evaluate if the 
benefit for the patient outweighs the risks.
6.3.2
Panobinostat - dosing modifications and delay
Patients should continue to receive therapy until progressive disease or relapse is documented, 
or study treatment is not tolerated. If study drug-related toxicities are observed, treatment can 


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be resumed only if these toxicities have resolved to the baseline level or to CTCAE ≤ grade 1, 
or as otherwise specified in the protocol.
The dose of PAN may be modified for a patient as per the dosing tables below (Table 6-2, Table 
6-4) during any cycle. Dose levels lower than 10 mg three times a week in combination with a 
minimum of 0.7 mg/m2 BTZ s.c, with or without Dex, are not permitted at any time of the study. 
When and if it is determined that a patient would require a dose below 10 mg three times week 
in combination with the minimum dose of BTZ s.c, the patient should be discontinued from 
study treatment. Continuation of dosing with PAN without BTZ s.c at any dose is not permitted 
in TP1, nor in TP2 except in case BTZ s.c is interrupted due to peripheral neuropathy.
Table 6-2
Dosing level reductions for re-initiation of panobinostat
Current dosing level
Dose reduction
20 mg/day
Modify to 15 mg/day
15 mg/day
Modify to 10 mg/day
10 mg/day
No further reduction, discontinue dosing permanently
Table 6-3 is recommended for PAN - dosing modifications and delay. Investigators may use 
their discretion when making temporary dose interruption or dose-reduction decisions unless 
otherwise specified in the guidelines below.
Table 6-3
Criteria for panobinostat dosing delays, dose-reductions, and re-
initiation of treatment due to study drug-related toxicity (excluding QT 
prolongation)
Worst Toxicity
CTCAE Grade* unless otherwise specified (Value)
Dose Modification Guidelines
At any time during a cycle of therapy 
(including intended day of dosing)
HEMATOLOGICAL TOXICITIES
Thrombocytopenia (PLT)
Grade 3 (PLT < 50 x 109/L) 
uncomplicated
No change in dosing
Grade 4 (PLT < 25 x 109/L)
or Grade 3 (PLT < 50 x 109/L) 
with bleeding
Temporarily discontinue dosing until resolved 
to ≤ Grade 2, or baseline, then, restart at 
reduced dose level as per Table 6-2
In PANORAMA-1, thrombocytopenia typically recovered to baseline by the start of the next 21-day cycle. The 
median time to onset was one month and the median time to recovery was 12 days. Platelet transfusions may 
be required, if clinically indicated
Neutropenia (ANC)
Grade 3 uncomplicated
ANC < 1.0 - 0.5 x 109/L 
Temporarily discontinue dosing until resolved 
to ≤ Grade 2 or baseline, then, restart at 
same dose level
Grade 4 (ANC < 0.5 x 109/L)
Temporarily discontinue dosing until resolved 
to ≤ Grade 2 or baseline, then, restart at 
reduced dose level as per Table 6-2
Grade 3 febrile neutropenia
Temporarily discontinue dosing until fever 
resolved and ANC ≤ Grade 2, then restart at 
reduced dose level as per Table 6-2
In case of grade 3 or 4 neutropenia, physicians should consider the use of growth factors (e.g. G-CSF) 
according to local guidelines.
Anemia
Grade 2 (Hgb < 10.0 g/dL)
No change in dosing - Consider supportive 
measures


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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 dosing)
Grade 3 (Hgb < 8.0 - 6.5 g/dL)
or Grade 4 (Hgb < 6.5 g/dL)
Temporarily discontinue dosing and use 
supportive measures until resolved to ≤ 
Grade 2, or baseline, then, restart at reduced 
dose level as per Table 6-2, if required
NON-HEMATOLOGICAL TOXICITIES
CARDIAC
Cardiac - Prolonged QT interval**
Please refer to Section 6.3.2.6 and Section 
7.2.2.7
GASTROINTESTINAL
Diarrhea
Grade 2 (4-6 stools/day over 
baseline, etc) persisting despite 
the use of optimal antidiarrheal 
medications
Temporarily discontinue dosing until resolved 
to ≤ Grade 1, or baseline, then restart at 
unchanged dose level
Grade 3 (≥ 7 stools/day over 
baseline, etc) despite the use of 
optimal antidiarrheal 
medications
Temporarily discontinue dosing until resolved 
to ≤ Grade 1, or baseline, then restart 
reduced by one dose level
Grade 4 (life-threatening 
consequences, hemodynamic 
collapse, etc) despite the use of 
optimal antidiarrheal 
medications
Discontinue dosing
Note: At the first sign of abdominal cramping, loose stools, or onset of diarrhea, it is recommended that the 
patient be treated with anti-diarrheal medication (e.g. loperamide). Prophylactic anti-emetics should be 
administered at the discretion of the physician and in accordance with local medical practice.
Fluid and electrolyte blood levels, especially potassium, magnesium and phosphate, should be monitored 
periodically during therapy and corrected as clinically indicated to prevent potential dehydration and electrolyte 
disturbances
Replacement i.v. fluids and electrolytes may be used as appropriate.
Please also see Section 6.3.2.6
Vomiting/Nausea
Grade 1 & 2
not requiring treatment
or controlled using standard 
anti-emetics
Maintain dose level
Grade 3 or 4 vomiting
or Grade 3 nausea that cannot 
be controlled despite the use of 
standard anti-emetics
Temporarily discontinue dosing until resolved 
to ≤ grade 1, or baseline, then restart reduced 
by one dose level
Note: Prophylactic anti-emetics should be administered at the discretion of the physician and in accordance 
with local medical practice. Fluid and electrolyte blood levels, especially potassium, magnesium and 
phosphate, should be monitored periodically during therapy and corrected as clinically indicated to prevent 
potential dehydration and electrolyte disturbances
Fatigue
Grade 3
Temporarily discontinue dosing until resolved 
to ≤ Grade 2, or baseline, then:
●
If resolved within 7 days after suspending 
dosing, then restart at an unchanged dose 
level
●
If resolved in more than 7 days after 
suspending dosing, then restart dosing 
reduced by one dose level


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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 dosing)
Grade 4
Temporarily discontinue dosing until resolved 
to ≤ Grade 2, or baseline, then restart dosing 
reduced by one dose level
Note: Most of the treatments for fatigue in cancer patients are for treating symptoms and providing emotional 
support because the causes of fatigue that are specifically related to cancer have not been determined. Some 
of these symptom-related treatments may include adjusting the dosages of pain medications, administering red 
blood cell transfusions or blood cell growth factors, diet supplementation with iron and vitamins, and 
antidepressants or psychostimulants.
HEPATIC
Total Bilirubin
Grade 3 or 4
Temporarily discontinue dosing until resolved 
to ≤ Grade 2, or baseline, then restart dosing 
reduced by one dose level
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 dose level and continuation of treatment is at the discretion 
of the Investigator.
AST/SGOT, ALT/SGPT
> 5-20 x ULN
Temporarily discontinue dosing until resolved 
to ≤ grade 1 (or ≤ grade 2 if liver infiltration 
with tumor is present), or baseline, then:
●
If resolved within 7 days restart at 
unchanged dose level
●
If resolved in more than 7 days, then 
reduce dosing by one dose level
> 20 x ULN
Temporarily discontinue dosing until resolved 
to ≤ grade 1, or baseline, then restart dosing 
reduced by one dose level
All dose modifications should be based on the worst preceding toxicity.
* Common Terminology Criteria for Adverse Events (CTCAE Version 4.03)
General guidelines for PAN dose modifications due to adverse events related to study drug are 
provided below. If such adverse event(s) are considered possibly related to BTZ s.c or Dex, the 
relevant 
dose-modification 
guidelines 
for 
each 
should 
be 
followed 
(see Section 6.6.3).
6.3.2.1
Grade 2 non-hematologic toxicity
Patients experiencing CTCAE grade 2 non-hematologic adverse event(s), 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 study treatment (PAN/BTZ/Dex), 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. Study treatment may then be restarted 
at the same dose and schedule or one dose level lower. If the same intolerable grade 2 adverse 
event(s) occurs again, PAN treatment must again be temporarily discontinued until the toxicity 
resolves to ≤ CTCAE grade 1 and be restarted at one dose level lower. At the discretion of the 
Investigator and in consultation with the Sponsor, patients with grade ≥ 2 adverse events of 


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major organs (e.g., heart, lungs, CNS) may be discontinued from further study therapy without 
being retreated with a dose reduction.
6.3.2.2
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 6-3, must have their treatment temporarily discontinued until the adverse 
event resolves to ≤ CTCAE grade 1 or baseline unless otherwise specified in Table 6-3. If the 
AE was considered related to PAN, the drug should then be restarted at one dose level lower. 
If the AE was considered not related to PAN, then therapy may be restarted (when the AE 
resolves to ≤ grade 1 or baseline) at the current dose.
6.3.2.3
Management of diarrhea
Patients must be instructed to contact their physician at the onset of diarrhea. Patients should 
be encouraged to maintain adequate oral hydration (at least 240 ml every 2 hours,) with the 
onset of diarrhea. Also, patients should be instructed to stop all lactose-containing products and 
alcohol consumption. Each patient should be instructed to have loperamide readily available 
and to begin treatment for diarrhea at the first episode of poorly formed or loose stools or the 
earliest onset of bowel movements more frequent than normally expected for the patient. At the 
beginning of each cycle, each patient should be asked if they experienced any diarrhea. If 
symptoms were experienced, the site should question the patient regarding the actions taken for 
these symptoms.
Loperamide 4 mg should be taken at the first loose stool or more frequent than usual bowel 
movements, followed by 2 mg as needed, no more frequently than every 4 hours, not to exceed
a total of 16 mg in 24 hours. Patients with diarrhea ≥ grade 2 despite this loperamide regimen 
should interrupt treatment with PAN as described in Table 6-3. If the above regimen is 
inadequate then additional evaluation and treatment should be pursued as medically indicated. 
Replacement 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.
The use of drugs with laxative properties must be avoided because of the potential for 
exacerbation of diarrhea. Patients should be advised to contact their physician to discuss any 
laxative use.
6.3.2.4
Infection
Localized and systemic infections, including pneumonia, other bacterial infections, invasive 
fungal infections, such as aspergillosis or candidiasis and viral infections including hepatitis B 
virus and herpes simplex, have been reported in patients taking PAN. Of note, in PANORAMA-
1, whereas grade 3 and grade 4 neutropenia were observed in 28% and 7% of patients 
respectively, febrile neutropenia was observed in 1% of patients. Physicians and patients should 
be aware of the increased risk of infection with PAN.
PAN should not be initiated in patients with active infections. Treat pre-existing infections prior 
to starting treatment with PAN. Monitor patients for signs and symptoms of infections during 
treatment with PAN; if a diagnosis of infection is made, institute appropriate anti-infective 
treatment.


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6.3.2.5
Dose re-escalation
Patients receiving a reduced dose level of PAN due to toxicity 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 at least 9 scheduled doses at the reduced level have been administered and tolerated.
or
the adverse event due to which the dose was omitted/reduced is determined to be not related to 
PAN
Should this guidance be met, then the patient may be dose escalated as per Table 6-4.
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.
Table 6-4
Dosing re-escalation for panobinostat treatment
Current dosing level
Dose re-escalation
20 mg/day
No dose escalation allowed
15 mg/day
Increase to 20 mg/day
10 mg/day
Increase to 15 mg/day
6.3.2.6
Dose modifications of PAN 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. 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 local sites.
Patients must have QTcF < 450 msec to be eligible for the trial. If QTcF is ≥ 480 msec or above 
60 msec from baseline on a pre-dose ECG patients should be followed with triplicate ECGs. If 
a patient cannot be dosed due to prolonged QTcF for more than 7 days since last dose, patient 
must be discontinued from study treatment.


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Table 6-5
Dose reductions for QTc prolongation
Time Point
Average QTcF*
Action
Screening and pre-dose 
cycle 1 day 1
≥ 450 msec
Delay treatment
Correct any electrolyte abnormal values ** 
and repeat ECG, if the average QTcF ≥ 450 
msec, do not dose
Above 500 msec
Patient is not eligible
Post dose cycle 1 day 1
Pre/post-dose cycle 1 
day 5
Pre-dose day 1 of 
subsequent cycles
≥ 480 msec or above 60 msec from 
baseline for any pre-dose ECG 
after the patient has commenced 
treatment***
Omit dose
Correct any electrolyte abnormal values **
If unresolved within 7 days, discontinue 
treatment
If resolved within 7 days, resume treatment at 
prior dose for initial occurrence or at reduced 
dose if recurrent
Above 500 msec
Permanently discontinue treatment
*QTc F: Heart rate corrected QT interval using the Fredericia formula: QTc=QT/RR0.33
**: serum potassium, magnesium and phosphorus
***If a single pre-dose QTcF is ≥ 480 msec or 60 msec from baseline, subsequent ECGs should be performed 
in triplicate
6.3.3
Combination Therapy - dosing modifications and delay
Dose modifications for bortezomib and dexamethasone may be performed based on Table 6-6
and Table 6-7 below.
Table 6-6
Dose reduction steps for BTZ s.c
Drug
Starting Dose
1st Dose 
Reduction
2nd Dose 
Reduction
3nd Dose 
Reduction
4th Dose 
Reduction
BTZ 
s.c.
Cycles 1-8 
(TP1)
1.3 mg/m2 twice 
a week
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
Cycles 9 -12* 
(TP2)
1.3 mg/m2 once 
a week (OW)
D 1, 8, 22 & 29
1.0 mg/m2 OW
D 1, 8, 22 & 
29
0.7 mg/m2 OW
D 1, 8, 22 & 
29
Discontinue
Total BTZ dose to be administered is calculated using weight determined on Day 1 of each cycle
* TP2 therapy is started at dose level tolerated at completion of Cycle 8.
Table 6-7
Dose reduction steps for Dex
Starting Dose
Cycles 1-8 on
Days 1, 2, 4, 5, 8, 9, 11, 12
1st Dose Reduction
2nd Dose Reduction
Cycles 1-8 on
Days 1, 2, 4, 5, 8, 9, 11, 12*
20 mg/day of administration
8 or 12 mg/day of administration
Discontinue Dex
Cycles 9-12** (TP2)
on Days 1, 2, 8, 9, 22, 23, 29 and 30
20 mg/day of administration
8 or 12 mg/day of administration on 
Days 1, 2, 8, 9, 22, 23, 29 and 30
Discontinue Dex
* In case of weekly BTZ administration, Dex should be administered on Day 1, 2, 8 and 9.
** TP2 therapy is started at dose level tolerated at completion of Cycle 8


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6.3.3.1
Dose modification guidelines
Each Adverse Event must be attributed to a study drug if possible so that modifications can be 
made accordingly. Reduction of one agent and not the others is appropriate if toxicity is related 
primarily to one of the agents. If multiple toxicities are noted, the dose adjustment should be 
made according to the most severe toxicity guidelines. Investigators can use their discretion 
when making dose-reduction decisions unless otherwise specified in the guidelines below.
Table 6-8
Drug related adverse events dose modification guidelines for BTZ s.c
CTCAE Category
Dose Modification Guideline -
At any time during a cycle of therapy (including intended day of dosing)
Uncomplicated Gr 3 
Neutropenia (ANC < 1.0 x 109/L)
or uncomplicated Gr 3
Thrombocytopenia (PLT < 50 x 
109/L)
No change in dosing
≥ Febrile neutropenia
or Neutropenia Gr 4 (ANC < 0.5 
x 109/L)
and/or
Thrombocytopenia 
Gr 3 (PLT < 50 x 109/L) with 
bleeding,
or Gr 4 (PLT < 25 x 109/L)
Hold therapy until neutropenia and/or thrombocytopenia both resolve to ≤ Gr 2 ;
if only one dose was omitted prior to correction to these levels, BTZ s.c should 
be restarted at same dose,
if two or more doses were omitted - consecutively, or within the same cycle -
then BTZ s.c should be restarted at a reduced dose by one dose.
Peripheral Neuropathy 
See Table 6-9
Herpes Zoster reactivation any 
grade 
Hold therapy until lesions are dry. 
Other BTZ s.c related non-
hematologic toxicity ≥ Gr 3
Determine attribution of toxicity and hold therapy.
If toxicity resolves to ≤ Gr 2, resume therapy with one level dose reduction.
6.3.3.2
Management of patients with bortezomib-related neuropathic pain 
and/or peripheral sensory neuropathy
The neurotoxicity-directed questionnaire 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 dose modification.


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Table 6-9
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 (paresthesias and/or loss of reflexes) without pain or 
loss of function 
No action 
Gr 1 with pain or Gr 2 (interfering with function but not with 
activities of daily living) 
Reduce by one dose level
Gr 2 with pain or Gr 3 (interfering with 
activities of daily living) 
Hold BTZ s.c therapy until 
toxicity resolves to < Gr 2
When toxicity resolves, reinitiate with a reduction by 
one dose levels 
During TP2 cycles discontinue BTZ s.c
Gr 4 (Permanent sensory loss that interferes with function) Discontinue BTZ s.c
Grading based on NCI Common Terminology Criteria CTCAE v4.03
Table 6-10
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, decrease 
Dex dose by 1 dose level
> Gr 3 (requiring hospitalization or 
surgery)
Hold Dex until symptoms adequately controlled. 
Restart and decrease one dose level of current dose 
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 decrease Dex dose by 1 dose 
level; if edema persists despite above measures, 
discontinue Dex and do not resume.
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. If symptoms persist despite 
supportive medical intervention, discontinue Dex and
do not resume.
Musculoskeletal
Muscle weakness
> Gr 2 (symptomatic and
interfering with function +/-
interfering with activities of daily 
living)
Decrease Dex dose by one dose level. If weakness 
persists despite supportive medical intervention, 
decrease dose by one 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, 
decrease dose by one dose level until levels are 
satisfactory


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6.3.4
Follow-up for toxicities
Follow up on potential drug-induced liver injury (DILI) cases
Patients with transaminase increase combined with 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]
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 PK sample, as close as possible to last dose of study drug, 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 


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“potential drug-induced liver injury”. All events should be followed up with the outcome clearly 
documented.
6.4
Concomitant medications
All medications (excluding study treatment components and/or any prior chemotherapy and 
biologic or immunologic) and significant non-drug therapies (including physical therapy and 
blood or platelet transfusions) administered within 14 days prior to the administration of study 
treatment through 30 days after the last treatment of study drug, with reasons for therapy use, 
will be recorded in the Prior and Concomitant medication /Surgical and Medical Procedure
eCRF. Medications include not only physician prescribed medications, but also all over-the-
counter medications, vitamins, herbals and alternative therapies.
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the start of the study treatment. All medications (other than study drug) and 
significant non-drug therapies (including physical therapy and blood transfusions) administered 
after the patient starts treatment with study treatment must be listed on the Prior and 
Concomitant medication /Surgical and Medical Procedure after start of study treatment eCRF.
6.4.1
Permitted concomitant therapy
6.4.1.1
Growth factors
G-CSF may be initiated for an individual patient in accordance with local guideline of each site,
if the patient experiences febrile neutropenia and/or grade 3 or 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 darbepoietin prior to starting study treatment may continue to receive it throughout 
the study. Likewise these can be introduced during the study.
6.4.1.2
Bisphosphonate and anti-RANKL antibody therapy
Bisphosphonate therapy can be maintained if commenced prior to screening period. Mouth care 
is recommended in these patients. Anti-RANKL antibody (Denosumab) can be also maintained 
if commenced prior to screening period.
6.4.2
Permitted concomitant therapy requiring caution and/or action
6.4.2.1
Anti-coagulant therapy
PAN therapy, especially in combination with BTZ, is commonly associated with moderate to 
severe degree of thrombocytopenia. This may lead to an increase in the risk of bleeding 
especially if with concomitant administration of long acting anticoagulation, such as sodium 
warfarin (Coumadin®). It is recommended that patients who require anticoagulation therapy 
while on PAN 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 PAN but for such patients, a close and frequent monitoring 
of the coagulation parameters, including PT/INR should be followed and they should be 


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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.
6.4.2.2
CYP2D6 substrates
In in vitro assays, PAN was shown to inhibit the cytochrome P450 isoenzyme CYP2D6 at low 
micromolar ranges, thereby suggesting a potential risk of drug-drug interactions with 
concomitant medications that are also metabolized by CYP2D6. Clinical DDI study was 
conducted in patients where multiple PAN doses at 20 mg three-times-a-week increased Cmax 
and AUC of dextromethorphan by a mean of 1.8- and 1.6-fold respectively, but with no change 
in Tmax in 17 cancer patients. An approximately 2-fold increase in dextromethorphan AUC 
upon co-administration with PAN indicated that in vivo CYP2D6 inhibition of PAN is weak. In 
general, drugs that are CYP2D6 substrates and have large therapeutic index such as anti-emetics, 
anti-hypertensives, and anti-depressants are safe to be co-administered with PAN. However, 
caution is to be exercised when PAN is co-administered with medications that are exclusively 
metabolized by CYP2D6 and have a narrow therapeutic window (e.g., tamoxifen, anti-
arythmics, oxycodone). Patients should be carefully monitored for potential signs of toxicity 
and may require dose titration or dose reduction of a CYP2D6 substrate which have narrow 
therapeutic window.
6.4.2.3
Drugs that can inhibit CYP3A4/5
PAN is metabolized in vitro by CYP3A4/5. A clinical drug-drug interaction study with 
ketoconazole and PAN has recently been completed. The less than 2-fold increase in PAN AUC 
upon co-administration with ketoconazole suggests that CYP3A contribution to the total 
clearance of PAN is low (40%). The observed interaction is not considered clinically relevant, 
as PAN doses at least 2-fold greater than 20 mg (40 and 60 mg) have been safely administered 
in patients. CYP3A4 inhibitors should have no major impact on the exposure of PAN and may 
be co-administered when medically necessary.
6.4.2.4
Analgesics
Baseline analgesics for tumor-related (bone) pain should be maintained during the study. 
However, an increase in analgesic use for control of bone pain may indicate disease progression. 
If an increase in analgesic medication from baseline is required during the study, the patient 
should be evaluated for progression of disease/bone lesions.
6.4.2.5
Anti-emetics and anti-diarrheal medications
Prophylactic anti-emetics such as granisetron can be administered at the discretion of the 
Investigator. Granisetron is the preferred 5HT3 antagonist, due to the possibility of QT 
prolongation with the other 5HT3 antagonists (e.g. ondansetron, dolasetron, etc). Their use is 
prohibited (see Appendix1).
At the first sign of abdominal cramping, loose stools, or onset of diarrhea, it is recommended 
that the patient be treated with anti-diarrheal medication. See Section 6.3.2.3.


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6.4.2.6
Medications that have the potential to alter serum electrolytes
Patients taking concomitant medications that have the potential to alter serum electrolytes (e.g., 
diuretics) should be monitored very closely for electrolyte abnormalities as these can contribute 
to the risk of QT prolongation and ventricular arrhythmias. Electrolyte abnormalities should be 
corrected prior to dosing.
Other treatments, described in Section 6.4.1.2 and Section 6.4.2.7 are allowed as medically 
indicated and apply to the entire study duration or defined parts of the study.
6.4.2.7
Vitamin Supplements
Vitamin supplements are suggested in the event of peripheral neuropathy or for those patients 
deemed to be at risk, at the discretion of the investigator.
6.4.3
Prohibited concomitant therapy
See Appendix 1 for a full list of prohibited medications

Investigational agents

Chemo-, biologic or immunologic therapy and/or other investigational agents

DAC inhibitors

Strong CYP3A4/5 inducers
6.5
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 trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Novartis 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 EDC interface.
6.6
Study drug preparation and dispensation
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record eCRF.
6.6.1
Study drug panobinostat
Oral PAN will be supplied as 10-mg and 15-mg hard gelatin capsules and will be given on a 
flat scale of mg on a given day. The capsules are packaged in HDPE bottles with plastic child 
resistant closures or boxes. Each study site will be supplied by Novartis with study drug in 
identically-appearing packaging. Medication labels will be in the local language and comply 
with the legal requirements of Japan. They will include storage conditions for the drug (For 
details, see study drug handling procedure which is provided by Novartis)


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6.6.2
Bortezomib s.c.
Bortezomib (Velcade®) is a commercially available product that will be prescribed by the 
investigator and will be administered by site personnel at the study site.
Refer to the Product information sheet of Velcade® (bortezomib) for detailed information on 
handling and precautions (Velcade® Product information sheet and applicable health authority 
recommendations).
6.6.3
Dexamethasone oral
Dexamethasone (LenaDex®) will be sourced locally by each investigational site. Refer to the 
Dexamethasone LenaDex® product information for detailed information on handling and 
precautions regarding the use of tablets of dexamethasone for oral administration. On days when 
BTZ is administered, Dex should be taken prior to BTZ administration.
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. For most visits, there is a ± 3days window on assessments to take into account 
scheduling over public holidays if not explicitly specified otherwise. Assessments that are 
required at screening visit and on cycle 1 day 1 do not have to be repeated if performed ≤ 7 days 
prior to cycle 1 day 1 unless otherwise specified. All data obtained from these assessments must 
be supported in the patient’s source documentation.
No CRF will be used as a source document.
The table indicates which assessments produce data to be entered into the clinical database (D) 
or remain in source documents only (S) (“Category” column).


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Table 7-1
Visit evaluation schedule
Category
Reference to Section
Screening
Treatment Phase
Follow-up Phase
Treatment Phase 1
Treatment Phase 2
End of Treatment
30 day safety 
Follow-up
Disease Follow-
up
Study Evaluation 
Completion
Survival
Cycle 1
(day 1 to 21)
Cycle 2 - 8
(day 1 to 21)
After Cycle 9
(day 1 to 42)
Day of cycle
- 21 to -
1
1
2
3
4
5
8
9
10
11
1
4
8
11
1
8
22
29
Informed consent
D
7.1.1
X
Patient history
Demography
D
7.1.1
X
Inclusion/exclusion 
criteria
D
5.2, 
5.3
X
Medical history/ 
current medical 
conditions
D
7.1.1
X
Diagnosis & 
history of MM
D
7.1.1
X
Prior 
antineoplastic 
therapy
D
7.1.1
X
Bone Marrow
FISH
D
7.2.1
X
Administration
Bortezomib (BTZ)
D
6.1
X
X
X
X
X
X
X
X
X
X
X
X
Panobinostat 
(PAN)
D
6.1
Days 1-3 -5 + 8-10-12 (3 times weekly, 2 weeks on & 1 week off, 
3 weeks cycle)
Days 1-3-5, 8-10-12 
& 22-24-26, 29-31-
33
(6 weeks cycle)


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Category
Reference to Section
Screening
Treatment Phase
Follow-up Phase
Treatment Phase 1
Treatment Phase 2
End of Treatment
30 day safety 
Follow-up
Disease Follow-
up
Study Evaluation 
Completion
Survival
Cycle 1
(day 1 to 21)
Cycle 2 - 8
(day 1 to 21)
After Cycle 9
(day 1 to 42)
Day of cycle
- 21 to -
1
1
2
3
4
5
8
9
10
11
1
4
8
11
1
8
22
29
Dexamethasone 
(Dex) 
D
6.1
Days 1-2-4-5 + 8-9-11-12
Days 1-2-8-9 +
22-23-29-30
Physical assessments
Vital signs 
D
7.2.2
X 
X
X
X
X
X
Height
D
7.2.2
X
Weight / BSA
D
7.2.2
X 
X
X
X
X
Physical 
examination 
S
7.2.2
X 
X
X
X
X
ECOG PS
D
7.2.2
X 
X
X
X
X
Efficacy assessments
Investigator 
response 
assessment
D
7.2.1
X
X
X
X
X
Electrophoresis 
(Serum and urine)
D
7.2.1
X
X
X
X
X
X
X
Immunofixation 
(Serum and urine)
D
7.2.1
X
X
X
X
X
X
Serum 
immunogloblin
D
7.2.1
X
X
X
X
X
X
X
Skeletal survey
D
7.2.1
X


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Category
Reference to Section
Screening
Treatment Phase
Follow-up Phase
Treatment Phase 1
Treatment Phase 2
End of Treatment
30 day safety 
Follow-up
Disease Follow-
up
Study Evaluation 
Completion
Survival
Cycle 1
(day 1 to 21)
Cycle 2 - 8
(day 1 to 21)
After Cycle 9
(day 1 to 42)
Day of cycle
- 21 to -
1
1
2
3
4
5
8
9
10
11
1
4
8
11
1
8
22
29
Evaluation of soft-
tissue 
plasmacytomas
D
7.2.1
X
X
X
X
X
X
CT or MRI 2
D
7.2.1
X
X
X
X
X
Bone Marrow 
D
7.2.1
X
Safety assessments
Hematology3
D
7.2.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation
D
7.2.2
X
X
Biochemistry
D
7.2.2
X
X
X
X
X
X
X
X
X
Urinalysis
D
7.2.2
X
X
Thyroid function
D
7.2.2
X
X
Pregnancy test
D
7.2.2
X
X
X
X
X
12-lead ECG
D
7.2.2
X
X
X
X
LVEF
D
7.2.2
X
X
Adverse Events
D
8.1, 
8.3
X
Continuous
Prior/Concomitant 
medications
D
6.4
X
Continuous
Pharmacokinetics
PAN Blood 
samples
D
7.2.7
X
X
X
X
X
X
BTZ Blood 
samples
D
7.2.7
X
X
X


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Category
Reference to Section
Screening
Treatment Phase
Follow-up Phase
Treatment Phase 1
Treatment Phase 2
End of Treatment
30 day safety 
Follow-up
Disease Follow-
up
Study Evaluation 
Completion
Survival
Cycle 1
(day 1 to 21)
Cycle 2 - 8
(day 1 to 21)
After Cycle 9
(day 1 to 42)
Day of cycle
- 21 to -
1
1
2
3
4
5
8
9
10
11
1
4
8
11
1
8
22
29
PRO
QoL 
questionnaires
D
7.2.5
X
X
X
X
X
Other
Post antineoplastic 
therapy
D
X
Continuous
Survival
D
X
2. In case of plasmacytoma is/are present at screening, assessment of that lesion(s) by MRI or CT is required at screening, and thereafter every 6 weeks during 
treatment phase, end of treatment and follow-up, i.e.: at day 1 of cycle 3, cycle 5, cycle 7, cycle 9, 10, 11, and 12.
3. In case of once week BTZ administration, hematology test at Day4 and Day 11 and biochemistry at day11 are not mandatory between cycle 2 to cycle 8.


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7.1.1
Screening
Screening examination (Visit 1) is to include the procedures found in Table 7-1 and should 
occur within 21 days prior to baseline (C1D1). The informed consent must be signed prior to 
ANY screening procedure being performed.
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 3 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 3 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.
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. 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.
If the plasma cell count 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.
7.1.1.1
Eligibility screening
Patient eligibility will be checked by the Sponsor once all screening procedures are completed. 
The eligibility check form will be sent from the site to the Sponsor for evaluation. Upon 
confirmation of eligibility, the Sponsor will return the signed eligibility check form to the site. 
The investigator site will then be allowed to assign treatment to the patient.
7.1.1.2
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.
7.1.1.3
Patient demographics and other baseline characteristics
Standard demographic information and medical history will be collected. Baseline assessments 
will be collected as per Table 7-1.


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7.1.2
Treatment period
The maximum duration of the study treatment period is 48 weeks or until disease progression, 
unacceptable toxicity, death, or discontinuation from the study treatment due to any other reason. 
For details of assessments, refer to Table 7-1. For most visits, there is a ± 3days window on 
assessments.
If a patient requires a dose delay > 21 days from the intended day of the next scheduled dose, 
the patient should be discontinued from the study treatment. If, however, the patient was clearly 
benefiting from study treatment and the cause of delay has resolved, the patient may be able to 
restart study treatment upon agreement of the Investigator and the Sponsor.
7.1.3
Discontinuation of study treatment
Patients may voluntarily withdraw from 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 to determine the primary reason for this decision and record this information in the 
patient’s chart and on the appropriate eCRF 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, on balance, he/she 
believes that continuation would be detrimental to the patient’s well-being.
Study treatment must be discontinued under the following circumstances:

Pregnancy

Use of prohibited treatment, as described in Appendix 1

Any other protocol deviation that results in a significant risk to the patient’s safety

Study Terminated by Sponsor

Patient/guardian decision

Physician decision

Lost to follow-up

Death
Patients may permanently stop the study treatment for one of the following reasons:

Technical Problems

Protocol deviation
Patients who discontinue study treatment should NOT be considered withdrawn from the study. 
They should return for the assessments indicated in Table 7-1. If they fail to return for unknown 
reasons, every effort (e.g., telephone, email, letter) should be made to contact them as specified 
in Section 7.1.5.
Patients who become pregnant during the trial must be withdrawn (Section 8.3). Patients who 
become pregnant must cease all efficacy assessments regardless of whether or not they 
developed Progressive Disease.
Patients who discontinue study treatment during the treatment phase should be scheduled for a 
visit as soon as possible and within 7 days after the last dose of study treatment, at which time 


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all of the assessments listed for the EOT visit will be performed. If a patient withdraws from 
treatment at a study visit, EOT assessments do not need to be repeated. An End of Treatment 
Phase Disposition eCRF page should be completed, giving the date and reason for stopping 
study treatment.
At a minimum, all patients who discontinue study treatment, including those who refuse to 
return for a final visit, be contacted for safety evaluations within 30 days after the last dose of 
study treatment. The investigator should inquire about any AE observed/concomitant 
medication taken during this 30-day period. This can be done via a phone contact. 
Antineoplastic therapies will be captured on the 'Antineoplastic therapies since discontinuation 
of study treatment' eCRF page following the last study treatment.
If patients refuse to return for these visits or are unable to do so, every effort should be made to 
contact them or a knowledgeable informant by telephone to determine the survival status.
Patients who discontinue study treatment should be considered withdrawn from the study after 
the final visit assessments are performed or when it is clear that the patient will not return for 
these assessments.
If a patient discontinues study treatment, but continues study assessments, (e.g. during post 
treatment follow up phase as detailed in Table 7-1), the patient remains on study until such time 
as he/she completes protocol criteria for ending study assessments. At that time, the reason for 
study completion should be recorded on the End of Post Treatment Phase Disposition (Study 
Phase Completion) eCRF page.
Patients who discontinue study treatment should enter the survival follow-up period or continue 
tumor assessments when appropriate. For patients who discontinue treatment for reasons other 
than documented disease progression, relapse 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, withdrawal of consent or End of study.
7.1.3.1
Additional guidance for premature withdrawal
If a patient will have no further study data collected because he/she withdraws from the study 
completely, the investigator must determine the primary reason for a patient’s premature 
withdrawal from the study and record this information on the End of Treatment Phase 
Completion eCRF as applicable. The investigator must show "due diligence" by documenting 
in the source documents steps taken to contact the patient, e.g., dates of telephone calls, 
registered letters, etc. If the patient was still taking study medication at the time of the 
withdrawal, the End of Treatment eCRF should also be completed.
Patients may voluntarily withdraw from the study or be discontinued from the study at the 
discretion of the investigator at any time.
7.1.4
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 
longer, and does not want any further visits or assessments, and does not want any further study 
related contact.


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Novartis 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 to determine 
the primary reason for this decision and record this information.
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.
7.1.5
Follow up period
7.1.5.1
Safety follow up
All patients will be followed for AEs and SAEs for at least 30 days following the last dose of 
study treatment at the end of treatment phase.
The investigator should inquire about any AE observed/concomitant medication taken during 
this 30-day period. This can be done via a phone contact. Antineoplastic therapies will be 
captured on the 'Antineoplastic therapies since discontinuation of study treatment' eCRF page 
following the last study treatment.
7.1.5.2
Post-Treatment Follow-up
If a patient completes or discontinues study treatment in the absence of PD or relapse, disease
assessments every 6 weeks +/- 3 days should continue to be performed from the EOT visit until 
PD/relapse(by investigator), death, lost to follow-up, withdrawn consent to efficacy follow-up 
occurs or End of study; however, safety assessments do not need to continue to be performed.
If a patient decides to discontinue from the study treatment, they must be asked if they agree 
for continuation of efficacy assessments in absence of dosing with study treatment. 
Antineoplastic therapies since completion or discontinuation of study treatment will continue 
to be collected.
Once the patient ceases disease follow-up, the reason for completion should be recorded on the 
Study Phase Completion Disposition eCRF page.
7.1.5.3
Survival follow-up
All patients who had PD/relapse as per investigator assessment or withdrew consent from 
further study assessments will subsequently be followed for survival information every 12 
weeks +/- 14 days until death, lost to follow-up, withdrawal of consent for survival follow-up
or the End of study. The investigator or his designee will collect this survival information and 
any new anti-neoplastic therapies for all patients until the final survival analysis.
Follow-up can be done via a phone contact. Antineoplastic therapies will be captured on the 
'Antineoplastic therapies since discontinuation of study treatment' eCRF page following the last 
dose of the study treatment.


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7.1.5.4
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.
7.2
Assessment types
7.2.1
Efficacy assessments
7.2.1.1
M-protein, immunoglobulins fractions (serum and urine)
M-protein and immunoglobulins fractions (measured by Protein Electrophoresis) must be 
performed at visits indicated in Table 7-1. A 24hr urine sample must be collected for the 
assessments. More frequent assessments may be performed if medically indicated as 
determined by the Investigator, and these evaluations should be recorded on the Unscheduled 
Visit eCRF.
Per modified EBMT criteria any assessment indicating a response needs to be repeated after 6 
weeks to confirm the response level.
If progressive disease is suspected based on M-protein result a repeat assessment is required to 
confirm PD. No time window applies for the confirmation of PD. It is recommended to repeat 
the assessment as soon as possible.
Assessments are to be performed at the central laboratory, 
7.2.1.2
Immunofixation (serum and urine)
Immunofixation assessment will be performed to qualify and to confirm any response better 
than PR at visits indicated in Table 7-1. Assessments are to be performed at the central 
laboratory, 
7.2.1.3
Serum immunoglobulins
Serum immunoglobulins assessment will be performed at visits indicated in Table 7-1.
Assessments are to be performed at the central laboratory, 
 
7.2.1.5
Bone Marrow
A bone marrow (BM) aspirate will need to be collected for a plasma cell (PC) count, FISH and 
standard cytogenetics at visit indicated in Table 7-1 and at the following times. PC count will 
be performed at each trial center at:


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
Screening, to determine eligibility

On study, a repeat bone marrow aspirate for PC count is required, within 3 weeks of other 
disease assessments results suggestive of CR per EBMT criteria (not nCR), in order to 
qualify CR, 
 by flow cytometry at the central laboratory, LSI. 
All efforts should be taken to not delay BM aspirate PC count when other criteria for CR 
are met
Standard cytogenetics will be assessed at each trial center at screening visit.
7.2.1.6
Skeletal survey (bone X- ray)
Skeletal survey should be performed at screening. If results of a skeletal survey performed 
within 8 weeks prior to screening visit are available, and if there is no clinical indication to 
repeat, then skeletal survey need not to be repeated at screening visit.
Bone X-ray oriented by symptom location (e.g. bone pain), are to be performed if medically 
indicated and to assess PD as determined by the Investigator, and these evaluations should be 
recorded on the Unscheduled Visit eCRF.
7.2.1.7
Evaluation of soft- tissue plasmacytomas
Soft tissue plasmacytoma must be assessed by clinical examination at visit indicated in
Table 7-1. In case of findings at any time, assessment by MRI or CT is required.
7.2.1.7.1 Plasmacytoma present at screening
If plasmacytoma(s) is already known or detected at screening, in addition to repeating clinical 
assessment as described above, assessment by CT or MRI is required every 6 weeks as 
mentioned Table 7-1. The same imaging technique should be used throughout the trial.
More frequent assessments should be performed in case of findings or if medically indicated as 
determined by the Investigator. These evaluations should be recorded on the Unscheduled Visit 
eCRF. The same imaging technique should be used throughout the trial.
7.2.1.8
Serum calcium variables
Hypercalcemia will be assessed for disease evaluation during study until end of follow-up. The 
total serum calcium, serum albumin or ionized serum calcium assessment as part of the 
biochemistry assessments is to be performed at visit indicated in Table 7-1. Assessments are to 
be performed at each trial center.
7.2.2
Safety assessments
Safety will be monitored by the assessments described below as well as the collection of AEs 
at every visit. For details on AE collection and reporting, refer to Section 8.


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7.2.2.1
Physical examination
Physical examinations will include an examination of general appearance, skin, neck (including 
thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, and a 
basic nervous system evaluation. Information about the physical examination must be present 
in the source documentation at the study center. For the assessment schedule refer to Table 7-
1.
7.2.2.2
Vital signs
Vital signs include body temperature, respiratory rate, sitting blood pressure and sitting pulse 
measurements. For the assessment schedule refer to Table 7-1.
7.2.2.3
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, 
but without shoes) will be measured. BSA will be calculated as defined by the institution or as 
published in (Mosteller et al 1987). Height will be measured at screening only. For the 
assessment schedule for weight refer to Table 7-1.
7.2.2.4
Performance status
ECOG performance status will be assessed as per the assessment schedule (refer to Table 7-1).
Assessment of ECOG performance status (Table 7-2) will be performed within the time 
windows described above of the scheduled assessment, even if study medication is being held. 
More frequent examinations may be performed at the investigator’s discretion, if medically 
indicated.
Table 7-2
ECOG performance status scale
Score
Performance Status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g. light housework, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
7.2.2.5
Laboratory evaluations
The standard clinical laboratory analyses described Table 7-3 are to be performed by the study 
site’s local laboratories according to Table 7-1. Laboratory tests will be collected and analyzed 
on the scheduled day, even if study medication is being withheld. More frequent examinations 
may be performed at the investigator’s discretion if medically indicated and these results should 
be recorded on the Unscheduled Visit eCRFs as applicable.


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Table 7-3
Clinical laboratory parameters collection plan
Test Category
Test Name
Hematology (Local)
Hemoglobin, Platelets, Red blood cells, White blood cells with Differential (Basophils, 
Eosinophils, Lymphocytes, Monocytes, Neutrophils)
Biochemistry (Local)
BUN, β-2 Microglobulin, creatinine, sodium, potassium, Fasted glucose, total calcium 
(corrected for serum albumin) or ionized calcium, albumin, total protein, total bilirubin, 
LDH, alkaline phosphatase, AST/SGOT, ALT/SGPT, phosphorous and magnesium. If 
total bilirubin > ULN, direct and indirect bilirubin should be performed.
Coagulation (Local)
Prothrombin time (PT) or International normalized ratio (INR), activated partial 
thromboplastin time (aPTT), fibrinogen 
Urinalysis (Local)
Dipstick examination includes: protein, glucose, blood, and specific gravity
Microscopic examination is only required if dipstick result is abnormal, it includes: 
WBC/HPF, RBC/HPF
Thyroid (Local)
T3 [free], T4 [free], TSH
7.2.2.6
Pregnancy and assessments of fertility
During screening, all pre-menopausal women who are not surgically sterile will have a serum 
hCG-β pregnancy test. On Cycle 1 Day 1 prior to dosing and at subsequent cycles and at EOT, 
serum or urinary pregnancy test will be performed. A positive pregnancy test requires 
immediate interruption of study treatment until the assessment is confirmed. If positive, the 
patient must be discontinued from the study treatment.
7.2.2.7
Electrocardiogram (ECG)
12-lead ECGs will be performed at a minimum at visits indicated in Table 7-1 as indicated in 
Table 7-4. With regard to Cycle1 day5, pre-dose ECGs can be done on Cycle1 Day 4 visit when 
patient is at the site for BTZ s.c administration but not post-dose ECGs of Day 5 as relative to 
PAN dosing. All ECGs will be read at each trial center.
Table 7-4
ECG assessment monitoring schedule
Cycle
Day of cycle
ECG monitoring
Screening
3 sequential ECGs separated by at least 5-10 minutes
Cycle 1
1, 5
Pre-dose: 
Single ECG 
Post-dose at 3 hours ± 0.5 hour:
Single ECG
Cycle 2-8
1
Pre-dose: 
Single ECG
QTcF interval, QTcB interval, QT interval, RR interval, PR interval, QRS duration and ventricular rate are 
collected to eCRF.
QTc F: Heart rate corrected QT interval using the Fredericia formula: QTc=QT/RR0.33
7.2.2.8
Cardiac imaging - MUGA (multiple gated acquisition) scan or 
echocardiogram
A baseline MUGA scan or echocardiogram to assess LVEF will be performed at visits indicated 
in Table 7-1. At day 1 Cycle 1 unless the above screening assessment was correct and obtained 
≤ 7 days prior to first administration of study treatment. If the result from this MUGA/ECHO 
shows a clinically relevant change (e.g. a reduction of >5% or as defined by the institution), a 
formal cardiac evaluation should be sought and a repeat MUGA/echo be conducted at the 


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beginning of every-other treatment cycle (or at the discretion of the cardiologist/investigator). 
More frequent assessments may be performed if medically indicated as determined by the 
Investigator, and these evaluations should be recorded on the Unscheduled Visit eCRF.
7.2.3
Tolerability
In addition to general safety data, information on dose reductions will be collected.
7.2.4
Resource utilization
Not applicable
7.2.5
Patient reported outcomes
The Functional Assessment of Cancer Therapy Gynecology Oncology Group Neurotoxicity 
scale (FACT/GOG-NTX) is an 11 item measure to assess neurotoxicity from systemic 
chemotherapy. The recall period for this measure is the past 7 days.
Patient questionnaires should be completed before any study drug administrations at the visits 
indicated in Table 7-1. Questionnaires should be completed in the patient’s local language at 
the beginning of the study visit prior to any interaction with the study investigator including 
any tests, treatments or receipt of results from any tests to avoid biasing the patient’s perspective. 
Attempts should be made to collect all questionnaires for all patients, including those who 
discontinue prior to the study evaluation completion visit.
Completed questionnaires, including both responses to the questions and any unsolicited 
comments written by the patient, should be reviewed and assessed by the investigator before 
the clinical examination for responses which may indicate potential AEs or SAEs. This review 
should be documented in study source records.
7.2.6
Pharmacokinetics
PK sample collection will be performed in patients who agree to blood samplings for the PK 
assessments of PAN and BTZ.
The following conditions are to be followed on the days of PK: Each patient should have a meal 
(breakfast) shortly before administration of any components of study treatment. The order of 
administration of the three study treatment components will be 1) PAN, 2) Dex and 3) BTZ.
PK sampling schedule is as follows, i.e. at:

C1 D1, prior to dosing of PAN, BTZ s.c and Dex

C1 D1, serial blood collection following dosing of PAN, BTZ s.c and Dex

C1 D2 and D3, 2 samples (24 hrs and 48 hrs post C1D1 dose)

C1 D8, prior to dosing of PAN, BTZ s.c and Dex

C1 D8, serial blood collection following dosing of PAN, BTZ s.c and Dex

C1 D9 and D10, 2 samples (24 hrs and 48 hrs post C1D8 dose)
PK collections for both BTZ and PAN may be collected at the same time (6 mL of whole blood 
at the common collection time points) provided that dose administration of BTZ s.c and PAN 


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is in tandem. Please record dosing time for each drug and collection times on the appropriate 
eCRF pages.
At specified time points (Table 7-5 and Table 7-6), 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 and BTZ, 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. Plasma will be aliquoted and transferred to a polypropylene 
screw-cap tube, the tube capped, and the sample mixed briefly and then immediately placed in 
a freezer set at ≤ -60ºC until shipment to the central laboratory for both PAN and BTZ plasma 
PK samples. Refer to the [LBH589D1201 PK Laboratory Manual] for detailed instructions for 
the collection, handling, and shipping of samples.
Residual plasma samples after drug concentration measurement may be used for further 
pharmacokinetic investigations for PAN and BTZ (e.g., protein binding, metabolism, etc).
Table 7-5
Pharmacokinetic blood collection log for panobinostat
Dose Reference ID
PK Sample 
number
Cycle (Period 
number)
Study day
Time
Blood 
volume 
(mL)
1
1
1
1
0 (pre-dose)
2
1
2
1
1
0.5 h
2
1
3
1
1
1 h
2
1
4
1
1
2 h
2
1
5
1
1
3 h
2
1
6
1
1
4 h
2
1
7
1
1
8 h
2
1
8
1
2
24 h
2
1
9
1
3
48 h (before day 3 
dosing)
2
2
201*
10
1
8
0 (pre-dose)
2
2
11
1
8
0.5 h
2
2
12
1
8
1 h
2
2
13
1
8
2 h
2
2
14
1
8
3 h
2
2
15
1
8
4 h
2
2
16
1
8
8 h
2
2
17
1
9
24 h 
2
2
18
1
10
48 h (before day 
10 dosing)
2
Total volume
36
Unscheduled samples
NA
NA
100x
NA
NA
Unscheduled
2


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Dose Reference ID
PK Sample 
number
Cycle (Period 
number)
Study day
Time
Blood 
volume 
(mL)
*: Dose reference ID to collect previous dose information
Unscheduled blood samples will be uniquely, sequentially numbered 1001, 1002,…(for panobinostat)
Note: The plasma samples collected for PAN PK will be also used for measurement of the metabolite BJB432, 
if feasible.
Table 7-6
Pharmacokinetic blood collection log for bortezomib
Dose Reference ID
PK Sample 
number
Cycle
(Period number)
Study day
Time
Blood 
volume 
(mL)
3
301*
101
1
8
0 (pre-dose)
4
3
102
1
8
0.083 h
4
3
103
1
8
0.25 h 
4
3
104
1
8
0.5 h
4
3
105
1
8
1 h
4
3
106
1
8
2 h
4
3
107
1
8
3 h
4
3
108
1
8
4 h
4
3
109
1
8
8 h
4
3
110
1
9
24 h 
4
3
111
1
10
48 h (before day 
10 dosing)
4
Total volume
44
Unscheduled samples
NA
NA
200x
NA
NA
Unscheduled
4
*: Dose reference ID to collect previous dose information
Unscheduled blood samples will be uniquely, sequentially numbered 2001, 2002,…(for bortezomib)
7.2.7
PK sample labelling
The pharmacokinetic samples will be labeled as Table 7-7.
Table 7-7
PK sample labelling
Study Code:
CLBH589D1201
Study drug
panobinostat (PAN) or bortezomib (BTZ) 
Subject Number:
____________ (e.g. 0501-00001)
Date of Collection: dd/mm/yr
Day____ Month _____ Year______
Sample Number:
See Table 7-5 and Table 7-6
Cycle and study day
See Table 7-5 and Table 7-6
All label information should be prepared on the label.
7.2.8
Analytical method
7.2.8.1
Panobinostat
Plasma samples for PAN PK will be assayed for concentrations of PAN (and the metabolite, 
BJB432, if feasible) using a validated liquid chromatography-tandem mass spectrometry assay 


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(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.
7.2.8.2
Combination agent - bortezomib
The plasma samples for BTZ PK will be assayed for concentrations of BTZ with a validated 
LC-MS/MS assay with LLOQ of approximately 0.1 ng/mL. Values below LLOQ will be 
reported as zero. Missing values will be labeled accordingly.
7.2.9
PK analysis
PK parameters listed in Table 7-7 will be calculated from concentration-time data for PAN (and 
the metabolite BJB432, if feasible) and BTZ using Phoenix WinNonlin (Pharsight, Mountain 
View, CA).
Table 7-8
Noncompartmental pharmacokinetic parameters of panobinostat and 
bortezomib
AUClast
The AUC from time zero to the last measurable concentration sampling time (Tlast) 
(ng*h/mL )
AUC0-24h
The AUC from time zero to 24 h (ng*h/mL )
AUC0-48h
The AUC from time zero to 48 h (ng*h/mL )
AUCinf
The AUC from time zero to infinity (ng*h/mL )
Cmax
The maximum (peak) observed plasma concentration (ng/mL)
Tmax
The time to reach maximum (peak) plasma concentration (h)
Lambda_z
The terminal elimination rate constant (h-1)
T1/2
The elimination half-life associated with the terminal slope (Lambda_z) of a semi 
logarithmic concentration-time curve (h)
CL/F
The apparent total body clearance of drug from the plasma ( L/h)
Vz/F
The apparent volume of distribution during terminal phase (associated with Lambda_z) (L)
These parameters will be calculated if feasible. For a metabolite BJB432, the same parameters will be 
calculated, except for CL/F and Vz/F, if feasible.
8
Safety monitoring and reporting
8.1
Adverse events (AEs)
8.1.1
Definitions and reporting
An AE 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 AEs 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).
AEs that begin or worsen after informed consent should be recorded in the Adverse Events 
eCRF. Conditions that were already present at the time of informed consent should be recorded 


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in the Medical History page of the patient’s eCRF. AE monitoring should be continued for at 
least 30 days following the last dose of study treatment. AEs (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 AE.
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03. If CTCAE grading does not exist for an AE, the severity of mild, 
moderate, severe, and life-threatening, corresponding to Grades 1 - 4, will be used. CTCAE 
Grade 5 (death) will not be used in this study; rather, information about deaths will be collected 
though a Death eCRF. The occurrence of AEs 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. AEs 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:
1. The severity grade (CTCAE Grade 1-4)
2. Its duration (Start and end dates)
3. Its relationship to the study drug (Reasonable possibility that AE is related: No, Yes)
or
Its relationship to the study drug (Reasonable possibility that AE is related: No,
Yes, investigational treatment, Yes, the study treatment (non-investigational), Yes, both 
and/or indistinguishable)
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)
6. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown)
7. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1.
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 eCRF.
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 (for example, as per EBMT criteria for MM), 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 
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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 eCRF. 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 
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.
8.2
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

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 
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8.2.2
Reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence.
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. 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.
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, and submit the completed form within 24 hours Novartis. 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 sent to the same contact(s) to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original 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 Novartis study treatment, an oncology Novartis 
Drug Safety and Epidemiology (DS&E) department associate may urgently require further 
information from the investigator for Health Authority reporting. Novartis 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
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 


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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 must 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.
8.4
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.
8.5
Data Monitoring Committee
Not applicable.
8.6
Steering Committee
Not applicable.
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 


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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 
to enable appropriate age-related normal ranges to be used in assessing laboratory test results.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review 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. Novartis 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
This study use Electronic Data Capture (EDC), the designated investigator staff will enter the 
data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs 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 eCRFs 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 eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner.
9.4
Database management and quality control
Novartis 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 


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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 relating to protein electrophoresis, immunofixation, immunoglobulin and 
PK will be processed centrally and the results will be sent electronically to Novartis.
At the conclusion of the study, the occurrence of any protocol deviations will be determined. 
Once 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.
After database lock, the investigator will receive a CD-ROM or paper copies of the patient data 
for archiving at the investigational site.
10
Statistical methods and data analysis
The primary analysis of study data will be performed when all patients have been treated for 24 
weeks or discontinued treatment. Additionally, follow-up efficacy and safety data will also be 
summarized in a separate report.
In the review process of panobinostat submission for indication of relapsed or refractory MM
in Japan, 
 requested sponsor to conduct additional interim report to present the key 
efficacy and safety information in public per approximately 6 months basis. Prior to the primary 
analysis time point, no statistical testing will be conducted as key efficacy in the interim report.
10.1
Analysis sets
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients who took at least one dose of study treatment.
10.1.2
Safety Set
The Safety Set includes all patients who received at least one dose of study medication.
10.1.3
Pharmacokinetic analysis set
The pharmacokinetic analysis set for PAN (PAS-PAN) consists of all patients with at least one 
evaluable PK data of PAN. PAS-BTZ consists of all patients with at least one evaluable PK 
data of BTZ.
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data (including disease characteristics) will be summarized 
descriptively for FAS.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be presented.


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10.3
Treatments (study treatment, concomitant therapies, 
compliance)
Data on the study treatment administration will be summarized. The duration of treatment and 
relative dose intensity of each of the components of study treatment will be summarized using 
descriptive statistics.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized.
10.4
Primary objective
The primary objective of the study is to assess efficacy of panobinostat (PAN) by nCR+CR rate 
after all patients have been treated for 8 cycles or discontinued treatment. The nCR+CR rate is 
based on modified EBMT criteria per investigator assessment in patients with relapsed multiple 
myeloma or relapsed and refractory multiple myeloma.
10.4.1
Variable
The proportion of patients with a near Complete Response (nCR) or complete response (CR) as 
their best overall response is definition for nCR+CR rate. The nCR+CR rate will be assessed 
according to modified EBMT criteria.
10.4.2
Statistical hypothesis, model, and method of analysis
The primary analysis will be based on a single-sample binomial test (normal approximation) at 
the one-sided 5% significance level, analyzed in the FAS.
The study targets the nCR+CR rate of 25%. A response rate of 10% or less is considered as an 
insufficient level of activity for the proposed patient population. Therefore the null and the 
alternative hypothesis are defined as follows: Ho: nCR+CR rate ≤ 10%, Ha: nCR+CR rate > 
10%.
10.4.3
Handling of missing values/censoring/discontinuations
For the purposes of the primary analysis, patients with a best overall response of ‘Unknown’ 
(UNK) will be treated as non-responders in estimating the nCR+CR rate in the FAS.
10.5
Secondary objectives
The key secondary objective is to evaluate progression free survival (PFS), defined as time from 
first dose of study treatment to progression or death due to any cause per investigator in patients 
with relapsed multiple myeloma or relapsed and refractory multiple myeloma.
Other secondary efficacy objectives are to evaluate overall response rate (ORR), overall 
survival (OS), minimal
response rate (MRR), time to response (TTR), time to 
progression/relapse (TTP) and duration of response (DOR).
The secondary safety objective is to assess safety of the combination therapy.
The secondary pharmacokinetic objective is to assess the PK of PAN and bortezomib (BTZ) in 
a subset of patients.


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Population and grouping for the analyses
The secondary efficacy variables will be analyzed using the FAS. For all safety analyses, the 
safety set will be used. For all PK analyses, pharmacokinetic analysis sets will be used.
10.5.1
Key secondary objective(s)
Progression free survival (PFS) is defined as the time from first dose of study treatment to 
progression or death due to any cause.
Survivorship functions will be estimated by using the Kaplan-Meier product-limit method and 
displayed as graphs. Median PFS time and its two-sided 95% confidence intervals will be 
reported.
A patient who has not progressed/ relapsed, or died at the date of the analysis cut-off or when 
he/she receives any further anti-cancer therapy would have his/her PFS censored at the time of 
the last adequate response assessment before or at the cut-off date or before start of further anti-
cancer therapy. An adequate response assessment is considered any disease assessment 
indicating response status apart from “unknown” or “not done”.
10.5.2
Other secondary efficacy objectives
Other secondary efficacy variables include overall response rate (CR, nCR or PR), minimal
response rate (MRR), time to response (TTR), time to progression/relapse (TTP) and duration 
of response (DOR). The assessment of these endpoints will be based on modified EBMT criteria 
per investigator assessment.
Overall response rate (ORR) is defined as the proportion of patients with CR or nCR or PR.
Overall survival (OS) is defined as time from first dose of study treatment to death.
Time to response (TTR) is the time between date of first dose of study treatment until first 
documented response (CR or nCR or PR).
Duration of response (DOR) is defined as the time from the first documented occurrence of 
response (PR or nCR or CR) until the date of the first documented disease progression or relapse 
or death due to multiple myeloma.
Time to progression/relapse (TTP) is defined as the time from the date of first dose of study 
treatment to the date of the first documented disease progression or relapse.
Estimated ORR along with corresponding 95% confidence intervals will be presented.
Estimated MRR along with corresponding 95% confidence intervals will be presented.
Median TTR, DOR and TTP along with corresponding 95% confidence intervals will be 
presented.
ORR, MRR, TTR and TTP will be analyzed based on the FAS. However, DOR will be analyzed 
based on data from responders (CR or nCR or PR) in the FAS.


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10.5.3
Safety objectives
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
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 30+1 after last dose of study medication.
10.5.3.2 Adverse events (AEs)
Summary tables for adverse events (AEs) have to include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs. However, all safety data 
(including those from the pre and post-treatment periods) will be listed and those collected 
during the pre-treatment and post-treatment period are to be flagged.
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment.
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and 
tabulated by type of adverse event.
10.5.3.3 Laboratory abnormalities
For laboratory tests covered by the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03 the study’s biostatistical and reporting team will grade laboratory data 
accordingly. For laboratory tests covered by CTCAE, a 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, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges.
The following by-treatment summaries will be generated separately for hematology, 
biochemistry and urinary laboratory tests:

frequency table for newly occurring on-treatment grades 3 or 4 (see below for details)

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)
10.5.3.4 Other safety data
ECG

shift table baseline to worst on-treatment result for overall assessments

listing of ECG evaluations for all patients with at least one abnormality.


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Vital signs
Definitions of notably abnormal results have to part of the RAP.

shift table baseline to worst on-treatment result

table with descriptive statistics at baseline, one or several post-baseline time points and 
change from baseline to this/these post-baseline time points.
10.5.4
Pharmacokinetics
Summary statistics (n, arithmetic mean, median, SD, geometric mean, coefficient of variation 
CV (%) and geometric CV (%), minimum and maximum) will be presented for plasma 
concentrations of PAN (and its metabolite BJB432, if feasible) and BTZ at each scheduled time 
point for each analyte. Graphical presentation will also be provided on mean concentration at 
each scheduled time point for each analyte. PK parameters will be calculated from individual 
concentration-time data for each analyte. Summary statistics will be presented for all PK 
parameters except Tmax. For Tmax, only median, minimum, and maximum values will be 
presented.
10.5.5
Biomarkers
Not applicable.
10.5.6
Patient-reported outcomes
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.
Calculated scores and changes from baseline will be summarized by visit.
In addition, for each domain and item of FACT/GOG-NTX questionnaires, summaries will be 
provided for changes from baseline for each response category of the Global Change Question 
as indicated by the patient and the investigator at C3D1, C7D1, and post-treatment assessment.
10.7
Interim analysis
Not applicable.
10.8
Sample size calculation
Sample size assumptions in this trial are based on the data from the PANORAMA-1 study, 
which enrolled a similar patient population; i.e. patients with relapsed multiple myeloma or 


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relapsed-and-refractory myeloma. Considering BTZ was currently widely used in newly 
diagnosed MM and relapsed/refractory MM in Japan, it is expected that most patients in this 
study have BTZ containing regimen as a prior line of therapy. Based on the data from the 
PANORAMA-1 study, for patients previously treated with BTZ , the nCR+CR rate for PAN is 
expected to be around 25 %. nCR+CR rate of 10 % or less is considered as an insufficient level 
of activity for the proposed patient population. Based on the normal distribution, approximately 
33 patients are required to reject a null hypothesis of nCR+CR rate ≤ 10% vs. a target nCR+CR 
rate of 25% or more, with a one-sided alpha of 0.05 and at least 80% power.
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 Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.
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 -approved informed consent or, if incapable of doing so, 
after such consent has been provided by a legally acceptable representative of the patient. In 
cases where the patient’s representative gives consent, the patient should be informed about the 
study to the extent possible given his/her understanding. If the patient is capable of doing so, 
he/she should indicate assent by personally signing and dating the written informed consent 
document or a separate assent form. 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.
Novartis 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 Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.


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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.
11.4
Discontinuation of the study
Novartis 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 
Publication of study protocol and results.
11.5
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as //clinicaltrials.gov. Interim data will be published periodically. 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 trial, 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 Novartis-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 trial necessary for the reconstruction and evaluation of the trial. 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 
trial.
Data collection is the responsibility of the clinical trial 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 


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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 trial 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. 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 Novartis or designee or Health 
Authorities.
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 Novartis 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 Novartis 
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 Novartis, 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, 
Novartis 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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Uttamsingh V., Lu C., Miwa G., et al. (2005). Relative contributions of the five major human 
cytochromes P450, 1A2, 2C9, 2D6, and 3A4, to the hepatic metabolism of the proteasome 
inhibitor bortezomib. Drug Metab Dispos. 2005 Nov;33(11):1723-8
Velcade™ US Prescribing Information
Vidriales M.B. and Anderson K.C. (1996). Adhesion of multiple myeloma cells to the bone 
marrow microenvironment: implications for future therapeutic strategies. Mol Med Today 
1996;2(10):425-431
Weber D.M., Chen C., Niesvizky R., et al. (2007). Lenalidomide plus Dexamethasone for 
Relapsed Multiple Myeloma in North America. N Engl J Med 2007;357:2133-42
Wolf JL, Siegel D, Matous J, et al. (2008) A Phase II study of oral panobinostat (LBH589) in 
adult patients with advanced refractory multiple myeloma [Abstract 2774]. Blood (ASH 
Annual Meeting Abstracts). 2008;112
Younes A, Sureda A, Ben-Yehuda D, et al. (2009) Phase II study of oral panobinostat in 
patients with relapsed/refractory Hodgkin Lymphoma (HL) after high-dose chemotherapy 
with autologous stem cell transplant (ASCT) [Abstract 0088]. Haematologica (EHA Annual 
Meeting Abstracts). 2009;94(suppl.2):34
Zangari M, Tricot G, Zeldis J. et al. (2001). Results of phase I study of CC-5013 for the 
treatment of multiple myeloma (MM) patients who relapse after high dose chemotherapy 
(HDCT). Blood 2001;775a (A3226)


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14
Appendices
14.1
Appendix 1: Co-medications which prohibited for use, are known 
to prolong the QT interval and/or induce Torsades de Pointes, 
are strong CYP3A4/5 inhibitors, are CYP2D6 substrates, or are 
moderate CYP3A4 inducers
14.1.1
Medication prohibited during the treatment period
The following medications are prohibited:

Any investigational medication (other than PAN)

Chemo-, biologic or immunologic therapy and/or other investigational agents 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.

Any medication which is known to be a strong CYP3A4 inducer* (e.g. avasimibe, 
carbamazepine, Phenobarbital, phenytoin, rifabutin, or St. John’s wort). Co-administration 
of rifampin, a strong CYP3A4 inducer is expected to decrease exposure of BTZ by at least 
45%. Efficacy may be reduced when Velcade® is used in combination with strong 
CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not 
recommended in patients receiving Velcade®.
*This list of strong CYP3A4 inducers was compiled from the FDA’s “Guidance for Industry, 
Drug Interaction Studies;” from the Indiana University School of Medicine’s “Clinically 
Relevant” Table; from the University of Washington’s Drug Interaction Database; and from 
Pursche et al (2008). 6. Any use of hematopoietic growth factor receptor agonists (including 
but not limited to:erythropoietin, romiplostim, or eltrombopag).

Drugs that are known to prolong the QT interval and/or induce Torsade de Pointes 
ventricular arrhythmia
14.1.2
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 of the medications listed in Table 14-1 and 
cannot either discontinue from this treatment or switch to an alternative medication prior to 
enrollment in a PAN clinical study, will be excluded from the study. Patients enrolled in a PAN 
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 PAN treatment (e.g., for 72 hours) during administration with these 
drugs or withheld medications in Table 14-1 for at least 72 hours when PAN 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 PAN especially in the presence of electrolyte 
abnormalities, notably decreased potassium or magnesium levels commonly associated with 
diuretic usage.


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In general, medications listed in Table 14-1 should be avoided. Medications listed in Table 14-
2 and Table 14-3 are to be used with caution when co-administered with PAN. The use of any 
of the drugs in, Table 14-1, Table 14-2 and Table 14-3 in combination with PAN 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
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


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^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 PAN.
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:
//azcert.org/medical-pros/drug-lists/drug-lists.cfm (Version 3/25/2008).
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, see Table 14-3) has been associated with Torsades 
de points and QT prolongation but has not been shown to cause Torsades de pointes. Therefore, 
ondansetron is not per se prohibited to be combined with PAN but caution is to be exercised 
and close monitoring for signs and symptoms of QT prolongation is recommended.
14.1.3
Medications which are known strong CYP3A4/5 inhibitors to be used 
with caution
PAN is a substrate of CYP3A4 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 PAN in study [CLBH589B2110].
Multiple ketoconazole doses at 400 mg increased Cmax and AUC of PAN by 1.6- and 1.8-fold, 
respectively, but with no change in Tmax or half-lives in 14 cancer patients. The less than 2-
fold increase in PAN AUC upon co-administration of a strong CYP3A inhibitor is considered 
a weak drug inhibition and not clinically relevant, as PAN doses at least 2-fold greater than the 
evaluated 20 mg dose (i.e., 40 mg and 60 mg) have been safely administered in patients. Thus, 
co-administration of PAN with a moderate or weak CYP3A inhibitor is allowed. However, 
clinical monitoring of signs and symptoms of PAN treatment related adverse events is 
recommended when long-term (≥ 1 week) concomitant administration of any strong CYP3A 
inhibitors and PAN is medically indicated or investigated in a clinical study.
BTZ is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of 
ketoconazole, increased the exposure of BTZ by 35% in 12 patients. Therefore, patients should 
be closely monitored when given BTZ in combination with strong CYPA4 inhibitors (e.g. 
ketoconazole, ritonavir).
Patients with impaired liver function (as defined by NCI CTEP criteria) are recommended not 
to receive PAN concomitantly with strong CYP3A inhibitors because potential interaction has 
not been established in this population.


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Table 14-2
Medications which are known strong CYP3A4/5 inhibitors to be used 
with caution
Macrolide antibiotics*
●
telithromycin
●
troleandomycin
Antifungals (azoles)
●
ketoconazole
●
itraconazole
●
posaconazole
●
voriconazole
Antidepressants
●
nefazodone
HIV protease inhibitors:
●
indinavir
●
nelfinavir
●
ritonavir
●
saquinavir
●
lopinavir
Miscellaneous drugs or products
●
2Star fruit and pomegranate product and juice
●
conivaptan
* azithromycin and regular orange juice are 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 
PAN. 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 complied by using information listed under “draft guidance for industry, drug interaction 
studies, CDER 2006”, Indiana University School of Medicine drug interaction tables at 
//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: 
//medicine.iupui.edu/clinpharm/DDIs/ClinicalTable.asp.
14.1.4
Medications which are known CYP2D6 substrates to be used with 
caution
PAN was also shown to be a CYP2D6 inhibitor (Ki 0.17 µM) in vitro. Thus, clinical drug-drug 
interaction study with PAN as CYP2D6 inhibitor and dextromethorphan as CYP2D6 substrate 
was recently conducted in study [CLBH589B2109].
Multiple PAN doses increased Cmax and AUC of dextromethorphan by a mean of 1.8- and 1.6-
fold respectively, but with no change in Tmax in 17 cancer patients. An approximately 2-fold 
increase in dextromethorphan AUC upon co-administration with PAN indicated that in vivo 
CYP2D6 inhibition of PAN is weak.
As the study was conducted using a sensitive CYP2D6 substrate which resulted in a weak 
inhibition, drugs with a large therapeutic index such as anti-emetics, anti-hypertensives, and 
anti-depressants are generally safe to be co-administered with PAN.
Patients should be carefully monitored for potential signs and symptoms of toxicity and may 
require dose titration or dose reduction of a sensitive CYP2D6 substrate which also have a 


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narrow therapeutic window (e.g., the ratio of toxicity exposure is ≤ 2-fold higher than the 
efficacious or therapeutic exposure).
Table 14-3
Medications which are known CYP2D6 substrates to be used with 
caution
Beta blockers (listed below):
Antipsychotics (listed below):
S-metoprolol
aripiprazole
propafenone
haloperidol
timolol
risperidone
Antidepressants (listed below):
thioridazine
amitriptyline
Antiarrhythmics (listed below):
clomipramine
mexilletine
desipramine
flecainide
imipramine
Others (listed below):
fluoxetine
codeine
paroxetine
dextromethorphan
venlafaxine
tamoxifen
duloxetine
tramadol
Antiemetics (listed below):
ondansetron^
^Intravenous dolasetron is a CYP2D6 substrate and contraindicated for preventing nausea and vomiting 
associated with chemotherapy based on FDA drug safety communication dated December 17, 2010. Please 
see Table 14-1.
14.1.5
Medications which are known to be moderate inducers of CYP3A4 are 
to be used with caution
During the study, the use of moderate CYP3A4 inducers (e.g. bosentan, efavirenz, etravirine, 
modafinil, nafcillin, ritonavir, talviraline, tipranavir) is discouraged, and investigators should 
seek alternatives where possible. However, any concomitant use of moderate CYP3A4 inducers 
must be documented.
This is not a comprehensive list of medications which may induce 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: 
//medicine.iupui.edu/clinpharm/DDIs/ClinicalTable.asp, and “drug interaction database” from 
University of Washington.


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14.4
Appendix 4: Protocol Post-text Supplement - Guidelines for 
response assessment in Multiple Myeloma


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Novartis Oncology
Clinical Development
and
Biometrics and Data Management
Study no: CLBH589D1201
Harmonization of Efficacy Analysis of Multiple Myeloma Studies
Protocol Post-text Supplement:
Guidelines for response assessment in Multiple Myeloma
Authors:
 
Document type:
TA Specific Guideline
Document status:
Version 1: Final
Release date:
23-Oct-2009
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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List of abbreviations
Abbreviation
Details
ASO-PCR
allele-specific oligonucleotide polymerase chain reaction
BL
Baseline
BM
Bone marrow
CR
complete response
CT
Computed tomography
DAR
Dose administration record
DFS
Disease-free survival
diff
difference
DOR
Duration of response
decr.
Decrease
(e)CRF
(electronic) Case Report Form
incr.
Increase
MM
Multiple myeloma
MR
Minor response
MRI
Magnetic resonance imaging
NC
No change
nCR
Near-complete response
ORR
Overall response rate
OS 
Overall survival
PC
Plasma cells
PD
Progressive disease
PEP
Protein electrophoresis
PFS
Progression-free survival
PR
Partial response
RAP
Report and analysis plan
SPD
Sum of the products of the diameters
TNT
Time to next treatment
TTR
Time to response


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14.4.1
Introduction and scope
This document provides the working definitions and specifications for consistent and efficient 
analyses of efficacy for Novartis clinical studies assessing antineoplastic activity in multiple 
myeloma (MM).
This document is based on the following classification systems:

Uniform response criteria from the European Group for Blood and Bone Marrow 
Transplant (EBMT), International Bone Marrow Transplant Registry (IBMTR) and the 
American Bone Marrow Transplant Registry (ABMTR) (Bladé et al 1998), including 
modifications as used consecutively by Richardson et al (2003), Richardson et al (2005), 
Orlowski et al (2007), San Miguel et al (2008), and these response criteria will be referred 
to as the modified EBMT criteria.
The modified EBMT criteria for multiple myeloma are well established, endorsed by major 
institutions and health authorities, and widely used in clinical trials.
While making decisions on response criteria for primary, secondary 
 efficacy 
endpoints of a clinical trial on multiple myeloma, the above situation needs to be taken into 
account.
Other references were used to add recommendations (e.g. SWOG 2009).
The objectives of this document are:

to ensure that the definitions of responses in a clinical study protocol correctly reflect 
modified EBMT criteria in the target patient population

to provide guidance for the response assessment and clinical monitoring to ensure 
consistency with modified EBMT criteria in the target patient population.
Moreover, this document describes data handling and derivation rules. Respective sections may 
be used in the report and analysis plan (RAP) to provide further details. As for a usual Novartis 
template, comments are written in italic font. The protocol and RAP authors must take these 
comments into consideration and provide project or study specific details in the protocol. 
Specifically, definitions highlighted in bold italic font must be discussed, defined and then 
documented in the study protocol. Any deviations to this guideline must be clearly specified in 
the protocol with justification.


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14.4.2
Efficacy Assessments
Efficacy assessments based on modified EBMT 
 criteria are discussed in this section. 
Common assessments and issues associated with both modified EBMT 
 criteria are 
discussed in Section 14.4.2.1. Assessments and issues associated with specific response criteria 
are discussed in Section 14.4.2.2 (modified EBMT criteria) 
 
14.4.2.1 Assessments - General
14.4.2.1.1
Assessment of response
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 and also to the classification system used
2. schedule for response assessments should be included in the protocol
3. appropriate confirmation response assessments should be indicated in the protocol
4. guideline on following-up patients for PD or relapse (relapse is applicable for modified 
EBMT criteria only) 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 (e)CRF (i.e. not 
merged from several sources), if possible.
14.4.2.1.2
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 
level in serum as well as in urine
1. Protein electrophoresis (PEP): Provides quantitative measurements
2. Immunofixation (IF): Provides qualitative measurements (Present/absent). This is a more 
sensitive method than PEP.
The following are disease measurability criteria based on serum and urine M-protein measured 
by PEP:
1. Serum M-protein ≥ 1 g/dL
2. Urine M-protein ≥ 200 mg/24h.
The PEP has to be performed to assess serum and urine M-protein levels at baseline and post 
baseline. Both serum and urine M-protein should be measured by PEP routinely at post baseline 
even if the disease is non-measurable based on one or both of the criteria above at baseline.
Absence of serum/urine M-protein should be determined by Immunofixation.
Laboratory to laboratory variability in regard to assessments performed by PEP and IF could 
potentially be high. So, central laboratory for PEP and IF is recommended, specially for single 
arm non-randomized studies.


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14.4.2.1.3
Assessment of bone marrow for percent plasma cell
Bone marrow should be assessed for percent plasma cell. This assessment can be performed in 
terms of bone marrow aspirate and/or biopsy. The same method (aspirate versus biopsy) should 
be used throughout the trial, if possible. In case both aspirate and biopsy were done, the response 
criteria need to be satisfied by the both assessments.
Bone marrow samples can be drawn from either sternum or iliac crest. Percent plasma cell will 
be determined by using cytological examination.
In case of inadequate/uninterruptible bone marrow sample, the sampling must be repeated in a 
timely manner.
Bone marrow aspirate and/or biopsy should be performed for every patients at baseline.
Bone marrow sample collection process can be uncomfortable to patients. Standard practice is 
to perform bone marrow assessment only when it is essential. Therefore, recommendation is 
for performing bone marrow assessments under the following conditions:
1. to confirm some response categories
2. in case of clinical symptoms indicating issues associated with plasma cell in bone marrow
If bone marrow assessment for percent plasma cell was done at post baseline then results from 
this assessment must be used in determining PD/relapse (relapse is applicable for modified 
EBMT criteria only). Otherwise, PD/relapse will be determined based on mandatory 
assessments (See Section 14.4.2.2.3 and Section 14.4.2.3.7) and available (if there is any) non-
mandatory assessments only.
14.4.2.1.4
Assessment of soft tissue plasmacytomas
The following steps should be used to assess soft tissue plasmacytomas:
1. Each patient should be clinically examined for soft tissue plasmacytoma in each visit for 
response assessments.
2. For baseline or new soft tissue plasmacytoma(s) at post-baseline, in case of appearance or 
clinical suspicion of appearance of a soft tissue plasmacytoma, imaging by using CT or 
MRI should be performed to confirm and to determine size and location of the soft tissue 
plasmacytoma (if exists).
3. In case of existing soft tissue plasmacytoma(s) at baseline, size and location of soft tissue 
plasmacytoma(s) will be monitored and documented on the (e)CRF regularly by imaging 
according to the requirements of the individual study protocol. In addition, in between two 
consecutive assessments by CT/MRI, clinical examinations can be performed to monitor 
existing soft tissue plasmacytoma(s).
4. Size and location of identified soft tissue plasmacytoma(s) should be captured on the 
(e)CRF.


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The size should be captured in terms of longest perpendicular diameters
If any of the perpendicular diameters can not 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.
A value of 0 mm X 0 mm should be entered in case of disappearance of a soft tissue 
plasmacytoma
The same imaging technique should be used to assess soft tissue plasmacytoma of a patient 
throughout the course of the trial, if possible.
The size of the soft tissue plasmacytomas is defined as the sum of the products of the cross-
diameters (SPD) of each soft tissue plasmacytoma using the longest perpendicular diameters.
A definite increase in the size is defined as a ≥ 50% increase (and at least 10 mm2) of this sum 
from the nadir.
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 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 part of the soft tissue 
plasmacytoma should contribute to the SPD.
14.4.2.1.5
Assessment of lytic bone lesions
Full body (in 13 different body regions) skeletal survey using conventional X-rays or CT or 
MRI should be performed on every patient prior to treatment start. Overall interpretation (in 
terms of presence or absence of lytic bone lesion) of full body skeletal survey will be captured 
on the (e)CRF.
Post baseline assessments using bone X-ray/CT/MRI on targeted location should be performed 
if there is any medical indications (e.g. bone pain) as determined by the investigator. The 
following information will be captured on the (e)CRF: normal, unchanged, new lesion or 
increase in size of existing lesion(s).
The same imaging technique should be used to assess lytic bone lesions of a patient throughout 
the course of the trial, if possible.
14.4.2.1.6
Assessment of serum calcium levels
For each response classification, the determination of corrected serum calcium levels is required. 
The correction will be done according to the following formula (Ladenson et al 1978):
Corrected serum calcium [mg/dL] = measured serum calcium [mg/dL] + (3.5 - serum albumin 
[g/dL]) x 0.8.


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14.4.2.1.7
Baseline assessments
The following baseline assessments are mandatory:

PEP in urine and serum M-protein

Plasma cell count in bone marrow

Clinical examinations for soft tissue plasmacytomas. In case of known or detectable soft 
tissue plasmacytoma at baseline, further measurements are required at baseline by imaging 
techniques (CT/MRI)

Full body skeletal survey using imaging techniques X-ray.

Routine biochemistry including total serum calcium and albumin
For baseline assessments, no confirmation measurement is required.
14.4.2.1.8
Response assessments
Assessments to determine PD are largely dependent on change from 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.
If contradictory results are observed from different tests then all contradicting tests should be 
repeated unless PD is confirmed.
14.4.2.1.9
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 less than 
4 weeks prior to the first intake of study treatment/randomization.
All measurements required for a response assessment should be performed within a predefined 
time window. It is recommended to align this time window with the treatment cycle length.
Unless PD/relapse (relapse is applicable for modified EBMT criteria only) is observed, response 
status can not be determined if there is incomplete/missing response assessment within a time 
window. In this case, “unknown” will be used as response status for this time window.
In case of more than one measurements of any variable in the predefine time window, the latest 
non-missing measurement of this variable will be used. Exception: In case of one measurement 
qualifying for PD/relapse, this will be used for the response assessment irrespective of 
subsequent measurements of the same variable.
14.4.2.1.10
Response assessment by time point
The response assessment depends on the data of the respective measurements. In case the 
current assessment is not the first post-baseline assessment, response assessment also depends 
on previous response assessment.
For the first post baseline assessment, the rules as provided in Table 14-4 (modified EBMT 
criteria) 
 apply.
The general rule for subsequent assessments is that - except the classification of PD/relapse 
(relapse is applicable for modified EBMT criteria only) or unknown - only a “better” response 


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can be assigned for a specific time point. If the assessment does not allow for a better assessment 
the previous confirmed response class will be retained provided that there are sufficient data to 
support this. Therefore, at a given time point, there are four possibilities:
1. Maintaining the current response status, OR
2. Obtaining a better response, OR
3. Having PD/relapse (relapse is applicable for modified EBMT criteria only)
4. Unknown
14.4.2.1.11
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/relapse (relapse is applicable for 
modified EBMT criteria only). In case of PD/relapse, 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.
14.4.2.2 Response assessment - modified EBMT criteria
14.4.2.2.1
Measurable disease
For the modified EBMT criteria, a patient is considered to have measurable disease if at least 
one of the following two conditions is true at baseline:
1. Serum M-protein ≥ 1 g/dL
2. Urine M-protein ≥ 200 mg/24h
In case of none of the above criteria applies, the patient is considered to have non-measurable 
disease.
14.4.2.2.2
Eligibility
If response assessments for primary and secondary objectives are based on modified EBMT 
criteria, then only those patients who have measurable disease according to
Section 14.4.2.2.1 should be included in the trial.
14.4.2.2.3
Mandatory assessments
All assessments listed in Section 14.4.2.1.7 should be performed at baseline.
For every patient the following assessments have to be performed at every scheduled post
baseline visits for response assessment:
1. PEP serum M-protein
2. PEP urine M-protein
3. Soft-tissue plasmacytoma
4. Serum calcium and albumin
Note: Both serum and urine M-protein should be measured by PEP routinely at post baseline 
even if the disease was not measurable based on serum or urine M-protein measured by PEP at 
baseline.


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14.4.2.2.4
Response assessment
Response assessment according to modified EBMT criteria is described in Table 14-4 and 
presented in flow charts (Figure 14-1 to Figure 14-4).
Table 14-4
Response classification in MM according to modified EBMT criteria
Response category
Definition
Complete response 
(CR)
●
Absence of M-protein in serum and urine by immunofixation, maintained ≥ 6 
weeks (presence of oligoclonal bands consistent with oligoclonal immune 
reconstitution does not exclude CR), AND
●
< 5% plasma cells in bone marrow. No confirmation on bone marrow plasma cell 
(additional assessment) is needed to document CR except patients with non-
secretory myeloma where the bone marrow examination must be repeated after an 
interval of at least 6 weeks, AND
●
In case of presence of lytic bone lesion(s) at baseline, no increase in size or 
number of lytic bone lesions (development of a compression fracture does not 
exclude CR), AND
●
In case of presence of soft tissue plasmacytoma(s) at baseline, disappearance of 
any soft tissue plasmacytoma
Near-complete 
response (nCR)
All criteria of CR apply except that absence of serum and urine M-protein can not be 
confirmed by immunofixation.
Note: This category is not part of the original EBMT criteria (Bladé 1998). It is 
introduced to enable comparisons to other pivotal clinical trials in MM (e.g. 
Richardson et al 2003, Richardson et al 2005, Orlowski et al 2007, San Miguel et al 
2008).
Partial response (PR)
●
reduction in serum M-protein as measured by PEP from baseline either by ≥ 50% 
or to < 1 g/dL, maintained for ≥ 6 weeks AND
●
reduction in 24h urine M-protein as measured by PEP from baseline either by ≥ 
90% or to < 200 mg, maintained ≥ 6 weeks, AND
●
≥ 50% reduction from baseline in the size of soft tissue plasmacytomas (by 
CT/MRI), AND
●
no increase in size or number of lytic bone lesions (development of a 
compression fracture does not exclude PR)
●
for patients with non-secretory myeloma, in addition to the above, ≥ 50% 
reduction from baseline in plasma cells in a bone marrow aspirate and/or on biopsy 
(if both available then “and”, otherwise “or”), maintained for ≥ 6 weeks
Minimal response (MR)
●
25 to <50% reduction from baseline in serum M-protein as measured by PEP 
and absolute value is still ≥1 g/dL, maintained for ≥ 6 weeks, AND
●
50 to < 90% reduction from baseline in 24h urine M-protein as measured by PEP 
and absolute value is still ≥200 mg/24h, maintained for ≥ 6 weeks, AND
●
25 to < 50% reduction from baseline in the size of soft tissue plasmacytomas (by 
CT/MRI) AND
●
no increase in the size or number of lytic bone lesions (development of a 
compression fracture does not exclude MR)
●
For patients with non-secretory myeloma, in addition to the above, 25 to <50% 
reduction from baseline in plasma cells in a bone marrow aspirate and/or on biopsy, 
maintained for ≥ 6 weeks
No change (NC)
●
not meeting the criteria of either CR, nCR, PR, MR or PD/relapse


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Response category
Definition
Relapse from CR
●
reappearance/presence of serum or urine M-protein on immunofixation or PEP
confirmed by ≥ one further investigation and excluding oligoclonal immune 
reconstitution, OR
●
≥ 5% plasma cells in a bone marrow aspirate or on bone biopsy, OR
●
development of new soft tissue plasmacytoma(s),or reappearance of soft tissue 
plasmacytomas, OR
●
development of new lytic bone lesions or increase in the size of lytic bone lesions 
(development of a compression fracture does not exclude continued response and 
hence does not indicate PD), OR
●
development of hypercalcemia (corrected serum calcium >11.5 mg/dL, see 
Section 14.4.2.1.6) not attributable to any other cause. In case of preexisting 
hypercalcemia at baseline, this criterion applies only in case the corrected serum 
calcium level was ≤11.5 mg/dL during the course of the study. This criterion does 
qualify for relapse even if no previous calcium assessment.
There is no given time frame for the confirmation measurement of serum or urine M-
protein. A repetition and confirmation at any time qualifies for relapse.
Progressive disease 
(PD)*
●
25% increase from nadir in the serum M-protein as measured by PEP which 
must also be an absolute increase from nadir of at least 0.5 g/dL and absolute value 
of serum M-protein ≥ 1.0 g/dL, and confirmed by at least one repeated investigation, 
OR
●
25% increase from nadir in the 24h urine M-protein as measured by PEP which 
must also be an absolute increase from nadir of at least 200 mg/24h and confirmed 
by at least one repeated investigation, OR
●
25% increase from nadir in plasma cells in a bone marrow aspirate or on biopsy 
which must also be an absolute increase from nadir of at least 10%, OR
●
increase from baseline in size of existing lytic bone lesions, OR
●
development of new lytic bone lesion (development of a compression fracture 
does not exclude continued response and does not indicate PD), OR
●
definite increase (Section 14.4.2.1.4) from nadir in size of existing soft tissue 
plasmacytomas, OR
●
development of new soft tissue plasmacytomas, OR
●
development of hypercalcemia (corrected serum calcium > 11.5 mg/dL) for 
patients without hypercalcemia at baseline. In case of preexisting hypercalcemia at 
baseline, PD will only be assessed due to the hypercalcemia criterion in case the 
corrected serum calcium level was ≤11.5 mg/dL post-baseline and increased 
thereafter beyond 11.5.g mg/dL.
There is no given time frame for the confirmation measurement of serum or urine 
PEP. A repetition and confirmation at any time qualifies for PD.
* only for patients not being in CR
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.
14.4.2.2.5
Time frame of response assessments
Instructions in Section 14.4.2.1.9 should be followed.
In addition, confirmation assessments for a response should be performed at least 6 weeks after 
the initial diagnosis of response.
Confirmation assessments for PD (only required for PEP measurements) should be performed 
as soon as possible.


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14.4.2.2.6
Confirmation of response
To qualify for a CR, nCR, PR or MR, a confirmation measurement needs to be repeated, after 
at least 6 weeks. Declaring PD, if based on PEP measurements, also requires confirmation. 
Confirmation of PD (if based on PEP measurements) should be performed as soon as possible.
The following rules apply:

For confirmation of a CR, the following assessments are mandatory, after 6 weeks:

Immunofixation in serum and urine

Percent plasma cell in bone marrow (only in patients with non-secretory myeloma)

For confirmation of nCR, PR or MR, the following assessments are mandatory, after 6 
weeks:

Serum and urine M-protein measured by PEP

Percent plasma cell in bone marrow (only in patients with non-secretory myeloma)

For confirmation of relapse, the following assessments are mandatory, as soon as possible:

Only if relapse is indicated by serum M-protein: Serum M-protein assessed by 
immunofixation

Only if relapse is indicated by urine M-protein: Urine M-protein assessed by 
immunofixation

For confirmation of PD, the following assessments are mandatory, as soon as possible:

Only if PD is indicated by serum M-protein: Serum M-protein measured by PEP

Only if PD is indicated by urine M-protein: Urine M-protein measured by PEP
There is no need to repeat CT/MRI for plasmacytoma(s), X-ray/CT/MRI for lytic bone lesion(s) 
and assessment of corrected serum calcium for confirmation purpose.
If the confirmation assessments indicate a worse response category compared to the 
unconfirmed response category, then this worse response category will be considered as 
confirmed. If the confirmation assessments indicate a better response category compare to the 
unconfirmed response category, then the unconfirmed response category will be considered as 
confirmed. In this case, subsequent response assessments should be performed 6 weeks after 
the confirmatory assessment for the purpose of confirmation of the observed better response.


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14.4.3
Capturing response classification
Response classification can be obtained/determined from two different sources:
1. Response classification provided by investigators
2. Response classification derived from data collected in the (e)CRF
Source of response classification to use in the protocol defined efficacy analyses should be pre-
specified. In general, response classification provided by investigators will be used in the main 
analyses associated with protocol objectives.
In case of assessing response by 
 modified EBMT 
 criteria, the investigator 
should assess response only in terms of the primary classification system.
The best overall response can be determined and captured in (e)CRF by investigators.
14.4.4
Data sources
The data sources refers to disease-specific (e)CRF standard modules. It is not appropriate to 
deviate from these specifications
Table 14-7
Data sources
Data
CRF module
Specification
Relevant for
Modified 
EBMT
Response
Laboratory standard 
module
Value for serum calcium and serum 
albumin
Yes
Adverse events
Hyperviscosity*
No
Bone marrow standard 
module
Aspirate or biopsy can be used. Relevant 
variable is the count of plasma cells
Yes
Flow cytometry
Determination of aberrant plasma 
phenotypes in bone marrow
No
Plasmacytoma module
Capturing size and localization as well as 
examination technique
Yes
Bone lesion module
Capturing lesion size and location as well 
as imaging technique
Yes
PEP
Serum and urine M-protein assessment 
Yes
Immunofixation
Serum and urine M-protein assessment
Yes
FLC module
Immunoassay of serum for determination 
of FLC
No


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Data
CRF module
Specification
Relevant for
Modified 
EBMT
PCR module
ASO-PCR module for bone marrow PC
No
MM investigator’s 
response assessment
Capturing response categories as defined 
in Section 14.4.5.1 (separate module for 
modified EBMT 
)
Yes
Time 
frames
various
See list of variables in the response 
assessment part of this table. For each of 
these assessments the date needs to be 
captured. For definition of baseline use 
time of first use of study treatment (DAR 
standard module).
Yes
DAR - Dose administration record
14.4.5
Derivation rules
14.4.5.1 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 treatment/randomization until PD/relapse 
or end of study, whatever comes first.
If the first complete post-baseline response assessment indicates, for example, PR or better (For 
EBMT nCR and CR, 
) and no confirmation response 
assessment available then NC for EBMT criteria 
 will be considered 
as best overall response. For the case of MR in EBMT, similar approach will be considered to 
determined the best overall response.
Best overall response will be assigned according to the classification system in the following 
ascending order (Table 14-8).


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Table 14-8
Best overall response by classification system
Best overall 
response 
category
Classification
Comment
Modified 
EBMT
rank
CR
Yes
1
-
nCR
-
Yes
2
-
PR
Yes
3
-
MR
Yes
4
 
NC
-
Yes
5
Unknown
Yes
6
PD
Yes
7
.
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.
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 who had valid disease assessment at baseline.
 
14.4.5.2 Calculation of time-to-event variables
In case more than one response classification systems are used, the underlying response 
classification system to derive each of the time-to-event endpoints should be clearly specified 
in the protocol.
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 
treatment will be used as end date (duration = 1 day), i.e. time to event variables will never be 
negative.
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”.
Note: The term “relapse” used in the following sections is applicable for the modified EBMT 
criteria only.


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14.4.5.2.1
Overall survival
Overall survival (OS) is defined as the time from date of randomization/start of 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.
14.4.5.2.2
Progression-free survival
Progression-free survival (PFS) is defined as time from date of randomization/start of treatment 
to date of (1) death due to any cause or (2) PD/relapse.
If a patient has not had an event, PFS is censored at the last adequate response assessment date.
14.4.5.2.3
Duration of response
>> If the following variable is analyzed, it should be stated that this analysis might introduce 
a bias as it includes only responders. There have been reports where a treatment with a 
significantly higher response rate had a significantly shorter duration of response. The analysis 
of duration of responses should only be used as a descriptive analysis. If they are used as 
inferential comparison between treatments, clear justification must be given in the protocol. It 
should also be stated in the protocol if duration of response is to be calculated in addition for 
unconfirmed 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/relapse or death due to multiple myeloma.
In case a patient does not have PD/relapse 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.
14.4.5.2.4
Time to response
Time to response (TTR) is defined as the time between date of randomization/start of 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/relapse 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/relapse will be censored at their last adequate response 
assessment date which is different from “unknown” or “not done”.


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14.4.5.2.5
Time to relapse
Time to relapse is usable for modified EBMT criteria and is defined as the time between date 
of first documented CR to the date of first documented relapse.
In case a patient does not have relapse, time to relapse will be censored at the date of the last 
adequate assessment.
In general patients without CR are excluded from this analysis. However, there are several ways 
to address this issue. Clear instruction on this should be included in protocol.
14.4.5.3 Incomplete assessment dates
All investigation dates (e.g. X-ray, bone marrow aspirate) must be completed with day, month 
and year. If one or more investigation dates are incomplete but other investigation dates are 
available, this/these incomplete date(s) are not considered for calculation of the assessment date. 


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If all measurement dates have no day recorded, the 1st dayof the month is used for PD/relapse 
and last day of the month will be used for other response categories.
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation.
14.4.5.4 Incomplete dates for last contact or death
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact.
14.4.5.5 Event and censoring date, sensitivity analyses
This section outlines the possible event and censoring dates for PD/relapse (Table 14-9), 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:
Table 14-9
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/relapse at scheduled assessment date or 
before next scheduled assessment
(1) Date of PD/relapse
(2) Date of next scheduled assessment
Event
Event
C1 PD/relapse or death after exactly one missing 
assessment
(1) Date of PD/relapse (or death)
(2) Date of next scheduled assessment1 
Event
Event
C2 PD/relapse or death after two or more
missing assessments
(1) Date of last adequate assessment1
(2) Date of next scheduled assessment1
(3) Date of PD/relapse (or death)
Censor
Event
Event
D
No PD/relapse
(1) Date of last adequate assessment 
Censor
E
Treatment discontinuation due to ‘Disease 
PD/relapse’ without documented PD/relapse, 
i.e. clinical PD/relapse based on investigator 
claim 
(1) N/A
(2) Date of discontinuation (visit date at which 
clinical PD/relapse was determined) 
Ignored
Event
F
New anticancer therapy given
(1) Date of last adequate assessment
(2) Date of secondary anti-cancer therapy
(3) Date of secondary anti-cancer therapy
(4) N/A
Censor
Censor
Event
Ignored
G
Deaths due to reason other than multiple 
myeloma
(1) Date of last adequate assessment
Censor (only 
TTP and TNT)
1 PD/relapse
>> The primary analysis and the sensitivity analyses must be specified in the Study Protocol. 
Clearly define if and why options (1) are not used for situations C, E and (if applicable) F.


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Situations C (C1 and C2): PD/relapse 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/relapse 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/relapse’ without documented 
PD/relapse: By default, option (1) is used for situation E as patients without documented 
PD/relapse should be followed for PD/relapse after discontinuation of treatment. However, 
option (2) may be used as sensitivity analysis. If PD/relapse 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.
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 14-9 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
modified EBMT 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.


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14.4.6
Medical review of investigator’s response assessment
In case the investigator assesses response in the (e)CRF, this assessments 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 PD, the respective patients’ response needs to qualify the criteria 
for this category as defined in this document.


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14.4.7
References (available upon request)
Bladé J, Samson D, Reece D, et al (1998) Criteria for evaluating disease response and PD in 
patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell 
transplantation. Brit J Haem 102:111-1123
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
Durie BGM, Harousseau J-L, Miguel JS, et al (2007) Corrigenda/Erratum: International 
uniform response criteria for multiple myeloma. Leukemia 21:1134-1135
FDA Guideline: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, 
April 2005
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
San Miguel JF, Schlag R, Khuageva NK (2008) Bortezomib plus Melphalan and Prednisone 
for Initial Treatment of Multiple Myeloma. N Engl J Med 359:906-917
Orlowski RZ, Nagler A, Sonneveld P et al (2007) Randomized Phase III Study of Pegylated 
Liposomal Doxorubicin Plus Bortezomib Compared With Bortezomib Alone in Relapsed or 
Refractory Multiple Myeloma: Combination Therapy Improves Time to Progression. JCO 
25(25):3892-3901
Richardson PG, Barlogie B, Berenson J (2003) A Phase 2 Study of Bortezomib in Relapsed, 
Refractory Myeloma. N Engl J Med 348:2609-17.
Richardson PG, Sonneveld P, Schuster MW (2005) Bortezomib or High-Dose 
Dexamethasone for Relapsed Multiple Myeloma. N Engl J Med 352:2487-2498.
 
SWOG - Southwest Oncology Group (2009) Response assessment myeloma. Chapter 11C. 
Revision 2009, 13p


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14.4.8
Appendices
On the flow charts, start the assessment at the upper box of the respective chart and follow the 
arrows downwards in a stepwise manner. A diamond represents a decision with a “Yes” or “No” 
outcome. The response assessment stops at a colored box which provides the response category. 
A circle indicates that a flow chart continues at another page as indicated in legend.
Appendix A Modified EBMT - Flowchart of response assessment
Table 14-10
Overview: Flowcharts for response assessment according to EBMT
Flow chart
Description
Section in core 
document
Figure 14-1
Flowchart for response in patients with MM at 1st post-baseline 
assessment or previous NC according to modified EBMT criteria
14.4.2.2.4
Figure 14-2
Flowchart for response in patients with MM at 1st post-baseline 
assessment or previous NC according to modified EBMT criteria 
(link from Figure 14-1)
14.4.2.2.4
Figure 14-3
Flowchart for response in patients with MM at 1st post-baseline 
assessment or previous NC according to modified EBMT criteria 
(link from Figure 14-1 and Figure 14-2)
14.4.2.2.4
Figure 14-4
Flowchart for relapse in patients with MM after CR according to 
modified EBMT criteria
14.4.2.2.4


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Figure 14-1
Flowchart for response in patients with MM at 1st post-baseline 
assessment or previous NC according to modified EBMT criteria
14-2


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Figure 14-2
Flowchart for response in patients with MM at 1st post-baseline 
assessment or previous NC according to modified EBMT criteria
14-1
14-3
14-3
14-3


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Figure 14-3
Flowchart for response in patients with MM at 1st post-baseline 
assessment or previous NC according to modified EBMT criteria
14-2


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Figure 14-4
Flowchart for relapse in patients with MM after CR according to 
modified EBMT criteria


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SAP_000.pdf: 
Clinical Development
Panobinostat (LBH589)
Clinical Trial Protocol CLBH589D1201 / NCT02290431
A phase II, multi-center, single arm, open label study to evaluate the 
efficacy and safety of panobinostat in combination with bortezomib and 
dexamethasone in Japanese patients with relapsed/refractory multiple 
myeloma
RAP Module 3 – Detailed Statistical Methodology
Author:
 Trial Statistician
Document type:
RAP Documentation
Document status:
Amendment 5
Release date:
19-Nov-2018
Number of pages:
43
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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RAP Module 3
19-Nov-2018 (10:57)
CLBH589D1201
Document History – Changes compared to previous version of RAP module 3.
Version
Date
Changes
Final 1.0
3-Apr-2015
Amendment 
1
17-Jul-2015
-Reflected protocol amendment 1
(Section 1.1)  Added information regarding interim analysis. In the 
review process of panobinostat submission for indication of relapsed 
or refractory MM in Japan, 
 requested sponsor to conduct 
additional interim report to present the key efficacy and safety 
information in public per approximately 6 months basis.
(Section 1.5.2, 1.11, 2.14.4, 3.1, 4.7.1)  Deleted a sentence 
regarding 90% confidence interval.
-Added clarifications
(Section 4.1.3, Section 4.7.5.3) 
Clarified analysis plan for light chain Myeloma.
(Section 4.8.7)
Deleted qualitative ECG abnormalities analyses since these data are 
found as not collected.
(Section 4.10)
AUCinf, CL/F and Vz/F were added as PK parameters for BTZ.
Amendment
2
24-Feb-2016
- Changed Trial statistician’s name.
- Deleted the description of derivation of MM characteristics since 
the data is taken from CRF directly: added field to CRF.
Amendment 
3
27-Jul-2016
- Added the category of number of patients who entered the survival 
follow-up phase into Section 4.4 Patient disposition.
- Corrected eCRF page name. (Section 4.4, Section 4.8.1)
- Corrected the description of last administration date.
Amendment 
4
24-Jul-2017
- Definition of per protocol set (PP set) was added in section 1.2: 
Subjects and treatments to align with section 2.12: Definitions of 
analysis sets.
- Primary analysis by the PP set was added into sensitivity analysis. 
(Section 1.5.4)
- The instruction on eCRF page was deleted. (Section 2.15.2) 
- Safety follow-up period was corrected to 30 days. (Section 4.6)
- Causality definitions for study drug and study treatment were 
clarified. Some summary tables for AE, SAE and CNAE were added 
and updated. (Section 4.8.1, 4.8.2 and 4.8.3)
- AE analysis for clinical trial safety disclosure was added. (Section 
4.8.4)
- Heart rate was corrected to Pulse rate according to eCRF. (Section 
4.8.6)
- Drug-induced liver injury was added as part of safety assessments. 
(Section 4.8.9)
- The description was corrected according to the study design. 
(Section 4.10)
Amendment 
5
19-Nov-2018
- Statistical and analytical plan was updated. (Section 1.1)


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Version
Date
Changes
- Definition for pharmacokinetic analysis set was described in detail. 
(Section 1.2.4 and 2.12.4) and updated correctly (Section 1.10)
- Primary endpoint was clarified and corrected. 95% exact C.I. was 
added as exploratory analysis. (Section 1.5.1)
- Sensitivity analyses based on planned patients was added (Section 
1.5.3)
- Detailed description was added to original plan. (Section 1.6.1, 
1.6.2, 4.7.2 and 4.7.3)
- Unnecessary analysis plan for D1201 study was deleted and 
inappropriate plan was updated appropriately. (Section 1.3,1.6.2, 
1.7, 1.8, 1.9, 4.1, 4.2, 4.4, 4.5, 4.6, 4.7.4, 4.7.5, 4.8.2, 4.8.3, 4.8.5, 
4.9 and appendix 3)
- Name (CNAE and M8) was updated as per latest name. (Section 
1.8, 4.5.5 and 4.8.3)
- AESI list was updated based on latest eCRS. (Section 4.8.3)


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Statistical methods planned in the protocol and determination of sample size
Data will be analyzed by Novartis according to the data analysis section 10 of the study protocol 
which is available in Appendix 16.1.1 of the CSR.  Important information is given in the 
following sections and details are provided, as applicable, in Appendix 16.1.9 of the CSR.
1
Draft of Section 9.7 of CSR on Statistical methods
1.1
Statistical and analytical plans
The final analysis of study data will be performed when all patients have been treated for 8 
cycles (24 weeks) or discontinued prior to treatment for 8 cycles. 
In the review process of panobinostat submission for indication of relapsed or refractory MM 
in Japan, 
 requested sponsor to conduct additional interim report to present the key 
efficacy and safety information in public per approximately 6 months basis. At the prior to the 
final analysis time point, no statistical testing will be conducted as key efficacy in the interim 
report.
1.2
Subjects and treatments 
1.2.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients who took at least one dose of any study 
treatment component.
1.2.2
Safety Set
The Safety Set includes all patients who received at least one dose of study medication.
1.2.3
Per-protocol (PP) set
The PP set consists of all patients from the FAS without any major protocol deviation.
1.2.4
Pharmacokinetic analysis set
The pharmacokinetic analysis set for PAN (PAS-PAN) consists of all patients with at least one 
evaluable PK concentration of PAN.
A PK concentration is considered evaluable if:

The patient took the full scheduled dose in a respective cycle day (C1D1, D3, D5 and D8)

The patient did not vomit within 4 hours after dosing in a respective cycle day (C1D1 and 
D8)
The pharmacokinetic analysis set for BTZ (PAS-BTZ) consists of all patients with at least one 
evaluable PK concentration of BTZ.
A PK concentration is considered evaluable if:

The patient took the full scheduled dose in a respective cycle day (C1D1, D4 and D8)


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Additionally, a PK concentration can be considered to be not evaluable as per scientific 
judgement of PK scientist. When a PK concentration is considered not evaluable by PK scientist, 
the reason will be documented. Any PK samples with missing blood collection date or time, or 
missing associated study drug dosing date or time will be excluded from PK analysis.
1.3
Patient demographics and other baseline characteristics
Demographic and other baseline data (including disease characteristics) will be summarized 
descriptively for FAS.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented.
1.4
Treatments (study drug, other concomitant therapies, 
compliance)
Data on the study treatment administration will be summarized. The duration of treatment and 
relative dose intensity of each of the components of study treatment will be summarized using 
descriptive statistics.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized.
1.5
Analysis of the primary efficacy endpoint
1.5.1
Primary endpoint
The primary objective of the study is to assess efficacy of panobinostat (PAN) by nCR+CR rate 
after all patients have been treated for 8 cycles or discontinued from treatment which is based 
on modified EBMT criteria per investigator assessment in patients with relapsed or relapsed 
and refractory multiple myeloma.
The proportion of patients with a near Complete Response (nCR) or complete response (CR) as 
their best overall response is defined as nCR+CR rate. For all patients, the nCR+CR rate and 
its 2-sided 90% normally approximated confidence interval will be provided.
In addition, The nCR+CR rate and 2-sided 95% Clopper-Pearson exact confidence interval will 
be explored. Statistical hypothesis, model, and method of analysis
The primary analysis will be based on a single-sample binomial test (normal approximation) at 
the one-sided 5% significance level, analyzed in the FAS.
The study targets a nCR+CR rate of 25%. A nCR+CR rate of 10% or less is considered as an 
insufficient level of activity for the proposed patient population. Therefore the null and the 
alternative hypothesis are defined as follows: H0: nCR+CR rate ≤ 10%, Ha: nCR+CR rate > 
10%.
1.5.2
Handling of missing values/censoring/discontinuations
For the purposes of the primary analysis, patients with a best overall response of ‘Unknown’ 
(UNK) will be treated as non-responders in estimating the nCR+CR rate in the FAS.


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1.5.3
Sensitivity analyses
For the primary endpoint, following sensitivity analyses will be performed.

Primary analysis will be repeated using the PP set.

Primary analysis will be repeated based on planned number of patients.
If less than planned number of patients are available for the final analysis, then this 
analysis will be based on the planned number of patients and patients who have not be 
enrolled are considered non-responders.
1.5.4
Supportive analyses
Not applicable.
1.6
Analysis of secondary efficacy variables
The secondary efficacy variables will be analyzed using the FAS.
1.6.1
Key secondary endpoint
The key secondary objective is to evaluate progression free survival (PFS), defined as time from 
first dose of study treatment to the first documented PD (progressive disease) , relapse or death 
due to any cause per investigator based on modified EBMT criteria in patients with relapsed 
multiple myeloma or relapsed and refractory multiple myeloma.
Survivorship functions will be estimated by using the Kaplan-Meier product-limit method and 
displayed as graphs. Median PFS time and its two-sided 95% confidence intervals will be 
reported.
A patient who has not progressed/ relapsed, or died at the date of the last adequate response
assessment or when he/she receives any further anti-cancer therapy would have his/her PFS 
censored at the time of the last adequate response assessment before/ at the date of the last 
adequate response assessment or before start of further anti-cancer therapy. An adequate 
response assessment is considered any disease assessment indicating response status apart from 
“unknown” or “not done”.
1.6.2
Additional secondary efficacy endpoints
Other secondary efficacy objectives are to evaluate overall response rate (ORR), overall 
survival (OS), minimal
response rate (MRR), time to response (TTR), time to 
progression/relapse (TTP) and duration of response (DOR).
The assessment of these endpoints will be based on modified EBMT criteria per investigator 
assessment.
Overall response rate (ORR) is defined as the proportion of patients with CR or nCR or PR.
Overall survival (OS) is defined as time from first dose of study treatment to death.
Time to response (TTR) is the time between date of first dose of study treatment until first 
documented response (CR or nCR or PR).


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Duration of response (DOR) is defined as the time from the first documented occurrence of 
response (PR or nCR or CR) until the date of the first documented disease progression or relapse 
or death due to multiple myeloma.
Time to progression/relapse (TTP) is defined as the time from the date of first dose of study 
treatment to the date of the first documented disease progression, relapse or death due to 
multiple myeloma.
Estimated ORR along with corresponding 95% Clopper-Pearson exact confidence intervals will 
be presented.
Median TTR, DOR and TTP along with corresponding 95% confidence intervals will be 
presented.
ORR, MRR, TTR and TTP will be analyzed based on the FAS. However, DOR will be analyzed 
based on data from responders only (CR or nCR or PR) in the FAS.
1.8
Safety 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
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 30+1 after last dose of study medication.
Adverse events
Summary tables for adverse events (AEs) have to include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs. However, all safety data 
(including those from the pre and post-treatment periods) will be listed and those collected 
during the pre-treatment and post-treatment period are to be flagged.
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment.
Specific groupings of adverse events of special interest will be considered and summaries of 
these adverse events of special interest will be provided.
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and 
tabulated by type of adverse event.
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology version 21.0 or later.


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Laboratory data
For laboratory tests covered by the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03 the study’s biostatistical and reporting team will grade laboratory data 
accordingly. For laboratory tests covered by CTCAE, a 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, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges.
The following summaries will be generated separately for hematology, biochemistry, urinary 
laboratory tests and thyroid function test:

Frequency table for newly occurring on-treatment grades 1 - 4, any grade and grade 3/4 
values

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)
ECGs
Summary of worst change from baseline for QTcF will be generated.
Vital signs
Summary of worst change from baseline for vital signs (See Section 4.8.6) will be generated.
1.9
Patient-reported outcomes
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. Calculated scores will be summarized by visit.
1.10
Pharmacokinetics
For all PK analyses, PAS-PAN or PAS-BTZ will be used.
Plasma concentration of PAN and BTZ
Summary statistics (n, arithmetic mean, median, SD, geometric mean, coefficient of variation 
CV (%) and geometric CV (%), minimum and maximum) will be presented for plasma 
concentrations of PAN (and its metabolite BJB432, if available) and BTZ at each scheduled 
time point for each analyte. Graphical presentation will also be provided on geometric mean
and arithmetic mean concentration time profile at each scheduled time point for each analyte.
PK parameters of PAN and BTZ
PK parameters will be calculated from individual concentration-time data for each analyte.
Summary statistics included geometric and arithmetic means, n, SD, coefficient of variation 
(CV)% and CV% geometric mean, median, minimum and maximum will be presented for all 


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PK parameters except Tmax. For Tmax, only median, minimum, and maximum values will be 
presented.
1.11
Sample size calculation
Sample size assumptions in this trial are based on the data from the PANORAMA-1 study, 
which enrolled a similar patient population; i.e. patients with relapsed multiple myeloma or 
relapsed-and-refractory myeloma. Considering BTZ was currently widely used in newly 
diagnosed MM and relapsed/refractory MM in Japan, it is expected that most patients in this 
study have BTZ containing regimen as a prior line of therapy. Based on the data from the 
PANORAMA-1 study, for patients previously treated with BTZ, the nCR+CR rate for PAN is 
expected to be around 25 %. nCR+CR rate of 10 % or less is considered as an insufficient level 
of activity for the proposed patient population. Based on the normal distribution, approximately 
33 patients are required to reject a null hypothesis of nCR+CR ≤ 10% vs. a target nCR+CR of
25% or more, with a one-sided alpha of 0.05 and at least 80% power. 
1.12
Power for analysis of key secondary variables
Not applicable.
1.13
Interim analyses 
Not applicable.
Clinical Study Report - Appendix 16.1.9  Documentation of statistical methods
2
Statistical methods
2.1
Study drug and study treatment
Study drug refers to PAN. 
Study treatment refers to 

PAN + BTZ + Dex (investigational arm) 
Study treatment components refer to

PAN

BTZ

Dex
Study combination partner refers to BTZ and Dex.
2.2
Date of first administration of study drug
The date of first administration of study drug is derived as the first date when a non-zero dose 
of study drug was administered and recorded on the dose administration record (DAR) 
electronic case report form (eCRF). For the sake of simplicity, the date of first administration 
of study drug is also referred as start of study drug.


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2.3
Date of last administration of study drug
The date of last administration of study drug is defined as the last date when a non-zero dose of 
study drug was administered and recorded on the end-of-treatment eCRF. 
2.4
Date of first administration of study treatment
The date of first administration of study treatment is derived as the first date when a non-zero 
dose of any component of study treatment was administered and recorded on the DAR eCRF. 
For example, if the 1st dose of study drug A is administered on 04JAN2015, and the 1st dose of 
its combination partner, drug B, is administered on 03JAN2015, the date of the first 
administration of study treatment is on 03JAN2015). For the sake of simplicity, the date of the 
first administration of study treatment also referred as the start of study treatment.
2.5
Date of last administration of study treatment
The date of last administration of study treatment is derived as the last date when a non-zero 
dose of any component of study treatment was administered and recorded on the end-of-
treatment eCRF (PAN) or DAR eCRF (BTZ, Dex). For example, if the last dose of PAN is 
administered on 15APR2015, and the last dose of a combination partner, e.g., Dex, is 
administered on 17MAY2015, the date of last administration of study treatment is then on 
17MAY2010.
2.6
Baseline
Baseline is the result of an investigation describing the “true” uninfluenced state of the subject.
If more than one measurement (including additional and unscheduled visits) is obtained before 
first administration of study treatment, the last measurement sorted by date/time of assessment 
and/or number of repeat measurements, as applicable, that is prior to the first study treatment 
administration will be used as the baseline value.
For ECG, patients have more than 1 measurement at an assessment date, baseline is defined as 
average of the ECG measurements taken at pre-dose on C1D1 or if not available as average of 
the last available ECG assessment date within a 21 days window prior to C1D1.
If patients have no value as defined above, the baseline result was considered to be missing.
2.7
On-treatment assessment/event
All on-treatment assessments/events are any assessments/events obtained in the time interval:
[date of first administration of study treatment; date of last administration of study 
treatment +30 days], i.e., inclusive lower and upper limit. 
The calculation of study treatment duration may use different rules as specified in Section 4.5.
of RAP Module 3.
2.8
Screening failure
Screening failures are patients who have been screened and have failed the inclusion and 
exclusion criteria; these patients are never study treatment administered. 


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2.9
Time windows
For calculation of the investigator’s response assessment, the time window for (1) individual 
assessments and (2) confirmation of response are to be considered as defined in Appendix 4:
Post-text supplement to the Study Protocol.
For analyses of the FACT/GOG-Ntx, the following time windows were used for the analyses 
by time point according to the planned assessment schedule:
Table 2-1
Time window for FACT/GOG-Ntx
Time window
Definition
Planned 
assessment day
Baseline
Week 3
Baseline + 1 day to Day 32
22
Week 6
Day 33 to Day 53
43
Week 9
Day 54 to Day 74
64
Week 12
Day 75 to Day 95
85
Week 15
Day 96 to Day 116
106
Week 18
Day 117 to Day 137
127
Cont’d
. . .
. . 
Time windows are defined based on the day of first administration of study treatment (Day 1). 
In case there is more than 1 assessment within a time window, the closest to the planned 
assessment is used for analysis. In case there are assessments being equidistant to the planned 
assessment date, the first assessment is used for analysis.
2.10
Last contact date
The last contact date was derived for patients not known to have died at the analysis cut-off 
using the latest complete date among the following: 

All assessment dates (e.g. vital signs assessment, performance status/QoL assessment, and 
also assessment date in third-party data)

Medication dates including study medications, concomitant medications, and 
antineoplastic therapies administered after study treatment discontinuation

Adverse events dates

Last contact date collected on the ‘Survival information’ eCRF.
The last contact date was used for censoring of patients in the analysis of overall survival.
2.11
Data set
A unique cut-off date will be determined for 24-week analysis. Only data with an assessment 
or event start date (e.g., vital sign assessment date or start date of an AE) prior to or on the cut-
off date will be included in the analysis. For example, if the cut-off date is 15JUN2015, an AE 
starting on 13JUN2015 is reported, whereas an AE with a start date of 17JUN2015 is not 
reported.


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All events with a start date before or on the cut-off date and an end date after the cut-off date 
are reported as ‘continuing at the cut-off date’. The same rule was applied to events starting 
before or on the cut-off date and not having a documented end date. This approach applies in 
particular to AE and concomitant medication reports. For these events, the end date is not 
imputed and therefore did not appear in the listings.
If it is required to impute an end date for performing a specific analysis (e.g., for a dose 
administration record with a missing end date or an end date after the cut-off date, the latter is 
imputed as end date to allow the calculation of treatment exposure duration and dose intensity), 
the imputed date is displayed and flagged in the listings.
2.12
Definitions of analysis sets
2.12.1
Full analysis set (FAS) 
The Full Analysis Set (FAS) comprises all patients who took at least one dose of any study 
treatment component.
2.12.2
Safety set
The Safety Set includes all patients who received at least one dose of study medication.
2.12.3
Per-protocol (PP) set
The PP set consists of all patients from the FAS without any major protocol deviation. 
2.12.4
Pharmacokinetic (PK) set
The pharmacokinetic analysis set for PAN (PAS-PAN) consists of all patients with at least one 
evaluable PK concentration available of PAN. 
A PK concentration is considered evaluable if:

The patient took the full scheduled dose in a respective cycle day (C1D1, D3, D5 and D8)

The patient did not vomit within 4 hours after dosing in a respective cycle day (C1D1 and 
D8)
The pharmacokinetic analysis set for BTZ (PAS-BTZ) consists of all patients with at least one 
evaluable PK concentration available of BTZ.
A PK concentration is considered evaluable if:

The patient took the full scheduled dose in a respective cycle day (C1D1, D4 and D8)
Additionally, a PK concentration can be considered to be not evaluable as per scientific 
judgement of PK scientist. When a PK concentration is considered not evaluable by PK scientist, 
the reason will be documented. Any PK samples with missing blood collection date or time, or 
missing associated study drug dosing date or time will be excluded from PK analysis.


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2.13
Concomitant medications with specific impact on the analysis
2.13.1
Further anti-neoplastic therapy
Patients who take additional anti-neoplastic therapy before discontinuing study treatment (i.e., 
anti-neoplastic therapy other than study treatment) were identified as protocol deviations. Their 
efficacy data were censored so that response assessments made after the first intake of an anti-
neoplastic drug were not included in analyses. Clinical review of individual study data is 
required in order to identify those anti-neoplastic medications which are considered disallowed.
2.14
General statistical methodology
2.14.1
Baseline comparability
Not applicable.
2.14.2
Multiple assessments within post-baseline visits
If there are multiple measurements within the same post-baseline visit, the last measurement 
within the visit (sorted by date and as available by time) will be used in the analysis by visit. 
For any analyses regarding outliers, abnormal assessments or changes from baseline, all post-
baseline values will be included (i.e., scheduled, unscheduled, repeat). This applies to 
quantitative and qualitative variables. 
2.14.2.1 12-lead ECG assessments
The visit date recorded in the database will be used as the date of ECG. For all patients, a 
minimum of 3 ECGs are usually measured at screening, and single ECG is measured at other 
time points. If any patient has more than 1 measurement at a specific timepoint, the average of 
all available measurements will be used for the analysis of change from baseline as well as for 
the identification of notable values.  If there are unscheduled measurements, they were included 
for analyses of notable values and listing. For the unscheduled measurements, the individual 
records will be used for analyses.
2.14.3
Center pooling 
All study centers will be combined for the analysis. Due to expected small size of centers, no 
center effect will be assessed. However, protocol deviations, the number of patients will be 
summarized by center. 
2.14.4
Sample size calculation
Sample size assumptions in this trial are based on the data from the PANORAMA-1 study, 
which enrolled a similar patient population; i.e. patients with relapsed multiple myeloma or 
relapsed-and-refractory myeloma. Considering BTZ was currently widely used in newly 
diagnosed MM and relapsed/refractory MM in Japan, it is expected that most patients in this 
study have BTZ containing regimen as a prior line of therapy. Based on the data from the 
PANORAMA-1 study, for patients previously treated with BTZ, the nCR+CR rate for PAN is 
expected to be around 25 %. nCR+CR rate of 10 % or less is considered as an insufficient level 


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of activity for the proposed patient population. Based on the normal distribution, approximately 
33 patients are required to reject a null hypothesis of nCR+CR ≤ 10% vs. a target nCR+CR of 
25% or more, with a one-sided alpha of 0.05 and at least 80% power. 
2.14.5
Power for analysis of critical secondary variables
Not applicable.
2.14.6
Conversion factors
A month will be calculated as (365.25 / 12) = 30.4375 days. 
For the conversion of laboratory values measured in units as used by local laboratories to SI 
units, standard Novartis conversion factors will be used. 
2.15
Implementation of response guidelines
Response and progression evaluation will be performed according to the modified European 
Group for Blood and Marrow Transplantation (EBMT) criteria as defined in Appendix 4: Post-
text supplement to the Study Protocol. The text below gives more detailed instructions and rules 
to provide further details needed for programming.
2.15.1
Progressive disease/relapse
Progressive disease (PD)/relapse should only be assigned if it is documented by the investigator 
as per modified EBMT criteria per investigator’s response assessment page. Thus, for analyses 
of PFS and variables of efficacy based on modified EBMT response assessment, only the 
investigator’s response assessment eCRF page will be considered as data source.  
2.15.2
Best overall response
The best overall response will be assessed by modified EBMT criteria as per investigator 
assessment. The definitions and the details on the derivation are given in Appendix 4: Post-text 
supplement to the Study Protocol. 
Only response assessments performed before the start of any additional anti-neoplastic therapies 
were considered in the assessment of best overall response. 
2.15.3
Determination of missing adequate response assessments and 
censoring reason
In this section, the ‘missing adequate response assessment’ is defined as an assessment not done 
or classified as ‘unknown’. For simplicity, the ‘missing adequate response assessment’ was 
referred as ‘missing assessment’.
As detailed in Table 2-2, the PFS censoring and event date options depend on the presence and 
the number of missing assessments. For example:

In the analysis of PFS, an event occurring after 2 or more missing assessments is censored 
at the last adequate response assessment (i.e. at the last adequate response assessment 
before the 2 or more missing assessments) 


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An exact rule to determine whether there are any missing assessments is therefore needed. This 
rule was based on the distance between the last adequate response assessment date and the event 
date.
The threshold D1 is defined as the interval between the response assessments plus the protocol-
allowed window around the assessments. Similarly, the threshold D2 is defined as 2 times the 
protocol-specified interval between the response assessments plus the protocol allowed window 
around the assessments. For these derivations, the end of treatment visit was considered as 
scheduled visit.
During treatment phase: The threshold D1 is defined as 21 + 6 = 27 days and the threshold D2 
as (2 * 21) + 6 = 48 days. 
During follow-up phase: The threshold D1 is defined as 42 + 6 = 48 days and the threshold D2 
as (2 * 42) + 6 = 90 days.
Similarly, a threshold D3 is defined as (3 * 21) + 6 = 69 days in treatment phase and (3 * 42) + 
6 days = 132 days during follow-up phase. 
The analysis assumed 1 missing assessments if the distance between the last adequate response 
assessment and the event date is within (D1, D2] and 2 or more missing assessment if the 
distance is larger than D2. More than 2 missing assessments are assumed if the distance is larger 
than D3.
The same definition of D2 was used to determine the PFS-censoring reason. If the distance 
between the last adequate response assessment date and the earliest one of the following dates: 

Analysis cut-off date

Start date of additional anti-neoplastic therapy 

Date of study discontinuation due to consent withdrawal to disease follow-up

Date of study discontinuation due to loss to follow-up
is smaller or equal to D2, the censoring reason was then either 1.”Ongoing without PFS event”, 
2. “Adequate assessment not available” including lost to follow-up, withdrawal of consent to 
disease follow-up and other, 3. “New cancer therapy added”. However, if this distance is larger 
than D2, the censoring reason was then designated as 4. “Events documented after ≥2 missing 
adequate response assessments”. Table 1-5 is summarizing the criteria to derive the PFS 
censoring reason.
Table 2-2
Derivation of PFS censoring reason
PFS censoring reason
Definition
1
Ongoing without PFS event
Patient is still eligible for further disease follow-up at the 
analysis cut-off date
2
Adequate response 
assessment not available
Patient is not available for further disease follow-up at the 
analysis cut-off date. The patient stopped disease follow-up 
for any of the subordinated reasons
2.1
- Lost to follow-up
Patient is lost to follow-up as documented at end of 
treatment or study evaluation completion


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PFS censoring reason
Definition
2.2
- Withdrawal of consent to 
disease follow-up
Patient withdrew consent to disease follow-up as 
documented after end of treatment  or study evaluation 
completion
2.3
- Other
Patient stopped disease follow-up due to the following 
reasons as documented at study evaluation completion: 
Protocol deviation, technical problems 
3
New cancer therapy added
Start of new anti-cancer therapy as documented in the
“Antineoplastic therapies since discontinuation of study 
drug” eCRF.
4
Events documented after ≥2 
missing adequate response 
assessments
Patient experienced PFS event with 2 or more missing 
adequate response assessment preceding the PFS event.
3
Statistical analysis outputs
3.1
Hypothesis and test statistic
The null hypothesis and alternative hypothesis are stated in the Study Protocol (Section 10.4.2) 
for nCR+CR.
The primary analysis will be based on a single-sample binomial test (normal approximation) at 
the one-sided 5% significance level, analyzed in the FAS.
The study targets an nCR+CR of 25%. A response rate of 10% or less is considered as an 
insufficient level of activity for the proposed patient population. Therefore the null and the 
alternative hypothesis are defined as follows: Ho: nCR+CR ≤ 10%, Ha: nCR+CR > 10%. 
3.2
Kaplan-Meier (KM) estimates
An estimate of the survival function will be constructed using the KM (product-limit) method 
as implemented in PROC LIFETEST with METHOD=KM option (see example below).
PROC LIFETEST data=dataset METHOD=KM CONFTYPE=LOGLOG ; 
TIME survtime*censor(1) ;
RUN ;

survtime represents variable containing event/censor times

censor represents censoring variable (1=censored, 0=event) 
The median survival was obtained along with 95% CIs calculated from PROC LIFETEST 
output using the method of Brookmeyer & Crowley (1982).
KM estimates of the survival function with 95% CIs were summarized for the median, the 25th
and 75th percentile, if appropriate. The standard error of the KM estimate was calculated using 
Greenwood’s formula (Collett 1994).
The PROC LIFETEST statement used the option CONFTYPE=LOGLOG. The CONFTYPE 
option specifies the transformation applied to the survival function to obtain the pointwise CIs 
and the CIs for the quartiles of the survival times. The LOGLOG keyword specifies the 


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complementary log-log transformation g(x)=log(-log(x)) which ensures that the pointwise CIs
are always within interval [0,1] (Collett 1994; Lachin 2000). 
4
Statistical methods used in reporting
4.1
Background and demographic characteristics
The FAS will be used for all baseline and demographic summaries and listings.  
4.1.1
Basic demographic and background data
All demographic and background data will be listed in detail. Qualitative data will be 
summarized by means of contingency tables and quantitative data will be summarized by 
appropriate descriptive statistics (i.e., mean, standard deviation, median, minimum, and 
maximum). The following variables will be summarized:

Age [years]

Age category (<65 years/ ≥65 years/ missing)

Sex (male/ female/ missing)

Race (Asian/ missing)

Ethnicity (Japanese/ missing)

ECOG PS (0/ 1/ 2/  Missing)

Body weight [kg]

Body height [cm]

Body surface area (BSA) [m2]
4.1.2
Protocol eligibility criteria 
Protocol eligibility criteria deviation on eCRFs will be listed.
4.1.3
Diagnosis and characteristics of multiple myeloma
Summary statistics will be tabulated for diagnosis and characteristics of MM and depending on 
the data collected on the eCRF include the following: 

Time since diagnosis [months], (< 6 months/ ≥6 months and <1 year/ ≥1 year and <2 
years/ ≥2 years and < 5 years/ ≥5 years/ missing)

Involved light chains (kappa/ lambda/ indeterminate/ missing)

Immunoglobulin (Ig) class (IgG/ IgA/ IgM/ IgD/ IgE/ indeterminate/ missing)

Light chain Multiple Myeloma (yes/ no/ missing)

Renal function (renal impairment/ no renal impairment/ missing)
“No renal impairment” is defined as a baseline CCR ≥ 90 mL/min and “renal impairment” 
as a baseline CCR < 90 mL/min (for calculation of CCR see Appendix 1)

Cytogenetic risk group (normal risk/ poor risk/ unknown/ missing) 


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Cytogenetic poor risk group includes all patients with any of the following cytogenetic 
abnormalities at baseline: t(4, 14), t(14, 16), 17p deletion. The cytogenetic normal risk group 
includes all patients with none of these abnormalities at baseline

Clinical staging of MM according to the International Staging System (ISS, Appendix 2): 
(Stage I/ Stage II/ Stage III/ not assessed/ missing)

Serum PEP assessment [g/dL]

Serum M-protein by immunofixation (present/ absent/ not assessable/ missing)

Urine PEP assessment [mg/24h]

Urine M-protein by immunofixation (present/ absent/ not assessable/ missing)

Plasma cells in bone marrow as assessed by aspirate or biopsy [%]

Soft tissue plasmacytoma (present/ absent/ missing)

Lytic bone lesions (present/ absent/ missing)
4.1.4
Medical history
Medical history and ongoing conditions, including MM-related conditions and symptoms will 
be summarized and listed. Separate summaries will be presented for ongoing and historical 
medical conditions. The summaries will be presented by primary system organ class and 
preferred term. Medical history/current medical conditions are coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) terminology.
4.1.5
Prior anti-neoplastic therapy
The number and percentage of patients receiving any prior anti-neoplastic therapy and prior 
anti-neoplastic radiotherapy will be summarized for the full analysis set:
For Prior antineoplastic therapy,

Prior antineoplastic regimens (yes/ no/ missing)

Number of prior line of therapy

Prior lines of MM therapy (1/ 2 and 3/ >3/ missing)

Prior use of medications:

Bortezomib

Lenalidomide

Thalidomide

Pomalidomide

Oral Melphalan (defined as setting is not CONDITIONING FOR SCT)

Combined bortezomib and lenalidomide

Combined bortezomib+IMiDs (defined as prior use of thalidomide and/or 
lenalidomide and/or pomalidomide)

Combined bortezomib+dexamethasone

IMiDs

Other

Prior last line


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
Bortezomib

Lenalidomide

Thalidomide

Pomalidomide

Oral Melphalan

Combined bortezomib and lenalidomide

Combined bortezomib+IMiDs

Combined bortezomib+dexamethasone

Other
For prior use of medications and last line, frequencies will be presented separately for additional 
drug(s) in case the frequency is ≥10%.

Prior stem cell transplantation (yes/ no/ autologous/ allogenic)

Number of prior stem cell transplantations

MM characteristics (relapsed and refractory/ relapsed/ other)

Best response to last line of anti-MM therapy (CR/ nCR/ PR etc.)

Time from last therapy to progression [months]

Reason for discontinuation of therapy (toxicity/ disease progression/ completed prescribed 
regimen/ adverse event (s)/ unknown/ other/ missing)
For Prior antineoplastic radiotherapy,

Prior radiotherapy (yes/ no/ missing)

Locations of prior radiotherapy 
Prior anti-neoplastic therapy will be listed for medications and radiotherapy.
Prior anti-neoplastic medications will be summarized by ATC class, preferred term. Significant 
prior anti-neoplastic medications will be identified from the summaries mentioned above unless 
specified otherwise. Prior radio-, photo or light therapies will be summarized as prior 
radiotherapy.
4.1.6
Other
All data collected at baseline, including childbearing potential and pregnancy test results will 
be listed.
4.2
Protocol deviation summaries 
The number and percentage of patients in the FAS with any protocol deviation will be tabulated 
by the deviation category (as specified in the SSD documents). All protocol deviations will be 
listed.
4.3
Groupings for analysis
The number and percentage of patients in each analysis set (definitions are provided in Section 
2.12) will be summarized. 


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4.4
Patient disposition 
The FAS will be used for the patient disposition summaries. The following frequencies will be 
provided:

Number (%) of patients who are still on-treatment (based on the absence of the ‘End of 
Treatment Phase Disposition’ page)

Number (%) of patients who entered study treatment phase 2 (See protocol Section 4.1)

Number (%) of patients who discontinued prematurely the study treatment (based on ‘End 
of Treatment’ page)

Number (%) of patients who completed the study per protocol (based on ‘End of Post 
Treatment Phase Disposition’ page)

Number (%) of patients by reason for end of study treatment (based on ‘End of Treatment
Phase Disposition’ page)

Number (%) of patients who entered the post-treatment evaluation phase (based on ‘End 
of Treatment Phase Disposition’ page)

Number (%) of patients who entered the post-treatment evaluation and who discontinued 
the study (based on ‘End of Post Treatment Phase Disposition’ page)

Number (%) of patients who entered the post-treatment evaluation and who continues to 
be followed (based on the absence of the ‘End of  Post Treatment Phase Disposition’ 
page)

Reasons for discontinuation from the post-treatment evaluation phase (based on ‘End of 
Post Treatment’ page) 

Number (%) of patients who entered the survival follow-up phase (based on ‘End of 
Treatment’ or ‘End of Post Treatment’ page).
4.5
Study treatment
Duration of study treatment exposure [days], cumulative dose [PAN and Dex: mg, BTZ: 
mg/m^2], dose intensity (DI) [PAN and Dex: mg/day, BTZ: mg/(m^2 x day) ] and relative dose 
intensity (RDI) [%] will be summarized. In addition, the duration of exposure to study treatment 
will be categorized into time intervals (Section 4.5.1); frequency counts and percentages will 
be presented for the number of patients in each interval. The number of patients who have dose 
changes or interruptions, as well as their reasons, will be summarized. 
Cumulative dose, DI and RDI will be summarized by overall, by treatment phase and by cycle. 
Similarly, the number of patients who have dose changes or interruptions will also be 
summarized by treatment phase. 
Listings of all doses of the study treatment along with dose change reasons will be produced. 
The safety set will be used for all summaries and listings of study treatment. 
4.5.1
DAR date imputation
In the calculation of treatment exposure duration, if a dosing record has either a missing end 
date (for the last record for that treatment component) or an end date after the cut-off date, the 


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cut-off date will be used as the end date in case the cut-off date is earlier than the derived end 
date as per imputation rules. Such imputed data will be flagged in the listings. 
Where a date is recorded as a partial date, the missing day will be imputed as follows:
Start date: The day will be imputed by the 15th of the month. If day and month are missing day 
and month will be imputed by July 1st of the year. If there is a record indicating that the dose 
record started earlier, the start date will be imputed by the end date of the previous record + 1 
day. In case the imputed start date is later than the complete end date, the record will not be 
considered for analysis.
End date: The day will be imputed by the 15th of the month, and if day and month are missing 
then by July 1st of the year. If there is a record indicating that this started later, the end date will 
be imputed by the start date of the next record - 1 day. In case the imputed end date is earlier 
than the complete start date, the record will not be considered for analysis.
Imputed DAR start and end dates will be flagged in the listings. 
4.5.2
Duration of study treatment exposure
Duration of study treatment exposure and study treatment component exposure will be 
summarized. 
Duration of study treatment exposure
The following algorithm will be used to calculate the duration of study treatment exposure for 
patients who took at least one dose of any of the components of the study treatment: 
Duration of exposure (days) = [(date of last administration of study treatment) – (date 
of first administration of study treatment) + 1 day]
Duration of study treatment component exposure
Duration of exposure to any single component of study treatment will be calculated as
Duration of exposure (days) = [(date of last administration of study treatment 
component) – (date of first administration of study treatment component) + 1 day]
For the date of last administration of study drug (PAN), BTZ and Dex, the DAR page will be 
used. The calculation of ‘duration of exposure’ does not consider the potential ‘lagging effect’ 
from the last dose.
The duration of exposure includes the periods of temporary interruption (of any component of 
the study treatment for any reason). ‘Date of last administration of study drug /component’ and 
‘date of first administration of study drug /component’ is defined in Section 2. For patients who 
did not take any study treatment, the duration of exposure is defined as 0 days.
The following categories for exposure to study treatment will be analyzed:

< 3 weeks

≥ 3 weeks and < 6 weeks

≥ 6 weeks and < 12 weeks

≥ 12 weeks and < 24 weeks


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
≥ 24 weeks and ≤ 48 weeks

> 48 weeks
4.5.3
Cycle definition
Cycle length will be calculated based on visit date. The beginning of a cycle will be calculated 
from the first visit with non-zero dose of any component of study treatment of that cycle. Each 
cycle ends the day before the next cycle starts. Cycle length will be calculated for all cycles 
(except the last cycle) as follows:
Cycle length= (date of Day 1 of the next cycle – date of Day 1 of the current cycle).
A patient can discontinue the study early. As a consequence, the last cycle may not be a 
complete treatment cycle.  Therefore, the last cycle length will be calculated as follows: 
Last cycle length= [(date of last administration of study treatment + X) –
(day 1 of 
the last cycle date) + 1].
where X is the number of days remaining to complete the exposure time of the last dose of the 
study treatment component or the number of days from last administered dose to the next 
planned dose taking into account the minimal allowed dosing interval. In case the last dose of 
a cycle was taken later than the scheduled cycle length, X will be set to 0 days.
For example, for BTZ on a 21-day cycle with a Day 1 to 8 regimen, X=0 if the last BTZ dose 
is given on Day 1; X=13 if last dose is given on day 8.
The special handling of the last cycle length is to carefully calculate DI.  This is different from 
the purpose of calculating ‘duration of exposure’, where the ‘last dose lagging effect’ is not 
included. 
In case the length of the last cycle is more than scheduled, the actual length will be taken (date 
of end of treatment visit).
4.5.4
Study day
For the study day calculation, if the event or assessment date is after the treatment start date, 
the following calculations listed below apply: 
The study day for all assessments will be calculated as:
The date of the assessment / event - start date of study treatment + 1 day.
For any assessment or events that happened prior to the start of the study drug, e.g., time 
since diagnosis of disease, the study days (in negative) will be calculated for safety assessments 
as:
    Study Day = Event date - Date of first study treatment.
Note that the day of first dose of study treatment is Day 1 and the day before the date of first 
study treatment is Day – 1, not Day 0. 
The study day will be displayed in the data listings.


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4.5.5
Partial dates
As a common rule, whenever an imputation is implemented, the imputed date needs to be in the 
reasonable range of the event.  For example, if a date is known to be within the trial period and 
imputation makes it after the last known contact date, the last known contact date would be 
used.
Partial dates will be listed as such. The general approach is to impute partial dates when further 
analysis is required.  This includes in particular incomplete dates for AE start and end date, 
concomitant/prior medication start and end date, date of diagnosis of MM. 
In general, no imputation will be made when the year is missing (exceptions are described in 
Programming Datasets Specifications: PDS). In case the imputed date reveals in date that is not 
plausible with study key dates, the imputed date is to be replaced with those (e.g. when an AE 
start date results in a date prior to start of study treatment then the AE start date will be set to 
the start of study treatment date). These rules do not apply when determining the censoring date 
for time-to-event variables (see Appendix 4: Post-text supplement to the Study Protocol for 
details).
4.5.6
Cumulative dose
The cumulative dose is defined as the total dose given during the study treatment exposure and 
will be summarized by study treatment component. For patients who did not take any drug the 
cumulative dose is by definition equal to 0. 
4.5.7
DI and RDI
The following DI or planned DI (PDI) calculations apply for both Sc and oral dosing.  In the 
case of s.c. dosing, the dose was given based on BSA; calculation of DI or PDI involves BSA 
in the division.  If the dose is given regardless of BSA, the same formula can be used by 
replacing BSA by 1 m2 in the formula. Both DI and RDI for the study period will be summarized 
separately for each of the study treatment components, in which the denominator of DI or PDI 
calculation uses “the sum of all cycle length”.  
While the ‘sum of all cycle lengths’ is not the same as ‘duration of study treatment exposure’, 
they are identical in the continuous dosing regimen. DI, PDI, or RDI will be calculated for each 
study treatment component or study drug only. No calculation for study treatment combination 
will be done.
DI by cycle analysis
PAN and Dex
1. For cycles except last cycle or last cycle with length as scheduled or longer

PDI_c [mg/day] = (Total planned dose per cycle [mg]) / planned cycle length [days]

DI _c [mg/day] = (Total actual dose in an actual cycle [mg]) / actual cycle length [days]
2. For last cycle that is shorter than scheduled


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
PDI_c [mg/day] = (Total planned dose for actual duration [mg]) / actual duration [days] of 
study treatment in last cycle (Section 4.5.3)

DI_c [mg/day] = (Total actual dose for actual cycle [mg]) / actual duration [days] of study 
treatment in last cycle 
3. For all cycles

RDI_c [%] = DI_c [mg/day] / PDI_c [mg/day] * 100
BTZ
In this trial, BTZ is intravenously administered which requires an adjustment of dose intensity 
calculation by BSA. Since the body weight is provided at day 1 of each cycle the BSA needs to 
be derived for each cycle as: 
BSA [m2] = 234.94 * (height [cm]**0.422) * (weight [kg]**0.515) / 10000 
(Gehan and George formula)
1. For cycles except last cycle or last cycle with length as scheduled or longer

PDI_c [mg/m2/day] = (Total planned dose [mg] / BSA [m2]) / planned cycle length [days]

DI _c [mg/m2/day] = (Total actual dose in actual cycle [mg] / BSA [m2]) / actual cycle 
length [days]
2. For last cycle that is shorter than scheduled

PDI_c [mg/m2/day] = (Total planned dose for actual duration [mg]/ BSA [m2] in last 
cycle) / actual duration [days] of study treatment in last cycle (Section 4.5.3)

DI_c [mg/m2/day] = (Total actual dose for actual cycle (mg) / BSA (m2)] / actual duration 
[days] of study treatment in last cycle
3. For all cycles

RDI_c [%] = DI_c [mg/m2/day] / PDI_c [mg/m2/day] * 100
DI over study period
PAN and Dex
Dose intensity (DI) for patients with non-zero duration of exposure is defined as follows:









k
i
i
1
day
)
lengths
cycle
actual
(
mg
dose
Cumulative
mg/day
DI
and i =1,2,3,…,k are the indices for the cycle.
For patients who did not take any drug the DI is by definition equal to zero.
Note: 



i
i
length
cycle
actual
may not be equal to the duration of the study treatment exposure.
Planned dose intensity (PDI) for patients with non-zero duration of exposure is defined as 
follows:


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1. Last cycle length is shorter as or equal to the planned length











1
1
lentgh
cycle
last
actual
)
lengths
cycle
Planned
(
mg
dose
planned
Total
mg/day
PDI
k
i
i
day
i =1,2,3,…,k are the indices for the cycle. k is the actual total number of cycles
2. Last cycle length is longer than planned









k
i
i
1
day
lengths)
cycle
Planned
(
mg
dose
planned
Total
mg/day
PDI
i =1,2,3,…,k are the indices for the cycle. k is the actual total number of cycles
For patients who did not take any drug the PDI is by definition equal to zero.
Relative dose intensity (RDI) is defined as follows:
RDI [%] = DI [mg/day] / PDI [mg/day] * 100
BTZ
Dose intensity (DI) for patients with non-zero duration of exposure is defined as:











k
i
i
k
i
1
1
2
i
i
2
day
)
lengths
cycle
actual
(
m
BSA
mg
dose)
Cumulative
(
)
day
/
m
(mg/
DI
i =1,2,3,…,k are the indices for the cycle. 
For patients who did not take any drug the DI is by definition equal to zero.
Planned dose intensity (PDI) for patients with non-zero duration of exposure is defined as:
1. Last cycle length is shorter as or equal to the planned length













1
1
i
1
2
2
day
length
cycle
last
actual
)
lengths
cycle
planned
(
mg/m
dose
planned
Total
/day
m
mg/
PDI
k
i
k
i
i =1,2,3,…,k are the indices for the cycle. k is the actual total number of cycles
2. Last cycle length is longer than planned











k
1
i
k
1
i
2
2
day
lengths)
cycle
planned
(
mg/m
dose
planned
Total
/day
m
mg/
PDI
i =1,2,3,…,k are the indices for the cycle. k is the actual total number of cycles


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For patients who did not take any drug the PDI is by definition equal to zero.
Relative dose intensity (RDI) is defined as:
RDI (%) = 100 x DI [mg/m2/day] / PDI [mg/m2/day]
Frequencies for RDI will be produced by study treatment component and treatment phase for 
the following categories:

0 to < 50%

50 to < 70%

70 to < 90%

90 to < 110%

≥ 110%
4.5.8
Dose changes or interruptions
The number of patients who have dose changes or interruptions and the reasons for such 
changes /interruptions will be summarized by study treatment component.
If one drug is permanently discontinued (before a protocol planned discontinuation date) while 
the other is ongoing, such discontinuations will be classified as a change.
Dose changes and interruptions will be tabulated separately.
4.6
Concomitant therapy and anti-neoplastic therapies since 
discontinuation of study drug
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
besides the study treatment that were intentionally administered to a subject preceding or 
coincident with the study assessment period.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List to allow for categorization by preferred term. In addition to categorizing 
medication data by preferred term, drugs are classified according to their ATC classification in 
order to present and compare how they are being utilized. The ATC classification allows to 
summarize medications by a high-level common drug class.
Concomitant medications and significant non-drug therapies taken concurrently with the study 
drug will be listed and summarized by ATC class and preferred term by means of frequency 
counts and percentages. These summaries will include medications starting on or after the start 
of study treatment 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. 
The safety set will be used for all concomitant medication summaries and listings. Listings and 
summaries of prior medications and anti-neoplastic therapies since discontinuation of study 
drug will be based on the FAS.


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Anti-neoplastic therapies since discontinuation of study drug will be summarized by ATC class
and preferred term by means of frequency counts and percentages in separate summaries. 
Bisphosphonates and anti-RANKL antibodies are not considered as anti-neoplastic therapy.
Number of patients with at least 1 transfusion of blood products by transfusion type will be 
summarized. For this analysis of transfusions, only transfusions received after start of study 
treatment and up to 30 days after last dose will be considered.
4.7
Efficacy evaluations
4.7.1
Primary efficacy
The primary endpoint of the study is nCR+CR rate based on modified EBMT criteria as defined 
in Appendix 4 to the Study Protocol and as assessed by the investigator. The nCR+CR rate is 
defined as the proportion of patients with a near Complete Response (nCR) or complete 
response (CR) as their best overall response. The nCR+CR rate and 2-sided 90% normally 
approximated confidence interval will be assessed.
The primary analysis will be based on a single-sample binomial test (normal approximation) at 
the one-sided 5% significance level, analyzed in the FAS.
The study targets an nCR+CR of 25%. A response rate of 10% or less is considered as an 
insufficient level of activity for the proposed patient population. Therefore the null and the 
alternative hypothesis are defined as follows: H0: nCR+CR ≤ 10%, Ha: nCR+CR > 10%. 
For the purposes of the primary analysis, patients with a best overall response of ‘Unknown’ 
(UNK) will be treated as non-responders in estimating the nCR+CR rate in the FAS.
4.7.2
Key secondary efficacy
The progression free survival (PFS) based on modified EBMT criteria, defined as time from 
first dose of study treatment to progression, relapse or death due to any cause per investigator. 
For PFS, survivorship functions will be estimated by using the Kaplan-Meier product-limit 
method and displayed as graphs. The 25th, 50th (median), and 75th percentile of the PFS and 
its two-sided 95% confidence intervals will be calculated in the FAS. 
A patient who has not progressed/ relapsed, or died at the date of the last adequate response
assessment or when he/she receives any further anti-cancer therapy would have his/her PFS 
censored at the time of the last adequate response assessment before/ at the date of the last 
adequate response assessment or before start of further anti-cancer therapy. An adequate 
response assessment is considered any disease assessment indicating response status apart from 
“unknown” or “not done”.
The event and censoring times for PFS are depicted in Table 4-1.
Table 4-1
Event and censoring dates used in PFS
Situation
Options for end-date1
Outcome
A
No baseline assessment 
Start date of treatment
Censor


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Situation
Options for end-date1
Outcome
B
PD/relapse at scheduled assessment 
date or before next scheduled 
assessment
Date of PD/relapse
Event
C1
PD/relapse or death after exactly 
one missing assessment
Date of PD/relapse/death 
Event
C2
PD/relapse or death after two or 
more missing assessments
Date of last adequate assessment 
before PD/relapse or death (i.e. 
before the 2 or more missing 
assessments)
Censor
D
No PD/relapse/death
Date of last adequate assessment2
Censor
E
Treatment discontinuation due to 
‘Disease PD/relapse’ without 
documented PD/relapse, i.e. clinical 
PD/relapse based on investigator 
claim 
N/A
Ignored
F
New anticancer therapy given3
Date of last adequate assessment 
before start of new anticancer 
therapy
Censor
1 PD/relapse
2 In case there is no adequate assessment, the end date is the date of first administration of study 
treatment
3 New anticancer therapy given without documented evidence of PD/relapse 
4.7.3
Secondary efficacy 
Overall response rate (ORR) is defined as the proportion of patients with CR or nCR or PR 
per investigator’s assessment based on modified EBMT criteria. The estimated ORR along with 
corresponding 2-sided 95% exact CIs as derived by the Clopper-Pearson method will be 
presented. The reasons for best overall response resulting in “unknown” will be summarized  in 
the FAS.
Overall survival (OS) is defined as time from first dose of study treatment to death due to any 
cause. If a patient is not known to have died, survival will be censored at the date of last contact. 
Survival status, reason for censoring and death cause will be listed. Patients not known to have 
died will be censored for ‘Lost to follow-up’ if the time between their last contact date and the 
analysis cut-off date is longer than 3 months and 2 weeks (104 days). For OS, survivorship 
functions will be estimated by using the Kaplan-Meier product-limit method and displayed as 
graphs. The 25th, 50th (median), and 75th percentile of the OS and its two-sided 95% 
confidence intervals will be calculated in the FAS. 
Time to response (TTR) is the time between date of first dose of study treatment until first 
documented response (CR or nCR or PR) by the investigator based on modified EBMT criteria. 
Patients who do not experience CR, nCR or PR will be censored at maximum follow-up (i.e. 
first patient-first visit (FPFV) to the date of the last adequate response assessment used for the 
analysis) for patients who had a PFS event (i.e., either progressed, relapsed or died due to any 
cause) or at the last adequate response assessment date otherwise. For TTR, survivorship 


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functions will be estimated by using the Kaplan-Meier product-limit method and displayed as 
graphs. The 25th, 50th (median), and 75th percentile of the TTR and its two-sided 95% 
confidence intervals will be calculated in the FAS. 
Time to progression/relapse (TTP) is defined as the time from the date of first dose of study 
treatment to the date of the first documented disease progression, relapse or death due to 
multiple myeloma. For TTP, survivorship functions will be estimated by using the Kaplan-
Meier product-limit method and displayed as graphs. The 25th, 50th (median), and 75th 
percentile of the TTP and its two-sided 95% confidence intervals will be calculated in the FAS. 
Duration of response (DOR) is defined as the time from the first documented occurrence of 
response (PR or nCR or CR) until the date of the first documented disease progression or relapse 
or death due to multiple myeloma. For DOR, survivorship functions will be estimated by using 
the Kaplan-Meier product-limit method and displayed as graphs. The 25th, 50th (median), and 
75th percentile of the DOR and its two-sided 95% confidence intervals will be calculated in the 
FAS. DOR will be analyzed based on data from responders (CR or nCR or PR) in the FAS.
4.7.5
Other variables
4.7.5.1
Bone marrow assessment
Bone marrow variables as assessed by aspirate and biopsy will be listed. 
Bone marrow aspirate

Plasma cells [%] 

Was the specimen adequate for assessment (Yes/ No)

If no: 

Dry tap/ hemodiluted/ other

Repeated bone marrow aspirate/ bone marrow biopsy collected

Was specimen adequate for cellularity (Yes/ No)
Bone marrow biopsy

Plasma cells [%] 

Was biopsy specimen adequate for cellularity (Yes/ No)

Cellularity (Hypocellular/ Normocellular/ Hypercellular/ Not assessable/ Aplastic)

Percentage of cellularity [%]


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4.7.5.2
Serum/ urine assessment by PEP
The following variables will be listed:
Serum

Serum albmin

Total serum protein

Serum M-protein

Globulin data (Alpha1, Alpha 2 …)
Urine

Urine albmin

Total utine protein 

Urine M-protein

Globulin data (Alpha1, Alpha 2 …)
Serum and urine M-protein by PEP will be summarized individually.
4.7.5.3
Involved light chain and light chain MM
Serum and urine result will be listed.
4.7.5.4
Immunofixation
Serum and urine monoclonal band will be listed.
4.7.5.6
Soft Tissue Plasmacytoma (STP) assessment
The STP assessment variables by CT/MRI and clinical assessment will be listed individually. 
4.7.5.7
Skeletal survey
The following skeletal survey variables will be listed: 

Method (XRAY/ CT SCAN (WITH CONTRAST) …)

Number of lytic bone lesions

Lesion location and number of lesion
4.7.5.8
ECOG Performance Status (PS)
Shift tables comparing the baseline PS with the worst result during post-baseline will be 
summarized.


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4.8
Safety evaluation
The assessment of safety will be based mainly on the frequency of AEs and on the number of 
laboratory values that fall outside of pre-determined ranges. Other safety data (e.g., ECG, vital 
signs and special tests) will be considered as appropriate.
All safety outputs will use the safety set. The safety summary tables will include only 
assessments collected no later than 30 days after study treatment discontinuation. All safety 
assessments will be listed and those collected later than 30 days after study treatment 
discontinuation will be flagged.
4.8.1
AEs
Coding and grading of AEs
AEs will be assessed according to the Common Terminology Criteria for AEs (CTCAE 
version 4.03. 
If CTCAE grading does not exist for an AE, grades 1 to 4 corresponding to the severity of mild, 
moderate, severe, and life-threatening will be used. CTCAE grade 5 (death) will not be used in 
studies; rather, this information will be collected in the “Death” eCRF pages. 
Reporting of AEs
All AEs recorded during the study will be listed and summarized. AEs will be summarized by 
presenting the number and percentage of patients having at least one AE (regardless of study 
drug treatment in each primary system organ class) and for each preferred term using MedDRA 
coding. A patient with multiple occurrences of an AE will be counted only once in the respective 
AE category. 
AE summaries will be presented by primary system organ class, preferred term, and maximum 
CTC grade. A patient with multiple CTC grades for an AE category will be summarized under 
the maximum CTC grade recorded for the event. In the summaries presented by grade, all AEs 
will be pooled regardless of whether they are CTC-gradable or not, i.e., regardless of whether 
the question “CTCAE” on the AE CRF is answered ‘Yes’ or ‘No’.
AE summaries will include all treatment-emergent AEs starting on or after Study Day 1 (i.e. on 
or after the day of the first intake of study treatment) and starting no later than 30 days after 
study treatment discontinuation. The incidence of treatment-emergent AEs (new or worsening 
from baseline) will be summarized by system organ class, severity (based on CTC grades), AE 
type, relation to the study drug. AEs starting prior to Study Day 1 and AEs starting later than 
30 days after study treatment discontinuation will be flagged in the listings. 
Regarding the relationship to the study drug, if the AE was considered as reasonable possibility 
that AE is related is 'Yes, investigational treatment' or 'Yes, other study treatment (non-
investigational)' or 'Yes, both and/or indistinguishable', the AE is considered as with suspected 
relationship to study treatment. If causality is 'Yes, investigational treatment' or 'Yes, both 
and/or indistinguishable', the AE is considered as with suspected relationship to study drug.


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The frequency of all CTC grades and grade 3 and 4 AEs will be summarized separately. Any 
information collected (e.g., CTC grades, relatedness to study drug, action taken etc.) will be 
listed as appropriate.
Summaries of AEs with suspected relationship to study treatment will be provided.
Deaths reportable as serious AEs (SAEs) and non-fatal SAEs will be listed by patient.
4.8.2
AE summaries
The following incidences of AE summaries will be produced:

AEs regardless of study treatment relationship by primary system organ class and 
preferred term and maximum severity

AEs with suspected relationship to study treatment by primary system organ class, 
preferred term and maximum severity

AEs with an overall incidence rate of 10% or more, regardless of study treatment 
relationship by primary system organ class and preferred term 

On-treatment deaths by primary system organ class and preferred term

SAEs regardless of study treatment relationship by primary system organ class and 
preferred term 

SAEs with suspected relationship to study treatment by primary system organ class and 
preferred term

AEs leading to study drug discontinuation, regardless of study treatment relationship by 
primary system organ class and preferred term 

AEs requiring dose adjustment or temporarily study-drug interruption regardless of study 
treatment relationship by primary system organ class and preferred term 

AEs requiring additional therapy regardless of study treatment relationship by primary 
system organ class and preferred term.
4.8.3
Advers events of special interest (AESI)
Specific groupings of AESIs will be considered and the number of patients with at least 1 AE 
within each grouping will be reported. Such groups consist of AEs for which there is a specific 
clinical interest in connection with PAN (i.e. where PAN may influence a common mechanism 
of action responsible for triggering them) or which are similar in nature (although not identical). 
The groups are defined as per Table 4-3 and in PDS. These groupings are based on standardized 
MedDRA queries and Novartis MedDRA queries. A NMQ is a customized group of search 
terms which defines a medical concept for which there is no official SMQ available or the 
available SMQ does not completely fit to the need. It may include a combination of single 
terms and/or an existing SMQ, narrow or broad.
In case that eCRS (electronic Case Retrieval Strategy) for LBH589 is updated at analysis timing, 
safety topic of interests should be align with latest eCRS with the condition of SP flag.


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Table 4-2
Advers events of special interest
Safety topic of interest
MedDRA Term
MedDRA 
Qualifier
Carcinogenicity/Second primary 
malignancy
Carcinogenicity/Second primary 
malignancy [LBH589] (CMQ)
Hepatic Dysfunction
Hepatic Dysfunction [LBH589] (CMQ)
Narrow
Hypothyroidism
Hypothyroidism [LBH589] (CMQ)
Narrow
Ischaemic colitis
Ischaemic colitis [LBH589] (CMQ)
Narrow
Ischaemic heart disease
Ischaemic heart disease (SMQ)
Narrow
Medication errors
Medication errors (SMQ)
Broad
QTc prolongation
Torsade de pointes/QT prolongation 
(SMQ)
Broad
Renal Dysfunction
Acute renal failure (SMQ)
Broad
Severe Diarrhea
Diarrhoea (excl infective) [DOVITINIB] 
(CMQ)
Broad
Severe haemorrhage and 
thrombocytopenia - for 
thrombocytopenia
Haematopoietic thrombocytopenia 
(SMQ)
Narrow
Severe Hemorrhage and 
thrombocytopenia - for hemorrhage
Haemorrhage terms (excl laboratory 
terms) (SMQ)
Severe infections  (including 
reactivation of hepatitis B infection)
Hepatitis B Infection [STANDARD] 
(NMQ)
Broad
Severe infections (including 
leukopenia)
Haematopoietic leukopenia (SMQ)
Narrow
Severe infections (including 
pneumonia)
Infectious pneumonia [STANDARD] 
(NMQ)
Broad
Severe infections (including sepsis)
Sepsis [STANDARD] (NMQ)
Narrow
Tachyarrhythmias
Tachyarrhythmias [LBH589] (CMQ)
Venous Thromboembolism
Embolic and thrombotic events, venous 
(SMQ)
Overall summary of AESIswill be provided: 

All AEs

CTC grade 3 or 4 AEs regardless of study treatment relationship

CTC grade 3 or 4 AESIs with suspected study treatment relationship 

SAEs

AEs leading to study drug discontinuation

AEs requiring dose adjustment or temporarily study-drug interruption
4.8.4
Clinical trial safety disclosure
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on on-
treatment AEs (i.e., treatment-emergent AEs) which are not serious AEs with an incidence 
greater than 5% and on on-treatment serious AEs and serious AEs suspected to be related to 
study treatment will be provided by primary system organ class and preferred term.


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If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same system organ class and preferred term:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one serious AE / serious AE suspected to be related to 
study treatment / non-serious AE has to be checked in a block e.g., among AE's in a ≤ 1 day 
gap block, if at least one serious AE is occurring, then one occurrence is calculated for that 
serious AE.
The number of deaths resulting from serious AEs suspected to be related to study treatment and 
serious AEs irrespective of study treatment relationship will be provided by primary system 
organ class and preferred term.
4.8.5
Laboratory data
On analyzing laboratory assessments, data from all sources (central and local laboratories) will 
be combined. The summaries will include all laboratory assessments collected no later than 30
days after study treatment discontinuation. All laboratory assessments will be listed and those 
collected later than 30 days after study treatment discontinuation will be flagged in the listings. 
The values will be listed by laboratory parameter and patient.
Laboratory data will be converted into SI units and classified into CTC grades according to the 
National Cancer Institute CTCAE (NCI-CTCAE). A severity grade of 0 will be assigned when 
the value is within normal limits. In the unlikely case when a local laboratory normal range 
overlaps into the higher (i.e. non-zero) CTC grade, the laboratory value will still be taken as 
within normal limits and assigned a CTC grade of 0.
For analyses, values as reported from the laboratory and converted to SI units will be used. In 
addition, the following derivations will be done:

Corrected calcium (mg/dL) = total serum calcium (mg/dL) + 0.8 * (3.5 - serum albumin 
[g/dL]). Both values (total serum calcium and serum albumin) have to be taken from the 
same sample (i.e. identical sample date)Absolute blood counts: In case the lab presented 
blood counts as percentage of the total white blood cell count, the absolute blood counts 
will be derived. Both the percent blood count and the total white blood cell count have to 
be taken from the same blood sample (i.e. identical sample date).
The following summaries will be produced for the laboratory data (by laboratory parameter):

Number and percentage of patients with worst post-baseline CTC grade for hematology 
and biochemistry laboratory parameters. Each patient will be counted only for the worst 
grade observed post-baseline. 
Patients will be considered evaluable (included in “Total” column) for this analysis if 
they are at risk at baseline and have at least one post baseline value for the laboratory 
parameter. A patient is considered at risk at baseline, if the baseline of this patient is:

Missing or grade 0 for new or worsening from baseline to grade 1 category


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
Missing or less than grade 2 for new or worsening from baseline to grade 2 category

Missing or less than grade 3 for new or worsening from baseline to grade 3 category

Missing or less than grade 4 for new or worsening from baseline to grade 4 category

Shift tables using CTC grades to compare baseline to the worst post-baseline value will be 
produced for hematology and biochemistry laboratory parameters with CTC grades.

For laboratory parameters where CTC grades are not defined (eg., thyroid hormones), shift 
tables to the worst post-baseline value will be produced using the low/normal/high 
classifications based on laboratory reference ranges. 
The following listing will be produced for the laboratory data:

Listing of all laboratory data with values flagged to show the corresponding CTC grades 
and the classifications relative to the laboratory reference. 
Imputation rule for laboratory values
All safety laboratory values which are reported as ‘<x’ or ‘>x’ will be imputed as follows:

Lab values ‘<x’ will be imputed to 0

Lab values ‘>x’ will be imputed to x
Efficacy laboratory values (i.e. total serum protein, serum M protein, total urine protein and 
urine M band protein), ‘<x’ and ‘>x’ data entries will be imputed as follows:

Lab values ‘<x’ will be imputed to 0.99*x

Lab values ‘>x’ will be imputed to 1.01*x
These imputed values will be flagged in the listings.
For all the differential counts, values in % will be converted to absolute values, as
Absolute Value  = (value (%)*WBC) / 100
In order to derive the corresponding absolute normal range, the following scenarios 
(depending on the availability of the % range and the absolute range for the differential) will 
be considered:

1st scenario: % range missing and absolute range missing
Use pre-defined normal range reported in the Merck manual

2nd scenario: % range missing and absolute range NOT missing
Use the absolute range provided by the site 

3rd scenario: % range NOT missing and absolute range NOT missing
Use the absolute range provided by the site 

4th scenario: % range NOT missing and absolute range missing
The % normal limits (i.e. LLN and ULN) are divided by 100 and multiplied by the 
corresponding normal limits of WBC count, e.g. for neutrophils (NEU):

LLN for NEU count = (LLN for WBC count) * (LLN for NEU % / 100)


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
ULN for NEU count = (ULN for WBC count) * (ULN for NEU % / 100)
4.8.6
Vital signs
Vital sign assessments are performed in order to characterize basic body function. The variables 
collected in studies: height [cm], body temperature [°C], pulse rate [beats per minute (bpm)], 
systolic and diastolic blood pressure [mmHg], and respiratory rate [breaths per minute].
Patients with clinically notable vital sign abnormalities will be listed and assessments collected 
later than 30 days after study treatment discontinuation will be flagged in the listings. The 
criteria 
for 
clinically 
notable 
abnormalities 
are 
depicted 
in 
Table 
4-4
and 
Table 4-5.
Table 4-3
Clinically notable elevated vital sign values
Variable
Criteria
Systolic BP
180 mmHg and an increase 20 mmHg from baseline
Diastolic BP
105 mmHg and an increase 15 mmHg from baseline.
Body temperature
39.1°C (102.3°F)
Pulse rate
120 bpm with increase from baseline of 15 bpm
Respiratory rate
≥ 30 bpm
Table 4-4
Clinically notable vital sign below normal values
Variable
Criteria
Systolic BP
90 mmHg and a decrease 20 mmHg from baseline
Diastolic BP
50 mmHg and a decrease 15 mmHg from baseline
Body temperature
35°C (95°F)
Pulse rate
50 bpm with decrease from baseline of 15 bpm
Respiratory rate
≤ 10 breaths per minute
The number of patients with notably abnormal vital signs will be provided. 
Population for analysis
Systolic blood pressure, diastolic blood pressure and Pulse rate:

Patients are considered at risk if they have a baseline and at least one post-baseline 
assessment.
Body temperature:
Patients are considered at risk if:

Baseline is missing or < 39.1°C for abnormality “39.1°C”.

Baseline is missing or > 35°C for abnormality “35°C”.
Respiratory rate:
Patients are considered at risk if:

Baseline is missing or < 30 bpm for abnormality “30 bpm”.

Baseline is missing or > 10 bpm for abnormality “10 bpm”.


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All vital sign assessments will be listed by variable. 
4.8.7
Handling of missing values
Any baseline AE or any post-baseline AE with a missing grade will be reported as missing.
4.8.8
ECG
Analyses of QT prolongation will be based on QTcF measurement. In general, QTcF would be 
referred to as QTc throughout the document. 
Baseline definition
Quantitative ECG assessments:
Baseline is defined as an average of all pre-dose ECGs performed on Cycle 1 Day 1 if available. 
Otherwise, the average of all pre-dose ECG measurements taken on most recent day prior to 
the start of any study treatment within 21 days is considered as baseline. Unscheduled visits are 
included.
Qualitative ECG assessments:
Baseline is defined as the last assessment (or set of assessments) at prior to the first dose of 
study treatment within 21 days. Unscheduled visits are included.
Population for analysis
Quantitative ECG assessments:
Patients will be considered evaluable (included in “Total”) for outlier analysis if they are at risk 
at baseline and have at least one post-treatment ECG measurement. For change from baseline 
analyses they have to have at least one baseline ECG measurement and one post-baseline 
measurement.
A patient is considered at risk at baseline, if the baseline of this patient is missing or:

≤ 450 ms for abnormality “value of > 450 ms and ≤ 480 ms”

≤ 480 ms for abnormality “value of > 480 ms and ≤ 500 ms”

≤ 500 ms for abnormality “value of > 500 ms”
Qualitative ECG assessments
A patient is considered at risk for each individual finding if the baseline of the patient is: missing 
or with baseline being normal for that particular finding.
QTc analysis
Notable abnormalities will be summarized for the following:

An increase of 30 to 60 ms in QTc 

An increase of > 60 ms in QTc 

Patients with any QTc value of > 450 and ≤ 480 ms

Patients with any QTc value of > 480 and ≤ 500 ms

Patients with any QTc value of > 500 ms


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Cardiac imaging
All cardiac imaging variables will be listed.
4.8.9
Drug-induced liver injury
All data recorded at the “Liver Events” eCRF pages for patients meeting the potential drug-
induced liver injury (DILI) criteria will be listed if available.
4.9
Patient-reported outcomes
In this study, the Functional Assessment of Cancer Therapy Gynecology Oncology Group 
Neurotoxicity Scale (FACT/GOG-NTX, version 4.0) will be collected and assessed.
In order to summarize patient-reported outcome (PRO) variables, assessments will be time 
slotted using time-windows (Table 2-1). The baseline assessment is defined according to the 
rule for efficacy variables (Section 2.6).
The FAS will be used for all PRO summaries and listings. 
4.9.1
FACT/GOG-NTX questionnaire
Assessment schedule
The questionnaire was to be completed at screening and at Cycle 1 Day 1 (C1D1) immediately 
prior to starting study drug, Day 1 of each cycle and again at the study completion visit.
Data derivation
For the FACT/GOG-NTX subscales (Table 4-6), lower values denote higher neurotoxicity 
ranging from 0 to 44. Scoring will be done according to the instructions of the authors (Cella 
1997) as detailed in Appendix 3.
Table 4-5
FACT/GOG-NTX scales
(Sub)Scale
Item numbers
Score range
Physical well-being (PWB)
GP1 to GP7
0 – 28
Social/family well-being (SWB)
GS1 to GS7
0 – 28
Emotional well-being (EWB)
GE1 to GE6
0 – 24
Functional well-being (FWB)
GF1 to GF7
0 – 28
Neurotoxicity subscale (NtxS)
Ntx1 to Ntx9, HI12, An6
0 – 44
FACT/GOG-Ntx Total Score
PWB+SWB+EWB+FWB+NtxS
0 – 152
Analyses

Calculated scores will be summarized by time window. 
4.10
Pharmacokinetic analyses
Pharmacokinetics
The PK set-PAN and PK set-BTZ will be used for the following analyses for PAN and BTZ, 
respectively. 


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Plasma concentration data of PAN and BTZ: 
Summary statistics will be presented for plasma PAN (and its metabolite BJB432, if feasible)
and BTZ concentrations at each scheduled time point for PAN on C1D1 and C1D8, respectively, 
and for BTZ on C1D8. Graphical presentation will also be provided on mean concentration at 
each scheduled time point for PAN on C1D1 and C1D8, respectively, and for BTZ on C1D8. 
Summary statistics will include n, arithmetic mean, median, SD, geometric mean, coefficient 
of variation CV (%) and geometric CV (%), minimum and maximum.
PK parameters of PAN and BTZ: 
The aforementioned summary statistics will be presented for all PK parameters except Tmax 
(specifically, if feasible, AUClast, AUC0-48h, AUC0-24h, AUCinf, Cmax, Lambda_z, T1/2, 
CL/F, Vz/F for PAN and BJB432 on C1D1 and C1D8, and AUClast, AUC0-48h, AUC0-24h,
AUCinf, Cmax, Lambda_z, T1/2, CL/F, Vz/F for BTZ on C1D8). For Tmax, only median, 
minimum, and maximum will be presented.
Analytical method
The plasma samples from all patients will be assayed for PAN, BTZ, and its metabolite BJB432
(if feasible) concentrations by Novartis using a validated liquid chromatography-tandem mass 
spectrometry method (LC-MS/MS). Values below the lower limit of quantification (LLOQ) 
will be reported as 0 ng/mL.  Missing values will be labeled accordingly.
5
References
[Brookmeyer R. and Crowley J. (1982)] A Confidence Interval for the Median Survival Time, 
Biometrics 38, 29-41
[Collet D (1994)] Modelling survival data in medical research. London, Chapman & Hall
[Lachin J (2000)] Biostatistical methods: The assessment of relative risk. New York; John 
Wiley & Sons, Inc.


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Appendix 1 – Calculation of glomerular filtration rate (GFR)
The baseline GFR will be calculated for each patient according to the following Cockcroft-
Gault equitation (Cockcroft & Gault 1976). 
,
where
CCR Creatinine clearance (used to estimate GFR)
SCR Serum creatinine
const
factor = 1.0 for males
0.85 for females
Appendix 2 – Calculation: clinical staging of MM
Patient’s clinical stage of multiple myeloma will calculated according to the International 
Staging System (ISS, Greipp et al 2005) as depicted in Figure 5-1.
Figure 5-1
ISS classification
Serum β2-
microglobulin ≥ 5.5 
mg/L?
Stage III
Yes
Serum β2-micro-
globulin or serum albumin 
missing?
No
Not assessed
Yes
Serum β2-micro-
globulin < 3.5 mg/L 
and serum albumin 
≥ 3.5 g/dL?
Stage I
No
Yes
Stage II
No


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Appendix 3 - Scoring guides
FACT/GOG-NTX
FACT/GOG-Ntx Scoring Guidelines (Version 4)
Instructions:*
1. Record answers in "item response" column. If missing, mark with an X
   
2. Perform reversals as indicated, and sum individual items to obtain a score.
3. Multiply the sum of the item scores by the number of items in the subscale, then divide by 
the number of items answered.  This produces the subscale score.
4. Add subscale scores to derive total scores (TOI, FACT-G & FACT/GOG-Ntx). 
5. The higher the score, the better the QOL.
Subscale
  Item Code    Reverse item?       Item response        
Item Score
PHYSICAL
GP1
4
-
________
=________
WELL-BEING
GP2
4
-
________
=________
   (PWB)
GP3
4
-
________
=________
      
GP4
4
-
________
=________
      
GP5
4
-
________
=________
      
GP6
4
-
________
=________
      
GP7
4
-
________
=________
              Sum individual item scores: ________  
                      Multiply by 7: ________
Divide by number of items answered: ________=PWB subscale core
SOCIAL/FAMILY
GS1
0
+
________
=________
WELL-BEING
GS2
0
+
________
=________
    (SWB)
GS3
0
+
________
=________
      
GS4
0
+
________
=________
      
GS5
0
+
________
=________
   
GS6
0
+
________
=________
      
GS7
0
+
________
=________
             Sum individual item scores: ________  
                     Multiply by 7: ________
  Divide by number of items answered: ________=SWB subscale score
EMOTIONAL
GE1
4
-
________
=________
WELL-BEING
GE2
0
+
________
=________
    (EWB)
GE3
4
-
________
=________
      
GE4
4
-
________
=________
     
GE5
4
-
________
=________
GE6
4
-
________
=________
             Sum individual item scores: ________  
                     Multiply by 6: ________
Score range: 0-28
Score range: 0-28
Score range: 0-24


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Divide by number of items answered: ________=EWB subscale score
FUNCTIONAL  
GF1
0
+
________
=________
WELL-BEING 
GF2
0
+
________
=________
     (FWB)
GF3
0
+
________
=________
      
GF4
0
+
________
=________
      
GF5
0
+
________
=________
      
GF6
0
+
________
=________
      
GF7
0
+
________
=________
             Sum individual item scores: ________  
                     Multiply by 7: ________
Divide by number of items answered: ________=FWB subscale score
Subscale
         Item Code       Reverse item?            Item response        
Item Score
NEUROTOXICITY
Ntx1
4
-
________
=________
SUBSCALE
Ntx2
4
-
________
=________
   (NtxS)
Ntx3
4
-
________
=________
Ntx4
4
-
________
=________
Ntx5
4
-
________
=________
HI 12
4
-
________
=________
Ntx6
4
-
________
=________
Ntx7
4
-
________
=________
Ntx8
4
-
________
=________
Ntx9
4
-
________
=________
An6
4
-
________
=________
              Sum individual item scores:________  
                  Multiply by 11 : ________
Divide by number of items answered: ________=Ntx Subscale score
To Derive a FACT/GOG-Ntx total score:
_________ + __________ + __________ + __________ + __________ =________=FACT/GOG-Ntx Total 
              (PWB score)  (SWB score)   (EWB score)  (FWB score)   (NtxS score)
       score
When there are missing data, prorating subscale scores is acceptable as long as more than 50% 
of the items were answered (e.g., a minimum of 4 of 7 items, 4 of 6 items, etc). The FACT/GOG 
Ntx total score is considered appropriate to score as long as overall item response rate is greater 
than 80% (e.g., at least 31 of 38 items completed)
In detail:
1. PWB, SWB, EWB, FBW and NtxS scores will only be derived in case > 50% of the 
corresponding items have been answered.
Score range: 0-28
Score range: 0-152
Score range: 0-44


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2. The FACT/GOG Ntx total score will be derived when >80% of the underlying items have 
been answered (>= 31 out of 38 items). If this is the case, it is derived out of the prorated 
subscores as described above (see 1). In addition, the total score will only be calculated if 
each of the component subscales scores is valid.