Clinical trial NCT02720510
Conditions: Multiple Myeloma
Keywords: multiple myeloma farydak panobinostat LBH589 ASCT transplant
Sponsor: Novartis Pharmaceuticals
Start date: 2016-06-14; Completion date: 2017-05-22
Enrollment: 6 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a multicenter, open-label, randomized phase II study which were to enroll 112 newly diagnosed symptomatic multiple myeloma patients in a 1:1 fashion. Patients were to enroll at approximately 20 centers in the United States.

Patients were to undergo stem cell mobilization with plerixafor plus Granulocyte Colony Stimulating Factor (G-CSF), according to investigator discretion, after 4 cycles of induction therapy. Study treatment interruption for stem cell collection were not to exceed 30 days. All patients were to receive one additional cycle of study treatment after stem cell collection and then proceed to autologous transplant using melphalan 200mg/m2(140mg/m2 for patients \> 70 years), as conditioning.

After Autologus Stem Cell Transplant( ASCT), patients still on study were to initiate maintenance therapy within the 60-120 day period following ASCT, provided they have adequate blood count and clinical recovery. Patients in the RVD arm were to initiate maintenance therapy with lenalidomide alone, and patients in RVD-panobinostat arm were to receive lenalidomide + panobinostat maintenance. Lenalidomide were to be dosed orally at 10mg/day continuously in both arms, increasing to 15mg/day after the first 84 day cycle. Panobinostat were to be dosed at 10mg three times a week, every other week. Total planned duration of maintenance therapy were to be 3 years.

Patients were to remain on study treatment until they complete the maintenance phase, or until they experience disease progression, unacceptable toxicity, or at the discretion of the Investigator.

Detailed description:

Arms: arm 1: Revlimid, Velcade, dexamethasone and Farydak arm 2: Revlimid, Velcade and Dexamethasone
Interventions: intervention 1: Revlimid intervention 2: Velcade intervention 3: dexamethasone intervention 4: Farydak
Intervention descriptions: intervention 1: Revlimid was used with dexamethasone to treat patients with multiple myeloma intervention 2: Velcade was a proteasome inhibitor indicated for treatment of patients with multiple myeloma intervention 3: Dexamethasone was a steroid used to treat patients with multiple myeloma. intervention 4: FARYDAK® (panobinostat) capsules was a prescription medicine used, in combination with bortezomib and dexamethasone, to treat adults with a type of cancer called multiple myeloma after at least 2 other types of treatment have been tried.

Protocol documents:
Prot_000.pdf: 
Clinical Development
LBH589 / Panobinostat / Farydak®
Oncology Clinical Protocol CLBH589DUS106 / NCT02720510
A Randomized, Phase II trial evaluating the efficacy and 
safety of lenalidomide, bortezomib and dexamethasone 
(RVD) with or without panobinostat in transplant eligible, 
newly diagnosed Multiple Myeloma
Authors
Document type
Oncology Clinical Study Protocol
EUDRACT number
Not applicable
Version number
00 (Original Protocol)
Development phase
II
Document status
Final
Release date
19-Jan-2016
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Template version 19-Nov-2015


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Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................5
List of tables ........................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms.................................................................................................................8
Protocol summary:...............................................................................................................9
1
Background........................................................................................................................12
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............12
1.2
Introduction to investigational treatment(s) and other study treatment(s).............20
1.2.1
Overview of Panobinostat.....................................................................20
2
Rationale............................................................................................................................23
2.1
Study rationale and purpose...................................................................................23
2.2
Rationale for the study design ...............................................................................24
2.3
Rationale for dose and regimen selection..............................................................24
2.4
Risks and benefits..................................................................................................24
3
Objectives and endpoints...................................................................................................25
4
Study design ......................................................................................................................27
4.1
Description of study design ...................................................................................27
4.2
Timing of interim analyses and design adaptations...............................................28
4.3
Definition of end of the study................................................................................28
4.4
Early study termination..........................................................................................28
5
Population..........................................................................................................................29
5.1
Patient population..................................................................................................29
5.2
Inclusion criteria ....................................................................................................29
5.3
Exclusion criteria...................................................................................................30
6
Treatment...........................................................................................................................33
6.1
Study treatment......................................................................................................33
6.1.2
Dosing administration for induction and maintenance .........................34
6.1.3
Ancillary treatments..............................................................................36
6.1.4
Guidelines for continuation of treatment ..............................................36
6.1.5
Treatment duration................................................................................37
6.2
Dose modifications................................................................................................37
6.2.1
Dose modification and dose delay ........................................................37
6.2.2
Follow-up for toxicities.........................................................................48
6.3
Concomitant medications ......................................................................................49


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6.3.1
Permitted concomitant therapy .............................................................49
6.3.2
Permitted concomitant therapy requiring caution and/or action...........50
6.3.3
Prohibited concomitant therapy ............................................................50
6.4
Patient numbering, treatment assignment or randomization .................................52
6.4.1
Patient numbering .................................................................................52
6.4.2
Treatment assignment or randomization...............................................52
6.4.3
Treatment blinding................................................................................52
6.5
Study drug preparation and dispensation...............................................................53
6.5.1
Study drug packaging and labeling.......................................................53
6.5.2
Drug supply and storage........................................................................53
7
Visit schedule and assessments .........................................................................................54
7.1
Study flow and visit schedule................................................................................54
7.1.1
Screening...............................................................................................60
7.1.2
Treatment period...................................................................................62
7.1.3
Discontinuation of Study Treatment .....................................................63
7.1.4
Replacement policy...............................................................................64
7.1.5
Withdrawal of Consent .........................................................................64
7.1.6
Follow up for Safety Evaluations..........................................................64
7.1.7
Lost to follow-up...................................................................................64
7.2
Assessment types...................................................................................................64
7.2.1
Efficacy assessments.............................................................................64
7.2.2
Safety and tolerability assessments.......................................................66
7.2.3
Resource utilization...............................................................................71
8
Safety monitoring and reporting........................................................................................71
8.1
Adverse events.......................................................................................................71
8.1.1
Definitions and reporting ......................................................................71
8.1.2
Laboratory test abnormalities................................................................72
8.2
Serious adverse events...........................................................................................73
8.2.1
Definitions.............................................................................................73
8.2.2
Reporting...............................................................................................73
8.3
Emergency unblinding of treatment assignment ...................................................74
8.4
Pregnancies............................................................................................................74
8.5
Warnings and precautions......................................................................................74
8.6
Data Monitoring Committee..................................................................................74
8.7
Steering Committee ...............................................................................................75
9
Data collection and management.......................................................................................75


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9.1
Data confidentiality ...............................................................................................75
9.2
Site monitoring ......................................................................................................75
9.3
Data collection.......................................................................................................76
9.4
Database management and quality control............................................................76
10 Statistical methods and data analysis ................................................................................77
10.1
Analysis sets ..........................................................................................................77
10.1.1
Full Analysis Set ...................................................................................77
10.1.2
Safety Set ..............................................................................................77
10.1.3
Per-Protocol Set ....................................................................................77
10.2
Patient demographics/other baseline characteristics .............................................77
10.3
Treatments (study treatment, concomitant therapies, compliance) .......................78
10.3.1
Study treatment .....................................................................................78
10.3.2
Concomitant medications......................................................................78
10.4
Primary objective...................................................................................................78
10.4.1
Variable.................................................................................................78
10.4.2
Statistical hypothesis, model, and method of analysis..........................78
10.4.3
Handling of missing values/censoring/discontinuations.......................79
10.4.4
Supportive analyses...............................................................................79
10.5
Secondary objectives .............................................................................................79
10.5.1
Key secondary objective(s)...................................................................79
10.5.2
Other secondary efficacy objectives .....................................................79
10.5.3
Safety objectives ...................................................................................80
82
10.7
Interim analysis......................................................................................................83
10.8
Sample size calculation..........................................................................................83
10.9
Power for analysis of key secondary variables......................................................83
11 Ethical considerations and administrative procedures ......................................................83
11.1
Regulatory and ethical compliance........................................................................83
11.2
Responsibilities of the investigator and IRB/IEC/REB.........................................83
11.3
Informed consent procedures.................................................................................84
11.4
Discontinuation of the study..................................................................................84
11.5
Publication of study protocol and results...............................................................84
11.6
Study documentation, record keeping and retention of documents.......................85
11.7
Confidentiality of study documents and patient records .......................................85
11.8
Audits and inspections...........................................................................................86
11.9
Financial disclosures..............................................................................................86


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12 Protocol adherence ............................................................................................................86
12.1
Amendments to the protocol..................................................................................86
13 References (available upon request)..................................................................................87
14 Appendices ........................................................................................................................93
14.1
Appendix 1: Co-medications which are known to prolong the QT interval 
and/or induce Torsades de Pointes, are strong CYP3A4/5 inhibitors/inducers 
or sensitive CYP2D6 substrates.............................................................................93
14.1.1
Medications which are known to prolong the QT interval and/or 
induce Torsades de Pointes ventricular arrhythmia should be 
avoided..................................................................................................93
14.1.2
Dose reduce panobinostat when combined with medications which 
are known strong CYP3A inhibitors.....................................................95
14.1.3
Medications which are known strong CYP3A inducers are to be 
avoided..................................................................................................97
14.1.4
Medications which are known sensitive CYP2D6 substrates or 
substrates with narrow therapeutic index are to be avoided .................97
14.1.5
References (available upon request) .....................................................98
14.2
Appendix 2: ECOG performance status scale......................................................104
List of figures
Figure 1-1
Complete Response Rates in Upfront Myeloma...................................16
Figure 4-1
Study design..........................................................................................28
Figure 6-1
Induction Dosing Schedule – Arm 1.....................................................33
Figure 6-2
Induction Dosing Schedule – Arm 2.....................................................34
Figure 6-3
Maintenance Dosing Schedule – Arm 1................................................34
Figure 6-4
Maintenance Dosing Schedule – Arm 2................................................34
Figure 14-1
International Staging System ................................................................99


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List of tables
Table 1-1
Prognostic impact of response level post induction in patients with 
newly diagnosed multiple myeloma undergoing autologous 
transplant...............................................................................................14
Table 1-2
Best Responses with high vs low dose dexamethasone........................17
Table 1-3
Overall response rate by Induction therapy ..........................................18
Table 3-1
Objectives and related endpoints ..........................................................26
Table 6-2
Dose reduction steps for S.C BTZ ........................................................37
Table 6-3
Dose reduction steps for oral Dex.........................................................38
Table 6-4
Dose reduction steps for REV...............................................................38
Table 6-5
Dose reduction steps for PAN*.............................................................38
Table 6-6
Criteria for interruption and re-initiation of PAN, REV, and BTZ 
treatment................................................................................................39
Table 6-7
Drug related adverse events dose modification guidelines for BTZ.....43
Table 6-8
Recommended dose modification for BTZ-related neuropathic pain 
and/or peripheral sensory neuropathy...................................................43
Table 6-9
Dex dose modifications.........................................................................44
Table 6-10
Proposed anti-diarrheal medications.....................................................45
Table 6-11
Diarrhea management and PAN/BTZ dose modifications....................46
Table 6-12
Criteria for dose interruption of PAN due to QTcF prolongation.........48
Table 6-13
Preparation and dispensing ...................................................................53
Table 7-1
Visit evaluation schedule ......................................................................55
Table 7-2
Local clinical laboratory parameters collection plan ............................68
Table 7-3
ECG collection plan..............................................................................70
Table 14-1
Medications which are known to prolong the QT interval and/or 
induce Torsades de pointes to be avoided.............................................93
Table 14-2
Medications which are known strong CYP3A inhibitors .....................96
Table 14-3
Medications which are known strong CYP3A inducers are to be 
avoided..................................................................................................97
Table 14-4
Medications which are known sensitive CYP2D6 substrates or 
substrates with a narrow therapeutic index are to be avoided...............98
Table 14-5
Response classification in MM according to IMWG criteria .............100
Table 14-6
Additional response categories in MM according to IMWG criteria .102
Table 14-7
ECOG performance status scale..........................................................104


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List of abbreviations
AE
Adverse Event
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
ASCT
Autologus Stem Cell Transplant
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
b.i.d.
bis in diem/twice a day
BLRM
Bayesian Logistic Regression Model
BTZ
Bortezomib
CR
Complete Response
CRF
Case Report/Record Form; the term CRF can be applied to either EDC or Paper
CRO
Contract Research Organization
CSR
Clinical study report
CSR addendum
An addendum to Clinical Study Report (CSR) that captures all the additional information that 
is not included in the CSR
Dex
Dexamethasone
DLT
Dose Limiting Toxicity
DS&E
Drug Safety and Epidemiology
ECG
Electrocardiogram
G-CSF
Granulocyte-Colony Stimulating Factor
HDAC
Histone Deacetylase
i.v.
intravenous(ly)
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IMWG
International Myeloma Working Group
IRB
Institutional Review Board
IRT
Interactive Response Technology that includes Interactive Voice Response System and 
Interactive Web Response System
MAP
Master Analysis Plan documents project standards in the statistical methods which will be 
used within the individual clinical trial RAP documentation
MRD
Minimal Residual Disease
MTD
Maximum Tolerated Dose
nCR
Near Compete Response
o.d.
omnia die/once a day
ORR
Overall Response Rate
p.o.
per os/by mouth/orally
PHI
Protected Health Information
RAP
The Report and Analysis Plan (RAP) is a regulatory document which provides evidence of 
preplanned analyses
REB
Research Ethics Board
REV
Revlimid
RP2D
Recommended Phase II Dose
RVD
Revlimid, Velcade, Dexamethasone
SAE
Serious Adverse Event
SOP
Standard Operating Procedure


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study subject or study patient
Control drug
A study treatment used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or evaluate 
comparative effects of the investigational drug
Cohort
A group of newly enrolled patients treated at a specific dose and regimen (i.e. 
treatment group) at the same time
Cycles
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g.: q28 days)
Dose level
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment
Point/time of patient entry into the study; the point at which informed consent 
must be obtained (i.e. prior to starting any of the procedures described in the 
protocol)
Investigational drug
The study treatment whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug.”
Investigational treatment
Drug whose properties are being tested in the study as well as their associated 
placebo and active treatment controls (when applicable). This also includes 
approved drugs used outside of their indication/approved dosage, or that are 
tested in a fixed combination. Investigational treatment generally does not 
include other study treatments administered as concomitant background therapy 
required or allowed by the protocol when used in within approved 
indication/dosage
Medication number
A unique identifier on the label of each study treatment package which is linked 
to one of the treatment groups of a study
Other study treatment
Any drug administered to the patient as part of the required study procedures 
that was not included in the investigational treatment
Patient Number (Patient No) 
A unique identifying number assigned to each patient/subject/healthy volunteer 
who enrolls in the study
Randomization number
A unique treatment identification code assigned to each randomized patient, 
corresponding to a specific treatment arm assignment
Stage related to study timeline
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc.
Stop study participation
Point/time at which the patient came in for a final evaluation visit or when study 
treatment was discontinued whichever is later
Study treatment
Includes any drug or combination of drugs in any study arm administered to the 
patient (subject) as part of the required study procedures, including placebo and 
active drug run-ins.
In specific examples, it is important to judge investigational treatment component 
relationship relative to a study treatment combination; study treatment in this 
case refers to the investigational and non-investigational treatments in 
combination.
Study treatment 
discontinuation
Point/time when patient permanently stops taking study treatment for any reason
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 visits or assessments, and
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Protocol summary: 
Title
A Randomized, Phase II trial evaluating the efficacy and safety of lenalidomide, 
bortezomib and dexamethasone (RVD) with or without panobinostat in transplant 
eligible, newly diagnosed Multiple Myeloma
Sponsor and Clinical 
Phase
Novartis Pharmaceuticals
Phase II
Investigation type
Drug
Study type
Interventional
Purpose and rationale
In data presented at ASH 2015, the combination of RVD and panobinostat in newly 
diagnosed MM patients showed an ORR of 94%, with a 46% CR/nCR rate after 4 
cycles. This marked improvement from historical data reporting CR/nCR rates of 
approximately 7% warrants further investigation of this combination in this 
population.
Primary Objective(s) and 
Key Secondary Objective
Primary Objective: To evaluate the efficacy  of the combination of RVD + 
panobinostat compared to RVD alone
Key Secondary Objective: To assess MRD negativity after 4 cycles of induction by 
next gen sequencing
Secondary Objectives
To assess best overall response rate (ORR) and MRD negativity after ASCT and 
maintenance 
To assess depth of response by IMWG criteria
To assess the duration of response
To assess overall survival and progression free survival at three years
To assess the toxicity and tolerability
Study design
This is a multicenter, open-label, randomized phase II study which will enroll 112
newly diagnosed symptomatic multiple myeloma patients in a 1:1 fashion. Patients 
will be enrolled at approximately 20 centers in the United States. 
Patients will undergo stem cell mobilization with plerixafor plus G-CSF (according 
to investigator discretion) after 4 cycles of induction therapy. Study treatment 
interruption for stem cell collection may not exceed 30 days.  All patients will 
receive one additional cycle of study treatment after stem cell collection and then 
proceed to autologous transplant using melphalan 200mg/m2(140mg/m2 for 
patients > 70 years), as conditioning. 
After ASCT, patients still on study will initiate maintenance therapy within the 60-
120 day period following ASCT, provided they have adequate blood count and 
clinical recovery. 
Patients in the RVD arm will initiate maintenance therapy with lenalidomide alone, 
and patients in RVD-panobinostat arm will receive lenalidomide + panobinostat 
maintenance. Lenalidomide will be dosed orally at 10mg/day continuously in both 
arms, increasing to 15mg/day after the first 84 day cycle. Panobinostat will be 
dosed at 10mg three times a week, every other week. Total planned duration of 
maintenance therapy will be 3 years.
Patients will remain on study treatment until they complete the maintenance phase, 
or until they experience disease progression, unacceptable toxicity, or at the 
discretion of the Investigator.
Population
Newly diagnosed Multiple Myeloma patients who plan to receive autologous stem 
cell transplantation.
Inclusion criteria
Patient must be newly diagnosed with multiple myeloma, based on IMWG 2014 
definition (Rajkumar et al 2014)
Patient must have measurable disease defined by at least 1 of the following 
conditions present at screening:

Serum M-protein by PEP ≥ 1.0 g/dL (≥ 10 g/L).

Urine M-protein by PEP ≥ 200 mg/24 hours.


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
Involved serum free light chain level ≥ 10 mg/dL (≥ 100 mg/L), provided that 
the serum free light chain ratio is abnormal.
Patient has an ECOG performance status (PS) ≤ 2
Patient has the following laboratory values within 3 weeks before starting study 
drug:

Absolute neutrophil count (ANC) ≥ 1.0 x 109 /L

Platelet count ≥ 75 x 109 /L

Calculated creatinine clearance ≥ 50 mL/min (using Cockcroft-Gault formula) 
Exclusion criteria
Patient received prior treatment with DAC inhibitors including Panobinostat
Patient taking any anti-cancer therapy concomitantly (bisphosphonates are 
permitted only if commenced prior to the start of screening period)
Patient who received:

prior anti-myeloma chemotherapy or medication 

experimental therapy or biologic immunotherapy including monoclonal 
antibodies ≤ 4 weeks prior to start of study.

prior radiation therapy ≤ 4 weeks or limited field radiotherapy ≤ 2 weeks prior 
start of study.
Patient has not recovered from all therapy-related toxicities associated with above 
listed treatments to < grade 2 CTCAE.
Clinically significant, uncontrolled heart disease and/or recent cardiac event (within 
6 month prior to screening), such as: 

History of angina pectoris, symptomatic pericarditis, or myocardial infarction 

Left Ventricular Ejection Fraction (LVEF) < 45%  as determined by 
echocardiogram (ECHO) or Multiple Gated acquisition (MUGA)

History or presence of any cardiac arrhythmias, e.g. ventricular, 
supraventricular, nodal arrhythmias, or conduction abnormality

Complete left bundle branch block (LBBB), bifascicular block

Corrected QT (QTcF) ≥ 450 ms for males and females using Fridericia’s 
correction on screening ECG (as average of triplicate ECGs)

History of documented congestive heart failure (New York Heart Association 
functional classification III-IV)
Investigational and 
reference therapy
Arm 1 – Lenalidomide, bortezomib, dexamethasone, panobinostat
Arm 2 – Lenalidomide, bortezomib, dexamethasone
Efficacy assessments

Serum and urine sample collection for central and local M-protein assessment 
by PEP, and IF 

Serum sample collection for FLC assessment

Cytogenetics in bone marrow by local assessment

Plasma cell count in bone marrow by local assessment

Additional central response assessments in bone marrow (MRD)

Assessment of soft tissue plasmacytoma

Imaging assessment by CT/MRI/PET 

Full body skeletal survey

Response assessment by Investigator
Safety assessments

Physical examination

Vital signs

Height and weight

Performance status

Laboratory evaluations


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
Hematology

Chemistry

Electrolytes

Thyroid

Coagulation

Troponin I

Creatinine Clearance

Pregnancy and assessments of fertility

Electrocardiogram

MUGA/ECHO
Data analysis
The sample size of the study is based on the assumption that in the RVD alone 
arm the nCR/CR rate will be 7% and adding Pano to RVD will improve the nCR/CR 
rate to 25%. For one sided alpha=0.05, fifty patients in each arm will have 81% 
power to detect this improvement.
The primary endpoint will be analyzed based on nCR/CR rate of the combination of 
panobinostat with bortezomib, lenalidomide and dexamethasone (P-RVD) vs RVD 
in newly diagnosed multiple myeloma patients after 4 cycles of therapy. The 
analysis will be based on Investigator assessment of response.
Key words
Myeloma, bortezomib, lenalidomide, dexamethasone, newly-diagnosed, 
panobinostat


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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
Multiple myeloma (MM) is a malignant proliferation of plasma cells which accounts for 10% 
to 15% of all hematologic malignancies and 20% of deaths related to cancers of the blood and 
bone marrow in adults. Approximately 24,000 people in the US will receive a new diagnosis 
of MM in 2014 (Howlader et al 2014). Despite a survival that improved from 45 to 60 months 
after the introduction of newer therapies (particularly proteasome inhibitors and 
immunomodulatory drugs, commonly called “IMiDs”, often used in combination with 
dexamethasone), all patients ultimately progress and the disease remains incurable (Kumar et 
al 2014). 
MM is characterized by excessive proliferation of plasma cells resulting in production of 
monoclonal proteins, which can lead to end-organ damage. The hallmarks of MM are bone 
marrow failure, renal failure, and bone disease. Symptoms related to bone marrow 
dysfunction include anemia, decreased white blood cells leading to increased susceptibility to 
infection, and decreased platelet counts leading to increased susceptibility to bleeding
(Rajkumar 2013). Patients with MM suffer from bone pain and fractures as a result of 
osteolytic lesions. They also suffer from the symptoms and complications of renal failure 
which further contribute to worsening anemia. These signs and symptoms are commonly 
denoted as CRAB (Calcium elevation, Renal dysfunction, Anemia, Bone destruction)
(Rajkumar 2013).
A feature of MM that is thought to contribute to recurrent relapses and disease persistence is 
the presence of multiple malignant clones from the time of initial diagnosis onwards (Egan et 
al 2012). Such clonal heterogeneity has been demonstrated with several methods including 
whole genome sequencing (WGS) on patient tumor samples followed longitudinally from the 
point of initial diagnosis (Egan et al 2012).
Overall Goals of Therapy of Induction Therapy in NDMM
Given the clonal heterogeneity of MM in its initial stages, standard therapy for newly 
diagnosed MM (NDMM) has traditionally employed combination therapy with multiple drugs 
having different mechanisms of action, with the intent to maximally cytoreduce the disease, 
and achieve deep responses to induction therapy (Rosinol et al 2014). The preferred 
therapeutic program for NDMM involves combination induction therapy followed by 
autologous stem cell transplantation (ASCT), followed by prolonged maintenance therapy to 
maintain disease control and prolong remissions (Rajkumar 2013). The overall goal of 
induction therapy and ASCT in NDMM is to achieve maximal reduction of tumor burden, as 
measured by both M-protein reduction and plasma cell clearance in the marrow (Lonial et al 
2014). Additional more sensitive tools to measure depth of response include minimal residual 
disease (MRD) assessment using multi-color flow cytometry and ASO-PCR (Lonial et al 
2014).


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Achieving deep responses (defined as nCR/CR by mEBMT criteria and >VGPR by IMWG 
criteria) strongly correlated with PFS and overall survival  in several randomized studies of 
frontline therapy in NDMM (Lahuerta et al, Gertz et al, Moreau et al, Alegre et al). The 
incorporation of ASCT in the era of conventional chemotherapy increased the rates of CR in 
patients with NDMM, which translated into improved PFS in most randomized studies (Cavo 
et al 2010, Kumar et al 2012, Wang et al 2010, Ladetto et al 2010), but these regimens were 
limited to younger more fit patients who were eligible for high dose therapy. In a meta-
analysis of 21 studies in NDMM (10 prospective and 11 retrospective) totaling 4,990 patients, 
highly significant associations between maximal response and outcomes were noted. 
Specifically, maximal response post-ASCT was associated with prolonged OS (P<0.0001), 
and prolonged TTP/PFS/EFS (P<0.00001) (Channan Khan et al 2010) Furthermore, durability 
of deep responses is also an important predictor of overall survival. In a retrospective analysis 
by Barlogie et al of patients enrolled in a total therapy 2 (TT2) study, median OS was 
significantly longer (not reached) in patients who sustained CR for > 36 months compared to 
the non-CR group (5.6 years) and those who lost CR before 36 months (1.6 years) (Barlogie et 
al 1999). 
Prior to the advent of novel therapies in multiple myeloma, achieving deep responses with 
induction therapy alone was not common, and therefore, meaningful measurements of the 
impact of depth of response on outcomes were available primarily in patients undergoing 
ASCT (Lonial et al 2014). However, there were trends toward improved survival in those 
patients who achieved deep responses to pre-transplant induction therapy alone, although the 
association was less robust. In subsequent studies of induction therapies employing novel 
agents, the association between quality of response and PFS/OS continued to hold, even in 
older patients who were able to better tolerate the novel agents compared to traditional 
chemotherapy. In a meta-analysis of phase 3 bortezomib trials totaling 2086 transplant-
eligible patients, the improved quality of responses with bortezomib regimens (> VGPR and 
CR) corresponded to improvements in PFS and OS (Nooka et al 2011). 
An additional important factor with induction therapy that impacts survival outcomes is time 
to achieving CR. Compelling evidence has emerged from several randomized studies that 
improved outcomes are associated with response quality at each treatment stage (post-
induction, post-transplant, post-consolidation, etc). In a large phase 3 study (IFM 2005-01), in 
which 482 patients were randomized to bortezomib vs. non-bortezomib based induction 
therapy, PFS was significantly longer for patients achieving VGPR post-induction compared 
to post-transplant (median 41.1 months vs. 31.1 months) (Moreau et al 2011). Importantly, 
achieving < VGPR overall and post-induction were negative prognostic factors in the 
multivariate analysis. Table 1-3 shows the differences in outcomes based on quality of 
response post- induction therapy across various studies comparing induction regimens for 
transplant-eligible patients with NDMM. In a meta-analysis of 21 studies in NDMM patients 
undergoing ASCT, post-induction response was strongly associated with OS (P=0.0015) and 
TTP/PFS/EFS (P<0.00001) (Channan Khan et al 2010). Together, these data demonstrate the 
importance of achieving deep responses early with induction therapy, in order to allow 
subsequent treatment stages to further deepen and maintain the response, and maximize PFS 
and OS.


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Table 1-1
Prognostic impact of response level post induction in patients with 
newly diagnosed multiple myeloma undergoing autologous transplant
Reference
Treatment
Response
N
PFS/EFS
OS
Lahuerta et al
GEM2000ASCT
IFN+prednisone
CR
nCR
PR
SD
101
96
346
63
53% (5 yr EFS)
49%
34%
33%
78% (5 yr)
65%
63%
56% (p 0.02 CR vs. 
SD)
Dytfeld et al
VDD + ASCT
>VGPR
< VGPR
16
14
77.8% (4 yr PFS)
53.8% (p<0.05)
92.9% (4yr)
64.3% (p : 0.027)
Gertz et al
T or R regimenASCT
PR
<PR
232
54
22.1 mo (mPFS)
13.1 mo (p<0.001)
73.5 mo (mos)
30.4 mo (p<0.001)
Moreau et al
VD or VAD + DCEP
ASCT
>VGPR
<VGPR
125
357
41.2 mo (mes)
29 mo (p<0.0001)
---
Allègre et al
HD-ASCT + IFN main
CR
PR
SD
56
153
25
35 mo. (MPs)
28 mos.
20 mo (p<0.001 
CR/PR vs. SD)
39
36
24 (p<0.001 CR/PR 
vs. SD)
Galli et al
Total therapy 1
CR
>VGPR
PR/SD
SD
17
29
81
18
65% (5yr EFS)
54%
24%
27% (p : 0.025 CR 
vs.< CR)
63%
63%
47%
56% (p : 0.31 CR vs 
< CR)
Minimal residual disease (MRD) assessment
As quality of response to induction therapy improve with combination regimens employing 
novel agents, more sensitive tools to measure minimal residual disease (MRD) have evolved. 
These further stratify CR into immunophenotypic CR (iCR) and molecular CR (mCR) (Lonial 
et al 2014). Immunophenotypic CR assessment employs multiparametric flow cytometry with 
fluorescent antibodies against multiple plasma cell proteins to characterize and quantify 
plasma cell burden in the bone marrow with high sensitivity, ranging from 10-4 to 10-6 (Paiva 
et al 2011). Molecular CR is assessed with allele specific oligonucleotide PCR, using primers 
directed against the variable heavy chain gene sequence specific to the tumor cells (Martinez-
Sanchez et al 2008), providing the ability to assess MRD with very high sensitivity using 
peripheral blood samples (Martinez-Sanchez et al 2008). More recently, next generation 
sequencing based platforms have also been used to molecularly quantify MRD (Mahindra et 
al 2012, Munshi et al 2013).
The prognostic utility of MRD measurement with these tools has been demonstrated in 
several studies in NDMM. In a prospective analysis of nearly 300 NDMM patients treated 
with the GEM2000 protocol, assessment of iCR (sensitivity 10-4) was done at day 100 post-
transplantation. 147 patients had achieved CR, with 58% MRD positive and 42% MRD 
negative (iCR). Both PFS and OS were significantly longer for the MRD negative patients; 
median PFS 71 vs. 31 months (p<0.001) and 5 year OS 80% vs. 62% (p=0.002), respectively 
(Paiva et al 2008). The benefit was independent of immunofixation status (nCR/CR). 
However, patients who had both CR (IFE negative) and iCR (MRD negative) had a 5 year 
PFS and OS rate of 62% and 87% respectively. In contrast, MRD positive patients in CR had 


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corresponding 5 year PFS and OS rates of 30% and 59%, respectively. Another study, IFM, in 
which patients with NDMM received RVD induction, ASCT, followed by RVD 
consolidation, iCR rates were assessed using 7 color flow cytometry (sensitivity 10-5) at the 
completion of each stage of therapy. Estimated 3 year PFS for those patients who achieved 
iCR was 100%, compared to 77% for all patients (Roussel et al 2014). 
MRD assessment by nested PCR has also been shown to be a reliable predictor of PFS in 
some studies. In a study of consolidation therapy with bortezomib, thalidomide, and 
dexamethasone (VTD) in patients with NDMM who completed ASCT, 39 patients who 
achieved >VGPR with ASCT were analyzed by nested PCR (sensitivity 10-5) to evaluate 
mCR in addition to CR (Ladetto et al 2010). After VTD consolidation therapy, CR and mCR 
improved to 49% and 18%, from 15% and 3% before consolidation, respectively. All patients 
who achieved mCR were relapse free after a median follow up of 42 months, while 11 
patients with MRD positivity relapsed (Ladetto et al 2010). Recently, MRD assessment using 
a commercially available next generation sequencing (NGS) platform (ClonoSEQTM assay, 
Adaptive Biotechnologies) was evaluated in several studies (Faham et al 2012, Martinez-
Lopez et al 2014). MRD negativity by NGS was prognostic of both time to progression 
(median 80 vs. 31 months, p<0.0001) and OS (median not reached vs. 81 months, p=0.02) 
(Martinez-Lopez et al 2014). Together, these data demonstrate the role of MRD negativity (as 
defined by iCR and mCR), as a clinically meaningful endpoint in NDMM, in light of very 
compelling evidence of its utility as a surrogate marker for PFS, TTP, and OS.
Evolution of Induction Therapy for Myeloma
Induction therapy for patients with newly diagnosed myeloma has changed dramatically over 
the past 20 years. After the initial observation that melphalan and prednisone was an active 
combination for patients with myeloma, further combinations were tested incorporating 
agents such as BCNU, vincristine, doxorubicin, and cyclophosphamide. While it was 
determined in small phase II studies that these more aggressive combination regimens had a 
higher response rate, the incidence of true CR, using our current definitions, were quite low 
(Figure 1-1) and toxicity associated with these combinations was quite high (Myeloma 
Trialists collaborative Group 1998). In this setting, the higher response rate seen with older 
regimens was not associated with a survival advantage due in large part to toxicity, and an 
inadequate definition of complete response (CR was defined as a 75% reduction in the m-
protein, a measure that now would be considered a partial response). It was around this time 
that several groups were beginning to explore the potential benefit of high dose therapy with 
melphalan and autologous bone marrow transplant as a treatment modality for relapsed 
myeloma, and then demonstrated that there were patients who appeared to have durable and 
long term remissions with this therapy. For most of these patients, the durable responses were 
associated with the achievement of complete responses (Bensinger 2008). The IFM 94 trial 
established the benefit of HDT, where patients were randomized to receive either HDT or 
conventional chemotherapy (Attal et al 1996). What was gleaned from those original trials of 
HDT was the observation that patients who enjoyed the longest duration of remission and 
overall survival appeared to have achieved the best responses following HDT; ie, patients in 
CR appeared to gain more benefit from HDT than those who did not (Alvarez et al 2005, 
Alexanian et al 2001, Wang et al 2008). However, patients achieving a CR as currently 


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defined are not cured. Thus improved definitions and treatments are needed to better quantify 
and eradicate the malignant plasma cell clone.
Figure 1-1
Complete Response Rates in Upfront Myeloma
The next major step in the treatment of transplant eligible patients was the development of 
thalidomide, which demonstrated significant activity in the setting of relapsed myeloma, and 
was identified as an active agent when combined with dexamethasone in the induction setting 
as well. Rajkumar and colleagues in ECOG performed a randomized trial comparing 
thalidomide and dex (TD) versus dex alone (D) and demonstrated a higher overall response 
rate, without the need for IV access or hospitalization for these patients (Rajkumar et al 2008, 
Rajkumar et al 2002, Rajkumar et al 2006). While the data from the ECOG trial demonstrated 
an improvement in overall response, the CR rate remained low (<10%) and thus patients who 
received induction therapy with TD still required some HDT in order to enhance the CR rate 
and improve overall survival (OS) (Rajkumar et al 2008). A paper from a group of patients 
who did not undergo HDT but received either TD or D alone as induction demonstrated a 
median overall survival of 3 years for the TD arm, further supporting the observation that 
achievement of CR results in improved OS, and that the goal of induction therapy should be 
to enhance CR rates (Rajkumar et al 2008). Most recently, a randomized French trial 
compared patients who received either VAD or TD as induction therapy, and demonstrated 
that while the overall response rate was higher for the TD group, there was no difference in 
post-transplant outcomes (Macro et al 2006). These data in aggregate suggest that induction 
regimens that do not induce a high CR rate require HDT in order to achieve a CR, which is 
then associated with a survival advantage (Blade et al 2005). 
Lenalidomide based induction
Induction therapy utilizing the immunomodulatory derivative of thalidomide, lenalidomide 
was based upon encouraging data seen in the relapsed/refractory setting using the combination 
of lenalidomide and dexamethasone (Weber et al 2007, Dimopoulos et al 2007). Rajkumar 
and colleagues from the Mayo Clinic initially reported in a small pilot study of lenalidomide 


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and dexamethasone as induction therapy with an overall response rate of 91% and a VGPR or 
better rate of 31% (Rajkumar et al 2005). The CR/nCR rate from the initial analysis of this 
study was 11%, and with longer follow up improved to 18% with 54% of patients achieving a 
VGPR or better (Lacy et al 2007). 
Two large randomized trials were conducted to evaluate the benefit of Len/dex in newly 
diagnosed myeloma. The ECOG E4A03 trial, which randomized 445 patients to receive either 
lenalidomide/high dose dexamethasone (LD) or lenalidomide/low dose dexamethasone (Ld) 
demonstrated that while there was more toxicity within the LD arm, the overall response rate 
for LD was superior to Ld (82% vs 70%, p<0.05) (Table 1-2) (Siegel et al 2010). There was 
no difference in progression free survival between the 2 arms, and while overall survival 
continued to favor the Ld arm, for patients younger than age 65, there was real difference in 
OS with a higher response rate for LD.
Table 1-2
Best Responses with high vs low dose dexamethasone
The SWOG group evaluated LD vs high dose dexamethasone alone (LD vs D, SWOG S0232 
trial). Similar to the ECOG trial, the overall response rate for LD was 84%, with 22% of 
patients achieving a CR (Zonder et al 2007). Clearly LD is an active induction regimen with 
reasonable safety and a high overall response rate. Data from most trials in aggregate suggest 
that 45-55% of patients achieve a VGPR or better, and around 22% of patients achieve a CR 
from lenalidomide and dexamethasone, with a lower overall response rate seen with a lower 
dose of dexamethasone. 
Bortezomib based induction
The initial experience with bortezomib as induction therapy for myeloma came from 
Jagannath and colleagues who evaluated the response rate for bortezomib with or without 
dexamethasone as induction therapy (Jagannath et al 2005). The overall response rate from 
this trial was 88% with 25% of patients achieving a CR/nCR. Richardson and colleagues 
presented data in a trial that we joined them on using single agent bortezomib with an overall 
response rate of 45% and 10% of patients achieving a CR/nCR (Anderson et al 2006). 
Two phase III trials were performed evaluating the effects of bortezomib based inductions. 
The first was from Harousseau and colleagues in which 482 patients were randomized to 
receive either VAD or velcade/dex (VD) as induction therapy (Harousseau et al 2007). 
Patients then went on to receive a single course of high dose therapy and autologous 
transplant. After the completion of induction therapy, the overall response rate for the VAD 
ORR ( CR+PR)
>VGPR
CR/nCR
ECOG E4A03
LD vs Ld
LD vs Ld
LD vs Ld
Response in 4 cycles
82% vs 70%
44% vs 26%
Best Response
82% vs 71%
53% vs 42%
SWOG S0232
LD vs D
LD vs D
LD vs D
Best response
84% vs 53%
22% vs 4%
Table 1-2: Response rates for 2 large phase III trials using lenalidomide as induction therapy demonstrates high 
overall and CR rate following 4 cycles of induction therapy.


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arm was 62.8% compared with 80% following VD induction (p<0.001, Table 1-3). Following 
high dose therapy and autologous transplant, the proportion of patients who achieved a VGPR 
or better rate continued to favor VD over VAD (61.7% vs 41.7%, p<0.001). Importantly, this 
benefit in depth of response occurred independent of the presence of an elevated β2M or 
adverse cytogenetic risk groups (Jagannath et al 2007, Sagaster et al 2007).
In another similarly large phase III study from an Italian group, Cavo and colleagues 
presented a randomized trial comparing VTD (velcade, thalidomide and dexamethasone) vs 
TD (thalidomide and dexamethasone) as initial therapy (Cavo et al 2007). Following primary 
therapy, the overall response rate clearly favored the 3 drug combination over the 2 drug 
combination (Table 1-3), with 36% of patients achieving either a complete response or near 
complete response (CR/nCR). Again, response to induction was found to be independent of 
adverse prognostic factors such as the presence of deletion of chromosome 13 or the presence 
of (4:14). 
Both the Italian and French randomized studies are very important as they are the first 
examples of studies where the choice of induction therapy had a positive effect on post-
transplant outcomes (Table 1-3). Clearly more follow up is needed to evaluate the TTP and 
effects on OS for this approach, but given that OS and TTP have mirrored the CR rate for 
most transplant based trials, it appears that the addition of newer agents will impact not only 
the quality of response (higher CR), but may also impact survival. However, it still appears 
that the CR rate following induction therapy is suboptimal, suggesting that alternative 
induction regimens that induce a higher CR rate and take advantage of potential mechanisms 
of synergy are clearly needed. Bortezomib or lenalidomide with dexamethasone are not 
sufficient. 
Table 1-3
Overall response rate by Induction therapy
The combination of bortezomib with lenalidomide is a strategy supported by preclinical data 
suggesting that the combination of an immunomodulatory agent with bortezomib is at least 
additive in killing plasma cells (Mitsiades et al 2002, Richardson et al 2006), and the clinical 
observation that the combination of lenalidomide and bortezomib is very active in the 
relapsed disease setting (Richardson et al 2007). Data on the RVD combination in newly 
diagnosed patients demonstrated an overall response rate of 98%, with 52% of patients 
achieving a VGPR or better.  An update of this data where all 62 patients were evaluable for 
response demonstrated an overall response rate of 100% in the maximal planned dose cohort, 
ORR ( CR+PR)
>VGPR
CR/nCR
Harousseau et al
VAD vs VD
VAD vs VD
VAD vs VD
Induction
62.8% vs 80%
18.6% vs 46.7%
8.3% vs 21.3%
Post-Transplant
72.8% vs 89.4%
41.7% vs 61.7%
23.6% vs 35%
Cavo et al
TD vs VTD
TD vs VTD
TD vs VTD
Induction
80% vs 93%
27% vs 60%
9% vs 36%
Post 1st Transplant
54% vs 77%
28% vs 57%
Table 1-3: Response rates for 2 large phase III trials using bortezomib as induction therapy 
demonstrates high overall and CR rate following 4 cycles of induction therapy.


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with 70% of patients achieving a VGPR or better, and 22% achieving a CR at the maximum 
planned dose (Richardson et al 2008). This makes RVD one of the most active induction 
regimens that has been tested, and sets a new standard against which future regimens are 
compared. Furthermore, this trial was a result of preclinical science that predicted the 
synergistic CR and overall response rate for the combination. Despite the high response rate 
to RVD therapy, the rate of nCR/CR after 4 cycles of induction therapy with this regimen is 
low (6% to 7%), as reported in several studies (Richardson et al 2008, Kumar et al 2012). 
High quality responses are only achieved with prolonged courses of induction therapy 
(averaging 6 to 8 cycles). 
The introduction of drugs with novel mechanisms of action including HDAC inhibitors and 
others, affords the opportunity to deliver more effective combination therapies in frontline 
treatment of MM, with the potential to achieve maximal cytoreduction and deep clinical 
responses with significantly shorter courses of induction than with regimens currently used. 
This can decrease the risk of adverse events associated with prolonged courses of combination 
therapy, and potentially minimize the biological emergence of resistant clones owing to 
decreased time for clonal evolution. Given the mounting clinical evidence supporting the role 
of achieving early deep responses as a surrogate for improved PFS and OS, there remains a 
need for novel induction regimens that result in high CR rates early into the course of 
induction therapy for NDMM. 
Maintenance therapy in NDMM
The efficacy and safety of maintenance therapy with both PIs and IMIDs after maximal 
cytoreduction has been studied in several studies. In general, randomized studies have 
demonstrated improved PFS (Mccarthy et al 2010, Palumbo et al 2012, Attal et al 2012) and 
OS (Mccarthy et al 2010) with lenalidomide maintenance. Maintenance therapy with low dose 
lenalidomide after induction/ASCT has demonstrated improved PFS and OS in patients with 
newly diagnosed multiple myeloma. In the Cancer and Leukemia Group B (CALGB) 100104 
study, 462 multiple myeloma patients were randomized to lenalidomide 10 mg daily or 
placebo after single autologous HCT. The median time to progression (TTP) was 46 months 
for the lenalidomide arm and 27 months for the placebo arm (P < .001). At a median follow-
up of 34 months, the 3-year OS rates were 88% for the lenalidomide arm and 80% for the 
placebo arm (P =.028). A total of 23 out of 231 patients (10%) on lenalidomide arm 
discontinued maintenance due to adverse events. In the Intergroupe Francophone du Myélome 
(IFM) 05-02 study, 605 myeloma patients were randomized to lenalidomide 10 mg daily 
versus placebo until disease progression after single or tandem autologous HCT The median 
PFS was 41 months for the lenalidomide arm and 23 months for the placebo arm (P < .001).  
The OS was 74% for the lenalidomide arm and 76% for the placebo arm (P = .7) at a median 
follow-up of 45 months. A total of 83 patients (27%) discontinued lenalidomide due to 
adverse events.  Fixed duration of maintenance therapy with lenalidomide was studied in a 
recent trial conducted by the IFM in newly diagnosed patients who received RVD induction, 
ASCT, and consolidation followed by one year of lenalidomide maintenance. Three year PFS 
and OS reported in this study were 77% and 100%, respectively.
Borezomib has also been studied as a maintenance therapy in NDMM patient who underwent 
ASCT. In a phase 3 study of 827 patients with NDMM randomized to induction with VAD or 
bortezomib, doxorubicin, dexamethasone (BDD) followed by ASCT, patients were assigned 


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to maintenance with thalidomide (VAD arm) or bortezomib (BDD) arm (Sonneveld et al). 
The CR rate overall were 24% and 36% for the VAD and BDD arms respectively. 
Maintenance therapy with thalidomide and bortezomib improved the responses in 24% and 
23% of patients, respectively. Median PFS was 28 months in the VAD vs. 36 months in BDD 
arm, respectively.
While studies of maintenance therapies have shown that responses can be deepened after 
induction and ASCT with low dose continuous therapy, and lead to improved PFS and OS, 
the optimal duration of maintenance therapy is still unclear. Ideally, one should balance the 
overall PFS and OS benefits of maintenance therapy with the risk of accumulated toxicity 
associated with continuous exposure to drugs commonly used in maintenance, including PIs 
and IMIDs. Lenalidomide maintenance was associated with increased toxicity compared to 
placebo in randomized studies, with higher grade 3/4 hematologic toxicity (48% vs. 17%, 
p<0.001) and secondary malignancies (8% vs. 3%, p=0.008) (Mccarthy et al 2012). 
Nevertheless, the PFS and OS benefits realized with continuous therapy in large phase 3 
studies, particularly in high risk disease subgroups, support the practice of continuing 
maintenance until disease progression (Mccarthy et al 2012). 
As rates of MRD negativity with induction and transplant improve with the addition of novel 
therapies in the newly diagnosed setting, finite duration of maintenance therapy is being 
explored in ongoing studies. In the phase 2 IFM study by Roussel et al, in which patients 
discontinue lenalidomide maintenance after 1 year, median PFS and OS are 77% and 100%, 
respectively (Roussel et al 2014). Longer term follow up is required before meaningful 
comparisons can be made with studies employing treatment until relapse/progression model. 
Nevertheless, the strategy of finite maintenance duration is feasible and needs to be further 
explored, particularly in patients who are in iCR/mCR, to better understand the optimal 
duration of such therapy in the setting of disease undetectable by such sensitive methods.
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of Panobinostat
Panobinostat (LBH589) belongs to a structurally novel cinnamic hydroxamic acid class of 
compounds and is a pan-inhibitor of Class I, II, and IV histone (and non-histone) DACs 
(HDAC) which are epigenetic modulators and important cancer targets due to the 
dysregulation of these enzymes in many types of tumors. DAC enzymes also target lysine 
groups on various non-histone proteins such as p53, α-tubulin, Hsp90, and HIF1-α; thus 
panobinostat is also referred to as a pan-DAC inhibitor. 
Through its effects on histone acetylation and gene expression, as well as on the oncogenic 
function of non-histone proteins such as Hsp90, panobinostat offers a multifaceted approach 
for the inhibition of cancer cell proliferation and survival. Panobinostat is highly effective at 
inhibiting the HDAC activity of the majority of class I, IIa, IIb, and IV isoforms at low 
nanomolar concentrations, and is the most potent pan-HDAC inhibitor developed to date, 
including those which already received regulatory approval in indications other than MM in 
select countries, including the US. 


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Panobinostat (Farydak®) has received approval from the FDA in Feb 2015 for the treatment 
of patients with multiple myeloma who have received at least 2 prior regimens, including 
bortezomib and an immunomodulatory agent.
1.2.1.1
Non-clinical experience
In multiple models, panobinostat has been shown to impact several pathways that are critical 
to the biology of MM. These include the up-regulation of cyclin-dependent kinase inhibitor 
p21 leading to cell-cycle arrest and apoptosis, the disruption of the signaling pathway between 
MM cells and bone marrow stromal cells, and the inhibition of the aggresome protein 
degradation pathway by hyperacetylation of α-tubulin.
It has been demonstrated that panobinostat is effective as a single agent in multiple in-vitro 
and ex-vivo experiments, including in cells known to be resistant to standard of care agents.
The combination of bortezomib and panobinostat has been shown to be synergistic in in-vitro 
and in-vivo models of MM (Ocio et al 2010). The combination of these two agents results in a 
synergistic inhibition of the unfolded protein response pathways (aggresome, proteasome) 
which are particularly relevant to MM.
1.2.1.2
Clinical experience
The FDA approval of panobinostat for the treatment of patients with multiple myeloma who 
have received at least 2 prior regimens, including bortezomib and an immunomodulatory 
agent received in Feb 2015 was primarily based on data from a large, double-blind, placebo-
controlled Phase III study [CLBH589D2308] of panobinostat in combination with bortezomib 
and dexamethasone (PAN arm) compared to placebo in combination with bortezomib and 
dexamethasone (PBO arm) in 768 relapsed or relapsed and refractory MM patients (excluding 
bortezomib-refractory patients) with a primary endpoint of progression free survival (PFS) 
(San Miguel et al 2014).
Additional data included results from a supportive Phase II study [CLBH589DUS71] in 55 
relapsed and bortezomib-refractory MM patients who received at least 2 prior lines of therapy 
including an IMiD (Richardson et al 2013), as well as safety and efficacy data from Phase Ib 
study [CLBH589B2207] (San Miguel et al 2013).
Studies B2201, B2202, B2203, B2211, B2101 and B2102 evaluated panobinostat as a single 
agent in patients with other hematological malignancies and solid tumors and provide 
additional information on the general safety profile at the relevant dose of 20 mg.
The pharmacokinetic profile of panobinostat has been characterized in a total of 14 single-
agent clinical trials conducted in patients with various hematologic malignancies and solid 
tumors. 
The registration Study D2308 met its primary objective, demonstrating a statistically 
significant and clinically important reduction in the risk of progression or death of 37% with 
PAN+BTZ+Dex over the standard regimen of PBO+BTZ+Dex (hazard ratio [HR] 0.63; 95% 
Confidence Interval [CI]: 0.52, 0.76; p <0.0001). Median progression free survival was 
significantly longer in the panobinostat group than in the placebo group (11·99 months [95% 
CI 10·32–12·94] vs 8·08 months [7·56–9·23]; hazard ratio [HR] 0·63, 95% CI 0·52–0·76; 
p<0·0001). The proportion of patients achieving an overall response did not differ between 


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treatment groups (235 [60·7%, 95% CI 55·7–65·6] for panobinostat vs 208 [54·6%, 49·4–
59·7] for placebo; p=0·09); however, the proportion of patients with a complete or near 
complete response was significantly higher in the panobinostat group than in the placebo 
group (107 [27·6%, 95% CI 23·2–32·4] vs 60 [15·7%, 12·2–19·8]; p=0·00006). Final overall 
survival data are available and although there was a trend toward the Median overall survival 
was 40.8 months (95% CI35.0-44.8–) for the panobinostat group and 35.8 months (29.0-40.6) 
for the placebo group (HR 0.94, 95% CI 0.78–1.14; p=0.5435) (San Miguel et al 2015).
Consistent benefit was also shown in the Phase II study DUS71 in a more advanced and 
heavily pre-treated patient population with an ORR of 34.5% (1 near-complete response and 
18 partial responses). An additional 10 patients achieved minimal response, for a clinical 
benefit rate of 52.7%. Progression-free survival was 5.4 months (Richardson et al 2013).
In study D2308, patients who received PAN+BTZ+Dex generally experienced more adverse 
events (AEs) than patients receiving PBO+BTZ+Dex. This increase in AEs was not 
unexpected given the overlapping safety profiles of panobinostat and bortezomib, including 
myelosuppression, fatigue and gastrointestinal (GI) toxicity. 
The 3 most frequent severe categories of events were blood disorders, GI toxicities, 
metabolism disorders and infections and infestations.

The rate of grade 3/4 thrombocytopenia laboratory abnormalities was higher in the PAN 
arm (67.4% vs. 31.4%). In this context, the rate of grade 3/4 hemorrhage (mostly GI) was 
low in both arms (4.2% vs. 2.4%). Thrombocytopenia AEs led to discontinuation in 1.6% 
and 0.5% of patients in the PAN and PBO arms, respectively.

GI toxicities were more common in the PAN arm than in the PBO arm, mostly due to 
diarrhea (grade 3/4: 25.5% vs. 8%), nausea (grade 3/4: 5.5% vs. 0.5%), and vomiting 
(grade 3/4: 7.3% vs. 1.3%). Diarrhea was a reason for treatment discontinuation in 4.5% 
and 1.6% of patients in the PAN and PBO arms, respectively.

The rate of grade 3/4 infections was higher in the PAN arm (31.2% vs. 23.9%). These 
grade 3/4 infections were primarily pneumonia and sepsis. These severe infections were 
preceded by a severe neutropenia in only 20% of patients. Patients in the PAN arm 
experienced more severe neutropenia, but few were grade 4 (6.6% vs. 2.4%). Febrile 
neutropenia were infrequent (1.0% vs. 0.5%).

Elderly patients (≥ 65 years) generally had a higher level of toxicity compared to younger 
patients, in particular for severe (grade 3/4) thrombocytopenia (72.5% vs. 56.6%), 
diarrhea (31.3% vs. 21.3%) and asthenia/fatigue (48.1% vs. 18.1%).
Thirty patients (7.9%) in the PAN arm died on treatment compared to 18 (4.8%) in the PBO 
arm. The primary causes of death were disease progression (1.0% vs. 1.6%) and AEs (6.8% 
vs. 3.2%) in the PAN vs. PBO arms. The main causes of these deaths included infections and 
hemorrhages. The cases were complex and confounded by the natural history of the disease 
and concurrent comorbidities. 
In a more advanced and heavily pretreated population, the safety data from studies DUS71 
and B2207 were consistent with the Phase III Study D2308. In study DUS71, 18% patients 
discontinued therapy because of an AE suspected to be study treatment related, and there was 
only one (1.8%) on-treatment death due to AE (a multi-organ failure).


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2
Rationale
2.1
Study rationale and purpose
In patients with newly diagnosed multiple myeloma, rapid attainment of good quality 
response (nCr/CR) is critical, as achieving deeper responses earlier in the course of therapy 
has been shown to correlate with improved PFS and OS. Furthermore, achieving MRD 
negativity with frontline therapy, as measured by iCR and mCR, is an important predictor of 
long term progression free survival9.
Rates of CR with currently used combination regimens including RVD and more recently, 
Carfilzomib-lenalidomide, dexamethasone (KRD) are less than 13% at the completion of 
induction therapy with 4 cycles (Richardson et al, Zimmerman et al). High quality responses 
with these regimens are only achieved with prolonged courses of induction therapy (averaging 
6 to 8 cycles) (Richardson et al) or induction therapy followed by ASCT and consolidation 
(Zimmerman et al 2014). Accordingly, there remains a need for novel induction regimens that 
result in high CR rates early into the course of induction therapy for NDMM.
The introduction of drugs with novel mechanisms of action including HDAC inhibitors and 
others, affords the opportunity to deliver more effective combination therapies in frontline 
treatment of MM, with the potential to achieve maximal cytoreduction and deep clinical 
responses with significantly shorter courses of induction than with regimens currently used. 
This can decrease the risk of adverse events associated with prolonged courses of combination 
therapy, and potentially minimize the biological emergence of resistant clones owing to 
decreased time for clonal evolution. 
The dramatic improvement in nCR/CR rates seen with panobinostat in the relapsed/refractory 
setting6 suggest equal or improved rates of nCr/CR in the newly diagnosed setting. The 
combination of bortezomib/lenalidomide/dexamethasone (RVD) with the addition of 
Panobinostat in newly diagnosed myeloma patients has been studied in a phase I trial. The 
RP2d from this study was panobinostat 10mg administered 3 times a week 2 weeks on/1 week 
off with full dose RVD (bortezomib administered on twice weekly on day 1, 4, 8, 11). The 
toxicity limiting higher doses of panobinostat was limited to diarrhea (which resolved with 
supportive care). Importantly, interim results, presented at ASH 2015, showed nCR/CR rate of 
46%, compared to historical nCR/CR rate of <10% after 4 cycles of RVD alone. 
Given the important role of maintenance therapy in deepening responses post-induction and 
AST, and prolonging PFS and OS, combination maintenance therapy with novel drugs like 
panobinostat may further improve these clinical endpoints, particularly in the setting of high 
risk disease. In a recent phase 2 study, panobinostat was shown to be safe and efficacious 
when added to full dose lenalidomide-dexamethasone in patients with relapsed/refractory 
myeloma. Results published at ASH 2015 from 26 patients on this study showed an ORR of 
38% and CBR of 73% in a highly refractory group of patients (85% len refractory, 35% pom 
refractory, 54% bortez refractory, and 23% Carfilzomib refractory). Grade 3/4 toxicities 
(regardless 
of 
drug 
attribution) 
were 
primarily 
hematologic, 
with 
neutropenia, 
thrombocytopenia, and anemia noted in 40%, 23%, and 4% respectively13. Grade 3/4 nonheme 
AEs included infections in 5 (1 while neutropenic), 3 diarrhea (transient), 4 fatigue & 1 
pulmonary embolus and 1 pt each with: neck pain, QTc prolongation & weight loss 13.


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In light of the dramatic improvements in nCR/CR rates after induction with RVD-
panobinostat reported in the single arm phase 1 study by Shah et al, we propose to conduct a 
phase 2 open-label randomized study comparing RVD with RVD+panobinostat induction in 
patients with  newly diagnosed multiple myeloma who are transplant eligible. Based on 
evidence from phase 1b and 2 studies supporting the safety and clinically meaningful efficacy 
of lenalidomide+panobinostat in RRMM, patients who complete induction and transplant will 
proceed 
to 
maintenance 
therapy 
for 
three 
years 
with 
lenalidomide 
or 
lenalidomide+panobinostat. 
2.2
Rationale for the study design
This is a multicenter, open-label, randomized phase II study which will enroll 112 newly 
diagnosed symptomatic multiple myeloma patients in a 1:1 fashion. Patients will be enrolled 
at approximately 20 centers in the United States. 
In data presented at ASH 2015, the combination of RVD and panobinostat in newly diagnosed 
MM patients showed an ORR of 94%, with a 46% CR/nCR rate. This marked improvement 
from historical data reporting CR/nCR rates of approximately 7% warrants further 
investigation of this combination in this population. 
2.3
Rationale for dose and regimen selection
[CLBH589BUS80T] was a single center, dose escalation trial of panobinostat plus RVD. No 
DLTs were observed during the first dose cohort of 10mg panobinostat three times a week, 
two weeks on and one week off, 25mg revlimid QD for 14 days, 1.3 mg/m2 of bortezomib on 
days 1, 4, 8 and 11 and 20mg of dexamethasone the day of and the day after bortezomib 
administration. The next dose level escalated the dose of panobinostat to 15mg, where two 
DLTs were observed. One patient experienced a DLT which included grade four 
thrombocytopenia, grade 3 diarrhea and grade 4 hypocalcemia. A second patient experienced 
grade 3 diarrhea that resolved immediately with supportive care, however grade 3 diarrhea 
with/without supportive care was considered a DLT. Therefore, the first dose cohort was 
considered the maximally tolerated dose and is the dose further studied in the expansion 
cohort.
2.4
Risks and benefits 
The risk to subjects in this trial may be minimized by adherence to the eligibility criteria and 
study procedures, and close clinical monitoring. There may be unforeseen risks with the study 
treatment which could be serious.
A phase Ib study [CLBH589BUS80T] investigating panobinostat in combination with RVD 
in NDMM is ongoing at 
. As of ASH 2015, 42 patients have been treated with 
this combination. In 48 patients evaluable for response, the Investigator reports an ORR of 
94%, noting that this regimen led to a significant depth of response with a CR/nCR rate of 
46%. Grade 3/4 hematologic toxicities included anemia (5/50), neutropenia (7/50) and 
thrombocytopenia (18/50). Grade 3/4 non-hematologic toxicities included ALT elevation 
(1/50), AST elevation (1/50), constipation (2/50), diarrhea (4/50), dyspnea (2/50) 
fatigue/muscle weakness (6/50), syncope (3/50), nausea (3/50) peripheral neuropathy (2/50), 
rash (2/50), DVT/VTE (3/50). Rates of thrombocytopenia are consistent with what was 


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reported in the phase III PANORAMA-1 trial, and rates of diarrhea appear to be improved, 
although patient numbers are small. 
In data reported in the abstract (n=42), treatment emergent serious adverse events related to 
therapy observed were grade 3 pneumonia (9), grade 2 fever (5), grade 3-4 venous 
thromboembolic events (2), grade 3 diarrhea (2), atrial fibrillation (2). Other events included 1 
pt each with grade 3 cellulitis, grade 3 myocardial infarction (MI), grade 3 febrile 
neutropenia, grade 2 diarrhea, grade 2 seizure, grade 3 hypotension and grade 3 sinusitis. 1 pt 
had a second primary malignancy – a newly diagnosed breast cancer during cycle 9 of 
therapy. 
Patients will be followed closely during the induction phase of the study and through 
transplant. Adverse events will be monitored as described in Section 7.
3
Objectives and endpoints
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 the efficacy  of the combination of RVD + 
panobinostat compared to RVD alone
nCR/CR rate of the combination of panobinostat with bortezomib, lenalidomide 
and dexamethasone (P-RVD) vs RVD in newly diagnosed multiple myeloma 
patients after 4 cycles of therapy
Key secondary
Refer to Section 10.5.1
To assess MRD negativity (mCR) after 4 cycles of 
induction by Next Gen Sequencing
MRD negativity by ClonoSEQTM assay (Adaptive Biotechnologies) 
Other secondary
Refer to Section 10.5.2
To assess best overall response rate (ORR) and MRD 
negativity after ASCT and maintenance 
ORR (CR + PR)  and MRD negativity after ASCT and maintenance
To assess depth of response by IMWG criteria
Rate of VGPR, CR and sCR
Refer to Section 10.6
To assess the duration of response
Duration of response
To assess overall survival and progression free survival 
at three years
Overall survival and progression free survival at three years
To assess the toxicity and tolerability
Rates of AEs and SAEs


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4
Study design
4.1
Description of study design
This is a multicenter, open-label, randomized phase II study which will enroll 112 newly 
diagnosed symptomatic multiple myeloma patients in a 1:1 fashion. Patients will be enrolled 
at approximately 20 centers in the United States. The dosing information is as follows:
After completing 4 cycles of induction, all patients will undergo stem cell mobilization with 
G-CSF and plerixafor as per institutional protocol for this mobilization regimen. Study 
treatment interruption for stem cell collection may not exceed 30 days. All patients will 
receive one additional cycle of study treatment after stem cell collection and then proceed to 
autologous transplant using melphalan 200mg/m2 (140mg/m2 for patients > 70), as 
conditioning. All patients must initiate transplant within 28 days of the completion of cycle 5. 
After ASCT, patients still on study will initiate maintenance therapy within the 60-120 day 
period following ASCT, provided they have adequate blood count and clinical recovery.  
Criteria for starting a patient on maintenance therapy are as follows: 

The ANC is ≥1,000/μL;

The platelet count is ≥75,000/μL

Adequate organ function as detailed in inclusion criteria (Section 5.2)
Patients in the RVD arm will initiate maintenance therapy with lenalidomide alone, and 
patients in RVD-panobinostat arm will receive lenalidomide + panobinostat maintenance. 
Lenalidomide will be dosed orally at 10mg/day continuously in both arms. After the first 84 
day cycle, the dose of lenalidomide should increase to 15mg/day.  Panobinostat will be dosed 
at 10mg three times a week, every other week. Total planned duration of maintenance therapy 
will be 3 years.
Patients will remain on study treatment until they complete the maintenance phase, or until 
they experience disease progression, unacceptable toxicity, or at the discretion of the 
Investigator.


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Figure 4-1
Study design
4.2
Timing of interim analyses and design adaptations
An interim analysis will be performed for the primary endpoint after all patients have 
completed 4 cycles of induction therapy. A second interim analysis will be performed after all 
patients complete ASCT. 
4.3
Definition of end of the study
The study will end when all enrolled patients have completed or discontinued study treatment 
AND have at least 3 years of follow up from study entry. (Secondary endpoints include PFS 
and OS rates at 3 years from study entry.)
Patients who discontinue study treatment for toxicity during the induction phase will be 
followed every 3 weeks for primary and secondary endpoints until documented disease 
progression or initiation of a new cancer therapy. All patients will be followed every 12 weeks 
for overall survival until the completion of the study as defined above. 
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 to perform an end of treatment visit. Patients in 
survival follow-up should be contacted for a final survival visit for Study Evaluation 


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Completion assessments. 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
Adult female or male patients with measurable newly diagnosed multiple myeloma who are 
transplant eligible.
Patients enrolled in this study are not permitted to participate in additional parallel 
investigational drug or device studies. Patients who have completed the study may not be 
enrolled for a second course of treatment. 
The investigator or designee must ensure that only patients who meet all the following 
inclusion and none of the exclusion criteria are randomized into the study. For guidelines on 
re-screening of patients after they failed the initial screening please refer to Section 7.1.2.
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. Patient must be newly diagnosed with multiple myeloma, based on following IMWG 2014 
definition (Rajkumar et al 2014):

Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary
plasmacytoma and any one or more of the following myeloma defining events:

Evidence of end organ damage that can be attributed to the underlying plasma
cell proliferative disorder, specifically:
a. Hypercalcaemia
b. Renal insufficiency
c. Anemia
d. Bone lesions: one or more osteolytic lesions 
2. Patient must have measurable disease defined by at least 1 of the following conditions
present at screening:

Serum M-protein by PEP ≥ 1.0 g/dL (≥ 10 g/L).

Urine M-protein by PEP ≥ 200 mg/24 hours.


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
Involved serum free light chain level ≥ 10 mg/dL (≥ 100 mg/L), provided that the 
serum free light chain ratio is abnormal.
3. Patient must be eligible for autologous stem cell transplantation based on the 
investigator’s clinical judgement. 
4. Patient has an ECOG performance status (PS) ≤ 2
5. 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 (> 50 x 109 /L for patients in whom > 50% of bone 
marrow nucleated cells are plasma cells)
c. AST and ALT ≤ 2.5 x ULN
d. Serum total bilirubin ≤ 1.5 ULN except for patients with Gilbert’s syndrome who may 
only be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN 
e. Calculated creatinine clearance ≥ 50 mL/min (using Cockcroft-Gault formula) 
f.
Ionized calcium greater or equal to lower normal limits (> LLN), and not higher than 
CTCAE grade 2 in case of elevated value.
6. Patient must have the following laboratory values within normal limits or corrected to 
within normal limits with supplements before the first dose of any study medication: 
Serum sodium, potassium, magnesium, phosphorus. 
7. 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 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
8. Patient’s age is ≥ 18 and <75 years at time of signing the informed consent
9. Patient has provided written informed consent prior to any screening procedures
10. Patient is able to swallow capsules
11. Patient must be able to adhere to the study visit schedule and other protocol requirements
12. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at 
screening and a negative urine pregnancy test at baseline 
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Any concomitant anti-cancer therapy (other than 
bortezomib/lenalidomide/dexamethasone; bisphosphonates are permitted only if 
commenced prior to the start of screening period)
2. Unresolved diarrhea ≥ CTCAE grade 2 or presence of medical condition associated with 
chronic diarrhea (such as irritable bowel syndrome, inflammatory bowel disease).


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3. Allogeneic stem cell transplant recipient presenting with graft versus host disease either 
active or requiring immunosuppression
4. Patient has shown intolerance to bortezomib or to dexamethasone or components of these 
drugs or has any contraindication to one or the other drug, following locally applicable 
prescribing information
5. Patient has grade ≥ 2 peripheral neuropathy or grade 1 peripheral neuropathy with pain on 
clinical examination at screening
6. Patient received prior treatment with DAC inhibitors including Panobinostat
7. Patient needing valproic acid for any medical condition during the study or within 5 days 
prior to first administration of panobinostat/study treatment.
8. Patient taking any anti-cancer therapy concomitantly (bisphosphonates are permitted only 
if commenced prior to the start of 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:
a. prior anti-myeloma chemotherapy or medication including IMiDs and Dex ≤ 3 weeks 
prior to start of study.
b. experimental therapy or biologic immunotherapy including monoclonal antibodies ≤ 4 
weeks prior to start of study.
c. prior radiation therapy ≤ 4 weeks or limited field radiotherapy ≤ 2 weeks prior start of 
study.
11. Patient has not recovered from all therapy-related toxicities associated with above listed 
treatments to < grade 2 CTCAE.
12. Patient has undergone major surgery ≤ 2 weeks prior to starting study drug or who have 
not recovered from side effects of such therapy to < grade 2 CTCAE
13. Patients with evidence of mucosal or internal bleeding
14. Clinically significant, uncontrolled heart disease and/or recent cardiac event (within 6 
month prior to screening), such as: 
a. History of myocardial infarction (MI), angina pectoris, coronary artery bypass graft 
(CABG) within 6 months prior to starting study treatment
b. Left Ventricular Ejection Fraction (LVEF) < 45% as determined by echocardiogram 
(ECHO) or Multiple Gated acquisition (MUGA)
c. Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left 
bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II 
and third degree AV block) 
d. 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.
e. Resting bradycardia defined as < 50 beats per minute
f.
Complete left bundle branch block (LBBB), bifascicular block
g. Long QT syndrome, family history of idiopathic sudden death or congenital long QT 
syndrome, or any of the following:


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
Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or 
hypomagnesemia, history of cardiac failure, or history of clinically 
significant/symptomatic bradycardia

Concomitant medication(s) with a known risk to prolong the QT interval and/or 
known to cause Torsades de Pointe that cannot be discontinued or replaced by 
safe alternative medication. 

Inability to determine the QTcF interval 
a.
Any clinically significant ST segment and/or T-wave abnormalities 
b.
Corrected QT (QTcF) ≥ 450 ms for males and females using Fridericia’s 
correction on screening ECG (as average of triplicate ECGs)
c.
History of documented congestive heart failure (New York Heart 
Association functional classification III-IV)
d.
Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 
160 mm Hg and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or 
without anti-hypertensive medication. Initiation or adjustment of 
antihypertensive medication (s) is allowed prior to screening. 
e.
Other clinically significant heart disease and vascular disease
15. 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
16. Patient has impairment of gastrointestinal (GI) function or GI disease that may 
significantly alter the absorption of panobinostat (e.g. ulcerative disease, uncontrolled 
nausea, vomiting, malabsorption syndrome, obstruction, or stomach and/or small bowel 
resection) 
17. Patient has any other concurrent severe and/or uncontrolled medical conditions (e.g., 
uncontrolled diabetes, active or uncontrolled infection, chronic obstructive or chronic 
restrictive pulmonary disease including dyspnea at rest from any cause, uncontrolled 
thyroid dysfunction) that could cause unacceptable safety risks or compromise compliance 
with the protocol
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. Sexually active males unless they use a condom during intercourse while taking the drug 
during treatment, and for 6 months after stopping treatment and should not father a child 
in this period. A condom is required to be used also by vasectomized men as well as 
during intercourse with a male partner in order to prevent delivery of the drug via semen
20. Pregnant or nursing (lactating) women.
21. 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 of study medication. Highly effective contraception 
methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception


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
Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). The vasectomized male 
partner should be the sole partner for that subject

Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
6
Treatment
6.1
Study treatment
The terms “investigational study drug(s)” or “study drug(s)” will refer to oral panobinostat 
(also known as LBH589 or Farydak® or PAN) capsules, to bortezomib (also known as BTZ 
or Velcade®), to revlimid (also known as REV or Revlimid®) and to oral dexamethasone 
(also known as Dex) tablets. “Study treatment” refers to the combination of PAN, BTZ, REV 
and Dex or BTZ, REV and Dex, depending on treatment assignment. 
6.1.1
Dosing regimen
Table 6-1
Induction dose and treatment schedule
Study treatments
Pharmaceutical form and 
route of administration
Dose
Frequency and/or Regimen
PAN
Capsule for oral use
10 mg
Days 1,3,5,8,10,12, of a 21 day 
cycle
BTZ
Sub-cutaneous Injection
1.3 mg/m2
Days 1, 4, 8, 11
REV
Capsule for oral use
25 mg
QD Days 1-14
DEX
Tablet for oral use
20 mg
PO Days 1, 2, 4, 5, 8, 9, 11, 12
Figure 6-1
Induction Dosing Schedule – Arm 1 
(3-week cycles)
Week 1
Days 1-7
Week 2
Days 8-14
Week 3
Days 15 - 21
Panobinostat (PAN)
1
3
5
8
10
12
Rest period
Bortezomib (BTZ)
1
4
8
11
Rest period
Dexamethasone (Dex)
1
2
4
5
8
9
11
12
Rest period
Revlimid (REV)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Rest period


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Figure 6-2
Induction Dosing Schedule – Arm 2 
(3-week cycles)
Week 1
Days 1-7
Week 2
Days 8-14
Week 3
Days 15 - 21
Bortezomib (BTZ)
1
4
8
11
Rest period
Dexamethasone (Dex)
1
2
4
5
8
9
11
12
Rest period
Revlimid (REV)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Rest period
Figure 6-3
Maintenance Dosing Schedule – Arm 1 
12-week (84 
day) cycles 
Week 1, 5 and 9
Week 2, 6 and 10
Week 3, 7 and 11
Week 4, 8 and 12
Panobinostat 
(PAN) - Days
1
3
5
1
3
5
Revlimid 
(REV) –
Days
1
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
3
4
5
6
7
Figure 6-4
Maintenance Dosing Schedule – Arm 2 
12-week 
(84 day) 
cycles
Week 1, 5 and 9
Week 2, 6 and 10
Week 3, 7 and 11
Week 4, 8 and 12
Revlimid 
(REV)
1
2
3
4
5
6
7
1 2
3
4
5
6
7
1
2
3
4
5
6
7
1
2
3
4
5
6
7
6.1.2
Dosing administration for induction and maintenance
6.1.2.1
Induction dosing administration
6.1.2.1.1 Panobinostat (PAN)
Patients will self-administer panobinostat as follows:

The panobinostat dose may be taken with or without food. 

Each dose of panobinostat should be taken with a glass of water (approximately 8 
ounces/240mL). Patients should be instructed to swallow the capsules whole and not
chew them.

During all phases of this study, panobinostat should be taken at the same time on each
day of administration. Doses should be separated by a minimum of 30 hours within the
week of dosing.

Every effort must be made for the patient to take 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 PAN dosing must again be on Monday, Wednesday, 
Friday). 


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
Patients must avoid grapefruits, grapefruit juice, pomegranate, starfruit, starfruit juice,
Seville oranges (also in form of bitter orange marmalade) and Seville orange juice during the
entire study treatment period.

If the patient forgets to take a dose of panobinostat, then he/she should take study drug
within 12 hours after the missed dose. If more than 12 hours have passed, then that
missed dose should be omitted and the patient should continue treatment with the next 
scheduled dose.

If vomiting occurs after intake of study drug, then no re-dosing of the patient is allowed 
before the next scheduled dose.

During the induction phase, panobinostat should be taken on days 1, 3, 5, 8, 10, and 12 of 
a 21 day cycle. (Table 6-1)

During the maintenance phase, panobinostat should be taken on days 1, 3 and 5, every 
other week of a 12 week (84 day) cycle. (Table 6-3)
6.1.2.1.2 Lenalidomide (REV) 
Patients will self-administer revlimid as per the package insert and the site personnel’s 
instructions

Lenalidomide is an oral drug supplied in 25mg, 10mg or 5mg capsules.

Administration of Lenalidomide will be at approximately the same time each day. If a 
dose of lenalidomide is vomited, the patient should continue with the regular schedule of 
the drug at the next dose. If a dose of lenalidomide is missed, it should be taken as soon as 
possible on the same day. If it is missed for the entire day, it should not be made up.

Lenalidomide capsules should be swallowed whole, and should not be broken, chewed or 
opened.

Patients who take more than the prescribed dose of lenalidomide should be instructed to 
seek emergency medical care if needed and contact study staff immediately.

Research center personnel will review the dosing instructions with subjects. Subjects will 
be asked to bring any unused drug and empty drug containers to the research center at 
their next visit. Research personnel will count and record the number of used and unused 
drug at each visit. 

During induction phase, patients will take REV orally on days 1 through 14 of a 21 day
cycle. (Table 6-1 and Table 6-2)

During maintenance phase, patients will take REV orally daily, continuously for a 12 
week (84 day) cycle. (Table 6-3 and Table 6-4)
6.1.2.1.3 Bortezomib (BTZ) Administration
Site personnel will administer BTZ as per package insert:

The actual BTZ dose will be defined based on the BSA of the patient which is calculated 
from the patient’s weight determined on Day 1 of every cycle. 
To calculate the BSA the following formula is recommended:

Gehan and George Equation: BSA (m2) = 0.0235 x Height(cm)0.42246 x 
Weight(kg)0.51456


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
The BSA can be calculated as per standard practice at site. However, the same 
formula/method should be consistently used for all BSA calculations of a patient.

During induction phase, patients will receive BTZ by subcutaneous injection on days 1, 4, 
8 and 11 of a 21 day cycle. (Table 6-1 and Table 6-2)
6.1.2.1.4 Dexamethasone (Dex) Administration
Patients will self-administer dexamethasone as per the package insert and the site personnel’s 
instructions:

On the days when BTZ is administered, the patient should bring in their dexamethasone 
tablets, so that they can take them at the site within 15 – 30 minutes prior to the BTZ 
injection.

On the day after the BTZ injection the patient will take dexamethasone at home as 
instructed.

During induction phase, patients will take oral dexamethasone on days 1, 2, 4, 5, 8, 9, 11 
and 12 of a 21 day cycle. (Table 6-1 and Table 6-2)
6.1.2.2
Dosing Diaries
At the beginning of each cycle, patients will be given a dosing diary to document the self-
administered doses of PAN, REV and Dex. The completed dosing diary should be brought 
back to the site at the beginning of each cycle (starting with Cycle 2) and at EOT and be 
reviewed by the study personnel for drug accountability records and consideration when 
entering the dosing information in the respective Dose Administration Record page CRF.
6.1.3
Ancillary treatments 
The following ancillary treatments are required while on study treatment:

Antiviral prophylaxis (e.g. valacyclovir or equivalent)

Proton pump inhibitors (e.g. lansoprazole) while taking dexamethasone
The following ancillary treatments can be administered while on study treatment at the 
investigator’s discretion:

Antibiotic prophylaxis (e.g. in first one or two cycles of study treatment)

Growth factor prophylaxis after Cycle 1 (no growth factors should be given 
prophylactically in Cycle 1)

Prophylactic anti-emetics
The preferred 5HT3 antagonist is granisetron. Other 5HT3 antagonists (e.g. ondansetron, 
dolasetron, etc) should be avoided due to possibility of QT prolongation. 
For details please also refer to Section 6.4 for permitted concomitant medication and 
permitted concomitant medication to be used with caution or concomitant medication that is 
prohibited during the study.
6.1.4
Guidelines for continuation of treatment 
Please refer to Section 6.3 Dose Modifications.


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6.1.5
Treatment duration
Patients will be treated with RVD +/- panobinostat for four cycles, followed by stem cell 
collection and one additional cycle of treatment. After stem cell transplant, patients will 
proceed to maintenance therapy for a period of three years. Patients will remain on treatment 
until such time as their maintenance period ends, or they experience disease progression, 
unacceptable toxicity, or at the discretion of the Investigator (Section 7.1.5).
6.2
Dose modifications 
6.2.1
Dose modification and dose delay
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment. The following 
guidelines need to be applied:
Patients unable to tolerate the minimum dose level of Dex may continue treatment with PAN, 
REV and BTZ alone.

Patients requiring permanent discontinuation of PAN, BTZ or REV must discontinue all 
study treatment.

If a patient requires a PAN, REV and/or BTZ dose delay of more than 28 days from the 
intended day of the next scheduled dose, the patient should be discontinued from study 
treatment. If, however, the patient was clearly benefitting from study treatment and the 
cause of the delay has resolved, the patient may be able to restart study treatment upon 
agreement of the Investigator and the Sponsor. This option should be used with the highest 
amount of caution keeping the safety of the patient in mind, and evaluating whether or not 
the benefit outweighs the risk.
These changes must be recorded on the Dosage Administration Record CRF.
The following table (Table 6-2) provides information on dose modifications of PAN, REV 
and BTZ for common toxicities.
Adverse events will be graded using the CTCAE criteria version 4.03.
General guidelines for panobinostat dose modifications due to adverse events related to study 
drug are provided below. If such adverse event(s) are considered possibly related to 
bortezomib, revlimid or dexamethasone, the relevant dose-modification guidelines for each 
should be followed.
6.2.1.1
Dose reductions for BTZ/Dex/REV
Table 6-2
Dose reduction steps for S.C BTZ
Drug
Starting Dose
1st Dose Reduction
2nd Dose Reduction
3nd Dose Reduction
BTZ S.C.
1.3 mg/m2 twice a 
week (BIW)
D 1, 4, 8 & 11
1.0 mg/m2 
D 1, 4, 8 & 11
0.7 mg/m2 
D 1, 4, 8 & 11
Discontinue
Total BTZ dose to be administered is calculated using weight determined on Day 1 of each cycle


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Table 6-3
Dose reduction steps for oral Dex
Drug
Starting Dose 
1st Dose Reduction
2nd Dose Reduction
3rd Dose Reduction
Dex 
20 mg PO the day 
of and 1 day after 
BTZ injection
10 mg PO the day of 
and 1 day after BTZ 
injection
6 mg PO the day of 
and 1 day after BTZ 
injection
Discontinue Dex
Continue with PAN/BTZ alone
Dexamethasone tablets should be taken approximately 15-30 minutes prior to BTZ s.c. injection; and 
approximately at the same time the following day.
Table 6-4
Dose reduction steps for REV
Induction Phase (21 Day Cycle)
Starting Dose 
1st Dose Reduction
2nd Dose Reduction
3rd Dose Reduction 
25 mg QD, Days 1-14
20 mg QD
15 mg QD
Discontinue
Maintenance Phase Beginning at Cycle 6 (84 day cycle)
Starting Dose (Cycle 6)
1st Dose Reduction
2nd Dose Reduction
3rd Dose Reduction 
10 mg QDay Days 1-84
5 mg QDay
Discontinue
----
Starting Dose (Cycle 7+)
1st Dose Reduction
2nd Dose Reduction
3rd Dose Reduction 
15 mg QDay Days 1-84
10 mg QDay
5 mg QDay
Discontinue
6.2.1.2
Dose reduction for PAN
Panobinostat dosing may be modified based on Table 6-5 below. An investigator can use 
his/her discretion when making dose-reduction decisions unless otherwise specified in the 
guidelines below. Any plan to deviate from these guidelines must be previously discussed 
with and agreed upon by the Sponsor.
Table 6-5
Dose reduction steps for PAN*
Induction Phase (21 day cycles)
Starting Dose 
1st Dose Reduction
2nd Dose Reduction
10 mg TIW, two weeks on-one week off
5 mg TIW, two weeks on-one week off
Discontinue
Maintenance Phase (84 day cycle)
Starting Dose 
1st Dose Reduction
2nd Dose Reduction
10 mg TIW, every other week
5 mg TIW, every other week
Discontinue
*Perform dose reduction of panobinostat only if patient experiences recurrence of toxicity on current dose (i.e 
patient can be re-treated at same dose level if first occurrence of > grade 3/4 toxicity resolves as defined in Table 
6-6).


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6.2.1.3
Dose reduction criteria for specific toxicity 
Table 6-6
Criteria for interruption and re-initiation of PAN, REV, and BTZ 
treatment 
Worst Toxicity
CTCAE Grade* unless otherwise specified (Value)
Hematologic toxicity
Drug
PAN dose
REV dose
BTZ dose
Platelet count 
(PLT) 
decreased 
Grade 3 (PLT 
< 50 x 109/L –
25 x 109/L) 
uncomplicated
No change
No change
No change
Grade 4 (PLT 
< 25 x 109/L)
or Grade 3 
(PLT < 50 x 
109/L – 25 x 
109/L) with 
bleeding
Interrupt**
until resolved to ≤ 
Grade 2, or 
baseline:
If first occurrence 
on current dose, 
restart PAN at the 
same dose; if 
second 
occurrence on 
current dose, 
restart with 
reduced dose of 
PAN by one dose 
level (see Table 6-
5).
Interrupt**
until resolved to ≤ Grade 2;
Restart at a reduced dose by one 
dose level (see Table 6-4).
Interrupt**
until resolved to ≤ 
Grade 2;
if only one dose 
was omitted prior 
to correction to 
these levels, BTZ 
should be 
restarted at same 
dose;
if two or more 
doses were 
omitted -
consecutively, or 
within the same 
cycle - then BTZ 
should be 
restarted at a 
reduced dose by 
one dose level 
(see Table 6-2).
Neutrophil 
count (ANC) 
decreased 
Grade 3 
uncomplicated
ANC < 1.0 -
0.75 x 109/L  
No change
No change
No change
Grade 3
ANC < 0.75 -
0.5 x 109/L
Single occurrence 
within cycle, no 
change in dosing. 
Two or more 
occurrences within 
cycle, hold until 
return to ≤Grade 
2 (ANC ≥ 1.0 x 
109/L), and restart 
at same dose.
Start GCSF daily on day one of next 
cycle continue GCSF as needed 
and maintain doses of REV
No change


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Worst Toxicity
CTCAE Grade* unless otherwise specified (Value)
Grade 4 (ANC 
< 0.5 x 109/L)
Interrupt**
If patient was not 
receiving GCSF 
therapy, initiate 
GCSF therapy.
Interrupt PAN until 
resolved to ≤ 
Grade 2, or 
baseline. 
If first occurrence 
on current dose, 
restart PAN at the 
same dose; if  
second 
occurrence on 
current dose, 
restart with 
reduced dose of 
PAN by one dose 
level 
Interrupt**
If patient was not receiving GCSF 
therapy, initiate GCSF therapy.
Interrupt REV until resolved to ≤ 
Grade 2, or baseline. Restart at a 
reduced dose by one dose level
Interrupt** 
until neutropenia 
resolved to ≤ 
Grade 2;
if only one dose 
was omitted prior 
to correction to 
these levels, BTZ 
should be 
restarted at same 
dose;
if two or more 
doses were 
omitted -
consecutively, or 
within the same 
cycle - then BTZ 
should be 
restarted at a 
reduced dose by 
one dose level 
Grade 3 
febrile 
neutropenia
(ANC < 1.0 x 
109/L, with a 
single 
temperature 
of >38.3C 
(101F) or a 
sustained 
temperature 
of ≥38C 
(100.4F) 
for > 1 hour)
Interrupt**
until fever 
resolved and ANC 
≤ Grade 2 If first 
occurrence on 
current dose, 
restart PAN at the 
same dose; if  
second 
occurrence on 
current dose, 
restart with 
reduced dose of 
PAN by one dose 
level
Interrupt**
until fever resolved and ANC ≤ 
Grade 2, then, restart at reduced 
dose level of REV.
Interrupt** 
until neutropenia 
resolved to ≤ 
Grade 2;
if only one dose 
was omitted prior 
to correction to 
these levels, BTZ 
should be 
restarted at same 
dose;
if two or more 
doses were 
omitted -
consecutively, or 
within the same 
cycle - then BTZ 
should be 
restarted at a 
reduced dose by 
one dose level 
* Common Terminology Criteria for Adverse Events (CTCAE Version 4.03)
**: PAN, REV and BTZ dosing should be interrupted at occurence of this event
Non Hematologic toxicity
Drug
PAN dose
REV dose
BTZ dose
Diarrhea
Grade 1 & 2
See Table 6-11
No change
See Table 6-11
Grade 3 
See Table 6-11
Interrupt until
resolved to ≤ grade 2, then re-start
at a reduced dose by one dose 
level
See Table 6-11


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Worst Toxicity
CTCAE Grade* unless otherwise specified (Value)
Grade 4
See Table 6-11
Discontinue treatment
See Table 6-11
Nausea/
vomiting
Grade 1& 2 no 
requiring 
treatment or 
controlled 
using standard 
anti-emetics
No Change
No change
No change
Grade 3 or 4
vomiting or
Grade 3
nausea that
cannot be
controlled
despite the
use of
standard anti-
emetics
Interrupt until 
resolved to <
Grade 1. 
If first occurrence 
on current dose, 
restart PAN at the 
same dose; if  
second 
occurrence on 
current dose, 
restart with 
reduced dose of 
PAN by one dose 
level 
Interrupt until resolved to < Grade 
1. Restart at a reduced dose by one 
dose level
Interrupt until 
resolved to <
Grade 1. if only 
one dose was 
omitted prior to 
correction to these 
levels, BTZ should 
be restarted at 
same dose;
if two or more 
doses were 
omitted -
consecutively, or 
within the same 
cycle - then BTZ 
should be 
restarted at a 
reduced dose by 
one dose level 
AST/ALT 
increase
> 5.0-20.0 x 
ULN
Temporarily 
interrupt dosing 
until resolved to ≤ 
Grade 1, or 
baseline, then:
●
If resolved 
within 7 days 
restart at the 
same dose level
●
If resolved in 
more than 7 days, 
then, restart at 
reduced dose by 
one dose level
Interrupt until resolved to < Grade 
1, or baseline, then:
If resolved within 7 days restart at 
the same dose level
●
If resolved in more than 7 days, 
then, restart at reduced dose 
Interrupt until 
resolved to <
Grade 1, or 
baseline, then:
If resolved within 7 
days restart at the 
same dose level
●
If resolved in 
more than 7 days, 
then, restart at 
reduced dose 
> 20.0 x ULN
Temporarily 
interrupt dosing 
until resolved to ≤ 
Grade 1, or 
baseline.
If first occurrence 
on current dose, 
restart PAN at the 
same dose; if  
second 
occurrence on 
current dose, 
restart with 
reduced dose of 
PAN by one dose 
level 
Interrupt until resolved to < Grade 
1, or baseline, then restart at a 
reduced dose by one dose level. 
Interrupt until 
resolved to <
Grade 1, or 
baseline, then 
restart at reduced 
dose 


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Worst Toxicity
CTCAE Grade* unless otherwise specified (Value)
Total Bilirubin
Grade 3
Temporarily 
interrupt dosing 
until resolved to ≤ 
Grade 2, or 
baseline:
If first occurrence 
on current dose, 
restart PAN at the 
same dose; if  
second 
occurrence on 
current dose, 
restart with 
reduced dose of 
PAN by one dose 
level 
Interrupt until resolved to < Grade 2 
and restart at reduced dose
Interrupt until 
resolved to <
Grade 2 and 
restart at same 
dose
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.
Fatigue
Grade 3
Temporarily 
interrupt dosing 
until resolved to ≤ 
Grade 2, or 
baseline, then:
●
If resolved 
within 7 days, 
then restart at the 
same dose level
●
If resolved in 
more than 7 days, 
then, restart at 
reduced dose 
level
Interrupt until resolved to < Grade 2 
and restart at reduced dose level
Interrupt until 
resolved to <
Grade 2 and 
restart at same 
dose
Peripheral 
neuropathy
Any Grade 
No change
No change
See Table 6-8
HSV 
reactivation
Any grade
No change
No change
See Table 6-7
Renal 
dysfunction
Calculated 
GFR 15-30 
ml/min
No change
Interrupt until resolved to > 30ml/min 
and restart at reduced dose level 
No change
Cardiac-
Prolonged 
QTcF
Please refer to Section 6.2.1.6.3 (see Table 6-5)
Other drug 
related non 
hematologic 
toxicity 
> Grade 3
Determine attribution of toxicity if possible and hold appropriate therapy. Follow 
at least weekly. If toxicity resolves to ≤ Grade 2 therapy may be resumed, 
unless the investigator decides otherwise. In case therapy will be resumed, 
consideration for one level dose reduction of appropriate drug will be given. 
All dose modifications should be based on the worst preceding toxicity.
* Common Terminology Criteria for Adverse Events (CTCAE Version 4.03)
** It is critical that electrolyte abnormalities be followed closely and corrected prior to dosing
*** See also concomitant medication


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Table 6-7
Drug related adverse events dose modification guidelines for BTZ 
CTCAE Category
Dose Modification Guideline -
At any time during a cycle of therapy (including intended day of 
dosing)
HEMATOLOGICAL TOXICITIES
(ANC, PLT)
See Table 6-6
NON-HEMATOLOGICAL TOXICITIES
Peripheral Neuropathy 
See Table 6-8
Herpes Zoster reactivation any grade 
Hold therapy until lesions are dry. 
Other BTZ 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 (see Table 6-6).
6.2.1.4
Management of patients with BTZ-related neuropathic pain and/or 
peripheral sensory neuropathy
The neurotoxicity-directed questionnaire (FACT/GOG-Ntx) is a useful tool for determining 
the presence and intensity of neuropathic pain and/or peripheral neuropathy from the patient’s 
perspective. Neuropathic symptoms are more prominent than abnormalities on the clinical 
examination. After the patient completes the neurotoxicity-directed questionnaire, the 
questionnaire should be reviewed to assist with the evaluation of the onset and intensity of 
peripheral neuropathy and other neurotoxicities that may possibly require intervention or dose 
modification.
Table 6-8
Recommended dose modification for BTZ-related neuropathic pain 
and/or peripheral sensory neuropathy
Severity of Peripheral Neuropathy
Signs and Symptoms 
Modification of Dose and Regimen 
Gr 1 (Asymptomatic; loss of deep tendon reflexes 
or paresthesia) 
No action 
Gr 1 with pain or Gr 2 (Moderate symptoms; limiting
instrumental ADL) a
Reduce by one dose level (see Table 6-6)
Gr 2 with pain or Gr 3 (Severe symptoms; limiting 
self-care ADL) 
Hold BTZ therapy until toxicity resolves to < Gr 2
When toxicity resolves, reinitiate with a reduction by one 
dose level (see Table 6-6)
If no more dose reductions are possible, discontinue BTZ
Gr 4 (Life-threatening consequences; urgent 
intervention indicated)
Discontinue BTZ
Grading based on NCI Common Terminology Criteria CTCAE v4.03
NCI Common Toxicity Criteria website - http://ctep.info.nih.gov/reporting/ctc.html 


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Table 6-9
Dex dose modifications
Dexamethasone dose modifications
Gastrointestinal
Dyspepsia, gastric or duodenal
ulcer, gastritis Gr 1-2 (requiring 
medical management)
Treat with H2 blockers, sucralfate, or omeprazole. If 
symptoms persist despite above measures, reduce Dex 
by one dose level (see Table 6-7)
> Gr 3 (requiring hospitalization or 
surgery)
Hold Dex until symptoms adequately controlled. Restart 
and reduce one dose level (see Table 6-7) along with 
concurrent therapy with H2 blockers, sucralfate, or 
omeprazole. If symptoms persist despite above 
measures, discontinue Dex and do not resume.
Acute pancreatitis
Discontinue Dex and do not resume.
Cardiovascular
Edema
> Gr 3 (limiting function and
unresponsive to therapy or
anasarca)
Diuretics as needed, and reduce Dex by one dose level 
(see Table 6-7); if edema persists despite above 
measures, reduce another dose level. Discontinue Dex 
and do not resume if symptoms persist despite second 
reduction.
Neurology
Confusion or Mood alteration
> Gr 2 (interfering with function +/-
interfering with activities of daily 
living)
Hold Dex until symptoms resolve. Restart with one dose 
level reduction (see Table 6-7). If symptoms persist 
despite above measures, discontinue Dex
do not resume.
Musculoskeletal
Muscle weakness
> Gr 2 (symptomatic and
interfering with function +/-
interfering with activities of daily 
living)
Reduce Dex by one dose level (see Table 6-7). If 
weakness persists despite above measures reduce 
another dose level. Discontinue Dex and do not resume if 
symptoms persist.
Metabolic
Hyperglycemia
> Gr 3 or higher
Treatment with insulin or oral hypoglycemics as needed. If 
uncontrolled despite above measures, reduce by one 
dose level (see Table 6-7) until levels are satisfactory.
6.2.1.5
Management of Diarrhea (including PAN and BTZ dose modifications)
Patients should be instructed to contact the physician/other study personnel at the first sign of 
diarrhea. The patient should also be instructed on the use of loperamide and lomotil at home 
(see Table 6-11).
At the beginning of every cycle, each patient should be asked if he/she experienced any 
diarrhea and if any self-care measures were taken for this event. The study personnel should 
ensure that adverse event(s) of diarrhea and use of concomitant anti-diarrheal medication are 
documented on the relevant pages of the CRF as needed.
If the regimen described below is inadequate or at the investigator’s discretion, additional 
evaluation and treatment should be pursued including hospitalization as needed. Replacement 
i.v. fluids and electrolytes may be used as appropriate. Additional treatment should be 
provided in accordance with institutional standard of care and/or local guidelines.
At the time of the first screening visit:
History and physical are documented and patient is counseled on diet, use of laxatives, as 
follows:

Take thorough history of diarrhea and obtain a description of number of stools and stool 
composition (e.g. watery, blood, mucus in stool)


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
Assess the patient for fever, abdominal pain, cramps, distension, bloating, nausea, 
vomiting, dizziness, weakness (i.e., rule out sepsis, clostridium difficile, bowel 
obstruction, or dehydration)

Obtain patient’s medication profile (i.e., to identify and limit the use of any diarrhea 
causing agents)

Obtain dietary profile and counsel patient on dietary modifications:

Instruct the patient to stop all lactose-containing products

Instruct the patient to stop taking laxatives, bulk fiber (i.e. Metamucil®), and stool 
softeners (docusate sodium; Colace®)

Instruct the patient to drink 8 to 10 large glasses of clear liquids per day (i.e. water, 
Pedialyte®, Gatorade®, broth)

Instruct the patient to eat frequent small meals (bananas, rice, applesauce, Ensure®, 
toast)

Instruct the patient to stop consuming high-osmolar food supplements such as Ensure 
Plus® and Jevity Plus® (with fiber)
The patient should be given loperamide and lomotil to take home in order to be able to have 
anti-diarrheal medications if needed. Additional loperamide and lomotil should be given to 
the patient during study treatment as needed, based on the amounts taken.
Proposed diarrhea management after 1st screening visit and during study treatment
Table 6-11 and Table 6-12 describe the anti-diarrheal medications and other diarrhea 
management steps (including dose modifications) proposed after the first screening visit, 
respectively.
Table 6-10
Proposed anti-diarrheal medications 
Medication
Dose
Step 1
standard dose loperamide (Imodium)
4 mg followed by 2 mg every 4 hours OR after 
each loose stool (maximum 16 mg/day).
Step 2
high dose loperamide (Imodium)
4 mg followed by 2 mg every 2 hours OR 4 
mg every 4 hours (maximum of 16 mg/day)
Step 3
diphenoxylate and atropine (Lomotil)
5 mg every 6 hours
Dose modifications for bortezomib and dexamethasone may be performed based on Table 6-
2, Table 6-6 and Table 6-7 below. Further clarification can be obtained in consultation with 
the Sponsor.


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Table 6-11
Diarrhea management and PAN/BTZ dose modifications
Diarrhea CTCAE grade
Diarrhea management
PAN and BTZ dosing
Prior to first planned dose
Grade 1
Increase of < 4 stools / day over baseline; 
mild increase in ostomy output compared 
to baseline
Standard dose loperamide
Give full dose of both PAN and 
BTZ
On study treatment
Grade 1
Increase of < 4 stools / day over baseline; 
mild increase in ostomy output compared 
to baseline
Standard dose loperamide
Give full dose of PAN and BTZ
Grade 2
increase of 4-6 
stools / day over 
baseline; moderate 
increase in ostomy 
output compared to 
baseline
Grade 2
High dose loperamide
Interrupt both, PAN and BTZ
when improved to 
Grade 1 w/i 24h
Modify antidiarrheal 
medication as appropriate
Restart both, PAN and BTZ, at 
current doses
Grade 2 for > 24h 
Start diphenoxylate/atropine, 
continue high dose loperamide
Interrupt both, PAN and BTZ
when improved to 
Grade 1 w/i 48 h
Modify antidiarrheal 
medication as appropriate
Restart both, PAN and BTZ, at 
current doses 
Grade 2 for > 48h
Continue 
diphenoxylate/atropine and 
high dose loperamide
Interrupt both PAN and BTZ
when improved to
Grade 1 
after  >48 h
Modify antidiarrheal 
medication as appropriate
Dose reduce BTZ first by one 
dose level (Table 6-2). Continue 
PAN at the same dose on the first 
occasion. If second occasion, 
restart PAN at a reduced dose by 
one dose level (Table 6-5)
Grade 3
increase of ≥7 
stools /
day over baseline; 
incontinence; 
hospitalization 
indicated; severe 
increase in ostomy 
output  compared to 
baseline; self-
limiting care ADL
Grade 3
High dose loperamide and 
diphenoxylate/atropine
Consider hospitalization for 
monitoring / volume 
management
Interrupt both, PAN and BTZ
until diarrhea 
improves 
to Grade 1
Continue high dose 
loperamide and 
diphenoxylate/atropine and 
supportive care until ≤ Grade 1
Interrupt both, PAN and BTZ
when improved to 
Grade 1
Modify antidiarrheal 
medication as appropriate
Dose reduce BTZ first by one 
dose level (Table 6-2). Continue 
PAN at the same dose on the first 
occasion. If second occasion, 
restart PAN at a reduced dose by 
one dose level (Table 6-5)
Grade 4
Life threatening 
consequences; 
urgent intervention 
indicated 
Grade 4
Hospitalize and provide 
intensive supportive care and 
antidiarrheals
Discontinue study treatment


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6.2.1.6
Management of other non-hematologic toxicities
6.2.1.6.1 Grade 2 non-hematologic toxicity
Patients experiencing CTCAE grade 2 non-hematologic adverse event(s) not listed in Table 6-
4, which the patient believes is/are tolerable and in the Investigator’s judgment is/are 
acceptable, may continue treatment at the current dose and schedule. More frequent patient 
monitoring may be required, and patients must be informed to call the Investigator 
immediately if there is any worsening of symptoms.
If a patient experiences new (or treatment emergent) grade 2 non-hematologic adverse 
event(s) considered at least possibly related to panobinostat, 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. Panobinostat treatment may then be 
restarted at the same dose and schedule. If the same intolerable grade 2 adverse event(s) 
occurs again, panobinostat treatment must again be temporarily interrupted until the toxicity 
resolves to ≤ CTCAE grade 1 and can be restarted at reduced dose level if current PAN dose 
was 10mg, and at same dose level if current PAN dose was 5mg (see Table 6-3). At the 
discretion of the Investigator and in consultation with the Sponsor, patients with grade ≥ 2 
adverse events of major organs (e.g. heart, lungs, CNS) may be discontinued from further 
study therapy without being retreated with a dose reduction.
6.2.1.6.2 Grade 3 or 4 non-hematologic toxicity
Patients experiencing new (or treatment emergent) CTCAE grade 3 or 4 non-hematologic AEs 
not listed in Table 6-4, must have their treatment temporarily interrupted until the adverse 
event resolves to ≤ CTCAE grade 1 or baseline unless otherwise specified in Table 6-4. If the 
AE was considered related to panobinostat, the drug should then be restarted at reduced dose 
level if current PAN dose was 10mg, and at same dose level if current PAN dose was 5mg 
(see Table 6-3). If the AE was considered not related to panobinostat then therapy may be 
restarted (when the AE resolves to ≤ grade 1 or baseline) at the current dose; if a dose 
reduction is considered it must be agreed upon by the Investigator and the Sponsor prior to the 
patient being dose reduced.
6.2.1.6.3 Dose modification of panobinostat for prolonged QTcF interval
All cardiac events should be treated as per the local standard of care and referred to a 
cardiologist if clinically indicated. The local readings of ECGs will use the Fridericia 
correction for QTc interval assessment: QTcF. Any final decisions concerning dose 
modifications or permanently discontinuing the patient from study drug due to QTcF 
prolongation will be based on the assessment performed by the Investigator and after 
discussion between the Investigator and Sponsor. Any plan to deviate from these guidelines 
must be previously discussed and agreed upon by the Sponsor.


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Table 6-12
Criteria for dose interruption of PAN due to QTcF prolongation
Time Point
Average QTcF*
Action
Screening and pre-
dose cycle 1 day 1
≥ 450 msec
Correct any electrolyte abnormal values ** and repeat ECG, if 
the average QTcF ≥ 450 msec, do not commence treatment
Post-dose cycle 1 
days 1 and 5
≥ 480 msec or above 
60 msec from baseline
Correct any electrolyte abnormal values ** and repeat ECG in 
triplicate (3 ECGs 5 to 10 minutes apart). Monitor QTcF until 
prolongation is resolved
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
Patient must discontinue treatment
Pre-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***
Correct any electrolyte abnormal values ** and repeat ECG in 
triplicate (3 ECGs 5 to 10 minutes apart), if the average QTcF 
≥ 480 msec, do not dose.  If the average QTcF is < 480 msec, 
resume dosing.
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
6.2.2
Follow-up for toxicities
Patients whose treatment is interrupted or permanently discontinued due to an adverse event 
or clinically significant laboratory value, must be followed up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for 4 weeks, and 
subsequently at approximately 4-week intervals, until resolution or stabilization of the event, 
whichever comes first. Appropriate clinical experts such as ophthalmologist, endocrinologist, 
dermatologist, psychiatrists etc. should be consulted as deemed necessary. 
Further guidelines and recommendations for the management of specific study drug 
combination induced toxicities (diarrhea and cardiac toxicities) are provided in Section 6.3.1.3
and Section 6.3.1.4. All patients must be followed up for adverse events and serious adverse 
events for 30 days following the last dose of study treatment.
If an adverse event requiring treatment interruption resolves to < grade 1 within the same 
cycle, resume dosing as scheduled for that cycle. During the induction phase, If an adverse 
event requiring treatment interruption resolves to < grade 1 after the end of a cycle (D21), 
resume dosing with a brand new cycle. Otherwise, continue dosing according to current cycle 
schedule. For adverse events requiring treatment interruption during the maintenance phase, 
dosing can be resumed within the same cycle, provided that the AE resolves to ≤grade 1 
within 28 days.


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6.3
Concomitant medications 
6.3.1
Permitted concomitant therapy
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications (other than study drug) and significant 
non-drug therapies (including physical therapy, herbal/natural medications and blood 
transfusions) administered during the study must be listed on the Concomitant Medications or 
the Procedures and Significant Non-Drug Therapies CRF.
6.3.1.1
Growth factors
Granulocyte colony stimulating factor (G-CSF) or
granulocyte-macrophage colony 
stimulating factor (GM-CSF) should not be used prophylactically in the first cycle. G-CSF 
may be initiated for an individual patient in accordance with American Society of Clinical
Oncology’s guidelines (Smith et al 2006), if the patient experiences febrile neutropenia and/or 
grade 4 neutropenia for > 7 days. Growth factors may then be administered prophylactically 
in all subsequent cycles for that patient.
Patients who were receiving available recombinant erythropoiesis stimulating agents such as 
epoetin and darbepoietin prior to starting study treatment may continue to receive it 
throughout the study. Likewise these can be introduced during the study. Investigators should 
follow available guidelines on criteria for initiation, target and doses provided in ASCO/ASH 
guidelines (Rizzo et al 2010).
6.3.1.2
Bisphosphonate Therapy
Bisphosphonate therapy is permitted only if commenced prior to the start of screening period. 
Mouth care is recommended in these patients. 
Bisphosphonates may be given according to their product license and routine clinical practice, 
at the investigator’s discretion.
Patients taking bisphosphonates prior to entering the study should continue with the same 
bisphosphonate treatment, given as per local medical practice.
6.3.1.3
Anti-emetic medication
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). These should be avoided.
6.3.1.4
Anti-diarrheal medication
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. Please refer to Section 6.3.1.4 for 
details on management of diarrhea.
6.3.1.5
Prophylaxis treatment
Please refer to Section 6.1.2 for ancillary treatment.


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6.3.2
Permitted concomitant therapy requiring caution and/or action
6.3.2.1
Anti-coagulant therapy/ anti-platelet therapy
Panobinostat therapy, especially in combination with bortezomib, is commonly associated 
with moderate to severe degree of thrombocytopenia. This may lead to an increase in the risk 
of bleeding especially if co-administered with long acting anticoagulation, such as sodium 
warfarin (Coumadin®). It is recommended that patients who require anticoagulation therapy 
while on panobinostat therapy use low molecular weight heparin (LMWH). However, if the 
use of LMWH is not feasible or indicated, patients on vitamin K inhibitors such as sodium 
warfarin may continue such therapy while on panobinostat but for such patients, a close and 
frequent monitoring of the coagulation parameters, especially PT/INR should be followed and 
maintained within a therapeutic range (suggested INR 2-3). Warfarin should be used with 
caution and the dose of sodium warfarin may be adjusted as needed while on study treatment. 
It is recommended that if the platelet count falls below 50 x 109/L, withholding of 
thromboprophylaxis be considered to minimize the risk of bleeding. Newer direct FX and 
thrombin inhibitors should not be used as there is no effective antidote available and fresh 
frozen plasma is not effective in reversing their effects.
For patients requiring anti-platelet therapy while on panobinostat, Aspirin ≤ 325mg or Plavix 
≤ 75mg daily are allowed. It is recommended that anti-platelet therapy be held if platelet 
counts fall below 50 x 109/L.
6.3.2.2
Medications that are known to be strong CYP3A inhibitors
See Section 14.1.
Panobinostat is a substrate of CYP3A with minor involvement of CYP2D6, and CYP2C19 in 
in vitro evaluation of its metabolism. Thus, a clinical drug-drug interaction study was 
conducted using ketoconazole, a strong CYP3A inhibitor, in combination with panobinostat in 
study [CLBH589B2110].
Multiple ketoconazole doses at 400 mg increased Cmax and AUC of panobinostat by 1.6- and 
1.7-fold, respectively, but with no change in Tmax or half-lives in 14 cancers patients. The 
less than 2-fold increase in panobinostat AUC upon co-administration of a strong CYP3A 
inhibitor is considered a weak drug inhibition. Patients with impaired liver function (as 
defined by NCI CTEP criteria, Synold et al 2007) are recommended not to receive 
panobinostat concomitantly with strong CYP3A inhibitors due to lack of safety data in this 
population.
6.3.3
Prohibited concomitant therapy
The following medications are prohibited during this study:

Systemic anticoagulation or drugs that inhibit platelet function, WITH THE EXCEPTION 
OF (see Section 6.4.2):

Aspirin ≤ 325 mg/day

Plavix  ≤ 75 mg/day

Low molecular weight heparin (LMWH).


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
Titrated dose warfarin may be used in patients requiring chronic anticoagulation

Any investigational medication (other than PAN)

Chemo-, biologic or immunologic therapy is not allowed while the patient is on study 
treatment. Palliative radiation therapy may be permitted, but the need for radiation therapy 
is usually indicative of disease progression.

DAC inhibitors, including valproic acid, for any clinical indication while on PAN 
treatment.
6.3.3.1
Drugs that are known to prolong the QT interval and/or induce 
Torsade de Pointes ventricular arrhythmia
Patients who are currently receiving treatment with any of the medications in Section 14.1.1
which have a known risk of prolonging the QT interval or inducing Torsades de pointes and 
cannot either discontinue this treatment or switch to a different medication prior to study 
enrollment, will be excluded from the study. Patients may not begin treatment with any of the 
medications listed in Section 14.1.1 unless this is discussed with the Sponsor and an approval 
is granted by the Sponsor.
Sponsor may agree to temporarily discontinue panobinostat treatment during administration 
with these drugs.
Ensure that patient is off panobinostat treatment for at least 72 hours prior to starting 
treatment with a medication listed in Section 14.1.2.
It is of importance to avoid combining drugs listed in Table 14-1 (QT prolonging drugs) and 
Table 14-2 (CYP3A inhibitors) in the presence of electrolyte abnormalities notably decreased 
potassium or magnesium levels commonly associated with diuretic usage.
The current panobinostat guidance (as specified in Section 14.1) includes an updated list of 
medications which was developed in collaboration with an external cardiologist consultant 
and is based on the ARIZONA CERT website on drugs that prolong the QT interval and/or 
induce Torsades de Pointes or ventricular arrhythmia.
6.3.3.2
Medications which are known strong CYP3A inducers are to be 
avoided
Panobinostat plasma exposure was reduced by 20% or more when combined with bortezomib 
and dexamethasone (B2207 and D2308). Co-administration of panobinostat with strong 
CYP3A inducers was not evaluated in a clinical trial however, an approximately 70% 
decrease in the systemic exposure of panobinostat in the presence of strong inducers of 
CYP3A was observed in simulations using mechanistic models. Therefore, the concomitant 
use of strong CYP3A inducers should be avoided.
6.3.3.3
Medications which are known sensitive CYP2D6 substrates or 
substrates with narrow therapeutic index 
Panobinostat was also shown to be a CYP2D6 inhibitor (Ki 0.17 µM) in vitro.  Thus, clinical 
drug-drug interaction study with panobinostat as CYP2D6 inhibitor and dextromethorphan as 
CYP2D6 substrate was recently conducted in study [CLBH589B2109].


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Panobinostat increased the median Cmax and AUC of a sensitive substrate of CYP2D6 by 
approximately 80% and  60%, respectively; however these increase were highly variable 
(increased the Cmax and AUC0-∞ of dextromethorphan by 20% to 200% and 20% to 130% 
(interquartile ranges), respectively).
Avoid co-administrating panobinostat with sensitive CYP2D6 substrates (Table 14-4) or 
CYP2D6 substrates that have a narrow therapeutic index (i.e., thioridazine, pimozide). If 
concomitant use of CYP2D6 substrates is unavoidable, monitor patients frequently for 
adverse reactions.
6.4
Patient numbering, treatment assignment or randomization
6.4.1
Patient numbering
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned 
when the patient is first enrolled for screening and is retained as the primary identifier for the 
patient throughout his/her entire participation in the 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.
6.4.2
Treatment assignment or randomization
Patients will be assigned to one of the 2 treatment arms (Section 4.1 and Section 6.1) in a ratio 
of 1:1.
Randomization will be performed using random permuted block scheme. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the Interactive Response Technology (IRT) provider 
using a validated system that automates the random assignment of patient numbers to 
randomization numbers. These randomization numbers are linked to the different treatment 
arms, which in turn are linked to medication numbers.
Prior to dosing, all patients who fulfill all inclusion/exclusion criteria will be randomized via 
IRT to one of the treatment arms. The investigator or his/her delegate will call or log on to the 
IRT and confirm that the patient fulfills all the inclusion/exclusion criteria. The IRT will 
assign a randomization number to the patient, which will be used to link the patient to a 
treatment arm and will specify a unique medication number for the first package of study 
treatment to be dispensed to the patient. The randomization number will not be communicated 
to the caller.
6.4.3
Treatment blinding
Not applicable.


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6.5
Study drug preparation and dispensation
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
PAN, REV and Dex as per protocol. Study drug(s) will be dispensed to the patient by 
authorized site personnel only. BTZ will be reconstituted and handled as per the 
manufacturer’s instructions by the responsible site personnel and administered as 
subcutaneous injection at the site.
All dosages prescribed to the patient and all dose changes during the study must be recorded 
on the Dosage Administration Record CRF.
Table 6-13
Preparation and dispensing
Study treatments
Dispensing
Preparation
PAN 
PAN capsules are given to the patient on the 1st day of a cycle 
by study personnel. Additional capsules including instructions for 
administration are dispensed by study personnel on an 
outpatient basis.
Patients will be provided with adequate supply of study 
treatment for self-administration at home until at least the first 
day of the subsequent cycle.
Not applicable
BTZ s.c.
Not applicable 
Refer to product 
information
Dex 
Dex tablets are given to the patient on the day of BTZ s.c. 
injection by study personnel. Additional tablets including 
instructions for administration are dispensed by study personnel 
on an outpatient basis.
Patients will be provided with adequate supply of study 
treatment for self-administration at home until at least the first 
day of the subsequent cycle.
Not applicable
REV
REV capsules are provided to the patient via a prescription. 
Additional capsules including instructions for administration are 
dispensed by study personnel on an outpatient basis.
Patients will be provided with adequate supply of study 
treatment for self-administration at home until at least the first 
day of the subsequent cycle.
Refer to local product 
information.
6.5.1
Study drug packaging and labeling
Each study site will be supplied by Novartis with PAN (LBH589 5mg and 10mg) capsules.  
Site personnel will add the patient number on the label. 
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the drug but no information about the 
patient.
6.5.2
Drug supply and storage
Study treatments must be received by designated personnel at the study site, handled and 
stored safely and properly, and kept in a secured location to which only the investigator and 
designated site personnel have access. Upon receipt, the PAN should be stored according to 
the instructions specified on the drug labels and in the Investigator’s Brochure.


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Bortezomib, dexamethasone and Revlimid should be stored according to the local product 
information. 
6.5.2.1
Study drug compliance
The total daily doses of study treatment (PAN/BTZ/REV and Dex) taken, the date of dose, 
information regarding dose change, dose interruption, permanent discontinuation and 
reason(s), as well as information whether the study drug was dispensed in error, will be 
recorded on the respective Dose Administration Record of the CRF. For BTZ the dose 
prescribed in mg/m2 will also be captured.
Compliance will be assessed by the investigator and/or study personnel at each patient visit 
and information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each 
patient visit.
Patients will be asked to record self-administered PAN/REV/Dex doses in a dosing diary, and 
to bring in the diary (together with any unused study medication or empty study medication 
bottles, as applicable) on Day 1 of every cycle starting with Cycle 2, as well as at the EOT 
visit. The information in the diary will be reviewed and new diaries will be dispensed by site 
personnel at the beginning of each cycle and information will be used to support/record 
information on PAN/REV/Dex dosing on the respective Dose Administration Record CRF
page.
6.5.2.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return 
all unused study treatment and packaging on a regular basis, at the end of the study or at the 
time of study treatment discontinuation.
At study close-out, and, as appropriate during the course of the study, the investigator will 
return all used and unused study treatment, packaging, 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.
It’s preferred that the study drug supply is destroyed on site, after your CRA has had an 
opportunity to perform drug accountability.  If this is not possible, drug can be destroyed at 
the local Novartis facility, Drug Supply group or third party, as appropriate.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. 


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Table 7-1
Visit evaluation schedule
Day of cycle
Category
Protocol Section
Screening
Study Treatment
End of treatment
Long
-term 
FU
Induction
21 days/cycle
Maintenance
84 day cycles
Survival  
FU
Cycle (C) 1
21 days/cycle
Cycle 2 – 5
21 days/cycle
Cycle 6
Cycle 
7+
Day 
-21 
to 1
1
(BL)
4
8
11
1
4
8
11
21 
(only 
cycle 
4)
1
29
57
1
EOT
Every
90 
days
Obtain informed consent 
(IC)
D
11.3
X
Registration / Randomization with IRT/IWRS
Registration after signing of 
IC
S
6.4.2
X
Randomization if eligible
D
6.4.2
X
Patient history
Demography
D
7.1.1.3
X
Inclusion/exclusion criteria
D
5.2/5.3
X
Medical History
D
7.1.1.3
X
MM Diagnosis/history and 
extent of cancer
D
7.1.1.3
X
Local cytogenetics (FISH)
D
7.1.1.3
X
Prior/concomitant 
medications and non-drug 
therapy
D
7.1.1.3
Continuously from 14 days prior to first dose until 30 days after last dose of study treatment


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Day of cycle
Category
Protocol Section
Screening
Study Treatment
End of treatment
Long
-term 
FU
Induction
21 days/cycle
Maintenance
84 day cycles
Survival  
FU
Cycle (C) 1
21 days/cycle
Cycle 2 – 5
21 days/cycle
Cycle 6
Cycle 
7+
Day 
-21 
to 1
1
(BL)
4
8
11
1
4
8
11
21 
(only 
cycle 
4)
1
29
57
1
EOT
Every
90 
days
Transfusions of blood 
products
D
7.1.1.3
Continuously from 14 days prior to first dose until 30 days after last dose of study treatment
Efficacy / Disease Assessment
M-Protein by Protein Electrophoresis (PEP)
- in serum (sPEP)
D
7.2.1.1
X
X
X
X
X
X
X
X
- in urine (uPEP)
D
7.2.1.1
X
X
X
X
X
X
X
X
M-Protein by Immunofixation (IF)
- in serum (sIF)
D
7.2.1.1
X
X
X
X
X
X
X
X
- in urine (uIF)
D
7.2.1.1
X
X
X
X
X
X
X
X
Free light chain protein assessment (FLC)
- in serum (sFLC)
D
7.2.1.2
X
X
X
X
X
X
X
X
Local plasma cell count in bone marrow (PCC)
- Plasma cell count (2-4 
color flow)
D
7.2.1.2
X
X
X
During the study as 
clinically indicated to 
confirm CR, sCR, 
and PD for patients 
with non-measurable 
disease
X
Assessment of soft tissue plasmacytoma (STP)
- By CT/MRI/PET
D
7.2.1.6
X
During the study as clinically indicated to confirm CR, sCR; and PD for patients 


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Day of cycle
Category
Protocol Section
Screening
Study Treatment
End of treatment
Long
-term 
FU
Induction
21 days/cycle
Maintenance
84 day cycles
Survival  
FU
Cycle (C) 1
21 days/cycle
Cycle 2 – 5
21 days/cycle
Cycle 6
Cycle 
7+
Day 
-21 
to 1
1
(BL)
4
8
11
1
4
8
11
21 
(only 
cycle 
4)
1
29
57
1
EOT
Every
90 
days
with non-measurable disease
Full body skeletal survey (FBSS)
- by X-ray and/or CT/MRI
D
7.2.1.7
X
During the study as clinically indicated; In case of newly symptomatic areas with 
no finding by X-ray a targeted CT/MRI assessment should be performed.
Response assessment by 
investigator
D
7.2.1.8
X
X
X
X
X
X
X
MRD assessment in 
marrow for component of 
mCR (ClonoSEQTM)
D
7.2.1.5
X
In all patients who are in CR on or after 
C4D21
Clinical examination
Physical exam (including brief 
neurological exam)
S
7.2.2.1
X
X
X
X
X
X
X
Vital signs
D
7.2.2.2
X
X
X
X
X
X
X
X
Height
D
7.2.2.3
X
Weight / BSA calculated by 
site
D
7.2.2.3
X
X
X
X
X
X
X
X
ECOG Performance status
D
7.2.2.4
X
X
X
X
X
X
X
X
Local laboratory assessments
Hematology
D
7.2.2.5.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
D
7.2.2.5.2
X
X
X
X
X
X
X
X
X
X
X
X
X


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Day of cycle
Category
Protocol Section
Screening
Study Treatment
End of treatment
Long
-term 
FU
Induction
21 days/cycle
Maintenance
84 day cycles
Survival  
FU
Cycle (C) 1
21 days/cycle
Cycle 2 – 5
21 days/cycle
Cycle 6
Cycle 
7+
Day 
-21 
to 1
1
(BL)
4
8
11
1
4
8
11
21 
(only 
cycle 
4)
1
29
57
1
EOT
Every
90 
days
Calcium
D
If total calcium is abnormal, collect ionized calcium
Electrolytes
D
7.2.2.5.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Thyroid
D
7.2.2.5.4
X
Coagulation
D
7.2.2.5.5
X
Troponin I
D
7.2.2.5.6
X
Creatinine Clearance –
calculated using Cockroft-Gault
D
7.2.2.5.7
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy tests for women of childbearing potential
- In serum (w/i 7 days of 1st 
planned dose)
D
7.2.2.5.8
X
- In urine
D
7.2.2.5.8
X
X
X
X
X
X
Cardiac Assessments
Central 12-lead ECG up to C 
16
(unscheduled as clinically 
indicated)
D
7.2.2.6.1
X
X
X
X
X
As clinically indicated
X
Cardiac Imaging 
(MUGA/ECHO)
D
7.2.2.6.2
X
As clinically indicated
Adverse events
Adverse events
D
8
Continuously after signed ICF until 30 days after last study treatment


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Day of cycle
Category
Protocol Section
Screening
Study Treatment
End of treatment
Long
-term 
FU
Induction
21 days/cycle
Maintenance
84 day cycles
Survival  
FU
Cycle (C) 1
21 days/cycle
Cycle 2 – 5
21 days/cycle
Cycle 6
Cycle 
7+
Day 
-21 
to 1
1
(BL)
4
8
11
1
4
8
11
21 
(only 
cycle 
4)
1
29
57
1
EOT
Every
90 
days
Study treatment administration and new antineoplastic therapies after discontinuation of study treatment
Panobinostat (PAN)
S
6.1.2.1.1
Day 1, 3, 5, 8, 10, 12, two weeks on one week off, 21 day cycles
(for dose reductions please refer to Section 6.3)
Day, 1, 3, 5, every other 
week of 28 day cycles
Revlimid (REV)
S
6.1.2.1.2
Every day, two weeks on one week off
Continuously for 28 day 
cycles
Dexamethasone (Dex) p.o.
S
6.1.2.1.4
D1, 2, 4, 5, 8, 9, 11, 12
Bortezomib (BTZ) s.c.
S
6.1.2.1.3
D1, 4, 8, 11
Dispensing and/or review of 
patient paper dosing diary 
by study personnel
S
6.1.2.2
X
X
X
X
X
X
Survival Follow-up (until all patients have completed 3 years of follow-up from study entry
Follow-up for survival 
endpoints
D
4.3
Beginning at study entry, all patients will be followed for survival for 3 years.


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7.1.1
Screening
Following signature of the main study Informed Consent (ICF), the majority of screening 
assessments will be performed within 21 days prior to first dose on Cycle 1 Day 1. There are a 
few assessments (serum pregnancy test for WOCBP) that will need to be performed within 7 
days of first planned dose of study treatment (see Table 7-1 for detailed list of assessments to 
be performed).
Note: Any screening assessment that is done outside the screening window (Day -21 to Day 1 
or Day -7 to Day 1 as applicable) must be repeated prior to randomization.
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.
If the bone marrow sample collected at screening was inadequate/uninterpretable for
assessment of FISH and/or PCC, it should be repeated within 21 days of the original
collection date prior to randomization.
A new ICF will need to be signed if the investigator chooses to re-screen the patient after a 
patient has screen failed. The same Subject ID number will be used, and all required screening 
activities must be performed when the patient is re-screened for participation in the study. An 
individual patient may be re-screened twice 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.
Informed Consent CRF should be completed as appropriate.
7.1.1.1
Eligibility screening 
Following registering in the IRT for screening, patient eligibility will be checked once all 
screening procedures are completed. If patient meets all eligibility criteria, the site personnel 
can proceed with the randomization of the patient in the IRT. In addition, the Randomization 
page in the CRF will be completed.
At the end of the screening phase, the Screening Log will be completed for all patients.
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 


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on 
the 
Screening 
Log. 
The 
demographic 
information, 
informed 
consent, 
and 
Inclusion/Exclusion pages must also be completed for Screen Failure patients. No other data 
will be entered into the clinical database for patients who are screen failures, unless the patient 
experienced a Serious Adverse Event during the Screening Phase (see Section 8 for SAE 
reporting details). If the patient fails to be randomized, the IRT must be notified within 2 days 
of the screen fail that the patient was not randomized.
If the patient is randomized but then does not start study treatment, the patient will be part of 
the full analysis set, and will be followed for efficacy and survival in the long-term follow-up. 
The IRT must be notified within 2 days of the fact, that the randomized patient will not 
receive study treatment and moved to the long-term follow-up.
7.1.1.3
Patient demographics and other baseline characteristics
During the screening period, the following data must be collected/evaluated and recorded for 
all randomized patients on the appropriate CRFs:

After the main study ICF is signed the patient will be registered with IRT.

Demography (date of birth and initials, sex, information on child-bearing status of female 
patients, race, ethnicity).

Medical history (e.g., important medical, surgical, and allergic conditions from the 
patient’s medical history which could have an impact on the patient’s evaluation) / current 
medical conditions (e.g., all relevant current medical conditions which are present at the 
time of signing informed consent). Ongoing medical conditions, symptoms and disease 
which are recorded on the Medical History CRF should include the toxicity grade.

Diagnosis of Multiple Myeloma and extent of cancer (including staging at study entry).

BM aspirate/biopsy for cytogenetics (FISH) to be performed prior to study entry

All other medications and significant non-drug therapies including ancillary medication  
taken within 14 days before first dose is administered must be recorded on the Prior and 
Concomitant Medication CRF and updated on a continual basis if there are any new 
changes to the medication. Medications include prescription medications, over-the-counter 
medications, vitamins, and herbal and alternative therapy.

Transfusions of blood products administered within 14 days prior to first dose must be 
recorded on the Prior Blood Transfusion CRF.
In addition, the following assessments must be performed and recorded for all randomized 
patients on the appropriate CRFs:

Complete physical examination (including brief neurological exam, see Section 7.2.2.1 for 
details, results will not be recorded on CRF, but as appropriate on medical history or 
adverse event CRF page)

Eastern Cooperative Oncology Group (ECOG) performance status

Height, Weight, BSA (although the Gehan and George equation is recommended (see 
Section 6.1.1), the BSA can be calculated as per standard practice at the site. However, the 
same formula/method should be consistently used for the BSA calculation for a patient 
throughout the study)

Vital signs (sitting blood pressure, sitting pulse, respiratory rate and body temperature)


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
Serum pregnancy test performed in WOCBP (within 7 days of first planned dose)

Cardiac imaging (MUGA/ECHO) 

Central 12-Lead ECG 

Local laboratory evaluations (hematology, chemistry, electrolytes, thyroid, coagulation, 
troponin I, creatinine clearance calculated based on serum creatinine based on Cockroft-
Gault formula) 

Disease assessments

Central laboratory evaluations: 

In serum: M- protein by PEP and IF, 

Local laboratory evaluations:

In serum: FLC protein assessment

In urine: M-protein by PEP and IF

Local plasma cell count in bone marrow 

Bone marrow aspirate for diagnostic sample for MRD assessment by ClonoSEQTM
assay 

Clinical assessment of soft tissue plasmacytomas (STP)

Assessment of STP by CT/MRI 

Full body skeletal survey by X-ray (and/or CT/MRI) 
7.1.2
Treatment period
After randomization using the IRT, approximately 112 patients will receive study treatment in 
21-day cycles during the induction phase and in 84-day cycles in the maintenance phase until 
disease progression, unacceptable toxicity, death, or discontinuation from the study treatment 
due to any other reason (see Section 7.1.5), as described below.
•
Induction Phase (Cycles 1 to 5): Newly diagnosed multiple myeloma patients randomized 
to the first arm will receive bortezomib (BTZ) twice a week, dexamethasone (Dex) four 
times a week, revlimid (REV) seven days a week, and panobinostat (PAN) three times a 
week, two weeks on, one week off, on a 21-day cycle.  Patients randomized to the second 
arm will receive bortezomib (BTZ) twice a week, dexamethasone (Dex) four times a 
week, and revlimid (REV) seven days a week two weeks on, one week off, on a 21-day 
cycle. 
•
Maintenance Phase (Cycles 6+): Patients randomized to the first arm will receive 
revlimid (REV) seven days a week continuously and panobinostat (PAN) three days a 
week, every other week on an 84-day cycle. Patients randomized to the second arm will 
receive revlimid (REV) seven days a week continuously on an 84-day cycle.
See Table 7-1 for details of assessments during the treatment period. The general visit 
window during induction is +/- 3 days and during maintenance +/- 7 days, unless otherwise 
specified for specific assessments in Section 7.2.


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7.1.3
Discontinuation of Study Treatment
Patients may voluntarily discontinue from the study treatment for any reason at any time. If
a patient decides to discontinue from the study treatment, the investigator must make every 
effort (e.g. telephone, e-mail, letter) to determine the primary reason for this decision and 
record this information in the patient’s chart and on the appropriate CRF pages. They may be 
considered withdrawn if they state an intention to withdraw, fail to return for visits, or become 
lost to follow-up for any other reason.
The investigator should discontinue study treatment for a given patient if, he/she believes that
continuation would be detrimental to the patient’s well-being.
Study treatment must be discontinued under the following circumstances:

Emergence of the following adverse events (including lab abnormalities, as applicable):

Adverse events that require discontinuation of study treatment as per Table 6-5, Table 
6-8 or Table 6-12.

Adverse events that require dose reductions beyond the permitted dose reductions of 
PAN/REV/BTZ outlined in Table 6-3 and Table 6-6, respectively

Adverse events that lead to a PAN, REV and/or BTZ dose delay of more than 28 days 
from the intended day of the next scheduled dose, unless the patient was clearly
benefitting from study treatment and the cause of the delay has been resolved.

Pregnancy

Dose interruption of PAN, REV and/or BTZ of more than 28 days from the intended day
of the next scheduled dose for any reasons, unless the patient was clearly benefitting from 
study treatment and the cause of the delay has been resolved.

Start of new anti-neoplastic therapy

Documented disease progression (by investigator)

Death

For use of prohibited treatment refer to Section 6.4.3 and Section 14.1.

Any other protocol deviation that results in a significant risk to the patient’s safety
Patients who discontinue study treatment should undergo an end of treatment visit within 7 
days of last dose (whichever, study drug (PAN/BTZ/Dex/REV) was given last) and enter the 
30 day follow-up period (either post-treatment follow-up for efficacy (see Section 7.1.6) or 
survival follow-up (see Section 7.1.7) based on the reason for discontinuation). For 
assessments performed at the end of treatment visit please refer to Table 7-1. 
If the decision to discontinue study treatment is made on the day of a regular visit, this visit 
may become the EOT visit rather than having the patient return for an additional visit. 
The reason for discontinuation of study treatment should be recorded on the End of Treatment 
Disposition CRF page.
The investigator must also contact the IRT to register the patient’s discontinuation from 
study treatment.


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7.1.4
Replacement policy 
Patients who do not proceed directly to ASCT after induction phase will be replaced. It is 
expected that approximately 15% of patients will need to be replaced.  
7.1.5
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.
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 must make every effort (e.g. telephone, e-mail, 
letter) 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.
7.1.6
Follow up for Safety Evaluations
All patients must have safety evaluations for 30 days after the last dose of study treatment.
Data collected should be added to the Adverse Events CRF and the Concomitant Medications 
CRF.
7.1.7
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
Serum and urine sample collection for central and local M-protein 
assessment by PEP, and IF 
Blood (serum) and 24-h urine for M-protein assessment will be collected at screening, cycle 1 
day 1 and the start of every cycle thereafter. An additional assessment of serum and urine for 
PEP and IF will be done on cycle 4 day 21 prior to stem cell collection. Serum samples will 
be sent to a central lab for analysis. Samples will be processed and shipped as per instructions 


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in the respective laboratory manual. Urine samples will be evaluated locally. During the 
course of autologous transplant, no labs will be collected. 
7.2.1.2
Serum sample collection for local FLC assessment
Blood (serum) for FLC assessment will be collected at screening and at the start of each cycle
during induction,on cycle 4 day 21 prior to stem cell collection, every 28 days during cycle 6 
and at the start of every cycle thereafter. FLC will be analyzed locally. During the course of 
autologous transplant, no labs will be collected. 
7.2.1.3
Cytogenetics in bone marrow by local assessment
A bone marrow aspirate/biopsy for cytogenetics (by FISH) should be performed during the 21 
day screening period. Assessment of cytogenetics by FISH will be evaluated locally. 
7.2.1.4
Plasma cell count in bone marrow by central assessment
A bone marrow aspirate/biopsy for plasma cell quantification should be performed at 
screening, cycle 4 day 21, cycle 6 day 1 (prior to the start of maintenance), and EOT. 
Additional Bone marrow aspirates/biopsies should be performed throughout the trial, at any 
point after cycle 4 day 21, to confirm a Complete Response. Assessment of PCC will be 
evaluated locally. 
Either BM aspirate or biopsy can be used for plasma cell quantification. However, the same 
method should be used throughout the trial, if possible. In case both, BM aspirate and BM 
biopsy were performed, the diagnostic/response criteria need to be satisfied by both 
assessments and the highest of both percent values should be used.
7.2.1.5
Minimal Residual disease assessments in bone marrow (MRD)
Additional assessment for depth of response will evaluate for the presence of  molecular CR 
(mCR) and will be performed and analyzed using the commercially available ClonoSEQ 
assay (Adaptive Biotechnologies) (Faham et al 2014). A bone marrow aspirate should be 
performed during the screening period and sent for central analysis using the kits provided. A 
repeat aspirate sample should be sent for analysis if a patient achieves CR. When performing 
the aspirate for PCC to confirm CR, ensure that you have an additional aspirate in the 10cc 
EDTA tube for central MRD analysis
For additional response categories in MM according to IMWG criteria see Table 14-6 of
Section 14.1.5.1. 
7.2.1.6
Assessment of soft tissue plasmacytoma
7.2.1.6.1 Imaging assessment by CT/MRI/PET 
Baseline imaging assessment: A CT/MRI/PET to assess presence of soft tissue plasmacytoma 
will be performed at screening within 21 days of start of study treatment (Day -21 to Day -1 
prior to Cycle 1 Day 1).
Any imaging assessments already completed during the regular work-up of the patient within 
21 days prior to start of treatment, including before signing the main study ICF, can be 


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considered as the baseline images for this study. Any imaging assessments obtained after 
randomization cannot be considered baseline images. 
Post-baseline imaging assessments:
Repeat imaging should be done as clinically indicated or to confirm CR, sCR, and PD for all 
patients. Imaging assessments should be performed using the same imaging modality used at 
baseline, irrespective of study treatment interruption or actual dosing (see Table 7-1). 
7.2.1.7
Full body skeletal survey
Any X-ray and/or CT/MRI already completed during the regular work-up of the patient within 
21 days prior to start of treatment, including before signing the main study ICF, can be 
considered as the baseline X-ray and/or CT/MRI images for this study. Any X-ray and/or 
CT/MRI imaging assessments obtained after randomization cannot be considered baseline 
images.
Post-baseline, a full body skeletal survey will only be completed as clinically indicated, e.g. to 
document a response of PR or better, or to evaluate disease progression.
7.2.1.8
Response assessment by Investigator
The response assessment by Investigator should be based on all available data (including 
central data) as per IMWG guidelines (see Table 14-5 and Table 14-6). Response assessments 
by investigator will be done once per cycle beginning with cycle 2.
7.2.2
Safety and tolerability assessments
Safety will be monitored by assessing physical examinations, ECOG performance status, 
height and weight, vital signs, ECG, laboratory assessments including hematology, chemistry, 
electrolytes, thyroid function, coagulation, troponin I, and calculated creatinine clearance, as 
well as collecting of the adverse events at every visit. For details on AE collection and 
reporting, refer to Section 8.
7.2.2.1
Physical examination
A complete physical examination at screening will include the examination of general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, 
back, lymph nodes, extremities, vascular and neurological. Physical examination is to be 
performed according to the visit schedule as outlined in Table 7-1. All subsequent physical 
exams should be abbreviated.
Significant findings that were present prior to the signing of informed consent must be 
included in the Medical History page on the patient’s CRF. Significant new findings that 
begin or worsen after informed consent must be recorded on the Adverse Event page of the 
patient’s CRF. 
7.2.2.2
Vital signs
Vital signs include blood pressure and pulse measurements, body temperature and respiratory 
rate will be monitored as per the visit schedule (see Table 7-1). After the patient has been 


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sitting for five minutes, with back supported and both feet placed on the floor, systolic and 
diastolic blood pressure and pulse will be measured. Body temperature may be measured 
orally or via ear.
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 as per visit schedule (see Table 7-1). Height 
will only be measured at the screening visit, whereas weight will be measured on Day 1 of 
every cycle and at the EOT visit. The weight measured on Day 1 of a cycle will be used by 
the study personnel to calculate the BSA of the patient for a specific cycle. Although the use 
of the Gehan and George equation (see Section 6.1.1) is recommended, the BSA can be 
calculated as per standard practice at the site. However, the same formula/method should be 
used consistently throughout the study. The BSA calculated at the beginning of every cycle 
will be used to calculate the total BTZ s.c. dose/day to be administered during a specific 
cycle.
7.2.2.4
Performance status
The performance status for a patient will be assessed according to the ECOG performance 
status scale (Section 14.2) following the visit evaluation schedule given in Table 7-1.
7.2.2.5
Laboratory evaluations
All lab parameters outlined in Table 7-3, will be evaluated locally as per the visit evaluation 
schedule (see also Table 7-1). Novartis must be provided with a copy of the lab certification 
and tabulation of the normal ranges for all lab parameters of all local labs used. 
The local lab results will be entered on the respective Local Laboratory CRF pages.
During the study treatment, all lab results should be available prior to administration of 
PAN/BTZ/REV, in order for the investigator to implement dose modifications based on the 
lab results as necessary (e.g. interrupt dosing, see Section 6.3, and Table 6-2, Table 6-4, Table 
6-5, and Table 6-8 for details).
Abnormal laboratory values or test results constitute an AE only, if they induce clinical signs 
or symptoms, and are considered clinically significant (i.e. require dose modification and/or 
interruption of study treatment, lead to clinical symptoms, cause study treatment 
discontinuation or constitute in and of itself an SAE) or require therapy. These events should 
be recorded on the AE CRF as well as the appropriate laboratory CRF and/or comments CRF 
page. If the administration of study treatment is delayed/modified due to unacceptable lab 
toxicities (see Section 6.3), re-evaluation should at a minimum be performed prior to the next 
scheduled study treatment.
Additional labs parameters should be evaluated as clinically indicated. These results will be 
recorded on the Unscheduled Visit CRF.
7.2.2.5.1 Hematology
Hematology tests are performed as indicated in Table 7-3. 


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7.2.2.5.2 Chemistry
Clinical chemistry tests are performed as indicated in Table 7-3. 
7.2.2.5.3 Electrolytes
Electrolytes are performed as indicated in Table 7-3. 
7.2.2.5.4 Thyroid
Thyroid function tests are performed as indicated in Table 7-3.
7.2.2.5.5 Coagulation
The coagulation tests are performed at screening as indicated in (Table 7-3). The coagulation 
profile should be repeated as clinically indicated and the results should be recorded on the 
Unscheduled Visit CRF. If the patient is receiving Coumadin or other anti-coagulant therapy 
then the coagulation parameters should be monitored more frequently at the discretion of the 
investigator (please also see Section 6.3.2.1).
7.2.2.5.6 Troponin I
Troponin should be evaluated as indicated in Table 7-3.
7.2.2.5.7 Creatinine Clearance
The creatinine clearance is calculated as indicated in Table 7-3 using the Cockroft-Gault 
formula.
7.2.2.5.8 Pregnancy and assessments of fertility
Since highly effective contraception is required pregnancy testing should be done as indicated 
in Table 7-2. In case of a positive test, the investigator must contact Novartis to discuss 
options for the patient. 
Post-menopausal women must have been amenorrheic for ≥ 12 months in order to be 
considered ‘of no-childbearing potential’.
Table 7-2
Local clinical laboratory parameters collection plan
Hematology 
Complete blood cell count (RBC and WBC) with absolute differential (neutrophils, 
basophils, eosinophils, lymphocytes, monocytes, blast cells, other), hemoglobin, 
platelet count
To be performed at:
Screening
Cycles 1-5: Days 1, 4, 8, 11 (Cycle 4 only: Day 21); Cycle 6: Days 1, 29 and 57; 
Day 1 of Cycles 7+ 
End of treatment 
Unscheduled: as clinically indicated


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Basic Metabolic Panel
ionized serum calcium (if total calcium is abnormal, collect ionized calcium), 
sodium, potassium, BUN/urea, creatinine, phosphorus, magnesium, glucose
To be performed at:
Screening
Cycles 2-5: Days 4 and 11
Unscheduled: as clinically indicated
Creatinine Clearance 
(CCL) calculated
CCL is calculated by the site using Cockroft Gault formula based on serum 
creatinine results in µmol/L (Cr), age, weight (Wt) in kg and sex of patient.
Cockcroft-Gault CCL = (140-age) * (Wt in kg) * (0.85 if female) / (72 * Cr)
On days where weight is not determined as per protocol the last determined weight 
closest to the visit date can be used (e.g. weight determined on Day 1 of the same 
cycle).
To be calculated at:
Screening
Cycle 1: Days 1, 4, 8, 11; Cycles 2-5: Day 1 & 8 (Cycle 4 only: Day 21); Cycle 6 
Days 1, 29 and 57; Cycles 7+ Day 1;
End of treatment 
Unscheduled: as clinically indicated
Complete Metabolic Panel
Basic Metabolic Panel plus:
Serum albumin, total protein, total bilirubin, direct and indirect bilirubin (only if 
total bilirubin is abnormal) AST/SGOT, ALT/SGPT, Beta 2 microglobulin, LDH.
Biochemistry tests should be performed after the patient has fasted, if possible.
To be performed at:
Screening
Cycle 1: Days 1, 4, 8, 11; Cycles 2-5: Day 1 & 8 (Cycle 4 only: Day 21); Cycle 6 
Days 1, 29 and 57; Cycles 7+ Day 1
Unscheduled: as clinically indicated
End of treatment 
Unscheduled: as clinically indicated
Thyroid
Thyroid Stimulating Hormone (TSH) and free T4 (thyroxine).
To be performed at:
Screening
End of treatment 
Coagulation
Prothrombin time (PT) or International normalized ratio [INR]), activated partial 
thromboplastin time (APTT) and fibrinogen; 
To be performed at:
Screening
Unscheduled: as clinically indicated
Other lab test
Troponin 1
Troponin 1 
To be performed at:
Screening
Pregnancy Test
for all women (female 
patients) of childbearing 
potential
(WOCP)
Pregnancy test in serum:
Screening (within 7 days prior to the first planned dose of study treatment)
End of treatment
Pregnancy test in urine:
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7.2.2.6
Cardiac assessments 
7.2.2.6.1 Electrocardiogram (ECG)
Standard 12-lead ECGs will be performed according to Table 7-3. On days when ECGs are to 
be performed, the patient should take their study medication at this site, after the pre-dose 
ECGs have been performed. 
The pre-dose ECGs should be performed prior to the planned dose of PAN and BTZ. The 2h 
post-dose ECGs should be performed around the 2h post-dose time point. Triplicate ECGs 
should be used in the event that QTcF prolongation > 480 msec is observed. Triplicate ECGs 
should be continued until average QTcF is < 480 msec for 3 consecutive cycles.
Information on the performance of the ECG will be documented on the ECG CRF page, or on 
the Unscheduled Visit CRF page, as applicable. 
Review of all ECGs at site:
Treatment decisions should be based on the real-time assessment of QTcF values at the site, 
as determined by the automated machine reading or as measured and calculated by trained 
personnel at the site. All cardiac events should be treated as per the local standard of care and 
referred to a specialist, if clinically indicated (see Section 6.3.1 for required dose 
modifications for prolonged QTcF). Any final decisions concerning dose modifications or 
permanently discontinuing the patient from study drug due to QTcF prolongation will be 
made after discussion between the Investigator and Sponsor as needed.
It is advisable to perform the screening at least 3 days prior to planned first dose.
Table 7-3
ECG collection plan
Cycle
Day of cycle
ECG monitoring
Screening
n/a
12 Lead ECG to assess eligibility a
Cycle 1
1 and 4
Pre-dose and 2h post PAN dose:
12 lead ECG b
Cycle 2 to Cycle 5
1
Pre-dose:
12 lead ECG
Cycles 6+
As clinically indicated
Pre-dose: 
12 lead ECG
End of Treatment 
n/a
12-Lead ECG 
a Triplicate ECGs should be used in the event that QTcF prolongation > 480 msec is observed. Triplicate ECGs 
should be continued until average QTcF is < 480 msec for 3 consecutive cycles.
b Refer to Table 6-12 for the recommended dose modifications due to QTcF prolongation
7.2.2.6.2 Cardiac imaging - MUGA (multiple gated acquisition) scan or 
echocardiogram
A MUGA scan or ECHO to assess left ventricular ejection fraction (LVEF) will be performed 
within the screening period prior to the first administration of study treatment. Additional, 
unscheduled assessments may be performed at the Investigator’s discretion if there are signs 
or symptoms of cardiotoxicity and will be recorded on the Unscheduled Visit CRF page.


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The LVEF result and a general comment on the interpretation of the assessment will be 
recorded on the Cardiac Imaging CRF page.
7.2.3
Resource utilization
Not applicable.
8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An adverse event is defined as the appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s), or medical condition(s) that occur after patient’s signed 
informed consent has been obtained.
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s).
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s CRF. Adverse event monitoring should 
be continued for at least 30 days (or 5 half-lives, whichever is longer) following the last dose 
of study treatment. Adverse events (including lab abnormalities that constitute AEs) should be 
described using a diagnosis whenever possible, rather than individual underlying signs and 
symptoms. When a clear diagnosis cannot be identified, each sign or symptom should be 
reported as a separate Adverse Event.
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03.
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, corresponding to Grades 1 - 4, will be used. CTCAE Grade 5 (death) will 
not be used in this study; rather, information about deaths will be collected though the Study 
Evaluation Completion page.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be 
evaluated to determine:

The severity grade (CTCAE Grade 1-4)

Its duration (Start and end dates) (add or Ongoing at End of Study for NOVDD)

Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes)
or


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Its relationship to the study treatment (Reasonable possibility that AE is related: No,
Yes, investigational treatment, Yes, the study treatment (non-investigational), Yes, both 
and/or indistinguishable)

Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)

Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)

Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown) Delete for NOVDD Trials as outcome 
is not collected

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 CRF.
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome.
8.1.1.1
Adverse Events related to ASCT
Adverse events that occur while the patient is off treatment for transplant and are considered 
to be solely attributable to the transplant will be captured on a separate Adverse Event page.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or 
require changes in study treatment), should be recorded on the Adverse Events CRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g. anemia 
instead of low hemoglobin). Laboratory abnormalities that meet the criteria for Adverse 
Events should be followed until they have returned to normal or an adequate explanation of 
the abnormality is found. When an abnormal laboratory or test result corresponds to a 
sign/symptom of an already reported adverse event, it is not necessary to separately record the 
lab/test result as an additional event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or 
as per 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.


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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 (for the purposes of this study, inpatient hospitalization for 
stem cell collection or autologous transplant will not be considered a serious adverse 
event)

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event
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 in English, and submit the completed form within 24 hours to Novartis. Detailed 
instructions regarding the submission process and requirements for signatures will be
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Follow-up information is submitted in the same way as the original SAE Report.. Each re-
occurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the patient continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the 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
Emergency unblinding of treatment assignment
Not applicable.
8.4
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to 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 
of the possible relationship to the study treatment to 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.
8.5
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.
8.6
Data Monitoring Committee 
Not applicable.


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8.7
Steering Committee 
The steering committee will be established comprising investigators participating in the trial, 
i.e. not being Novartis representatives from the Clinical Trial Team.
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also 
develop recommendations for publications of study results including authorship rules. The 
details of the role of the Steering Committee will be defined in a Steering Committee charter.
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.
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 


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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
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (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.
Central lab data, including MRD assessment and M-protein assessments, will be transferred 
periodically throughout this study.  Data will be transferred via WDCS and will be reconciled 
with the clinical database.
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 system. Medical history/current medical conditions and adverse events will be 
coded using the Medical dictionary for regulatory activities (MedDRA) terminology.
Samples and/or data will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Randomization codes and data about all study treatments dispensed to the patient and all IRT 
assigned dosage changes will be tracked using an Interactive Response Technology. The 
system will be supplied by a vendor(s), who will also manage the database. The data will be
sent electronically to Novartis personnel (or designated CRO).
At the conclusion of the study, unused drug supplies will be returned to Novartis personnel (or 
designated CRO). The occurrence of any protocol violations will be determined. After these 
actions have been completed and the data has been verified to be complete and accurate, the 
database will be declared locked and made available for data analysis. Authorization is 


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required prior to making any database changes to locked data, by joint written agreement 
between the Statistician and Medical Director.
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 data will be analyzed by a designated CRO. It is planned that the data from all centers
that participate in this study will be used, so that an adequate number of patients will be 
available for analysis.
Data cut-off date for the clinical study report will be when the last patient completes 4 cycles 
of induction and has corresponding efficacy assessments, or discontinues study treatment. The 
analysis performed for the CSR as described above will be considered primary. The CSR will 
be updated with additional efficacy and safety data from patients continuing in the study 
including the three year follow-up for survival.
Unless, otherwise specified all statistical tests will be performed at a two-sided significance 
level of 0.05.
10.1
Analysis sets
Type here
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been 
assigned by randomization. According to the intent to treat principle, patients will be analyzed 
according to the treatment (and strata, if applicable) they have been assigned to during the 
randomization procedure.
10.1.2
Safety Set
The Safety Set includes all patients who received at least one dose of study medication. 
Patients will be analyzed according to the study treatment (regimen) they actually received.
A precise definition of “actually received” will be added in the RAP.
10.1.3
Per-Protocol Set
The Per-Protocol Set (PPS) consists of all patients from the FAS population who received at 
least one dose of the study drug and had no major protocol deviation. Protocol deviations 
leading to exclusion from the PP population will be justified and specified in the study 
Validation and Planning (VAP) and Report and Analysis Plan (RAP) documents prior to the 
data base lock.
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data, including disease characteristics, will be summarized 
descriptively by treatment group and for all patients for the FAS.


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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.
10.3
Treatments (study treatment, concomitant therapies, 
compliance)
10.3.1
Study treatment
Data on the study treatment administration will be summarized all study drugs (panobinostat, 
lenalidomide, bortezomib and dexamethasnae). The duration of treatment and relative dose 
intensity of each of the components of study treatment will be summarized using descriptive 
statistics. Dose adjustments and interruptions for panobinostat and bortezomib will also be 
summarized.
10.3.2
Concomitant medications
Concomitant medications and significant non-drug therapies will be summarized.
10.4
Primary objective
The primary objective for this trial is to evaluate the efficacy of the combination of RVD + 
panobinostat compared to RVD alone.
10.4.1
Variable
The primary endpoint will be analyzed based on nCR/CR rate of the combination of 
panobinostat with bortezomib, lenalidomide and dexamethasone (P-RVD) vs RVD in newly 
diagnosed multiple myeloma patients after 4 cycles of therapy. The analysis will be based on 
Investigator assessment of response.
10.4.2
Statistical hypothesis, model, and method of analysis
The study is designed to test the following statistical hypothesis:
H0: nCR/CR rate (RVD combination) - nCR/CR rate (PVD alone=0% versus 
H1: nCR/CR rate (RVD combination) - nCR/CR rate (PVD alone=0% versus >= 18%
This test will be performed using a Z-test at one-sided siginificance level of 0.05. 
In addition, point estimate and exact 95% two-sdied confidence interval of of nCR/CR rate in 
ecah arm and of the difference in rates in the two will be calculated. 
The confirmative analysis based on the FAS set will take place after all evaluable patients 
complete the first four cycles of induction for the primary endpoint. Sensitivity analysis will
be performed in the Per-Protocol set.


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10.4.3
Handling of missing values/censoring/discontinuations
Missing data will not be imputed in any manner, except for overall response rate. A patient
who discontinues for any reason before the data cut-off date of the CSR without a confirmed
assessment of response will be considered a non-responder.
10.4.4
Supportive analyses
Sensitivity analysis of the primary endpoint adjusting for adverse cytogenetic risk and ISS 
disease stage at baseline will be performed in FAS and the Per-Protocol set.
Details of the sensitivity analysis will be included in the Statistical Analysis Plan before the 
data base lock.
10.5
Secondary objectives
10.5.1
Key secondary objective(s)
The key secondary objective of this study is to assess MRD negativity after 4 cycles of 
induction by next gen sequencing. Data for this analysis will be provided by a central 
laboratory. The corresponding endpoint will be MRD negativity by next gen sequencing after 
4 cycles of induction therapy. 
10.5.2
Other secondary efficacy objectives
There are a number of additional secondary efficacy objectives:

To assess best overall response rate (ORR) and MRD negativity after ASCT and 
maintenance. This endpoint will be analyzed by ORR (CR + PR) by Investigator 
assessment and MRD negativity by next gen sequencing (data provided by a central 
laboratory) after ASCT and maintenance.

To assess depth of response by IMWG criteria. This will be measured by the rate of 
VGPR, CR and sCR by Investigator assessment.

To assess the duration of response. This will be analyzed by determining the duration of 
response based on Investigator assessment according to the clinical database.

To assess overall survival and progression free survival rates three years after study entry.
OS and PFS will be analyzed once the last patient to enter the study completes 3 years of 
therapy.. 
Progression-free survival (PFS) is defined as the time from the date of first study drug to the 
date of the first documented disease progression or confirmed relapse or death due to any 
cause. 
Overall survival (OS) is defined as the time from date of first study drug to date of death due 
to any cause. 
Progression-free survival and overall survival will be summarized by using Kaplan-Meier 
product-limit method and displayed as graphs. If applicable, estimates of the 25th percentile, 
median and 75th percentile and their respective 95% confidence intervals will be provided. 
All analyses will be based on the FAS population.


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The point estimate and 95% confidence interval of best overall response and MRD negativity 
rate and depth of response will be provided in the FAS set.
The duration of overall response (DOR) is defined as the time from the date of first
documented occurrence of confirmed response (CR or nCR or PR) to the date of the first
documented confirmed disease progression or confirmed relapse or death due to multiple
myeloma. Patients who do not have a confirmed response by the data cut-off date of the CSR
will be excluded from the analysis of DOR.
For CSR primary analysis of the time to events (DOR and PFS), a patient who didn’t have the 
event at the date the analysis data cut-off would be censored at the time of the cut-off or at the 
last adequate assessment in case of a discontinued patient. An adequate response assessment 
is considered any disease assessment indicating disease status apart from “unknown” or “not 
done”.
For OS, if a patient is not known to have died, survival will be censored at the date of the last 
contact.
All analyses of the secondary endpoints except OS and PFS will occur after all evaluable 
patients complete transplant and begin maintenance. 
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. All listings and tables will be presented by
treatment group. 
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 x days after last dose of 
study medication
3. post-treatment period: starting at day x+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 by treatment group.
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and 
tabulated by type of adverse event and treatment group.


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Specific safety event categories (SEC) may be considered. Such categories consist of one or 
more well-defined safety events which are similar in nature and for which there is a specific 
clinical interest in connection with the study treatment(s).
For each specified SEC, number and percentage of patients with at least one event part of the 
SEC will be reported.
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 bio-statistical 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.
In cases the lower limits of normal ranges used in CTCAE definition have to be replaced by a 
clinical meaningful limit expressed in absolute counts.
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)

classification to compare baseline to the worst on-treatment value.

listing of all laboratory data with values flagged to show the corresponding CTCAE 
grades and the classifications relative to the laboratory normal ranges.
 
 
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.
Vital signs
Definitions of notably abnormal results have to part of the CDP, MAP, CSP and 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.


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10.5.3.5 Supportive analyses for secondary objectives 
Not applicable.
10.5.3.6 Tolerability
Not applicable.


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10.7
Interim analysis
There will be two planned interim analyses for this trial. The first will take place after all 
evaluable patients complete the first four cycles of induction for the primary endpoint. At this 
time the confirmative analysis of the primary endpoint and descriptive summary of all other 
efficacy data will be performed. The second interim analysis will occur after all evaluable 
patients complete transplant and begin maintenance. At the second interim, analysis of all 
secondary efficacy endpoints except OS and PFS will take place. At each interim analysis, all 
safety data will be summarized.
No adjustment of the significance level for the tests (s) of the efficacy endpoints will be 
necessary as result of these interim analyses. 
10.8
Sample size calculation
The sample size of the study is based on the assumption that in the RVD alone arm the 
nCR/CR rate will be 7% and adding Pano to RVD will improve the nCR/CR rate to 25%. For 
one sided alpha=0.05, fifty patients in each arm will have 81% power to detect this 
improvement. To get 50 evaluable patients in each arm an additional 6 patients will be 
randomized in each arm for a total of 112 patients.
PASS 2008 was used to calculate the sample sizes.
10.9
Power for analysis of key secondary variables
The power analysis for the key secondary variable of molecular CR (mCR) is based on the 
assumption that the mCR rate at 4 cycles will be 4% with RVD alone and will increase to 
15% if panobinostat is added to RVD. For a one sided alpha=0.05, fifty patients in each arm 
will have 81% power to detect this improvement. 
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 


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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/IEC/REB-approved informed consent.
Informed consent must be obtained before conducting any study-specific procedures (i.e. all 
of the procedures described in the protocol). The process of obtaining informed consent 
should be documented in the patient source documents. The date when a subject’s Informed 
Consent was actually obtained will be captured in their CRFs.
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.
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 
Section 4.4.
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. 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.


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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 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.


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


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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
^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.


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This is not a comprehensive list of medications which may prolong the QT interval and/or 
induce Torsades de pointes. This list of medications was developed in collaboration with an 
external cardiology consultant, and represents those medications which are deemed to have an 
unacceptable risk of co-administration with panobinostat.
The following website may be referenced as a supplemental guide for drugs which have been 
associated with Torsades de pointes or prolonging the QT interval but at this point lack 
substantial evidence for causing Torsades de pointes: http://www.azcert.org/medical-
pros/drug-lists/drug-lists.cfm.
Medications listed on the website which do not appear in Table 14-1 above may be used with 
caution at the discretion of the investigators.
Ondansetron (a known CYP2D6 substrate, Table 14-3 has been associated with Torsades de 
pointes and QT prolongation but has not been shown to cause Torsades de pointes. Therefore, 
ondansetron is not per se prohibited to be combined with panobinostat but caution is to be 
exercised and close monitoring for signs and symptoms of QT prolongation is recommended.
14.1.2
Dose reduce panobinostat when combined with medications which 
are known strong CYP3A inhibitors
Panobinostat is a substrate of CYP3A4/5 with minor involvement of CYP2D6, and CYP2C19 
in in vitro evaluation of its metabolism. Thus, a clinical drug-drug interaction study was 
conducted using ketoconazole, a strong CYP3A inhibitor, in combination with panobinostat in 
study [CLBH589B2110].
Multiple ketoconazole doses at 400 mg increased Cmax and AUC of panobinostat by 1.6- and 
1.7-fold, respectively, but with no change in Tmax or half-lives in 14 cancers patients. The 
less than 2-fold increase in panobinostat AUC upon co-administration of a strong CYP3A 
inhibitor is considered a weak drug inhibition. However, panobinostat dose should be reduced 
from 20 mg to 10 mg when combined with medications which are known strong CYP3A 
inhibitors. If patients are already at reduced doses of panobinostat 15 mg or 10 mg, 
combination with a strong CYP3A inhibitors should be avoided. If this is not avoidable, 
patients should be monitored closely for toxicity.


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Table 14-2
Medications which are known strong CYP3A inhibitors
Antibiotics
telithromycin
troleandomycin
Protease inhibitors
Indinavir
lopinavir
nelfinavir
ritonavir
saquinavir
tipranavir
Antifungals
itraconazole
ketoconazole
posaconazole
voriconazole
Antivirals
boceprevir
telaprevir
Others
cobicistat
conivaptan
elvitegravir
mibefradil
nefazodone
Miscellaneous drugs or products
Star fruit and pomegranate product and juice
* 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 panobinostat. This drug is thus not listed 
again in Table 14-3.
This is not a comprehensive list of medications which may inhibit CYP3A4/5. The above list 
was compiled by using information listed under “draft guidance for industry, drug interaction 
studies, CDER 2006”, Indiana University School of Medicine drug interaction tables at 
http//medicine.iupui.edu/clinpharm/DDIs/ClinicalTable.asp and “drug interaction database” 
from University of Washington.
Additional updated versions with moderate and weak CYP3A inhibitors, which are meant to 
be 
used 
as 
a 
guide, 
may 
be 
found 
at 
the 
following 
website: 
http://medicine.iupui.edu/clinpharm/DDIs/ClinicalTable.asp.


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


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


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Figure 14-1
International Staging System
14.1.5.1 Response assessment per IMWG criteria
Response assessment according to IMWG criteria is described in Table 14-5 and Table 14-6. 
For assessing response, criteria for PD should be assessed first. When PD can be ruled out, 
criteria for positive response should be checked.
For patients with non-measurable disease at baseline or missing baseline assessments of M-
protein in urine and serum and FLC, only PD criteria will be checked. In case PD is not met, 
“unknown” should be assigned.
The response categories sCR, CR, VGPR, PR and PD need to be confirmed. The criteria are 
defined in Section 14.1.5.1.1 and Section 14.1.5.1.2.
For patients with measurable disease at baseline by one component only (serum M-protein or 
urine M-protein), the measurable component will be used to derive MR or PR. However, 
VGPR and CR categories require serum and urine studies regardless of whether disease at 
baseline was measurable on serum, urine, both, or neither. Irrespective of the measurability 
(M-protein measurable by PEP in serum, urine, or both), M-protein should be investigated 
regularly in both serum and urine and needs to be considered for response assessment.
Assessments to determine PD are dependent on change from nadir.


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Table 14-5
Response classification in MM according to IMWG criteria
Response category
Definition*
Stringent complete 
response (sCR)

CR criteria as defined below AND

normal FLC ratio AND

Absence of clonal PCs in bone marrow analyzed by immunohistochemistry or 2- to 
4-color flow cytometry#.
Complete response 
(CR)

Negative immunofixation of serum and urine AND

In case of presence of soft tissue plasmacytoma(s) at baseline, disappearance of 
any soft tissue plasmacytoma(s), AND

< 5% plasma cells in bone marrow.

In case the only measurable disease at baseline is the serum FLC assessment, a 
normal FLC ratio of 0.26 to 1.65 is required additionally to qualify for CR.
Very good partial 
response (VGPR)

Serum and/or urine M-protein detectable by immunofixation but not on PEP OR 
((≥ 90% reduction from baseline in serum) AND (urine M-protein < 100 mg/24h))
AND

In case of presence of soft tissue plasmacytoma(s) at baseline, a reduction in the 
SDP by ≥ 50% from baseline is required
In case the only measurable disease in a patient at baseline is the serum FLC level 
(i.e. no measurable disease in serum and urine PEP), a decrease of > 90% in the 
difference between involved and uninvolved FLC levels from baseline is required.
Partial response (PR)

(≥ 50% reduction from baseline in serum M-protein) AND
(≥ 90% reduction from baseline in 24h urine M-protein OR urine M-protein < 
200 mg/24h)
If the serum and urine M-protein are not measurable at baseline a ≥ 50% 
reduction from baseline in the difference between involved and uninvolved FLC 
levels is required in place of the M-protein criteria.
If serum and urine M-protein are not measurable, and serum FLC assay is also 
not measurable, ≥ 50% reduction from baseline in percent plasma cells in bone 
marrow is required instead of M-protein measurement, provided baseline 
percentage in plasma cells in bone marrow was ≥ 30%.
AND

In case of presence of soft tissue plasmacytoma(s) at baseline, a reduction in the 
SPD by ≥ 50% from baseline is required.
Stable disease (SD)

Not meeting the criteria for mCR, sCR, CR, VGPR, PR, PD


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


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Table 14-6
Additional response categories in MM according to IMWG criteria
Response 
category
Definition*
Molecular 
complete response 
(mCR)

All criteria of a CR
AND

negative by ASO-PCR (minimal sensitivity 10-5) or equivalent methods such 
as BCR sequencing
Immunophenotypic 
CR (iCR)

All criteria of sCR
AND

Absence of phenotypically aberrant PCs (clonal) in BM with a minimum of 1 
million total BM cells analyzed by multiparametric flow cytometry (>4 colors)
Minimal response 
(MR)

(Reduction from baseline in serum M-protein by ≥25%) and
(reduction from baseline in 24h urine M-protein by ≥50%)
AND

In case of soft tissue plasmacytomas at baseline, a reduction in the size of 
≥25% is required
AND

No increase in size or number of lytic bone lesions (development of 
compression fracture does not exclude response)
Minimal response should only be assessed in patients with relapsed or 
refractory myeloma.
For VGPR, PR and MR: In case disease is measurable in serum or urine only, criteria for 
serum and urine M-protein are to be checked for the measurable samples only (i.e. serum or 
urine).
14.1.5.1.1
Confirmation of response
According to IMWG criteria, confirmation of response is required for all response categories 
other than SD. The intention of this confirmation is to rule out laboratory or other errors 
(Durie et al 2006). For response confirmation, a consecutive assessment at any time is 
sufficient; no time window is specified by IMWG. Therefore, confirmation assessment can be 
performed on the same day of the initial assessment. It is recommended to do the confirmation 
assessment as soon as possible. This confirmation should be obtained in all instances by M-
protein assessments (tests may include part or all of tests PEP/sFLC depending on 
measurability and response level). Details need to be specified in the study protocol.
Response assessments should be captured in the CRF per time point without considering 
confirmation. This applies to response assessments by investigator as well as by IRC.
For confirmation of response, the following rules apply which will be implemented for 
statistical analyses:

It is not required to repeat assessments on bone marrow. However, at least one bone 
marrow assessment is required to qualify for CR or better (sCR, iCR or mCR). 

In case imaging studies were done, it is necessary that they exclude evidence of PD with
regard to new lytic bone lesions for mCR, iCR, sCR, CR, VGPR, PR, MR and SD. 


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Imaging is indicated in case of clinical suspicion of new or worsened lytic bone lesions 
e.g. bone pain.

In case the confirmation assessment revealed a better category compared to the previous 
assessment (e.g. VGPR after PR), the response category of the previous assessment will 
be considered as confirmed (PR).

In case the confirmation assessment revealed a worse category compared to the previous 
assessment (e.g. VGPR after CR), the response category of the subsequent assessment will 
be considered as confirmed (VGPR).

In case of repeated measurements of a variable at a given response assessment resulting in 
more values than required for an assessment and confirmation, the worst assessment has to 
be considered for response assessment by applying the rules given above.
14.1.5.1.2
Confirmation of PD
Declaration of PD requires confirmation in case the PD was determined based on M-protein 
measurement. There is no minimum time interval but confirmation of increase in M-protein or 
FLC should be done as soon as possible.
PD has to be assessed and entered in the CRF per time point without considering 
confirmation. Confirmed PD will be determined by statistical analyses.
This applies to PD assessments by investigator as well as by IRC.


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14.2
Appendix 2: ECOG performance status scale
This scale is used by doctors and researchers to assess how a patient's disease is progressing, 
assess how the disease affects the daily living abilities of the patient, and determine 
appropriate treatment and prognosis.
Table 14-7
ECOG performance status scale
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., 
Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982.
Credit to: the Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair.
Post-Authorization Safety Study (PASS)
Is this a PASS study - If yes, follow instructions below
Yes
No

SAP_001.pdf: 
Clinical Development 
LBH589 / Panobinostat / Farydak®
CLBH589DUS106 / NCT02720510
A Randomized, Phase II trial evaluating the efficacy and 
safety of lenalidomide, bortezomib and dexamethasone 
(RVD) with or without panobinostat in transplant eligible, 
newly diagnosed Multiple Myeloma 
Statistical Analysis Plan (SAP) – Short Closeout CSR deliverables 
Author: 
Document type: 
SAP Documentation 
Document status: 
Final 
Release date: 
09-Feb-2017
Number of pages: 
21 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Document History – Changes compared to previous final version of SAP 
 
 
Date 
Time 
Reason for 
Outcome for update 
Section and title 
point 
update 
impacted 
(Current) 
09- 
Feb- 
2017 
Prior 
to 
DB 
lock 
Creation of 
final 
version 
N/A - First version 
NA 
 
 
 
 
 
 


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Table of contents 
Table of contents .................................................................................................................. 3 
List of abbreviations ............................................................................................................ 5 
1 
Introduction .......................................................................................................................... 7 
1.1 
Study design ............................................................................................................. 7 
Figure 1-1 Study Design ............................................................................................................. 8 
1.1.1 
Timing of interim analyses and design adaptations ................................. 8 
1.1.2 
Definition of end of the study ................................................................. 9 
1.1.3 
Early study termination ........................................................................... 9 
1.2 
Study objectives and endpoints ................................................................................ 9 
2 
Statistical methods ............................................................................................................. 10 
2.1 
Data analysis general information ......................................................................... 10 
2.1.1 
General definitions ................................................................................ 10 
2.2 
Analysis sets .......................................................................................................... 12 
2.2.1 
Subgroup of interest .............................................................................. 12 
3 
General Strategies for Data Presentation ........................................................................... 12 
3.1 
Patient disposition, demographics and other baseline characteristics .................... 12 
3.1.1 
Patient disposition ................................................................................. 12 
3.1.2 
Demographic and baseline characteristics variables ............................. 13 
3.2 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 14 
3.2.1 
Study treatment / compliance ................................................................ 14 
3.3 
Efficacy Evaluations .............................................................................................. 15 
3.3.1 
Disease assessment ................................................................................ 15 
3.4 
Analysis of the primary objective .......................................................................... 15 
3.4.1 
Primary endpoint ................................................................................... 16 
3.4.2 
Statistical hypothesis, model, and method of analysis .......................... 16 
3.4.3 
Handling of missing values/censoring/discontinuations ....................... 16 
3.4.4 
Supportive analyses ............................................................................... 16 
3.5 
Analysis of the key secondary objective ................................................................ 16 
3.5.1 
Key secondary endpoint ........................................................................ 16 
3.5.2 
Statistical hypothesis, model, and method of analysis .......................... 16 
3.5.3 
Handling of missing values/censoring/discontinuations ....................... 16 
3.6 
Analysis of secondary efficacy objective(s) .......................................................... 16 
3.6.1 
Secondary endpoints ............................................................................. 17 
3.6.2 
Handling of missing values/censoring/discontinuations ....................... 17 


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3.7 
Safety analyses ....................................................................................................... 17 
3.7.1 
Adverse events (AEs) ............................................................................ 17 
3.7.2 
Deaths .................................................................................................... 18 
3.7.3 
Laboratory data ..................................................................................... 18 
3.7.4 
Other safety data .................................................................................... 19 
3.8 
Pharmacokinetic endpoints .................................................................................... 19 
3.9 
PD and PK/PD analyses ......................................................................................... 19 
3.10 
Patient-reported outcomes...................................................................................... 19 
 
 19 
 
 19 
 
 19 
3.13 
Interim analysis ...................................................................................................... 19 
4 
Sample size calculation ..................................................................................................... 19 
5 
Change to protocol specified analyses ............................................................................... 20 
6 
Appendix............................................................................................................................ 20 
6.1 
Imputation rules ..................................................................................................... 20 
6.1.1 
Study drug ............................................................................................. 20 
6.1.2 
AE date imputation................................................................................ 20 
6.2 
AEs coding/grading ............................................................................................... 21 
6.3 
Laboratory parameters derivations ........................................................................ 21 
6.4 
Statistical models ................................................................................................... 21 
6.5 
Rule of exclusion criteria of analysis sets .............................................................. 21 
7 
Reference ........................................................................................................................... 21 


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List of abbreviations 
AE 
ALT 
ASCT 
Adverse event 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
Autologus Stem Cell Transplant 
ATC 
Anatomical Therapeutic Classification 
Bid 
BSA 
BTZ 
CR 
CRF 
CRO 
CSP 
CSR 
CSR addendum 
bis in diem/twice a day 
Body Surface Area 
Bortezomib 
Complete Response 
Case Report/Record Form; the term CRF can be applied to either EDC or Paper 
Contract Research Organization 
Clinical Study Protocol 
Clinical Study report 
An addendum to Clinical Study Report (CSR) that captures all the additional 
information that is not included in the CSR 
CTC 
Common Toxicity Criteria 
CTCAE 
CxDx 
DAR 
Dex 
DI 
DLT 
DMC 
DRP 
EBMT 
EC 
ECG 
ECOG 
eCRF 
Common Terminology Criteria for Adverse Events 
Cycle x Day x 
Dose Administration Record 
Dexamethasone 
Dose Intensity 
Dose Limiting Toxicity 
Data Monitoring Committee 
Data Review Plan 
European Group for Blood and Bone Marrow Transplant 
Ethics Committee 
Electrocardiogram 
Eastern Cooperative Oncology Group 
Electronic Case Report Form 
FAS 
Full Analysis Set 
iCR 
IMWG 
IRB 
Immunophenotypic Complete Response 
International Myeloma Working Group 
Institutional Review Board 
IVR 
Interactive Voice Response 
IWR 
mCR 
MedDRA 
MM 
MR 
MRD 
No Change 
NCI 
nCR 
o.d. 
ORR 
Interactive Web Response 
Molecular Complete Response 
Medical Dictionary for Drug Regulatory Affairs 
Multiple Myeloma 
Minimal Response 
Minimal Residual Disease 
No Change 
National Cancer Institute 
Near Complete Response 
Once Daily 
Overall Response Rate 


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OS 
PAN 
p.o. 
PD 
PDI 
Overall Survival 
Panobinostat 
per os/by mouth/orally 
Progressive Disease 
Planned Dose Intensity 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
PPS 
PR 
PRO 
PS 
PT 
Per-Protocol Set 
Partial Response 
Patient-reported Outcomes 
Performance Status 
Preferred Term 
qd 
Qua’que di’e / once a day 
QoL 
Quality of Life 
RAP 
 
RDI 
REV 
RVD 
SAE 
SAS 
SAP 
sCR 
SD 
SEC 
SOC 
SS 
TBL 
TEAE 
TFLs 
VAP 
VGPR 
The Report and Analysis Plan (RAP) is a regulatory document which provides 
evidence of preplanned analyses 
Relative Dose Intensity 
Revlimid 
Revlimid, Velcade, Dexamethasone 
Serious Adverse Event 
Statistical Analysis System 
Statistical Analysis Plan 
Stringent Complete Response 
Stable Disease 
Special Event Category 
System Organ Class 
Safety Set 
Total Bilirubin 
Treatment Emergent Adverse Event 
Tables, Figures, Listings 
Validation and Analysis Plan 
Very Good Partial Response 
WHO 
World Health Organization 


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1 
Introduction 
This document contains details of the statistical methods which will be used in the phase II 
clinical trial of the clinical study protocol (CSP) CLBH589DUS106. This statistical analysis 
plan (SAP) module is prepared based on Original CSP, Case Report Form (CRF) version 324. 
Mock tables and listing mocks are included in TLF shells. This SAP aims to provide 
information and details around the analysis to be performed for the short closeout CSR for the 
study. 
In data presented at ASH 2015, the combination of RVD and panobinostat in newly diagnosed 
Multiple Myeloma (MM) patients showed an Objective response rate (ORR) of 94%, with a 
46% CR/nCR rate after 4 cycles. This marked improvement from historical data reporting 
CR/nCR rates of approximately 7% warrants further investigation of this combination in this 
population. 
Data will be analyzed by statistical software SAS® version 9.4 according to the data analysis 
section 10 of the CSP which is available in Appendix 16.1.1 of the Clinical Study Report 
(CSR). Important information is given in the following sections and details are provided, as 
applicable, in Appendix 16.1.9 of the CSR. 
The study has been terminated for further enrollment. The decision to terminate the study is 
not related to study efficacy or safety. However, it is because of availability of multiple drugs 
and their valuable treatment options in the market, for the treatment of multiple myeloma. 
Hence only a short closeout CSR will be published for currently enrolled patients. The SAP 
will cover the details only around the analysis to be performed for the short closeout CSR. All 
analyses as per the protocol will not be within the s cope of this short closeout CSR. The 
modules to be included in this short closeout CSR will be demographic characteristics, 
disposition, exposure and key safety data for AEs. 
 
 
1.1 
Study design 
This is a multicenter, open-label, randomized phase II study which will enroll 112 newly 
diagnosed symptomatic multiple myeloma patients in a 1:1 fashion. There will be no 
stratification done while randomization. Patients will be enrolled at approximately 20 centers 
in the United States. The dosing information is as follows: 
After completing 4 cycles of induction, all patients will undergo stem cell mobilization with 
G-CSF and plerixafor as per institutional protocol for this mobilization regimen. Study 
treatment interruption for stem cell collection may not exceed 30 days. All patients will 
receive one additional cycle of study treatment after stem cell collection and then proceed to 
autologous transplant using melphalan 200mg/m2 (140mg/m2 for patients > 70), as 
conditioning. All patients must initiate transplant within 28 days of the completion of cycle 5. 
After Autologus Stem Cell Transplant (ASCT), patients still on study will initiate 
maintenance therapy within the 60-120 day period following ASCT, provided they have 
adequate blood count and clinical recovery. Criteria for starting a patient on maintenance 
therapy are as follows: 


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• 
The ANC is ≥ 1,000/μL; 
• 
The platelet count is ≥ 75,000/μL 
• 
Adequate organ function as detailed in inclusion criteria (Section 5.2 of the CSP) 
Patients in the RVD arm will initiate maintenance therapy with lenalidomide alone, and 
patients in RVD-panobinostat arm will receive lenalidomide + panobinostat maintenance. 
Lenalidomide will be dosed orally at 10mg/day continuously in both arms. After the first 84 
day cycle, the dose of lenalidomide should increase to 15mg/day. Panobinostat will be dosed 
at 10mg three times a week, every other week. Total planned duration of maintenance therapy 
will be 3 years. 
Patients will remain on study treatment until they complete the maintenance phase, or until 
they experience disease progression, unacceptable toxicity, or at the discretion of the 
Investigator. 
 
Figure 1-1 Study Design 
 
 
 
1.1.1 Timing of interim analyses and design adaptations 
Not Applicable 


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1.1.2 Definition of end of the study 
Not Applicable 
1.1.3 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 to perform an end of treatment visit. Patients in 
survival follow-up should be contacted for a final survival visit for Study Evaluation 
Completion assessments. 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 Institutional Review 
Board (IRB) and/or Ethics Committee (EC) of the early termination of the trial. 
The study design and other plans were for the initially planned study. However since the trial 
is terminated, patients have been switched to follow up phase directly after induction phase. 
 
1.2        Study objectives and endpoints 
 
Table 1-1 Table for study objectives and related endpoints 
Objectives 
Endpoints 
Primary: 
To evaluate the efficacy of the combination 
of RVD + panobinostat compared to RVD 
alone 
Primary: 
nCR/CR 
rate 
of 
the 
combination 
of 
panobinostat with bortezomib, lenalidomide 
and dexamethasone (P-RVD) vs RVD in 
newly diagnosed multiple myeloma patients 
after 4 cycles of therapy 
Key Secondary: 
To  assess  MRD  negativity  (mCR)  after  4 
cycles of induction by Next Gen Sequencing 
Key Secondary: 
MRD negativity by ClonoSEQTM 
assay 
(Adaptive Biotechnologies) 
Other Secondary: 
 To assess best overall response rate 
(ORR) and MRD negativity after 
ASCT and maintenance 
 To assess depth of response by 
IMWG criteria 
 To assess the duration of response 
 To 
assess 
overall 
survival 
and 
progression free survival at  three 
years 
 To assess the toxicity and tolerability 
Other Secondary: 
 ORR (CR + PR) and MRD negativity 
after ASCT and maintenance 
 Rate of VGPR, CR and sCR 
 Duration of response 
 Overall survival and progression free 
survival at three years 
 Rates of AEs and SAEs 


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These were the objectives and related endpoints for the initially planned study. However , 
since the trial is terminated and only a short closeout CSR is to be published, these objectives 
and endpoints will not be assessed any more. Only key safety endpoints will be assessed and 
reported as stated in below sections. 
 
 
2 
Statistical methods 
2.1 
Data analysis general information 
Data will be analyzed by Novartis and/or the designated Contract Research Organization 
(CRO), according to the data analysis section of the CSP. All statistical analyses will be 
performed using SAS® Version 9.4. 
The planned statistical analysis is described in Section 10 of the protocol (Appendix 16.1.9 of 
the CSR). Data from all participating centers will be combined so that an adequate number of 
patients are available for analysis. 
The CSR will be updated with key safety data from patients in the study. 
Analysis visit windows will not be applied to the data analysis to handle unscheduled 
measurements unless otherwise specified. 
For descriptive summaries, categorical data will be presented as frequencies and percentages, 
and continuous data as mean, standard deviation, median, 25th and 75th percentile, minimum, 
and maximum. 
Unless otherwise specified, all statistical tests will be performed at a two-sided significance 
level of 0.05 and confidence intervals will be calculated with 95% confidence. 
 
2.1.1 
General definitions 
 
2.1.1.1 
Study drug and study treatment 
The terms “investigational study drug(s)” or “study drug(s)” or “study treatment 
component(s)” will refer to: 
 Oral panobinostat (also known as LBH589 or Farydak® or PAN) Capsules 
 Sub-cutaneous bortezomib (also known as BTZ or Velcade®) Injection 
 Oral revlimid (also known as REV or Revlimid®) Capsules 
 Oral dexamethasone (also known as Dex) Tablets 


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“Study treatment” refers to the combination of PAN, BTZ, REV and Dex or BTZ, REV and 
Dex, depending on treatment assignment. 
 
2.1.1.2 
Date of first administration of study drug/study treatment 
component 
The date of first administration of study drug/study treatment component is derived as the first 
date when a non-zero dose of study drug was administered and recorded on the dose 
administration record (DAR) CRF. For the sake of simplicity, the date of first administration 
of study drug will also be referred as start of study drug. 
 
2.1.1.3 
Date of last administration of study drug/study treatment 
component 
The date of last administration of study drug is defined as the last date when a non-zero dose 
of study drug/study treatment component was administered and recorded on the DAR CRF. 
 
2.1.1.4 
Date of first administration of study treatment 
The date of first administration of study treatment is derived as the first date when a nonzero 
dose of any component of study treatment was administered and recorded on the DAR CRF. 
For example, if the 1st dose of study drug A is administered on 04JAN2010, and the 1st dose 
of its combination partner, drug B, is administered on 03JAN2010, the date of the first 
administration of study treatment is on 03JAN2010. For the sake of simplicity, the date of the 
first administration of study treatment will also be referred as the start of study treatment. 
 
2.1.1.5 
Date of last administration of study treatment 
The date of last administration of study treatment is derived as the last date when a nonzero 
dose of any component of study treatment was administered and recorded on the DAR CRF. 
For example, if the last dose of study drug A is administered on 15APR2010, and the last dose 
of a combination partner, drug B, is administered on 17MAY2010, the date of last 
administration of study treatment is then on 17MAY2010. 
 
2.1.1.6 
Baseline 
Baseline is the result of an investigation describing the “true” uninfluenced state of the subject. 
The last available assessment before the day of study treatment administration, or any 
measurement  at the day of  study treatment administration, definitely taken before  study 
treatment administration, should be taken as the “baseline” assessment. 
General guidance for baseline definition: 
Dependent on the variable, the baseline assessment will be done at screening (Day -21 to 1) or 
baseline (Cycle 1 Day 1 [C1D1]). Some assessments might be performed on both screening 
and C1D1. For such instances, C1D1 will be considered as baseline, provided the assessment 
has happened before the study drug administration. 
Baseline assessments should be obtained before the first study treatment intake based on the 
variables. Any assessment which is obtained outside of the protocol-defined screening period 
will not be considered for baseline unless otherwise specified. 


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2.2        Analysis sets 
The following analysis sets will be used in the analyses: 
Full Analysis Set: The Full Analysis Set (FAS) comprises of all patients to whom study 
treatment has been assigned by randomization. According to the intent to treat principle, 
patients will be analyzed according to the treatment (and strata, if applicable) they have been 
assigned to during the randomization procedure. 
Safety Set: The Safety Set (SS) includes all patients who received at least one dose of study 
medication. Patients will be analyzed according to the study treatment (regimen) they actually 
received, i.e. if a patient was randomized to RVD+PAN treatment arm but mistakenly 
received RVD arm only, then the patient will be counted in the RVD arm for all analysis 
pertaining to safety set. 
Per-Protocol Set: The Per-Protocol Set (PPS) consists of all patients from the FAS 
population who received at least one dose of the study drug and had no major protocol 
deviation. Protocol deviations leading to exclusion from the PPS will be justified and 
specified in the study Appendix 1 of Data Review Plan (DRP) and documents prior to the data 
base lock. 
 
2.2.1       Subgroup of interest 
Not Applicable. 
 
3 
General Strategies for Data Presentation 
All categorical data will be summarized by frequencies and percentages. Wherever categorical 
data is missing, a ‘Missing’ row will be included at the bottom with frequencies and 
percentages presented for it. 
Continuous data will be summarized with either standard descriptive statistics (i.e. the number 
of non-missing data points, arithmetic mean, standard deviation, minimum, median, 25th and 
75th percentile and maximum), or will be collapsed into categorical data and summarized as 
categorical data. 
 
3.1 
Patient disposition, demographics and other baseline 
characteristics 
 
3.1.1 
Patient disposition 
 
3.1.1.1 
Study discontinuation 
A complete account of patients randomized, treated and not treated will be provided, by 
number and % of patients for the FAS. The number and percentage of patients who complete 
study, and those who prematurely discontinue from the study will be summarized together 
with reasons for premature study discontinuation. 
The possible reasons for discontinuation of study are as follows: 
 Death 


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 Lost to follow up 
 Study terminated by the sponsor 
 Subject/Guardian withdrew consent 
 Physician decision 
 
 
A listing for data on final status of the patient in the study will be provided. A data listing of 
screened patients who did not take study drug will be also provided with reasons for screening 
failure. 
 
3.1.2 
Demographic and baseline characteristics variables 
Demographic and baseline characteristics data will be summarized using the FAS. All 
demographic and background data will also be listed. 
 
The following variables will be summarized by treatment group: 
 Age (years) 
 Age category 
o <65 years 
o 
≥65 years 
o 
missing 
 Sex 
o Male 
o Female 
o missing 
 Race 
o Caucasian 
o Black 
o Asian 
o Native American 
o Pacific Islander 
o Other 
o missing 
 Ethnicity 
o Hispanic/latino 
o Chinese 
o Indian (Indian subcontinent) 
o Japanese 
o Mixed ethnicity 
o Other 
o missing 
 Child bearing potential for female patients 
o Able to bear children 
o Premenarche 


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o Post menopausal 
o Sterile-of child bearing age 
 
Eastern Cooperative Oncology Group - Performance Status (ECOG PS) 
o 0 - Fully active, able to carry on all pre-disease performance without restriction 
o 1 - Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light house work, office work 
o 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 
o 3 - Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours 
o 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed 
or chair 
o Missing 
 Body weight (kg) 
 Body height (cm) 
 Respiratory rate (per min) 
 Body surface area (BSA) (m2) 
 Body mass index (BMI) (kg/m2) 
 
 
3.2 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
 
3.2.1 
Study treatment / compliance 
The  duration  of  exposure  (in  weeks)  of  each  of  the  overall  study  treatment  will  be 
summarized using the SS. 
Listings of all doses of the study treatment along with dose change reasons will be produced. 
 
3.2.1.1 
Duration of exposure to study treatment/study treatment component 
Duration of exposure to study treatment 
Duration of exposure to study treatment is considered by taking into account the duration of 
exposure to the RVD and Panobinostat: 
Duration of exposure to study treatment (days) = (latest of last dates of exposure to 
study treatment) – (date of first administration of study treatment) + 1. 
 
 
Duration of exposure will be divided into following categories: 
 <3 weeks 
 
>=3 - <6 weeks 
 
>=6 - <12 weeks 
 
>=12 - <24 weeks 


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 
>=24 - <48 weeks 
 >=48 weeks 
The date of last administration of study treatment (treatment component) is taken from CRF 
treatment completion page ‘last dose date’. 
Thus, duration of exposure will be calculated for study treatment as a whole. Summary of 
duration of exposure of study treatment will include continuous summaries using appropriate 
units of time. 
The duration includes the periods of temporary interruption (of any component of the study 
treatment for any reason). ‘Date of last administration of study treatment/ study treatment 
component’ and ‘date of first administration of study treatment/ study treatment component’ 
is defined in Section 2.1.1. 
For patients who did not take any study treatment the duration of exposure is defined as zero. 
If duration is calculated in months, the duration in days will be divided by 30.4375. 
 
3.2.1.2 
Study day 
 
For the study day calculation, if the event or assessment date is after the treatment start date, 
the study day 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 treatment start date, e.g., time since 
diagnosis of disease, the study days (in negative) will be calculated as: 
The date of the assessment / event - start date of 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. 
 
 
3.3 
Efficacy Evaluations 
 
3.3.1 
Disease assessment 
Not Applicable 
 
3.4 
Analysis of the primary objective 
The primary objective for this trial is to evaluate the efficacy of the combination of RVD + 
panobinostat compared to RVD alone. 
As stated earlier, the primary objectives and related endpoints for the initially planned study 
are no longer being assessed. Since the trial is terminated, only a short closeout CSR is to be 
published. Hence, all the analysis, as mentioned in protocol, will not be performed. Only key 
safety endpoints will be assessed and reported, and data listings will be provided as 
appropriate. 


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3.4.1 
Primary endpoint 
The primary endpoint is based on nCR/CR rate of the combination of panobinostat with 
bortezomib, lenalidomide and dexamethasone (P-RVD) vs RVD in newly diagnosed multiple 
myeloma patients after 4 cycles of therapy. 
For purpose of short closeout CSR, data for the responses of patients based on Investigator 
provided responses, will be listed. The primary endpoint will not be analyzed/summarized. 
 
3.4.2 
Statistical hypothesis, model, and method of analysis 
The response data will not be analyzed. 
 
3.4.3 
Handling of missing values/censoring/discontinuations 
Not Applicable 
 
3.4.4 
Supportive analyses 
Not Applicable 
 
3.5 
Analysis of the key secondary objective 
The key secondary objective for the study is to assess the MRD negativity ( mCR) after 4 
cycles of induction by Next Gen Sequencing. 
As stated earlier, the secondary objectives and related endpoints for the initially planned study 
are no longer being assessed. 
 
3.5.1 
Key secondary endpoint 
The key secondary endpoint was to assess MRD negativity after 4 cycles of induction by Next 
Gen Sequencing. 
 
3.5.2 
Statistical hypothesis, model, and method of analysis 
The MRD data will not be analyzed. 
 
3.5.3 
Handling of missing values/censoring/discontinuations 
Not Applicable 
 
3.6 
Analysis of secondary efficacy objective(s) 
The secondary objectives for the study are: 
 
To assess overall response rate (ORR) and MRD negativity after ASCT and 
maintenance. ORR will be assessed based on Investigator’s assessed responses 
for both IMWG and EBMT criteria. 
 
To assess depth of response by IMWG and EBMT criteria based on Investigator’s 
assessed responses 
 
To assess the duration of response by IMWG and EBMT criteria based on 
Investigator’s assessed responses 


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 
To assess overall survival and progression free survival three years after the study 
by IMWG and EBMT criteria based on Investigator’s assessed responses 
 
To assess the toxicity and tolerability 
 
Out of the above stated secondary endpoints, only toxicity and tolerability will be assessed 
based on the AE and SAE assessments. 
 
3.6.1 
Secondary endpoints 
The secondary end points for the study is to assess AEs and SAEs to check the toxicity and 
tolerability of the study treatment. Please refer to the Section 3.7 for Safety analysis details. 
 
3.6.2 
Handling of missing values/censoring/discontinuations 
Not Applicable 
 
3.7 
Safety analyses 
For all safety analyses, the SS will be used. All listings and tables will be presented by study 
treatment group. 
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. 
 
3.7.1 
Adverse events (AEs) 
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. If CTCAE grading does not exist for an adverse event, the 
severity of mild, moderate, severe, and life-threatening, corresponding to Grades 1 - 4, will be 
used. CTCAE Grade 5 (death) will not be used in this study; rather, info rmation about deaths 
will be collected though the Study Evaluation Completion page. Adverse events will be coded 
using the most recent version of the medical dictionary for regulatory activities (MedDRA) 
available at the time of each analysis. 
The AEs experienced by the patients in all the observation periods will be listed. The AEs 
reported in pre-treatment and post-treatment period will be flagged in the listing. In an AE 
listing, details will be provided for severity grade of AE, seriousness of AE, its relationship to 
study treatment, its duration, action taken, outcome, and whether medication or therapy was 
given to patient. 
Treatment Emergent Adverse Events (TEAEs) are defined as events, which start in on- 
treatment period, or which start in pre-treatment period but worsen in on-treatment period. 
Summary tables for all TEAEs will be provided by study treatment group. 


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AEs will be summarized by number and percentage of subjects having at least one AE, having 
at least one AE in each primary system organ cl ass (SOC) and for each preferred term (PT) 
using MedDRA coding. A subject with multiple occurrences of an AE will be counted only 
once in the respective AE category. A subject with multiple CTCAE grades for the same 
preferred term will be summarized under the maximum CTCAE grade recorded for the event. 
The tables will be summarized alphabetically by SOC and in decreasing frequency of PTs. 
The decreasing order of PTs will be based on the total count. 
AE overview table will be provided with information on num ber and percentage of patients 
having any AE, any SAE, any Severe AE, any AE leading to discontinuation of study drug, 
any fatal AE and deaths due to any cause. 
AEs will be presented by SOCs-PTs-Severity, regardless of its relationship to study drug. AEs 
having relationship to study drug will be presented by SOCs-PTs-Severity. SAEs will be 
presented by SOCs-PTs-Severity, regardless of its relationship to study drug. AEs leading to 
discontinuation will be presented by SOCs-PTs-Severity, regardless of its relationship to 
study drug. Non Serious AEs will be presented by SOCs-PTs, regardless of its relationship to 
study drug. 
 
3.7.1.1 
Adverse events of special interest / grouping of AEs 
Specific safety event categories (SEC) may be considered. Such categories consist of one or 
more well-defined safety events which are similar in nature and for which there is a specific 
clinical interest in connection with the study treatment(s). 
For each specified SEC, AEs will be listed as per SEC and number and percentage of patients 
with at least one event part of the SEC will be provided. 
The following is the list of SECs, also referred to as AEs of special interest. 
 Diarrhea 
 Fatigue 
 Cardiac events 
o Ischemic event 
o Severe arrhythmia [QT prolongation, T-wave changes, ST-T segment changes, 
ventricular tachycardia, torsade des pointes, severe bradycardia] 
 
3.7.2 
Deaths 
 
Separate summaries for on-treatment and all deaths (on-treatment and post-treatment) will be 
produced by study treatment group, SOC and PT. All deaths will be listed and post treatment 
deaths will be flagged. 
 
3.7.3 
Laboratory data 
Not Applicable 


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3.7.4 
Other safety data 
 
3.7.4.1 
ECG and cardiac imaging data 
 
3.7.4.1.1 ECG data 
Not Applicable 
 
3.7.4.1.2 Cardiac Imaging Data 
Not Applicable 
 
3.7.4.2 
Vital signs 
Not Applicable 
 
3.7.4.3 
Pregnancy Test 
Not Applicable 
 
3.8 
Pharmacokinetic endpoints 
Not Applicable 
 
3.9 
PD and PK/PD analyses 
Not Applicable 
 
3.10 
Patient-reported outcomes 
Not Applicable 
 
 
 
 
3.13 
Interim analysis 
Not Applicable 
 
4 
Sample size calculation 
The sample size of the study is based on the assumption that in the RVD alone arm the 
nCR/CR rate will be 7% and adding Pano to RVD will improve the nCR/CR rate to 25%. For 
one  sided  alpha=0.05,  fifty  patients  in  each  arm  will  have  81%  power  to  detect  this 


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improvement. To get 50 evaluable patients in each arm an additional 6 patients will be 
randomized in each arm for a total of 112 patients. 
PASS 2008 was used to calculate the sample sizes. 
As mentioned earlier, the trial is terminated for further enrollment. There is only 7 patients’ 
data available, before the closeout of the study. 
 
5 
Change to protocol specified analyses 
Not applicable. 
 
6 
Appendix 
6.1 
Imputation rules 
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. 
For dates known to be within the trial period, the last known contact date will be used if this 
imputation makes the date later than the last known contact date but within the trial 
completion date. If the imputed date is earlier than the first medication date, the first 
medication date will be used. 
 
6.1.1 
Study drug 
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 
cut-off date will be used as the end date. Such imputed data will be flagged in the listings. 
The protocol allows for continuous dosing record entry with start dates and end dates for all 
compounds of study treatment. A separate dosing record should be entered whenever there is 
a change in the dosing which can be due to dose change, delay or missed doses. If the start 
date and end date is on the same date then that DAR record will be called single dose DAR 
record. 
 
6.1.2 
AE date imputation 
For incomplete AE start dates, the date of treatment start will be used in case the imputation 
reveals in a date before the start of treatment. For the calculation of duration, the formula (end 
date – start date + 1 day) is used. If, as i t might occur in AE pages, the end date is complete 


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and the start date is partial, the above rule is applied as long as the start date is not later than 
the end date; otherwise the start and end date are the same. 
 
6.2 
AEs coding/grading 
Adverse events will be coded using the MedDRA version 18.1 or higher. 
AEs will be assessed according to the CTCAE version 4.03. 
6.3 
Laboratory parameters derivations 
 
Not Applicable 
 
6.4 
Statistical models 
Not Applicable 
 
6.5 
Rule of exclusion criteria of analysis sets 
Not Applicable 
 
7 
Reference 
Paul G. Richardson,corresponding author1 Wanling Xie et al. (2014) A phase 2 trial of 
lenalidomide, 
bortezomib, 
and 
dexamethasone 
in 
patients 
with 
relapsed 
and 
relapsed/refractory myeloma