Clinical trial NCT01102426
Conditions: Relapsed/Refractory Multiple Myeloma
Keywords: Multiple Myeloma Aplidin plitidepsin dexamethasone
Sponsor: PharmaMar
Start date: 2010-06-01; Completion date: 2017-11-01
Enrollment: 255 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study of Plitidepsin in combination with dexamethasone versus dexamethasone alone in patients with relapsed/refractory multiple myeloma.

Detailed description:
Phase III Study in Patients with Relapsed/Refractory Multiple Myeloma to compare the efficacy of plitidepsin in combination with dexamethasone vs. dexamethasone alone measured by progression-free survival (PFS) and to evaluate tumor response, duration of response (DR), overall survival (OS) and to rule out any effect of plitidepsin on the duration of the QT/QTc interval (time corresponding to the beginning of depolarization to re-polarization of the ventricles).

Arms: arm 1: plitidepsin + dexamethasone combination arm 2: dexamethasone single agent
Interventions: intervention 1: Plitidepsin intervention 2: Dexamethasone
Intervention descriptions: intervention 1: plitidepsin: powder and solvent for concentrate for solution for infusion. 2 mg vial + 4 ml ampoule. 5 mg/m2 intravenously (i.v.) over three hours on Day 1 and 15 every 4 weeks. dexamethasone: 4 mg tablet. 40 mg orally on Day 1, 8, 15 and 22 every four weeks at least one hour before plitidepsin infusion. intervention 2: 4 mg tablet. 40 mg orally on Day 1, 8, 15 and 22 every four weeks.

Protocol documents:
Prot_000.pdf: 
 
 
 
SPONSOR 
 
Pharma Mar, S.A. 
Avda de los Reyes, 1 
 
Polígono Industrial “La Mina” 
28770 Colmenar Viejo (Madrid), Spain 
Phone: + 34 918 466 000  
Fax:  
+ 34 918 466 003 
 
 
PharmaMar USA, Inc. 
230 Park Avenue, suite 1000 
New York, NY 10169 
USA 
Phone: +1 212 309 8737 
Fax: +1 646 435 5846 
 
 
 
 
CLINICAL TRIAL PROTOCOL 
 
 
Randomized, Multicenter, Open-label, Phase III Study of Plitidepsin in Combination 
with Dexamethasone vs. Dexamethasone Alone in Patients with Relapsed/Refractory 
Multiple Myeloma 
 
 
INVESTIGATIONAL MEDICINAL PRODUCTS: plitidepsin (Aplidin®) and 
dexamethasone. 
Protocol No.: APL-C-001-09 
EudraCT No.: 2009-016138-29 
NCT Code: 01102426 
 
 
 
Protocol version 4.0: 10 July 2017 
 


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Protocol APL-C-001-09
SPONSOR
Pharma Mar S.A.
Avenida de los Reyes, 1 
Polígono Industrial “La Mina”
28770 Colmenar Viejo, Madrid, Spain.
Phone: + 34 91 846 6000 /  Fax : + 34 91 846 6003
Pharma Mar USA, Inc.
205 East 42nd Street, suite 15003
New York, New York 10017, USA
Phone: + 1 646 880 4429
Fax : + 1 646 893 5856
CLINICAL TRIAL PROTOCOL
APL-C-001-09
(ADMYRE: Aplidin – Dexamethasone in RElapsed/Refractory MYeloma)
Randomized, Multicenter, Open-label, Phase III Study of Plitidepsin in 
Combination with Dexamethasone vs. Dexamethasone Alone in Patients with 
Relapsed/Refractory Multiple Myeloma 
INVESTIGATIONAL MEDICINAL PRODUCT: Aplidin® (plitidepsin)
Combination with: Dexamethasone
Protocol Code:
APL-C-001-09
EudraCT:
2009-016138-29
Protocol Version 4.0
Substantial Amendment #3 (edition 10 July 2017) is included
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) and 
the applicable regulatory requirements. 
Confidentiality statement
Information and data included in this protocol contain trade secrets and privileged or confidential 
information which is the property of the Sponsor. No person is authorized to make it public 
without written permission of the Sponsor.  These restrictions on disclosure will apply equally to 
all future information supplied to you which is indicated as privileged or confidential. This 
material may be disclosed to and used by your staff and associates as it may be necessary to 
conduct the clinical study.


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Protocol APL-C-001-09
STUDY CONTACTS
NAME AND ADDRESS
PHONE, FAX NUMBER, AND E-
MAIL ADDRESS
Sponsor: 
Pharma Mar S.A.
Pharma Mar USA, Inc.
Avda. de los Reyes, 1
Polígono Industrial “La Mina”
28770 Colmenar Viejo, Madrid, 
Spain.
205 East 42nd Street, suite 
15003
New York, New York 10017, 
USA
Phone:
+ 34 91 846 6000
Fax:
+ 34 91 846 6003
Phone:
+ 1 646 880 4429
Fax:
+ 1 646 893 5856
Responsible Physicians
José Rodríguez, MD.
Clinical Oncology.
Clinical Development. 
Pharma Mar S.A.
Sara Martínez González, MD
Clinical Oncology.
Clinical Development. 
Pharma Mar S.A.
Phone:
+ 34 91 846 6157
Fax:
+ 34 91 823 4504
E-mail: jrodriguez@pharmamar.com
Phone:
+ 34 91 823 4647
Fax:
+ 34 91 823 4504
E-mail: smgonzalez@pharmamar.com
Project Manager
Pilar García Paramio, PhD.
Clinical Operations.
Clinical Development. 
Pharma Mar S.A.
Phone:
+ 34 91 823 4597
Fax:
+ 34 91 846 6003
E-mail: mpgarcia@pharmamar.com
Study Coordinator
Eva Jiménez Martínez.
Clinical Operations.
Clinical Development. 
Pharma Mar S.A.
Phone:
+ 34 91 823 4566
Fax:
+ 34 91 846 6003
E-mail: ejimenez@pharmamar.com
Clinical Trial Monitor
Pharma Mar CRA.
Clinical Operations.
Clinical Development. 
Pharma Mar S.A.
Phone:
+ 34 91 846 6000
Fax:
+ 34 91 846 6003
Contract Research 
Organizations (CROs)
ICON Clinical Research .
South County Business Park.
Leopardstown, Dublin 18.
Ireland.
(Only in Greece):
Qualitis Ltd.
Clinical Research & Medical 
Consulting.
32 Olaf Palme str.
Zografou 157 71.
Attiki, Greece.
Phone:   +353 (0) 1 291 2000 
Fax:       +353 (0) 1 291 2700
Phone: + 30 210 7797750
Mobile: + 30 693 6623369
Fax: 
+ 30 210 7470441
Pharmacovigilance Contact
Laura Ferreira Alvarez.
Pharmacovigilance (PhV).
Clinical Development. 
Pharma Mar S.A.
Phone:    + 34 91 823 4557
Fax:
+ 34 91 846 6004
E-mail: phv@pharmamar.com
Out of office hours (GMT)
PhV service phone:
+ 34 681 263 592


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Protocol APL-C-001-09
STUDY CONTACTS
NAME AND ADDRESS
PHONE, FAX NUMBER, AND E-
MAIL ADDRESS
Central Laboratories for 
Specific Multiple Myeloma 
Tests
ICON Central Laboratories
South County Business Park 
Leopardstown, Dublin 18. 
Ireland.
ICON Central Laboratories 
123 Smith Street 
Farmingdale, NY 11735 
United States 
Phone:   +353 (0) 1 291 2000 
Fax:       +353 (0) 1 291 2201
Phone:   +1 631 777 8833 
Fax:       +1 631 777 3904
Clinical Pharmacology 
Contact
Salvador Fudio, MD.
Clinical Pharmacology. 
Clinical Development.
Pharma Mar S.A.
Phone:
+ 34 91 823 4521
Fax:
+ 34 91 823 4504
E-mail: sfudio@pharmamar.com
Central Laboratory for 
Pharmacokinetic Samples
Kristine Wagner-Caruso.
ICON Development Solutions.
8282 Halsey Road. 
Whitesboro, NY 13492, US.
Phone:
+ 1 315 768 2540
E-mail: Kristine.Wagner-
Caruso@iconplc.com
Central Laboratory for 
Troponin I Analysis
Josep Mª Mestres Alomar.
Tele-Test Analytika.
Montseny 11.
08012 Barcelona.
Spain.
Phone:
+ 34 93 415 44 27
Fax: 
+ 34 93 416 02 63
E-mail: jmestres@teletest.es
QTc Substudy Contact
Salvador Fudio, MD.
Clinical Pharmacology. 
Clinical Development.
Pharma Mar S.A.
Phone:
+ 34 91 823 4521
Fax:
+ 34 91 823 4504
E-mail: sfudio@pharmamar.com
Central Laboratory for ECG 
Readings (QT Substudy)
ERT.
Peterborough Business Park. 
Lynch Wood.
Peterborough, PE2 6FZ.
United Kingdom.
Phone:
+ 44 (0) 1733374825
Fax:
+ 44 (0) 7726695845
QT-Related Polymorphisms 
Assessments Laboratory
Transgenomic, Inc.
Five Science Park.
New Haven, CT06511.
USA.
Phone: +1 (877) 274 9432
Fax: 
+1 (855) 263 8668
A list of additional study contacts will be supplied as an additional document.


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Protocol APL-C-001-09
PRINCIPAL INVESTIGATORS
A complete list of investigators will be supplied as an additional document.


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TABLE OF CONTENTS
STUDY CONTACTS .................................................................................................................................2
A LIST OF ADDITIONAL STUDY CONTACTS WILL BE SUPPLIED AS AN ADDITIONAL 
DOCUMENT. PRINCIPAL INVESTIGATORS....................................................................................3
SYNOPSIS ..................................................................................................................................................8
SCHEDULE OF ASSESSMENTS AND PROCEDURES....................................................................22
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..........................................................25
1
INTRODUCTION............................................................................................................................29
1.1
OVERVIEW OF THE DISEASE....................................................................................................29
1.2
CURRENT TREATMENT FOR MULTIPLE MYELOMA ...............................................................29
1.2.1
Plitidepsin.............................................................................................................................30
1.3
INFORMATION ON STUDY DRUG: PLITIDEPSIN.......................................................................31
1.3.1
Name and Chemical Information .......................................................................................31
1.3.2
Non-clinical Data.................................................................................................................31
1.3.3
Clinical Data........................................................................................................................39
1.3.4
Safety Issues.........................................................................................................................42
1.4
INFORMATION ON STUDY DRUG: DEXAMETHASONE.............................................................48
1.5
STUDY RATIONALE ..................................................................................................................48
1.5.1
Rationale for the Proposed Drug Combination..................................................................48
2
OBJECTIVES ..................................................................................................................................49
2.1
PRIMARY OBJECTIVE...............................................................................................................49
2.2
SECONDARY OBJECTIVES ........................................................................................................49
3
OVERALL STUDY DESIGN..........................................................................................................49
4
PATIENT DEFINITION .................................................................................................................50
4.1
STUDY POPULATION.................................................................................................................50
4.2
PATIENT ELIGIBILITY..............................................................................................................50
4.2.1
Inclusion criteria .................................................................................................................50
4.2.2
Exclusion criteria.................................................................................................................52
5
PLAN OF STUDY............................................................................................................................53
5.1
PATIENT PARTICIPATION.........................................................................................................53
5.2
TREATMENT DISCONTINUATION..............................................................................................54
5.3
PROTOCOL DEVIATIONS..........................................................................................................54
5.4
REPLACEMENT OF PATIENTS...................................................................................................55
5.5
DURATION OF THE CLINICAL TRIAL.......................................................................................55
5.6
INDEPENDENT REVIEW AND DATA MONITORING COMMITTEES ...........................................56
5.7
PRE-TREATMENT ASSESSMENTS..............................................................................................56
5.8
PATIENT REGISTRATION..........................................................................................................58
5.9
PATIENT ASSIGNMENT TO TREATMENT GROUP.....................................................................58
5.10
PATIENT RANDOMIZATION......................................................................................................58
5.11
EVALUATION DURING TREATMENT.........................................................................................59
5.12
EVALUATION AT THE END OF TREATMENT ............................................................................61
5.13
FOLLOW-UP AFTER END-OF-TREATMENT VISIT....................................................................62
6
PHARMACOKINETICS.................................................................................................................62
7
TREATMENT..................................................................................................................................64
7.1
STUDY MEDICATIONS ..............................................................................................................64


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7.1.1
Quantitative and Qualitative Composition..........................................................................64
7.2
ADMINISTRATION OF STUDY MEDICATION ..............................................................64
7.3
CRITERIA FOR TREATMENT CONTINUATION AND RETREATMENT.........................................64
7.4
DOSE REDUCTION CRITERIA ....................................................................................................66
7.5
CONCOMITANT MEDICATION..................................................................................................68
7.5.1
Prophylactic Medication......................................................................................................68
7.5.2
Allowed Medications/Therapies ..........................................................................................68
7.5.3
Prohibited Medications/Therapies ......................................................................................69
7.5.4
Drug Accountability.............................................................................................................69
7.6
VERIFICATION OF COMPLIANCE WITH TREATMENT REGIMEN.............................................69
8
STUDY EVALUATIONS.................................................................................................................69
8.1
EFFICACY .................................................................................................................................69
8.2
SAFETY .....................................................................................................................................71
8.3
EVALUATION OF PHARMACOKINETICS...................................................................................71
9
ADVERSE EVENTS REPORTING................................................................................................71
9.1
DEFINITIONS.............................................................................................................................71
9.1.1
Adverse Event ......................................................................................................................71
9.1.2
Serious Adverse Event (SAE)..............................................................................................71
9.1.3
Unlisted /Unexpected Adverse Event...................................................................................73
9.1.4
Adverse Reactions................................................................................................................73
9.1.5
Adverse Events Related to Study Drugs ..............................................................................73
9.1.6
Expedited Reporting ............................................................................................................73
9.1.7
Assessment of Causal Relationship to the Study Drug.......................................................74
9.2
PROCEDURES............................................................................................................................74
9.2.1
Reporting of Adverse Events ...............................................................................................74
9.2.2
Reporting Serious Adverse Events ......................................................................................75
9.2.3
Reporting Pregnancy Cases Occurred within the Clinical Trial........................................75
10
STATISTICAL METHODS ............................................................................................................76
10.1
SAMPLE SIZE............................................................................................................................76
10.2
STATISTICAL ANALYSIS...........................................................................................................77
10.2.1
Demographics..................................................................................................................77
10.2.2
Safety ...............................................................................................................................77
10.2.3
Efficacy Analysis.............................................................................................................77
10.2.4
Pharmacokinetics............................................................................................................79
10.3
INTERIM ANALYSIS ..................................................................................................................79
11
ADMINISTRATIVE SECTION......................................................................................................80
11.1
ETHICS......................................................................................................................................80
11.2
MONITORING, AUDITING AND INSPECTING .............................................................................80
11.3
PATIENT INFORMED CONSENT ................................................................................................81
11.4
CONFIDENTIALITY/ PATIENTS IDENTIFICATION......................................................................81
11.5
CASE REPORT FORMS...............................................................................................................81
11.6
INSURANCE ...............................................................................................................................82
11.7
RECORDS RETENTION ..............................................................................................................82
11.8
USE OF INFORMATION AND PUBLICATION...............................................................................82
12
REFERENCES ................................................................................................................................83
13
APPENDICES..................................................................................................................................89
APPENDIX 1: CLINICAL MANAGEMENT OF HYPERSENSITIVITY REACTIONS TO PLITIDEPSIN® ........89
APPENDIX 2: PERFORMANCE STATUS (ECOG)...........................................................................91
APPENDIX 3: COCKCROFT AND GAULT’S FORMULA............................................................................92
APPENDIX 4: DIAGNOSTIC CRITERIA ...................................................................................................93
APPENDIX 5: INTERNATIONAL MYELOMA WORKING GROUP UNIFORM RESPONSE CRITERIA FOR 
MULTIPLE MYELOMA ............................................................................................................................94
APPENDIX 6: STAGING SYSTEMS ..........................................................................................................97


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APPENDIX 7: LISTS OF DRUGS THAT PROLONG THE QT INTERVAL AND/OR INDUCE TORSADES DE 
POINTES VENTRICULAR ARRHYTHMIA................................................................................................98
APPENDIX 8: QTC SUBSTUDY PROTOCOL..........................................................................................103
TABLES
Table 1. Plitidepsin: single-agent phase I trials in adult patients.........................................................40
Table 2. Final pharmacokinetic parameter estimates for plitidepsin. .................................................46
Table 3. Pre-treatment period.................................................................................................................56
Table 4. Evaluation during treatment ....................................................................................................59
Table 5. Sampling points for pharmacokinetic evaluations..................................................................63
Table 6. Criteria for continuation of treatment.....................................................................................65
Table 7. Dose reduction criteria for plitidepsin and dexamethasone...................................................67
FIGURES
Figure 1. MM1.S cell line, 48 h incubation.............................................................................................33
Figure 2. Activity of the combination plitidepsin + dexamethasone in MM cell lines........................34
Figure 3. Plitidepsin-dexamethasone molecular model of apoptosis....................................................36
Figure 4. Glucorticoids and the chromatin complex .............................................................................37


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Protocol APL-C-001-09
SYNOPSIS
TITLE
Randomized, Multicenter, Open-label, Phase III Study of Plitidepsin in 
Combination with Dexamethasone vs. Dexamethasone Alone in Patients 
with Relapsed/Refractory Multiple Myeloma 
CODE
APL-C-001-09
LOCATION OF 
INVESTIGATORS 
AND SITES
The complete list of investigators is available in a separate document.
NUMBER OF SITES
Approximately 40-80 centers worldwide.
CLINICAL
TRIAL 
OBJECTIVES
Primary

To compare the efficacy of plitidepsin in combination with
dexamethasone vs.
dexamethasone 
alone
as measured 
by
progression-free survival (PFS) in patients with relapsed/refractory 
multiple myeloma (MM).
Secondary

To evaluate tumor response according to the International Myeloma 
Working Group (IMWG) criteria.

To assess duration of response (DR) and overall survival (OS).

To assess efficacy in patients who undergo crossover from 
dexamethasone alone to plitidepsin and dexamethasone combination.

To characterize and compare the safety profile on both arms in this 
population.

To characterize the pharmacokinetics (PK) and pharmacokinetic
/pharmacodynamic (PK/PD) relationship.
PATIENT 
ELIGIBILITY 
Inclusion Criteria
1.
Age ≥ 18 years.
2.
Eastern Cooperative Oncology Group (ECOG) Performance 
Status (PS) ≤ 2 (see Appendix 2).
3.
Life expectancy ≥ 3 months.
4.
Patients previously diagnosed with multiple myeloma based on 
IMWG diagnostic criteria (see Appendix 4). 
5.
Patients must have relapsed or relapsed and refractory multiple 
myeloma (MM) (Appendix 5) after at least three but not more 
than six prior therapeutic regimens for MM, including induction 
therapy and stem cell transplant in candidate patients, which 
will be considered as only one regimen.


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Protocol APL-C-001-09
6.
Patients must have received previous bortezomib-containing and 
lenalidomide-containing
regimens
(or thalidomide where 
lenalidomide is not available), unless unable to tolerate either of 
them.
7.
Patients must have measurable disease defined as: 
a)
For secretory MM: any quantifiable serum monoclonal 
protein value and, where applicable, urine light-chain 
excretion ≥ 200 mg/24 hours. 
b) For oligo- or non-secretory MM: presence of soft tissue 
(not bone) plasmacytomas, as determined by clinical 
examination or applicable radiographs [i.e., magnetic 
resonance imaging (MRI), computed tomography (CT)-
scan], and/or by the presence of abnormal serum free light 
chains (sFLC): involved FLC level ≥ 10 mg/dl provided 
the serum FLC ratio is abnormal. 
8.
At least two-week washout period since the end of last therapy 
(six weeks if previous nitrosoureas-containing regimen), given 
recovery to grade ≤ 1 from any non-hematological related 
adverse event (AE) derived from previous treatment (excluding 
alopecia).
9.
Adequate bone marrow (BM), renal, hepatic, and metabolic 
function (assessed ≤ 7 days before inclusion in the study):
a) Absolute neutrophil count (ANC) ≥ 1.0 x 109/l (≥ 0.5 x 
109/l if due to extensive and documented BM involvement
by ≥ 50% of plasma cells in BM biopsy).
Screening of ANC should be independent of 
granulocyte-
and 
granulocyte/macrophage-colony 
stimulating factor (G-CSF and GM-CSF) support for at 
least one week and of pegylated G-CSF for at least two 
weeks.
b) Platelet count ≥ 50 x 109/l (≥25 x 109/l if due to extensive 
and documented BM disease involvement).
c) Hemoglobin ≥ 8.5 g/dl. 
Patients may receive red blood cells (RBC) and/or 
erythropoietin (EPO), and/or platelets transfusions in 
accordance with institutional guidelines.
d) Aspartate 
aminotransferase 
(AST) 
and 
alanine 
aminotransferase (ALT) ≤ 3.0 x the upper limit of normal
(ULN).
e) Total bilirubin ≤ 1.0 x ULN or direct bilirubin ≤ 1.0 x ULN 
when total bilirubin is above the upper limit of normal. 
f) Calculated creatinine clearance (CrCl) ≥ 30 ml/minute (by 
means of Cockcroft and Gault´s formula) (see Appendix 3).
g) Creatine phosphokinase (CPK) ≤ 2.5 x ULN.
h) Albumin ≥ 2.5 g/dl.
10. Left ventricular ejection fraction (LVEF) by echocardiogram 
(ECHO) or multiple-gated acquisition scan (MUGA) above the 
lower limit of normal (LLN).


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Protocol APL-C-001-09
11. Women of childbearing potential must have a negative serum 
pregnancy test before study entry. Both women and men must 
agree to use a medically acceptable method of contraception 
throughout the treatment period and for six months after 
discontinuation of treatment.                   
12. Voluntarily signed and dated written informed consent prior to 
any specific study procedure.
PATIENT 
ELIGIBILITY 
Exclusion Criteria
1.
Concomitant diseases/conditions:
a)
History or presence of angina, myocardial infarction, clinically 
relevant valvular heart disease, cardiac amyloidosis or 
congestive heart failure within the last 12 months.
b) Symptomatic arrhythmia (excluding anemia-related sinusal
tachycardia grade ≤ 2) or any arrhythmia requiring ongoing 
treatment, and/or prolonged QT-QTc grade ≥ 2; or presence of 
unstable atrial fibrilation. Patients with stable atrial fibrillation 
on treatment are allowed provided they do not meet any other 
cardiac or prohibited drug exclusion criterion.
c)
Active uncontrolled infection.
d) Morphological or cytological features of myelodysplasia and/or 
post-chemotherapy aplasia on BM assessment.
e)
Myopathy > grade 2 or any clinical situation that causes 
significant and persistent elevation of CPK (>2.5 x ULN in two 
different determinations performed one week apart).
f)
Known human immunodeficiency virus (HIV) infection (HIV 
testing is not required unless infection is clinically suspected).
g)
Known active hepatitis B or C virus (HBV or HCV) infection.
h) Limitation of the patient’s ability to comply with the treatment 
or follow-up requirements.
i)
Any other major illness that, in the Investigator’s judgment, will 
substantially increase the risk associated with the patient’s 
participation in this study.
j)
Peripheral neuropathy > grade 2.
2.
Women who are pregnant or breast feeding.
3.
Concomitant 
medications 
that 
include 
corticosteroids,
chemotherapy, or other therapy that is or may be active against MM, 
within two weeks prior to Cycle 1 Day 1. Concurrent corticosteroids 
are allowed, provided they are administered at an equivalent 
prednisone dose of ≤ 10 mg daily, as premedication for blood 
products only.
4.
Known history of peptic ulcer and/or major upper gastrointestinal 
bleeding episode occurring during last year before study entry 
and/or related to prior steroid-based therapy.
5.
Relevant history of mood-disturbances changes associated with 
previous steroid-based therapy.


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Protocol APL-C-001-09
6.
Disease-related symptomatic hypercalcemia despite optimal medical 
therapy.
7.
Known hypersensitivity to any involved study drug or any of its 
formulation components.
PATIENT 
ELIGIBILITY 
Number of patients
Approximately, 210 progression or death events will be needed for the 
evaluation of the primary endpoint (PFS). A total of approximately 250
patients will be randomized in a 2:1 ratio to:
1. Arm A (plitidepsin + dexamethasone combination): approximately 
167 patients.
2. Arm B (dexamethasone single agent): approximately 83 patients.
An early futility analysis will be performed with the data collected when 
40 patients in Arm A are evaluable for response.
Patients without valid disease evaluation during treatment will not be 
replaced for the main analysis, and will be analyzed as per ITT 
according to randomization.
CLINICAL TRIAL
DESIGN
Prospective, open-label, two-arm, 2:1 randomized phase III study. The 
efficacy of plitidepsin in combination with dexamethasone vs.
dexamethasone alone will be studied by means of PFS calculated using 
the IMWG uniform response criteria, and the evaluation of secondary 
efficacy endpoints. Patients in the control arm (dexamethasone alone, 
Arm B) who have documented disease progression according to 
Investigator’s
criteria, after a minimum of eight
weeks from 
randomization, should be offered crossover to the combination arm
(plitidepsin + dexamethasone, Arm A) upon Sponsor agreement.
An Independent Review Committee (IRC) consisting of medical 
specialists directly involved in the care of patients with MM but not 
taking part in this trial as investigators or sub investigators, will review 
all efficacy data and will assign the date of progression/censoring and 
objective response according to their independent evaluation. This IRC 
will be blinded regarding to treatment arm allocation and identity of the 
cases reviewed.
An Independent Data Monitoring Committee (IDMC), including 
specialists in MM and in medical statistics, will review the results of the 
protocol-specified analyses performed by an independent statistician, 
including investigators and IRC efficacy assessments and safety 
information. Then, the IDMC will provide advice on the conduct of the 
study.
Operational details for the IRC and IDMC will be detailed in the 
corresponding charters.


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Protocol APL-C-001-09
Duration of study 
period (per patient)
Patients will be evaluated at scheduled visits in up to three study 
periods:

Pre-treatment: from signature of informed consent to first 
administration of study drugs.

Treatment: up to 30 days after the day of the last dose of study 
drug administration, unless the patient starts any new antitumor 
therapy outside this clinical trial or dies, in which case the date of 
administration of this new therapy or the date of death will be 
considered the date of treatment discontinuation. An end-of-
treatment visit will be performed within 30 days ( ± two days) after 
last dose administration, unless the patient starts any new antitumor 
therapy outside this clinical trial, in which case the end-of-treatment 
visit should be performed immediately before the start of the new 
therapy (ideally the day before or the same day).

Follow-up: after treatment discontinuation, patients will be 
followed every four weeks until resolution of toxicities if any. 
Patients who discontinued treatment without progression will be 
followed every four weeks until disease progression or other 
antitumor therapy, whichever occurs first. After progression, all 
patients will be followed every three months for survival until death, 
or until the date of study termination, whichever occurs first.
Patients will be considered to be on-study from the signature of the 
informed consent to the end of the follow-up period. Patients will be 
considered to be on-treatment for the duration of their treatment and 30 
days following the last treatment dose. Those patients in the control arm 
(Arm B) who crossed over to the combination arm (Arm A) after 
disease progression will be considered on-treatment for the duration of 
their whole treatment (dexamethasone alone + dexamethasone in 
combination with plitidepsin) and during 30 days following the last 
treatment dose. 
Patients will receive the study medications while it is considered to be in 
their best interest. Specifically, treatment will continue until:

Disease progression (except for those patients treated with 
dexamethasone alone and eligible to be offered crossover to 
combination therapy).

Unacceptable toxicity.

Intercurrent illness of sufficient magnitude to preclude safe 
continuation of the study.

Patient refusal and/or non compliance with study requirements.

Protocol deviation with an effect on the risk/benefit ratio of the 
clinical trial.

Treatment delay > 2 weeks from the theoretical treatment date
(except in case of clear clinical benefit, with the Sponsor’s 
approval).

Requirement of > 2 dose reductions of either drug.


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Protocol APL-C-001-09
INVESTIGATIONAL
DRUG
Formulation

Plitidepsin will be supplied as a powder and solvent for concentrate 
for solution for infusion. The 2-mg vial should be reconstituted with
a 4-ml ampoule of reconstitution solution. The composition of 
reconstitution solution is Cremophor EL/ethanol/water for injection 
(15/15/70% v/v/v).

Commercially available dexamethasone formulations will be used.
Mode of 
administration, dose 
and schedule
1.
Arm A: 
a)
Dexamethasone: 40 mg orally on Day 1, 8, 15 and 22 every four 
weeks (q4wk) at least one hour before plitidepsin infusion.
b)
Plitidepsin: 5 mg/m2 intravenously (i.v.) diluted to a total 
volume of 250 ml in 0.9% saline (or 5% glucose) via a central 
venous catheter (suggested) or diluted to a total volume of 500 
ml in 0.9% saline (or 5% glucose) via a peripheral line. Infusion 
will be performed through a pump device over three hours 
(fixed rate) on Day 1 and 15 q4wk.
2.
Arm B: 
a)
Dexamethasone: 40 mg orally on Day 1, 8, 15 and 22 q4wk.
A cycle is defined as a four-week period.
Criteria for treatment 
continuation
Before the administration of each dose (re-treatment), patients must 
fulfill the baseline criteria defined in the following table:
Plitidepsin  
(Arm A)
Dexamethasone 
(Arm A and B)
  Day 1 a & 15 b
Day 1 a & 15
ANC
1.0 x 109/l or return to baseline 
values if extensive BM involvement 
-
Platelets
50 x 109/l or return to baseline 
values if extensive BM involvement
-
Hemoglobin
8.5 g/dl
8.5 g/dl
Direct bilirubin if total 
bilirubin is above the 
upper normal limit
1.0 x ULN
-
AST/ALT
Grade 2
-
Muscular toxicity 
(myalgia, muscular 
weakness, CPK 
increase) 
Grade 2
≤ Grade 2
Other non-
hematological drug-
related AEs (except for 
increased GGT and/or 
AP, not optimally 
treated nausea and 
vomiting or 
hypertension, alopecia)c
≤ Grade 1
≤ Grade 1
ECG, ECHO/MUGAd
Same as baseline
Same as baseline
a. If a patient does not meet the requirements for treatment continuation on Day 1 of the 
following cycle, the infusion of study drugs will be withheld until recovery or for a 
maximum of 14 days. After this period, if delay is due to toxicity assessed as related to study 


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Protocol APL-C-001-09
drug, a dose decrease of 20% is mandatory; up to a maximum of two individual dose 
reductions are allowed. Patients needing additional dose reductions must be withdrawn from 
the trial.
b. If a patient does not meet the requirements for treatment continuation on Day 15, the 
administration of plitidepsin will be omitted. Patients requiring frequent dose omissions may 
have a dose reduction of 20% upon Investigator and Sponsor agreement. In no case more 
than two dose reductions are allowed. 
c. Any grade accepted for increased GGT and/or AP, and up to grade 2 peripheral neuropathy.
d. To be performed every three months unless more frequent assessments are clinically 
indicated.
AEs: adverse event(s); ANC: absolute neutrophil count; AP: alkaline phosphatase; BM: bone 
marrow; AST/ALT: aspartate aminotransferase/alanine aminotransferase; CPK: creatine 
phosphokinase; GGT: -glutamyltranspeptidase; ECG: electrocardiogram; ECHO/MUGA: 
echocardiogram/multiple-gated acquisition scan.
Dose reduction criteria
Patients experiencing frequent dose omissions and/or unacceptable 
toxicity, defined as
less than 50% compliance with treatment schedule, and/or 
grade ≥ 3 febrile neutropenia, or 
grade 4 neutropenia and infection, or
grade 4 neutropenia lasting > 7 days (except for patients with 
extensive BM involvement), and/or 
grade 4 thrombocytopenia (except for patients with extensive BM 
involvement), and/or 
grade 4 thrombocytopenia with grade ≥3 bleeding (in patients 
with extensive BM involvement), and/or
any grade ≥ 3 clinically relevant non-hematological toxicity other 
than non-optimally treated nausea and vomiting, diarrhea lasting < 
48 hours and/or grade ≥ 3 asthenia/fatigue lasting < 5 days,
may continue treatment after reducing 20% of the dose of plitidepsin 
(first reduction to 4 mg/m2, and second reduction to 3.2 mg/m2), upon 
Sponsor agreement, if patient benefit is perceived. 
Dexamethasone doses are to be reduced by 50%, up to a maximum of 
two consecutive dose reductions (first one, 20 mg Days 1,8,15 and 22, 
and second, 20 mg Days 1 and 15 of each 28-day cycle), if a patient 
experiences 
muscular toxicity of grade ≥ 3 (weakness, myalgia and/or CPK 
elevations), or 
drug-related grade ≥ 3 fatigue, or 
mood disturbances or 
agitation of grade ≥ 2 or 
grade ≥ 3 fluid retention or 
grade 4 clinically documented infection 
these dose reductions are to be implemented independently from 
plitidepsin dose reductions, if required.
Once a dose reduction has been implemented, dose will not be re-
escalated thereafter. No more than two dose reductions (of either 
compound, if required) are allowed. Patients needing additional dose 
reductions must be withdrawn from the trial. 


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Protocol APL-C-001-09
Dose reduction criteria for both study drugs, plitidepsin and 
dexamethasone, are summarized in the following table:
Toxicity
Worst 
grade
Plitidepsin
Dexamethasone
Less than 50% compliance 
with treatment schedule
Decrease to 4 mg/m2, 
then to 3.2 mg/m2
No reduction
Febrile neutropenia
≥ 3
Decrease to 4 mg/m2, 
then to 3.2 mg/m2
No reduction
Neutropenia lasting > 7 
days
(except for patients with 
extensive BM involvement)
4
Decrease to 4 mg/m2, 
then to 3.2 mg/m2
No reduction
Thrombocytopenia 
(except for patients with 
extensive BM involvement )
4
Decrease to 4 mg/m2, 
then to 3.2 mg/m2
No reduction
Toxicity
Worst 
grade
Plitidepsin
Dexamethasone
Thrombocytopenia
with grade ≥ 3 bleeding 
(in patients with extensive 
bone marrow involvement)
4
Decrease to 4 mg/m2, 
then to 3.2 mg/m2
No reduction
Any clinically relevant 
and/or non- hematological 
toxicity (except non-
optimally treated nausea 
and vomiting, diarrhea < 
48 hours and/or 
asthenia/fatigue lasting < 5 
days)
≥ 3
Decrease to 4 mg/m2, 
then to 3.2 mg/m2
No reduction
Muscular toxicity 
(weakness, myalgia and/or 
CPK elevations)
≥ 3
First episode: decrease 
to 4mg/m2, then reduce 
dexamethasone; if 
toxicity recurs, reduce 
to 3.2 mg/m2
First reduce 
plitidepsin; if 
persistence, decrease 
dexamethasone to 20 
mg Days 1,8,15,22, of 
each cycle; if toxicity 
recurs, decrease again 
first plitidepsin and, if 
persistence, then 
decrease 
dexamethasone dose to 
20 mg Days 1 and 15 
of each cycle. Two 
dose reductions are 
allowed for either 
agent (only for 
muscular toxicity).
Mood 
disturbances/agitation
≥ 2
No reduction
First reduction to 20 
mg Days 1,8,15,22 of 
each cycle, then to 20 
mg Days 1 and 15 of 
each cycle.
Fluid retention
≥ 3
No reduction
First reduction to 20 
mg Days 1,8,15,22 of 
each cycle, then to 20 
mg Days 1 and 15 of 
each cycle.
Clinically documented 
infection
4
No reduction
First reduction to 20 
mg Days 1,8,15,22 of 
each cycle, then to 20 
mg Days 1 and 15 of 
each cycle.


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Protocol APL-C-001-09
Prophylactic 
medication
1.
Arm A: 
All patients must receive the following prophylactic medication 
20-30 minutes before infusion of plitidepsin:

Ondansetron 8 mg i.v. or equivalent (granisetron 3 mg i.v. 
preferred when available).

Diphenhydramine hydrochloride 25 mg i.v. or equivalent, and

Ranitidine 50 mg i.v. or equivalent.
Oral metoclopramide and/or extended oral ondansetron (or their 
equivalents) may be used as per Investigator’s criteria/institutional 
guidelines.
2.
Arm B: No prophylactic medication specified.
Allowed 
medications/therapies
1.
Platelet and red cells transfusions. 
2.
Erythropoietin.
3.
Bisphosphonates according to the American Society of Clinical 
Oncology (ASCO) guidelines.
4.
Therapies for the treatment of preexisting and/or emergent medical 
conditions not specifically forbidden as per protocol elsewhere.
5.
Antiemetics (excluding steroids) according to institutional or ASCO
guidelines.
6.
Granulocyte colony 
stimulating 
factor 
(G-CSF)/granulocyte-
macrophage colony stimulating factor (GM-CSF) according to 
institutional or ASCO guidelines.
7.
Palliative local radiation of a plasmacytoma. The irradiated lesion 
will then not be considered an area of measurable/evaluable disease.
8.
Systemic and/or local therapies for symptomatic relief, particularly 
in the case of diarrhea or skin toxicity.
9.
Patients in the plitidepsin + dexamethasone arm who develop grade 
≥ 2 muscular toxicity may be empirically treated with oral L-
carnitine at a total daily amount of up to 3 g, divided into three 
doses, until it decreases to grade ≤ 1.
10. Adequate analgesic medication, including opioids for symptomatic 
pain relief if indicated.
11. Drugs known to prolong QT interval and/or induce Torsades de 
Pointes should be avoided whenever possible (see Appendix 7, 
drugs labeled as 1). 
Prohibited 
medications/therapies
1.
Concomitant administration of any other antineoplastic therapy.
2.
Other investigational agents.
3.
Immunosuppressive therapies, except single bolus hydrocortisone 
used eventually as treatment for hypersensitivity reactions, if 
required.
4.
Primary prophylaxis with colony-stimulating factors such as G-CSF 


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Protocol APL-C-001-09
and GM-CSF.
EVALUATION 
CRITERIA
Primary endpoint:

Efficacy:

PFS, according to IRC assessment, as per intention-to-treat 
(ITT) analysis.
Secondary endpoints:

Efficacy: objective response rate (RR); best overall response 
including rate of minor response (MR) or better (according to the 
IMWG response criteria), RR to combination treatment in patients 
who crossed over after progression on dexamethasone alone; time-
to-event endpoints: DR, and OS. Intrapatient response and PFS 
comparison of patients who crossed over from Arm B to Arm A. 
Both IRC and Investigator’s assessment will be used for the 
determination of RR, DR and PFS.

Safety: patients are evaluable for general safety if they received at 
least one dose of study treatment. Safety will be evaluated in each 
arm separately. AEs will be graded according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events 
(CTCAE), version 4.
The primary study analysis will be based on externally assessed PFS 
data in the ITT efficacy population, defined as all patients randomized 
to either treatment arm.
PFS will be calculated from randomization to the first evidence of 
progressive disease (PD) (IMWG criteria) or death due to any cause. If 
the patient receives further antitumor therapy before PD and within the 
timeframe expected for first follow-up, PFS will be censored on the date 
of the last disease assessment prior to the administration of this 
antitumor therapy. If the patient is lost to follow-up for the assessment 
of progression, or has more than one missing follow-up between the date 
of last tumor assessment and the date of progression, death or further 
antitumor therapy, the PFS will be censored at the date of last valid 
tumor assessment before the missing evaluations.
DR will be calculated from the date of first documentation of response 
to the date of disease progression or death. The same censoring rules 
described above for PFS calculation will be also considered for DR.
OS is defined as the time from the date of randomization to the date of 
death or last contact. 
An external IRC, blinded to treatment arm, will assign the objective 
response and a progression or censoring date for each patient based on 
laboratory data, radiologic and bone marrow assessments when required, 
and evaluation of all relevant clinical information, according to a 
predefined algorithm provided in a separate charter.
By design, disease response will be assessed every four weeks 
symmetrically across treatment arms irrespectively of treatment delays 
or omissions. Disease assessments (e.g., serum or urine M protein, 
sFLC) and evaluation of extent of disease will be done within two weeks 


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Protocol APL-C-001-09
before randomization and every four weeks thereafter in the absence of 
PD while on treatment. If disease progression has not occurred at
treatment termination, then disease assessments should continue every 
four weeks until evidence of disease progression, start of subsequent 
anticancer treatment, or death, whichever occurs first.
PFS and objective tumor response will be assessed according to IMWG 
criteria. Centralized laboratory reports and copies of CT scans, MRI (in 
case of soft tissue plasmacytoma) and any other documented means to 
evaluate tumor response or progression should be available for IRC 
review.
PHARMACO-
KINETIC 
EVALUATIONS
Plitidepsin pharmacokinetics (PK) will be evaluated in a minimum of 
100 patients included in the plitidepsin/dexamethasone arm (Arm A).
A total of 13 blood samples will be collected during the first three 
infusions [infusions 1 and 2 of Cycle 1 (Days 1 and 15), and infusion 1 
of cycle 2 (Day 1)] using a sparse sampling schedule. Last sample will 
be collected immediately previous to infusion 2 of cycle 2 (Day 15) (see 
details in Table 5 of this protocol).  
Pharmacokinetic parameters will be calculated with population methods, 
using the population PK model previously developed with PK data from 
411 patients treated with single-agent plitidepsin. 
QT SUBSTUDY
The primary objective of the QT substudy is to assess the potential 
effects of plitidepsin administered at a therapeutic dose on the duration 
of the QT/QTc interval, measured by ECGs, in patients with 
relapsed/refractory multiple myeloma. Secondary objectives are: to 
evaluate QTc changes over the treatment period; to characterize the 
plitidepsin (real and estimated) whole blood concentration/QTc 
relationship (or PK/PD relationship); and to explore related ECG 
parameters.
This substudy will be conducted on patients included in study APL-C-
001-09 and randomized to the experimental arm (plitidepsin + 
dexamethasone), who voluntarily sign and date the informed consent 
form to participate in the QT substudy, and who fulfill the following at 
screening for the main study:

A 12-lead ECG consistent with normal cardiac conduction and 
function, showing sinus rhythm, pulse rate between 45 and 100 
bpm, QRS interval <120 ms, and PR interval <200 ms.

Blood pressure between 90 and 150 mmHg systolic, inclusive, 
and not higher than 90 mmHg diastolic.

Serum electrolyte levels ≤ grade 1 (i.e. Ionic Ca++:  1.0 – 1.5 
mmol/L; K+: 3 – 5.5 mmol/L; Mg++:  0.5 – 1.23 mmol/L). 

Prior exposure to anthracyclines at a cumulative dose of 
doxorubicin or equivalent, ≤ 450 mg/m². 

Patients who at screening are not on medication that is known to 


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Protocol APL-C-001-09
prolong the QT interval. Patients must have been off these 
medications for a minimum of 48 hours prior to plitidepsin 
administration on Day 1 and Day 15.
This substudy will be conducted at some of the sites participating in 
study APL-C-001-09.
Evaluations of the effect of plitidepsin on QTc:
ECGs will be obtained digitally using an ECG continuous 12-lead 
digital recorder on Day 1 and Day 15. The change in QTc from baseline 
to each postdose time point on Day 1 and Day 15 (ΔQTc) will be 
evaluated. The QTc measurements at each of the scheduled time points 
along with their corresponding real and estimated whole blood 
plitidepsin concentration will be compared to explore any concentration-
effect relationship for plitidepsin.
STATISTICAL 
CONSIDERATIONS
Randomization
Eligible patients will be stratified according to their ECOG-PS score (0 
and 1 vs. 2) and Durie-Salmon stage (I/II vs. III) and then randomized 
using a 2:1 randomization procedure to Arm A (plitidepsin in 
combination with dexamethasone) or Arm B (dexamethasone alone). 
Patients will be assigned to each group by strata random lists, so that a 
patient will have a two-thirds chance of getting Arm A (plitidepsin in 
combination with dexamethasone) and a one-third chance of getting 
Arm B (dexamethasone alone). The random permuted blocks method 
will be used; the size of the blocks in the randomization list will be fixed 
and not accessible to the investigators. To select the blocks, a uniform 
(0, 1) variable with a random seed will be used.
Sample size
Approximately 210 progression or death events would be needed in this 
trial to detect a HR of 0.625 in favor of the combination arm (equivalent 
to an increase of 60% in PFS, i.e., from 10 to 16 weeks, from 12 to 19.2 
weeks, from 16 to 25.6 weeks, etc.) with 90% power and 1-sided 2.5% 
significance level. As a preliminary hypothesis, it is estimated that up to 
250 randomized patients will be needed to achieve the 210 events in 24-
30 months.
Statistical Analyses
All randomized patients during the trial will be included in the final 
efficacy analyses, while the first 40 patients evaluable for response in 
Arm A will be included in an early futility analysis. A response rate 
(IMWG criteria) of at least 30% (twelve or more responses by IRC 
review) will be taken as threshold for continuation of the study. A 
minimum response rate of 30% has been considered as clinically 
significant in this setting. This result will ensure that the lower limit of 
the exact binomial 95% Confidence Interval for the response rate will be 
greater than 15% (95% CI in case of 12 responses would be 16.6% -
46.5%). 
No claim for superiority in efficacy will be formulated in this interim 
analysis and no alpha-spending for the analysis of PFS is foreseen.


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Protocol APL-C-001-09
The main analysis will be conducted after 210 progression and/or death 
events are observed. The PFS assessed by the IRC will be used for the 
primary analysis, while the Investigator assessment will be used for the 
secondary analysis of PFS.
An interim analysis of OS will be performed concomitantly with the 
final PFS analysis. A final analysis of OS will be performed when 80% 
of death events (approximately 200 death events) have occurred, or 24 
months after the inclusion of the last patient, whichever occurs first.
Note: Two years after the last patient accrual, on 19 May 2017, the final OS 
analysis was done based on a total of 195 death events (i.e., 76.5% of the 255 
randomized patients): 123 events in Arm A (plitidepsin plus dexamethasone) 
and 72 events in Arm B (dexamethasone). Then, the duration of this study is 
prolonged for six additional months, until 19 November 2017, in order to 
continue follow-up in the alive patients, and then to be able to reach the pre-
specified total of 80% of death events (approximately 204 death events) or even 
more. If the required death events are not achieved on 19 November 2017, the 
study might be further extended by three to six months.
The unstratified log-rank test will be used to compare the PFS of Arm A 
and B. A stratified log-rank test for the main endpoint (PFS) will be 
performed as supportive analysis. 
Secondary time-to-event endpoints (DR, OS) will be analyzed according 
to the Kaplan-Meier method and compared between treatment groups 
using the log-rank test. 
Counts and percentages, with their corresponding exact 95% confidence 
intervals, will be calculated for the response rate (IMWG criteria and, 
separately, minor response). The Fisher’s exact test will be used to 
compare the RRs of Arm A and B.
Both the IRC and Investigator’s assessments will be used for RR, PFS 
and DR.
Efficacy parameters vs. baseline covariates will be analyzed and 
appropriate tests will be used (i.e., Fisher's exact test and logistic 
regression for categorical variables; the log-rank test or Cox regression 
for time-to-event variables, etc.).
Exploratory intrapatient comparison of response and PFS (before and 
after crossover) will be performed for patients who switch from Arm B 
to Arm A after disease progression.
ANTICIPATED 
STUDY DATES

Protocol submission: 1Q2010.

Planned start date (first patient on study): 2Q2010.

Complete enrollment: 60 months (2Q2010-2Q2015).

Planned study termination date: it will be set after the occurrence of 
80% of death events, 24 months after the accrual of the last 
randomized patient, or IDMC recommendation (whichever occurs 
first).
Note: Two years after the last patient accrual, on 19 May 2017, the final 
OS analysis was done based on a total of 195 death events (i.e., 76.5% of 
the 255 randomized patients): 123 events in Arm A (plitidepsin plus 
dexamethasone) and 72 events in Arm B (dexamethasone). Then, the 


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Protocol APL-C-001-09
duration of this study is prolonged for six additional months, until 19 
November 2017, in order to continue follow-up in the alive patients, and 
then to be able to reach the pre-specified total of 80% of death events 
(approximately 204 death events) or even more. If the required death 
events are not achieved on 19 November 2017, the study might be further
extended by three to six months.
The futility analysis is foreseen after 40 patients evaluable for response 
are recruited in Arm A, approximately 12 months after the recruitment 
start.
All patients on active treatment at the date of study termination will be 
offered to continue to receive plitidepsin-based treatment off-study 
according to the Investigator’s criteria and upon Sponsor agreement.


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Protocol APL-C-001-09
SCHEDULE OF ASSESSMENTS AND PROCEDURES
PROCEDURE
Pre-
treatment
Treatment
First cycle
Treatment 
Subsequent cycles
End of 
treatment
Follow-
up 16
1
8
15
22
29=1
8
15
22
Written informed consent
Before any 
procedures
-
-
-
-
-
-
-
-
-
-
Demographic data
-14  to  0
-
-
-
-
-
-
-
-
-
-
Medical history/ Baseline condition
-14  to  0
-
-
-
-
-
-
-
-
-
-
Primary diagnosis / Prior 
treatment(s)
-14  to  0
-
-
-
-
-
-
-
-
-
-
Assessment of signs and symptoms1
-14  to  0
-
-
-
-
-
-
-
-
-
-
Complete physical examination, 
including weight and height1 and 
BSA.
-14  to  0
-
-
-
-

-
-
-

-
Performance status (ECOG)
-14  to  0

-

-

-

-


Vital signs (heart rate, blood 
pressure, temperature)
-14  to  0
-

-

-

-

-
Hematology2,3
-7  to  0
-
-

-

-

-

-
Coagulation tests2,4
-7  to  0
-
-
-
-

-
-
-

-
Biochemistry A2
-7  to  0
-
-

-

-

-

-
Biochemistry B2
-7  to  0
-
-
-
-

-
-
-

-
Pregnancy test (if applicable)5
-7  to  0
Repeat if applicable
-
ECG (before treatment on both 
arms) 6
-7  to  0

-

-

-

-

-
LVEF by ECHO or MUGA 7
-14 to 0
Every 12 weeks ( ± 2 week tolerance)

-
Pharmacokinetics 8
-



-
-
-
-
-
Intercurrent events, concomitant 
diseases and treatments
-14  to  0
Throughout study
-
Adverse events
NA
Throughout study
14
Local serum and Urine proteins9
-28 to 0
-
-
-
-
-
-
-
-
-
-
Central Lab Serum protein 10
NA

-
-
-

-
-
-

15
Central Lab Urine protein 11
NA

-
-
-

-
-
-

15
Serum β-2 microglobulin 
-14  to  0
Every 8 weeks
15
-
Bone marrow 12
-28  to  0
To confirm a presumed CR 
If  
clinically 
indicated
If 
clinically 
indicated 
Radiological tumor assessment only 
if soft tissue plasmacytoma is 
present at baseline 13
-28  to  0
Every 8 weeks or if response is observed or if 
clinically indicated

13
Skeletal evaluation 17
-28  to  0
(+1 week 
tolerance)
If clinical symptoms suggest new bone lesions

If 
clinically 
indicated 
Plitidepsin treatment (Arm A only)
-

-

-

-

-
-
-
Dexamethasone treatment (both 
arms)
-








-
-
QT substudy 18

See Appendix 8
-
A 2-day window is allowed for Hematology, Biochemistry A, Serum Protein, Urine Protein and Serum β-2 
Microglobulin.
A 5-day window is allowed for Biochemistry B and Coagulation Tests.
A 2-week window is allowed for radiological tumor assessment.
A 2-week window is allowed for LVEF assessment by ECHO or MUGA.


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Protocol APL-C-001-09
Note: windows for laboratory assessments only apply prior to the scheduled infusion (e.g., 2-day window = within 48 
hours before the next scheduled infusion, etc.). Windows for radiological tumor assessment and LVEF assessment by 
MUGA or ECHO apply whether prior to or after the correspondent scheduled infusion.
1.
Repeat prior to first infusion, if treatment will be administered more than 2 weeks after the screening tests.
2.
Repeat prior to first infusion, if treatment will be administered more than 1 week (2 days tolerance) after 
the screening tests. If CTCAE Grade ≥3 occurs, the abnormal test(s) should be assessed at least every 2-3 
days until recovery.
3.
At least every 2-3 days in the case of grade 4 non-febrile neutropenia and every day in case of grade 4 
febrile neutropenia.
4.
Close monitoring of patients taking oral anticoagulants is required. 
5.
Serum human chorionic gonadotropin (HCG). Repeat during treatment if applicable, always prior to study 
drug administration.
6.
It should allow rhythm definition (at least 30 seconds of duration). Before each study drug administration, 
symmetrically on both arms. After the first two cycles, ECG will be performed only on Day 1 of each 
cycle.
7.
During treatment, LVEF (when due) will be performed within 7 days of plitidepsin administration, except 
in non-primarily cardiac origin acutely ill hospitalized patients, until resolution. 
8.
Plitidepsin pharmacokinetics (PK) will be evaluated in at least 100 patients receiving both plitidepsin and 
dexamethasone. A total of 13 blood samples will be collected during the first three infusions [infusions 1 
and 2 of Cycle 1 (Days 1 and 15), and infusion 1 of Cycle 2 (Day 1)] using a sparse sampling schedule. 
Last sample will be collected immediately previous to infusion 2 of Cycle 2 (Day 15) (see details in Table 
5).
9.
Serum and urine protein analysis performed at the institution to assess/document disease relapse after last 
treatment will be used for screening (tests performed within 4 weeks prior to registration will be allowed).
10. Serum protein electrophoresis, immunoglobulins quantification, M-protein identification and quantification, 
serum free light chains (sFLC) ratio and immunofixation will be performed in the Central Lab starting on 
Day 1 of Cycle 1 prior to treatment (complete protein panel). Patients with secretory MM will be followed 
with serum electrophoresis, immunoglobulins quantification and M protein quantification; patients with 
oligo or non-secretory MM will be followed with sFLC ratio, in case it has been abnormal at study entry; in 
case of M protein disappearance, immunofixation will be done to confirm CR, and if CR is confirmed, 
sFLC ratio will be performed, to determine stringent complete response (sCR). All protein assays will be 
done symmetrically every four weeks (i.e., Day 1 of each 4-week cycle, with a window of ± 2 days) in both 
treatment arms, irrespectively of treatment delays or omissions.
11. Urine immunoelectrophoresis and immunofixation in Central Lab: on Day 1 of Cycle 1, and afterwards, 
only if Bence-Jones proteinuria was present at entering the study. To be done symmetrically every 4 weeks 
(with a window of ± 2 days) in both treatment arms, irrespectively of treatment delays or omissions.
12. At screening (within 4 weeks prior to registration). In all patients, BM evaluation is mandatory at screening 
and while on treatment in case of CR (including flow cytometry or immunohistochemistry, to demonstrate 
the presence of clonal plasma cells, only in those patients with presumed CR). In patients with non-
secretory MM, it must be repeated 6 weeks later to confirm response or as clinically indicated. 
13. In case of measurable soft tissue plasmacytoma, involvement assessments should be done to evaluate all 
known affected sites every 8 weeks to confirm response or as clinically indicated. In truly non-secretory 
patients who discontinued treatment without progression, and only evaluable by measurable 
plasmacytomas, radiological assessments should continue every 8 weeks until progression. 
14. Patients withdrawn with a drug-related AE should be followed until recovery. Beyond 30 days after the last 
administration of study drug, only those procedures that are relevant to any persisting toxicities need to be 
performed.
15. Only in patients who discontinued treatment without documented disease progression.
16. Bone marrow evaluation, radiological tumor assessment and skeletal evaluation will be performed only on 
pre-treatment and treatment evaluations. These evaluations will not be performed after the end of treatment. 
After the end of treatment, all patients will be followed every three months for survival until death, or until 
the date of study termination. The follow-up visits will be performed by phone only if the patient is unable 
to go to the study center owing to the seriousness of his/her disease. This will only apply to patients who 
are followed up after discontinuing treatment due to disease progression.
17. May be evaluated using CT-scan or X-ray, provided the same procedure is used throughout the study.
18. Optional substudy (a separate ICF needs to be signed).
Note: One patient was still undergoing treatment on 19 May 2017. However, as the primary endpoint of the study 
(progression-free survival) was fulfilled, and this extended follow-up is focused only on survival, no information such 
as central laboratory data or images will be sent for independent review. Nevertheless, laboratory determinations or 
images will be done locally, if clinically indicated, in order to perform tumor assessment.    


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Hematology: Differential white blood cells (WBC), hemoglobin, hematocrit and platelets.
Biochemistry A: AST, ALT, total bilirubin, direct bilirubin in case total bilirubin is above ULN, alkaline 
phosphatase (AP), creatinine, calculated creatinine clearance (Cockcroft and Gault´s formula; see Appendix 3), 
glucose, serum electrolytes (Na+, K+, Mg++, Ca++), creatine phosphokinase (CPK), CPK-MB fraction (should be 
measured only if CPK is abnormally high) and troponin I. 
Biochemistry B: Uric acid, lactate dehydrogenase (LDH), total proteins and albumin.
Coagulation tests: PT, PTT and INR.


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
ABP
Arterial Blood Pressure
AE(s)
Adverse Event(s)
ALL
Acute Lymphoblastic Leukemia
ALT
Alanine Aminotransferase
ANC 
Absolute Neutrophil Count
ANOVA
Analysis Of Variance
AP
Alkaline Phosphatase
ASCO
American Society of Clinical Oncology
ASH
American Society of Hematology
AST
Aspartate Aminotransferase
AUC
Area Under The Curve
βhCGs
Beta Human Chorionic Gonadotrophins
BM
Bone Marrow
Bmax
Maximal Plitidepsin Concentration into Red Blood Cells
BP
Blood Pressure
BPM
Beats Per Minute
BSA
Body Surface Area
CBP
CREB binding protein
CDK
Cyclin-dependent Protein Kinase
C
Cycle
CI
Confidence Interval
CL
Clearance
Cmax
Maximum Plasma Concentration
CPK
Creatine Phosphokinase
CPK-MB
Serum CPK Isoenzymes (Found In Cardiac Muscle)
CR
Complete Response
CrCl
Creatinine Clearance
CRF
Case Report Form
CRO
Contract Research Organization
CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
CT-scan
Computed Tomography Scan
CV
Cardiovascular
d/D
Day(s)
DI
Dose Intensity
DLT
Dose-Limiting Toxicity
DNA
Deoxyribonucleic Acid
DR
Duration of Response
ECG
Electrocardiogram


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ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
EOI
End of Infusion
EPO
Erythropoietin
ER
Endoplasmic Reticulum
EU
European Union
GC
Glucocorticoids
GCP
Good Clinical Practice
G-CSF
Granulocyte Colony Stimulating Factor
GGT
-Glutamyltranspeptidase
GI
Gastrointestinal
GM-CSF
Granulocyte/Macrophage Colony Stimulating Factor
GMT
Greenwich Mean Time
GR
GC Receptor
GSH
Gluthatione Reduced
h
Hour(s)
HAT
Histone Acetyltransferase
Hb
Hemoglobin
HBV
Hepatitis B Virus
HCG
Human Chorionic Gonadotropin
HCV
Hepatitis C Virus
HDAC
Histone Deacetylase
HIV
Human Immunodeficiency Virus
HBR
Heart Beating Rate
HR
Hazard Ratio; Heart Rate
IB
Investigator Brochure
IC50
Half Maximal Inhibitory Concentration
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committees
Ig
Immunoglobulin
IMWG
International Myeloma Working Group
IMP
Investigational Medicinal Product
INR
International Normalized Ratio
IRB
Institutional Review Board
IRC
Independent Review Committee
ISS
International Staging System
i.v.
Intravenous


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IVRS
Interactive Voice Response System
ITT
Intention-To-Treat
Kd
Plitidepsin Plasma Concentration at which the Plitidepsin Bound to Red Blood Cells is 
Half-maximal
LDA
Low Density Array
LDH
Lactate Dehydrogenase
LLN
Lower Limit of Normal
LVEF
Left Ventricular Ejection Fraction
MEF
Mouse Embryonic Fibroblast
MM
Multiple Myeloma
MP
Melphalan plus Prednisone
MR
Minor Response
MRI
Magnetic Resonance Imaging
ms
Milliseconds
MTD
Maximum Tolerated Dose
MTT
3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
MUGA
Multiple-gated Acquisition Scan
NCI
National Cancer Institute
NCI-CTC
National Cancer Institute Common Toxicity Criteria
NHL
Non-Hodgkin Lymphoma
NSCLC
Non-Small Cell Lung Cancer
ORR
Overall Response Rate
OS
Overall Survival
PCR
Polymerase Chain Reaction
PD
Progressive Disease; Pharmacodynamics
PFS
Progression-free Survival
PK
Pharmacokinetics
p.o.
Per os, Oral(ly)
PR
Partial Response
PS
Performance Status
PT
Prothrombin Time
PTT
Partial Thromboplastin Time
PTCL
Peripheral T-Cell Lymphoma 
Q2
Intercompartmental Exchange Flow for the Shallow Compartment
Q3
Intercompartmental Exchange Flow for the Deep Compartment
q4w
Every Four Weeks
qPCR
Quantitative Polymerase Chain Reaction
RBC
Red Blood Cell
RD
Recommended Dose
RNA
Ribonucleic Acid


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RP-HPLC
Reversed-Phase High Performance Liquid Chromatography
RR
Response Rate
RT
Plasma-to-blood Ratio; Reverse Transcription, Room Temperature
SAE(s)
Serious Adverse Event(s)
SCLC
Small Cell Lung Carcinoma
sCR
Stringent Complete Response
SCT
Stem Cell Transplantation
SD
Stable Disease
sFLC
Serum Free Light Chains
SOI
Start Of Plitidepsin Infusion
SPC
Summary of Product Characteristics
t1/2
Half-life
TdP
Torsades de Pointes
TSA
Trichostatin A
TTP
Time to Tumor Progression
ULN
Upper Limit of Normal
UV light
Ultraviolet Light
US
Ultrasound (Cardiac)
V1
Central Volume of Distribution
V2
Volume of Distribution of the Shallow Compartment
V3
Volume of Distribution of the Deep Compartment
VEGF
Vascular Endothelial Growth Factor
VEGFR-1
Vascular Endothelial Growth Factor Receptor Type-1
VGPR
Very Good Partial Response
Vss
Volume of Distribution in Steady State
WBC
White Blood Cells


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1
INTRODUCTION
Despite recent advances in the treatment of multiple myeloma (MM), most patients 
ultimately relapse. The disease remains incurable and there is an urgent need for 
developing new therapeutic options including investigational drugs. The addition of 
corticosteroids to active new investigational drugs in MM is a major way to improve the 
outcome, particularly because this agent has non-cross-resistance and a different 
toxicity profile when compared to other agents commonly used for MM treatment.
1.1
OVERVIEW OF THE DISEASE
MM is a malignant plasma-cell disorder characterized by the production of a 
monoclonal protein from plasma cells in the bone marrow (BM). Information from the 
National Cancer Institute (NCI) indicates that, in the USA, 19,920 new cases of MM 
will be diagnosed in 2009 and 10,690 patients will die from their disease (1). Similar 
figures occur in Europe, with an incidence of 6.0/100,000 habitants per year and a 
mortality rate of 4.1/100,000 habitants per year (2). In the Western hemisphere, about 
1% of cancer-related deaths are due to myeloma. Traditionally, MM has been staged 
according to the Durie-Salmon system, based on the amount of abnormal monoclonal 
immunoglobulin in the blood or urine; blood calcium levels; the amount of bone 
damage shown by X-rays, blood hemoglobin levels, and renal function (3). More 
recently, the International Staging System (ISS), which relies on the levels of albumin 
and beta-2-microglobulin, has been validated (4). Nevertheless, though both systems are 
based on easily obtained clinical and laboratory parameters, and predict for survival, it 
has recently been suggested that newer parameters should be included in the prognostic 
initial evaluation of MM patients (5, 6). The present recommendation is to include both 
classifications in clinical trials, as they provide complementary information (6).
Recent advances have identified new prognostic markers, such as the complete deletion 
of chromosome 13 or its long arm as detected by karyotyping, the t(4;14) or t(14;16) 
translocations, and the increased bone marrow microvascular density.
The disease primarily affects elderly individuals, with a median age of 60 years at 
diagnosis. From the time of diagnosis, the survival without treatment is between 6 to 12 
months and extends to three years with chemotherapy. MM is treatable but rarely 
curable. Most patients receive multiple treatments over the course of their disease, and 
the precise sequence of therapy and regimens used can be quite variable. With standard-
dose chemotherapy, patients have a median survival of 24–30 months. Twenty-five 
percent of patients survive five years or longer, and the 10-year survival is 
approximately 3% (1).
1.2
CURRENT TREATMENT FOR MULTIPLE MYELOMA
Failure of standard-dose chemotherapy to cure this disease has led to study the use of 
dose intensified chemotherapy regimens. Conditionings may involve ablative or reduced 
intensity, non-myeloablative regimens, and may be followed by autologous or 
allogeneic stem-cell rescue. Despite recent advances in supportive care measures, the 
morbidity and mortality related to intensified chemotherapy regimens are still of 
concern, particularly in the aged and frail population; therefore, this treatment option 
has been reserved only for younger patients with adequate performance status (7).


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Currently the standard treatment for suitable MM patients aged <65 years is induction 
chemotherapy followed by autologous stem-cell transplantation (SCT), which has been 
associated with increased response rates (complete response of 30-40%), overall 
survival (54-62 months) and event-free survival (25-43 months) when compared to 
traditional chemotherapy (7), although these results are currently being challenged by 
the high response rates achieved with the introduction of the so called “novel agents”, 
which are increasingly being used as part of first-line combinations.
In elderly patients, namely those over 65 years of age, SCT has been associated with 
unacceptably higher morbidity and mortality. Therefore, more conservative approaches, 
such as the use of standard-dose melphalan plus prednisone (MP) or prednisone alone 
(but at higher doses) have become a widely-accepted standard of care (8). However, MP 
is now challenged, as new therapeutic options like thalidomide, lenalidomide and 
bortezomib, initially approved in the relapsed/refractory setting, are now moving 
upfront as part of new combination regimens. Two recently finished randomized trials 
have shown the superiority of adding thalidomide to MP compared to MP alone in 
elderly patients (9, 10). Likewise, the VISTA trial has shown superiority when 
bortezomib was added to MP in a similar patient population (11).
In patients with relapsed or refractory MM, thalidomide, lenalidomide and bortezomib 
have been used as single agents, with responses of 30%, 38% and 27%, respectively
(12-14). However, in these and other studies evaluating therapies in relapsed/refractory 
MM patients (15-18), progression-free survival (PFS) and time to progression (TTP) 
were in the range of 4-9 months, thus demonstrating a step forward, but also the
limitations and the current need for new therapeutic options in this truly palliative 
disease setting.
Despite all these therapeutic advances, MM remains an incurable disease. No standard 
treatment is available and therapeutic options are limited, thus representing a clear 
unmet medical need. Options may include palliative care, steroid treatment, oral 
alkylating agents, or participation in clinical trials. Of note, a previous exploratory 
phase II trial in which plitidepsin was administered with or without the addition of 
dexamethasone has provided evidence of activity in this patient population (see details 
in Section 1.3.3.3).
In conclusion, all these innovative approaches have significantly changed the available 
therapeutic 
options, 
especially 
in 
elderly 
patients 
and 
in 
patients 
with 
relapsed/refractory MM, as they are not likely to show cross-resistance or the toxicities 
commonly seen with traditional chemotherapy regimens based on alkylators and 
anthracyclines. Nonetheless, newer toxicity patterns are also emerging, such as an 
increased thrombotic risk and neurotoxicity, which may be cumulative. These new 
drugs are being combined with classic agents, such as melphalan, prednisone and 
anthracyclines, as an upfront treatment; however, their exact role and sequence in the 
changing landscape of MM therapy remains to be defined.
1.2.1
Plitidepsin
The Sponsor is committed to the development of new drugs in an effort to broaden the 
spectrum of current antitumor therapies. Chemically, plitidepsin is a now fully synthetic 
natural occurring depsipeptide originally extracted from the Mediterranean Sea tunicate 


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Aplidium albicans. Although the main mechanism of action by which plitidepsin 
inhibits cell growth and/or induces cell death remains to be fully characterized, the 
major effects of plitidepsin can be at least partially attributed to a cell cycle block in the 
G0/G1 phases and the induction of apoptosis (19-21) via activation of the JNK pathway; 
this activation leads to a decreased production of intracellular glutathione, an increase in 
reactive oxygen species and an alteration of the mitochondrial membrane potential, 
ultimately leading to both caspases-dependant and independent apoptosis. In addition to 
the pro-apoptotic properties of plitidepsin, the molecule has demonstrated 
antiangiogenic properties in several pre-clinical models via direct activity on vascular 
endothelial growth factor (VEGF)-stimulated angiogenesis. In fact, plitidepsin has been 
demonstrated to reduce the secretion of VEGF and its receptor type 1 (VEGFR-1) from 
MOLT-4 human leukemia cells in vitro (22). It seems that the majority of the 
pharmacologic activity of plitidepsin can be attributed to a combination of these cellular 
effects in vivo.
Antitumor activity has been displayed by plitidepsin in in vitro and in vivo models. In 
addition, this observation has been sustained in early clinical trials as single agent, 
showing clinical responses in patients with hematological malignancies as well as solid 
tumors. The toxicity of plitidepsin in normal hematopoietic tissue is several folds lower 
than in tumor cells. More importantly, this observation translates into a lack of clinically 
significant hematological toxicity in clinical trials to date, even in leukemia/lymphoma 
patients with limited bone marrow reserve capacity. Consequently, plitidepsin may 
display a positive profile for combination with other agents in chemotherapy regimens, 
avoiding overlapping toxicity.
1.3
INFORMATION ON STUDY DRUG: PLITIDEPSIN
Please refer to the Investigator's Brochure (IB) for full information on plitidepsin.
1.3.1
Name and Chemical Information
Aplidin® is the trade name for plitidepsin [leucine, 1-(1,2-dioxopropyl) prolyl-N-
methyl-leucylthreonyl-4-amino-3-hydroxy-6-methylheptanoyl-4-hydroxy-2,5-dimethyl-
3-oxohexanoyl-N, 0-dimethyltyrosylprolyl, O-lactone)], a cyclic depsipeptide originally 
isolated from a Mediterranean marine tunicate, Aplidium albicans, which is currently 
manufactured by total synthesis. 
1.3.2
Non-clinical Data
1.3.2.1
Mechanism of Action in Cell Lines
The major effects of plitidepsin can be specifically attributed to the induction of 
apoptosis secondary to oxidative stress and activation of JNK activity. Exposure of 
cultured human cervical cancer (HeLa) cells to plitidepsin induced oxidative stress 
resulting in cellular apoptosis (23), and a rapid and sustained activation of JNK, p38 
MAPK and ERK in human breast cancer cells (MDA-MB-231) (24). In fact, genetically 
engineered mouse embryo fibroblast (MEFs) which did not express any JNK isoforms 
were at least an order of magnitude less sensitive to plitidepsin (21). JNK has been 
shown as a critical component in plitidepsin-induced cytotoxicity through a decrease in 
the intracellular reduced glutathione (GSH) levels which, in turn, increases the levels of 


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reactive oxygen species (24). Plitidepsin effects on the Rac1, a pleiotropic regulatory 
protein, would contribute to the sustained activation of JNK (19, 25). Additionally a cell 
cycle inhibitor, p27 (kip1), has been shown to determine plitidepsin sensitivity in vitro, 
on a panel of mouse sarcoma cells from resected tumors (26). Data on human renal cell 
carcinoma lines (A-498 and ACHN) confirmed the oxidative operating mechanism and 
recent studies on human melanoma cell lines (SK-MEL-28 and UACC-257) have again 
involved a Rac1/JNK pathway in the apoptotic cell arrest induced by plitidepsin (24, 
25), thus demonstrating a common mechanism in cells of different tumor origins. Latest 
studies have shown that plitidepsin is able to increase levels of cell membrane 
phospholipid oxidation and deoxyribonucleic acid (DNA) oxidation in vitro (19).
Apart from its pro-apoptotic properties, plitidepsin has also demonstrated 
antiangiogenic effects. The addition of the drug reduces the active secretion of VEGF 
and the expression of its receptor (VEGFR-1) on human leukemia (MOLT-4) cells in 
vitro (22), suggesting that the block of cell growth might be mediated by dual inhibition 
of VEGF autocrine loop. Supporting these findings, plitidepsin has been shown highly 
cytotoxic on acute myelogenous leukemia cells, both on regular cultures (K-562, HEL 
and HL-60) and on blasts obtained from patients (27). Furthermore, plitidepsin was able 
to reduce the secretion of VEGF in a dose-dependent manner, thus confirming previous 
observations. At the functional level, plitidepsin inhibited spontaneous and growth 
factor-induced angiogenesis, prevented proliferation, migration and invasiveness, and 
hampered formation of capillary-like tridimensional structures, in in vivo and in vitro
models (28).
In summary, it appears that the pharmacologic activity of plitidepsin can be attributed, 
at least in part, to a combination of pro-apoptotic and antiangiogenic effects in vivo.
1.3.2.2
In vitro and in vivo Data as Single Agent
In vitro studies demonstrated antiproliferative activity against a broad spectrum of 
tumor types, namely bladder cancer, breast cancer, stomach cancer, lung cancer, 
melanoma, neuroblastoma, prostate cancer, thyroid cancer (with IC50 values ranging 
from 10-7 to 10-9 M), and leukemia, myeloma and lymphoma (with IC50 values ranging 
from 10-8 to 10-9 M) (29). 
In addition, a model in MM has been explored (30). Plitidepsin exhibited, at clinically 
achievable concentrations, potent in vitro activity against primary MM tumor cells and a 
broad spectrum of human MM cell lines, including cells resistant to conventional (e.g., 
dexamethasone, alkylating agents, and anthracyclines) or novel (e.g., thalidomide and 
bortezomib) anti-MM agents. Plitidepsin was active against MM cells in the presence of 
proliferative/antiapoptotic cytokines or BM stromal cells and had additive or synergistic 
effects with some of the established anti-MM agents. The anti-MM effect of plitidepsin 
was associated with suppression of a constellation of proliferative/antiapoptotic genes 
and up-regulation of several potential regulators of apoptosis. 
In conclusion, plitidepsin showed consistent cytotoxic activity against a broad selection 
of human-derived solid tumors cell lines such as lung, breast, thyroid, prostate, stomach, 
bladder, and kidney, as well as human malignant cell lines of hematological origin.
In the hollow fiber in vivo model, in which athymic rats were treated with i.v. 
plitidepsin, tumors of the bladder, stomach, and prostate were shown to be susceptible 


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to the drug. In xenograft models, activity was noted against human renal and pancreatic 
tumors when injected to athymic mice. 
Additionally, the antitumor and antiangiogenic effects of plitidepsin were evaluated in 
the 5T33MM syngeneic orthotopic model of MM (31). In vitro, plitidepsin inhibited 
DNA synthesis and induced an arrest in transition from G0/G1 to S phase. Furthermore, 
plitidepsin induced apoptosis by lowering the mitochondrial membrane potential. For 
the in vivo experiment, i.p.-injected plitidepsin was well tolerated by the mice and 
reduced serum paraprotein concentration by 42% (p<0.001), while BM invasion with 
myeloma cells was decreased by 35% (p<0.001). Plitidepsin also reduced the myeloma-
associated angiogenesis to basal values. This antiangiogenic effect was confirmed in 
vitro and may be explained by inhibition of endothelial cell proliferation and vessel 
formation. In summary, these data indicate that plitidepsin is well tolerated in vivo and 
its antitumor and antiangiogenic effects support the use of the drug in MM (32).
1.3.2.3
In vitro and in vivo Data in Combination
Clinical experience in the management of MM patients supports the concept that drug 
combinations induce higher response rates than single agents. The ability of plitidepsin 
to increase the activity of other established anticancer agents was assessed in several 
human tumor cell lines. The combination of plitidepsin with dexamethasone that was 
selected for further development in solid tumors and preclinical data is summarized 
below.
1.3.2.3.1 Non-clinical Data of the Plitidepsin-Dexamethasone Combination
The combination of plitidepsin with dexamethasone was explored regarding the 
viability of MM1.S and U266-LR7 cells. Both non-constant ratio (for suboptimal doses 
of drugs) and constant ratio experimental designs were used. The effects of single and 
combined treatments after 72 hours were evaluated by MTT assays. The results clearly 
show that plitidepsin increased the anti-MM effect of dexamethasone. The combination 
was additive but tended to be synergistic at higher doses (30) (Figure 1).
0.2
0.4
0.6
0.8
1.0
2.0
4.0
6.0
Plitidepsin + Dexamethasone CR
Combination.
Fraction affected
Figure 1. MM1.S cell line, 48 h incubation
Similar results were obtained in a study by Medina et al. (Internal Report, March 2008), 
where the combination of plitidepsin and dexamethasone (at a fixed plitidepsin to 
dexamethasone ratio of 1:50) was tested in four MM cell lines (MM1.S, ARP, RPMI-


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8226 and MM1.R (dexamethasone-resistant). As shown in Figure 2, the combination 
(Apl+Dex) resulted in a significant increase in cell toxicity when added to the MM cell 
lines MM1.S, ARP, and RPMI-8226 compared to either drug alone (Apl/Dex). In 
contrast, only plitidepsin had an effect on the dexamethasone-resistant cell line, 
MM1.R.  
Figure 2. Activity of the combination plitidepsin + dexamethasone in MM cell lines
This combination was synergistic for the cell lines MM1.S, ARP, and RPMI-8226 at all 
tested (nanomolar) concentrations of the drugs, while it was additive for MM1.R at high 
concentrations.
1.3.2.3.2
Molecular Rationale Based on Dexamethasone Mechanism of Action and 
Similarities with Plitidepsin Activity.
The pleiotropic molecular effects elicited by the plitidepsin treatment do not allow 
concluding which pathways are the most important for its antitumor activity; however,
they offer a potentially unique mechanism of action and a major therapeutic advantage. 
In particular, they may account for the synchronized targeting of different specific 
proliferative/antiapoptotic pathways in MM tumor cells. In fact, gene expression 
profiling results in tumor cells provide a framework for designing a combinatorial 
therapy to potentiate each individual antitumor effect. It is likely that their pleiotropic 
and synergistic effects in vitro over MM cells may neutralize the pathways that enable 
tumors to evade cell death and to become resistant to anticancer treatment.
Glucocorticoids (GCs), such as dexamethasone, induce apoptosis in the hematological
lineage, while supporting the survival of several non-hematological tissues, such as the 
mammary gland, ovary, liver or fibroblasts (33-35). GCs exert their action through 
interaction with the intracellular GC receptor (GR), a ligand regulated transcription 
0
20
40
60
80
100
120
0.16
0.31
0.63
1.25
2.5
5
10
20
Apl
Dex
Apl+Dex
Aplidin nM
Dex nM
7.8         16.6       31.3       62.5       125        250
500       1000
0
20
40
60
80
100
120
0.16
0.31
0.63
1.25
2.5
5
10
20
Apl
Dex
Apl+Dex
Aplidin nM
Dex nM
7.8         16.6       31.3       62.5       125        250
500       1000
Aplidin nM
Dex nM
7.8         16.6       31.3       62.5       125        250
500       1000
0
20
40
60
80
100
120
0.16
0.31
0.63
1.25
2.5
5
10
20
Apl
Dex
Apl+Dex
Aplidin nM
Dex nM
7.8       16.6       31.3       62.5       125        250  
500       1000
0
20
40
60
80
100
120
0.16
0.31
0.63
1.25
2.5
5
10
20
Apl
Dex
Apl+Dex
Aplidin nM
Dex nM
7.8       16.6       31.3       62.5       125        250  
500       1000
Aplidin nM
Dex nM
7.8       16.6       31.3       62.5       125        250  
500       1000
0
25
50
75
100
125
0.16
0.31
0.63
1.25
2.5
5
10
20
Apl
Dex
Apl+Dex
Aplidin nM
Dex nM
7.8       16.6       31.3       62.5       125        250  
500       1000
0
25
50
75
100
125
0.16
0.31
0.63
1.25
2.5
5
10
20
Apl
Dex
Apl+Dex
Aplidin nM
Dex nM
7.8       16.6       31.3       62.5       125        250  
500       1000
Aplidin nM
Dex nM
7.8       16.6       31.3       62.5       125        250  
500       1000
0
20
40
60
80
100
120
0.16
0.31
0.63
1.25
2.5
5
10
20
Apl
Dex
Apl+Dex
Aplidin nM
Dex nM
7.8       16.6       31.3       62.5       125        250  
500       1000
0
20
40
60
80
100
120
0.16
0.31
0.63
1.25
2.5
5
10
20
Apl
Dex
Apl+Dex
Aplidin nM
Dex nM
7.8       16.6       31.3       62.5       125        250  
500       1000
Aplidin nM
Dex nM
7.8       16.6       31.3       62.5       125        250  
500       1000
ARP
MM1.S
RPMI-8226
MM1.R


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factor that positively or negatively alters the expression of specific target genes. In turn, 
GR either induces gene transcription by binding to specific DNA elements in the 
promoter-enhancer regions of responsive genes or reduces gene transcription by 
transrepression (35-38). 
Thus, dexamethasone acts over genes responsible for the induction of apoptosis in 
lymphoid cells, in which seems a plitidepsin complementary pathway, therefore
enhancing plitidepsin cytotoxicity (39-42). 
Like plitidepsin, GCs may induce apoptosis by directly regulating both the extrinsic and 
intrinsic apoptosis pathways. Death receptors (CD95 and TRAIL) and downstream 
effectors have been found deregulated by each of the drugs in the extrinsic pathway. 
Regarding the intrinsic and mitochondria-mediated pathways, which lead to release of 
pro-apoptotic molecules upon depolarization of the mitochondrial membrane potential, 
the apoptotic response is tightly regulated by the interaction between pro- and anti-
apoptotic Bcl-2 family members. Additionally, both, plitidepsin and dexamethasone, 
upregulate pro-apoptotic genes (TRAIL-Rl/DR4 and TRAIL-R2/DR5, Bax, Bak, Bad, 
Fas, FasL, TRAIL, Noxa, PIG3, Bim, Bik and Puma, Bcr-Abl (in CML), c-Myc, and
HDAC3), while they downregulate pro-survival genes (c-FLIP, MCl-I, Bel-X, and Bcl-
2) (36, 43).
On the other hand, both agents have been found to disrupt cellular redox state (e.g., 
ROS), and damage mitochondria in cells undergoing apoptosis, as an effect of the 
depolarization of mitochondrial membrane, which will enhance the expression of death 
receptors and ligands resulting again in the activation of the caspases cascade.
Moreover, plitidepsin-induced suppression of caspases inhibitors (FLIP, survivin) may 
contribute to the increased sensitivity of plitidepsin-treated MM cells to caspases-
dependent apoptosis by dexamethasone. Both agents deregulate Hsp90 complexes such 
as receptor, FKBP5, HSPs and DNAJs. 
Other molecules and pathways involved in the antiproliferative effect of both 
dexamethasone and plitidepsin, could yet contribute to the synergism of the 
combination. Plitidepsin downregulates genes with a documented role in oncogenic 
transformation in MM: Myb, Myc or Ras families, frequently mutated in MM cells, 
effect also seen after dexamethasone administration (44). Likewise, both had a 
synergistic effect on NF-kappaB (survival transcription factor) and its inhibitor (45, 46).
Besides, a synergistic effect may occur on the cell cycle, where the arrest induced by the 
combination may be mediated by their joint and coordinated regulation of the 
expression of CDKI (p21WAF1/CIP1, p27 KIP), INK4 family of proteins (p15INK4b, 
p18INK4c, p19INK4d), cycA, cycD1 and D2, suppression of CDK4, suppression of 
p107, or hypophosphorylation of Rb (35).


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Figure 3. Plitidepsin-dexamethasone molecular model of apoptosis
Plitidepsin treatment also reduces Erk (an extracellular signal-regulated kinase, ERK 
1/2) activation but increases activation of p38MAPK, enhancing GC sensitivity by the 
induction of apoptosis. Similarly, MAPK pathway activation by plitidepsin may 
improve GC effects.
Combined treatment with plitidepsin and dexamethasone suppresses genes involved in 
cytokine-induced proliferative/antiapoptotic signaling pathways and oncogenic 
transformation triggering MM proliferation: IGF-1R, IL-6R, gp130, CXCR-4 etc.
In addition to the documented effects induced by both drugs at the genomic level, some 
of the effects of dexamethasone seem to be non-specific, i.e., a non-genomic activity, 
with a quick activation of protein kinases, including the MAPK cascade, 
phosphatidylinositol-3 kinase (PI3K) and Akt. These non-specific effects could explain 
the short-term rapid synergism of the combination, since plitidepsin has also shown a 
rapid effect over the same pathways.
GR reduces gene transcription by interaction with proinflammatory transcription factors 
such as AP-1 (Fos-Jun heterodimers) and NF-kB (p65-p50 heterodimers). Both require 
the coactivator CREB binding protein (CBP) for maximal activity. Therefore, these data 
also suggest that alterations in chromatin structure may be important in modulating GC 
actions. 
On this regard, the direct inhibition of CBP-associated histone acetyltransferase (HAT) 
activity and the active recruitment of a histone deacetylase complex 2 (HDAC2) 
induced in cell lines treated with dexamethasone appear crucial (47, 48). Both 
complexes are closely related to chromatin remodeling and consequently, to the 
modulation of gene expression induced by dexamethasone. 
Plitidepsin
Plitidepsin


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Figure 4. Glucorticoids and the chromatin complex
Glucocorticoids induce the acetylation of specific lysine residues (K5 and K16) in 
histone H4. The consequences of this epigenetic activity are wide, e.g. preventing other 
transcription factors, such as activator protein 1 (AP-1) and nuclear factor қB (NF-қB), 
from activating their target genes by inhibition of acetylation of specific lysine residues 
in histone H4. This may also have an antiangiogenic potential (reducing VEGF 
expression). 
Therefore, histone H4 K5 acetylation can be considered as a marker of dexamethasone 
transactivation. Dexamethasone predominantly targeted acetylation on histone H4 K5 
and K16 in all subjects. However, GR complex inhibits acetylation of K8 and K12 by 
acting both as a direct inhibitor of CBP-associated histone acetylation and by recruiting 
HDAC2 to the p65-CBP HAT complex. Thus, it has been described that both HAT and 
HDAC activities coexist within same complex in the presence of p65 and GR and that 
they can each act independently.  This mechanism for glucocorticoid repression is novel 
and establishes that inhibition of histone acetylation brings an additional level of control 
of inflammatory/antiproliferative/apoptotic gene expression. This further suggests that 
pharmacological manipulation of specific histone acetylation status is a potentially 
useful approach for the treatment of dexamethasone-sensitive diseases. On this regard, 
the effects of dexamethasone have been shown to improve in the presence of 
trichostatin A (TSA), a classical potent in vitro HDAC inhibitor, and in the presence of 
SAHA, recently approved for its use in vivo at the clinical setting. HDACs were also 
pointed out to playing a role in dexamethasone repression. 
Further analysis of the epigenetic activity with dexamethasone revealed an induction of 
phosphorylation of Histone 3 at Ser10 (inhibited in response to TNFα) and histone 3 
methylation at Lysine 4 (H3K4 methylation). These two markers of the histone code are 
targets for rapid hyperacetylation upon treatment with the HDAC inhibitor sodium 
butyrate or with TSA. Moreover, most, if not all, available Lys in the H3 tail becomes
acetylated when they are marked with K4 methylation or S10 phosphorylation.
Such specificity suggests that the activation of HATs after treatment with 
dexamethasone together with an HDAC inhibitor is not at random.  
1.3.2.4
Toxicology
Plitidepsin, given by i.v. injection in daily x1 (dx1), dx5 or 3-cycle dx5 regimens, 
produced toxicological effects typical of cytotoxic antitumor agents. Tissues containing 
cells with a high turnover were especially targeted. In the dx1 and dx5 studies, the 
principal organs affected were the reticuloendothelial system and the gastrointestinal 
tract in all species, testes in the mouse and rat, and pancreas in the dog. The main organs 


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additionally affected were: epididymides, pancreas, heart, mammary gland and skeletal 
muscle in the rat and mouse, and liver, thymus and testes in the dog. In all three species, 
toxic effects were dose-related and generally fully or partially reversible. Most toxicities 
were reversible at the maximum tolerated dose (MTD) level at the end of an acute 
toxicity evaluation.
Of interest is the observation that the toxicity of plitidepsin in normal hematopoietic 
tissue (IC50: 150-2250 nM) was 1-3 orders lower than in tumor cells (IC50: 0.2-27 nM) 
(49). These and other data (50) indicate that plitidepsin might be a potential compound 
in multidrug chemotherapy regimen, assuming that it does not increase hematotoxicity 
significantly, which is often the dose-limiting toxicity of these regimens.
1.3.2.5
Safety Pharmacology
1.3.2.5.1 Cardiovascular System
The cardiovascular (CV) safety pharmacology evaluation of plitidepsin involved both in 
vitro and in vivo studies.
Briefly, no inhibition of the hERG tail current was found after a 15-min exposure of 
HEK293 cells stably transfected with hERG cDNA to a concentration of 1M of 
plitidepsin. Moreover, increasing concentrations of plitidepsin (10, 100 and 1000 nM) 
did not produce changes in the action potential morphology of isolated cardiac Purkinje 
fibers from dogs.
The effect of plitidepsin on CV parameters [arterial blood pressure (ABP), heart beating 
rate (HBR) and electrocardiogram (ECG) variables - PR interval, QRS duration, RR 
interval, and QT interval] was evaluated in conscious, telemetered dogs. Infusion of 
plitidepsin at doses up to 0.03 mg/kg (0.6 mg/m2) did not affect ABP. HBR increased 
from 2 to 48 hours after administration of 0.03 mg/kg (0.6 mg/m2) of plitidepsin. There 
were no significant effects on corrected QT (QTcF) at the studied plitidepsin doses. No 
ECG abnormalities were observed during or up to 8 hours after discontinuation of the 
plitidepsin infusion.
1.3.2.5.2 Respiratory System
Intravenous administration of up to 0.50 mg/kg (3 mg/m2) of plitidepsin to male rats did 
not significantly affect either respiratory rate or tidal volume. Significant decreases in 
tidal volume and respiratory rate were detected at 24 hours post-dosing with 1.50 mg/kg 
(9 mg/m2).
1.3.2.5.3 Neurotoxicity
Intravenous administration of up to 0.50 mg/kg (3 mg/m2) of plitidepsin to male rats did 
not produce gross behavioral or physiological state changes at any observation period. 
In rats treated with 1.5 mg/kg (9 mg/m2) occasional cage dispersion, increased 
cutaneous blood flow, diarrhea, and vocalization were observed. 


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1.3.3
Clinical Data
To date, plitidepsin has been evaluated in adult patients as single-agent or in 
combination with other antineoplastic drugs, and as single-agent in pediatric patients.
As of March 2009, more than 700 patients had been recruited into clinical trials with 
plitidepsin (PharmaMar internal data):

A phase I program using single-agent plitidepsin in adult patients with solid 
malignancies or non-Hodgkin lymphoma (NHL) has been completed. 

There are several finished or ongoing studies of plitidepsin in combination 
with other agents: 
-
Phase I trial of plitidepsin with carboplatin in patients with advanced 
solid malignancies or lymphoma: completed.
-
Phase Ib trial of plitidepsin in combination with bortezomib and 
dexamethasone in relapsed/refractory multiple myeloma: closed 
recruitment.
-
Phase Ib trial of plitidepsin in combination with sorafenib or 
gemcitabine in patients with solid tumors or lymphomas: open 
recruitment.
-
Phase Ib trial of plitidepsin in combination with bevacizumab or 
docetaxel in patients with solid tumors: open recruitment.
-
Phase I-II trial of plitidepsin in combination with dacarbazine as first-
line treatment in patients with unresectable advanced melanoma: the 
phase I part has been already completed. 

Phase II studies with single-agent plitidepsin have been conducted to 
evaluate its activity against different solid tumors and hematological 
malignancies.
Particularly of interest is a phase II trial of plitidepsin alone and/or with the addition of 
dexamethasone in patients with suboptimal response in relapsed/refractory multiple 
myeloma that has been recently completed. The final results of this trial were presented 
during the American Society of Hematology (ASH) meeting in December 2008 in San 
Francisco, USA (Abstract # 3700).
1.3.3.1
Single-Agent Phase I Trials
Results obtained in single-agent phase I trials in adult patients are summarized in Table 
1.


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Table 1. Plitidepsin: single-agent phase I trials in adult patients
24 h i.v.
d1,8,15
q4w
3 h i.v.
d1,15 
q4w
1 h i.v.
d1,8,15
q4w
24 h c.i.v.i. d1,15 q4w 
1 h i.v.
d1-5 
q3w
Plitidepsin 
alone
Plitidepsin +
L-carnitine
No. patients
35
27
49
47
20
37
Highest dose 
(mg/m2)
4.50 
6
3.60
7 
8
1.50
DLTs
muscular
hepatic
muscular
hepatic
muscular
muscular
muscular
flu-like
muscular 
emesis
skin rash 
diarrhea
RD (mg/m2)
3.75 
5
3.2 
5 
7 
1.2
DI at the RD 
(mg/m2/week)
2.8
2.5
2.4
2.5
3.5
2.0
24 h i.v. d 1,8,15 q4w: 24-hour intravenous infusion for three weeks every four weeks; c.i.v.i.: continuous intravenous infusion; 
DI: Dose intensity; DLT, dose-limiting toxicity; NCI-CTC, National Cancer Institute Common Toxicity Criteria; RD: 
recommended dose.
Hepatic = Increased values of serum enzymes (grade 3-4 CTCAE)
Muscular = myalgia, muscular weakness or elevated CPK (grade 3-4 NCI-CTC)
Of note, the proposed recommended dose (RD) for further developments as single agent 
after the extensive phase I program consistently delivered a similar dose intensity, 
around 2.5 mg/m2/week and a similar pattern of DLTs, without unexpected toxicities 
independently of schedule.
1.3.3.2
Single-Agent Phase II Trials
As single-agent in phase II clinical trials and up to March 2009, plitidepsin has been 
administered to patients with:

Unresectable advanced renal cancer or advanced colorectal cancer in objective 
progression (81 patients).

Unresectable advanced medullar thyroid carcinoma (16 patients).

Unresectable advanced carcinoma of the exocrine pancreas (19 patients).

Advanced non-small cell lung cancer (NSCLC) progressing after first-line 
chemotherapy (21 patients).

Advanced or metastatic transitional cell carcinoma of the urothelium relapsing 
or progressing after first-line chemotherapy (21 patients).

Small-cell lung carcinoma (SCLC) relapsing or progressing after first-line 
chemotherapy (19 patients).

Advanced or metastatic melanoma relapsing or progressing after first-line 
systemic therapy (37 patients).

Locally advanced or metastatic squamous cell carcinoma of the head and neck 
(10 patients).

Relapsing or refractory androgen-independent prostate adenocarcinoma (8 
patients).

Relapsed or refractory indolent NHL (8 patients).

Relapsed or refractory aggressive NHL (51 patients).

Relapsed or refractory multiple myeloma (51 patients).


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
Relapsed or refractory acute lymphoblastic leukemia (ALL) (17 patients).
The results from completed and ongoing phase II trials confirmed the preliminary safety 
profile described from the subset of patients treated at the proposed RD in phase I trials. 
For the 255 patients treated with plitidepsin in the dose-escalating phase I studies, most 
of the AEs and laboratory abnormalities which constituted DLTs consisted of transient 
liver biochemical disorders without clinical manifestations and muscular events, mainly 
myalgia, muscular weakness and creatine phosphokinase (CPK) elevations, without 
myoglobin increase or signs/symptoms of rhabdomyolysis. These events were in most 
cases mild, and reverted upon dose modification or drug discontinuation. Other 
common events were mild emesis and diarrhea and cutaneous events (erythema, 
pruritus, rash). Mild hypersensitivity reactions have been reported to be probably related 
to the Cremophor oil contained in the formulation. Of these, less than 3% had been 
serious (i.e., anaphylactic shock) and all reactions have been reversible after stopping 
the infusion and implementation of routine symptomatic treatment. No fatal events have 
occurred. Yet, allergic prophylaxis (Appendix 1) has been made mandatory in all 
subsequent trials since 2005. Of note, hematological toxicity was almost absent from 
plitidepsin single agent trials.
Non-serious cardiac events (rhythm alterations, ECG abnormalities) have been 
occasionally reported in association with plitidepsin treatment; however, severe and 
life-threatening cardiovascular events were rare and causality was usually confounded 
by underlying disease or pre-existing conditions. No chronic or dose-cumulative cardiac 
toxicity has been observed so far. Regular assessment of cardiac function and cardiac 
parameters (i.e., troponin I) and mandatory ECG monitoring have been implemented in 
all ongoing and planned trials in order to closely evaluate the cardiac safety profile of 
plitidepsin.
Regarding efficacy, plitidepsin alone has shown consistent antitumor activity in 
pretreated patients with renal cancer, melanoma, neuroblastoma, non-cutaneous mature 
aggressive peripheral T-cell lymphoma (PTCL) and multiple myeloma. In addition 
clinically meaningful stabilizations (≥ 3 months) have been achieved in patients with 
several others solid tumor types (i.e., colorectal cancer, neuroendocrine tumors, 
NSCLC, hepatocellular carcinoma, etc.). 
Based on the aforementioned results and its relative good tolerance, the clinical 
development of plitidepsin as a single agent in multiple myeloma, PTCL and melanoma, 
as well as combined with several agents (including dacarbazine for advanced malignant 
melanoma, bortezomib or lenalidomide for relapsed/refractory multiple myeloma, and 
sorafenib or gemcitabine for advanced solid tumors or lymphomas), is currently 
underway.
1.3.3.3
Phase II Trial of Plitidepsin in Combination with Dexamethasone
The safety and efficacy of plitidepsin in patients with relapsed or refractory MM have 
been investigated in a phase II study and final results have been reported (51). This was 
an open-label study of plitidepsin given as a 3-h infusion every two weeks, with the 
addition of dexamethasone allowed in patients with suboptimal response to plitidepsin 
alone (defined as PD after 3 cycles or SD after 4 cycles of plitidepsin). Primary 
endpoint was the objective response rate (ORR = CR+ PR [partial response] + MR 


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[minimum response]) according to strict Bladé criteria (52). Secondary endpoints were
time to progression (TTP) and safety. 
Between June 2004 and March 2008, 53 relapsed/refractory MM patients were included 
and 51 received plitidepsin-based therapy. The results showed a promising activity in 
this heavily treated subset of patients, resulting in an ORR of 12%, and up to 21% when 
dexamethasone was added (primary efficacy endpoint: ORR in the intent-to-treat 
population according to Myeloma Response Criteria). This benefit was also translated in 
terms of TTP. 
Patients received a median number of four prior lines of therapy (range: 1-18) and 47 of 
them were evaluable for response. During the first phase of the study, 21 patients
received plitidepsin as monotherapy. The overall response rate (ORR) for the first stage 
was 9%. During the second phase, 26 additional patients were evaluable for response. 
ORR to plitidepsin as monotherapy in this second cohort was 11%.
Dexamethasone was subsequently added to plitidepsin treatment in 18 patients 
evaluable for efficacy, being the response in this subgroup of 21%.
Overall, pooled data of all evaluable patients (n=47) receiving plitidepsin as 
monotherapy in the two stages resulted in an ORR of 12% (1 PR, 2 MR). Median time 
to progression (TTP) was 3 months (95% CI: 0.9-2.8 months) and median overall 
survival (OS) for the first 21 treated patients was 17 months. The addition of 
dexamethasone also increased median TTP to 4.2 months (95% CI: 3.4-7.7 months), 
which represented a 40% increase compared to plitidepsin alone (TTP of 3 months). 
The safety profile was acceptable and was not significantly changed after 
dexamethasone addition. Particularly the incidence of grade 3-4 drug-related 
hematological toxicity was very low, with only 11% and 21% of the patients 
experiencing grade 3-4 neutropenia and thrombocytopenia respectively with the 
combination (similar figures for plitidepsin alone) 
1.3.4
Safety Issues
1.3.4.1
Relevant Safety Information from Phase II Trials
The results from completed and ongoing phase II trials confirmed the preliminary safety 
profile described from the subset of patients treated at the proposed recommended dose 
in phase I trials. The majority of AEs and laboratory abnormalities which constituted 
dose-limiting toxicities consisted of transient liver biochemical disorders without 
clinical manifestations and muscular events, mainly myalgia, muscular weakness and 
creatine 
phosphokinase 
(CPK) 
elevations 
without 
myoglobin 
increase, 
or 
signs/symptoms of rhabdomyolysis. These events were in most cases mild, and reverted 
upon dose modification or drug discontinuation. Other common events were mild 
emesis and diarrhea and cutaneous events (erythema, pruritus, and rash) or 
hypersensitivity reactions. Serious hematological toxicity was negligible.
Non-serious cardiac events (rhythm alterations, ECG abnormalities) have been 
occasionally reported in association with plitidepsin treatment, however, severe and life-
threatening cardiovascular events were rare and causality was usually confounded by 
underlying disease or pre-existing conditions. A close monitoring of cardiac function is 
being implemented in ongoing trials to reassess the cardiac safety profile of plitidepsin.


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1.3.4.2
Clinical Safety
For each AE, figures represent the frequency of its worst grade by patient and regardless 
of causality. 
1.3.4.2.1 Muscular Adverse Events
Muscular AEs, together with CPK increases, constituted the main DLTs reported with 
plitidepsin when administered at the doses recommended for further development.
Most muscular AEs found in patients treated with the 1-hour infusion in the phase I trial 
were mild or moderate and consisted of myalgia (50%) and muscle weakness (17%), 
and only one grade 3-4 event was reported (muscle weakness, 7%). As for the other 
schedules, most muscular adverse events reported in patients in the three 1-hour 
infusion phase II trials, were mild or moderated myalgia (25%) and muscle weaknesses 
(15%). Grade ≥ 3 events were reported in eight occasions: two cases of myalgia and 
four of muscle weakness, one of muscle cramp and one of back pain (n=87).
1.3.4.2.2 Biochemical Laboratory Abnormalities
Grade ≥ 3 elevations of ALT and AST (aspartate aminotransferase) were reported in 
27.5% in the 1-hour Day 1, 8, 15 q4w schedule in phase II trials. However these 
elevations were transient and reversible being asymptomatic in the vast majority of 
cases. Other severe biochemical disorders were rare and no remarkable differences in 
incidence of biochemical or metabolic abnormalities were observed as compared to 
other schedules.
1.3.4.2.3 Gastrointestinal Symptoms
As for phase I and phase II trials, severe drug-related gastrointestinal AEs were 
uncommon, and none of them reached grade 4 severity. Nausea was the most frequent 
gastrointestinal event. Its incidence was higher with the 24-hour infusion schedule 
(64%) as compared to the 3-hour (47%) and the 1-hour infusion (35%) schedules. Grade 
3-4 emesis was rare in patients treated with 1-hour infusion.
1.3.4.2.4 Neurological Adverse Events
Specific neurological testing was performed only in the phase I trial evaluating the daily 
x 5 dosing. Test results showed a decrease in dynamometer readings in most patients 
without other abnormalities. There was no apparent correlation between dose level of 
plitidepsin and strength testing abnormalities in this trial. No grade 3 events were 
reported. Overall, the incidence of neurological AEs was generally low. 
1.3.4.2.5 Hematological Abnormalities
As for other schedules, the most common hematological abnormality in the 1-hour Day 
1, 8, 15 q4w schedule in phase II trials was hemoglobin decrease (90%). Lymphocyte 
decrease occurred in 66% of the patients, and thrombocytopenia was observed in 60% 
(26% of them were grade ≥ 3). However, taking into account the prior clinical 
experience with plitidepsin and its preclinical toxicology profile, it was concluded that 
most of these episodes of hematological abnormalities were not related to plitidepsin but 


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Protocol APL-C-001-09
to the underlying disease (acute leukemia, lymphoma and multiple myeloma). In fact, 
several patients already suffered from leukopenia and/or thrombocytopenia at baseline. 
In general, these events did not worsen after plitidepsin treatment, but rather their values 
improved significantly in patients showing objective response to treatment.
1.3.4.2.6 Constitutional Symptoms
Asthenia was the constitutional AE most frequently found in patients in phase II studies 
with single-agent plitidepsin. A total of 31% of patients treated with the 1-hour infusion 
had asthenia, with 8% of cases being grade 3-4. However, its significance may be 
confounded, since the underlying malignancy is frequently a cause of asthenia in cancer 
patients. 
Other severe AEs reported within this schedule were grade 3 edema in one patient (1%) 
and pyrexia also in one (1%) patient. Mild grade 1-2 pyrexia was reported in other 
schedules, particularly in the 3-hour i.v. infusion every two weeks (69% of patients). It 
was usually associated with shivering and developed within 24 hours after the start of 
the infusion.
One patient had multi-organ failure and died, most likely as a consequence of the 
underlying disease.
1.3.4.2.7 Infusion Site Events
When central venous access was not used, local problems related to drug administration 
were frequent, including erythema, pain during infusion and phlebitis. 
Injection site reactions were more common in patients receiving plitidepsin as a 24-hour 
infusion than with any other schedule. Shortening the infusion time was associated with 
a marked reduction in the incidence of injection site reactions. A total of 2% of patients 
reported infusion site reactions with the 3-hour infusion and 5 mg/m2 dose (1/3 of which 
were grade ≥ 3), and 1% of patients with mild-moderate events were found with the 1-
hour infusion schedule. In all cases, plitidepsin should be administered through infusion 
pumps with special filter-containing infusion lines, via central venous access.
1.3.4.2.8 Cardiac Safety
An update of the safety information on cardiac events occurred during clinical trials 
evaluating plitidepsin as single-agent treatment in adult patients with advanced solid 
tumors or hematological malignancies was done using a cutoff for data analysis of 20 
November 2008 (see Investigator Brochure). Forty-six of the 578 patients (8.0%) 
treated with plitidepsin as a single agent up to that cutoff date had at least one cardiac 
AE. Eleven of these 46 patients (1.9% of the total of 578 patients) had cardiac AEs 
related to plitidepsin and eight among them were reported as serious adverse events 
(SAEs). The majority of cardiac events occurred in phase II studies (37 of 46 for overall 
events), and particularly in two studies, APL-B-003-02 (pancreatic cancer) and APL-B-
011-02 (prostate cancer) with a higher than expected incidence. 
Cardiac AEs observed to date in plitidepsin trials are clinically heterogeneous; the most 
frequent type is harmless rhythm alterations, as no life-threatening ventricular 
arrhythmias occurred, while the rest of events are relatively infrequent. No fatal 


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outcome was reported as a consequence of all cardiac AEs analyzed. Relevant 
predisposing factors identified in univariate and multivariate analyses are mostly related 
with patient’s baseline characteristics and disease-related characteristics rather than with 
drug exposure or treatment-related characteristics, the analyzed cardiac events do not 
follow a dose cumulative pattern of occurrence, and none among all PK parameters 
explored did show a correlation, although other potential relevant factors remain yet to 
be identified and further characterized. As of 20 November 2008, with data available on 
578 adult advanced cancer patients treated with singe-agent plitidepsin, cardiac safety 
does not seem to be of special concern.
In order to fully monitor cardiac safety, additional cardiovascular explorations have 
become mandatory in all current and future plitidepsin protocols, including serial ECG 
and troponin I determination and periodic left ventricular ejection fraction (LVEF) 
measurement by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) 
testing. In addition, patients with a cardiovascular background or any prior interventions 
predisposing to cardiac toxicity are excluded from these protocols.
1.3.4.2.9
Conclusions on Safety Results
Plitidepsin alone or in combination with carboplatin, dacarbazine or dexamethasone has 
a tolerable safety profile with most AEs mild to moderate and usually reversible upon 
drug reduction or discontinuation. The negligible hematological toxicity makes this 
compound a good candidate for combination with standard chemotherapy. 
Overall, the currently available clinical data provide reassurance that the toxicity of 
plitidepsin appears to be acceptable in the clinical setting.
1.3.4.3
Summary of Pharmacokinetic Results
Pharmacokinetic data have been collected from patients in phase I and II studies 
following i.v. administration of plitidepsin using the following schedules: 24-hour 
infusion every week (Day 1 and 15 q4wk), 3-hour infusion every other week (Day 1 and 
15 q4wk), 1-hour infusion every week (Day 1, 8, 15 q4wk), 24-hour infusion every 
other week (Day 1 and 15 q4wk) and 1-hour infusion for five consecutive days every 
three weeks ( Day 1-5 q3wk). 
After non-compartmental analysis, plitidepsin was found to be widely distributed, with 
apparent volumes of distribution in steady state (Vss) of about 500 to 1350 l based on 
plasma, and from about 100 to 225 l based on whole blood, thus suggesting that blood 
cells are an important distribution compartment. Concentrations were about 3-fold 
higher in whole blood than in plasma. 
This initial characterization was updated after analyzing data from phase II clinical 
trials, with samples collected at later time points than in the phase I trials. Furthermore, 
patients included in phase II trials had samples taken for pharmacokinetic (PK)
evaluation during both the first and third treatment cycle, allowing for a more extensive 
analysis. Population methodology was used, as the phase II studies had sparse sampling.
Thus, the population PK analysis of plitidepsin was performed based on data from 13 
clinical studies, including all four adult patients, single-agent phase I studies (APL-A-
001-98, APL-A-002-98, APL-A-003-98 and APL-A-004-98) and nine phase II studies 


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(APL-B-001-01, APL-B-002-02, APL-B-005-02, APL-B-006-02, APL-B-007-02, APL-
B-011-02, APL-B-013-02, APL-B-014-03, APL-B-015-04), using the NONMEM 
software. Blood and plasma concentration-time data from phase I studies with extensive 
sampling were pooled with sparse PK sampling from patients with advanced cancer 
included in phase II studies. In these studies, patients received i.v. plitidepsin as 
monotherapy at doses ranging from 0.13 to 8.0 mg/m2 and given as 1-hour or 24-hour 
infusions weekly; 3-hour or 24-hour q2wk, or 1-hour infusion daily for five consecutive 
days every 21 days. In total, 411 patients and 5585 plitidepsin concentration 
measurements, including 2900 blood and 2685 plasma concentrations, were pooled in 
the population PK analysis.
An open, three-compartment disposition model with linear elimination and linear 
distribution from the central compartment to peripheral compartments was used to 
describe the PK of plitidepsin in plasma. The model was parameterized in terms of 
clearance (CL), central (V1) and peripheral volumes of distribution for the shallow (V2) 
and the deep (V3) compartments, intercompartmental exchange flows for shallow (Q2) 
and the deep (Q3) compartments. The concentration of plitidepsin into red blood cells 
was modeled as a non-linear function, where Bmax corresponds to the maximal 
plitidepsin concentration into red blood cells and kd is the plitidepsin plasma 
concentration at which the plitidepsin bound to red blood cells is half-maximal. 
Between and within subject variabilities were assumed to be log-normally distributed. 
Final parameter estimates describing the PK of plitidepsin in cancer patients are 
presented in Table 2. The plitidepsin initial fast distribution half-life was about 21
minutes followed by a dominant elimination half-life of about 8.9 hours and a terminal 
half-life of about 88 hours that constituted on average 27.2% of the overall area under 
the plasma concentration vs. time curve.
Table 2. Final pharmacokinetic parameter estimates for plitidepsin.
Pharmacokinetic 
parameter
Typical value*
Variability
Between patients 
(%)
Within patients 
(%)
V1 (l)
103 (8.87)
74.2 (30.5)
--
CL (l/h)a,b
28.7 (4.77)
55.0 (16.6)
38.3 (25.6)
V2 (l)b
417 (5.68)
55.1 (16.1)
--
Q2 (l/h)
136 (6.46)
64.0 (20.4)
--
V3 (l)
1320 (7.17)
88.7 (32.8)
--
Q3 (l/h) a
18.1 (6.13)
--
53.4 (19.1)
Bmax (g/l)
309 (10.2)
60.8 (12.9)
21.8 (27.5)
kd (g /l)
23.5 (11.8)
--
--
*Results expressed as parameter (RSE: relative standard error of parameter estimate, %).
a. Correlation between IIV of Cl and Q3 set to 1. Expansion factor of Q3 is 0.757 (RSE=17.2%).
b. Correlation between IIV of Cl and V2 is 0.521 (RSE= 19.1%).
Residual variability, expressed as percentage: 
-Blood: 24.5 (RSE = 7.35 %).
-Plasma: 38.1 (RSE =9.86 %).
Bmax: maximal plitidepsin concentration into red blood cells; kd: plitidepsin plasma concentration at 
which the plitidepsin bound to red blood cells is half-maximal; V1: central volume of distribution; V2: 
volume of distribution of the shallow compartment; V3: volume of distribution of the deep 
compartment; CL: clearance, Q2: intercompartmental exchange flow for the shallow compartment, 
Q3: intercompartmental exchange flow for the deep compartment.
As a summary, the main conclusions of the population PK report are:


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A three-compartment disposition model with linear elimination is suitable to 
describe the plasma PK profiles of plitidepsin after i.v. administration to 
cancer patients.
Non-linear binding to red blood cells is evident from blood concentrations. 
However, its clinical relevance is limited since the plasma concentrations 
achieved with the dosing regimens used in phase II program are below the 
estimated kd value and the effect of the hematocrit on blood concentrations is 
limited. 
No evidence of time-dependent kinetics was observed. Actually, plitidepsin 
systemic exposure following repeat i.v. administration q2wk evidenced 
minimal accumulation in plasma.
The subject-related covariates, including age, body weight, sex, laboratory liver 
function parameters (AST, ALT, ALP and total bilirubin) and renal function (creatinine 
clearance), total protein, serum albumin, hemoglobin levels and leukocytes counts had 
no discernable impact on the PK parameters of plitidepsin within the range of values 
evaluated and, consequently, plitidepsin dose adjustment on the basis of these covariates 
is not warranted.
Between and within patients variability in PK is moderate to large, but similar to other 
anticancer drugs.
The following Section details the individual PK results from the relevant phase I clinical 
trial in which the 3-hour infusion every two weeks was used.
1.3.4.3.1
Three-hour Every Two Weeks Intravenous Infusion Regimen of Plitidepsin 
(Study APL-A-001b-98)
Median half-life values were 35.3, 31.7, 31.5 and 38.5 hours following administration of 
plitidepsin at 3, 4, 5 and 6 mg/m2, respectively.  Corresponding clearance values were 
5.3, 4.1, 5.9 and 1.7 l/h, respectively and corresponding Vss values were 171, 148, 199 
and 130 l, respectively. Median Cmax at the same dose levels were 78.3, 97.5, 82.6 and 
294.9 ng/ml respectively, and median AUCinf were 967, 1772, 1392 and 6057 h*ng/ml 
respectively.
Plitidepsin AUCinf and Cmax values increased with dose, although dose-proportionality 
of plitidepsin in blood was not proven, most probably due to the limited sample size for 
all dose levels except for 5 mg/m2 and a high interpatient variability. 
The effect of age, weight and body surface area (BSA) on the pharmacokinetics of 
plitidepsin in blood were inconclusive. There were no statistically significant gender 
effects.
1.3.4.3.2
Excretion of Plitidepsin
Urinary excretion of unchanged compound is a minor elimination route, with average 
recoveries of 2-5% over 48 hours and maximum values below 15%. The major routes of 
elimination have not as yet been determined.


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There were no correlations between kinetic parameters and variations in hepatic and 
renal function in the population analysis of adult phase I results.
1.4
INFORMATION ON STUDY DRUG: DEXAMETHASONE
Please refer to the Dexamethasone Drug Information, provided as a separate document, 
for further information on dexamethasone.
1.5
STUDY RATIONALE
1.5.1
Rationale for the Proposed Drug Combination
Clinical development of anticancer treatments usually requires combination of more 
than one active drug for improving efficacy, with each agent having different targets or 
mechanisms of action in order to prevent or delay the development of tumor resistance. 
Ideally, from the preclinical point of view, drugs may have shown either additive or 
synergistic antitumor activity. It is equally important to avoid agents with overlapping 
toxicity profiles for the development of successful novel combinations. 
1.5.1.1
Plitidepsin
Plitidepsin (Aplidin®) is a novel anticancer compound that has shown activity as single 
agent in a recently completed phase II study in relapsed/refractory MM patients (51). In 
a first stage, this trial explored the objective response to plitidepsin at 5 mg/m2 as a 3-
hour i.v. infusion administered every two weeks (q2wk), with 10% of 21 evaluable 
patients having a PR and, additionally, 14% of patients having clinically meaningful 
disease stabilization (SD ≥ 3 months), with a median TTP of 2.3 months. Based on 
preclinical 
results 
that 
showed 
additive 
to 
synergistic 
effects 
of 
dexamethasone/plitidepsin combination (30), in a second stage of this phase II trial, 
patients who experienced suboptimal response (SD or PD) after three to four plitidepsin 
infusions were allowed to receive oral dexamethasone 20 mg daily on Days 1 through 4 
q2wk (160 mg total monthly dose) added to plitidepsin. In this cohort of patients, 28% 
of the 18 evaluable patients had an objective response and TTP was significantly 
prolonged to 4.2 months. A similar overall safety profile was found, although with a
slight increase in muscular events (mostly myalgia and reversible CPK increase) and a 
mild decrease in grade 3-4 transaminases increase. Of note, as much as two thirds of 
these patients had previously received bortezomib and thalidomide or lenalidomide and 
HDT and PBSC-T, whereas all patients had steroids as part of a prior therapy, with a 
median of four prior lines of systemic treatments. Although the trial design had 
limitations that precluded comparison between cohorts, both regimens were well 
tolerated and showed clinical activity in this heavily pretreated population for which
limited clinical options were available. The addition of dexamethasone after three to 
four cycles of plitidepsin did not change dramatically the response (some disease 
stabilizations were found in patients who were progressing on plitidepsin alone, and one 
patient who was stable responded after dexamethasone addition), but responses 
appeared to be more durable and steeped. Therefore, it seems logical to add 
dexamethasone to plitidepsin upfront in order to optimize any synergistic effect that 
may occur clinically to achieve a better and longer disease control. 


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This approach has been extensively used for most active agents in MM. In fact, 
corticosteroids have long been a central component of the treatment for MM, with  the 
most commonly used regimens being high-dose dexamethasone alone (53), melphalan 
and prednisone (8, 54), vincristine, doxorubicin, and dexamethasone (VAD) (55, 56),
thalidomide, lenalidomide
plus dexamethasone
(57-59),
and bortezomib plus 
dexamethasone. Moreover, dexamethasone can be used as monotherapy as well, the 
dose and regimen being typically around 20-40 mg on Days 1-4, 9-12, and 17-20 of a 
28- to 35-day cycle for a total of 240-480 mg per cycle (53), although adverse reactions 
may be observed including principally endocrine axis suppression, serious infections
derived from clinically relevant immunosuppression, and confusion or mood changes 
including acute psychosis. In fact, dose of dexamethasone has recently raised some 
concerns particularly after the ECOG 4A03 study. The Eastern Cooperative Oncology 
Group, compared the administration of lower doses of dexamethasone (40 mg d 1, 8, 15, 
and 22 p.o. q4wk, for a total monthly dose of 160 mg) plus lenalidomide with high-dose
dexamethasone at the usual dose (40 mg d 1-4, 9-12, and 17-20 p.o. q4wk, for a total 
monthly dose of 480 mg) plus the same lenalidomide regimen, and reported a 
significant improvement in overall survival with a better safety profile for the lower 
dose arm (60). A second study with lenalidomide plus dexamethasone in the 
relapsed/refractory setting showed that patients who had dose reductions of 
dexamethasone have shown a significantly higher overall response rate, including a 
higher complete response (CR), PFS and improved median overall survival, when 
compared to those who received dexamethasone at the assigned dose, with adverse 
events rates comparable between both groups (61). Finally, and based on data from last 
available publications on dexamethasone and bortezomib combinations (62),
dexamethasone administered at reduced doses (20 mg) the same day and the day after 
bortezomib infusion up to a total dose of 160 mg/cycle, has been associated with a 
better safety profile while maintaining the same level of activity.
2
OBJECTIVES
2.1
PRIMARY OBJECTIVE

To compare the efficacy of plitidepsin with dexamethasone vs. dexamethasone 
alone, as measured by PFS, in patients with relapsed/refractory MM.
2.2
SECONDARY OBJECTIVES

To evaluate tumor response according to the IMWG criteria (Appendix 5).

To assess duration of response (DR) and overall survival (OS).

To assess efficacy in patients who undergo crossover from dexamethasone alone to 
plitidepsin and dexamethasone combination.

To characterize and compare the safety profile on both arms in this population.

To characterize
the
PK and pharmacokinetic/pharmacodynamic (PK/PD) 
relationship.
3
OVERALL STUDY DESIGN
This is a prospective, open-label, two-arm, 2:1 randomized phase III study. The efficacy 
of plitidepsin in combination with dexamethasone (Arm A) vs. dexamethasone alone 


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(Arm B) will be studied by means of PFS calculated using the IMWG uniform response 
criteria (Appendix 5), and the evaluation of secondary efficacy endpoints. 
Patients in the control arm (dexamethasone alone, Arm B) who have documented 
disease progression according to the Investigator’s criteria after a minimum of eight 
weeks from randomization should be offered crossover to combination arm (plitidepsin 
+ dexamethasone, Arm A) upon Sponsor agreement.
An Independent Review Committee (IRC), consisting of medical specialists directly 
involved in the care of MM patients, but not being investigators or subinvestigators in 
this trial, will review all efficacy data and will assign the date of progression/censoring 
and objective response according to their independent evaluation. This IRC will be 
blinded to treatment arm allocation and identity of the cases reviewed (Section 5.6).
An Independent Data Monitoring Committee (IDMC), including specialists in MM and in 
medical statistics, will review the results of the analysis performed by an independent 
statistician. Then, the IDMC will advise the Sponsor about the study conduct.
Operational details for the above mentioned IRC and IDMC will be detailed in the 
corresponding charters.
4
PATIENT DEFINITION
4.1
STUDY POPULATION
A total of approximately 250 patients will be randomized in a 2:1 ratio (combination: 
dexamethasone alone).
An early futility analysis will be performed with data from 40 patients evaluable for 
response in Arm A. 
Patients without valid disease evaluation during treatment will not be replaced for the 
main analysis, and will be analyzed as per ITT according to randomization.
4.2
PATIENT ELIGIBILITY
4.2.1
Inclusion criteria
A patient is eligible for enrolment if all of the following inclusion criteria are met:
1. Age ≥ 18 years.
2. ECOG PS ≤ 2 (see Appendix 2).
3. Life expectancy ≥ 3 months.
4. Patients previously diagnosed with multiple myeloma based on IMWG diagnostic 
criteria (see Appendix 4).
5. Patients must have relapsed or relapsed and refractory multiple myeloma (MM)
(Appendix 5) after at least three, but not more than six, prior therapeutic regimens 
for MM, including induction therapy and stem cell transplant in candidate patients, 
which will be considered as only one regimen.


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6. Patients must have received previous bortezomib-containing and lenalidomide-
containing regimens (or thalidomide where lenalidomide is not available), unless 
unable to tolerate either of them.
7. Patients must have measurable disease defined as: 
a) For secretory MM: any quantifiable serum monoclonal protein value and, 
where applicable, urine light-chain excretion ≥ 200 mg/24 hours.
b) For oligo or non-secretory MM: presence of soft tissue (not bone) 
plasmacytomas, as determined by clinical examination or applicable 
radiographs [i.e., magnetic resonance imaging (MRI), computed 
tomography (CT)-scan], and/or by the presence of abnormal serum free 
light chains (sFLC): involved FLC level ≥ 10 mg/dl provided the serum 
FLC ratio is abnormal.
8. At least two-week washout period since the end of last therapy (six weeks if 
previous nitrosoureas-containing regimen), given recovery to grade ≤ 1 from any 
non-hematological related adverse event (AE) derived from previous treatment 
(excluding alopecia).
9. Adequate BM, renal, hepatic, and metabolic function (assessed ≤ 7 days before 
inclusion in the study):
a)
Absolute neutrophil count (ANC) ≥ 1.0 x 109/l (≥ 0.5 x 109/l if due to 
extensive and documented BM disease involvement by ≥ 50% of plasma 
cells in BM biopsy).

Screening of ANC should be independent of granulocyte- and 
granulocyte/macrophage-colony stimulating factors (G-CSF and 
GM-CSF) support for at least one week and of pegylated G-CSF 
for at least two weeks.
b)
Platelet count ≥ 50 x 109/l (≥ 25 x 109/l if due to extensive and 
documented BM disease involvement).
c)
Hemoglobin ≥ 8.5 g/dl.

Patients may receive red blood cells (RBC) and/or erythropoietin 
(EPO) and/or platelets transfusions in accordance with 
institutional guidelines.
d)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤ 3.0 x the upper limit of normal (ULN).
e)
Total bilirubin ≤ 1.0 x ULN or direct bilirubin ≤ 1.0 x ULN when total 
bilirubin is above the upper limit of normal.
f)
Calculated creatinine clearance (CrCl) ≥30 ml/minute (by means of 
Cockcroft and Gault´s formula) (Appendix 3).
g)
Creatine phosphokinase (CPK) ≤ 2.5 x ULN.
h)
Albumin ≥ 2.5 g/dl.
10. Left ventricular ejection fraction (LVEF) by echocardiogram (ECHO) or multiple-
gated acquisition scan (MUGA) above the lower limit of normal (LLN).


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11. Women of childbearing potential must have a negative serum pregnancy test before 
study entry. Both women and men must agree to use a medically acceptable method 
of contraception throughout the treatment period and for six months after 
discontinuation of treatment. 
12. Voluntarily signed and dated written informed consent prior to any specific study 
procedure.
4.2.2
Exclusion criteria
A patient will not be eligible for this study if any of the following exclusion criteria are 
met: 
1. Concomitant diseases/conditions:
a) History or presence of angina, myocardial infarction, clinically relevant valvular 
heart disease, cardiac amyloidosis or congestive heart failure within the last 12 
months.
b) Symptomatic arrhythmia (excluding anemia-related sinusal tachycardia grade 
≤ 2) or any arrhythmia requiring ongoing treatment, and/or prolonged QT-QTc 
grade ≥ 2; or presence of unstable atrial fibrilation. Patients with stable atrial 
fibrillation on treatment are allowed provided they do not meet any other cardiac 
or prohibited drug exclusion criterion.
c) Active uncontrolled infection.
d) Morphological
or cytological
features of myelodysplasia
and/or post-
chemotherapy aplasia on BM assessment.
e) Myopathy > grade 2 or any clinical situation that causes significant and 
persistent elevation of CPK (> 2.5 x ULN in two different determinations 
performed one week apart).
f)
Known human immunodeficiency virus (HIV) infection (HIV testing is not 
required unless infection is clinically suspected).
g) Known active hepatitis B or C virus (HBV or HCV) infection.
h) Limitation of the patient’s ability to comply with the treatment or follow-up 
requirements.
i)
Any other major illness that, in the Investigator’s judgment, will substantially 
increase the risk associated with the patient’s participation in this study.
j)
Peripheral neuropathy > grade 2.
2. Women who are pregnant or breast feeding.
3. Concomitant medications that include corticosteroids, chemotherapy, or other 
therapy that is or may be active against MM, within two weeks prior to Cycle 1 Day 
1. Concurrent corticosteroids are allowed, provided they are administered at an 
equivalent prednisone dose of ≤ 10 mg daily, as premedication for blood products
only.
4. Known history of peptic ulcer and/or major upper gastrointestinal bleeding episode 
occurring during last year before study entry and/or related to prior steroid-based 
therapy.


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5. Relevant history of mood-disturbances changes associated with previous steroid-
based therapy.
6. Disease-related symptomatic hypercalcemia despite optimal medical therapy.
7. Known hypersensitivity to any involved study drug or any of its formulation 
components.
5
PLAN OF STUDY
5.1
PATIENT PARTICIPATION
Patients will receive the study treatment for as long as it is considered beneficial for the 
patient (see Section 5.2). Patients will be evaluated at scheduled visits in up to three study 
periods: 
Pre-treatment: from the signature of the informed consent to the first administration of 
study drugs.
Treatment: up to 30 days after the day of the last dose of study drug administration, 
unless the patient starts any new antitumor therapy outside this clinical trial or dies, in 
which case the date of administration of this new therapy or the date of death will be 
considered the date of last treatment discontinuation. An end-of-treatment visit will be 
performed within 30 days (± two days) after last dose administration, unless the patient 
starts any new antitumor therapy outside this clinical trial, in which case the end-of-
treatment visit should be performed immediately before the start of the new therapy 
(ideally the day before or the same day).
Follow-up: After treatment discontinuation, patients will be followed every four weeks 
until resolution of toxicities if any. Patients who discontinued treatment without 
progression will be followed every four weeks until disease progression or other 
antitumor therapy whichever occurs first. After progression, all patients will be 
followed every three months for survival until death, or until the date of study 
termination, whichever occurs first. 
Study termination date is defined as the date in which 80% of death events occurred, 24 
months after the accrual of the last randomized patient, or IDMC recommendation 
(whichever occurs first).
Note: Two years after the last patient accrual, on 19 May 2017, the final OS analysis was done 
based on a total of 195 death events (i.e., 76.5% of the 255 randomized patients): 123 events in 
Arm A (plitidepsin plus dexamethasone) and 72 events in Arm B (dexamethasone). Then, the 
duration of this study is prolonged for six additional months, until 19 November 2017, in order 
to continue follow-up in the alive patients, and then to be able to reach the pre-specified total of 
80% of death events (approximately 204 death events) or even more. If the required death 
events are not achieved on 19 November 2017, the study might be further extended by three to 
six months.
Patients will be considered to be on-study from the signature of the informed consent to 
the end of the follow-up period. Patients will be considered to be on-treatment for the 
duration of their treatment and 30 days following the last treatment dose. Those patients 
in the control arm (Arm B) who crossed over to the combination arm (Arm A) after 
disease progression will be considered on-treatment for the duration of their whole 


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treatment (dexamethasone alone + dexamethasone in combination with plitidepsin) and 
during 30 days following the last treatment dose. 
Patients may withdraw consent at any time.
5.2
TREATMENT DISCONTINUATION
Patients will receive the study drugs while it is considered to be in their best interest. 
Specifically, treatment will continue until:

Disease progression (except for those patients treated with dexamethasone alone 
and eligible to be offered crossover to combination therapy).

Unacceptable toxicity.

Intercurrent illness of sufficient magnitude to preclude safety continuation of the 
study.

Patient refusal, and/or non compliance with study requirements.

Protocol deviation with an effect on the risk/benefit ratio of the clinical trial
(Section 5.3).

Treatment delay > 2 weeks from the theoretical treatment date (except in case of 
clear clinical benefit, with the Sponsors’ approval).

Requirement of > 2 dose reductions of either drug.
Patients who are withdrawn from Arm A for any reasons or from Arm B for any reason 
other than progression must not be re-treated in the context of this study at any time. For 
follow-up activities, please refer to Section 5.13.
5.3
PROTOCOL DEVIATIONS
A protocol deviation is defined as any departure from what is described in the protocol 
of a clinical trial approved by an Independent Ethics Committee/Institutional Review 
Board (IEC/IRB) and Competent Authorities. Therefore, it applies to deviations related 
to patient inclusion and clinical procedures (e.g., assessments to be conducted or 
parameters to be determined), and also to other procedures described in the protocol that 
concern the Good Clinical Practice (GCP) guidelines or ethical issues (e.g., issues 
related to obtaining the patients’ Informed Consent, data reporting, the responsibilities 
of the Investigator, etc.).
Deviations with no effects on the risk/benefit ratio of the clinical trial (such as minimal 
delays in assessments or visits) will be distinguished from those that might have an 
effect on this risk/benefit ratio, such as:

Deviations that might affect the clinical trial objectives, such as those involving the 
inclusion/exclusion criteria (which could mean that the patient is not eligible for the 
trial) and those having an effect on patient evaluability.

Deviations that might affect the patient’s well-being and/or safety, such as an 
incorrect dosing of the investigational medicinal product (plitidepsin) due to not 
following dose adjustment specifications or an incorrect preparation of the 
medication.


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
Deviations related to the following of GCP guidelines as described in the protocol 
and regulations in force, such as deviations when obtaining the Informed Consent or 
not following the terms established for reporting Serious Adverse Events, etc.
The Investigators may suggest to the Sponsor the authorization of certain protocol 
deviations, especially if they are related to the inclusion/exclusion criteria or if they may 
have an effect on the evaluability of the patients. As a general rule, NO deviations that 
may have an effect on the risk/benefit ratio of the clinical trial will be authorized. All 
protocol deviations considered particularly relevant, which are related to ethical issues, 
fulfillment of GCP guidelines and trial procedures, will be notified to the pertinent 
IEC/IRB and, if pertinent, to the relevant authorities as established by local regulations.
5.4
REPLACEMENT OF PATIENTS
The study analyses will be performed in the study population of all randomized patients. 
As detailed above (see Section 4.1), those patients not evaluable for response will not be 
replaced and they will be included in the final analyses. 
Patients not evaluable for response:

A patient evaluable for response should have measurable disease at baseline and 
should have completed at least one full cycle of treatment or have received two 
incomplete cycles followed by at least one response assessment, unless the patient 
had been withdrawn from the study due to early disease progression or drug-related 
toxicity, in which case the patient will be considered as “early progression” or 
“treatment failure”, respectively. 

Patients will be non-evaluable if there is a protocol deviation resulting in an 
impossibility of drawing conclusions about the efficacy of the study therapy.
These non-evaluable patients will be included in the general safety analysis (if 
appropriate) and in planned efficacy analyses.
Patients without valid disease evaluation during treatment will not be replaced for the 
main analysis and will be analyzed as ITT in either randomized arm. All randomized 
patients will be evaluable for the primary endpoint (PFS) in an ITT analysis.
The early futility analysis will be mainly based on the efficacy data of the first 40 
patients in Arm A evaluable for response. However, the IDMC will be provided with 
data from all randomized patients at that point in order to evaluate the safety profile and
advice on the further conduct of the study.
5.5
DURATION OF THE CLINICAL TRIAL

Protocol submission: 1Q2010.

Planned start date (first patient on study): 2Q2010.

Complete enrollment: 60 months (2Q2010 - 2Q2015).

Planned study termination date: it will be set after the occurrence of 80% of death 
events, 24 months after accrual of the last randomized patient, or IDMC 
recommendation (whichever occurs first). 
Note: Two years after the last patient accrual, on 19 May 2017, the final OS analysis was done based 
on a total of 195 death events (i.e., 76.5% of the 255 randomized patients): 123 events in Arm A 


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(plitidepsin plus dexamethasone) and 72 events in Arm B (dexamethasone). Then, the duration of this 
study is prolonged for six additional months, until 19 November 2017, in order to continue follow-up 
in the alive patients, and then to be able to reach the pre-specified total of 80% of death events 
(approximately 204 death events) or even more. If the required death events are not achieved on 19 
November 2017, the study might be further extended by three to six months.
The futility analysis is foreseen after 40 patients evaluable for response are recruited in 
Arm A, approximately 12 months after the recruitment start.
All patients on active treatment at the date of study termination will be offered to 
continue receiving plitidepsin-based treatment off-study according to the Investigator’s
criteria and upon Sponsor agreement.
5.6
INDEPENDENT REVIEW AND DATA MONITORING COMMITTEES
An Independent Review Committee (IRC), consisting of medical specialists directly 
involved in the care of MM patients, but not being investigators or subinvestigators in this 
trial, will review all efficacy data and will assign the date of progression/censoring and 
objective response according to their independent evaluation. This IRC will be blinded to 
treatment arm allocation and identity of the cases reviewed.
Pertinent clinical or laboratory records [protein M measurements in blood and urine and/or 
serum free light chains (sFLC) measurements in patient samples will be centralized for 
adequate monitoring and auditing purposes] and original copies of all tumor images, 
whenever appropriate, are to be made available by the Investigator on request from the 
Committee.
An Independent Data Monitoring Committee (IDMC), including specialists in MM and in 
medical statistics, will review the results of the analysis performed by an independent 
statistician. Then, the IDMC will advise the Sponsor about the study conduct.
A futility analysis will be performed when data from the 40 patients evaluable for efficacy 
in Arm A are available. The IDMC will advise on the further conduct of the study using 
the protocol-specified efficacy criteria for study continuation in addition to the evaluation 
of safety profile in both treatment arms.
Operational details for the above mentioned IRC and IDMC will be detailed in the 
corresponding charters.
5.7
PRE-TREATMENT ASSESSMENTS
During the pre-treatment period, and after signing the informed consent, patients should 
undergo a series of investigations to determine their eligibility for the study (Table 3).
Table 3. Pre-treatment period
PRE-TREATMENT INVESTIGATIONS
TIME
History and clinical 
examination
Written informed consent signed by the patient.
Demographic data.
Prior to any study-specific procedure.
Within two weeks prior to registration.


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PRE-TREATMENT INVESTIGATIONS
TIME
Medical history includes: 
Date and stage at first diagnosis.
Previous specific treatments (radiotherapy, 
chemotherapy, immunotherapy and
investigational agents), with dates; best response 
and date of progression or relapse.
Complete physical examination, including weight, 
height and BSA. 
Assessment of signs and symptoms.
Intercurrent events, concomitant diseases and 
treatments.
Baseline PS (ECOG), vital signs (heart rate, BP, 
temperature).
Repeat vital signs and PS (ECOG) on 
first infusion.
Repeat complete physical examination 
and signs and symptoms assessment 
prior to first infusion, if treatment will 
be administered > 2 weeks after the 
screening test.
Hematology
Differential WBC, hemoglobin, hematocrit and 
platelets.
Within one week prior to registration.
Repeat prior to first infusion, if 
treatment will be administered more 
than 1 week after the screening test.
Biochemistry
Biochemistry A: AST, ALT, total bilirubin, direct 
bilirubin (in case total bilirubin is above ULN),
AP, creatinine, calculated creatinine clearance 
(Cockcroft and Gault´s formula; see Appendix 3), 
glucose, serum electrolytes (Na+, K+, Mg++, 
Ca++), CPK (CPK-MB fraction should be 
measured only if CPK is abnormally high) and 
troponin I.
Biochemistry B: Uric acid, LDH, total proteins, 
albumin
Coagulation tests: PT, PTT and INR.
Within one week prior to registration.
Repeat prior to first infusion, if 
treatment will be administered more 
than 1 week after the screening test.
Pregnancy test, if 
applicable
Serum HCG
Within one week prior to registration.
Cardiac assessment
ECG: It should allow rhythm definition (at least 30 
seconds of duration).
Troponin I.
LVEF assessment by ECHO or MUGA.
Within one week prior to registration.
Within one week prior to registration.
Within two weeks prior to registration.
Local Serum protein Serum protein electrophoresis, immunoglobulins 
quantification, M-protein identification and 
quantification, serum free light chains (sFLC), 
sFLC ratio and immunofixation (complete protein 
panel). 
Within four weeks prior to 
registration.
Repeat on first infusion prior to 
treatment in the Central Lab on Day 1 
of Cycle 1.
Local Urine protein
Urine immunoelectrophoresis and 
immunofixation.
Within four weeks prior to registration
(up to two additional days of tolerance 
window).
Repeat on first infusion prior to 
treatment in the Central Lab on Day 1 
of Cycle 1.
Serum β-2 
microglobulin 
Within two weeks prior to registration.
Bone marrow
Within four weeks prior to 
registration.


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PRE-TREATMENT INVESTIGATIONS
TIME
Radiological tumor 
assessment only in 
case of soft tissue 
plasmacytoma(s)
present at baseline
Within four weeks prior to 
registration.
Skeletal evaluation
May be done using CT-scan or X-ray, provided the 
same procedure is used throughout the study.
Within four weeks prior to registration
(+1 week tolerance).
BSA: body surface area; PS-ECOG: performance status according to Eastern Cooperative Oncology Group; BP: blood pressure; WBC: white 
blood cells; AST: aspartate aminotransferase; ALT: alanine aminotransferase; ULN: upper limit of  normal; AP: alkaline phosphatase CPK: 
creatine phosphokinase; CPK-MB: serum CPK isoenzymes (found In cardiac muscle); CT: computed tomography; LDH: lactate 
dehydrogenase; PT: prothrombin time, PTT: partial thromboplastin time, INR: international normalized ratio; ECG: electrocardiogram; LVEF: 
left ventricular ejection fraction; ECHO: echocardiogram; MUGA: multiple-gated acquisition scan; HCG: human chorionic gonadotropin; FLC: 
free light chain; D, day; C, cycle.
5.8
PATIENT REGISTRATION
After ensuring that the patient meets all eligibility criteria and has given written 
informed consent, he/she can be registered in the study by means of the Interactive 
Voice Response System (IVRS, ICOPhone™). Authorized site staff will be provided 
with a personal user ID and PIN Code to access the system. To start the randomization 
process, the site responsible should dial the country-specific phone number supplied in 
the IVRS Manual (given as a separate document). The system will require the following 
information to be provided: patient number (six digits: four digits for site code, pre-
assigned, plus two numbers assigned consecutively for every site’s patients), date of 
birth, ECOG-PS score, Durie-Salmon stage at first diagnosis and planned treatment date 
(the planned treatment date must be seven days or less from the Randomization date). A 
confirmation report will be sent via e-mail once the randomization call will end, listing 
the above information plus the treatment arm the patient has been assigned to. The 
aforementioned patient number should be used on all future documentation and 
correspondence referring this patient.
A patient who has been treated prior to registration will not be accepted for the study at 
a later date.
5.9
PATIENT ASSIGNMENT TO TREATMENT GROUP
See Section 5.10 Patient Randomization.
5.10 PATIENT RANDOMIZATION
Eligible patients will be stratified according to their ECOG-PS score (0 and 1 vs. 2) and 
Durie-Salmon stage (I/II vs. III) and then randomized using a 2:1 randomization 
procedure to Arm A (plitidepsin in combination with dexamethasone) or Arm B 
(dexamethasone alone). Randomization will be used to avoid bias in the assignment of 
subjects to treatment, and to increase the likelihood that known and unknown subject 
attributes (e.g., demographics and baseline characteristics) are evenly balanced across 
treatment groups. 
Randomization of patients should occur as close in time as possible before 
administration of the first dose of study drug(s) and must occur within 7 days of the 
patient receiving the first dose of study treatment. Patients will be assigned to each 


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group by strata random lists, so that a patient will have a two-thirds chance of getting 
Arm A (plitidepsin in combination with dexamethasone) and a one-third chance of 
getting Arm B (dexamethasone alone). The random permuted blocks method will be 
used; the size of the blocks in the randomization list will be fixed and not accessible to 
the investigators. To select the blocks, a uniform (0, 1) variable with a random seed will 
be used.
5.11 EVALUATION DURING TREATMENT
Table 4. Evaluation during treatment
TREATMENT
INVESTIGATIONS
TIME
Clinical 
examination
Physical exam including weight, height
and BSA.
PS (ECOG), vital signs (heart rate, BP, 
body temperature).
Concomitant treatments.
On D1 of each cycle before study drug 
administration.
On D1 and D15 of every cycle before 
study drug administration.
Throughout the study.
Hematology 
Differential WBC, hemoglobin, 
hematocrit and platelets.
On D1 and D15 of every cycle before
study drug administration, with a 
window of -2 days.
If CTCAE grade ≥ 3 occurs, the 
hematological counts should be 
assessed at least every 2-3 days in the 
case of grade 4 non-febrile 
neutropenia and everyday in case of 
grade 4 febrile neutropenia.
Biochemistry 
Biochemistry A: AST, ALT, total 
bilirubin, direct bilirubin (in case total 
bilirubin is above ULN), AP, creatinine
(calculated creatinine clearance by 
Cockcroft and Gault´s formula; see 
Appendix 3), glucose, serum electrolytes 
(Na+, K+, Mg++, Ca++), CPK, (CPK-MB 
fraction should be measured only if CPK 
is abnormally high) and troponin I*. 
On D1 and D15 of every cycle before
study drug administration, with a 
window of -2 days.
If CTCAE grade ≥ 3 occurs, the 
abnormal test(s) should be assessed at 
least every 2-3 days until recovery. 
Biochemistry B: Uric acid, LDH, total 
proteins, albumin.
Coagulation tests: PT, PTT and INR.
On D1 of every cycle, except on D1 of 
Cycle 1, and with a window of -5 
days.
Pregnancy test
Serum HCG
Repeat if applicable; always prior to 
study drug administration.
Adverse Events 
Throughout the study.
Cardiac 
assessment
ECG: It should allow rhythm definition 
(at least 30 seconds of duration).
Troponin I*.
LVEF assessment by ECHO or MUGA.
Before each study drug 
administration, symmetrically in both 
arms. After the first two cycles, ECG
will be done only on D1 of each cycle.
Every 12 weeks, with a window of ± 2 
weeks. When due, LVEF will be 
performed within 7 days of plitidepsin 
administration, except in non-
primarily cardiac origin acutely ill 


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TREATMENT
INVESTIGATIONS
TIME
hospitalized patients, until resolution.
Pharmacokinetics
Plitidepsin PK will be evaluated in at 
least 100 patients receiving both 
plitidepsin and dexamethasone (Arm A). 
A total of 13 blood samples will be 
collected during the first three 
infusions [infusions 1 and 2 of Cycle 
1 (Days 1 and 15), and infusion 1 of 
cycle 2 (Day 1)] using a sparse 
sampling schedule (see details in 
Table 5)
Central Lab 
Serum protein
Patients with secretory MM will be 
followed with serum electrophoresis, 
immunoglobulins quantification and M 
protein quantification in the Central Lab 
starting on Day 1 of Cycle 1; patients 
with oligo or non-secretory MM, will be 
followed with sFLC ratio, in case it has 
been abnormal at study entry; in case of 
M protein disappearance, 
immunofixation will be done to confirm 
CR, and if CR is confirmed, sFLC ratio 
will be performed, to determine sCR.
All protein assays will be done 
symmetrically every four weeks (i.e., 
Day 1 of every 4-week cycle, with a 
window of ± 2 days) in both treatment
arms, irrespectively of treatment 
delays or omissions.
Central Lab Urine 
protein
Only if Bence-Jones proteinuria is 
present at entering the study, in the 
Central Lab starting on Day 1 of Cycle 1.
Every four weeks (with a window of ±
2 days) symmetrically in both 
treatment arms, irrespectively of 
treatment delays or omissions.
Serum β-2 
microglobulin 
Every 8 weeks (with a window of ±2 
days).
Bone marrow
In all patients while in treatment, BM 
evaluation is mandatory at screening and 
in case of CR (including flow cytometry 
or immunohistochemistry, to 
demonstrate the presence of clonal 
plasma cells, only in those patients with 
presumed CR).
In patients with non-secretory MM it 
must be repeated 6 weeks later to 
confirm response or as clinically 
indicated.
When serum protein indicates CR.
Radiological 
tumor assessment 
only in case of 
measurable soft 
tissue 
plasmacytoma
Every 8 weeks (with a window of 2 
weeks) or if response is observed or if 
clinically indicated.
Skeletal evaluation
May be done using CT-scan or X-ray, 
provided the same procedure is used 
throughout the study.
If clinical symptoms suggest new 
bone lytic lesion.
* In case of serum troponin I increase, an ECG and ECHO will be performed as soon as possible, as well as further studies if judged 
necessary by clinical investigator. Any increase of troponin I ≥ ULN together with evidence of cardiac damage by ECG or 
ECHO/MUGA will be followed accordingly by a cardiologist and the patient will immediately and definitively discontinue study 
treatment.
PS-ECOG: Eastern Cooperative Oncology Group; BSA: body surface area; BP: blood pressure; WBC: white blood cells; CTCAE: 
National Cancer Institute Common Terminology Criteria for Adverse Events; AST: aspartate aminotransferase; ALT: alanine 


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INVESTIGATIONS
TIME
aminotransferase; ULN: upper limit of  normal; AP: alkaline phosphatase; CPK: creatine phosphokinase; CPK-MB: serum CPK 
isoenzymes (found in cardiac muscle); CT: computed tomography; LDH: lactate dehydrogenase; PT: prothrombin time, PTT: partial 
thromboplastin time, INR: international normalized ratio; ECG: electrocardiogram; LVEF: left ventricular ejection fraction; ECHO: 
echocardiogram; MUGA: multiple-gated acquisition scan; PK: pharmacokinetics; HCG: human chorionic gonadotropin; BM: bone 
marrow; FLC: free light chain; CR: complete response; MM: multiple myeloma; sCR, stringent complete response; D, day.
Note: One patient was still undergoing treatment on 19 May 2017. However, as the primary 
endpoint of the study (progression-free survival) was fulfilled, and this extended follow-up is 
focused only on survival, no information such as central laboratory data or images will be sent 
for independent review. Nevertheless, laboratory determinations or images will be done locally, 
if clinically indicated, in order to perform tumor assessment.    
5.12 EVALUATION AT THE END OF TREATMENT
The end-of-treatment visit will be scheduled 30 days (± two days) after the 
administration of the last dose of the study therapy, unless another anticancer treatment 
is started before. In that case, the end-of-treatment visit should be performed 
immediately before the start of the new therapy (ideally the day before or the same day). 
At the time of patient discontinuation (regardless of the reason), the same complete 
work-up done before study entry will be repeated. 

Physical examination, weight and height.

ECOG performance status.

Vital signs.

Hematology and coagulation tests.

Biochemistry (A and B).

ECG: It should allow rhythm definition (at least 30 seconds of duration)

LVEF assessment by ECHO or MUGA.

Safety assessment (AEs).

Serum protein: serum protein electrophoresis, immunoglobulins quantification, 
M-protein identification and quantification, and serum sFLC if indicated.

Urine protein: Only if Bence-Jones proteinuria is present at entering the study.

Serum β-2 microglobulin: only if the patient discontinues treatment without 
documented disease progression.

Bone marrow (if clinically indicated).

Radiological tumor assessment only in case of soft tissue plasmacytoma present 
at entering the study.

Skeletal evaluation.

Concomitant treatments.
Adverse events must be assessed for 30 days after the administration of the last study 
treatment. All SAEs occurring within 30 days of the last study drug administration will 
be reported. Beyond this period of time, only those suspected to be treatment-related 
SAEs will be reported (Section 9.2.2).


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The Sponsor will evaluate any safety information that is spontaneously reported by an 
Investigator beyond the time frame specified in the protocol.
5.13 FOLLOW-UP AFTER END-OF-TREATMENT VISIT
Bone marrow evaluation, radiological tumor assessment and skeletal evaluation will be 
performed only on pre-treatment and treatment evaluations. These evaluations will not 
be performed after the end of treatment.
Patients who discontinued treatment without progression will be followed every four 
weeks until disease progression or other antitumor therapy, whichever occurs first. After 
progression, all patients will be followed every three months for survival until death, or 
until the date of study termination, whichever occurs first. Study termination date is 
defined as the date in which 80% of death events occurred, 24 months after the accrual 
of the last randomized patient, or IDMC recommendation (whichever occurs first).
Note: Two years after the last patient accrual, on 19 May 2017, the final OS analysis was done 
based on a total of 195 death events (i.e., 76.5% of the 255 randomized patients): 123 events in 
Arm A (plitidepsin plus dexamethasone) and 72 events in Arm B (dexamethasone). Then, the 
duration of this study is prolonged for six additional months, until 19 November 2017, in order 
to continue follow-up in the alive patients, and then to be able to reach the pre-specified total of 
80% of death events (approximately 204 death events) or even more. If the required death 
events are not achieved on 19 November 2017, the study might be further extended by three to 
six months.
All AEs suspected to be related to study drug must be followed after the time of therapy 
discontinuation until the event or its sequel resolve or stabilize at a level acceptable to 
the Investigator and the clinical monitor or his/her designated representative. After 
treatment discontinuation, patients will be followed every four weeks until resolution of 
toxicities, if any.
Additional parameters and/or increased frequency of observations should be performed 
at the Investigator’s discretion and according to the nature of the observed AEs. When 
available, autopsy data should be provided.
The follow-up visits will be performed by phone only if the patient is unable to go to the 
study center owing to the seriousness of his/her disease. This will only apply to patients 
who are followed up after discontinuing treatment due to disease progression.
6
PHARMACOKINETICS
Plitidepsin pharmacokinetics (PK) will be evaluated in at least 100 patients receiving 
both plitidepsin and dexamethasone (Arm A) at selected sites. Patients will be sampled 
during Days 1 and 15 of the Cycle 1 and on Day 1 of the Cycle 2 using a sparse 
sampling schedule. 
In the treatment infusions with blood sampling for pharmacokinetics, the infusion rate 
will be established so that it ensures that the total plitidepsin dose is infused over 3 
hours. Drug will be infused at a constant rate throughout the 3-hour period. In order to 
obtain reliable pharmacokinetic information, the infusion rate should not be modified 
once the infusion begins. If a variation in the infusion time eventually occurs, it is very 
important to reflect it in the CRF, writing clearly the time of the beginning and the end 


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of the infusion. The infusion rate should not be changed to maintain the scheduled 
duration of infusion. It would be enough just to record the actual duration in the CRF 
and in the pharmacokinetic sampling sheet in the cycles in which PK sampling is 
performed.
Blood samples will be obtained through a peripheral vein located in the contralateral 
side to that of the infusion. In any case, the sampling vein has to be different to that in 
which study drug is infused. Even the last sample must never be collected from the 
infusion catheter. If the blood sample is obtained from a catheter, the first ml of blood 
will be discarded to avoid the dilution of the sample with the solution used to keep it 
permeable.
Four-ml blood samples will be collected in sodium heparin tubes. Sample tubes will be 
gently inverted several times to assure adequate mixing with the heparin and the blood 
(without centrifugation) should be transferred to the provided polypropylene tubes and 
stored at -20ºC until the shipping to the analysis laboratory. The tubes will be provided 
by PharmaMar.
A total of 13 blood samples will be collected during the first three infusions (infusions 1 
and 2 of Cycle 1, and infusion 1 of Cycle 2) at the time points detailed in Table 5.
Table 5. Sampling points for pharmacokinetic evaluations.
Sample 
number
Cycle
Infusion
Time
(from start of each 
infusion)
Time*
(relative to EOI)
1
1
1
0 h
Preinfusion
2
1
1
3 h
Just before EOI
3
1
1
4 h
One hour after EOI
4
1
1
6 h
Three hours after EOI
5
1
2
0 h
Preinfusion
6
1
2
3 h
Just before EOI
7
1
2
4 h
One hour after EOI
8
1
2
6 h
Three hours after EOI
9
2
1
0 h
Preinfusion
10
2
1
3 h
Just before EOI
11
2
1
4 h
One hour after EOI
12
2
1
6 h
Three hours after EOI
13
2
1
~336
Two weeks after EOI**
*The length of the infusion is three hours.
**Previous to second infusion of the second cycle.
EOI: end of infusion.
The accurate recording of actual dosing and sampling times is much more important 
than the strict adherence to the scheduled times.
Once all samples from a patient have been collected they should be shipped to the 
central laboratory for pharmacokinetics as soon as possible, ideally the next shipping 
day. The time span between the moment the last PK sample for a patient has been 
collected and the shipment of all the samples from this patient to the central lab should 
not exceed two months.


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Samples will be identified with the following data: study reference, patient number, 
sample number, date and time of collection. At all time the confidentiality of patient’s 
data will be maintained.
A manual of instructions for sample collection, labeling, storage, and shipment will be 
provided as a separate document.
7
TREATMENT
7.1
STUDY MEDICATIONS
For information regarding dexamethasone please refer to Dexamethasone Drug 
Information, provided as a separate document. For detailed instructions regarding 
plitidepsin inventory, handling, reconstitution, dilution, storage, accountability and 
disposal, please refer to the updated Aplidin® Preparation Guide for Infusion, also 
provided as separate document.
Commercially available oral dexamethasone formulation will be provided by the 
Sponsor.
7.1.1
Quantitative and Qualitative Composition
7.1.1.1
Plitidepsin
Plitidepsin will be supplied as a powder and solvent for concentrate for solution for 
infusion. The 2-mg vial should be reconstituted with a 4-ml ampoule of reconstitution 
solution. The composition of reconstitution solution is Cremophor EL/Ethanol/Water 
for injection, 15%/15%/70% (v/v/v).
7.2
ADMINISTRATION OF STUDY MEDICATION
The administration of each study medication will be as follows:

Arm A:
a) Dexamethasone: 40 mg orally on Day 1, 8, 15 and 22 every four weeks 
(q4wk) at least one hour before plitidepsin infusion.
b) Plitidepsin: 5 mg/m2 intravenously (i.v.) diluted to a total volume of 250 ml 
in 0.9% saline (or 5% glucose) via a central venous catheter (suggested) or 
diluted to a total volume of 500 ml in 0.9% saline (or 5% glucose) via a 
peripheral line. Infusion will be performed through a pump device over three 
hours (fixed rate) on Day 1 and 15 q4wk.

Arm B: 
a) Dexamethasone: 40 mg orally on Day 1, 8, 15 and 22 q4wk.
A cycle is defined as a four-week period.
7.3
CRITERIA FOR TREATMENT CONTINUATION AND RETREATMENT
Patients may be treated with additional cycles of plitidepsin and dexamethasone or 
dexamethasone alone, as long as no unacceptable toxicity and/or disease progression is 
documented (see Section 5.2).


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Complete blood counts, blood chemistries and other tests will be done prior to starting 
the next treatment cycle (please refer to Section 5.7 and Section 5.11 for the full list of 
tests to be done before each drug administration and/or initiation of a new treatment 
cycle).
Table 6 lists the minimum requirements needed to re-expose the patient to the study 
drug(s) in each group. Other factors might be considered critical by the Investigator. In 
this case, these factors should be appropriately documented in the patient’s record and 
on the CRF, and discussed with the Sponsor.
If the criteria listed in Table 6 are not met on the day of the next planned dose, 
administration of the study drug(s) should be delayed. The criteria for treatment 
administration should be reevaluated weekly. The new cycle will start upon recovery to 
the values listed in those tables, for Day 1.
A maximum cycle delay of two weeks is allowed for recovery from drug-related AEs. If 
no recovery was found after the two-week delay, the patient should discontinue the 
treatment, except —upon Sponsor’s agreement— in cases of obvious patient benefit in 
continuing the treatment according to the investigator’s criteria. 
Before the administration of each dose (retreatment), patients must fulfill the baseline 
criteria defined in Table 6.
Table 6. Criteria for continuation of treatment
Criteria for continuation of 
treatment
Plitidepsin
(Arm A)
Dexamethasone
(Arm A and B)
Day 1 a and 15 b
Day 1 a and 15
ANC
1.0  x 109/l or return to baseline 
values if extensive BM involvement 
-
Platelets
50  x 109/l or return to baseline 
values if extensive BM involvement
-
Hemoglobin
8.5 g/dl
8.5 g/dl
Direct bilirubin if total bilirubin 
is above the upper normal limit
1.0 x ULN
-
AST/ALT
Grade 2
-
Muscular toxicity (myalgia, 
muscular weakness, CPK 
increase)
Grade 2
≤ Grade 2
Other non-hematological drug-
related AEs (except for 
increased GGT and/or AP, not 
optimally treated nausea and 
vomiting or hypertension, 
alopecia)c
≤ Grade 1
≤ Grade 1


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Criteria for continuation of 
treatment
Plitidepsin
(Arm A)
Dexamethasone
(Arm A and B)
Day 1 a and 15 b
Day 1 a and 15
ECG, ECHO/MUGAd
Same as baseline
Same as baseline
a.
If a patient does not meet the requirements for treatment continuation on Day 1 of the following cycle, the 
infusion of study drugs will be withheld until recovery or for a maximum of 14 days. After this period, if delay is 
due to toxicity assessed as related to study drug, a dose decrease of 20% is mandatory; up to a maximum of two 
individual dose reductions are allowed. Patients needing additional dose reductions must be withdrawn from the 
trial.
b. If a patient does not meet the requirements for treatment continuation on Day 15, the administration of plitidepsin
will be omitted. Patients requiring frequent dose omissions may have a dose reduction of 20% upon Investigator 
and Sponsor agreement. In no case more than two dose reductions are allowed
c. Any grade accepted for increased GGT and/or AP, and up to grade 2 peripheral neuropathy.
d. To be performed every three months unless more frequent assessments are clinically indicated.
AEs: adverse event(s); ANC: absolute neutrophil count; AP: alkaline phosphatase; BM: bone marrow; AST/ALT: 
aspartate aminotransferase/alanine aminotransferase; CPK: creatine phosphokinase; GGT: -glutamyltranspeptidase; 
ECG: electrocardiogram; ECHO/MUGA: echocardiogram/multiple-gated acquisition scan.
7.4
DOSE REDUCTION CRITERIA
Patients experiencing frequent dose omissions and/or unacceptable toxicity, defined as

less than 50% compliance with treatment schedule, and/or 

grade ≥ 3 febrile neutropenia, or 

grade 4 neutropenia and infection, or 

grade 4 neutropenia lasting > 7 days (except for patients with extensive BM 
involvement), and/or 

grade 4 thrombocytopenia (except for patients with extensive BM involvement),
and/or

grade 4 thrombocytopenia with grade ≥3 bleeding (in patients with extensive 
BM involvement), and/or

any grade ≥ 3 clinically relevant non-hematological toxicity other than non-
optimally treated nausea and vomiting, diarrhea lasting < 48 hours and/or grade 
≥ 3 asthenia/fatigue lasting < 5 days
may continue treatment after reducing 20% of the dose of plitidepsin (first reduction to 
4 mg/m2, and second reduction to 3.2 mg/m2), upon Sponsor agreement, if patient 
benefit is perceived. 
Dexamethasone doses are to be reduced by 50%, up to a maximum of two consecutive 
dose reductions (first one, 20 mg Days 1,8,15 and 22, and second, 20 mg Days 1 and 15 
of each 28-day cycle), if a patient experiences muscular toxicity of grade ≥ 3 (weakness, 
myalgia and/or CPK elevations), or drug-related grade ≥ 3 fatigue, or mood 
disturbances or agitation of grade ≥ 2 or grade ≥ 3 fluid retention or grade 4 clinically 
documented infection. These dose reductions are to be implemented independently from 
plitidepsin dose reductions, if required.
Dose reduction criteria for both study drugs are summarized in Table 7.


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Table 7. Dose reduction criteria for plitidepsin and dexamethasone.
Toxicity
Worst 
grade
Plitidepsin
Dexamethasone
Less than 50% compliance 
with treatment schedule
Decrease to 4 
mg/m2, then to 3.2 
mg/m2
No reduction
Febrile neutropenia
≥ 3
Decrease to 4 
mg/m2, then to 3.2 
mg/m2
No reduction
Neutropenia lasting > 7 days
(except for patients with 
extensive BM involvement)
4
Decrease to 4 
mg/m2, then to 3.2 
mg/m2
No reduction
Thrombocytopenia
(except for patients with 
extensive BM involvement )
4
Decrease to 4 
mg/m2, then to 3.2 
mg/m2
No reduction
Thrombocytopenia with 
grade ≥ 3 bleeding 
(in patients with extensive 
bone marrow involvement)
4
Decrease to 4 
mg/m2, then to 3.2 
mg/m2
No reduction
Any clinically relevant 
and/or non-hematological 
toxicity (except non-
optimally treated nausea and 
vomiting, diarrhea < 48 
hours and/or 
asthenia/fatigue lasting < 5 
days)
≥ 3
Decrease to 4 
mg/m2, then to 3.2 
mg/m2
No reduction
Muscular toxicity (weakness, 
myalgia and/or CPK 
elevations) 
≥ 3
First episode: 
decrease to 4 
mg/m2, then 
reduce 
dexamethasone; if 
toxicity recurs, 
reduce to 3.2 
mg/m2
First reduce plitidepsin; if 
persistence, decrease 
dexamethasone to 20 mg Days 
1,8,15,22 of each cycle; if 
toxicity recurs, decrease  again 
plitidepsin and, if persistence, 
then decrease dexamethasone 
dose to 20 mg Days 1 and 15 of 
each cycle. Two dose reductions 
are allowed for either agent (only 
for muscular toxicity).
Mood disturbances/agitation
≥ 2
No reduction
First reduction to 20 mg Days 
1,8,15,22 of each cycle, then to 
20 mg Days 1 and 15 of each 
cycle.
Fluid retention
≥ 3
No reduction
First reduction to 20 mg Days 
1,8,15,22 of each cycle, then to 
20 mg Days 1 and 15 of each 
cycle.


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Toxicity
Worst 
grade
Plitidepsin
Dexamethasone
Clinically documented 
infection
4
No reduction
First reduction to 20 mg Days 
1,8,15,22 of each cycle, then to 
20 mg Days 1 and 15 of each 
cycle.
Once a dose reduction has been implemented, dose will not be re-escalated thereafter. 
No more than two dose reductions (of either compound, if required) are allowed. 
Patients needing additional dose reductions must be withdrawn from the trial. 
7.5
CONCOMITANT MEDICATION
All tumor-specific prior chemotherapy, radiation therapy and all relevant information 
must be recorded on the patient's CRF.
In addition, reasonable efforts will be made to determine all treatments received by the 
patient during administration of the study drugs. This information must be documented 
in the concomitant therapy Section of the CRF.
Cardiac safety of plitidepsin will be monitored with ECG, LVEF and troponin I 
measurement during the trial. Some drugs may prolong QTC interval duration. These 
drugs are allowed as concomitant medication, and the investigators should be aware of 
this potential event.
Close monitoring of patients taking oral anticoagulants is required.
7.5.1
Prophylactic Medication
1. Arm A: 
All patients must receive the following prophylactic medication 20-30 minutes before 
infusion of plitidepsin:

Ondansetron 8 mg i.v. or equivalent (granisetron 3 mg i.v. preferred when 
available).

Diphenhydramine hydrochloride 25 mg i.v. or equivalent, and

Ranitidine 50 mg i.v. or equivalent.
Oral metoclopramide and/or extended oral ondansetron (or their equivalents) may be 
used as per Investigator’s criteria/institutional guidelines (63).
2. Arm B: No prophylactic medication specified.
7.5.2
Allowed Medications/Therapies
1. Platelet and red cells transfusions.
2. Erythropoietin.
3. Bisphosphonates during the study according to the ASCO guidelines (64).
4. Therapies for the treatment of preexisting and/or emergent medical conditions not 
specifically forbidden as per protocol elsewhere.


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5. Antiemetics (excluding steroids) according to institutional or ASCO guidelines (65).
6. Granulocyte colony stimulating factor (G-CSF)/granulocyte-macrophage colony 
stimulating factor (GM-CSF) and/or blood derived products transfusions, according 
to institutional or ASCO guidelines (66, 67).
7. Palliative local radiation of a plasmacytoma. The irradiated lesion will then not be 
considered an area of measurable/evaluable disease.
8. Systemic and/or local therapies for symptomatic relief, particularly in the case of 
diarrhea or skin toxicity.
9. Patients in the plitidepsin + dexamethasone arm who develop grade ≥ 2 muscular 
toxicity may be empirically treated with oral L-carnitine at a total daily amount of
up to 3 g, divided into three doses, until it decreases to grade ≤ 1.
10. Adequate analgesic medication, including opioids for symptomatic pain relief if 
indicated.
11. Drugs known to prolong QT interval and/or induce Torsades de Pointes should be 
avoided whenever possible (see Appendix 7, drugs labeled as 1).
7.5.3
Prohibited Medications/Therapies
1. Concomitant administration of any other antineoplastic therapy.
2. Other investigational agents.
3. Immunosuppressive therapies, except single bolus hydrocortisone used eventually as 
treatment for hypersensitivity reactions, if required.
4. Primary prophylaxis with colony-stimulating factors, such as G-CSF and GM-CSF.
7.5.4
Drug Accountability
Proper drug accountability will be done by the study monitor. The Institution 
responsible will keep records to allow a comparison of quantities of drug supplied and 
administered at each site.
All unused drug supplied by the Sponsor will be properly destroyed at the 
investigational site. Documentation of this procedure must be provided, or with the 
agreement of Sponsor returned to the drug repository.
7.6
VERIFICATION OF COMPLIANCE WITH TREATMENT REGIMEN
The compliance of the patient is under direct supervision of the Investigator.
8
STUDY EVALUATIONS
8.1
EFFICACY 
Primary

PFS, according to IRC assessment, as per intention-to-treat (ITT) analysis.


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Secondary 

Objective RR.

Best overall response including rate of minor response (MR) or better (according to 
the IMWG criteria) (Appendix 5).

RR to combination treatment in patients who crossed over after progression on 
dexamethasone alone.

Time-to-event endpoints: DR and OS.

Intrapatient response and PFS comparison of patients who crossed over from 
dexamethasone alone (Arm B) to plitidepsin plus dexamethasone combination (Arm 
A).
The primary study analysis will be based on externally assessed PFS data in the ITT 
efficacy population, defined as all patients randomized to either treatment arm.
PFS will be calculated from randomization to the first evidence of PD (IMWG criteria) 
or death due to any cause. If the patient receives further antitumor therapy before PD 
and within the timeframe expected for first follow-up, PFS will be censored on the date 
of the last disease assessment prior to the administration of this antitumor therapy. If the 
patient is lost to follow-up for the assessment of progression, or has more than one 
missing follow-up between the date of last tumor assessment and the date of 
progression, death or further antitumor therapy, the PFS will be censored at the date of 
last valid tumor assessment before the missing evaluations.
DR will be calculated from the date of first documentation of response to the date of 
disease progression or death. The same censoring rules described above for PFS 
calculation will be also considered for DR.
OS is defined as the time from the date of randomization to the date of death or last 
contact.
An external IRC, blinded to treatment arm, will assign a progression or censoring date 
for each patient based on laboratory data and radiologic and bone marrow assessments 
when required and evaluation of all relevant clinical information, according to a 
predefined algorithm provided in a separate charter. Both IRC and Investigator’s 
assessment will be used for the determination of RR, DR and PFS.
By design, disease response will be assessed every four weeks symmetrically across 
treatment arms irrespectively of treatment delays or omissions. Disease assessments 
(e.g., serum or urine M protein, serum FLC) and evaluation of extent of disease will be 
done within two weeks before randomization and every four weeks thereafter in the 
absence of PD while on treatment. If disease progression has not occurred at treatment 
termination, then disease assessments should continue every four weeks until evidence 
of disease progression, start of subsequent anticancer treatment, or death, whichever 
occurs first. 
PFS and objective tumor response will be assessed symmetrically across treatment arms 
every four weeks while on treatment, irrespectively of dose omissions or delays,
according to IMWG criteria. Centralized laboratory reports and copies of CT scans, 
MRI (in case of soft tissue plasmacytoma) and any other documented means to evaluate 
tumor response or progression should be available for IRC review.


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8.2
SAFETY
Patients are evaluable for general safety if they received at least one dose of the study 
treatment. Safety will be evaluated in each arm separately according to the actual 
treatment received.
AEs will be graded according to National Cancer Institute Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.
8.3
EVALUATION OF PHARMACOKINETICS
At least 100 patients will be evaluated for PK in patients receiving both plitidepsin and 
dexamethasone during the first three infusions. The effect of the concomitant 
administration of dexamethasone on the plitidepsin PK and the relationship between the 
plitidepsin PK exposure and toxicity/efficacy parameters will be evaluated.
9
ADVERSE EVENTS REPORTING
9.1
DEFINITIONS
9.1.1
Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient or a clinical 
investigation patient administered a pharmaceutical product which does not necessarily 
have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (e.g., an abnormal 
laboratory finding), or a disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Any event involving adverse drug reactions, illnesses with onset during the study or 
exacerbations of pre-existing illnesses should be recorded, including but not limited to 
clinically significant changes in physical examination findings and abnormal objective 
test findings (e.g., x-ray, ECG). The criteria for determining whether an abnormal 
objective test finding should be reported as an AE are as follows:

The test result is associated with clinically significant symptoms, and/or

The test result leads to a change in the study dosing or discontinuation from the 
clinical trial, significant additional concomitant drug treatment or other therapy, 
and/or

The test result leads to any of the outcomes included in the definition of a SAE, 
and/or

The test result is considered to be clinically relevant by the Investigator.
9.1.2
Serious Adverse Event (SAE)
A Serious Adverse Event (SAE) is any adverse experience occurring at any dose that:

Results in death (is fatal),

Is life-threatening,

Requires or prolongs inpatient hospitalization,

Results in persistent or significant disability or incapacity,


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
Is a congenital anomaly or birth defect, or

Is medically significant.

Is any suspected transmission of an infectious agent via a medicinal product.
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations such as an important medical event that may 
not be immediately life-threatening or result in hospitalization but may jeopardize the 
patient or may require intervention to prevent one of the outcomes listed in the above 
definition.
9.1.2.1
Death
Death as such is the outcome of a SAE and should not be used as the SAE term itself. 
Instead, the cause of death should be recorded as the SAE term. When available, the 
autopsy report will be provided to the Sponsor.
Grade 5 should be used for events which lead immediately and directly to death, and 
grade 4 should be used with outcome death for events which lead to death after a longer 
time period, and that may also be linked to additional morbidities.
9.1.2.2
Life Threatening Event
Any event in which the patient was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it were more severe.
9.1.2.3
Hospitalization or Prolongation of Hospitalization 
Any AE requiring hospitalization (or prolongation of hospitalization) that occurs or 
worsens during the course of a patient’s participation in a clinical trial must be reported 
as a SAE unless exempted from SAE reporting (see Section 9.2.2). Prolongation of 
hospitalization is defined as any extension of an inpatient hospitalization beyond the 
stay anticipated/required for the initial admission, as determined by the Investigator or 
treating physician.
Hospitalizations that do not meet criteria for SAE reporting are: 
a) Reasons described in protocol (e.g., study drug administration, protocol-required 
intervention/investigations, etc). However, events requiring hospitalizations or 
prolongation of hospitalization as a result of a complication of therapy 
administration or clinical trial procedures will be reported as SAEs.
b) Hospitalization or prolonged hospitalization for technical, practical or social
reasons, in absence of an AE.
c) Pre-planned hospitalizations: any pre-planned surgery or procedure must be 
documented in the source documentation. Only if the pre-planned surgery needs to 
be performed earlier due to a worsening of the condition, should this event 
(worsened condition) be reported as a SAE. 
Other situations that MUST NOT be considered as hospitalizations are the following:
d) An emergency visit due to an accident where the patient is treated and discharged.


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e) When the subject is held 24 hours for observation and finally is not admitted.
f) Planned treatments at sites not associated to a hospital and generally considered as 
minor surgical procedures (i.e., laser eye surgery, arthroscopy, etc).
9.1.3
Unlisted /Unexpected Adverse Event
An AE, the nature or severity of which is not consistent with the applicable reference 
safety information.
The Sponsor will use as the reference safety information for the evaluation of 
listedness/expectedness the following documents:

The current Investigator’s Brochure (IB) for any PharmaMar study drug without 
a marketing authorization or used outside the conditions of its marketing 
authorization.

The summary of product characteristics (SPC) or its national equivalent [i.e., 
U.S. package inserts (USPI)] for non-PharmaMar study drugs used within the 
conditions of its marketing authorization. For dexamethasone the expectedness 
will be assessed against the safety sections in the label maintained at 
http://www.drugs.com/pro/dexamethasone.html.
9.1.4
Adverse Reactions
All untoward and unintended responses to an investigational medicinal product related 
to any dose administered. This definition covers also medication errors and uses outside 
what is foreseen in the protocol, including overdose, lack of efficacy, misuse and abuse 
of the product.
9.1.5
Adverse Events Related to Study Drugs
An AE is considered related to a study drug/ investigational medicinal product (IMP) if 
the Investigator assessment of causal relationship to the study drug is “Y” (see below). 
The Investigator will assess the causal relationship of each of the study drugs to the 
SAE.
The Sponsor may also consider related to the study drug those events for which the 
Investigator assesses the causal relationship with the study drug as “Uk” when it cannot 
rule out a role of the study drug in the event. Refer to Section 10.1.6 for causality scale.
9.1.6
Expedited Reporting
The Sponsor is responsible for the appropriate expedited reporting of suspected unlisted 
/ unexpected and related serious adverse reactions (SUSARs), including the following 
events of special interest: misuse, overdose, medication error and abuse, to the 
Competent Authorities. The Sponsor will also report all SAEs, including those which
are unlisted / unexpected and related to the study drug(s), to the Investigators and to the 
Independent Ethics Committees/Institutional Review Boards (IECs/IRBs) according to 
the current legislation unless otherwise required and documented by the IECs/IRBs.


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9.1.7
Assessment of Causal Relationship to the Study Drug 
The Investigator must provide an assessment of causal relationship of each of the 
clinical trial study drugs (including combination and comparator products) to the SAE 
according to the following scale:
Y
There is a reasonable possibility that the study drug(s) caused the SAE
N
There is no reasonable possibility that the study drug(s) caused the SAE 
and other causes are more probable.
Uk
Only to be used in special situations where the Investigator has 
insufficient information (i.e. the patient was not seen at his/her centre) if 
none of the above can be used.
9.2
PROCEDURES
9.2.1
Reporting of Adverse Events
The Sponsor will collect AEs until 30 days after administration of the last dose of study 
drug(s) or until the start of a new antitumor therapy, whichever occurs first. All AEs 
suspected to be related to study drug(s) must be followed after the time of therapy 
discontinuation until the event or its sequelae resolve or stabilize at an acceptable level 
to the Investigator and the Sponsor.
All AEs, including misuse, overdose and abuse must be recorded using medical 
terminology in the source document and the CRF. Whenever possible the Investigator 
will record the main diagnosis instead of the signs and symptoms normally included in 
the diagnoses. 
Investigators must assess severity (grade) of the event following NCI-CTCAE v. 4 and 
assign relationship to each study drug; pursue and obtain information adequate both to 
determine the outcome and to assess whether it meets the criteria for classification as a 
SAE requiring immediate notification to PharmaMar or its designated representative. 
The Investigator must provide any relevant information as requested by the Sponsor in 
addition to that on the CRF.
Abnormal laboratory tests occurring during the study are AEs, but they should be 
collected only in the AE section of the CRF in some cases:

Is associated with clinically significant symptoms, and/or

Leads to a change in study dosing or discontinuation from the study, significant 
additional concomitant drug treatment or other therapy, and/or

Leads to any of the outcomes included in the definition of a SAE.

The test result is considered to be a clinically relevant by the Investigator.
Otherwise laboratory results should be reported in the corresponding section of the CRF 
(e.g. biochemistry, hematology).


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9.2.2
Reporting Serious Adverse Events 
The Sponsor will collect SAEs from the signing of the Informed Consent Form
onwards. If the patient is definitively included in the study, this information will also be 
recorded in the AE section of the CRF, if applicable. 
SAEs will be collected until 30 days after administration of the last dose of study 
drug(s) or until the start of a new antitumor therapy, whichever occurs first. Beyond this 
period of time, only those SAEs suspected to be related need to be reported. 
Nonetheless, the Sponsor will evaluate any safety information that is spontaneously 
reported by an Investigator beyond the time frame specified in the protocol.
Exemptions from SAE REPORTING:  Events of “disease progression” even if they 
fulfill any seriousness criterion (i.e., fatal, requiring hospitalization, etc) are exempted from 
SAE reporting and will only be reported in the applicable CRF page(s).
All SAEs (as defined above) regardless of treatment group or relationship to study 
drug/IMP must be reported immediately and always within 24 hours to the PharmaMar 
Pharmacovigilance Department by fax (+34 91 846 6004) or telephone (+34 91 846 
6054). Out of office hours (GMT), assistance on SAE reporting can be obtained by 
calling the Pharmacovigilance Service +34 91 823 47 49.  
The preferred reporting method is by faxing the completed “Serious Adverse Event 
Form” provided by Pharmamar. An initial report by telephone must be followed by a 
completed SAE form the investigational staff within one working day.
All SAEs suspected to be related to the study drug(s) must be followed until the event or
its sequelae resolves or stabilizes at an acceptable level by the Investigator and the 
clinical monitor or his/her designated representative.
9.2.3
Reporting Pregnancy Cases Occurred within the Clinical Trial
National regulations require that clinical trial Sponsors collect information on 
pregnancies occurring during clinical trials, in which exposure to the study drugs at any 
moment of the pregnancy, via either maternal or paternal exposure is suspected.
Therefore, pregnancy and suspected pregnancy (including a positive pregnancy test 
regardless of age or disease state) of a female patient or the female partner of a male 
patient occurring while the patient is on study drug, or within 30 days of the patient’s 
discontinuation visit, is considered an immediately reportable event.
The Investigator will report the following events immediately and always within 
24 hours from first knowledge:

Any occurrence of a pregnancy where any kind of exposure to the drug(s) is 
suspected

Possible exposure of a pregnant woman [this could involve a partner of a male 
patient or a pregnant female who came in contact with the study drug(s)]

All reports of elevated/ questionable or indeterminate beta human chorionic 
gonadotrophins (βhCGs)


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Immediately after detecting a case of suspected pregnancy in a female clinical trial 
patient, the decision on her continued participation in the clinical trial will be jointly 
taken by the trial patient, the Investigator and the Sponsor, with the patient’s best 
interest in mind. A decision to continue the pregnancy will require immediate 
withdrawal from the trial. If the trial is blinded, the Investigator will open the blind 
whenever the treatment information is needed for the management of the patient.
Any pregnancy, suspected pregnancy, or positive pregnancy test must be reported to 
PharmaMar Pharmacovigilance immediately by facsimile using the Pregnancy Report 
form. In the case of pregnancy of the female partner of a trial Patient the Investigator 
will obtain her informed consent to provide the information by using the applicable 
form provided by the Sponsor who will also advise the Investigator in these situations.
The Investigator will follow the pregnancy until its outcome, and must notify 
PharmaMar Pharmacovigilance the outcome of the pregnancy within 24 hours of first 
knowledge as a follow-up to the initial report.
For any event during the pregnancy, which meets a seriousness criterion (including fetal 
or neonatal death or congenital anomaly), the Investigator will also follow the 
procedures for reporting SAEs (complete and send the SAE form to PharmaMar 
Pharmacovigilance by facsimile within 24 hours of the Investigator’s knowledge of the 
event). 
All neonatal deaths that occur within 30 days of birth should be reported, without regard 
to causality, as SAEs. In addition, any infant death at any time thereafter that the 
Investigator suspects is related to the exposure to the study drug(s) should also be 
reported to PharmaMar Pharmacovigilance by facsimile within 24 hours of the 
Investigators’ knowledge of the event.
10
STATISTICAL METHODS
10.1 SAMPLE SIZE
1. Arm A (plitidepsin plus dexamethasone combination): approximately 167
patients.
2. Arm B (dexamethasone single agent): approximately 83 patients.
The number of patients randomized in the trial has been calculated based on PFS 
estimates obtained from the previous phase II study (APL-B-014-03). 
Approximately 210 progression or death events would be needed in this trial to detect a 
HR of 0.625 in favor of the combination arm (equivalent to an increase of 60% in PFS, 
i.e., from 10 to 16 weeks, from 12 to 19.2 weeks, from 16 to 25.6 weeks, etc.) with 90% 
power and 1-sided 2.5% significance level. As a preliminary hypothesis, it is estimated 
that up to 250 randomized patients will be needed to achieve the 210 events in 24-30 
months.


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10.2 STATISTICAL ANALYSIS
10.2.1 Demographics
Descriptive statistics (mean, median, standard deviation and 95% confidence interval, 
range of value, frequencies and percentages) will be used. Tables by randomization 
group will be displayed.
Comparative study with descriptive methods will be done to check that patients’ 
baseline characteristics are similar between treatment groups 
10.2.2 Safety 
Patients are evaluable for general safety if they received any study treatment. Safety will 
be evaluated in each arm separately according to the actual treatment received.
AEs will be graded according to CTCAE, version 4.0.
Descriptive statistics will be employed to characterize the profiles of drug-related 
adverse events, drug-related deaths, SAE and drug-related treatment discontinuation. 
Tables by randomization group will be displayed.
10.2.3 Efficacy Analysis
10.2.3.1 Early Futility Analysis
An early futility analysis will be performed when information from 40 patients in Arm 
A are evaluable for response. A response rate (IMWG criteria) of at least 30% (12 or 
more responses by IRC review) will be taken as threshold for continuation of the study. 
A minimum response rate of 30% has been considered as clinically significant in this 
setting. This result will ensure that the lower limit of the exact binomial 95% 
Confidence Interval for the response rate will be greater than 15% (95% CI in case of 12 
responses would be 16.6% - 46.5%).
However, the information from all randomized patients in both arms at that time will be 
used by the IDMC to evaluate the safety profile and to provide the Sponsor with a 
recommendation for the further study conduct. No claim for superiority in efficacy will 
be formulated in this interim analysis and no alpha-spending for the analysis of PFS is 
foreseen.
10.2.3.2 Patients’ Evaluability for Response 
All patients who have completed at least one evaluable cycle or who have received two 
uncompleted cycles followed by at least one response assessment not less than eight 
weeks (± one week) after treatment onset, will be considered evaluable for response. In 
addition, any eligible patients who receive at least one treatment cycle or have received 
two uncompleted cycles and experience disease progression or die due to progressive 
disease prior to response evaluation will be considered evaluable for response and will 
be categorized as an “early progression”. 


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Patients withdrawn due to drug-related toxicity without any tumor assessments after the 
start of study treatment will be considered as “treatment failures”.
Patients withdrawn due to significant clinical deterioration of unknown reason, 
hypersensitivity reactions, or refusal to continue on study for any reason or unrelated 
AEs without any disease assessments after the start of study treatment will be 
considered not evaluable for efficacy and their response will be categorized as “non 
evaluable”.
Binomial estimates with exact 95% CIs will be calculated for the analysis of response 
rate. Randomized patients not evaluable for response will be excluded from the 
denominator exclusively for the futility analysis but will be included in all final efficacy 
analyses.
10.2.3.3 Final PFS Analysis and Interim OS analysis
The final PFS analysis will be performed when at least 210 progression or death events 
are observed.
The PFS assessed by the Independent Review Committee (IRC) will be used for the 
primary analysis, while the Investigator assessment will be used for the secondary 
analysis of PFS.
The unstratified log rank test will be used to compare the PFS of Arm A and Arm B.
Secondary time-to-event endpoints (DR, OS) will be analyzed according to the Kaplan-
Meier method and compared between treatment groups using the log-rank test. A 
stratified log-rank test for the main endpoint (PFS) will be performed as supportive 
analysis. Both the IRC and Investigator’s assessments will be used.
Counts and percentages, with their corresponding exact 95% confidence intervals, will 
be calculated for the RR (IMWG criteria and, separately, minor response). The Fisher’s 
exact test will be used to compare the response rates of the Arm A and B.
10.2.3.4 Evaluation of Overall Survival
Although the study is powered for the evaluation of the main endpoint, PFS, two
analyses of OS will be performed to ascertain if a trend in OS is observed in favor of the 
experimental arm. An interim analysis of OS will be performed concomitantly with the 
final PFS analysis (see Section 10.2.3.3). A final analysis of OS will be performed when 
80% of death events (approximately 200 death events) have occurred or 24 months after 
the inclusion of the last patient, whichever occurs first. At the interim OS analyses, the 
significance level determined by the O’Brien-Fleming boundary with overall 2.5% 1-
sided significance level will be used.
Note: Two years after the last patient accrual, on 19 May 2017, the final OS analysis was done 
based on a total of 195 death events (i.e., 76.5% of the 255 randomized patients): 123 events in 
Arm A (plitidepsin plus dexamethasone) and 72 events in Arm B (dexamethasone). Then, the 
duration of this study is prolonged for six additional months, until 19 November 2017, in order 
to continue follow-up in the alive patients, and then to be able to reach the pre-specified total of 
80% of death events (approximately 204 death events) or even more. If the required death 


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events are not achieved on 19 November 2017, the study might be further extended by three to
six months.
It is anticipated that an indeterminate number of patients in the control arm will switch 
treatment after progression to plitidepsin plus dexamethasone. This could cause the size 
of the effect on OS to be difficult to interpret. Consequently, if the OS results show to 
be substantially influenced by crossover, the Sponsor will study the estimated effect of 
crossover by means of rank preserving structural failure time models for correcting for 
treatment changes (68).
10.2.3.5 Other Analyses of Efficacy
Efficacy parameters versus baseline covariates will be analyzed and appropriate tests
will be used (i.e., the Fisher exact test and logistic regression for categorical variables, 
the log-rank test or Cox regression for time-to-event variables, etc.).
Exploratory intrapatient comparison of response and PFS (before and after crossover) 
will be performed for patients who switch from Arm B to Arm A after disease 
progression.
10.2.4 Pharmacokinetics 
Pharmacokinetic parameters will be calculated using population methods, after pooling 
data from this study with data obtained in other plitidepsin single-agent studies. The 
effect of dexamethasone on the plitidepsin pharmacokinetics will be evaluated by 
testing the improvement in the “Objective Function” of the population model after the 
inclusion of a shift variable on every relevant PK parameter. Bayesian estimation of the 
individual PK parameters will be correlated with toxicity and response outcomes. 
Logistic regression will be used for dichotomic or categorical outcomes, such as 
response/no response or toxicity grade. For continuous outcomes, such as transaminase 
values, linear regression will be applied. The influence of the plitidepsin PK on time to 
event variables, such as PFS, will be evaluated using Cox regression.
10.3 INTERIM ANALYSIS
Protocol-specified analyses are foreseen at the time of the futility evaluation 
(approximately 40 evaluable patients for response in Arm A), final PFS analysis (main 
endpoint, approximately 210 progression or death events) and follow-up evaluation of 
OS when 80% of death events (approximately 200 death events) have occurred or 24 
months after the inclusion of the last patient, whichever occurs first. Accrual will be on-
hold while data for the futility analysis is being assessed.
Note: Two years after the last patient accrual, on 19 May 2017, the final OS analysis was done 
based on a total of 195 death events (i.e., 76.5% of the 255 randomized patients): 123 events in 
Arm A (plitidepsin plus dexamethasone) and 72 events in Arm B (dexamethasone). Then, the 
duration of this study is prolonged for six additional months, until 19 November 2017, in order 
to continue follow-up in the alive patients, and then to be able to reach the pre-specified total of 
80% of death events (approximately 204 death events) or even more. If the required death 
events are not achieved on 19 November 2017, the study might be further extended by three to 
six months.


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11
ADMINISTRATIVE SECTION
11.1 ETHICS 
This study will be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki and will be consistent with Good Clinical Practice 
(GCP) and applicable regulatory requirements.
Study personnel involved in conducting this trial will be qualified by education, training 
and experience to perform their respective task(s).
The study will be conducted in compliance with the protocol. The protocol, any 
amendments and the patient informed consent will receive Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) approval/favorable opinion prior to 
initiation. 
The decision of the IEC/IRB concerning the conduct of the study will be made in 
writing to the Investigator and a copy of this decision will be provided to the Sponsor 
before commencement of the study.
The Investigator and/or the Sponsor is/are responsible for keeping the IEC/IRB 
informed of significant new information about study drug.
All protocol amendments will be agreed upon by the Sponsor and the Investigator.
Administrative changes of the protocol are minor corrections and/or clarifications that 
have no impact on the way the study is to be conducted. 
11.2 MONITORING, AUDITING AND INSPECTING
The study will be monitored by regular site visits and telephone calls to the Investigator 
by the clinical trial monitor and/or the Contract Research Organization (CRO) clinical 
trial monitor (if applicable).
During site visits, the study monitor should revise original patient records, drug 
accountability records and document retention (study file). Additionally, the monitor 
should observe study procedures and will discuss any problem with the Investigator.
The Investigator should allocate adequate time for these visits.  The Investigator should 
also ensure that the monitor is given direct access (as per ICH GCP Guideline, Sections 
4.9.7 and 6.10) to source documents (i.e., hospital or private charts, original laboratory 
records, appointment books, etc.) of the patient which support data entered in the CRFs, 
as defined in the ICH GCP Guideline, Sections 1.51 and 1.52.
Systems with procedures will be implemented to assure the quality of every aspect of 
the study.  
During the course or at the end of the study, the Clinical Quality Assurance Department 
of PharmaMar or external auditors contracted by the Sponsor may conduct an onsite 
audit visit to the centers at anytime (ICH guideline glossary Section 1.6).


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Participation in this study implies acceptance of potential inspection by national or 
foreign health authorities.
11.3 PATIENT INFORMED CONSENT
The rights, safety and well being of the trial patients are the most important 
considerations and should prevail over interests of science and society. 
The Patient Information sheet will include all elements required by ICH, GCP and 
applicable Regulatory requirements.
The Investigator, or a person designated by the Investigator, must provide the patient 
with a copy of the consent form and written fully information about the study in 
language that is non-technical and easily understood. The Investigator should allow time 
necessary for the patient or the patient's legally acceptable representative to inquire 
about the details of the study; then, the informed consent must be freely signed and 
personally dated by the patient and by the person who conducted the informed consent 
discussion before commencement of the study.  The patient should receive a copy of the 
signed informed consent and any other written information provided to study patients 
prior to patient's participation in the trial.
During a patient's participation in the trial, any updates to the consent form and any 
updates to the written information will be provided to the patient.  
If there is a need to obtain new consent from the patients, the Investigator, or a person 
designated by the Investigator, should inform the patient of any new information 
relevant to the patient's willingness to continue participation in the study, before 
obtaining the written consent.
11.4 CONFIDENTIALITY/ PATIENTS IDENTIFICATION
The collection and processing of personal data from subjects enrolled in this study will 
be limited to those data that are necessary to investigate the efficacy, safety, quality, and 
utility of the investigational medicinal product used in this study. It is the Investigator’s 
responsibility that sufficient information appertaining to the identity of the patients will 
be retained.
The trial monitor, Sponsor’s auditor, IRB/IEC, or Competent Authorities should have 
direct access to all requested trial related records and agree to keep the identity of study 
patients confidential.
The data must be collected and processed with adequate precautions to ensure 
confidentiality and compliance with applicable data privacy protection laws and 
regulations.
11.5 CASE REPORT FORMS
Case report forms (CRFs) will be used for recording all data for each patient. It is the 
responsibility of the Investigator to ensure that the CRFs are properly and completely 


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filled in. CRFs must be completed for all patients who have given informed consent and 
have been admitted into the study.
The patient’s source documentation is the physician's patient records, and as such, they 
should be maintained at the study site. 
The data collected in the CRF will be entered into the Sponsor databases that comply 
with the Spanish Act which implements the Directive 95/46/EC of the European 
Parliament and of the Council of 24 October 1995 on the protection of individuals with 
regard to the processing of personal data. 
11.6 INSURANCE
The Sponsor will provide insurance or indemnity in accordance with the applicable 
regulatory requirements.
11.7 RECORDS RETENTION 
The Investigator/Institution should maintain trial documents according to ICH Topic E6 
Section 8 and as required by the applicable regulatory requirements.
Essential documents should be retained according to ICH guidelines or for a longer 
period of time, if required by the applicable regulations. 
11.8 USE OF INFORMATION AND PUBLICATION
Before the Investigators of this study submit a paper or abstract for publication or 
otherwise publicly disclose information concerning the studied IMP(s), the Sponsor 
must be provided with at least 60 days to review and approve the proposed publication 
or disclosure to ensure that confidential and proprietary data are protected. If the 
Sponsor determines that patentable subject matter is disclosed in such a proposed 
publication or disclosure, the publication or disclosure shall be withheld during the 
period of time that it is considered convenient. 
If the study is part of a multicenter study, the first publication of the study shall be made 
in conjunction with the presentation of a joint, multicenter publication of the study 
results with the Investigators and the Institutions from all appropriate sites contributing 
data, analysis and comments. However, if such a multicenter publication is not 
submitted within 12 months after conclusion, abandonment or termination of the study 
at all sites, the present study may be published individually in accordance with the 
procedure established before.
The order of the coauthors will reflect the relative contribution of each one of them to 
the study development and analysis. In general, the first author will be the Investigator 
who recruited the highest number of patients with information finally available for data 
analysis. Relevant Sponsor’s personnel who have fully participated in the study must be 
considered for co-authorship of the publication.


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12 REFERENCES
1.
National_Cancer_Institute. Information about MM and other plasma cell 
neoplasms: 
treatment, 
clinical 
trials, 
research, 
and 
statistics. 
wwwcancergov/cancertopics/types/myeloma. (27/01/09).
2.
Harousseau 
JL, 
Dreyling 
M. 
Multiple 
myeloma: 
ESMO 
clinical 
recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2008 
May;19 Suppl 2:ii55-7.
3.
Durie BG, Salmon SE. A clinical staging system for multiple myeloma. 
Correlation of measured myeloma cell mass with presenting clinical features, 
response to treatment, and survival. Cancer. 1975 Sep;36(3):842-54.
4.
Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Blade J, et al. 
International staging system for multiple myeloma. J Clin Oncol. 2005 May 
20;23(15):3412-20.
5.
Hari PN, Zhang MJ, Roy V, Perez WS, Bashey A, To LB, et al. Is the 
international staging system superior to the Durie-Salmon staging system? A 
comparison in multiple myeloma patients undergoing autologous transplant. 
Leukemia. 2009 Aug;23(8):1528-34.
6.
Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and 
response assessment of multiple myeloma. Leukemia. 2009 Jan;23(1):3-9.
7.
Fermand JP. Initial therapy for multiple myeloma: role of stem cell 
transplantation. ASCO Educational Book. 2008:375-9.
8.
Combination chemotherapy versus melphalan plus prednisone as treatment for 
multiple myeloma: an overview of 6,633 patients from 27 randomized trials. 
Myeloma Trialists' Collaborative Group. J Clin Oncol. 1998 Dec;16(12):3832-
42.
9.
Facon T, Mary JY, Hulin C, Benboubker L, Attal M, Pegourie B, et al. 
Melphalan and prednisone plus thalidomide versus melphalan and prednisone 
alone or reduced-intensity autologous stem cell transplantation in elderly 
patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet. 2007 
Oct 6;370(9594):1209-18.
10.
Hulin C, Facon T, Rodon P, Pegourie B, Benboubker L, Doyen C, et al. Efficacy 
of melphalan and prednisone plus thalidomide in patients older than 75 years 
with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol. 2009 
Aug 1;27(22):3664-70.
11.
San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff 
M, et al. Bortezomib plus melphalan and prednisone for initial treatment of 
multiple myeloma. N Engl J Med. 2008 Aug 28;359(9):906-17.
12.
Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, et al. 
Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J 
Med. 1999 Nov 18;341(21):1565-71.
13.
Knight R. IMiDs: a novel class of immunomodulators. Semin Oncol. 2005 
Aug;32(4 Suppl 5):S24-30.


CL_0092 5.0
Page 84 of 116
Protocol APL-C-001-09
14.
Jagannath S, Barlogie B, Berenson JR, Singhal S, Alexanian R, Srkalovic G, et 
al. Bortezomib in recurrent and/or refractory multiple myeloma. Initial clinical 
experience in patients with impared renal function. Cancer. 2005 Mar 
15;103(6):1195-200.
15.
Bross PF, Kane R, Farrell AT, Abraham S, Benson K, Brower ME, et al. 
Approval summary for bortezomib for injection in the treatment of multiple 
myeloma. Clin Cancer Res. 2004 Jun 15;10(12 Pt 1):3954-64.
16.
Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, 
et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N 
Engl J Med. 2005 Jun 16;352(24):2487-98.
17.
Kane RC, Farrell AT, Sridhara R, Pazdur R. United States Food and Drug 
Administration approval summary: bortezomib for the treatment of progressive 
multiple myeloma after one prior therapy. Clin Cancer Res. 2006 May 
15;12(10):2955-60.
18.
Hazarika M, Rock E, Williams G, Dagher R, Sridhara R, Booth B, et al. 
Lenalidomide in combination with dexamethasone for the treatment of multiple 
myeloma after one prior therapy. Oncologist. 2008 Oct;13(10):1120-7.
19.
Gonzalez-Santiago L, Suarez Y, Zarich N, Munoz-Alonso MJ, Cuadrado A, 
Martinez T, et al. Aplidin induces JNK-dependent apoptosis in human breast 
cancer cells via alteration of glutathione homeostasis, Rac1 GTPase activation, 
and 
MKP-1 
phosphatase 
downregulation. 
Cell 
Death 
Differ. 
2006 
Nov;13(11):1968-81.
20.
Erba E, Bassano L, Di Liberti G, Muradore I, Chiorino G, Ubezio P, et al. Cell 
cycle phase perturbations and apoptosis in tumour cells induced by aplidine. Br J 
Cancer. 2002 May 6;86(9):1510-7.
21.
Cuadrado A, Gonzalez L, Suarez Y, Martinez T, Munoz A. JNK activation is 
critical for Aplidin-induced apoptosis. Oncogene. 2004 Jun 10;23(27):4673-80.
22.
Broggini M, Marchini SV, Galliera E, Borsotti P, Taraboletti G, Erba E, et al. 
Aplidine, a new anticancer agent of marine origin, inhibits vascular endothelial 
growth factor (VEGF) secretion and blocks VEGF-VEGFR-1 (flt-1) autocrine 
loop in human leukemia cells MOLT-4. Leukemia. 2003 Jan;17(1):52-9.
23.
Garcia-Fernandez LF, Losada A, Alcaide V, Alvarez AM, Cuadrado A, 
Gonzalez L, et al. Aplidin induces the mitochondrial apoptotic pathway via 
oxidative stress-mediated JNK and p38 activation and protein kinase C delta. 
Oncogene. 2002 Oct 24;21(49):7533-44.
24.
Cuadrado A, Garcia-Fernandez LF, Gonzalez L, Suarez Y, Losada A, Alcaide 
V, et al. Aplidin induces apoptosis in human cancer cells via glutathione 
depletion and sustained activation of the epidermal growth factor receptor, Src, 
JNK, and p38 MAPK. J Biol Chem. 2003 Jan 3;278(1):241-50.
25.
Munoz-Alonso MJ, Gonzalez-Santiago L, Zarich N, Martinez T, Alvarez E, 
Rojas JM, et al. Plitidepsin Has a Dual Effect Inhibiting Cell Cycle and Inducing 
Apoptosis via Rac1/c-Jun NH2-Terminal Kinase Activation in Human 
Melanoma Cells 10.1124/jpet.107.132662. J Pharmacol Exp Ther. 2008 March 
1, 2008;324(3):1093-101.


CL_0092 5.0
Page 85 of 116
Protocol APL-C-001-09
26.
Moneo V, Serelde BG, Leal JF, Blanco-Aparicio C, Diaz-Uriarte R, Aracil M, et 
al. Levels of p27(kip1) determine Aplidin sensitivity. Mol Cancer Ther. 2007 
Apr;6(4):1310-6.
27.
Biscardi M, Caporale R, Balestri F, Gavazzi S, Jimeno J, Grossi A. VEGF 
inhibition and cytotoxic effect of aplidin in leukemia cell lines and cells from 
acute myeloid leukemia. Ann Oncol. 2005 Oct;16(10):1667-74.
28.
Taraboletti G, Poli M, Dossi R, Manenti L, Borsotti P, Faircloth GT, et al. 
Antiangiogenic activity of aplidine, a new agent of marine origin. Br J Cancer. 
2004 Jun 14;90(12):2418-24.
29.
Sasak H. The cytotoxic effects of Aplidin in a brad spectrum of human tumor 
types using the MTS proliferation assay. Cambridge, MA, USA: PharmaMar 
Inc; 2004. Report No.: PUSA-SR007.
30.
Mitsiades CS, Ocio EM, Pandiella A, Maiso P, Gajate C, Garayoa M, et al. 
Aplidin, a marine organism-derived compound with potent antimyeloma activity 
in vitro and in vivo. Cancer Res. 2008 Jul 1;68(13):5216-25.
31.
Radl J, De Glopper ED, Schuit HR, Zurcher C. Idiopathic paraproteinemia. II. 
Transplantation of the paraprotein-producing clone from old to young 
C57BL/KaLwRij mice. J Immunol. 1979 Feb;122(2):609-13.
32.
Caers J, Menu E, De Raeve H, Lepage D, Van Valckenborgh E, Van Camp B, et 
al. Antitumour and antiangiogenic effects of Aplidin in the 5TMM syngeneic 
models of multiple myeloma. Br J Cancer. 2008 Jun 17;98(12):1966-74.
33.
Herr I, Gassler N, Friess H, Buchler MW. Regulation of differential pro- and 
anti-apoptotic signaling by glucocorticoids. Apoptosis. 2007 Feb;12(2):271-91.
34.
Zhang C, Wenger T, Mattern J, Ilea S, Frey C, Gutwein P, et al. Clinical and 
mechanistic aspects of glucocorticoid-induced chemotherapy resistance in the 
majority of solid tumors. Cancer Biol Ther. 2007 Feb;6(2):278-87.
35.
Schaaf MJ, Cidlowski JA. Molecular mechanisms of glucocorticoid action and 
resistance. J Steroid Biochem Mol Biol. 2002 Dec;83(1-5):37-48.
36.
Schmidt S, Rainer J, Riml S, Ploner C, Jesacher S, Achmuller C, et al. 
Identification of glucocorticoid-response genes in children with acute 
lymphoblastic leukemia. Blood. 2006 Mar 1;107(5):2061-9.
37.
Adamson PC, Barrett JS. All dex'ed out with nowhere to go? J Clin Oncol. 2008 
Apr 20;26(12):1917-8.
38.
Zhou J, Cidlowski JA. The human glucocorticoid receptor: one gene, multiple 
proteins and diverse responses. Steroids. 2005 May-Jun;70(5-7):407-17.
39.
Distelhorst CW. Recent insights into the mechanism of glucocorticosteroid-
induced apoptosis. Cell Death Differ. 2002 Jan;9(1):6-19.
40.
Planey SL, Litwack G. Glucocorticoid-induced apoptosis in lymphocytes. 
Biochem Biophys Res Commun. 2000 Dec 20;279(2):307-12.
41.
Kofler R. The molecular basis of glucocorticoid-induced apoptosis of 
lymphoblastic leukemia cells. Histochem Cell Biol. 2000 Jul;114(1):1-7.


CL_0092 5.0
Page 86 of 116
Protocol APL-C-001-09
42.
Renner K, Ausserlechner MJ, Kofler R. A conceptual view on glucocorticoid-
lnduced apoptosis, cell cycle arrest and glucocorticoid resistance in 
lymphoblastic leukemia. Curr Mol Med. 2003 Dec;3(8):707-17.
43.
Oh HY, Namkoong S, Lee SJ, Por E, Kim CK, Billiar TR, et al. Dexamethasone 
protects primary cultured hepatocytes from death receptor-mediated apoptosis 
by upregulation of cFLIP. Cell Death Differ. 2006 Mar;13(3):512-23.
44.
Tissing WJ, Meijerink JP, den Boer ML, Pieters R. Molecular determinants of 
glucocorticoid sensitivity and resistance in acute lymphoblastic leukemia. 
Leukemia. 2003 Jan;17(1):17-25.
45.
Machuca C, Mendoza-Milla C, Cordova E, Mejia S, Covarrubias L, Ventura J, 
et al. Dexamethasone protection from TNF-alpha-induced cell death in MCF-7 
cells requires NF-kappaB and is independent from AKT. BMC Cell Biol. 
2006;7:9.
46.
Matthews JG, Ito K, Barnes PJ, Adcock IM. Defective glucocorticoid receptor 
nuclear translocation and altered histone acetylation patterns in glucocorticoid-
resistant patients. J Allergy Clin Immunol. 2004 Jun;113(6):1100-8.
47.
Ito K, Yamamura S, Essilfie-Quaye S, Cosio B, Ito M, Barnes PJ, et al. Histone 
deacetylase 2-mediated deacetylation of the glucocorticoid receptor enables NF-
kappaB suppression. J Exp Med. 2006 Jan 23;203(1):7-13.
48.
Ito K, Barnes PJ, Adcock IM. Glucocorticoid receptor recruitment of histone 
deacetylase 2 inhibits interleukin-1beta-induced histone H4 acetylation on 
lysines 8 and 12. Mol Cell Biol. 2000 Sep;20(18):6891-903.
49.
Gomez SG, Faircloth G, Lopez-Lazaro L, Jimeno J, Bueren JA, Albella B. In 
vitro hematotoxicity of Aplidine on human bone marrow and cord blood 
progenitor cells. Toxicol In Vitro. 2001 Aug-Oct;15(4-5):347-50.
50.
Faircloth G, Grant W, Nam S, Jimeno J, Meely K, Rinehart KL. Aplidine is a 
Novel, Marine Derived Depsipeptide with In Vivo Antitumor Activity. Am 
Assoc Ca Res. 1998;39:227.
51.
Mateos MV, Cibeira MT, Richardson PG, Blade J, Prosper F, Oriol A, et al. 
Final Results of a Phase II Trial with Plitidepsin (Aplidin) Alone and in 
Combination with Dexamethasone in Patients with Relapsed/Refractory 
Multiple Myeloma. 50th American Society of HematologyAnnual Meeting; 
2008; San Francisco, CA, USA; 2008. p. Poster Board III-782.
52.
Joan Bladé DS, Donna Reece, Jane Apperley, Bo BJörkstrand, Gösta Gahrton, 
Morie Gertz, Sergio Giralt, Sundarr Jagannath, David Vesole. Criteria for 
evaluation disease response and progression in patients with multiple myeloma 
treated by high-dose therapy and haematopoietic stem cell transplantation. 
British Journal of Haematology. 1998;102(5):1115-23.
53.
Alexanian R, Dimopoulos MA, Delasalle K, Barlogie B. Primary 
dexamethasone treatment of multiple myeloma. Blood. 1992 Aug 15;80(4):887-
90.
54.
Rajkumar SV, Gertz MA, Kyle RA, Greipp PR. Current therapy for multiple 
myeloma. Mayo Clin Proc. 2002 Aug;77(8):813-22.


CL_0092 5.0
Page 87 of 116
Protocol APL-C-001-09
55.
Sonneveld P, Suciu S, Weijermans P, Beksac M, Neuwirtova R, Solbu G, et al. 
Cyclosporin A combined with vincristine, doxorubicin and dexamethasone 
(VAD) compared with VAD alone in patients with advanced refractory multiple 
myeloma: an EORTC-HOVON randomized phase III study (06914). Br J 
Haematol. 2001 Dec;115(4):895-902.
56.
Barlogie B, Smith L, Alexanian R. Effective treatment of advanced multiple 
myeloma refractory to alkylating agents. N Engl J Med. 1984 May 
24;310(21):1353-6.
57.
Anagnostopoulos A, Weber D, Rankin K, Delasalle K, Alexanian R. 
Thalidomide and dexamethasone for resistant multiple myeloma. Br J Haematol. 
2003 Jun;121(5):768-71.
58.
Cavo M, Zamagni E, Tosi P, Cellini C, Cangini D, Tacchetti P, et al. First-line 
therapy with thalidomide and dexamethasone in preparation for autologous stem 
cell transplantation for multiple myeloma. Haematologica. 2004 Jul;89(7):826-
31.
59.
Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or 
with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 
2003 Jan 1;21(1):16-9.
60.
Rajkumar SV, Jacobus S, Callander N, Fonseca R, Vesole D, Williams MV, et 
al. Randomized trial of lenalidomide plus high-dose dexamethasone versus 
lenalidomide plus low-dose dexamethasone in newly diagnosed myeloma 
(E4A03), a trial coordinated by the Eastern Cooperative Oncology Group: 
Analysis of response, survival, and outcome wi. J Clin Oncol (Meeting 
Abstracts). 2008 May 20, 2008;26(15_suppl):8504-.
61.
Miguel JFS, Dimopoulos M, Weber D, Olesnyckyj M, Yu Z, Zeldis J, et al. 
Dexamethasone Dose Adjustments Seem To Result in Better Efficacy and 
Improved Tolerability in Patients with Relapsed/Refractory Multiple Myeloma 
Who Are Treated with Lenalidomide/Dexamethasone (MM009/010 Sub-
Analysis). 
ASH 
Annual 
Meeting 
Abstracts. 
2007 
November 
16, 
2007;110(11):2712-.
62.
Richardson P, Jagannath S, Raje N, Jakubowiak A, Lonial S, Ghobrial I, et al. 
Lenalidomide, Bortezomib, and Dexamethasone (Rev/Vel/Dex) in Patients with 
Relapsed or Relapsed/Refractory Multiple Myeloma (MM): Preliminary Results 
of a Phase II Study. ASH Annual Meeting Abstracts. 2007 November 16, 
2007;110(11):2714-.
63.
Gralla RJ, Osoba D, Kris MG, Kirkbride P, Hesketh PJ, Chinnery LW, et al. 
Recommendations for the use of antiemetics: evidence-based, clinical practice 
guidelines. American Society of Clinical Oncology. J Clin Oncol. 1999 
Sep;17(9):2971-94.
64.
Kyle RA, Yee GC, Somerfield MR, Flynn PJ, Halabi S, Jagannath S, et al. 
American Society of Clinical Oncology 2007 clinical practice guideline update 
on the role of bisphosphonates in multiple myeloma. J Clin Oncol. 2007 Jun 
10;25(17):2464-72.


CL_0092 5.0
Page 88 of 116
Protocol APL-C-001-09
65.
Kris MG, Hesketh PJ, Somerfield MR. American Society of Clinical Oncology 
Guideline for Antiemetics in Oncology: Update 2006. J Clin Oncol. 
2006;24:2932-47.
66.
Update of recommendations for the use of hematopoietic colony- stimulating 
factors: evidence based clinical practice guidelines. American Society of 
Clinical Oncology. J Clin Oncol. 1996;14(6):1957-19.
67.
American Society of Clinical Oncology. Recommendations for the use of 
hematopoietic colonystimulating factors: evidence-based, clinical practice 
guidelines. J Clin Oncol. 1994;12(11):2471-2.
68.
Robins JM, Tsiatis AA. Correcting for non-compliance in randomized trials 
using rank preserving structural failure time models. Commun Statist Theory 
Meth. 1991;20(8):2609-31.


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13 APPENDICES
APPENDIX 1: CLINICAL MANAGEMENT OF HYPERSENSITIVITY REACTIONS TO 
PLITIDEPSIN®
• If Severe/life threatening reactions (NCI CTCAE v4 ≥ grade 3)
Patients must have at least one of the following:
-Cardiovascular symptoms: hypertension ≥ 160/100 mmHg or tachycardia ≥ 
120bpm or hypotension (systolic pressure < 90mmHg) requiring vasopressor 
therapy, or anaphylactic shock or
-Respiratory symptoms: Angioedema, generalized wheezing and/or respiratory 
distress requiring oxygen therapy (pulse gasometry with < 92% O2 saturation at 
ambient air).
Then:
1) Immediately stop infusion. A trained physician must clinically assess the 
patient.
2) If pulse gasometry < 92% O2 saturation at ambient air, consider immediately 
O2 mask ± bronchodilators (i.e., generalized wheezing).
3) Administer diphenhydramine 50 mg i.v. or equivalent, and hydrocortisone 
100 mg up to a maximum of 300 mg i.v.
4) Add epinephrine (adrenaline) if clinically indicated. 
Do not re-start infusion. Withdraw the patient from the study.
Event should be reported as a serious adverse event. Send an SAE form by fax 
within 24 hrs.
Carry out final disease assessments, post-treatment evaluations and follow-up as 
required by protocol.


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CLINICAL MANAGEMENT OF HYPERSENSITIVITY REACTIONS TO PLITIDEPSIN®
(CONT.)
If Mild to Moderate reactions/not life threatening (NCI CTCAE v4.0 ≤ grade 2)
Patients may have any of the following: 
-Mild to moderate: facial and/or trunk flushing, rash and/or pruritus and/or mild 
dyspnea (shortness of breath) and/or coughing and/or chest discomfort.
BUT NONE of the previous severe/life threatening criteria.
Then:
1) Immediately stop infusion and assess vital signs and pulse gasometry. Ideally 
a trained physician must clinically assess the patient.
2) Check if premedication was administered properly (if not, administer it as per 
protocol and re-start infusion similarly as before, withholding it a minimum of 
30 minutes after premedication was given).
3) If symptoms persist after stopping infusion, give additional diphenhydramine, 
50 mg i.v. or equivalent, and hydrocortisone 100 mg bolus i.v. or equivalent.
4) Reassess symptoms and vital signs after 30 minutes.
4.A- If normal or improving, then infusion could be re-started at 1/3 (one 
third) of the initial drip rate during the first hour, and then, infusion rate 
could be increased according to tolerance. The decision about retreating the 
patient or not should be taken according to Investigator’s judgment on 
benefit/risk balance. Any further infusions should be initiated at this reduced 
rate and should be given with prophylactic premedication as per protocol. If 
no hypersensitivity reactions are observed, the rate of infusion to be applied 
could be set back to the initial one.
4.B- If there is no sign of improvement of symptoms after 30 minutes, a 
decision must be taken by the investigator in agreement with the patient in 
order to:
- Eventually repeat medication (anti-H1 and/or corticoids) if necessary 
and/or wait up to one hour for symptoms to resolve.
- Omit infusion until resolution (< two weeks) (in this case further 
infusions might start at a reduced rate, according to 4.A
-Withdraw the patient from study. 
- Report the event as a serious adverse only if it fulfills any of the 
seriousness criteria indicated in the SAE section of the protocol.


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APPENDIX 2: PERFORMANCE STATUS (ECOG)
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 5:649-655, 1982: 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. 


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APPENDIX 3: COCKCROFT AND GAULT’S FORMULA 
For calculating creatinine clearance:
[(140-age (years)) x weight (Kg)]
Creatinine clearance (ml/min)  =      
x G1
72 x serum creatinine (mg/dl)
[(140-age (years)) x weight (Kg)]
Creatinine clearance (ml/min)  =      
xG1
72 x serum creatinine (mol/l) x 
0.0113
1G(Gender)= 0.85 if Female; 1 if Male.
Reference:
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron. 1976;16(1):31-41.


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APPENDIX 4: DIAGNOSTIC CRITERIA 
Multiple myeloma:
All three criteria must be met, except as noted:
1) Clonal bone marrow plasma cells ≥ 10%.
2) Presence of serum and/or urinary monoclonal protein (except in patients with true 
non-secretory multiple myeloma).
3) Evidence of end-organ damage that can be attributed to the underlying plasma cell 
proliferative disorder, specifically
-
Hypercalcemia: serum calcium > 11.5 mg/100 ml or
-
Renal insufficiency: serum creatinine > 1.73 mmol/l
-
Anemia: normochromic, normocytic with a hemoglobin value of > 2 g/100 ml 
below the lower limit of normal or a hemoglobin value of 10 g/100 ml
-
Bone lesions: lytic lesions, severe osteopenia or pathologic fractures.
References: 
The International Myeloma Working Group. Criteria for the classification of 
monoclonal gammopathies, multiple myeloma and related disorders: a report of the 
International Myeloma Working Group. Br J Haematol 2003; 121: 749–757.
Rajkumar SV, Kyle RA. Multiple myeloma: diagnosis and treatment. Mayo Clinic 
Proc 2005; 80: 1371–1382.


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APPENDIX 5: INTERNATIONAL MYELOMA WORKING GROUP UNIFORM RESPONSE 
CRITERIA FOR MULTIPLE MYELOMA 
(Anderson KC, Kyle RA, Rajkumar SV, Stewart AK, Weber D, Richardson P. 
Clinically relevant end points and new drug approvals for myeloma. Leukemia 
2008; 22: 231–239).
Complete response (CR)
-
Negative immunofixation of serum and urine, and
-
Disappearance of any soft tissue plasmacytomas, and
-
<5% plasma cells in bone marrow.
Stringent complete response (sCR)
CR as defined above plus
-
Normal FLC ratio, and
-
Absence of clonal cells in bone marrow by immunohistochemistry or 
immunofluorescence.
Very good partial response (VGPR)
-
Serum and urine M-component detectable by immunofixation but not on 
electrophoresis or > 90% or greater reduction in serum M-component plus urine 
M-component of 100mg per 24 h.
Partial response (PR)
-
≥ 50% reduction of serum M protein and reduction in 24-h urinary M protein by 
≥ 90% or to < 200mg per 24 h.
-
If the serum and urine M protein are unmeasurable, a > 50% decrease in the 
difference between involved and uninvolved FLC levels is required in place of 
the M protein criteria.
-
If serum and urine M protein are unmeasurable, and serum free light assay is 
also unmeasurable, ≥ 50% reduction in bone marrow plasma cells is required in 
place of M protein, provided baseline percentage was > 30%.
-
In addition to the above criteria, if present at baseline, ≥ 50% reduction in the 
size of soft tissue plasmacytomas is also required.
Stable disease (SD) 
-
Not meeting criteria for CR, VGPR, PR or progressive disease


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Progressive disease (PD)
Increase of 25% from lowest response value in any one or more of the following:
-
Serum M-component (absolute increase must be ≥ 0.5 g/100 ml) and/or
-
Urine M-component (absolute increase must be ≥ 200mg per 24 h) and/or
-
Only in patients without measurable serum and urine M-protein levels: the 
difference between involved and uninvolved FLC levels (absolute increase must 
be > 100 mg/l)
-
Bone marrow plasma cell percentage (absolute % must be ≥ 10%)
-
Definite development of new bone lesions or soft tissue plasmacytomas or 
definite increase in the size of existing bone lesions or soft tissue plasmacytomas
-
Development of hypercalcemia (corrected serum calcium > 11.5 mg/100 ml) 
that can be attributed solely to the plasma cell proliferative disorder
Note: clarification to IMWG criteria for coding CR and VGPR in patients in whom the 
only measurable disease is by serum FLC levels: CR in such patients is defined as a 
normal FLC ratio of 0.26–1.65 in addition to CR criteria listed above. VGPR in such 
patients is defined as a > 90% decrease in the difference between involved and 
uninvolved free light chain (FLC) levels.
All response categories (CR, sCR, VGPR and PR) require two consecutive assessments 
made at any time before the institution of any new therapy; complete, PR and SD 
categories also require no known evidence of progressive or new bone lesions if 
radiographic studies were performed.
Radiographic studies are not required to satisfy these response requirements. Bone 
marrow assessments need not to be confirmed. 
For progressive disease, serum M-component increases of ≥ 1 gm/100 ml are sufficient 
to define relapse if starting M-component is ≥ 5 gm/100ml.
Additional response criteria for specific disease stages
(Anderson KC, Kyle RA, Rajkumar SV, Stewart AK, Weber D, Richardson P. Clinically 
relevant end points and new drug approvals for myeloma. Leukemia 2008; 22: 231–239).
Definition of relapsed myeloma and relapsed and refractory myeloma
-
Relapsed myeloma: at least one prior regimen, and not meeting criteria for 
relapsed and refractory myeloma
-
Relapsed and refractory myeloma: relapse of disease while on salvage 
therapy, or progression within 60 days of most recent therapy
Minor response (MR) in patients with relapsed refractory myeloma
-
≥ 25% but < 49% reduction of serum M protein and reduction in 24 h urine M 
protein by 50–89%, which still exceeds 200 mg per 24 h


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-
In addition to the above criteria, if present at baseline, 25–49% reduction in the 
size of soft tissue plasmacytomas is also required
-
No increase in size or number of lytic bone lesions (development of compression 
fracture does not exclude response)


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APPENDIX 6: STAGING SYSTEMS
Durie-Salmon Staging Criteria
Stage
Durie-Salmon Criteria
ISS Criteria
I
All of the following:

Hemoglobin value >10 g/dl

Serum calcium value normal or ≤12 
mg/dl

Bone x-ray, normal bone structure 
(scale 0) or solitary bone plasmacytoma 
only

Low M-component production rate

— IgG value <5 g/dl; IgA value <3 g/dl
Bence Jones protein <4 g/24 h
ß2-M <3.5 and Albumin ≥3.5
II
Neither stage I nor stage III
Neither stage I nor stage III
III
One or more of the following:

Hemoglobin value <8.5 g/dl

Serum calcium value >12 mg/dl

Advanced lytic bone lesions (scale 3)

High M-component production rate

— IgG value >7 g/dl; IgA value >5 g/dl

— Bence Jones protein >12 g/24 h
ß2-M >5.5
Durie-Salmon sub classifications (either A or B)
A: Relatively normal renal function (serum creatinine value <2.0 mg/dl
B: Abnormal renal function (serum creatinine value ≥2.0 mg/dl
New International Staging System 
Stage
Criteria
Median Survival (months)
    I
Serum ß2-microglobulin < 3.5 mg/L
62
Serum albumin 3.5 g/dl
    II
Not stage I or III*
44
    III
Serum ß2-microglobulin 5.5 mg/L
29
* There are two categories for stage II: serum ß2-microglobulin < 3.5 mg/l but serum 
albumin < 3.5 g/dl; or serum ß2-microglobulin 3.5 to < 5.5 mg/l irrespective of the 
serum albumin level.


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APPENDIX 7: LISTS OF DRUGS THAT PROLONG THE QT INTERVAL AND/OR INDUCE 
TORSADES DE POINTES VENTRICULAR ARRHYTHMIA
Source:  www.azcert.org
Because the evidence for risk of TdP is often imperfect, AZCERT, inc. has divided the 
drugs into four groups based on their analysis of the evidence:
1. Risk of TdP: Substantial evidence supports the conclusion that these drugs prolong 
QT intervals and have a risk of TdP when used as directed in labeling.
2. Possible risk of TdP: Substantial evidence supports the conclusion that these drugs 
can cause QT prolongation but there is insufficient evidence that the drugs, when 
used as directed in labeling, have a risk of causing TdP.
3. Conditional risk of TdP: Substantial evidence supports the conclusion that these 
drugs prolong QT and have a risk of developing TdP but only under certain known 
conditions.
A note about brand names: drugs are listed with up to two common brand names. 
There are many more brand names for some of the common drugs, such as 
pseudoephedrine and erythromycin. It is also important to look at the list of active drugs 
in medicines that contain a combination of drugs such as Zyrtec-D®, which contains 
pseudoephedrine.
Generic Name
(Brand Name)
Drug Class / Clinical Usage
Comments
Risk 
List
Alfuzosin (Uroxatral®)
Alpha1-blocker/benign prostatic 
hyperplasia
2
Amantadine (Symmetrel®) Dopaminergic/anti-viral/anti-
infective/Parkinson's disease
2
Amiodarone (Cordarone®) Anti-arrhythmic/abnormal heart 
rhythm
Females>Males,TdP risk 
regarded as low
1
Amiodarone (Pacerone®)
Anti-arrhythmic/abnormal heart 
rhythm
Females>Males,TdP risk 
regarded as low
1
Amisulpride (Solian® and 
others)
Antipsychotic, atypical
Risk of TdP with overdose - not 
available in U.S.
3
Amitriptyline (Elavil®)
Tricyclic 
antidepressant/depression
Risk of TdP with overdosage
3
Arsenic trioxide 
(Trisenox®)
Anti-cancer/leukemia
1
Artenimol + piperaquine 
(Eurartesim®)
Anti-malarial/
Not available in U.S.
2
Astemizole (Hismanal®)
Antihistamine/allergic rhinitis
No longer available in U.S.
1
Atazanavir (Reyataz®)
Protease inhibitor/HIV
2
Azithromycin 
(Zithromax®)
Antibiotic/bacterial infection
1
Bedaquiline (Sirturo®)
Anti-infective/drug-resistant 
Tuberculosis
Black Box for QT
2
Bepridil (Vascor®)
Anti-anginal/heart pain
Females>Males
1
Chloral hydrate (Noctec®)
Sedative/sedation/insomnia
2
Chloroquine (Aralen®)
Anti-malarial/malaria infection
1


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Generic Name
(Brand Name)
Drug Class / Clinical Usage
Comments
Risk 
List
Chlorpromazine 
(Thorazine®)
Anti-psychotic/anti-
emetic/schizophrenia/nausea
1
Ciprofloxacin (Cipro®)
Antibiotic/bacterial infection
Drug interaction risk - metabolic 
inhibitor
3
Cisapride (Propulsid®)
GI stimulant/heartburn
No longer available in U.S.
1
Citalopram (Celexa®)
Anti-depressant/depression
1
Clarithromycin (Biaxin®)
Antibiotic/bacterial infection
1
Clomipramine 
(Anafranil®)
Tricyclic 
Antidepressant/depression
3
Clozapine (Clozaril®)
Anti-psychotic/schizophrenia
2
Desipramine (Pertofrane®) Tricyclic 
Antidepressant/depression
Risk of TdP with overdosage
3
Diphenhydramine 
(Benadryl®)
Antihistamine/allergic rhinitis, 
insomnia
Risk of QT increase/TdP in 
overdosages
3
Diphenhydramine 
(Nytol®)
Antihistamine/allergic rhinitis, 
insomnia
Risk of QT increase/TdP in 
overdosages
3
Disopyramide (Norpace®)
Anti-arrhythmic/abnormal heart 
rhythm
Females>Males
1
Dofetilide (Tikosyn®)
Anti-arrhythmic/abnormal heart 
rhythm
Females > Males
1
Dolasetron (Anzemet®)
Anti-nausea/nausea, vomiting
2
Domperidone (Motilium®) Anti-nausea/nausea
Not available in U.S.
1
Doxepin (Sinequan®)
Tricyclic 
Antidepressant/depression
3
Dronedarone (Multaq®)
Anti-arrhythmic/atrial fibrillation
2
Droperidol (Inapsine®)
Sedative;anti-nausea/anesthesia 
adjunct, nausea
1
Eribulin (Halaven® )
Anti-cancer/metastatic breast 
neoplasias
2
Erythromycin (E.E.S.® )
Antibiotic;GI stimulant/bacterial 
infection; increase GI motility
Females>Males
1
Erythromycin 
(Erythrocin®)
Antibiotic;GI stimulant/bacterial 
infection; increase GI motility
Females>Males
1
Escitalopram (Cipralex®)
Anti-depressant/major 
depression/ anxiety disorders
1
Escitalopram (Lexapro®)
Anti-depressant/major 
depression/ anxiety disorders
1
Famotidine (Pepcid®)
H2-receptor antagonist/peptic 
ulcer/ GERD
2
Felbamate (Felbatrol®)
Anti-convulsant/seizure
2
Fingolimod (Gilenya®)
Immunosuppressant/multiple 
sclerosis
2
Flecainide (Tambocor®)
Anti-arrhythmic/abnormal heart 
rhythm
1
Fluconazole (Diflucan®)
Anti-fungal/fungal infection
Drug interaction risk- metabolic 
inhibitor. Can also increase QT 
at high doses - 800 mg/day
3
Fluoxetine (Sarafem®)
Anti-depressant/depression
3
Fluoxetine (Prozac®)
Anti-depressant/depression
3
Foscarnet (Foscavir®)
Anti-viral/HIV infection
2
Fosphenytoin (Cerebyx®)
Anti-convulsant/seizure
2
Galantamine (Reminyl®)
Cholinesterase inhibitor/ 
dementia, Alzheimer's
3


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Generic Name
(Brand Name)
Drug Class / Clinical Usage
Comments
Risk 
List
Gatifloxacin (Tequin®)
Antibiotic/bacterial infection
Oral/I.V. forms no longer 
available in U.S. and Canada, 
only ophthalmic
2
Gemifloxacin (Factive®)
Antibiotic/bacterial infection
2
Granisetron (Kytril®)
Anti-nausea/nausea and vomiting
2
Halofantrine (Halfan®)
Anti-malarial/malaria infection
Females>Males
1
Haloperidol (Haldol®)
Anti-psychotic/schizophrenia, 
agitation
TdP risk with I.V. or excess 
dosage
1
Ibutilide (Corvert®)
Anti-arrhythmic/abnormal heart 
rhythm
Females>Males
1
Iloperidone (Fanapt®)
Antipsychotic, 
atypical/schizophrenia
2
Imipramine (Norfranil®)
Tricyclic 
antidepressant/depression
TdP risk with excess dosage
3
Indapamide (Lozol®)
Diuretic/stimulate urine & salt 
loss
2
Isradipine (Dynacirc®)
Anti-hypertensive/high blood 
pressure
2
Itraconazole (Sporanox®)
Anti-fungal/fungal infection
Drug interaction risk - metabolic 
inhibitor
3
Ketoconazole (Nizoral®)
Anti-fungal/fungal infection
Prolongs QT & Drug interaction 
risk - metabolic inhibitor.
3
Lapatinib (Tykerb®)
Anti-cancer/breast cancer, 
metastatic
2
Lapatinib (Tyverb®)
Anti-cancer/breast cancer, 
metastatic
2
Levofloxacin (Levaquin®)
Antibiotic/bacterial infection
2
Levomethadyl (Orlaam®)
Opiate agonist/pain control, 
narcotic dependence
Not available in U.S.
1
Lithium (Eskalith®)
Anti-mania/bipolar disorder
2
Lithium (Lithobid®)
Anti-mania/bipolar disorder
2
Mesoridazine (Serentil®)
Anti-psychotic/schizophrenia
1
Methadone (Dolophine®)
Opiate agonist/pain control, 
narcotic dependence
Females>Males
1
Methadone (Methadose®)
Opiate agonist/pain control, 
narcotic dependence
Females>Males
1
Mirtazapine (Remeron®)
Anti-depressant/
2
Moexipril/HCTZ 
(Uniretic®)
Anti-hypertensive/high blood 
pressure
2
Moxifloxacin (Avelox®)
Antibiotic/bacterial infection
1
Nicardipine (Cardene®)
Anti-hypertensive/high blood 
pressure
2
Nilotinib (Tasigna®)
Anti-cancer/leukemia
2
Nortriptyline (Pamelor®)
Tricyclic 
Antidepressant/depression
3
Octreotide (Sandostatin®)
Endocrine/acromegaly, carcinoid 
diarrhea
2
Ofloxacin (Floxin®)
Antibiotic/bacterial infection
2
Olanzapine (Zyprexa®)
Antipsychotic, 
atypical/schizophrenia, bipolar
Combo c fluoxetine: Symbyax
2
Ondansetron (Zofran®)
Anti-emetic/nausea and vomiting
2
Oxytocin (Pitocin®)
Oxytocic/labor stimulation
2
Paliperidone (Invega®)
Antipsychotic, 
atypical/schizophrenia
2


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Generic Name
(Brand Name)
Drug Class / Clinical Usage
Comments
Risk 
List
Paroxetine (Paxil®)
Anti-depressant/depression
3
Pentamidine (NebuPent®)
Anti-infective/pneumocystis 
pneumonia
Females>Males
1
Pentamidine (Pentam®)
Anti-infective/pneumocystis 
pneumonia
Females>Males
1
Perflutren lipid 
microspheres (Definity®)
Imaging contrast 
agent/echocardiography
2
Pimozide (Orap®)
Anti-psychotic/Tourette's tics
Females>Males
1
Probucol (Lorelco®)
Antilipemic/hypercholesterolemia No longer available in U.S.
1
Procainamide (Pronestyl®) Anti-arrhythmic/abnormal heart 
rhythm
1
Procainamide (Procan®)
Anti-arrhythmic/abnormal heart 
rhythm
1
Protriptyline (Vivactil®)
Tricyclic 
antidepressant/depression
3
Quetiapine (Seroquel®)
Anti-psychotic/schizophrenia
2
Quinidine (Quinaglute®)
Anti-arrhythmic/abnormal heart 
rhythm
Females>Males
1
Quinidine (Cardioquin®)
Anti-arrhythmic/abnormal heart 
rhythm
Females>Males
1
Quinine sulfate 
(Qualaquin®)
Anti-malarial/malaria or leg 
cramps
TdP with overdose or drug-drug 
or drug food interaction
3
Ranolazine (Ranexa®)
Anti-anginal/chronic angina
2
Risperidone (Risperdal®)
Anti-psychotic/schizophrenia
2
Ritonavir (Norvir®)
Protease inhibitor/HIV
3
Roxithromycin* (Rulide®) Antibiotic/bacterial infection
*Not available in U.S.
2
Sertindole (Serdolect®)
Antipsychotic, atypical/anxiety, 
schizophrenia
Not available in U.S.
2
Sertindole (Serlect®)
Antipsychotic, atypical/anxiety, 
schizophrenia
Not available in U.S.
2
Sertraline (Zoloft®)
Anti-depressant/depression
3
Sevoflurane (Ulane®)
Anesthetic, general/anesthesia
Label warning for patients with 
congenital long QT or patients 
taking QT prolonging drugs
1
Sevoflurane (Sojourn®)
Anesthetic, general/anesthesia
Label warning for patients with 
congenital long QT or patients 
taking QT prolonging drugs
1
Solifenacin (VESIcare®)
muscarinic receptor 
anatagonist/treatment of 
overactive bladder
3
Sotalol (Betapace®)
Anti-arrhythmic/abnormal heart 
rhythm
Females>Males
1
Sparfloxacin (Zagam®)
Antibiotic/bacterial infection
No longer available in U.S.
1
Sunitinib (Sutent®)
Anti-cancer/RCC, GIST
2
Tacrolimus (Prograf®)
Immunosuppressant/Immune 
suppression
2
Tamoxifen (Nolvadex®)
Anti-cancer/breast cancer
2
Telithromycin (Ketek®)
Antibiotic/bacterial infection
2
Terfenadine (Seldane®)
Antihistamine/allergic rhinitis
No longer available in U.S.
1
Thioridazine (Mellaril®)
Anti-psychotic/schizophrenia
1
Tizanidine (Zanaflex®)
Muscle relaxant/
2
Trazodone (Desyrel®)
Anti-depressant/depression, 
insomnia
3


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Generic Name
(Brand Name)
Drug Class / Clinical Usage
Comments
Risk 
List
Trimethoprim-Sulfa 
(Septra® or Bactrim®)
Antibiotic/bacterial infection
Also available in DS (double 
strength)
3
Trimipramine 
(Surmontil®)
Tricyclic 
Antidepressant/depression
3
Vandetanib (Caprelsa®)
Anti-cancer/thyroid cancer
1
Vardenafil (Levitra®)
Phosphodiesterase 
inhibitor/vasodilator
2
Venlafaxine (Effexor®)
Anti-depressant/depression
2
Voriconazole (VFend®)
Anti-fungal/anti-fungal
2
Ziprasidone (Geodon®)
Anti-psychotic/schizophrenia
2


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APPENDIX 8: QTC SUBSTUDY PROTOCOL
An Uncontrolled, Open-label, Substudy within APL-C-001-09 Clinical Study 
(ADMYRE) in Patients with Relapsed/Refractory Multiple Myeloma, Evaluating 
the Potential Effects of Plitidepsin on the QT Intervals of the Electrocardiogram.
1. INTRODUCTION
Plitidepsin showed no relevant cardiac toxicity during preclinical/toxicology studies. 
However, other cyclic depsipeptides have been linked to increased cardiac toxicity, and 
thus a retrospective study of the cardiac adverse events [e.g., rhythm abnormalities, 
myocardial injury events, electrocardiogram (ECG) alterations] that occurred in all 
patients treated with single-agent plitidepsin was conducted. This study showed that the 
frequency of these events was not different to that reported in the age-matched healthy 
population, thereby suggesting that plitidepsin has a safe cardiac risk profile in cancer 
patients.[1]
1.1.  SUBSTUDY RATIONALE
An undesirable property of some drugs is their ability to delay cardiac repolarization, an 
effect that can be measured as prolongation of the QT interval on the surface 
electrocardiogram (ECG). The QT interval represents the duration of ventricular 
depolarization and subsequent repolarization, and is measured from the beginning of the 
QRS complex to the end of the T wave. A delay in cardiac repolarization creates an 
electrophysiological environment that favors the development of cardiac arrhythmias, 
most clearly torsades de pointes (TdP), but possibly other ventricular tachyarrhythmias 
as well. TdP is a polymorphic ventricular tachyarrhythmia that appears on the ECG as 
continuous twisting of the vector of the QRS complex around the isoelectric baseline. A 
feature of TdP is pronounced prolongation of the QT interval in the supraventricular 
beat preceding the arrhythmia. TdP can degenerate into ventricular fibrillation, leading 
to sudden death. While the degree of QT prolongation is recognized as an imperfect 
biomarker for proarrhythmic risk, in general there is a qualitative relationship between 
QT prolongation and the risk of TdP, especially for drugs that cause substantial 
prolongation of the QT interval. Because of its inverse relationship to heart rate, the 
measured QT interval is routinely corrected by means of various formulae to a less heart 
rate-dependent value known as the QTc interval. It is not clear, however, whether 
arrhythmia development is more closely related to an increase in the absolute QT 
interval or QTc. Most drugs that have caused TdP clearly increase both the absolute QT 
and the QTc (hereafter called QT/QTc). Documented cases of TdP (fatal and nonfatal) 
associated with the use of a drug have resulted in the withdrawal from the market of 
several drugs and relegation of other drugs to second-line status. Because prolongation 
of the QT/QTc interval is the ECG finding associated with the increased susceptibility 
to these arrhythmias, an adequate premarketing investigation of the safety of a new 
pharmaceutical agent should include rigorous characterization of its effects on the 
QT/QTc interval.[2]


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1.2. SUBSTUDY DESIGN RATIONALE
Plitidepsin is an anticancer agent that should not be administered to healthy subjects. 
Plitidepsin is administered at maximum tolerated dose, so it cannot be tested safely at 
supratherapeutic concentrations, even in cancer patients. 
The impact of the disease, together with age, comorbidities and comedications present 
in patients with cancer is such that they are unable to tolerate excessive testing. 
Therefore, the search for a precise characterization of the effects of the drug on the QTc 
must be carefully balanced against the feasibility of the study design. Furthermore, the 
duration of the QTc interval is a less-than-perfect marker of the risk of 
proarrhythmia.[3]
Patients with refractory malignancies and expected reduced survival could justifiably be 
excused from the burden of time-matched baseline ECG values and separate 
administration of a positive control.[4]
Therefore, this substudy will be conducted in patients who may benefit from the 
anticancer activity of plitidepsin at the recommended dose, such as those enrolled in 
clinical trial APL-C-001-09. The potential effects of a 5 mg/m2 plitidepsin dose given as 
a 3-hour intravenous infusion on the QTc interval duration will be assessed when the 
patient is treated with plitidepsin for the first time (Day 1 of Cycle 1). In order to detect 
any delayed drug effect on the QTc interval, these investigations will be repeated at the 
second infusion of plitidepsin (Day 15 of Cycle 1), when the drug is expected to reach 
the steady state in spite of plitidepsin’s long terminal half-life in blood, approximately 
88 hours, although concentrations on Day 15 are negligible.
This substudy will be conducted at some of the sites participating in study APL-C-001-
09.
Although the daily variability in QTc interval of cancer patients has not been well 
described, it may be even larger because enrolled patients are likely to have advanced 
age, concomitant medical problems and prior QT-prolonging chemotherapy.[5] For this 
reason, an intrapatient standard deviation of 18 milliseconds is assumed. To reduce 
intrapatient variability due to measurement error, it has been recommended that the 
baseline QTc be rigorously investigated and be expressed as the mean of multiple 
electrocardiogram assessments.[6] For this purpose, two sets of triplicate ECG tracings 
recorded before plitidepsin administration will be considered baseline assessments: one 
set before and one after prophylactic medication administration on Days 1 and Day 15.
Electrocardiogram assessments will be performed by means of continuous 12-lead ECG 
automated digital collection. 
All digital ECG continuous recordings will be sent to a third-party central ECG 
laboratory for measurement of intervals, diagnostics of abnormalities and review of 
ECG waveform morphology review. This will prevent the potential introduction of bias 
during the analysis of ECG recordings.


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1.3. DNA COLLECTION RATIONALE
Genetic variation can be an important contributory factor to interindividual differences 
in QT/QTc changes to drug exposure. The collection of an additional sample will allow 
for genetic evaluation of mutations associated with ion channelopathies in case marked 
drug-related changes of the QT/QTc interval are observed. Details are provided in 
Section 7.4 QT-Related Polymorphisms Assessment.
2. OBJECTIVES
Based on the aforementioned scientific background, the primary objective of the present 
substudy is to assess the potential effects of plitidepsin administered at a therapeutic 
dose on the duration of the QT/QTc interval, measured by ECGs, in patients with 
relapsed/refractory multiple myeloma.
Secondary objectives are: to evaluate QTc changes over the treatment period; to 
characterize the plitidepsin (real and estimated) whole blood concentration/QTc 
relationship (or PK/PD relationship); and to explore related ECG parameters.
3. OVERALL SUBSTUDY DESIGN
This is an uncontrolled, open-label, substudy within APL-C-001-09 clinical trial 
(ADMYRE) in patients with relapsed/refractory multiple myeloma, evaluating the 
potential effects of plitidepsin on the QT/QTc intervals of the ECG.
Patients will be enrolled as needed to ensure at least 36 evaluable patients with 
evaluable ECG data.
Patients will be admitted to the study site on Days 1 and 15 (at least 2 hours before 
plitidepsin administration) until completion of the pharmacokinetic (PK) blood sample 
collection scheduled at three hours after EOI. After completing all other baseline 
assessments on Days 1 and 15, a 12-lead continuous ECG recorder will be set in place 
and patients will be resting in a supine position for at least one hour prior to the start of 
the plitidepsin infusion (SOI).
Patients will be administered the prophylactic medication at 20-30 minutes before SOI.
Patients will be at the study site until completion of the PK blood sample collection at 
three hours after EOI and then will leave the study site. Patients will be asked to:
-
keep calm and relaxed until the next day (i.e., at 21 hours after EOI), when the 
ECG recorder will be removed.
-
remain in a supine position from 10 minutes before 6, 9 and 21 hours after EOI. 
Specific times will be reminded (see section 4.4 Patient’s Card)


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Meals on Day 1 and Day 15 should be standardized. Patients will have lunch at 
1.5 hours after EOI, which must be completed at least 30 minutes before the next PK 
blood sample collection (i.e., 3 hours after EOI). The activities of patients at the study 
site will be modified to avoid strenuous effort or emotional excitement.
An additional blood sample (10 mL) may be collected on Day 1 prior to treatment to 
allow for genetic evaluation of mutations associated with ion channelopathies, in case 
marked drug-related changes of the QT/QTc interval are observed. Participation in the 
QT-related polymorphisms assessment is optional.
Details on the timing of the treatment and assessments are given in the substudy’s 
Schedule of Assessments and Procedures (see below).
4. PATIENT DEFINITION
4.1. SUBSTUDY POPULATION
Patients will be enrolled in the substudy as needed to ensure that at least 36 patients 
have completed all required assessments (see Section 5.1).
The inclusion and exclusion criteria for enrolling patients in this substudy are described 
in the following sections.
4.2. PATIENT ELIGIBILITY
4.2.1. Inclusion Criteria
In order to be enrolled in the substudy, patients must satisfy the following criteria at 
screening for the main study:
1. Patient included in the clinical study APL-C-001-09 and randomized to the 
experimental arm (plitidepsin + dexamethasone).
2. Patient with voluntarily signed and dated informed consent to participate in the 
QT substudy.
3. A 12-lead ECG consistent with normal cardiac conduction and function, 
showing:

Sinus rhythm.

Pulse rate between 45 and 100 bpm.

QRS interval <120 ms.

PR interval <200 ms.
4. Blood pressure between 90 and 150 mmHg systolic, inclusive, and not higher 
than 90 mmHg diastolic.


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5. Serum electrolyte levels within seven days prior to first infusion, ≤ grade 1:

Ionic Ca++: 1.0 – 1.5 mmol/L.

K+: 3 – 5.5 mmol/L.

Mg++: 0.5 – 1.23 mmol/L.
4.2.2. Exclusion Criteria
Patients who meet any of the following criteria will be excluded from participating in 
the substudy:
1. Has heart rhythm disturbances (e.g. atrial fibrillation), unusual T wave and U 
wave (if present) morphology, personal or family history of Long QT Syndrome, 
ECG findings of complete left bundle branch block, permanent ventricular 
pacemaker, or Brugada Syndrome.
2. Has any skin condition likely to interfere with ECG electrode placement, or a 
history of breast implant or thoracic surgery likely to cause abnormality in 
electrical conduction.
3. Prior exposure to anthracyclines at a cumulative dose of doxorubicin or 
equivalent greater than 450 mg/m².
4. Patients who at screening are on medication that is known to prolong the QT 
interval (refer to Appendix 7 of the main protocol). Patients must have been off 
these medications for a minimum of 48 hours prior to plitidepsin administration 
on Day 1 and Day 15.
5. History of illegal drug use or alcohol abuse within six months before study drug 
administration.
4.3. ACTIVITIES AND SUBSTANCES THAT PATIENTS MUST AVOID
DURING THE SUBSTUDY
Potential patients must be willing to adhere to the following prohibitions and 
restrictions during the course of the substudy to be eligible for participation.
1. Must refrain from jogging, strenuous exercises of all types, and sunbathing from 
48 hours before Days 1 and 15 until after the end of the continuous ~24-hour 
ECG recording on Days 1 and 15.
2. May not consume beverages containing alcohol from 24 hours before Days 1 
and 15 until after the end of the continuous ~24-hour ECG recording on Days 1 
and 15.
3. Must refrain from using any methylxanthine-containing products, (e.g., 
chocolate bars or beverages, coffee, tea, or colas) from 48 hours before Days 1 
and 15 until after the end of the continuous ~24-hour ECG recording on Days 1 
and 15.


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4. Patients may consume standard meals during their stay at the study site. Meals 
will not contain spicy foods (i.e., black pepper, hot peppers, wasabi, etc). 
Excessive food consumption will not be permitted.
4.4. PATIENT’S CARD
The Investigator will provide the patient with a card listing all prohibited activities and 
substances during the substudy. This card will contain blank spaces for the Investigator 
to write down the specific times of the ECG timepoints at 6, 9 and 21 hours after EOI. 
The Investigator must remember to tell the patient that he/she must remain in a supine 
position from 10 minutes before these times.
5. PLAN OF SUBSTUDY
5.1. COMPLETION
A patient will be considered to have completed the substudy if he/she has evaluable 
ECG data. 
5.2. WITHDRAWAL/DISCONTINUATION FROM THE SUBSTUDY
A patient will be withdrawn from the substudy for any of the following reasons:
-
Withdrawal of substudy ICF.
-
The patient does not comply with the substudy requirements, including inclusion 
criteria, exclusion criteria, and prohibitions and restrictions.
Patients who withdraw from the substudy will be replaced as needed in order to ensure 
that at least 36 evaluable patients complete the substudy.
5.3.
WITHDRAWAL
FROM
QT-RELATED
POLYMORPHISMS
ASSESSMENT ONLY
A patient may withdraw his/her consent for the QT-related polymorphisms assessment 
while being evaluable for the substudy. In such a case, collected blood samples will be 
destroyed. To initiate the sample destruction process, the Investigator must notify the 
Sponsor’s center contact and request sample destruction. In turn, the Sponsor’s center 
contact will ask the central lab contact to destroy the sample. If requested, the 
Investigator will receive written confirmation from the Sponsor/central lab that the 
sample has been destroyed.
6. TREATMENT
6.1. PROPHYLACTIC MEDICATION
During the substudy (Cycle 1 of main study), all patients must receive the following 
prophylactic medication at 20-30 minutes before infusion of plitidepsin:


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
Palonosetron 0.25 mg i.v. (tropisetron 5 mg i.v. could be considered if 
palonosetron is not available).

Dexchlorpheniramine 5 mg i.v. or chlorpheniramine 10 mg i.v., 
(dexchlorpheniramine 6 mg p.o. or chlorpheniramine 10-15 mg p.o. could be 
considered, if i.v. formulations are not available).

Ranitidine 50 mg i.v. or cimetidine 300 mg i.v.
Oral aprepitant may be used as per Investigator’s criteria/institutional guidelines. 
Metoclopramide should be avoided.
The use of alternative prophylactic medications should be discussed in advance with the 
Sponsor.
6.2. PROHIBITED MEDICATIONS/THERAPIES
Drugs known to prolong QT interval and/or induce torsades de pointes are prohibited 
(refer to Appendix 7 of the main protocol). Patients must have been off these
medications for a minimum of 48 hours prior to plitidepsin administration on Days 1 
and 15.
7. SUBSTUDY EVALUATIONS
7.1. SUBSTUDY PROCEDURES
The substudy’s Schedule of Assessments and Procedures summarizes the frequency and 
timing of continuous ECG recorder placement for pharmacodynamic (PD) assessments 
and PK and QT-related polymorphisms sample collection.
A 10 mL blood sample will be collected on Day 1 from patients who have consented to 
participate in the QT-related polymorphisms assessment of the substudy.
7.2. PHARMACOKINETIC EVALUATIONS
Plitidepsin PK assessment in patients participating in the substudy will be the same as 
the one conducted on patients in Arm A of the main study. Please refer to the main 
study protocol, Section 6.2.
7.3. PHARMACODYNAMIC EVALUATIONS
Patients will wear a continuous ECG recorder on Days 1 and 15, from prior to 
prophylaxis administration to 21 hours after EOI. This ECG recorder will be provided 
by ERT after the study site has registered online at ERT’s MYSTUDY PORTALTM. 
Registration details will be provided to the site coordinator at each participating site.
The ECG recorder will be set in place once all safety assessments scheduled for the 
main study (i.e., vital signs, blood sample extraction for laboratory tests, and ECG) have 
been conducted.


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On Day 1 and Day 15, serial ECGs with stable resting heart rate will be extracted from 
the continuous recording in triplicate (three 10-second digital ECGs in close succession) 
within a 10 minute (±5min) window at each scheduled time point of the ECG 
assessments:

Pre-prophylaxis (Predose 1), post-prophylaxis and prior to SOI (Predose 2)*, 
1.5 after SOI, just before the end of infusion (EOI)*, 0.5, 1*, 3*, 6, 9, and 21 
hours after EOI.
*Triplicate ECGs will be extracted prior to the corresponding PK blood sample 
collection.
Patients will remain in the same comfortable supine position for at least 10 minutes 
before and after the time points for ECG and PK collection. Physical activity, external 
stimulation, and meal ingestion should be regulated to keep activity and emotional 
excitement to a minimum. ECG recordings at time points 6, 9 and 21 hours after EOI 
will be ambulatory.
All digital continuous ECG recordings will be sent to a third-party, central ECG 
laboratory (for triplicate ECG extraction at the scheduled time window, measurement of 
intervals, diagnostics of abnormalities and review of ECG waveform morphology). 
Quality assurance procedures will be used to ensure high precision and consistency of 
QT interval measurements.
For the triplicate ECGs collected at each time point, the average of the three 
measurements for each ECG parameter will be considered for all listing and statistical 
analyses described below. 
7.3.1. QT Correction Methods
QT will be corrected for heart rate using the following methods:

Primary: Fridericia’s correction method (QTcF).[7]

Secondary: Bazett’s correction method (QTcB).[8]
7.3.2. Pharmacodynamic Endpoints
In principle, for each patient and each postdose time point on Day 1 and Day 15, 
baseline QTc intervals will be the mean of the Predose 1 and Predose 2 QTc values for 
that patient on Day 1.
If the mean Predose 2 QTc value of all evaluable patients is ≥10 ms longer than of the 
mean Predose 1 QTc value, an effect of prophylactic medication on QTc cannot be 
ruled out; therefore, individual Predose 2 QTc values will be considered as the baseline 
values.
The change from baseline (ΔQTc) will be calculated using the corresponding baseline 
QTc values. Specifically:

ΔQTc at time t: Difference in QTc between scheduled time point t and 
baseline.


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The primary pharmacodynamic (PD) endpoint will be ΔQTc at each scheduled time 
point. ΔQTc will be summarized where QTc is derived using both the QTcF and QTcB 
correction methods whereby QTc denotes a general notation of corrected QT using 
either method.
7.4. QT-RELATED POLYMORPHISMS ASSESSMENT
A 10 mL blood sample will be collected on Day 1 from patients who consented to take 
part in the QT-related polymorphisms assessment of the substudy at the time point 
indicated in the substudy’s Schedule of Assessments and Procedures (see below). 
Participation in the QT-related polymorphisms assessment is optional.
A manual of instructions for sample collection, labeling, storage, and shipment will be 
provided as a separate document (Instruction Manual for the Collection, Labeling, 
Storage and Shipment of Pharmacokinetic Samples).
If a patient shows marked drug-related changes of the QTc interval and a genetic cause 
is suspected, that individual sample will be analyzed.
Genes currently hypothesized to potentially be relevant to irregular QT/QTc intervals 
such as KCNE1, KCNE2, KCNH2, KCNQ1 and SCN5A will be considered for 
genotyping.
When the ECG database will be locked, if no marked drug-related changes are 
observed, all samples for QT-related polymorphisms assessment from the substudy will 
be destroyed.
7.4.1. Confidentiality of Samples for QT-related Polymorphisms Assessment
PharmaMar shall comply with the Directive 95/46/EC of the European Parliament and 
of the Council of 24 October 1995 on the protection of individuals with regard to the 
processing of personal data and on the free movement of such data.
Appropriate technical and organizational measures to protect the genetic data against 
unauthorized disclosures or access, accidental or unlawful destruction, or accidental loss 
or alteration will be put in place. Sponsor personnel whose responsibilities require 
access to personal data agree to keep the identity of substudy patients confidential.
Samples will be stored until the ECG database has been locked, when the decision on 
whether it is necessary to rule out mutations associated with ion channelopathies, is 
made.
7.5. 12-LEAD ECG ACQUISITION
ECGs will be obtained digitally using a Mortara Instrument (Milwaukee, WI, USA) H-
12+ ECG continuous 12 lead digital recorder, which will obtain ECGs on Day 1 and 
Day 15. The ECGs are stored continuously on a flash card and will not be available for 
review until the card is received by ERT and analyzed. ECGs to be used in the analysis 
will be selected by predetermined time points as detailed below and will be read 
centrally using a high-resolution manual on-screen caliper semiautomatic method with 
annotations. In this trial using pre-treatment ECGs as the baseline, the H-12+ recording 


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will be started approximately 1 hour prior SOI through approximately 21 hours post 
EOI in order to obtain the baseline ECGs as detailed below.
ECGs for the treatment days will be obtained as triplicate (3) 12-lead ECGs at each time 
point which will be downloaded from the H-12+ flash card approximately one minute 
apart on Day 1 and Day 15.  On Day 1 and Day 15, baseline ECGs will be extracted (in 
triplicate) pre-prophylaxis (Predose 1), post-prophylaxis and prior to SOI (Predose 2).  
On Day 1 and Day 15, triplicate ECGs will be extracted at the following time points: 1.5 
after SOI, just before the EOI, 0.5, 1, 3, 6, 9 and 21 hours after EOI.
7.6. ECG ANALYSIS METHODS
ECGs will be sent to ERT for a treatment-blinded high-resolution measurement of the 
cardiac intervals, and morphological assessment by a central cardiologist. 
The 12-lead digital continuous ECG signal for each session in each patient will be 
recorded on compact flash memory cards provided to the site. The patient’s unique 
identification number and demographic information will be recorded for each card. ERT 
will generate a 10-second, 12-lead digital ECG at each time point specified in the 
protocol. If targeted ECG time points are artifactual and of poor quality, ERT will 
capture analyzable 10-second ECGs as close as possible to the targeted time points.
Digital ECGs will be transmitted to ERT’s validated data management system, 
EXPERT. Interval duration measurements will be collected using computer assisted 
caliper placements on three consecutive beats. Trained analysts will then review all 
ECGs for correct lead and beat placement and will adjudicate the pre-placed algorithm 
calipers as necessary using the proprietary validated electronic caliper system applied 
on a computer screen. A cardiologist will then verify the interval durations and perform 
the morphology analysis, noting any T-U wave complex that is compatible with an 
effect on cardiac repolarization. 
The ECG analysis will be conducted in Lead II, or in Lead V5 if Lead II is not 
analyzable. If Lead V5 is not analyzable then Lead V2 will be used, followed by the 
most appropriate lead if necessary. ECG readers will be blinded to patient identifiers, 
and visit. All ECGs for a given patient will be analyzed by the same reader. Quality 
Assurance reports for inter- and intra-observer variability will be produced by the 
central ECG laboratory and provided to the Sponsor.
On-screen measurements of the RR, PR, QRS, and QT interval durations will be 
performed and variables for QTcF, QTcB, and heart rate (HR) will be obtained by the 
following processes:
Interval measurements will be obtained by the following method: 

Three (3) RR 
mean RR Interval is reported.

Three (3) PR 
mean PR Interval is reported.

Three (3) QRS 
mean QRS Width is reported.

Three (3) QT 
mean QT Interval is reported.
The following calculations will be made from the interval measurements:


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Three (3) QTcF measurements- QTc correction by the Fridericia’s formula

QTcF1 = QT1/3RR1

QTcF2 = QT2/3RR2

QTcF3 = QT3/3RR3

Mean QTcF = (QTcF1 + QTcF2 + QTcF3)/3
Three (3) QTcB measurements- QTc correction by the Bazett’s formula

QTcB1 = QT1/RR1

QTcB2 = QT2/RR2

QTcB3 = QT3/RR3

Mean QTcB = (QTcB1 + QTcB2 + QTcB3)/3
Three (3) Heart Rate measurements

HR1 = 60 / RR1 

HR2 = 60 / RR2 

HR3 = 60 / RR3 

Mean HR = (HR1 + HR2 + HR3)/3
Each fiducial point (onset of P wave, onset of Q wave, offset of S wave, and offset of T 
wave) will be electronically marked. The original ECG waveform and such annotations 
will be saved separately in XML format for independent review.
8. STATISTICAL METHODS
A non-inferiority limit of 20 ms will be used for the comparison of the effects of 
plitidepsin on the QT/QTc intervals.
8.1. SAMPLE SIZE
Using a standard deviation of 18 ms in a sample size of 36 evaluable patients, the 
probability that the upper limit of the one-sided 95% confidence interval (CI) for the 
difference in mean QTc between each time point and baseline (ΔQTc) will fall below 20 
ms is 80%, when the true difference in means equals 5 ms.
8.2. PHARMACODYNAMIC ANALYSES
The primary objective of this substudy is to measure the potential effect of plitidepsin 
on QTc. The primary comparison of interest will be ΔQTc at each scheduled time point. 
A non-inferiority criterion of 20 ms will be used to establish that postdose QTc is not 
inferior to baseline. Evaluable patients who have evaluable ECG data will be included 
in the primary analysis.
A mixed effect analysis of variance (ANOVA) model will be fitted with the QTc data as 
the dependent variable and intervention (baseline vs. postdose), scheduled time point t 
of measurement (where t will be baseline, 1.5 after SOI, just before the EOI, 0.5, 1, 3, 6, 
9 and 21 hours after EOI) and treatment period (Day 1 and Day 15) as fixed effects and 
patient as a random effect. Using the estimated least square means and intrapatient 
variance obtained from this model, a one-sided 95% CI will be calculated for the 


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difference in mean QTc between baseline and each scheduled time point t. Non-
inferiority will be concluded if at each scheduled time point the upper-limit of the one-
sided 95% CI falls below 20 ms.
Mean ECG parameters (QT, QTc, RR, heart rate, QRS, and PR) and corresponding 
changes from baseline will be listed and summarized descriptively by time point t. Plots 
of mean QTc changes from baseline (ΔQTc) vs. the scheduled time point t will be 
prepared.
The incidence count and percentage of patients with QTc increase from baseline 
(ΔQTc) >30-60 ms and >60 ms will be tabulated for each time point t, age and gender. 
The incidence count and percentage of patients with any postdose QTc values >450 ms 
and >480 ms, will be tabulated for each time point t, and gender. Patients with QTc 
values >500 ms will be listed.
The incidence count of patients with PR >200 ms, QRS >120 ms, heart rate >100 bpm
and <50 bpm, and ST segment and T and U wave abnormalities will be reported. The 
incidence count of patients with abnormalities in the ST segment (e.g. flat, depressed, 
elevated) and T wave (i.e. present or absent) and U wave (e.g. flattened, inverted, 
biphasic and notched) will be reported.
8.3. PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES
The PK/PD analyses will be based on data collected from the scheduled time points of 
ECG measurement and:
1. their corresponding whole blood plitidepsin concentration.
2. their estimated whole blood plitidepsin concentration at the corresponding ECG 
time point by means of population PK modeling.
Evaluable patients (i.e., those who have evaluable ECG data) who withdraw before 
completing both days (i.e., Days 1 and 15) will be included in these analyses. Plots of 
individual QTc changes from baseline (ΔQTc) vs. the corresponding plitidepsin blood 
concentrations will be prepared to explore any concentration-effect relationship for 
plitidepsin.
The concentration–QTc relationship will be assessed  using a linear mixed effects 
analysis of the relationship between ΔQTc data and plitidepsin concentration according 
to the equation: ΔQTc = α + β*[plitidepsin], where inter-individual variability will be 
estimated for both intercept (α) and slope (β). The effect of treatment period (i.e. Day 1 
or Day 15) on slope and intercept will also be evaluated. If the intercept term is not 
significant, the model will be re-fit with a zero intercept term. The predicted value of 
ΔQTc (along with 90% CI) will be estimated at the mean maximum plasma (Cmax) 
values of plitidepsin.
Additionally, in a complementary PK/PD analysis, the relationship between QTc and 
plitidepsin whole blood concentration will be assessed using linear mixed effect 
modeling to estimate the maximal change (mean and upper 95% confidence limit) in the 
QTc associated with therapeutic concentrations of plitidepsin.


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9. REFERENCES
1.
Soto-Matos, A., et al., Plitidepsin has a safe cardiac profile: a comprehensive 
analysis. Mar Drugs, 2011. 9(6): p. 1007-23.
2.
E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic 
Potential for Non-Antiarrhythmic Drugs. Guidance for Industry. , F.a.D.A. U.S. 
Department of Health and Human Services, Center for Drug Evaluation and 
Research, Center for Biologics Evaluation and Research, ICH. , Editor Oct. 
2005.
3.
Morganroth, J., R.R. Shah, and J.W. Scott, Evaluation and management of 
cardiac safety using the electrocardiogram in oncology clinical trials: focus on 
cardiac repolarization (QTc interval). Clin Pharmacol Ther, 2010. 87(2): p. 
166-74.
4.
Rock, E.P., et al., Assessing proarrhythmic potential of drugs when optimal 
studies are infeasible. Am Heart J, 2009. 157(5): p. 827-36, 836 e1.
5.
Mason, J.W., et al., Electrocardiographic reference ranges derived from 79,743 
ambulatory subjects. J Electrocardiol, 2007. 40(3): p. 228-34.
6.
Varterasian, M., et al., Consideration of QT/QTc interval data in a phase I study 
in patients with advanced cancer.Clin Cancer Res, 2004. 10(17): p. 5967-8; 
author reply 5968-9.
7.
Fridericia, L.S., Die Systolendauer im Elektrokardiogramm bei normalen 
Menschen und bei Herzkranken.Acta Medica Scandinavica, Stockholm, 1920. 
57: p. 469-486.
8.
Bazett, H., An analysis of the time-relationship of electrocardiograms. Heart, 
1919. 70: p. 353-370.


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SCHEDULE OF ASSESSMENTS AND PROCEDURES
PROCEDURE
Screening
Day 1 Cycle 1
Day 15 Cycle 1
-2 hours
-30 min
predose
0
+3 hours 
(just before EOI)
+4 hours 
(1-h after EOI)
+4.5 hours 
(1.5-h after EOI)
+6 hours 
(3-h after EOI)
-2 hours
-30 min
predose
0
+3 hours 
(just before EOI)
+4 hours 
(1-h after EOI)
+4.5 hours
(1.5-h after EOI)
+6 hours 
(3-h after EOI)
Written substudy-specific informed consent
Before any
procedures
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Written IC for QT-related polymorphisms assessment *
-14  to  0
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Review of substudy-specific inclusion/exclusion criteria
-14  to  0
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Patient admission at the study site and Holter placement **
-

-
-
-
-
-
-
-

-
-
-
-
-
-
-
Intravenous prophylaxis medication
-
-

-
-
-
-
-
-
-

-
-
-
-
-
-
Blood sample (10 mL) for QT-related polymorphisms
-
-
-

-
-
-
-
-
-
-

-
-
-
-
-
PK blood sample (4 mL)
-
-
-

-

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Plitidepsin treatment 
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Meal
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* Patient participation in QT-related polymorphisms assessment is optional. Sample will be collected on Day 1.
** The ECG recorder will be set in place once all safety assessments scheduled for the main study (i.e., vital signs, blood sample extraction for laboratory 
tests, and ECG) have been conducted.
ECG, electrocardiogram; EOI, end of infusion; IC, Informed Consent; PK, pharmacokinetics.

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
APL-C-001-09 (NCT01102426) 
 
(ADMYRE: Aplidin – Dexamethasone in RElapsed/Refractory MYeloma) 
 
Randomized, Multicenter, Open-label, Phase III Study of Plitidepsin in 
Combination with Dexamethasone vs. Dexamethasone Alone in Patients with 
Relapsed/Refractory Multiple Myeloma 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version: v6.0 
Date: 15-June-2017     
 


 
2 of 164 
TABLE OF CONTENTS  
 
1 
STUDY RATIONALE 
7 
2 
STUDY DESIGN 
8 
3 
OBJECTIVES AND ENDPOINTS 
9 
3.1 
Primary objective 
9 
3.2 
Secondary objectives 
9 
3.3 
Endpoints 
9 
4 
PATIENTS EVALUABILITY CRITERIA 
9 
4.1 
Analysis sets definitions 
9 
4.2 
Efficacy populations 
10 
4.3 
Safety population 
10 
5 
SAMPLE CONSIDERATIONS 
11 
5.1 
Randomization 
11 
5.2 
Sample size 
12 
6 
STATISTICAL METHODOLOGY FOR EFFICACY 
13 
6.1 
Planned analyses and definitions 
13 
6.1.1 
Early futility analyses 
13 
6.1.2 
Final analyses 
13 
6.2 
Efficacy analysis methods 
16 
6.2.1 
Primary endpoint 
16 
6.2.2 
Supportive PFS analyses 
16 
6.2.3 
Secondary analyses 
16 
7 
STATISTICAL METHODOLOGY FOR SAFETY 
19 
7.1 
Toxicity and adverse events 
19 
7.2 
Clinical laboratory evaluation 
20 
7.3 
Vital signs, physical examination, left ventricular ejection fraction (LVEF) and 
electrocardiogram findings 
20 
7.4 
Deaths and other Serious Adverse Events 
20 
8 
OTHER ANALYSES 
20 
8.1 
Baseline and demographic data 
21 
8.2 
Treatment administration 
21 
8.3 
Subsequent therapy 
21 
8.4 
Protocol deviations 
22 
8.5 
Pharmacokinetic analyses 
22 
8.6 
Imputation of incomplete dates 
22 
8.7 
Subgroup analyses 
22 
8.8 
Methods for handling missing data 
23 
8.9 
Interim and group sequential analyses 
23 
8.10 
Data analysis for the Independent Data Monitoring Committee 
23 
8.11 
Identification of fixed or random effects models 
23 
8.12 
Analyses of the effects of plitidepsin on the QTc interval 
23 
8.13 
Analyses of performance status as an index of quality of life 
23 
9 
STATISTICAL SOFTWARE 
23 
APPENDIX I 
23 


 
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10 Study Patients 
24 
10.1 
Patient disposition 
24 
10.2 
Reasons for treatment discontinuation 
25 
10.3 
Protocol deviations 
27 
11 Efficacy Evaluation 
28 
11.1 
Demographic and other baseline characteristics 
28 
11.1.1 Patient characteristics at baseline 
28 
11.1.2 Disease at diagnosis, time from diagnosis and current disease 
28 
11.1.3 Skeletal sites involved at baseline 
31 
11.1.4 Prior anticancer therapy 
32 
11.1.5 Prior history 
35 
11.1.6 Physical examination, vital signs, electrocardiogram and other tests 
35 
11.1.7 Hematological values at baseline 
37 
11.1.8 Biochemical values at baseline 
38 
11.1.9 Other metabolic values at baseline 
39 
11.1.10 
Signs and symptoms at baseline 
39 
11.1.11 
Concomitant therapy and procedures at baseline 
40 
11.2 
Measurements of treatment compliance 
41 
11.3 
Efficacy analysis 
42 
11.3.1 Primary analysis 
42 
11.3.2 Supportive PFS analyses 
42 
11.3.3 Sensitivity analyses of PFS 
44 
11.3.4 Secondary analyses 
46 
11.3.5 Characteristics of responders 
60 
11.3.6 Efficacy analysis by age 
61 
11.3.7 Efficacy analysis based on genetic risks 
65 
11.3.8 Efficacy analysis in patients resistant or refractory to last 
lenalidomide/thalidomide or last bortezomib therapy 
67 
11.3.9 Efficacy analysis in patients refractory to last prior therapy 
71 
11.3.10 
Efficacy analysis in patients exposed to IMiD therapies 
73 
11.3.11 
Efficacy analysis in patients exposed to PIs therapies 
74 
12 Safety Analysis 
77 
12.1 
Extent of exposure 
77 
12.1.1 Treatment administration 
77 
12.1.2 Cycle delays 
78 
12.1.3 Dose omissions 
80 
12.1.4 Dose reductions 
82 
12.1.5 Infusions temporarily interrupted 
84 
12.1.6 Prophylactic medication administration 
84 
12.2 
Adverse Events (AEs) 
85 
12.2.1 Adverse events 
85 
12.2.2 Display of adverse events 
85 
12.3 
Serious Adverse Events and deaths. 
88 
12.3.1 Serious Adverse Events 
88 
12.3.2 Deaths 
89 
12.4 
Clinical laboratory evaluation 
90 
12.4.1 Hematological abnormalities 
90 


 
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12.4.2 Biochemical abnormalities 
92 
12.4.3 Other metabolic parameters 
93 
12.4.4 Laboratory values over time 
95 
12.5 
Vital signs, physical findings, LVEF, ECG and other tests related to safety 97 
12.5.1 Vital signs and physical findings 
97 
12.5.2 LVEF, ECG and other related tests 
97 
12.6 
Concomitant therapy / procedures according to the ATC classification. 
98 
12.7 
Safety analysis in special subgroups 
99 
12.8 
Time to PS (ECOG) deterioration as index of QoL 
101 
13 DB Listings 
102 
14 References 
103 
15 Revision History 
104 
 


 
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ABBREVIATIONS AND GLOSSARY 
AE(s) 
Adverse Event(s) 
AP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AP 
Alkaline Phosphatase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BL 
Baseline 
BM 
Bone Marrow 
BMI 
Body Mass Index 
BSA 
Body Surface Area 
C 
Cycle/s 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
Confidence Interval 
CPK 
Creatine Phosphokinase 
CPK-MB 
Serum CPK Isoenzymes (Found In Cardiac Muscle) 
CR 
Complete Response 
CRF 
Case Report Form 
CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
CT-scan 
Computed Tomography Scan 
d/D 
Day(s) 
DB 
Data Base 
DF 
Degrees of Freedom 
DI 
Dose Intensity 
DR 
Duration of Response 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EMA 
European Medicines Agency 
EPO 
Erythropoietin 
FU 
Follow-up 
G-CSF 
Granulocyte Colony Stimulating Factor 
h 
Hour(s) 
Hb 
Hemoglobin 
HDT 
High-dose Therapy 
HR 
Hazard Ratio 
IA 
Investigator Assessment 
Ig 
Immunoglobulin 
IDMC 
Independent Data Monitoring Committee 
IMiD 
Immunomodulatory drug 
IMWG 
International Myeloma Working Group 
INR 
International Normalized Ratio 
IPCW 
Inverse Probability of Censoring Weighting 
IR 
Independent Review 
IRC 
Independent Review Committee 
ISS 
International Staging System 
ITT 
Intention-to-treat 
i.v. 
Intravenous 
IVRS 
Interactive Voice Response System 
LDH 
Lactate Dehydrogenase 
LR 
Log-rank Test 
LVEF 
Left Ventricular Ejection Fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MM 
Multiple Myeloma 


 
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MR 
Minor Response 
MRI 
Magnetic Resonance Imaging 
MUGA 
Multiple-gated Acquisition Scan 
NA 
Not Applicable 
NCI-CTC 
National Cancer Institute Common Toxicity Criteria 
NE 
Not  Evaluable 
NOS 
Not Otherwise Specified 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBSC-T 
Peripheral Blood Stem Cell Transplantation 
PD 
Progressive Disease 
PFS 
Progression-free Survival 
PIs 
Proteasome inhibitors 
PK/PD 
Pharmacokinetic/Pharmacodynamic 
PR 
Partial Response 
PS 
Performance Status 
q4wk 
Every Four Weeks 
QoL 
Quality of Life 
RBC 
Red Blood Cell 
RPSFT 
Rank Preserving Structural Failure Time 
RR 
Response Rate 
SAE(s) 
Serious Adverse Event(s) 
sCR 
Stringent Complete Response 
SCT 
Stem Cell Transplantation 
SD 
Stable Disease 
sFLC 
Serum Free Light Chains 
SOC 
System Organ Class 
TTP 
Time to Tumor Progression 
ULN 
Upper Limit of Normal 
UK 
Unknown 
VGPR 
Very Good Partial Response 
vs. 
versus 
WBC 
White Blood Cells 
WHO 
World Health Organization 
wk 
Week 
WPC 
Worst per Cycle 
WPP 
Worst per Patient 
 
Treatment Arm A: Plitidepsin in combination with dexamethasone 
Treatment Arm B: Dexamethasone alone 


 
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1 STUDY RATIONALE 
Clinical development of anticancer treatments usually requires combination of more than 
one active drug for improving efficacy, with each agent having different targets or 
mechanisms of action in order to prevent or delay the development of tumor resistance. 
Ideally, from the preclinical point of view, drugs may have shown either additive or 
synergistic antitumor activity. It is equally important to avoid agents with overlapping 
toxicity profiles for the development of successful novel combinations.  
Plitidepsin (Aplidin®) is a novel anticancer compound that has shown activity as a single 
agent in a recently completed phase II study in relapsed/refractory multiple myeloma (MM) 
patients. In a first stage, this trial explored the objective response to plitidepsin at 5 mg/m2 
as a 3-hour i.v. infusion administered every two weeks (q2wk), with 10% of 21 evaluable 
patients having a partial response (PR) and, additionally, 14% of patients having clinically 
meaningful disease stabilization (SD ≥ 3 months), with a median time to progression (TTP) 
of 2.3 months. Based on preclinical results that showed additive to synergistic effects of 
dexamethasone/plitidepsin combination, in a second stage of this phase II trial, patients 
who experienced suboptimal response (stable disease (SD) or progressive disease (PD)) 
after three to four plitidepsin infusions were allowed to receive oral dexamethasone 20 mg 
daily on days 1 through 4 q2wk (160 mg total monthly dose) added to plitidepsin. In this 
cohort of patients, 28% of the 18 evaluable patients had an objective response and TTP was 
significantly prolonged to 4.2 months. A similar overall safety profile was found, although 
with a slight increase in muscular events (mostly myalgia and reversible CPK increase) and 
a mild decrease in grade 3-4 transaminases increase. Of note, as much as two thirds of these 
patients had previously received bortezomib, thalidomide or lenalidomide and high-dose 
therapy (HDT) and peripheral blood stem cell transplantation (PBSC-T), whereas all 
patients had steroids as part of a prior therapy, with a median of four prior lines of systemic 
treatments. Although the trial design had limitations that precluded comparison between 
cohorts, both regimens were well tolerated and showed clinical activity in this heavily 
pretreated population for which limited clinical options were available. The addition of 
dexamethasone after three to four cycles of plitidepsin did not change dramatically the 
response (some disease stabilizations were found in patients who were progressing on 
plitidepsin alone, and one patient who was stable responded after dexamethasone addition), 
but responses appeared to be more durable and steeped. Therefore, it seems logical to add 
dexamethasone to plitidepsin upfront in order to optimize any synergistic effect that may 
occur clinically to achieve a better and longer disease control.  
This approach has been extensively used for most active agents in MM. In fact, 
corticosteroids have long been a central component of the treatment for MM, with the most 
commonly used regimens being high-dose dexamethasone alone, melphalan and 
prednisone, 
vincristine, 
doxorubicin, 
and 
dexamethasone 
(VAD), 
thalidomide, 
lenalidomide plus dexamethasone, and bortezomib plus dexamethasone. Moreover, 
dexamethasone can be used as monotherapy as well, the dose and regimen being typically 
around 20-40 mg on days 1-4, 9-12, and 17-20 of a 28- to 35-day cycle for a total of 240-
480 mg per cycle, although adverse reactions may be observed including principally 
endocrine axis suppression, serious infection derived from clinically relevant 
immunosuppression, and confusion or mood changes including acute psychosis. In fact, 


 
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dose of dexamethasone has recently raised some concerns particularly after the Eastern 
Cooperative Oncology Group (ECOG) 4A03 study. The ECOG, compared the 
administration of lower doses of dexamethasone (40 mg d 1, 8, 15, and 22 p.o. q4wk, for a 
total monthly dose of 160 mg) plus lenalidomide with high-dose dexamethasone at the 
usual dose (40 mg d 1-4, 9-12, and 17-20 p.o. q4wk, for a total monthly dose of 480 mg) 
plus the same lenalidomide regimen, and reported a significant improvement in overall 
survival with a better safety profile for the lower dose arm. A second study with 
lenalidomide plus dexamethasone in the relapsed/refractory setting showed that patients 
who had dose reductions of dexamethasone have shown a significantly higher overall 
response rate, including a higher complete response, progression-free survival (PFS) and 
improved median overall survival, when compared to those who received dexamethasone at 
the assigned dose, with adverse events rates comparable between both groups. Finally, and 
based on data from last available publications on dexamethasone and bortezomib 
combinations, dexamethasone administered at reduced doses (20 mg) the same day and the 
day after bortezomib infusion up to a total dose of 160 mg/cycle, has been associated with a 
better safety profile while maintaining the same level of activity. 
 
2 STUDY DESIGN 
This will be a prospective, multicenter, open-label, two-arm, 2:1 randomized phase III 
study of plitidepsin in combination with dexamethasone vs. dexamethasone alone in 
patients with relapsed/refractory MM. 
The primary study endpoint is progression free survival (PFS). 
 Treatment Arm A:  
o Dexamethasone: 40 mg orally on Day 1, 8, 15 and 22 every four weeks (q4wk) 
at least one hour before plitidepsin infusion. 
o Plitidepsin: 5 mg/m2 intravenously (i.v.) diluted to a total volume of 250 ml in 
0.9% saline via a central venous catheter (suggested) or diluted to a total volume 
of 500 ml in 0.9% saline via a peripheral line. Infusion will be performed 
through a pump device over three hours (fixed rate) on Day 1 and 15 q4wk. 
 
 Treatment Arm B:  
o Dexamethasone: 40 mg orally on Day 1, 8, 15 and 22 q4wk. 
Patients in the control arm (dexamethasone alone, Arm B) who have documented disease 
progression after a minimum of eight weeks from randomization should be offered to cross 
over to combination arm (plitidepsin + dexamethasone, Arm A) upon Sponsor agreement. 
Patients may be treated with additional cycles of plitidepsin and dexamethasone or 
dexamethasone alone, as long as no unacceptable toxicity and/or disease progression is 
documented. 
 


 
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3 OBJECTIVES AND ENDPOINTS 
3.1 
Primary objective 
 To compare the efficacy of plitidepsin in combination with dexamethasone vs. 
dexamethasone alone as measured by progression-free survival (PFS) in patients with 
relapsed/refractory multiple myeloma (MM). 
3.2 
Secondary objectives 
 To evaluate tumor response according to the international myeloma working group 
(IMWG) criteria. 
 To assess duration of response (DR) and overall survival (OS). 
 To assess efficacy in patients who undergo crossover from dexamethasone alone to 
plitidepsin and dexamethasone combination.  
 To characterize and compare the safety profile on both arms in this population. 
 To characterize the pharmacokinetics (PK) and pharmacokinetic/pharmacodynamic 
(PK/PD) relationship. 
 
3.3 
Endpoints 
Primary endpoint:  
  PFS, according to independent review committee (IRC) assessment, as per 
intention-to-treat (ITT) analysis. 
 
Secondary endpoints:  
 Objective RR. 
 Best overall response including rate of minor response (MR) or better (according to 
the IMWG criteria).  
 Response and progression-free survival to combination treatment in patients who 
crossed over after progression on dexamethasone alone. 
 Time-to-event endpoints: DR and OS.  
 Safety as per-protocol will be evaluated in each arm separately. Adverse events 
(AEs) will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE), version 4. 
 PK/PD parameters. 
 
4 PATIENTS EVALUABILITY CRITERIA 
The study population will include patients who have relapsed or refractory MM after all 
standard available therapy. To be enrolled in this study, the patients must meet all inclusion 
criteria and no exclusion criteria.  
4.1 
Analysis sets definitions 
“All Randomized Patients” analysis set is defined as all patients who are randomized to 
either treatment arm, independent of whether they received the study drug. 


 
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“All Treated Patients” analysis set is defined as all randomized patients who receive at least 
part of one dose or infusion of the investigational agents. 
“All Evaluable Patients” analysis set is defined as all randomized patients who have 
completed at least one full cycle of treatment or have received two incomplete cycles 
followed by at least one response assessment not less than eight weeks (± one week) after 
treatment onset. Patients withdrawn from the study due to early disease progression or 
treatment-related toxicity will be considered as “early progression” or “treatment failure”, 
respectively, even though they have not received a full cycle. Patients withdrawn due to 
significant clinical deterioration of unknown reason, hypersensitivity reactions, or refusal to 
continue on study for any reason or unrelated AEs without any disease assessments after 
the start of study treatment or those patients with a protocol deviation resulting in an 
impossibility of drawing conclusions about the efficacy of the study therapy will be 
considered not evaluable for efficacy and their response will be categorized as “non 
evaluable”. 
“All Responder Patients” analysis set is defined as all evaluable patients who have minor 
response or better as overall best response. 
“All Crossover Patients” analysis set is defined as all patients randomized to Arm B who 
have documented disease progression after their eighth week from randomization and cross 
over to Arm A. 
4.2 
Efficacy populations 
The “All Randomized Patients” analysis set will be used for the primary endpoint analysis 
of Progression-free survival (PFS) and the main efficacy analysis, as well as for all OS 
analyses. 
For futility analysis based on objective response rate, the “All Evaluable Patients” analysis 
set will be used. 
The “All Randomized Patients” and “All Evaluable Patients” datasets will be used for the 
final analysis of RR. 
The “All Responder Patients” dataset will be used for the duration of response (DR) 
calculation. 
The “All Crossover Patients” dataset will be used for the exploratory intrapatient 
comparison of response and PFS (before and after crossover). 
4.3 
Safety population 
The safety analysis is based on the “All Treated Patients” analysis set. 


 
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5 SAMPLE CONSIDERATIONS  
5.1 
Randomization 
 
Patients fulfilling all eligibility criteria will be stratified according to the Eastern 
Cooperative Oncology Group (ECOG) Performance Status (PS) score (0 and 1  vs. 2) and 
Durie-Salmon stage at diagnosis (I/II vs. III) and then randomized using a 2:1 
randomization procedure to Arm A (plitidepsin in combination with dexamethasone) or 
Arm B (dexamethasone alone). Randomization will be used to avoid bias in the assignment 
of patients to treatment, and to increase the likelihood that known and unknown patient 
attributes (e.g., demographics and baseline characteristics) are evenly balanced across 
treatment groups. 
Randomization of patients should occur as close in time as possible before administration 
of the first dose of study drug(s) and must occur within 7 days of the patient receiving the 
first dose of study treatment. The randomization number and treatment code will be 
assigned after phoning into the Interactive Voice Response System (IVRS). 
On the basis of the patient identification and stratum information, the IVRS will assign a 
treatment code, which will dictate the treatment assignment for that patient. 
Eligible patients 
III 
I-II 
Durie-Salmon Stage  
at diagnosis 
PS = 0-1
PS = 2
PS = 0-1
PS = 2 
Group 1 
Group 4 
Group 3 
Group 2 
Patients 
Arm A 
Arm A 
Arm B 
Arm A 
Arm A 
Arm B 
....... 
RANDOMIZATION
Patients 
Arm A 
Arm A 
Arm B 
Arm A 
Arm A 
Arm B 
....... 
Patients 
Arm A 
Arm A 
Arm B 
Arm A 
Arm A 
Arm B 
....... 
Patients 
Arm A 
Arm A 
Arm B 
Arm A 
Arm A 
Arm B 
....... 


 
12 of 164 
Patients will be assigned to each group by strata random list, so that a patient will have a 
two-thirds chance of getting Arm A (plitidepsin in combination with dexamethasone) and a 
one-third chance of getting Arm B (dexamethasone alone). The random permuted blocks 
method will be used; the size of the blocks in the randomization list will be fixed and not 
accessible to investigators. To select the blocks, a uniform (0, 1) variable with a random 
seed will be used. 
5.2 
Sample size 
The number of patients randomized in the trial has been calculated based on PFS estimates 
obtained from the previous phase II study (APL-B-014-03). 
1. Arm A (plitidepsin plus dexamethasone combination): approximately 167 patients. 
2. Arm B (dexamethasone single agent): approximately 83 patients. 
Approximately 210 progression or death events would be needed in this trial to detect a HR 
of 0.625 in favor of the combination arm (equivalent to an increase of 60% in PFS, i.e., 
from 10 to 16 weeks, 12 to 19.2 weeks, 16 to 25.6 weeks) with 90% power and 1-sided 
2.5% significance level. As a preliminary hypothesis, it is estimated that up to 250 
randomized patients will be needed to achieve the 210 events in 24-30 months. For the 
calculation of the number of events needed, the target HR to be detected is 0.625, with 90% 
power and 2.5% unilateral significance level. This is equivalent to a minimum 60% 
increase in PFS, which has been considered statistically and clinically significant by the 
Sponsor. 
An early futility analysis will be performed with the data collected when 40 patients in Arm 
A are evaluable for response. A response rate (IMWG criteria) of at least 30% (twelve or 
more responses by IRC review) will be taken as threshold for continuation of the study. A 
minimum response rate of 30% has been considered as clinically significant in this setting. 
This result will ensure that the lower limit of the exact binomial 95% Confidence Interval 
for the response rate will be greater than 15% (95% CI in case of 12 responses would be 
16.6% - 46.5%).  
 However, the efficacy and safety information from all randomized patients in both arms at 
that time will be used by the independent data monitoring committee (IDMC) to provide 
the Sponsor with a recommendation for further study conduct.  
The final PFS analysis will be performed when at least 210 progression or death events are 
observed. 
An interim analysis of OS will be performed concomitantly with the final PFS analysis. In 
addition, a final analysis of OS will be performed when 80% of death events 
(approximately 200 death events) have occurred or 24 months after the inclusion of the last 
patient, whichever occurs first. At the interim OS analyses, the significance level 
determined by the O’Brien-Fleming (1) boundary with overall 2.5% 1-sided significance 
level will be used. 
 


 
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6 STATISTICAL METHODOLOGY FOR EFFICACY 
6.1 
Planned analyses and definitions 
Protocol-specified analyses are foreseen at the time of the futility evaluation 
(approximately 40 patients in Arm A), final PFS analysis (main endpoint, approximately 
210 progression or death events) and follow-up evaluation of OS at 24 months after the 
inclusion of the last patient or 80% of death events (approximately 200 death events), 
whichever occurs first. Accrual will be on-hold while data for the futility analysis is being 
assessed, when 40 patients in Arm A fully evaluable for response have been accrued. 
6.1.1 Early futility analyses 
An early futility analysis will be performed when information from the first 40 patients in 
Arm A are evaluable for response. A response rate (IMWG criteria) of at least 30% (12 or 
more responses by IRC review) will be taken as threshold for continuation of the study. A 
minimum response rate of 30% has been considered as clinically significant in this setting. 
This result will ensure that the lower limit of the exact binomial 95% Confidence Interval 
for the response rate will be greater than 15% (95% CI in case of 12 responses would be 
16.6% - 46.5%).  
However, the efficacy and safety information from all randomized patients in both arms at 
that time will be used by the IDMC to provide the sponsor with a recommendation for the 
further study conduct. No claim for superiority in efficacy will be formulated in this interim 
analysis and no alpha-spending for the analysis of PFS is foreseen. 
6.1.2 Final analyses 
Primary endpoint.  
Efficacy will be assessed by comparing the PFS in each treatment arm.  
Progression-free survival (PFS) is defined as the time from the date of randomization to 
the date of documented progressive disease (PD) by IMWG criteria or death (regardless of 
the cause of death). If the patient receives further antitumor therapy before PD, PFS will be 
censored on the date of the last disease assessment prior to the administration of this 
antitumor therapy. If the patient is lost to follow-up for the assessment of progression, or 
has more than one missing follow-up between the date of last tumor assessment and the 
date of progression, death or further antitumor therapy, the PFS will be censored at the date 
of last valid tumor assessment before the missing evaluations. 
An external review committee blinded to treatment arm will assign the objective response 
and a progression or censoring date for each patient based on laboratory data, radiologic 
and bone marrow assessments when required and evaluation of all relevant clinical 
information; then, this information will be merged with the date of death from the death 
report forms and with further antitumor therapy data for the calculation of PFS. Patients 
with missing IRC evaluations will have their PFS censored at randomization date. 
The primary study analysis will be based on externally assessed PFS data in the “All 
Randomized Patients” population, defined as all patients randomized to either treatment 
arm. 


 
14 of 164 
By design, disease response will be assessed every four weeks symmetrically across 
treatment arms irrespectively of treatment delays or omissions. Disease assessments (e.g., 
serum or urine M-spike, sFLC) and evaluation of extent of disease will be done within two 
weeks before randomization and every four weeks thereafter in the absence of PD while on 
treatment. If disease progression has not occurred at treatment termination, then disease 
assessments should continue every four weeks until evidence of disease progression or 
other antitumor therapy, whichever occurs first, and then will be followed every three 
months for survival until death, or until the date of study termination, whichever occurs 
first.   
Study termination date is defined as the date in which 80% of death events occurred, 24 
months after the accrual of the last randomized patient, or IDMC recommendation 
(whichever occurs first). 
PFS and objective tumor response will be assessed according to IMWG criteria. 
Centralized laboratory reports and copies of computed tomography scans (CT-scans), 
magnetic resonance imaging (MRI) (in case of soft tissue plasmacytoma) and any other 
documented means to evaluate tumor response or progression should be available for IRC 
review. 
For patients within the “All Crossover Patients” dataset, the PFS is defined as the time from 
the day of the last disease assessment, before the first administration of the combination, to 
the date of documented progressive disease (PD) by IMWG criteria or death (regardless of 
the cause of death). The same censoring rules described above for PFS calculation will be 
considered. 
Secondary endpoints. 
Objective response is defined as having minor response (MR) or better as best overall 
response based on the IMWG criteria (See Appendix 5 of the clinical protocol). The 
objective response rate (RR) is calculated as the number of objective responders divided by 
the number of patients in the “All Evaluable Patients” and “All Randomized Patients” 
analysis sets.  
For patients within the “All Crossover Patients” dataset, the reference value for the 
calculation of response after crossover will be the protein value determined immediately 
before the administration of the combination of plitidepsin plus dexamethasone after 
crossover.  
The duration of objective response (DR) will be analyzed in all patients for whom at least a 
MR has been observed. Duration of response will be calculated from the date of first 
documentation of response (not the confirmation) to the date of disease progression or 
death with the same censoring rules as PFS. 
Overall survival (OS) is defined as the time from the date of randomization to the date of 
death or last contact.  
Symmetry of evaluations. 
Assessments must be done consistently in both treatment arms to ensure a symmetrical 
assessment of tumor response and progression. Every effort should be made to ensure that 


 
15 of 164 
these assessments are done on the required date, although a window of ±2 days will be 
allowed.  
Sensitivity analyses of PFS. 
The impact of potential asymmetry of assessments or missing tumor evaluations on the PFS 
analysis will be assessed by three imputation analyses as follows: 
In the key primary analysis of PFS, a patient’s event date is taken as the first date of 
documented disease progression based on IMWG criteria. This may potentially delay the 
time to actual disease progression, especially when there is a missing assessment prior to 
the documented disease progression.  
In the first sensitivity analysis, the midpoint of the last two assessment dates on or prior to 
the documented disease progression will be used to impute the actual date of the disease 
progression. For those patients who have disease progression in the first assessment, the 
midpoint of randomization date and the documented disease progression will be used. For 
those patients who die, the midpoint between last disease assessment without PD and the 
date of death will be used. For patients without documented disease progression, the PFS 
will be censored following the same rules than in the main analysis.  
In the second sensitivity analysis, the following imputation method will be used to make 
sure the disease assessments fall exactly ix4 weeks after randomization.  
 
Recorded Time Window 
(weeks from randomization) 
Imputed Time  
(weeks from randomization) 
[0 ; 6 [ 
4 
[6 ; 10 [ 
8 
[10 ; 14[ 
12 
… 
… 
[i x 4 – 2 ; i x 4 + 2[ 
i x 4 
In the third sensitivity analysis, disease progression will be assumed for the first missing 
scheduled assessment following the last evaluation without progression. 
A sensitivity analysis of PFS in the “All Evaluable Patients” population according to IRC 
and investigator assessment will be performed in order to present the results in the 
population described in the protocol. 
 
Due to the variability of the protein used for the disease assessment, a sensitivity analysis of 
PFS requiring the confirmation of the disease progression by IRC assessment will be 
performed. Patients who die within the timeframe expected for the confirmation of PD, will 
be considered as PD confirmed by death. Those patients without confirmation of PD with a 
second disease assessment due to crossover, further antitumor therapy, lost to follow-up or 
other reasons, will be censored. The same censoring rules described above for PFS 
calculation will be considered. 


 
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6.2 
Efficacy analysis methods 
6.2.1 Primary endpoint 
For the evaluation of the main primary endpoint (PFS), the ”All Randomized Patients” 
population, the data from the Independent Review Committee (IRC), and the unstratified 
log-rank test will be used to compare both treatment arms. The final PFS analysis will be 
performed when at least 210 progression or death events are observed. 
Cox regression will be used to calculate the risk reduction in PFS 
6.2.2 Supportive PFS analyses 
A stratified log-rank test for the main endpoint (PFS by IRC) will be performed as 
supportive analysis. 
A Cox regression stratifying by randomization factors and using only treatment as covariate 
will be used to calculate the risk reduction in PFS. 
PFS by investigator assessment in the ‘All Randomized Patients’ population will be 
analyzed according to the Kaplan-Meier method. The corresponding unstratified and 
stratified log-rank tests will be used to evaluate the differences between. Besides, Cox 
regressions will be performed to calculate the risk reduction in PFS, stratifying by 
randomization factors and using only treatment as covariate.  
The reasons for censoring, and the concordance between the IRC and investigator 
evaluation of PFS will be shown using counts and percentages.  
6.2.3 Secondary analyses 
Overall survival: 
Although the study is powered for the evaluation of the main endpoint PFS, two analyses of 
OS will be performed to ascertain if a trend in OS is observed in favor of the experimental 
arm. A first analysis of OS will be performed concomitantly with the final PFS analysis. In 
addition, a second analysis of OS will be performed when 80% death events (approximately 
200 death events) have occurred or 24 months after the inclusion of the last patient, 
whichever occurs first. At the interim OS analysis the significance level determined by the 
O’Brien-Fleming boundary with overall 2.5% 1-sided significance level will be used. 
OS analyses will be performed according to the Kaplan-Meier method and the unstratified 
and stratified log rank tests will be used in order to ascertain if clinically significant OS 
effect in favor of the experimental arm is observed.  
It is anticipated that an indeterminate number of patients in the control arm will switch 
treatment after progression to plitidepsin plus dexamethasone. This could cause the size of 
the effect on OS to be difficult to interpret. Consequently, if the OS results show to be 
substantially influenced by crossover, the Sponsor will study the estimated effect of 
crossover in a first sensitivity analysis excluding the patients who crossed over and a 
second analysis censoring survival at the time of crossover. Estimates of the unbiased effect 
in survival will be studied by means of, rank preserving structural failure time (RPSFT) 


 
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models for correcting for treatment changes (2), by the inverse probability of censoring 
weighting (IPCW) method (6) and by means of the two-stage method proposed by Latimer 
et al. (7) in order to try to control any bias caused by treatment crossover. 
The following time-dependent covariates will be included in the IPCW analysis: ECOG, 
Body Surface Area (BSA), m-protein value (serum/urine), number of adverse events 
grade≥3, bone marrow plasma cells, creatinine, LDH, hemoglobin and corrected serum 
calcium. Also, baseline covariates such us gender, age, MM type (i.e.: IgG, IgA, light chain 
myeloma, non-secretory), number of prior lines of anticancer treatment, status (relapsed vs. 
relapsed/refractory), refractory status to bortezomib, lenalidomide/thalidomide prior 
therapy, refractory status to last prior therapy, refractory status to IMiD therapy, refractory 
status to PIs therapy, genetic risk, previous SCT, time from diagnosis to randomization, 
time from last progression before randomization, International Staging System, Durie-
Salmon stage, presence of plasmacytomas, presence of lytic lesions, number of 
plasmacytomas, sum of the dimensions of plamacytomas,  will be included. 
The reasons for censoring of OS will be shown using counts and percentages.  
An analysis will be carried out in the subpopulation of patients without crossover or 
subsequent therapy in order to investigate the isolated effect of study treatments in survival 
in this subpopulation. It will be also carried out in the subpopulation of patients without 
crossover or subsequent therapy and with event in the primary analysis of PFS by IRC. 
 
Response rate: 
Binomial estimates with exact 95% CIs will be calculated for the analysis of response rate. 
Randomized patients not evaluable for response will be excluded from the denominator 
exclusively for the futility analysis, but will be included in all the final efficacy analyses. A 
supportive analysis will be also done in the “All Evaluable Patients” population.  
The magnitude of response, in patients with secretory MM, will be described by waterfall 
plots showing the best M-spike reduction from baseline. 
A supportive analysis of response rate will be performed taking into account PR or better as 
best overall response based on the IMWG criteria. 
 
Duration of response: 
Duration of objective response will be analyzed according to the Kaplan-Meier method and 
compared between treatment groups using the log-rank test. 
DR requiring confirmation of PD for determination of PFS will be analyzed according to 
the Kaplan-Meier method and compared between treatment groups using the log-rank test. 
DR for patients who have PR or better as best overall response based on the IMWG criteria 
will be calculated as a supportive analysis. 
Time to response: 
Time to response will be analyzed according to the Kaplan-Meier method and compared 
between treatment groups using the log-rank test. 


 
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Time to response for patients who have PR or better as best overall response based on the 
IMWG criteria will be also calculated as a supportive analysis. 
 
Analysis of crossover: 
Descriptive frequency tables with the number of patients who switch from Arm B to Arm A 
after disease progression will be calculated. 
Exploratory intrapatient comparison of response and PFS (before and after crossover) will 
be performed for patients who switch from Arm B to Arm A after disease progression. 
The patients within the “All Crossover Patients” dataset will be listed with the cycle when 
the crossover occurs, and the response and PFS before and after crossover. 
A comparison of the baseline characteristics in patients with Crossover vs. No crossover 
will be done to rule out that patients with crossover can have a better prognosis than 
patients without crossover. For two-stage method a logistic stepwise regression and the 
comparison of PFS between patients with crossover versus patients with no crossover is 
performed to check the assumption of no ‘unmeasured confounders’. Post-progression 
survival data is adjusted by a Weibull parametric accelerated failure time model. 
A listing of patients with crossover will be provided in order to confirm if PD was seen 
before crossover and if this PD was confirmed. 
Statistics of the time (in months) from study initiation to crossover will also be included. 
 
Analysis of prognostic factors, subgroup analysis and multivariate analyses: 
Univariate evaluation of the influence of different prognostic factors on the main efficacy 
endpoints will be performed by using the following covariates: Gender, age, baseline 
ECOG, Body Surface Area (BSA), MM type (i.e.: IgG, IgA, light chain myeloma, non-
secretory), number of prior lines of anticancer treatment, status (relapsed vs. 
relapsed/refractory) refractory status to bortezomib, lenalidomide/thalidomide prior 
therapy, refractory status to last prior therapy, refractory status to IMiD therapy, refractory 
status to PIs therapy, genetic risk, previous SCT, time from diagnosis to randomization, 
time from last progression before randomization, International Staging System, Durie-
Salmon stage, bone marrow plasma cells, bone lytic lesions (Y/N), plasmacytomas at 
baseline (Y/N), number of lesions at baseline, sum of the dimensions of plamacytomas, 
creatinine (≥2 mg/dl vs. < 2 mg/dl), LDH, hemoglobin and corrected serum calcium (>11.5 
mg/100ml vs. ≤11.5 mg/100ml). 
Exploratory subgroup analyses will be performed by means of logistic regression, Kaplan-
Meier analysis and Cox regression. The different subgroup analyses will be summarized by 
means of Forest plots. 
Cox proportional hazard models for PFS and OS and logistic regression models for RR will 
include the prognostic factors specified for the univariate analysis. More relevant and 
explanatory covariates from the univariate analysis will be included in the multivariate 
analyses (p-value < 0.10). Prognostic factors with more than 10% missing values will be 
excluded in the multivariate analyses.  


 
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The analyses above mentioned will be also performed for the sensitivity analysis of PFS 
with confirmation of PD by IRC. 
In addition, and in order to check if there are differences in the main efficacy endpoint 
between different continents/geographical areas, multivariate analyses of PFS by IRC, 
adding region as a covariate, will be performed. The variable “region” will be created with 
four categories (Europe, Asia, Oceania, and USA) and then three Cox regressions will be 
performed.  
1) PFS by IRC with arm, region and interaction term.  
2) PFS by IRC with arm and region as main effects. 
3) Full model selected in the multivariate analysis of PFS by IRC, including region as 
variable. 
 
Symmetry of evaluations. 
Wilcoxon test will be used to compare time to disease assessments between treatment arms. 
Moreover, Kaplan-Meier curves of the time from randomization to first and second disease 
assessment will be plotted. 
An analysis of the median time window between the first documentation of PD and PD 
confirmation in a second assessment will be done to rule out that confirmation of PD could 
have been advanced or delayed in any of the treatment groups. 
 
Sensitivity analyses of PFS. 
For the three sensitivity analyses using imputation methods for the date of progression, 
similar unstratified log-rank test as for the key primary PFS analysis will be performed, 
based on the imputed data sets. 
Interval censoring methods will be used for the comparison of PFS in both arms by IRC 
and investigator assessment. An iterative algorithm developed by Turnbull(3) will be used 
to compute a non-parametric maximum likelihood estimate of the cumulative distribution 
function for the data. After that, the log-rank score of permutational test will be calculated 
and the normalized test statistic and associated p-value will be presented to test the 
difference between the two treatment groups. 
 
7 STATISTICAL METHODOLOGY FOR SAFETY 
Patients are evaluable for general safety if they received any study treatment. Safety will be 
evaluated in each arm separately according to the actual treatment received. 
7.1 
Toxicity and adverse events  
All the adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). 
The toxicity evaluation will be coded with the National Cancer Institute-Common Toxicity 
Criteria (NCI-CTC), version 4. 


 
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As far as all the toxicities are concerned, the NCI-CTC grade will be used wherever an 
NCI-CTC grading exists. Otherwise, the severity will be noted. As a convention, the term 
«Grade» will always be used. Toxicities will be described according to the worst NCI-CTC 
grade or, for toxicities which do not form the subject of NCI-CTC classification, according 
to the worst severity. 
Summary of overall adverse events will be done by body system and preferred term, by 
severity (worst toxicity grade), by relationship to the study drug/s, and by AE outcome. 
Tables will be sorted by body system/preferred term and by the highest incidence. 
A frequency table will be made for the AEs leading to cycle delay, dose reduction, skipped 
dose, or withdrawal of study medication. Adverse events with outcome of death will also be 
presented by relationship to the study drugs. 
7.2 
Clinical laboratory evaluation 
Laboratory results will be classified according to the NCI-CTC version 4.  
For hematology values: absolute neutrophil count, lymphocyte count, WBC count, platelet 
count and hemoglobin worst grade per patient and per cycle will be displayed.  
Overall cross tabulation will be presented for the worst grade during treatment versus the 
baseline toxicity grading of anemia, lymphopenia, leukopenia, neutropenia and 
thrombocytopenia. 
The worst grade per patient during treatment and per cycle will be also calculated for the 
biochemical tests: ALT, AST, Total bilirubin, AP, CPK, creatinine, calcium, potassium, 
sodium, glucose and albumin. 
Time and duration of AST and ALT increases in cycles with grade 3-4 abnormality will be 
tabulated. 
Overall cross tabulation will be presented for the worst grade during treatment versus the 
baseline toxicity grading of AST and ALT increase. 
If appropriate, the laboratory abnormalities before and after crossover in patients who 
switch arm after progression will be compared descriptively.  
7.3 
Vital signs, physical examination, left ventricular ejection fraction (LVEF) and 
electrocardiogram findings 
Tabulation will be made summarizing the performance status, body weight, LVEF and 
electrocardiogram abnormalities at baseline and during the treatment for each patient. 
7.4 
Deaths and other Serious Adverse Events 
Deaths and other Serious Adverse Events will be tabulated. 
 
8 OTHER ANALYSES 
Non-continuous variables will be described in frequency tables using counts and 
percentages. Continuous variables will be described by median, minimum and maximum. 


 
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8.1 
Baseline and demographic data 
Baseline data such as demographics, multiple myeloma history, prior therapy, prior relevant 
history, signs and symptoms, electrocardiogram, LVEF, protein measurements, laboratory 
values and concomitant medication (ATC-WHO coded) will be described following 
standard tables detailed in Appendix I. When two or more assessments have been done for 
the same parameter, the last assessment before the first drug administration will be taken 
into account for the analysis. 
8.2 
Treatment administration 
Total cumulative dose, time on treatment, dose intensity and relative dose intensity, cycle 
delay, and dose reductions will be described following standard tables detailed in Appendix 
I. 
Total cumulative dose by drug, expressed in mg/m² for plitidepsin, or in mg of 
dexamethasone, is the sum of all the product doses from the first cycle until last cycle 
including the dose received in last cycle. 
Patients will be considered to be on-treatment for the duration of their treatment and 30 
days following the last treatment dose. Those patients in the control arm (Arm B) who 
crossed over to the combination arm (Arm A) after disease progression will be considered 
on-treatment for the duration of their whole treatment (dexamethasone alone + 
dexamethasone in combination with plitidepsin) and during the first 30 days following the 
last treatment dose. If the patient starts any new antitumor therapy outside this clinical trial 
or dies within 30 days of last treatment dose, the date of administration of this new therapy 
or the date of death will be considered the date of treatment discontinuation. 
However, as a convention, for dose intensity calculation purposes, the duration of the last 
cycle is considered to be 28 days. If the patient starts any new antitumor therapy outside 
this clinical trial or dies within 28 days of last cycle initiation this will be taken into account 
for the calculation of the duration of the last cycle. 
Intended dose intensity is the planned dose per cycle divided by the planned number of 
weeks by cycle (2.5mg/m2/wk for plitidepsin, 40mg/wk for dexamethasone). 
Absolute dose intensity is the actual cumulative dose divided by the number of weeks of 
treatment. Relative dose intensity (%) is the ratio of absolute dose intensity divided by the 
intended dose intensity. 
The item «Infusion delayed/ omitted: yes/no» in the case report form (CRF) will be used to 
calculate the delay (on day 1 infusion) or skipped infusions (on day 15 infusion).  For 
cycles considered as delayed by the investigator, the delay will be calculated as: 
Delay:  Date of current drug administration – Date of previous drug administration – 28.  
The first infusion of the first cycle will be excluded from all cycle delay and cycle 
modification calculations. 
8.3 
Subsequent therapy 
A table summarizing the subsequent therapies received after treatment discontinuation will 
be shown.  


 
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Time to first subsequent therapy or death will be analyzed as a measure of the time from 
randomization to treatment failure that leads to the need of a further treatment regimen 
(regardless the method of PD detection or the components of the PD). 
8.4 
Protocol deviations 
Analysis of inclusion/exclusion criteria deviations, retreatment restrictions, used 
concomitant medication and clinically relevant discontinuations will be done as described 
in Appendix I.   
8.5 
Pharmacokinetic analyses 
Methods for pharmacokinetics will be described in a separate document. 
8.6 
Imputation of incomplete dates 
The dates of certain historical or current clinical activities are key component for statistical 
analysis. Incomplete date appears when day, month or year is/are missing, and it could be 
imputed so that variables like time to and duration of certain event can be calculated. If 
none of day, month and year is available, then the date is missing, no imputation is 
necessary. 
Before randomization 
If day of a date is unknown then the imputed day will be 15, if the month is also unknown 
then the imputed date will be July 1st. This assumption will be valid if the imputed date is 
earlier than the randomization date; otherwise the imputed date will be the first day of the 
randomization month if only the day is missing, or the 15th day of the month prior to the 
randomization date (i.e. 15/Month of randomization date - 1/Year) if day and month are 
missing. 
After end of treatment 
To ensure the most conservative approach for the main time-to-event variables (i.e. PFS 
and OS) that can be affected by missing values the following rules will be implemented: if 
the day of a date is unknown then the imputed day will be 1. This assumption will be valid 
if the imputed date occurs later than the last drug administration date; otherwise the 
imputed date will be the last drug administration date plus 1 day. 
8.7 
Subgroup analyses 
Analysis of efficacy profile by age in order to characterize a potential benefit of the drug in 
elderly population is planned. Exploratory efficacy subgroup analyses according to genetic 
risk, the refractory status to prior therapies such as bortezomib, lenalidomide/thalidomide, 
last prior therapy, IMiD therapy and PIs are planned. No other specific subgroup analysis is 
planned for efficacy. However, the influence of the study strata and other prognostic factors 
on the efficacy endpoints will be studied in the multivariate analysis. 
No formal statistical allowance will be made for multiple subgroup investigations, but any 
apparent subgroup interactions will be interpreted appropriately in a cautious way. 
Analysis of safety profile by age, gender and body mass index (BMI) will be provided as 
specified in section 12.7. 


 
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Handling of multicenter data 
No randomization or stratification by center will be performed as the sample size by center 
is expected to be low. Further “by center” analyses may be performed upon request if 
appropriate. 
Handling of multiple comparisons 
Single comparison of PFS between arm A and B will be made for the primary endpoint. No 
adjustment, except for the sequential OS analyses described in section 5.1, will be made for 
multiple comparisons in secondary analyses. 
8.8 
Methods for handling missing data 
Missing values will be tabulated with their frequency but they will not be included in the 
calculation of percentages. 
8.9 
Interim and group sequential analyses 
See details of the interim analyses and stopping rules in sections 5.1 and 6.1. 
8.10 Data analysis for the Independent Data Monitoring Committee 
These analyses will be specified in the independent data monitoring committee charter, in a 
separate document. 
8.11 Identification of fixed or random effects models 
Not applicable 
8.12 Analyses of the effects of plitidepsin on the QTc interval 
A substudy will be conducted to assess the potential effects of plitidepsin on the QTc 
interval of patients with relapsed/refractory multiple myeloma enrolled in clinical trial 
APL-C-001-09. These analyses will be specified in a separate document. 
8.13 Analyses of performance status as an index of quality of life 
Since patient reported outcome questionnaires have not been collected in this study, 
indirect measures of improvement like time to first performance status deterioration will be 
analyzed according to the Kaplan-Meier method.  
 
9 STATISTICAL SOFTWARE 
EAST v5.2 has been used to calculate sample size. SAS v9 (4) will be used for all statistical 
analysis outputs. Stata v14 or greater will be used for the analysis of crossover by RPSFT 
method. 
 
APPENDIX I 
All tables will be created at the time of each analysis planned in the protocol if applicable, 
and at study end. 


 
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10 Study Patients 
10.1 Patient disposition  
Main characteristics concerning inclusion in the study, patient crossover from arm B to arm 
A, withdrawal from the study and protocol deviations will be displayed in this section. 
 
Table 10.1.1 Number of patients included, treated and evaluable for the main endpoint. 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
All Randomized Patients 
 
 
 
 
 
 
Eligible patients* 
 
 
 
 
 
 
All Treated Patients 
 
 
 
 
 
 
All Evaluable Patients 
 
 
 
 
 
 
All Crossover Patients 
NA 
NA 
 
 
 
 
(*)Patients meeting all inclusion criteria and not meeting any exclusion criteria. 
 
Listing 10.1.2 Patients randomly assigned to one treatment arm and treated in the other one 
by mistake 
Patient id. 
Assigned arm by randomization 
Treatment received 
… 
 
 
 
Listing 10.1.2a Patients assigned to the wrong stratum by mistake 
Patient id. 
Assigned stratum by randomization 
Actual stratification values 
… 
 
 
 
Listing 10.1.2b Comparison of Durie-Salmon at IVRS and baseline value 
Patient id. 
Durie-Salmon value at IVRS 
Actual Durie-Salmon value 
… 
 
 
 
Listing 10.1.2c Comparison of ECOG PS at IVRS and baseline value 
Patient id. 
PS ECOG value at screening  
PS ECOG value at IVRS 
Last ECOG before start of 
study treatment 
… 
 
 
 
 
 
 
 


 
25 of 164 
Table 10.1.3 Patients accrual by institution 
 
 
 
Arm A 
Arm B 
Total 
No. included 
Country 1 
Institution 1 
 
 
 
… 
 
 
 
Total 
 
 
 
… 
Institution 1 
 
 
 
… 
 
 
 
Total 
 
 
 
Total 
Institution 1 
 
 
 
… 
 
 
 
Total 
 
 
 
No. treated 
Country 1 
Institution 1 
 
 
 
… 
 
 
 
Total 
 
 
 
… 
Institution 1 
 
 
 
… 
 
 
 
Total 
 
 
 
Total 
Institution 1 
 
 
 
… 
 
 
 
Total 
 
 
 
Table 10.1.4 Study dates 
 
Arm A 
Arm B 
Total 
Date of first randomization 
 
 
 
Date of first dose of the first patient 
 
 
 
Date of last randomization 
 
 
 
Date of first dose of the last patient 
 
 
 
Date of last dose 
 
 
 
Date of last follow-up* 
 
 
 
(*) Last follow-up or exam or procedure before clinical cut-off or study closure 
Table 10.1.5 Last cycle in Arm A before crossover 
Last cycle before crossover 
Crossover patients 
N 
% 
Cycle 1 
X 
XX.X 
Cycle 2 
 
 
… 
 
 
Total 
 
 
 
10.2 Reasons for treatment discontinuation 
 
Table 10.2.1 Study discontinuation 
Reason 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
End of study (study stopped) 
 
 
 
 
 
 
Patient refusal 
 
 
 
 
 
 
Never treated* 
 
 
 
 
 
 
Death (due to toxicity)** 
 
 
 
 
 
 
Death (non-treatment-related)*** 
 
 
 
 
 
 
Investigator decision 
 
 
 
 
 
 
Other **** 
 
 
 
 
 
 
Lost to follow-up 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
(*) See Listing 10.2.3  (**) Cause of death = Toxicity (study drug related) (***) Cause of death = Malignant disease or 
Other (****) See Listing 10.2.2  


 
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Listing 10.2.2 Study discontinuation due to other reason 
Arm 
Patient id. 
Specify 
… 
 
 
Listing 10.2.3 Patients randomized but not treated 
Arm 
Patient id. 
Off-study reason 
… 
 
 
 
Table 10.2.4 Treatment discontinuation 
Reason 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
Progressive disease 
 
 
 
 
 
 
Toxicity  
 
 
 
 
 
 
Patient refusal 
 
 
 
 
 
 
Investigator decision 
 
 
 
 
 
 
Death (due to toxicity)* 
 
 
 
 
 
 
Death (non-treatment-related)** 
 
 
 
 
 
 
Other *** 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
(*) Cause of death = Toxicity (study drug related) (**) Cause of death = Malignant disease or Other (***) Specify (see 
listing 10.2.6) 
 
Table 10.2.5 Reasons for treatment discontinuation by cycles received 
Reason 
Arm A 
Arm B 
Total 
Last cycle 
Last cycle 
Last cycle 
1 2 …**** 
Total 
1 
2 
… 
Total 
1 
2 
… 
Total 
Progressive disease 
 
 
 
 
 
 
 
 
 
 
 
 
Toxicity 
 
 
 
 
 
 
 
 
 
 
 
 
Patient refusal 
 
 
 
 
 
 
 
 
 
 
 
 
Investigator decision 
 
 
 
 
 
 
 
 
 
 
 
 
Death (due to toxicity)* 
 
 
 
 
 
 
 
 
 
 
 
 
Death (non-treatment-related)** 
 
 
 
 
 
 
 
 
 
 
 
 
Other *** 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
(*) Cause of death = Toxicity (study drug related) (**) Cause of death = Malignant disease or Other (***) Specify (see 
listing 10.2.6) (****) Cycles > % will be grouped as 6-10, 10-20 and >20. 
 
When reason for discontinuation is toxicity or study treatment-related death, identify 
patients and describe them in depth here. 
Listing 10.2.6 Reasons for treatment discontinuation other than progressive disease. 
Arm 
Patient id. 
Reason 
Last cycle 
Comments  
… 
 
 
 
 
 
Listing 10.2.7 Treatment discontinuation due to AEs 
Arm 
Patient 
id. 
Cycle 
Preferred  
term code 
Adverse 
event 
reported 
(verbatim) 
Grade  
Relationship  
Onset 
date 
Resolved 
date 
Significant 
consequences 
… 
 
 
  
 
 
 
 
 
Action taken: study drug withdrawal 
 
 


 
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10.3 Protocol deviations  
 
Listing 10.3.1 Protocol deviations 
Arm 
Patient id. 
Deviation type 
Description 
… 
 
 
 
 
 
 


 
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11 Efficacy Evaluation 
11.1 Demographic and other baseline characteristics 
11.1.1 Patient characteristics at baseline 
Table 11.1.1.1 Baseline characteristics: Gender 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
Male 
X 
XX.X 
X 
XX.X 
X 
XX.X 
Female  
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Table 11.1.1.2 Baseline characteristics: Age at treatment registration 
 
 
N 
Median 
Min 
Max 
Age (years) 
Arm A 
 
 
 
 
Arm B 
 
 
 
 
Total 
 
 
 
 
Table 11.1.1.3 Baseline characteristics: Age grouped 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
18-64 
X 
XX.X 
X 
XX.X 
X 
XX.X 
65-74 
 
 
 
 
 
 
75-84 
 
 
 
 
 
 
≥85 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Table 11.1.1.4 Baseline characteristics comparison by treatment arm 
Variable** 
Value 
N 
Arm A 
Arm B 
p-value* 
Sex 
F 
XXX 
XX (XX.X%) 
XX (XX.X%) 
X.XXXX 
M 
XXX 
XX (XX.X%) 
XX (XX.X%) 
 
Age 
Median(range) XXX 
XX.X (XX-XX) 
XX.X (XX-XX) 
X.XXXX 
… 
 
 
 
 
 
(*)Fisher’s exact test (categorical variables); Mann-Whitney-Wilcoxon (continuous variables) 
(**)Sex, age, region, PS (ECOG), BSA, Durie Salmon stage, International Staging System, Secretory/Non-secretory, MM 
type, time from diagnosis, time from last PD, number of prior lines, status to prior therapy, status to prior bortezomib 
therapy, status to prior thalidomide/lenalidomide therapy, status to prior IMiD therapy, status to prior PIs therapy, stem 
cell transplantation, plasma cells, hemoglobin, creatinine, calcium, genetic risk, lytic lesions and plasmacytomas. 
 
11.1.2 Disease at diagnosis, time from diagnosis and current disease  
Table 11.1.2.1 Time from diagnosis to randomization 
 
 
N 
Median 
Min 
Max 
Time from diagnosis to 
randomization (months) 
Arm A 
 
 
 
 
Arm B 
 
 
 
 
Total 
 
 
 
 
 
 
 


 
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Table 11.1.2.2 Time from last PD/relapse  
 
 
N 
Median 
Min 
Max 
Time from last PD* to first infusion 
(weeks) 
Arm A 
 
 
 
 
Arm B 
 
 
 
 
Total 
 
 
 
 
(*)PD date will be taken from MM History form. If the day or the month or the full date is missing, further information 
will be taken from Prior anticancer therapy form. After that, if the date is still incomplete, imputation rules described in 
section 8.6 will be used.      
Table 11.1.2.3 Multiple Myeloma type at diagnosis 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
Secretory 
X 
XX.X 
X 
XX.X 
X 
XX.X 
   G 
 
 
 
 
 
 
   A 
 
 
 
 
 
 
   M 
 
 
 
 
 
 
   Light chain 
 
 
 
 
 
 
   Other 
 
 
 
 
 
 
Non-secretory 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Table 11.1.2.4 Durie-Salmon stage at diagnosis. 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
I-A 
X 
XX.X 
X 
XX.X 
X 
XX.X 
I-B 
 
 
 
 
 
 
II-A 
 
 
 
 
 
 
... 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Table 11.1.2.5 International Staging System stage at diagnosis. 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
I 
X 
XX.X 
X 
XX.X 
X 
XX.X 
II 
 
 
 
 
 
 
III 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Listing 11.1.2.6 Cytogenetic, karyotype and FISH at first diagnosis.  
Arm 
Patient id. 
Cytogenetic at first 
diagnosis 
Karyotype at first 
diagnosis 
FISH at first diagnosis 
… 
 
 
 
 
Table 11.1.2.7 Genetic risks at diagnosis. 
Genetic Risks* 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
High risk 
X 
XX.X 
X 
XX.X 
X 
XX.X 
Intermediate risk 
 
 
 
 
 
 
Good prognostic 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
(*)Patients will be classified in “high risk”, “intermediate risk” or “good prognosis” according to their genetic results 
(cytogenetic or FISH) at by clinical review. Further details in section 11.3.7. 
 
 


 
30 of 164 
Table 11.1.2.8 Baseline characteristics: MM protein measurements (Serum*) 
 
Arm A 
Arm B 
Total 
N Median 
Min 
Max 
N 
Median Min 
Max 
N 
Median 
Min 
Max 
Total Ig G (mg/dL) 
X 
X.X 
X.X 
X.X 
X 
X.X 
X.X 
X.X 
X 
X.X 
X.X 
X.X 
Total Ig A (mg/dL) 
 
 
 
 
 
 
 
 
 
 
 
 
Total Ig M (mg/dL) 
 
 
 
 
 
 
 
 
 
 
 
 
* Based on central lab assessments. 
Table 11.1.2.9 Baseline characteristics: MM protein measurements (Serum) 
 
Arm A 
Arm B 
Total 
N 
Median 
Min 
Max 
N 
Median Min 
Max 
N 
Median 
Min 
Max 
M-
spike(SPE)(g/dL) 
X 
X.X 
X.X 
X.X 
X 
X.X 
X.X X.X 
X 
X.X 
X.X 
X.X 
Kappa (mg/L) 
 
 
 
 
 
 
 
 
 
 
 
 
Lambda (mg/L) 
 
 
 
 
 
 
 
 
 
 
 
 
sFLC ratio 
 
 
 
 
 
 
 
 
 
 
 
 
* Based on central lab assessments. 
Listing 11.1.2.10 Baseline characteristics: MM protein type  
Arm 
Patient id. 
Serum / Urine 
Type 
… 
 
 
 
* Based on central lab assessments. 
Table 11.1.2.11 Baseline characteristics: MM protein measurements (24h Urine analysis) 
 
Arm A 
Arm B 
Total 
N 
Median 
Min 
Max 
N 
Median 
Min 
Max 
N 
Median 
Min 
Max 
Protein -24h urine 
(mg/24 h) 
X 
X.X 
X.X 
X.X 
X 
X.X 
X.X 
X.X 
X 
X.X 
X.X 
X.X 
Urine M-spike 
(UPE) (Bence 
Jones) (g/24 hrs) 
 
 
 
 
 
 
 
 
 
 
 
 
Urine M-protein 
(Bence Jones) 
(mg/L) 
 
 
 
 
 
 
 
 
 
 
 
 
Kappa (mg/L) 
 
 
 
 
 
 
 
 
 
 
 
 
Lambda (mg/L) 
 
 
 
 
 
 
 
 
 
 
 
 
* Based on central lab assessments. 
Table 11.1.2.12 Baseline characteristics: Immunofixation urine 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
Positive 
X 
XX.X 
X 
XX.X 
X 
XX.X 
Negative 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
* Based on central lab assessments. 
Table 11.1.2.13 Baseline characteristics: Non-secretory myeloma 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
Yes 
X 
XX.X 
X 
XX.X 
X 
XX.X 
No 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
* Based on central lab assessments. 
 
 


 
31 of 164 
Table 11.1.2.14 Baseline characteristics: Percentage of bone marrow plasma cells 
 
Arm A 
Arm B 
Total 
N 
Median 
Min 
Max 
N 
Median 
Min 
Max 
N 
Median 
Min 
Max 
Plasma cells 
in smears 
(%) 
X 
X.X 
X.X 
X.X 
X 
X.X 
X.X 
X.X 
X 
X.X 
X.X 
X.X 
Plasma cells 
in biopsy 
(%) 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 11.1.2.15 Baseline characteristics: Bone marrow assessment  
Arm 
Patient 
id. 
Date 
Method* 
%Plasma 
cells in 
smears 
%Plasma 
cells in 
biopsy 
Cytogenetic 
Karyotype 
FISH 
… 
 
 
 
 
 
 
 
 
(*)Aspiration/Biopsy 
Table 11.1.2.16 Genetic risks at baseline. 
Genetic Risks* 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
High risk 
X 
XX.X 
X 
XX.X 
X 
XX.X 
Intermediate risk 
 
 
 
 
 
 
Good prognostic 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
(*)Patients will be classified in “high risk”, “intermediate risk” or “good prognosis” according to their genetic results 
(cytogenetic or FISH) at by clinical review. Further details in section 11.3.7. 
 
 
11.1.3 Skeletal sites involved at baseline 
Listing 11.1.3.1 Baseline characteristics: Skeletal/soft tissue evaluation 
Arm 
Patient 
id. 
Date of 
assessment 
No lesion / 
NA 
Type 
Anatomic 
localization 
Method 
Measurements 
for soft tissue 
lesions (mm) 
Diffuse 
osteoporosis 
… 
 
 
 
 
 
 
XXX x XXX  
Table 11.1.3.2 Baseline characteristics: Skeletal sites involved at baseline 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
Yes 
X 
XX.X 
X 
XX.X 
X 
XX.X 
    Plasmacytoma 
 
 
 
 
 
 
    Bone (Lytic lesion) 
 
 
 
 
 
 
No 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 


 
32 of 164 
Table 11.1.3.3 Baseline characteristics: Number of lesions 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
 Plasmacytoma 
X 
XX.X 
X 
XX.X 
X 
XX.X 
     1 
 
 
 
 
 
 
     2 
 
 
 
 
 
 
… 
 
 
 
 
 
 
Bone (Lytic lesion) 
 
 
 
 
 
 
     1 
 
 
 
 
 
 
     2 
 
 
 
 
 
 
… 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Table 11.1.3.4 Baseline characteristics: Sum of plasmacytomas dimensions 
 
 
N 
Median 
Min 
Max 
Sum of plamacytomas product of 
diameters 
Arm A 
 
 
 
 
Arm B 
 
 
 
 
Total 
 
 
 
 
 
11.1.4 Prior anticancer therapy 
Listing 11.1.4.1 Patients with prior radiotherapy 
Arm 
Patient id. 
Site (Anatomic) 
Total dose (Gy) 
First dose 
Last dose 
… 
 
 
 
 
 
Table 11.1.4.2 Number of patients with prior radiotherapy 
Prior radiotherapy 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
Yes 
X 
XX.X 
X 
XX.X 
X 
XX.X 
No 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Table 11.1.4.3 Number of lines of prior systemic therapy 
No. lines 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
1 
X 
XX.X 
X 
XX.X 
X 
XX.X 
2 
 
 
 
 
 
 
... 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Median (Range) 
 
 
 
 
 
 
Table 11.1.4.4 Prior anticancer agents 
Antineoplastic and 
Immunomodulating agents (ATC-
class.) 
Arm A 
Arm B 
Total 
 
N 
% 
N 
% 
N 
% 
Antineoplastic Agents (L01) 
X 
XX.X 
X 
XX.X 
X 
XX.X 
…. 
 
 
 
 
 
 
…. 
 
 
 
 
 
 
 
 
 


 
33 of 164 
Table 11.1.4.5 Status regarding response to prior therapy 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
Relapsed* 
X 
XX.X 
X 
XX.X 
X 
XX.X 
Relapsed/Refractory** 
 
 
 
 
 
 
(*)Relapsed myeloma: at least one prior regimen, and not meeting criteria for relapsed and refractory myeloma. 
(**) Relapsed/refractory myeloma: non responder or relapse of disease while on salvage therapy, or progression within 60 
days of most recent therapy.  
Table 11.1.4.6 Status regarding response to bortezomib therapy 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
Relapsed* 
X 
XX.X 
X 
XX.X 
X 
XX.X 
Relapsed/Refractory** 
 
 
 
 
 
 
Refractory*** 
 
 
 
 
 
 
(*)Relapsed myeloma: at least one prior bortezomib regimen, and not meeting criteria for relapsed and refractory / 
refractory myeloma. 
(**) Relapsed/refractory myeloma: relapse of disease while on salvage therapy, or progression within 60 days of last 
bortezomib therapy.  
(***)Refractory myeloma: non responder to last bortezomib therapy.  
Table 11.1.4.7 Status regarding response to lenalidomide therapy 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
Relapsed* 
X 
XX.X 
X 
XX.X 
X 
XX.X 
Relapsed/Refractory** 
 
 
 
 
 
 
Refractory*** 
 
 
 
 
 
 
(*)Relapsed myeloma: at least one prior lenalidomide regimen, and not meeting criteria for relapsed and refractory / 
refractory myeloma. 
(**) Relapsed/refractory myeloma:  relapse of disease while on salvage therapy, or progression within 60 days of last 
lenalidomide therapy.  
(***)Refractory myeloma: non responder to last lenalidomide therapy.  
Table 11.1.4.8 Status regarding response to thalidomide therapy 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
Relapsed* 
X 
XX.X 
X 
XX.X 
X 
XX.X 
Relapsed/Refractory** 
 
 
 
 
 
 
Refractory*** 
 
 
 
 
 
 
(*)Relapsed myeloma: at least one prior thalidomide regimen, and not meeting criteria for relapsed and refractory / 
refractory myeloma. 
(**) Relapsed/refractory myeloma: relapse of disease while on salvage therapy, or progression within 60 days of last 
thalidomide therapy.  
(***)Refractory myeloma: non responder to last thalidomide therapy.  
 
 


 
34 of 164 
Table 11.1.4.9 Status regarding response to bortezomib, lenalidomide/thalidomide therapy 
(*) 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
Resistant or refractory to 
lenalidomide/thalidomide and 
bortezomib therapies * 
X 
XX.X 
X 
XX.X 
X 
XX.X 
Resistant or refractory to 
lenalidomide/thalidomide therapy but 
not refractory to bortezomib ** 
 
 
 
 
 
 
Resistant or refractory to bortezomib 
therapy but not refractory to 
lenalidomide and thalidomide *** 
 
 
 
 
 
 
Other than the above 
 
 
 
 
 
 
 (*) Resistant or refractory myeloma: non responder or relapse of disease while on salvage therapy, or progression within 
60 days of therapy.  
Table 11.1.4.10 Status regarding response to last therapy 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
Relapsed* 
X 
XX.X 
X 
XX.X 
X 
XX.X 
Relapsed/Refractory** 
 
 
 
 
 
 
Refractory*** 
 
 
 
 
 
 
(*)Relapsed myeloma: at least one prior regimen, and not meeting criteria for relapsed and refractory / refractory 
myeloma. 
(**) Relapsed/refractory myeloma: relapse of disease while on salvage therapy, or progression within 60 days of last 
therapy.  
(***)Refractory myeloma: non responder to last therapy.  
Table 11.1.4.11 Status regarding response to IMiD therapy 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
Relapsed* 
X 
XX.X 
X 
XX.X 
X 
XX.X 
Relapsed/Refractory** 
 
 
 
 
 
 
Refractory*** 
 
 
 
 
 
 
(*)Relapsed myeloma: at least one prior IMiD regimen, and not meeting criteria for relapsed and refractory / refractory 
myeloma. 
(**) Relapsed/refractory myeloma: relapse of disease while on salvage therapy, or progression within 60 days of IMiD 
therapy.  
(***)Refractory myeloma: non responder to IMiD therapy.  
Table 11.1.4.12 Status regarding response to PIs therapy 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
Relapsed* 
X 
XX.X 
X 
XX.X 
X 
XX.X 
Relapsed/Refractory** 
 
 
 
 
 
 
Refractory*** 
 
 
 
 
 
 
(*)Relapsed myeloma: at least one prior PIs regimen, and not meeting criteria for relapsed and refractory / refractory 
myeloma. 
(**) Relapsed/refractory myeloma: relapse of disease while on salvage therapy, or progression within 60 days of PIs 
therapy.  
(***)Refractory myeloma: non responder to PIs therapy.  
Table 11.1.4.13 TTP to last prior anticancer therapy 
 
 
N 
Median 
Min 
Max 
Time to progression. Last 
anticancer therapy (months) 
Arm A 
 
 
 
 
Arm B 
 
 
 
 
Total 
 
 
 
 
*In case of non-PD to last therapy, TTP will be calculated until the date of informed consent.  


 
35 of 164 
Table 11.1.4.14 Response to last therapy 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
sCR  
X 
XX.X 
X 
XX.X 
X 
XX.X 
CR  
 
 
 
 
 
 
VGPR 
 
 
 
 
 
 
PR 
 
 
 
 
 
 
MR 
 
 
 
 
 
 
SD 
 
 
 
 
 
 
PD 
 
 
 
 
 
 
Listing 11.1.4.15 Patients who have been previously treated with Bortezomib, 
Lenalidomide or Thalidomide.  
Arm 
Patient 
id. 
Regimen # 
Agents 
(Literal) 
Agents 
(ATC4) 
Start 
date 
End 
date 
Best 
Response 
Progression 
date 
TTP 
(months) 
… 
 
 
 
 
 
 
 
 
 
Table 11.1.4.16 Prior stem cell transplantation 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
0 
X 
XX.X 
X 
XX.X 
X 
XX.X 
1 
 
 
 
 
 
 
≥2 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Type 
N 
% 
N 
% 
N 
% 
Autologous 
X 
XX.X 
X 
XX.X 
X 
XX.X 
Allogeneic 
 
 
 
 
 
 
 
11.1.5 Prior history 
Listing 11.1.5.1 Prior history  
Arm 
Patient id. Description 
Onset Date 
Resolved Date 
Ongoing 
… 
 
 
 
 
 
 
11.1.6 Physical examination, vital signs, electrocardiogram and other tests 
For the physical examination, vital signs, electrocardiogram and other tests, the last 
examination available before treatment will be described in the following tables. 
Table 11.1.6.1 Baseline characteristics: Physical exam 
Physical examination 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
Normal 
X 
XX.X 
X 
XX.X 
X 
XX.X 
Abnormal* 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
(*)See tables of signs and symptoms and prior history for details 
 
 


 
36 of 164 
Table 11.1.6.2 Baseline characteristics: Physical exam and vital signs. 
Arm 
Parameter 
 
 
 
 
N 
Median 
Min 
Max 
Arm A 
Weight (kg.) 
 
 
 
 
Height (cm.) 
 
 
 
 
BSA (m2) 
 
 
 
 
Heart rate (beats/min) 
 
 
 
 
Systolic blood pressure (mmHg) 
 
 
 
 
Diastolic blood pressure (mmHg) 
 
 
 
 
Temperature (ºC) 
 
 
 
 
Arm B 
Weight (kg.) 
 
 
 
 
Height (cm.) 
 
 
 
 
BSA (m2) 
 
 
 
 
Heart rate (beats/min) 
 
 
 
 
Systolic blood pressure (mmHg) 
 
 
 
 
Diastolic blood pressure (mmHg) 
 
 
 
 
Temperature (ºC) 
 
 
 
 
Total 
Weight (kg.) 
 
 
 
 
Height (cm.) 
 
 
 
 
BSA (m2) 
 
 
 
 
Heart rate (beats/min) 
 
 
 
 
Systolic blood pressure (mmHg) 
 
 
 
 
Diastolic blood pressure (mmHg) 
 
 
 
 
Temperature (ºC) 
 
 
 
 
Table 11.1.6.3 Baseline characteristics: ECOG Performance Status 
PS 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
0 
X 
XX.X 
X 
XX.X 
X 
XX.X 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Table 11.1.6.4 Baseline characteristics: Electrocardiogram 
ECG 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
Normal 
X 
XX.X 
X 
XX.X 
X 
XX.X 
Abnormal* 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
(*)See tables of signs and symptoms or prior history for details 
Listing 11.1.6.5 Baseline characteristics: Left Ventricular Ejection Fraction (LVEF) 
Arm 
Patient 
id. 
Not done 
Date 
LVEF (%) 
Interpretation 
Institutional normal range 
(%) 
Method 
… 
 
 
 
 
 
 
 
Table 11.1.6.6 Baseline characteristics Median and range of LVEF 
Arm 
N 
Median 
Range 
Arm A 
MUGA 
 
 
 
ECHO 
 
 
 
Both 
 
 
 
Arm B 
MUGA 
 
 
 
ECHO 
 
 
 
Both 
 
 
 
Total 
MUGA 
 
 
 
ECHO 
 
 
 
Both 
 
 
 


 
37 of 164 
Table 11.1.6.7 Baseline characteristics: Adequate contraception 
Adequate birth control 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
Yes 
X 
XX.X 
X 
XX.X 
X 
XX.X 
No 
 
 
 
 
 
 
NA* 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
(*) Specify reasons 
Table 11.1.6.8  Baseline characteristics: Pregnancy test 
Pregnancy test 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
Yes 
X 
XX.X 
X 
XX.X 
X 
XX.X 
No 
 
 
 
 
 
 
NA* 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
(*) Specify reasons 
 
11.1.7 Hematological values at baseline 
Table 11.1.7.1 Hematological abnormalities at baseline   
 
Arm A 
Arm B 
N 
Grade  
1 
… 
Grade  
4 
All* 
N 
Grade  
1 
… 
Grade  
4 
All* 
 
N 
N 
% 
… 
N 
% 
N 
% 
 
N 
% 
… 
N 
% 
N 
% 
Leukopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thrombocytopenia  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neutropenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lymphopenia  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(*)Any grade 
 
Table 11.1.7.2 Hematology values at baseline 
 
Arm A 
Arm B 
Total 
Median (range) 
Median (range) 
Median (range) 
WBC (109/L) 
 
 
 
Hemoglobin (g/dL) 
 
 
 
Hematocrit (%) 
 
 
 
Platelets (109/L) 
 
 
 
Neutrophils (109/L) 
 
 
 
Lymphocytes (109/L) 
 
 
 
Plasma cells (109/L) 
 
 
 
Listing 11.1.7.3 Hematological tests not assessed at baseline 
Arm 
Patient id. 
Lab. test 
… 
 
 
Listing 11.1.7.4 Hematological abnormalities at baseline. Grade ≥ 2 
Arm 
Patient id 
Parameter 
Value 
Grade 
… 
 
 
 
 
 
 
 


 
38 of 164 
11.1.8 Biochemical values at baseline 
 
Table 11.1.8.1 Biochemical abnormalities at baseline 
 
Arm A 
Arm B 
N 
Grade  
1 
… 
Grade  
4 
All* 
N 
Grade  
1 
… 
Grade  
4 
All* 
 
N 
N 
% 
… 
N 
% 
N 
% 
 
N 
% 
… 
N 
% 
N 
% 
AST increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALT increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total bilirubin 
increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AP increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Creatinine increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CPK increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(*)Any grade 
 
Table 11.1.8.2 Biochemical values at baseline 
 
Arm A 
Arm B 
Total 
Median (range) 
Median (range) 
Median (range) 
AST (xULN) 
 
 
 
ALT (xULN) 
 
 
 
Total bilirubin (xULN) 
 
 
 
Direct bilirubin (xULN) 
 
 
 
AP (xULN) 
 
 
 
Creatinine (xULN) 
 
 
 
Cr. Clearance (Calculated) (ml/min) 
 
 
 
Cr. Clearance* (Measured) (ml/min) 
 
 
 
CPK (xULN) 
 
 
 
CPK MB (IU/L) 
 
 
 
Cardiac Troponin I (ng/ml) 
 
 
 
Total proteins (g/dL) 
 
 
 
Albumin (g/dL) 
 
 
 
Uric acid (mg/dL) 
 
 
 
LDH (xULN) 
 
 
 
Beta-2-microglobulin (mg/L) 
 
 
 
(*)If available 
Listing 11.1.8.3 Biochemical tests not assessed at baseline 
Arm 
Patient id. 
Lab. test 
… 
… 
 
*CPKMB to be assessed as missing only if CPK>ULN 
Listing 11.1.8.4 Biochemical abnormalities at baseline. Grade ≥ 2 
Arm 
Patient id 
Parameter 
Value 
Grade 
… 
 
 
 
 
 
 
 
 


 
39 of 164 
11.1.9 Other metabolic values at baseline 
Table 11.1.9.1 Other metabolic abnormalities at baseline 
 
Arm A 
Arm B 
N 
Grade  
1 
… 
Grade  
4 
All* 
N 
Grade  
1 
… 
Grade  
4 
All* 
 
N 
N 
% 
… 
N 
% 
N 
% 
 
N 
% 
… 
N 
% 
N 
% 
Hyperglycemia  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypoglycemia  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
…. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypoalbuminemia  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(*)Any grade 
 
Table 11.1.9.2 Other metabolic values at baseline 
 
Arm A 
Arm B 
Total 
 
Median (range) 
Median (range) 
Median (range) 
Sodium (mmol/L) 
 
 
 
Potassium (mmol/L) 
 
 
 
Calcium (mmol/L) 
 
 
 
Magnesium (mmol/L) 
 
 
 
Glucose (mmol/L) 
 
 
 
Listing 11.1.9.3 Metabolic tests not assessed at baseline 
Arm 
Patient id. 
Lab. test 
… 
… 
 
Listing 11.1.9.4 Metabolic abnormalities at baseline. Grade ≥ 2 
Arm 
Patient id 
Parameter 
Value 
Grade 
… 
 
 
 
 
 
11.1.10 Signs and symptoms at baseline 
Table 11.1.10.1 Patients with signs and symptoms at baseline 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
No. signs and symptoms per patient 
 
 
 
 
 
 
0 
1 
2 
 
 
 
 
 
 
 3 
 
 
 
 
 
 
Median (Range) 
 
 
 
 
 
 
 
Table 11.1.10.2 Signs and symptoms at baseline  
SOC 
Preferred Term 
Arm A 
Arm B 
N 
Grade  
1 
… 
Grade  
4 
All* 
N 
Grade  
1 
… 
Grade  
4 
All* 
 
 
N 
N 
% 
… 
N 
% 
N 
% 
 
N 
% 
… 
N 
% 
N 
% 
Gastrointestinal 
disorders 
Constipation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diarrhea NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General disorders 
and administration 
site conditions 
Fatigue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(*)Any grade 


 
40 of 164 
Listing 11.1.10.3 Signs and Symptoms at baseline 
Arm 
Patient id. 
Sign/symptom 
Grade 
Onset date 
Relationship 
Treated* 
… 
 
 
 
 
 
 
(*)See details in Listing 11.2.11.3 
 
11.1.11 Concomitant therapy and procedures at baseline 
Concomitant medication at baseline according to the ATC classification. 
Table 11.1.11.1 Agents of concomitant therapy started at baseline 
Medication Term 
(ATC level 1 ) 
Medication Term 
(ATC level 2) 
Medication Term 
(ATC level 4) 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
 
 
 
X 
XX.X 
X 
XX.X 
X 
XX.X 
 
Table 11.1.11.2 Summary of concomitant medication at baseline 
 
Arm A 
Arm B 
Total 
No. of systems at BL (ATC1 level) 
N 
% 
N 
% 
N 
% 
0 
 
 
 
 
 
 
1 
2 
 3 
 
 
 
 
 
 
Median (range) 
 
 
 
 
 
 
No. of indications at BL (ATC2 level) 
 
 
 
 
 
 
0 
1 
2 
 3 
 
 
 
 
 
 
Median (range) 
 
 
 
 
 
 
No. of agents at BL (ATC4 level) 
 
 
 
 
 
 
0 
1 
2 
 
 
 
 
 
 
 3 
 
 
 
 
 
 
Median (range) 
 
 
 
 
 
 
Listing 11.1.11.3  Concomitant therapy/procedures at baseline 
Arm 
Patient 
id. 
Type 
Drug 
name / 
Procedure 
ATC 
Code 
Route 
Total 
daily dose Start date 
Reason for 
use 
Indication for 
therapeutic 
reason 
… 
 
 
 
 
 
 
 
 
 
Listing 11.1.11.4 Therapy with antiarrythmics and drugs known to prolong QT at baseline. 
Arm 
Patient id. 
Start date 
ATC Code 
Type 
Reason for use  
… 
 
 
 
 
 
Taken from concomitant therapy dataset. 
Listing 11.1.11.5  Therapy with EPO or G-CSF at baseline. 
Arm 
Patient id. 
Start date 
ATC Code 
Type 
Reason for use  
… 
 
 
 
 
 
Taken from concomitant therapy dataset. ATC codes L03AA and B03XA 
 


 
41 of 164 
11.2 Measurements of treatment compliance 
Not applicable. 
 
 


 
42 of 164 
11.3 Efficacy analysis 
11.3.1 Primary analysis 
Table 11.3.1.1 PFS (Independent Review assessment and “All Randomized Patients” 
population) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.1.1)  
 
11.3.2 Supportive PFS analyses 
In the ‘time-to-event variables’, the unstratified and stratified log-rank test will be used to 
evaluate the differences between treatment arms and the median values of time-dependent 
parameters. Their fixed-time estimations will be analyzed according to the Kaplan-Meier 
method. Median follow-up assessments will be calculated using the Kaplan-Meier method 
reversing the censoring values (5). Whenever it is not specified, the unstratified test is used. 
Table 11.3.2.1  PFS (Investigator Assessment and “All Randomized Patients” population) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.2.1)  
 
Table 11.3.2.2 PFS (Independent Review assessment and “All Randomized Patients” 
population). Stratified. 
  
Arm A 
Arm B  
Stratum 1 
 
 
N 
 
 
Events 
 
 
Censored 
 
 
Median PFS 
 
 
PFS at 6 months 
 
 
Stratum 2 
 
 
N 
 
 
…. 
 
 
…. 
 
 
Log-Rank* /  p-value** / HR (95% CI) : 
(*)Stratified log-rank test statistic. (**) p-value from stratified log-rank test 
 
 


 
43 of 164 
Table 11.3.2.3  PFS (Investigator Assessment and “All Randomized Patients” population). 
Stratified comparison.   
  
Arm A 
Arm B  
Stratum 1 
 
 
N 
 
 
Events 
 
 
Censored 
 
 
Median PFS 
 
 
PFS at 6 months 
 
 
Stratum 2 
 
 
N 
 
 
Events 
 
 
…. 
 
 
…. 
 
 
Log-Rank* /  p-value** / HR (95% CI) : 
(*)Stratified log-rank test statistic. (**) p-value from stratified log-rank test 
 
Table 11.3.2.4 PFS – Concordance between Independent Review assessment and 
Investigator assessment ( “All Randomized Patients” population)  
 
Arm A (N=XX) 
Arm B (N=YY) 
Total (N=ZZ) 
 
N 
% 
N 
% 
N 
% 
Event by investigator 
 
 
 
 
 
 
  Agreement on event 
 
 
 
 
 
 
      Same date 
 
 
 
 
 
 
      Later date 
 
 
 
 
 
 
      Earlier date 
 
 
 
 
 
 
Censored by investigator 
 
 
 
 
 
 
  Agreement on censoring 
 
 
 
 
 
 
      Same date 
 
 
 
 
 
 
      Different date 
 
 
 
 
 
 
Agreement on status 
 
 
 
 
 
 
Agreement on status and 
date 
 
 
 
 
 
 
XX, YY, ZZ = Patients evaluable for both Independent review assessment and investigator assessment 
 
Table 11.3.2.5  PFS – Reason of censoring ( “All Randomized Patients” population)  
Reason of censoring 
Independent review assessment 
Investigator assessment 
Arm A 
Arm B 
Arm A 
Arm B 
N 
% 
N 
% 
N 
% 
N 
% 
Lost to follow-up 
 
 
 
 
 
 
 
 
Subsequent therapy 
 
 
 
 
 
 
 
 
>1 missing assessment 
 
 
 
 
 
 
 
 
Still on treatment 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 


 
44 of 164 
11.3.3 Sensitivity analyses of PFS 
 
Table 11.3.3.1  PFS (midpoint imputation method of PD dates) (Independent Review 
assessment and “All Randomized Patients” population) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.3.1) . 
See imputation methods in section 6.1. 
 
Table 11.3.3.2  PFS (weeks from randomization imputation method of PD dates) 
(Independent Review assessment and “All Randomized Patients” population) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.3.2) . 
See imputation methods in section 6.1. 
 
Table 11.3.3.3  PFS (missing assessment imputation method of PD dates)  (Independent 
Review assessment and “All Randomized Patients” population) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.3.3). 
See imputation methods in section 6.1. 
 
Two tables and figures 11.3.3.4 and 11.3.3.5 will be performed describing the PFS outcome 
by Independent Review and Investigator assessment, respectively, using interval censoring 
methods. 
Table 11.3.3.6 PFS (Independent Review assessment and “All Evaluable Patients” 
population) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.3.6)  


 
45 of 164 
Table 11.3.3.7  PFS (Investigator Assessment and “All Evaluable Patients” population) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.3.7)  
Table 11.3.3.8   PFS with confirmation of PD (Independent Review assessment and “All 
Randomized Patients” population) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.3.8)  
Table 11.3.3.9   PFS with confirmation of PD (Investigator Assessment and “All 
Randomized Patients” population) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.3.9)  
Table 11.3.3.10   Time to PD confirmation (Independent Review Assessment and “All 
Randomized Patients” population) 
 
Arm A 
Arm B 
p-value 
Median 
95% CI 
Median 
95% CI 
Time to PD 
confirmation 
(days) 
 
 
 
 
 
Table 11.3.3.11   Time to PD confirmation (Investigator Assessment and “All Randomized 
Patients” population) 
 
Arm A 
Arm B 
p-value 
Median 
95% CI 
Median 
95% CI 
Time to PD 
confirmation 
(days) 
 
 
 
 
 
 
 
 
 


 
46 of 164 
11.3.4 Secondary analyses 
11.3.4.1 OS analyses 
 
Table 11.3.4.1.1 OS (“All Randomized Patients” population) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.4.1.1). 
 
Table 11.3.4.1.2 OS stratified comparison (“All Randomized Patients” population) 
  
Arm A 
Arm B  
Stratum 1 
 
 
N 
 
 
Events 
 
 
Censored 
 
 
Median OS 
 
 
OS at 12 months 
 
 
OS at 24 months 
  
 
Stratum 2 
 
 
N 
 
 
Events 
 
 
…. 
 
 
…. 
 
 
Log-Rank* /  p-value** / HR (95% CI) : 
(*)Stratified log-rank test statistic. (**) p-value from stratified log-rank test 
 
Table 11.3.4.1.3 OS (“All Randomized Patients” population excluding crossover patients) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.4.1.3). 
 
Table 11.3.4.1.4 OS (“All Randomized Patients” population censoring crossover patients at 
cross-over date) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.4.1.4). 
 


 
47 of 164 
Table 11.3.4.1.5 OS (“All Randomized Patients” population and IPCW method) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.4.1.5). 
 
Table 11.3.4.1.6 OS (“All Randomized Patients” population and RPSFT method) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.4.1.6). 
 
A forest plot (Figure 11.3.4.1.7)  with the summary of hazard ratios for PFS and OS in the 
different analysis populations will be shown to check the consistency across the different 
measurements. 
 
Table 11.3.4.1.8  OS – Reason of censoring ( “All Randomized Patients” population)  
Reason of censoring 
Arm A 
Arm B 
N 
% 
N 
% 
Alive 
 
 
 
 
Lost to follow-up 
 
 
 
 
Withdrawal of consent 
 
 
 
 
 
Table 11.3.4.1.9 OS (Subpopulation without crossover or subsequent therapy) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.4.1.9). 
 
Table 11.3.4.1.10 OS (Subpopulation of patients with event in the primary analysis and 
without crossover or subsequent therapy) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.4.1.10). 


 
48 of 164 
Table 11.3.4.1.11 OS (“All Randomized Patients” population and Two-stage method) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.4.1.11). 
 
A forest plot (Figure 11.3.4.1.12)  with the summary of hazard ratios for OS in the different 
analysis populations will be shown to check the consistency across the different 
measurements. 
 
Supportive analyses needed to adjust OS by crossover by the two-stage method 
 
Table 11.3.4.1.13 Logistic regression (Crossover patients vs no crossover patients) 
Analysis of Maximum Likelihood Estimates* 
Variable Label 
Variable 
values 
DF 
Parameter 
Estimate 
Standard 
Error 
Chi-
Square 
Pr > ChiSq 
Odds 
Ratio 
95% Odds 
Ratio 
Confidence 
Limits 
 
 
 
 
 
 
 
 
 
* Logistic regression 
See list of covariates in section 6.2.3 
 
Table 11.3.4.1.14 PFS (Crossover patients vs no crossover patients) 
  
Crossover 
No crossover  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
Kaplan-Meier plot will be also shown (Figure 11.3.4.1.14). 
 
Table 11.3.4.1.15 Post progression survival (Weibull adjustment) 
Analysis of Maximum Likelihood Parameter Estimates 
Parameter 
 
DF 
Estimate 
Standard 
Error 
95% Confidence Limits 
Chi-Square 
Pr > ChiSq 
Intercept 
 
 
 
 
 
 
 
 
Treatment arm 
- 
 
 
 
 
 
 
 
Treatment arm 
Crossover 
 
 
 
 
 
 
 
Scale 
 
 
 
 
 
 
 
 
Weibull Shape 
 
 
 
 
 
 
 
 
 
11.3.4.2 Response rate by independent review committee 
 
Table 11.3.4.2.1 Response rate by IMWG (Independent Review assessment and “All 
Randomized Patients” population) 
Response 
Arm A 
Arm B 
N 
% 
N 
% 
sCR  
 
 
 
 


 
49 of 164 
CR  
 
 
 
 
VGPR 
 
 
 
 
PR 
 
 
 
 
MR 
 
 
 
 
SD 
 
 
 
 
PD 
 
 
 
 
Unknown* 
 
 
 
 
 (*) Including NE and insufficient data available. 
 
Table 11.3.4.2.2 Response rate estimates by IMWG (Independent Review assessment and 
“All Randomized Patients” population) 
 
Arm A 
Arm B 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Response rate 
 
 
 
 
 
 
Binomial exact estimator and 95% confidence interval 
 
Table 11.3.4.2.3 Response rate comparison by IMWG (Independent Review assessment 
and “All Randomized Patients” population) 
Response rate 
Arm A 
Arm B 
Fisher exact test 
(p-value) 
N 
% 
N 
% 
sCR+CR+VGPR+PR+MR 
 
 
 
 
 
SD+PD+UK* 
 
 
 
 
(*) Including NE and insufficient data available. 
 
Table 11.3.4.2.4 Response rate by IMWG (Independent Review assessment and “All 
Evaluable Patients” population) 
Response 
Arm A 
Arm B 
N 
% 
N 
% 
sCR  
 
 
 
 
CR  
 
 
 
 
VGPR 
 
 
 
 
PR 
 
 
 
 
MR 
 
 
 
 
SD 
 
 
 
 
PD 
 
 
 
 
 
Table 11.3.4.2.5 Response rate estimates by IMWG (Independent Review assessment and 
“All Evaluable Patients” population) 
 
Arm A 
Arm B 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Response rate 
 
 
 
 
 
 
Binomial exact estimator and 95% confidence interval 
 
 
 


 
50 of 164 
Table 11.3.4.2.6 Response rate comparison by IMWG (Independent Review assessment 
and “All Evaluable Patients” population) 
Response rate 
Arm A 
Arm B 
Fisher exact test 
(p-value) 
N 
% 
N 
% 
sCR+CR+VGPR+PR+MR 
 
 
 
 
 
SD+PD 
 
 
 
 
 
Table 11.3.4.2.7 Response rate by IMWG at early futility analysis (Independent Review 
assessment and “All Evaluable Patients” population) 
Response 
Arm A 
Arm B 
N 
% 
N 
% 
sCR  
 
 
 
 
CR  
 
 
 
 
VGPR 
 
 
 
 
PR 
 
 
 
 
MR 
 
 
 
 
SD 
 
 
 
 
PD 
 
 
 
 
 
Table 11.3.4.2.8 Response rate estimates without MR by IMWG (Independent Review 
assessment and “All Randomized Patients” population) 
 
Arm A 
Arm B 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Response rate 
 
 
 
 
 
 
Binomial estimates and 95% exact confidence interval 
 
Table 11.3.4.2.9 Response rate comparison without MR by IMWG (Independent Review 
assessment and “All Randomized Patients” population) 
Response rate 
Arm A 
Arm B 
Fisher exact test 
(p-value) 
N 
% 
N 
% 
sCR+CR+VGPR+PR 
 
 
 
 
 
MR+SD+PD+UK* 
 
 
 
 
(*) Including NE and insufficient data available. 
 
Table 11.3.4.2.10 Response rate estimates without MR by IMWG (Independent Review 
assessment and “All Evaluable Patients” population) 
 
Arm A 
Arm B 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Response rate 
 
 
 
 
 
 
Binomial estimates and 95% exact confidence interval 
 
Table 11.3.4.2.11 Response rate comparison without MR by IMWG (Independent Review 
assessment and “All Evaluable Patients” population) 
Response rate 
Arm A 
Arm B 
Fisher exact test 
(p-value) 
N 
% 
N 
% 
sCR+CR+VGPR+PR 
 
 
 
 
 
MR+SD+PD 
 
 
 
 
 
Table 11.3.4.2.12 Median Time to Response (Independent Review assessment) 
 
Arm A 
Arm B 
Median 
95% CI  
Median 
95% CI  
Time to response* 
 
 
 
 
(*)sCR, CR, VGPR, PR or MR 


 
51 of 164 
 
Table 11.3.4.2.13 Median Time to Response without MR  (Independent Review 
assessment) 
 
Arm A 
Arm B 
Median 
95% CI  
Median 
95% CI  
Time to response* 
 
 
 
 
(*)sCR, CR, VGPR or PR 
11.3.4.3 Response rate by investigator assessment 
 
Table 11.3.4.3.1 Response rate by IMWG (Investigator assessment and “All Randomized 
Patients” population) 
Response 
Arm A 
Arm B 
N 
% 
N 
% 
sCR  
 
 
 
 
CR  
 
 
 
 
VGPR 
 
 
 
 
PR 
 
 
 
 
MR 
 
 
 
 
SD 
 
 
 
 
PD 
 
 
 
 
Unknown* 
 
 
 
 
 (*) Including NE and insufficient data available. 
 
Table 11.3.4.3.2 Response rate estimates by IMWG (Investigator assessment and “All 
Randomized Patients” population) 
 
Arm A 
Arm B 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Response rate 
 
 
 
 
 
 
Binomial estimates and 95% exact confidence interval 
 
Table 11.3.4.3.3 Response rate comparison by IMWG (Investigator assessment and “All 
Randomized Patients” population) 
Response rate 
Arm A 
Arm B 
Fisher exact test 
(p-value) 
N 
% 
N 
% 
sCR+CR+VGPR+PR+MR 
 
 
 
 
 
SD+PD+UK* 
 
 
 
 
(*) Including NE and insufficient data available. 
 
Table 11.3.4.3.4 Response rate by IMWG (Investigator assessment and “All Evaluable 
Patients” population) 
Response 
Arm A 
Arm B 
N 
% 
N 
% 
sCR  
 
 
 
 
CR  
 
 
 
 
VGPR 
 
 
 
 
PR 
 
 
 
 
MR 
 
 
 
 
SD 
 
 
 
 
PD 
 
 
 
 
 
 
 


 
52 of 164 
Table 11.3.4.3.5 Response rate estimates by IMWG (Investigator assessment and “All 
Evaluable Patients” population) 
 
Arm A 
Arm B 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Response rate 
 
 
 
 
 
 
Binomial estimates and 95% exact confidence interval 
 
Table 11.3.4.3.6 Response rate comparison by IMWG (Investigator assessment and “All 
Evaluable Patients” population) 
Response rate 
Arm A 
Arm B 
Fisher exact test 
(p-value) 
N 
% 
N 
% 
sCR+CR+VGPR+PR+MR 
 
 
 
 
 
SD+PD 
 
 
 
 
 
 
Table 11.3.4.3.7 Response rate estimates without MR by IMWG (Investigator assessment 
and “All Randomized Patients” population) 
 
Arm A 
Arm B 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Response rate 
 
 
 
 
 
 
Binomial estimates and 95% exact confidence interval 
 
Table 11.3.4.3.8 Response rate comparison without MR by IMWG (Investigator assessment 
and “All Randomized Patients” population) 
Response rate 
Arm A 
Arm B 
Fisher exact test 
(p-value) 
N 
% 
N 
% 
sCR+CR+VGPR+PR 
 
 
 
 
 
MR+SD+PD+UK* 
 
 
 
 
(*) Including NE and insufficient data available. 
 
Table 11.3.4.3.9 Response rate estimates without MR by IMWG (Investigator assessment 
and “All Evaluable Patients” population) 
 
Arm A 
Arm B 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Response rate 
 
 
 
 
 
 
Binomial estimates and 95% exact confidence interval 
 
Table 11.3.4.3.10 Response rate comparison without MR by IMWG (Investigator 
assessment and “All Evaluable Patients” population) 
Response rate 
Arm A 
Arm B 
Fisher exact test 
(p-value) 
N 
% 
N 
% 
sCR+CR+VGPR+PR 
 
 
 
 
 
MR+SD+PD 
 
 
 
 
 
Table 11.3.4.3.11 Median Time to Response (Investigator assessment) 
 
Arm A 
Arm B 
Median 
95% CI  
Median 
95% CI  
Time to response* 
 
 
 
 
(*)sCR, CR, VGPR, PR or MR 
 
 
 


 
53 of 164 
Table 11.3.4.3.12 Median Time to Response without MR  (Investigator assessment) 
 
Arm A 
Arm B 
Median 
95% CI  
Median 
95% CI  
Time to response* 
 
 
 
 
(*)sCR, CR, VGPR or PR 
 
11.3.4.4 Duration of response 
 
Table 11.3.4.4.1 DR (Independent Review assessment and “All Responder Patients” 
population) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median DR 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
DR at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.4.4.1)  
 
Table 11.3.4.4.2 DR (Investigator assessment and “All Responder Patients” population) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median DR 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
DR at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.4.4.2)  
 
Table 11.3.4.4.3 DR without MR (Independent Review assessment and “All Responder 
Patients” population) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median DR 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
DR at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.4.4.3)  
 
Table 11.3.4.4.4 DR without MR (Investigator assessment and “All Responder Patients” 
population) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median DR 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
DR at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.4.4.4)  
 
 
 


 
54 of 164 
Table 11.3.4.4.5 DR with PD confirmation (Independent Review assessment and “All 
Responder Patients” population) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median DR 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
DR at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.4.4.5)  
 
Table 11.3.4.4.6 DR with PD confirmation (Investigator assessment and “All Responder 
Patients” population) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median DR 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
DR at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.4.4.6)  
 
11.3.4.5 Analysis of crossover 
 
Table 11.3.4.5.1 RR to combination treatment in patients who crossed over from Arm B to 
Arm A (“All Crossover Patients” population) 
 
After crossover (N,%) 
sCR 
CR 
VGPR 
PR 
MR 
SD 
PD 
NE 
Before 
crossover 
sCR 
 
 
 
 
 
 
 
 
CR 
 
 
 
 
 
 
 
 
VGPR 
 
 
 
 
 
 
 
 
PR 
 
 
 
 
 
 
 
 
MR 
 
 
 
 
 
 
 
 
SD 
 
 
 
 
 
 
 
 
PD 
 
 
 
 
 
 
 
 
NE 
 
 
 
 
 
 
 
 
 
Table 11.3.4.5.2 Intrapatient PFS comparison of patients who crossed over from Arm B to 
Arm A (“All Crossover Patients” population) 
PFS 
Before crossover 
After crossover 
Median 
 
 
PFS at 6 months 
 
 
 
Table 11.3.4.5.3 PFS comparison of patients (“All Randomized Patients” population) 
PFS 
Arm A 
Arm B 
Before crossover 
After crossover 
Median 
 
 
 
PFS at 6 months 
 
 
 
Listing 11.3.4.5.4  Best response and PFS before and after crossover. 
Patient id. 
Cycle of 
crossover 
Best response 
PFS 
Before crossover 
After crossover 
Before crossover 
After crossover 
… 
 
 
 
 
 


 
55 of 164 
 
Listing 11.3.4.5.5  Best response and PFS before in crossover patients. 
Patient 
id. 
Independent review assessment 
Investigator assessment 
Best 
response 
PFS 
PFS event 
PD 
confirmation 
Best 
response 
PFS 
PFS event 
PD 
confirmation 
… 
 
 
 
 
 
 
 
 
Table 11.3.4.5.6 Time to crossover  
 
N 
Median 
Min 
Max 
Time to crossover (months) 
 
 
 
 
Table 11.3.4.5.7  Baseline characteristics comparison patients without crossover vs 
crossover 
Variable** 
Value 
N 
Without Crossover 
Crossover 
p-value* 
Sex 
F 
XXX 
XX (XX.X%) 
XX (XX.X%) 
X.XXXX 
M 
XXX 
XX (XX.X%) 
XX (XX.X%) 
 
Age 
Median(range) XXX 
XX.X (XX-XX) 
XX.X (XX-XX) 
X.XXXX 
… 
 
 
 
 
 
(*)Fisher’s exact test (categorical variables); Mann-Whitney-Wilcoxon (continuous variables) 
(**)Sex, age, PS (ECOG), BSA, Durie Salmon stage, International Staging System, Secretory/Non-secretory, MM type, 
time from diagnosis, time from last PD, number of prior lines, status to prior therapy, status to prior bortezomib therapy, 
status to prior thalidomide/lenalidomide therapy, status to prior IMiD therapy, status to prior PIs therapy, stem cell 
transplantation, plasma cells, hemoglobin, creatinine, calcium, genetic risk, lytic lesions and plasmacytomas. 
 
11.3.4.6 Follow-up 
 
Table 11.3.4.6.1 Median FU for PFS 
 
Arm A 
Arm B 
Median 
95% CI  
Median 
95% CI  
Follow-up 
 
 
 
 
 
Table 11.3.4.6.2 Median FU for OS 
 
Arm A 
Arm B 
Median 
95% CI  
Median 
95% CI  
Follow-up 
 
 
 
 
 
11.3.4.7 Symmetry of evaluations 
 
Table 11.3.4.7.1 Time to MM assessments  
MM assessment 
Treatment group 
n 
Median (days) 
Wilcoxon p-value 
1 
Arm A 
 
 
 
  
Arm B 
 
 
2 
Arm A 
 
 
 
  
Arm B 
 
 
… 
Arm A 
 
 
 
  
Arm B 
 
 
 
This table will be complemented with a boxplot showing the time to first, second, third and 
further MM assessments by treatment arm (Figure 11.3.4.7.1). 
 


 
56 of 164 
Table 11.3.4.7.2  Time to first assessment 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median to first assessment 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
Kaplan-Meier plot will be also shown (Figure 11.3.4.7.2)  
 
Table 11.3.4.7.3  Time to second assessment 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median second assessment 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
Kaplan-Meier plot will be also shown (Figure 11.3.4.7.3)  
 
11.3.4.8 Univariate analyses 
Table 11.3.4.8.1 Univariate analysis of PFS (Independent Review assessment and “All 
Randomized Patients” population) 
 
Arm A 
Arm B 
 
Prognostic factors** 
Median 
(months) 
Lower 
95% 
Confidence 
Limit 
Upper 
95% 
Confidence 
Limit 
Median 
(months) 
Lower 
95% 
Confidence 
Limit 
Upper 
95% 
Confidence 
Limit 
 
p-value* 
Gender 
 
 
 
 
 
 
 
Age 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
(*) Cox regression. (**) See covariate listing in section 6.2.3. A forest plot with the summary of HR will be also shown 
(Figure 11.3.4.8.1)  
 
Table 11.3.4.8.2 Univariate analysis of PFS (Investigator Assessment and “All Randomized 
Patients” population) 
 
Arm A 
Arm B 
 
Prognostic factors** 
Median 
(months) 
Lower 
95% 
Confidence 
Limit 
Upper 
95% 
Confidence 
Limit 
Median 
(months) 
Lower 
95% 
Confidence 
Limit 
Upper 
95% 
Confidence 
Limit 
 
p-value* 
Gender 
 
 
 
 
 
 
 
Age 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
(*) Cox regression. (**) See covariate listing in section 6.2.3. A forest plot with the summary of HR will be also shown 
(Figure 11.3.4.8.2)  
 
 
 


 
57 of 164 
Table 11.3.4.8.3 Univariate analysis of OS (Independent Review assessment and “All 
Randomized Patients” population) 
 
Arm A 
Arm B 
 
Prognostic factors** 
Median 
(months) 
Lower 
95% 
Confidence 
Limit 
Upper 
95% 
Confidence 
Limit 
Median 
(months) 
Lower 
95% 
Confidence 
Limit 
Upper 
95% 
Confidence 
Limit 
 
p-value* 
Gender 
 
 
 
 
 
 
 
Age 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
(*) Cox regression. (**) See covariate listing in section 6.2.3. A forest plot with the summary of HR will be also shown 
(Figure 11.3.4.8.3)  
 
Table 11.3.4.8.4 Univariate analysis of OS (Investigator Assessment and “All Randomized 
Patients” population) 
 
Arm A 
Arm B 
 
Prognostic factors** 
Median 
(months) 
Lower 
95% 
Confidence 
Limit 
Upper 
95% 
Confidence 
Limit 
Median 
(months) 
Lower 
95% 
Confidence 
Limit 
Upper 
95% 
Confidence 
Limit 
 
p-value* 
Gender 
 
 
 
 
 
 
 
Age 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
(*) Cox regression. (**) See covariate listing in section 6.2.3. A forest plot with the summary of HR will be also shown 
(Figure 11.3.4.8.4)  
 
Table 11.3.4.8.5 Univariate analysis of RR (Independent Review assessment and “All 
Randomized Patients” population) 
 
Arm A 
 
Arm B 
 
 
Prognostic factors** 
N 
RR 
Proporti
on  
(%) 
95% CI 
 
N 
RR 
Proporti
on  
(%) 
95% CI 
 
 
p-value* 
Gender 
 
 
 
 
 
 
 
 
 
Age 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
(*) Logistic regression. (**) See covariate listing in section 6.2.3. A forest plot with the summary of ORR confidence 
intervals will be also shown (Figure 11.3.4.8.5)  
 
Table 11.3.4.8.6 Univariate analysis of RR (Investigator Assessment and “All Randomized 
Patients” population) 
 
Arm A 
 
Arm B 
 
 
Prognostic factors** 
N 
RR 
Proporti
on  
(%) 
95% CI 
 
N 
RR 
Proporti
on  
(%) 
95% CI 
 
 
p-value* 
Gender 
 
 
 
 
 
 
 
 
 
Age 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
(*) Logistic regression. (**) See covariate listing in section 6.2.3. A forest plot with the summary of ORR confidence 
intervals will be also shown (Figure 11.3.4.8.6)  
 
 
 


 
58 of 164 
Table 11.3.4.8.7 Univariate analysis of PFS with PD confirmation (Independent Review 
assessment and “All Randomized Patients” population) 
 
Arm A 
Arm B 
 
Prognostic factors** 
Median 
(months) 
Lower 
95% 
Confidence 
Limit 
Upper 
95% 
Confidence 
Limit 
Median 
(months) 
Lower 
95% 
Confidence 
Limit 
Upper 
95% 
Confidence 
Limit 
 
p-value* 
Gender 
 
 
 
 
 
 
 
Age 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
(*) Cox regression. (**) See covariate listing in section 6.2.3. A forest plot with the summary of HR will be also shown 
(Figure 11.3.4.8.7)  
 
11.3.4.9 Multivariate analyses 
 
Table 11.3.4.9.1 Multivariate analysis of PFS (Independent Review assessment and “All 
Randomized Patients” population) 
Analysis of Maximum Likelihood Estimates* 
Variable Label 
Variable 
values 
DF 
Parameter 
Estimate 
Standard 
Error 
Chi-
Square 
Pr > ChiSq 
Hazard 
Ratio 
95% Hazard 
Ratio 
Confidence 
Limits 
 
 
 
 
 
 
 
 
 
* Cox regression 
See list of covariates in section 6.2.3 
 
Table 11.3.4.9.2 Multivariate analysis of PFS (Investigator assessment and “All 
Randomized Patients” population) 
Analysis of Maximum Likelihood Estimates* 
Variable Label 
Variable 
values 
DF 
Parameter 
Estimate 
Standard 
Error 
Chi-
Square 
Pr > ChiSq 
Hazard 
Ratio 
95% Hazard 
Ratio 
Confidence 
Limits 
 
 
 
 
 
 
 
 
 
* Cox regression 
See list of covariates in section 6.2.3 
 
Table 11.3.4.9.3 Multivariate analysis of RR (Independent Review assessment and “All 
Evaluable Patients” population) 
Analysis of Maximum Likelihood Estimates* 
Variable Label 
Variable 
values 
DF 
Parameter 
Estimate 
Standard 
Error 
Chi-
Square 
Pr > ChiSq 
Odds 
Ratio 
95% Odds 
Ratio 
Confidence 
Limits 
 
 
 
 
 
 
 
 
 
* Logistic regression 
See list of covariates in section 6.2.3 
 
 
 


 
59 of 164 
Table 11.3.4.9.4 Multivariate analysis of RR (Investigator assessment and “All Evaluable 
Patients” population) 
Analysis of Maximum Likelihood Estimates* 
Variable Label 
Variable 
values 
DF 
Parameter 
Estimate 
Standard 
Error 
Chi-
Square 
Pr > ChiSq 
Odds 
Ratio 
95% Odds 
Ratio 
Confidence 
Limits 
 
 
 
 
 
 
 
 
 
* Logistic regression 
See list of covariates in section 6.2.3 
 
Table 11.3.4.9.5 Multivariate analysis of OS (“All Randomized Patients” population) 
Analysis of Maximum Likelihood Estimates* 
Variable Label 
Variable 
values 
DF 
Parameter 
Estimate 
Standard 
Error 
Chi-
Square 
Pr > ChiSq 
Hazard 
Ratio 
95% Hazard 
Ratio 
Confidence 
Limits 
 
 
 
 
 
 
 
 
 
* Cox regression 
See list of covariates in section 6.2.3 
 
Table 11.3.4.9.6 Multivariate analysis of PFS by region (Independent Review assessment 
and “All Randomized Patients” population) 
Analysis of Maximum Likelihood Estimates* 
Variable Label 
Variable 
values 
DF 
Parameter 
Estimate 
Standard 
Error 
Chi-
Square 
Pr > ChiSq 
Hazard 
Ratio 
95% Hazard 
Ratio 
Confidence 
Limits 
 
 
 
 
 
 
 
 
 
* Cox regression 
See list of covariates in section 6.2.3 
 
Table 11.3.4.9.7 Multivariate analysis of PFS with PD confirmation (Independent Review 
assessment and “All Randomized Patients” population) 
Analysis of Maximum Likelihood Estimates* 
Variable Label 
Variable 
values 
DF 
Parameter 
Estimate 
Standard 
Error 
Chi-
Square 
Pr > ChiSq 
Hazard 
Ratio 
95% Hazard 
Ratio 
Confidence 
Limits 
 
 
 
 
 
 
 
 
 
* Cox regression 
See list of covariates in section 6.2.3 
 
 
 


 
60 of 164 
11.3.4.10 
Best Protein reduction 
 
Table 11.3.4.10.1 Best M-spike reduction from baseline 
M-spike 
reduction from 
baseline 
Arm A 
Arm B 
N 
Median 
Min 
Max 
N 
Median 
Min 
Max 
Serum (g/dL) 
 
 
 
 
 
 
 
 
Urine 
(mg/24hrs) 
 
 
 
 
 
 
 
 
Waterfall plot (Figure 11.3.4.9.1) will be also shown for all patients with at least one post-baseline M-spike evaluation. 
Applicable only for patients with secretory multiple myeloma. Central lab evaluation. 
 
11.3.5 Characteristics of responders  
A summary of the main characteristics of patients showing clinical benefit, defined as 
patients with MR or better as best response or SD longer than 6 months assessed by 
Independent Review or by Investigators will be shown. 
 
Listing 11.3.5.1 Characteristics of patients with clinical benefit.  
Arm 
Patient 
id. 
Gender  
PS 
Age 
Primary 
MM 
type 
Relapsed / 
Refractory 
ISS 
No. 
of 
prior 
lines 
Cycles 
received 
Best 
response 
IMWG 
(IA) 
Best 
response 
IMWG 
(IR) 
PFS 
(IA) 
DR 
(IA) 
PFS 
(IR) 
DR 
(IR) 
OS 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IR- Independent review IA- Investigator assessment 
 
 
 


 
61 of 164 
11.3.6 Efficacy analysis by age 
If there is a group of patients with scarce percentage of patients (i.e. 5%), it will be joined 
to the nearest group of age. Age ≥ 85 to Age 75-84, age 75-84 to age 65-74 and age 65-74 
to age 18-64. 
Table 11.3.6.1 PFS (Independent Review assessment and “All Randomized Patients” 
population) by age 
Age 
 
Arm A 
Arm B 
Parameter 
p-value 
Age 18-64  
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Age 65-74 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Age 75-84 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Age ≥85 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.6.1a/b/c/d)  
 
 
 
 


 
62 of 164 
Table 11.3.6.2  PFS (Investigator Assessment and “All Randomized Patients” population) 
by age 
Age 
 
Arm A 
Arm B 
Parameter 
p-value 
Age 18-64  
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Age 65-74 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Age 75-84 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Age ≥85 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.6.2a/b/c/d)  
 
 


 
63 of 164 
Table 11.3.6.3 OS (“All Randomized Patients” population) by age 
Age 
  
Arm A 
Arm B  
Parameter 
p-value 
Age 18-64 
 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
Age 65-74 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
 
Age 75-84 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
 
Age ≥85 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.6.3a/b/c/d). 
 
 
 


 
64 of 164 
Table 11.3.6.4 Response rate by IMWG (Independent Review assessment and “All 
Randomized Patients” population) by age 
Age 
Response 
Arm A 
Arm B 
N 
% 
N 
% 
 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 
Age 18-64 
PR 
 
 
 
 
 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
Age 65-74 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 
 
PR 
 
 
 
 
 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 
 
PR 
 
 
 
 
Age 75-84 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 
Age ≥85 
PR 
 
 
 
 
 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 (*) Including NE and insufficient data available. 
 
Table 11.3.6.5 Response rate estimates by IMWG (Independent Review assessment and 
“All Randomized Patients” population) by age 
Age 
 
Arm A 
Arm B 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Age 18-64 
Response rate  
 
 
 
 
 
Age 65-74 
Response rate  
 
 
 
 
 
Age 75-84 
Response rate  
 
 
 
 
 
Age ≥85 
Response rate  
 
 
 
 
 
Binomial exact estimator and 95% confidence interval 
 
 
 


 
65 of 164 
11.3.7 Efficacy analysis based on genetic risks 
 
Patients will be classified in “high risk”, “intermediate risk” or “good prognosis” according 
to their genetic results (cytogenetic or FISH) at diagnosis or study entry.  
 
Patients with translocations such as t(4;14), t(14;16), t(14;20), del 17, del 13 or single 
alterations such as +1q or +1p will be classified as “high risk”; patients with translocations 
such as t(11;14), t(6;14) or other will be classified “intermediate risk”; and finally, those 
patients with single alterations of trisomies 3, 5, 6, 9, 11, 15, 19 or 21 will be classified as 
“good prognosis”. This classification will be done by clinical review. 
 
Results from independent review assessment are shown in the following tables. ). In case of 
a high difference between independent review and investigator assessments,  RR and PFS 
tables in this section will be duplicated to show the results according to the investigator 
assessment and they will be differentiate with “b” (i.e. 11.3.7.1 will be 11.3.7.1b). 
 
Table 11.3.7.1  PFS (Independent Review assessment and “All Randomized Patients” 
population) by genetic risks 
Cytogenetic profile 
 
Arm A 
Arm B 
Parameter 
p-value 
High risk 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Intermediate risk 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Good prognosis 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.7.1a/b/c)  
 
 
 


 
66 of 164 
Table 11.3.7.2 OS (“All Randomized Patients” population) by genetic risks 
Cytogenetic profile 
  
Arm A 
Arm B  
Parameter 
p-value 
High risk 
 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
Intermediate risk 
 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
 
Good prognosis 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.7.2a/b/c). 
 
Table 11.3.7.3 Response rate by IMWG (Independent Review assessment and “All 
Randomized Patients” population) by genetic risks 
Cytogenetic profile 
Response 
Arm A 
Arm B 
N 
% 
N 
% 
 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 
High risk 
PR 
 
 
 
 
 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 
Intermediate risk 
PR 
 
 
 
 
 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 
 
PR 
 
 
 
 
Good prognosis 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 (*) Including NE and insufficient data available. 
 
 
 


 
67 of 164 
Table 11.3.7.4 Response rate estimates by IMWG (Independent Review assessment and 
“All Randomized Patients” population) by genetic risks 
Cytogenetic 
profile 
Arm A 
Arm B 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
High risk 
 
 
 
 
 
 
Intermediate 
risk 
 
 
 
 
 
 
Good prognosis  
 
 
 
 
 
Binomial exact estimator and 95% confidence interval 
 
11.3.8 Efficacy analysis in patients resistant or refractory to last 
lenalidomide/thalidomide or last bortezomib therapy 
 
Patients will be classified in four groups according to their response to prior 
lenalidomide/thalidomide or bortezomib therapies.  
 
-Resistant or refractory to lenalidomide/thalidomide and bortezomib therapies 
-Resistant or refractory to lenalidomide/thalidomide therapy but not refractory to 
bortezomib 
-Resistant or refractory to bortezomib therapy but not refractory to lenalidomide and 
thalidomide 
-Other than the above  
 
Results from independent review assessment are shown in the following tables. ). In case of 
a high difference between independent review and investigator assessments,  RR and PFS 
tables in this section will be duplicated to show the results according to the investigator 
assessment and they will be differentiate with “b” (i.e. 11.3.8.1 will be 11.3.8.1b). 
 
 
 
 


 
68 of 164 
Table 11.3.8.1  PFS (Independent Review assessment and “All Randomized Patients” 
population) by lenalidomide/thalidomide or bortezomib prior therapies 
Prior therapies 
 
Arm A 
Arm B 
Parameter 
p-value 
Resistant or refractory to 
lenalidomide/thalidomide 
and bortezomib therapies 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Resistant or refractory to 
lenalidomide/thalidomide 
therapy but not refractory 
to bortezomib 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Resistant or refractory to 
bortezomib therapy but 
not refractory to 
lenalidomide and 
thalidomide 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Other than the above 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.8.1a/b/c/d)  
 
 


 
69 of 164 
Table 11.3.8.2 OS (“All Randomized Patients” population) by lenalidomide/thalidomide or 
bortezomib prior therapies 
Prior therapies 
  
Arm A 
Arm B  
Parameter 
p-value 
Resistant or refractory to 
lenalidomide/thalidomide 
and bortezomib therapies 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
Resistant or refractory to 
lenalidomide/thalidomide 
therapy but not refractory 
to bortezomib 
 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
 
Resistant or refractory to 
bortezomib therapy but 
not refractory to 
lenalidomide and 
thalidomide 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
 
Other than the above 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.8.2a/b/c/d). 
 
 
 


 
70 of 164 
Table 11.3.8.3 Response rate by IMWG (Independent Review assessment and “All 
Randomized Patients” population) by lenalidomide/thalidomide or bortezomib prior 
therapies 
Prior therapies 
 
Response 
Arm A 
Arm B 
N 
% 
N 
% 
 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 
Resistant or refractory to 
lenalidomide/thalidomide and bortezomib 
therapies 
PR 
 
 
 
 
 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
Resistant or refractory to 
lenalidomide/thalidomide therapy but not 
refractory to bortezomib 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 
 
PR 
 
 
 
 
 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 
 
PR 
 
 
 
 
Resistant or refractory to bortezomib 
therapy but not refractory to lenalidomide 
and thalidomide 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 
 
PR 
 
 
 
 
Other than the above 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 (*) Including NE and insufficient data available. 
 
 
 


 
71 of 164 
Table 11.3.8.4 Response rate estimates by IMWG (Independent Review assessment and 
“All Randomized Patients” population) by lenalidomide/thalidomide or bortezomib prior 
therapies 
Prior therapies 
Arm A 
Arm B 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Resistant or refractory to 
lenalidomide/thalidomide 
and bortezomib therapies 
 
 
 
 
 
 
Resistant or refractory to 
lenalidomide/thalidomide 
therapy but not refractory 
to bortezomib 
 
 
 
 
 
 
Resistant or refractory to 
bortezomib therapy but 
not refractory to 
lenalidomide and 
thalidomide 
 
 
 
 
 
 
Other than the above 
 
 
 
 
 
 
Binomial exact estimator and 95% confidence interval 
 
11.3.9 Efficacy analysis in patients refractory to last prior therapy 
 
Patients will be classified as refractory to last prior therapy or other.  
 
Results from independent review assessment are shown in the following tables. ). In case of 
a high difference between independent review and investigator assessments,  RR and PFS 
tables in this section will be duplicated to show the results according to the investigator 
assessment and they will be differentiate with “b” (i.e. 11.3.9.1 will be 11.3.9.1b). 
 
 
Table 11.3.9.1  PFS (Independent Review assessment and “All Randomized Patients” 
population) by refractory patients to last prior therapy 
Prior therapy 
 
Arm A 
Arm B 
Parameter 
p-value 
Refractory to last prior 
therapy 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Other 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.9.1a/b)  
 
 
 


 
72 of 164 
Table 11.3.9.2 OS (“All Randomized Patients” population) by refractory patients to last 
prior therapy 
Prior therapy 
  
Arm A 
Arm B  
Parameter 
p-value 
Refractory to last prior 
therapy 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
 
Other 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.9.2a/b). 
 
Table 11.3.9.3 Response rate by IMWG (Independent Review assessment and “All 
Randomized Patients” population) by refractory patients to last prior therapy 
Prior therapy 
 
Response 
Arm A 
Arm B 
N 
% 
N 
% 
 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 
Refractory to last prior therapy 
PR 
 
 
 
 
 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 
 
PR 
 
 
 
 
Other 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 (*) Including NE and insufficient data available. 
 
Table 11.3.9.4 Response rate estimates by IMWG (Independent Review assessment and 
“All Randomized Patients” population) by refractory patients to last prior therapy 
Prior therapy 
Arm A 
Arm B 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Refractory to last prior 
therapy 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
Binomial exact estimator and 95% confidence interval 
 
 


 
73 of 164 
11.3.10 Efficacy analysis in patients exposed to IMiD therapies 
 
Patients who were exposed to IMiD therapies (pomalidomide, thalidomide or lenalidomide) 
will be classified as responders or refractory  
 
Results from independent review assessment are shown in the following tables. ). In case of 
a high difference between independent review and investigator assessments,  RR and PFS 
tables in this section will be duplicated to show the results according to the investigator 
assessment and they will be differentiate with “b” (i.e. 11.3.10.1 will be 11.3.10.1b). 
 
 
Table 11.3.10.1  PFS (Independent Review assessment and “All Randomized Patients” 
population) in patients exposed to IMiD 
Prior therapy 
 
Arm A 
Arm B 
Parameter 
p-value 
Refractory to IMiD 
therapy 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Responders 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.9.1a/b)  
Table 11.3.10.2 OS (“All Randomized Patients” population) in patients exposed to IMiD 
Prior therapy 
  
Arm A 
Arm B  
Parameter 
p-value 
Refractory to IMiD 
therapy 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
 
Responders 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.9.2a/b). 
 
 
 


 
74 of 164 
Table 11.3.10.3 Response rate by IMWG (Independent Review assessment and “All 
Randomized Patients” population) in patients exposed to IMiD 
Prior therapy 
 
Response 
Arm A 
Arm B 
N 
% 
N 
% 
 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 
Refractory to IMiD therapy 
PR 
 
 
 
 
 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 
 
PR 
 
 
 
 
Responders 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 (*) Including NE and insufficient data available. 
 
Table 11.3.10.4 Response rate estimates by IMWG (Independent Review assessment and 
“All Randomized Patients” population) in patients exposed to IMiD 
Prior therapy 
Arm A 
Arm B 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Refractory to IMiD 
therapy 
 
 
 
 
 
 
Responders 
 
 
 
 
 
 
Binomial exact estimator and 95% confidence interval 
 
11.3.11 Efficacy analysis in patients exposed to PIs therapies 
 
Patients who were exposed to PIs therapies (bortezomib or carfilzomib) will be classified as 
responders or refractory  
 
Results from independent review assessment are shown in the following tables. ). In case of 
a high difference between independent review and investigator assessments,  RR and PFS 
tables in this section will be duplicated to show the results according to the investigator 
assessment and they will be differentiate with “b” (i.e. 11.3.11.1 will be 11.3.11.1b). 
 
 
 


 
75 of 164 
Table 11.3.11.1  PFS (Independent Review assessment and “All Randomized Patients” 
population) in patients exposed to PIs 
Prior therapy 
 
Arm A 
Arm B 
Parameter 
p-value 
Refractory to PIs therapy 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Responders 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.9.1a/b)  
 
Table 11.3.11.2 OS (“All Randomized Patients” population) in patients exposed to PIs 
Prior therapy 
  
Arm A 
Arm B  
Parameter 
p-value 
Refractory to PIs therapy 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
 
Responders 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.9.2a/b). 
 
Table 11.3.11.3 Response rate by IMWG (Independent Review assessment and “All 
Randomized Patients” population) in patients exposed to PIs 
Prior therapy 
 
Response 
Arm A 
Arm B 
N 
% 
N 
% 
 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 
Refractory to PIs therapy 
PR 
 
 
 
 
 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 
 
PR 
 
 
 
 
Responders 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 (*) Including NE and insufficient data available. 


 
76 of 164 
 
Table 11.3.11.4 Response rate estimates by IMWG (Independent Review assessment and 
“All Randomized Patients” population) in patients exposed to PIs 
Prior therapy 
Arm A 
Arm B 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Refractory to PIs therapy  
 
 
 
 
 
Responders 
 
 
 
 
 
 
Binomial exact estimator and 95% confidence interval 
 
 


 
77 of 164 
12 Safety Analysis 
 
Safety analysis will be carried out on the “All Treated Patients” population.  
12.1 Extent of exposure 
12.1.1 Treatment administration 
 
Table 12.1.1.1  Number of cycles administered and dose intensity 
 
Arm A 
Arm B 
No. of cycles administered per patient 
N 
% 
N 
% 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
… 
 
 
 
 
Median (range) 
 
 
 Time on treatment (weeks) 
Median  
Range 
 
 
Plitidepsin cumulative dose (mg/m²) 
 
NA 
Median 
Range 
Plitidepsin dose intensity (mg/m²/wk) 
 
NA 
Median 
Range 
Plitidepsin relative dose intensity (%)  
 
NA 
Median 
Range 
Dexamethasone cumulative dose (mg) 
 
 
Median 
Range 
Dexamethasone dose intensity (mg/wk) 
 
 
Median 
 
Range 
 
Dexamethasone relative dose intensity (%)  
 
 
Median 
 
 
Range 
 
NA: Not applicable. Cycles after crossover will be excluded. 
 
 
 


 
78 of 164 
Table 12.1.1.2 Number of cycles administered and dose intensity after crossover 
 
After crossover 
No. of cycles administered per patient 
N 
% 
1 
 
 
2 
 
 
3 
 
 
… 
 
 
Median (range) 
 
 Time on treatment (weeks) 
Median  
Range 
 
Plitidepsin cumulative dose (mg/m²) 
 
Median 
Range 
Plitidepsin dose intensity (mg/m²/wk) 
 
Median 
Range 
Plitidepsin relative dose intensity (%)  
 
Median 
Range 
Dexamethasone cumulative dose (mg) 
 
Median 
Range 
Dexamethasone dose intensity (mg/wk) 
 
Median 
Range 
Dexamethasone relative dose intensity (%)  
 
Median 
 
Range 
 
12.1.2 Cycle delays  
12.1.2.1 Number of patients and cycles with dosing delay, any relationship 
Listing 12.1.2.1.1 Delays 
Arm 
Patient 
id. 
Cycle 
Day 
Agent 
Previous 
cycle 
Previous 
cycle start 
date 
Delayed 
cycle 
start date 
Dose Delay 
calculated. 
(days) 
Reason 
for dose 
delay 
Dose 
Delay 
Spec. 
… 
 
 
 
 
 
 
 
 
 
 
Results after crossover will be highlighted 
 
Table 12.1.2.1.2 Number of patients and cycles with dosing delay, any relationship 
 
Arm A 
Arm B 
Total 
 
N 
% 
N 
% 
N 
% 
No. of patients treated 
 
 
 
 
 
 
No. of patients with any dose delay 
 
 
 
 
 
 
No. of cycles administered 
 
 
 
 
 
 
No. of cycles susceptible to be delayed* 
 
 
 
 
 
 
No. of cycles with dosing delay** 
 
 
 
 
 
 
No. of patients with  
 
 
 
 
 
 
No cycles delayed 
 
 
 
 
 
 
1 cycle delayed  
 
 
 
 
 
 
2 cycles delayed 
 
 
 
 
 
 
 3 cycles delayed 
 
 
 
 
 
 
(*) All cycles excluding first cycle. (**) Denominator= Number of cycles susceptible to be delayed  
Cycles after crossover will be excluded 


 
79 of 164 
 
Table 12.1.2.1.3 Number of patients and cycles with dosing delay according to the 
relationship 
 
Arm A 
Arm B 
Treatment-related** 
Non-treatment-related 
Treatment-related** 
Non-treatment-related 
N 
% 
N 
% 
N 
% 
N 
% 
No. of patients with  
 
 
 
 
 
 
 
 
1 cycle delayed  
 
 
 
 
 
 
 
 
2 cycles delayed 
 
 
 
 
 
 
 
 
 3 cycles delayed 
 
 
 
 
 
 
 
 
No. of cycles with 
dosing delay* 
 
 
 
 
 
 
 
 
(*) Denominator= Number of cycles susceptible to be delayed. (**)Hematological reason, non-hematological reason or 
both 
Cycles after crossover will be excluded 
 
Table 12.1.2.1.4 Length of dosing delay. 
 
Arm A 
Arm B 
Treatment-
related** 
Non-treatment-
related 
Total 
Treatment-
related** 
Non-treatment-
related 
Total 
Length of 
delay  
Median 
(range) 
 
 
 
 
 
 
Length of delay 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
<= 7 days 
 
 
 
 
 
 
 
 
 
 
 
 
>7 days and <=14 
days 
 
 
 
 
 
 
 
 
 
 
 
 
> 14 days 
 
 
 
 
 
 
 
 
 
 
 
 
(*) Denominator= Number of cycles susceptible to be delayed. (**)Hematological reason, Non-hematological reason or 
both 
Cycles after crossover will be excluded 
 
12.1.2.2 Number of delays according to cycle number 
 
Table 12.1.2.2.1 Number and reasons of delays according to cycle number 
 
No. of 
patients 
No. of 
delays 
Treatment-
related* 
 
 
Treatment-related 
 
Non-
treatment-
related* 
Hematological 
reason 
Non-
hematological 
reason 
Both 
N 
% N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
 
Arm A 
 
Cycle 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle nth 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arm B 
Cycle 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle nth 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(*) Denominator= Number of cycles susceptible to be delayed. 
Cycles after crossover will be excluded 
 
 
 
 


 
80 of 164 
Table 12.1.2.2.2 Dose reduction in cycles delayed 
 
Reduction 
Yes 
No 
N 
% 
N 
% 
 
Arm A 
 
Cycle 2 
 
 
 
 
… 
 
 
 
 
Cycle nth 
 
 
 
 
Total 
 
 
 
 
 
Arm B 
 
Cycle 2 
 
 
 
 
… 
 
 
 
 
Cycle nth 
 
 
 
 
Total 
 
 
 
 
Cycles after crossover will be excluded 
 
The distribution of delays according to the cycle administered will be studied by means of 
counts and percentages. The reasons for cycle delay will be detailed, specifying how many 
were due to treatment or not.  
 
Listing 12.1.2.2.3 Cycle delays due to AEs 
Arm 
Patient 
id. 
Cycle Preferred  
term code 
Adverse 
event 
reported 
(verbatim) 
Grade  Relationship  Onset 
date 
Resolved date 
Significant 
consequences 
… 
 
 
  
 
 
 
 
 
AEs with action = ‘Dose delayed’ or ‘Reduced and delayed’. Results after crossover will be highlighted 
 
12.1.3 Dose omissions 
Listing 12.1.3.1.1 Dose omissions 
Arm 
Patient id. 
Cycle 
Day 
Agent omitted Cycle start date Reason for 
dose omission 
Dose 
omission 
Spec. 
… 
 
 
 
 
 
 
 
Results after crossover will be highlighted 


 
81 of 164 
Table 12.1.3.1.2 Number of patients and cycles with dose omitted, any relationship 
 
Arm A 
Arm B 
Total 
 
N 
% 
N 
% 
N 
% 
No. of patients treated 
X 
XX.X 
X 
XX.X 
X 
XX.X 
No. of patients with any dose omitted 
 
 
 
 
 
 
No. of patients with: 
 
 
 
 
 
 
No plitidepsin omissions 
 
 
NA 
 
 
1 cycle with plitidepsin dose omitted  
 
 
 
 
2 cycles with plitidepsin dose omitted 
 
 
 
 
 3 cycles with plitidepsin dose omitted 
 
 
 
 
No. of patients with: 
 
 
 
 
 
 
No dexamethasone omission 
 
 
 
 
 
 
1 cycle with dexamethasone dose omitted  
 
 
 
 
 
 
2 cycles with dexamethasone dose omitted 
 
 
 
 
 
 
 3 cycles with dexamethasone dose omitted 
 
 
 
 
 
 
No. of cycles administered 
 
 
 
 
 
 
No. of cycles susceptible to have any dose omitted*  
 
 
 
 
 
 
No. of cycles with plitidepsin dosing omitted** 
 
 
NA 
 
 
No. of cycles with dexamethasone  dosing omitted** 
 
 
 
 
 
 
No. of cycles with plitidepsin dosing omitted 
(treatment-related) 
 
 
NA 
 
 
No. of cycles with dexamethasone  dosing omitted 
(treatment-related) 
 
 
 
 
 
 
(*) All cycles excluding first cycle. (**) Denominator= Number of cycles susceptible to have a dose omission  
NA: Not applicable. Cycles after crossover will be excluded 
 
Table 12.1.3.1.3 Number of cycles with treatment-related dose omission by patient 
 
Arm A 
Arm B 
Total 
 
N 
% 
N 
% 
N 
% 
No. of patients with: 
X 
XX.X 
X 
XX.X 
X 
XX.X 
No omission 
 
 
 
 
 
 
1 cycle with treatment-related plitidepsin dose omitted 
 
 
NA 
 
 
2 cycles with treatment-related plitidepsin dose omitted 
 
 
 
 
 3 cycles with treatment-related plitidepsin dose omitted 
 
 
 
 
No. of patients with: 
 
 
 
 
 
 
No omission 
 
 
 
 
 
 
1 cycle with treatment-related dexamethasone dose omitted 
 
 
 
 
 
 
2 cycles with treatment-related dexamethasone dose omitted 
 
 
 
 
 
 
 3 cycles with treatment-related dexamethasone dose omitted 
 
 
 
 
 
 
Denominator= Number of patients that were on treatment on day 14 of cycle 1. 
NA: Not applicable. Cycles after crossover will be excluded 
 


 
82 of 164 
Table 12.1.3.1.4 Reasons for dose omissions 
Reasons for omissions 
 
Arm A 
Arm B 
Total 
 
N 
% 
N 
% 
N 
% 
Plitidepsin 
Treatment-related 
X 
XX.X 
NA 
X 
XX.X 
Hematological 
 
 
 
 
Non-hematological 
 
 
 
 
Both 
 
 
 
 
Non–treatment-related 
 
 
 
 
Dexamethasone 
Treatment-related 
X 
XX.X 
X 
XX.X 
X 
XX.X 
Hematological 
 
 
 
 
 
 
Non-hematological 
 
 
 
 
 
 
Both 
 
 
 
 
 
 
Non-treatment-related 
 
 
 
 
 
 
NA: Not applicable. Cycles after crossover will be excluded 
 
Listing  12.1.3.2 Dose omissions due to AEs 
Arm 
Patient 
id. 
Cycle 
Preferred  
term code 
Adverse 
event 
reported 
(verbatim) 
Grade 
Relationship 
Onset 
date 
Resolved 
date  
Significant 
consequences 
… 
 
 
  
 
 
 
 
 
AEs with action = ‘Dose skipped” on day 8, 15 or 22. Results after crossover will be highlighted 
 
12.1.4 Dose reductions 
All dose reductions should be considered and described, specifying the reason for 
reduction (hematological toxicity, non-hematological toxicity or other causes).  
Listing 12.1.4.1.1 Dose reductions 
Arm 
Patient 
id. 
Cycle 
Day 
Agent 
reduced 
Cycle start 
date 
Previous 
dose 
Reduced 
dose 
Reason for 
dose 
reduction 
Dose 
reduction 
Spec. 
… 
 
 
 
 
 
 
 
 
 
Results after crossover will be highlighted 


 
83 of 164 
Table 12.1.4.2 Number of patients and cycles with dose reduction, any relationship 
 
Arm A 
Arm B 
Total 
 
N 
% 
N 
% 
N 
% 
No. of patients treated 
X 
XX.X 
X 
XX.X 
X 
XX.X 
No. of patients with any dose reduced 
 
 
 
 
 
 
No. of patients with: 
 
 
NA 
 
 
No plitidepsin reduction 
 
 
 
 
1 cycle with plitidepsin dose reduced  
 
 
 
 
2 cycles with plitidepsin dose reduced 
 
 
 
 
No. of patients with: 
 
 
 
 
 
 
No dexamethasone reduction 
 
 
 
 
 
 
1 cycle with dexamethasone dose reduced 
 
 
 
 
 
 
2 cycles with dexamethasone dose reduced 
 
 
 
 
 
 
No. of cycles administered 
 
 
 
 
 
 
No. of cycles susceptible to have any dose reduced*  
 
 
 
 
 
 
No. of cycles with plitidepsin dose reduced ** 
 
 
NA 
 
 
No. of cycles with dexamethasone  dose reduced** 
 
 
 
 
 
 
No. of cycles with plitidepsin dose reduced 
(Treatment-related) 
 
 
NA 
 
 
No. of cycles with dexamethasone  dose reduced 
(Treatment-related) 
 
 
 
 
 
 
(*) All cycles excluding first cycle of those patients who have only received the first infusion. (**) Denominator= Number 
of cycles susceptible to have a dose omission  
NA: Not applicable. Cycles after crossover will be excluded 
 
 
Table 12.1.4.3 Number of patients and cycles with dose reduction according to the 
relationship 
Reasons for reductions 
 
Arm A 
Arm B 
Total 
 
N 
% 
N 
% 
N 
% 
Plitidepsin 
No. of cycles with dose reductions* 
 
NA 
 
Treatment-related 
X 
XX.X 
X 
XX.X 
Hematological 
 
 
 
 
Non-hematological 
 
 
 
 
Both 
 
 
 
 
Non-treatment-related 
 
 
 
 
Dexamethasone 
No. of cycles with dose reductions* 
 
 
 
Treatment-related 
X 
XX.X 
X 
XX.X 
X 
XX.X 
Hematological 
 
 
 
 
 
 
Non-hematological 
 
 
 
 
 
 
Both 
 
 
 
 
 
 
Non–treatment-related 
 
 
 
 
 
 
 (*) Denominator= Number of cycles susceptible to have a dose omission. (**)Hematological reason, non-hematological 
reason or both. 
NA: Not applicable. Cycles after crossover will be excluded 
 
 
Listing  12.1.4.4 Dose reductions due to AEs 
Arm 
Patient 
id. 
Cycle 
Preferred  
term code 
Adverse 
event 
reported 
(verbatim) 
Grade 
Relationship 
Onset 
date 
Resolved 
date  
Significant 
consequences 
… 
 
 
  
 
 
 
 
 
AEs with action = ‘Dose reduced/adjusted’ or ‘Reduced and delayed’. Results after crossover will be highlighted 


 
84 of 164 
 
12.1.5 Infusions temporarily interrupted  
A listing of the patients who had infusions temporarily interrupted with the corresponding 
reasons will be provided. 
Listing  12.1.5.1 Interrupted Infusions listing. 
Arm 
Patient id. 
Cycle 
Infusion 
Interrupted 
Reason 
… 
 
 
 
Yes 
 
Results after crossover will be highlighted 
12.1.6 Prophylactic medication administration  
A listing of the patients who have not received Ondansetron, Diphenhydramine and 
Ranitidine or equivalents in the Arm A with the corresponding reasons will be reported. 
Listing  12.1.6.1 Patients and cycles without prophylactic medication administration 
Arm 
Patient id. 
Cycle 
Infusion 
Prophylactic 
medication not 
taken* 
Reason 
 
… 
 
 
 
 
(*) Ondansetron, diphenhydramine or ranitidine. 
 
 


 
85 of 164 
12.2 Adverse Events (AEs) 
12.2.1 Adverse events 
As far as all the toxicities are concerned, the NCI-CTC grade will be used wherever an 
NCI-CTC grading exists. Otherwise, the severity will be noted. As a convention, the term 
«Grade» will always be used. Toxicities will be described according to the worst NCI-CTC 
grade or, for toxicities which do not form the subject of NCI-CTC classification, according 
to the worst severity. 
In this section the adverse events will be described and different tables will be created for 
events related to treatment (stated as related to at least one of the two trial medications or 
unknown relationship). In case of a high frequency of adverse events attributable only to 
one of the investigational drugs, all tables in this section will be duplicated to show adverse 
events related to plitidepsin or dexamethasone (i.e. table 12.2.2.2, additional tables 
12.2.2.2p and 12.2.2.2d).  
Type of toxicity and worst grade or severity by cycle and by patient will be summarized 
according to the Preferred Term coded with MedDRA. Tables will be organized per 
category of events using System Organ Class of MedDRA. 
12.2.2 Display of adverse events 
 
Table 12.2.2.1 Summary of adverse events. 
Category 
Arm A 
Arm B 
N (%) 
N (%) 
Patients with at least one AE regardless relationship 
 
 
Any treatment-related AE 
 
 
Any grade 3/4 AE 
 
 
Any grade 3/4 treatment-related AE 
 
 
Any SAE in DB 
 
 
Any treatment-related SAE  
 
 
Any grade 3/4 SAE  
 
 
Any grade 3/4 treatment-related SAE  
 
 
AEs leading to death 
 
 
AEs treatment-related leading to death 
 
 
AEs leading to dose delay 
 
 
AEs leading to dose reduction 
 
 
AEs leading to treatment discontinuation 
 
 
AEs treatment-related leading to treatment discontinuation 
 
 
Events with onset date after crossover will be excluded 
 
 


 
86 of 164 
Table 12.2.2.2 Evolution of myeloma-related AEs at baseline 
 
Arm A 
Worst grade per patient 
Total 
0 
1 
… 
N 
% 
N 
% 
N 
% 
N 
% 
Baseline 
Fatigue  
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
Bone Pain 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
Myopathy 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
……………………. 
                                 Arm B 
Fatigue  
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
Bone Pain 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
Myopathy 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
Events with onset date after crossover will be excluded 
 
Table 12.2.2.3 Treatment-related adverse events. Worst grade by patient 
SOC 
Preferred Term 
Arm A 
Arm B 
Grade  
1 
… 
Grade  
4 
All* 
Grade  
1 
… 
Grade  
4 
All* 
 
 
N 
% 
… 
N 
% 
N 
% 
N 
% 
… 
N 
% 
N 
% 
Blood and 
lymphatic system 
disorders 
Anemia NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diarrhea NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac disorders 
Arrhythmia NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(*) Any grade. Events with onset date after crossover will be excluded 
 
Table 12.2.2.4 Treatment-related adverse events. Worst grade by cycle 
 SOC 
Preferred Term 
Arm A 
Arm B 
Grade  
1 
… 
Grade  
4 
All* 
Grade  
1 
… 
Grade  
4 
All* 
 
 
N 
% 
… 
N 
% 
N 
% 
N 
% 
… 
N 
% 
N 
% 
Blood and 
lymphatic system 
disorders 
Anemia NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diarrhea NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac disorders 
Arrhythmia NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Any grade. Events with onset date after crossover will be excluded 
 
 
 


 
87 of 164 
Table 12.2.2.5 Treatment-related adverse events in “All Crossover Patients” population. 
Worst grade by patient 
SOC 
Preferred Term 
Before crossover 
After crossover* 
Grade  
1 
… 
Grade  
4 
All** 
Grade  
1 
… 
Grade  
4 
All** 
 
 
N 
% 
… 
N 
% 
N 
% 
N 
% 
… 
N 
% 
N 
% 
Blood and 
lymphatic system 
disorders 
Anemia NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diarrhea NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac disorders 
Arrhythmia NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(*)All events with onset date ≥ administration date after crossover (**) Any grade 
 
Table 12.2.2.6 Adverse Events regardless of relationship. Worst grade by patient 
SOC 
Preferred Term 
Arm A 
Arm B 
Grade  
1 
… 
Grade  
4 
All* 
Grade  
1 
… 
Grade  
4 
All* 
 
 
N 
% 
… 
N 
% 
N 
% 
N 
% 
… 
N 
% 
N 
% 
Blood and 
lymphatic system 
disorders 
Anemia NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diarrhea NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac disorders 
Arrhythmia NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(*) Any grade. Events with onset date after crossover will be excluded 
 
Table 12.2.2.7 Adverse Events regardless of relationship. Worst grade by cycle 
SOC 
Preferred Term 
Arm A 
Arm B 
Grade  
1 
… 
Grade  
4 
All* 
Grade  
1 
… 
Grade  
4 
All* 
 
 
N 
% 
… 
N 
% 
N 
% 
N 
% 
… 
N 
% 
N 
% 
Blood and 
lymphatic system 
disorders 
Anemia NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diarrhea NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac disorders 
Arrhythmia NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(*) Any grade. Events with onset date after crossover will be excluded 
 
Table 12.2.2.8 Adverse Events regardless of relationship in “All Crossover Patients” 
population. Worst grade by patient 
SOC 
Preferred Term 
Before crossover 
After crossover* 
Grade  
1 
… 
Grade  
4 
All** 
Grade  
1 
… 
Grade  
4 
All** 
 
 
N 
% 
… 
N 
% 
N 
% 
N 
% 
… 
N 
% 
N 
% 
Blood and 
lymphatic system 
disorders 
Anemia NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diarrhea NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac disorders 
Arrhythmia NOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(*)All events with onset date ≥ administration date after crossover (**) Any grade.  
 
Listing 12.2.2.9 Treatment-related grade 3-4 adverse events. Worst grade by patient 
Arm 
Patient id. 
SOC Name 
Preferred term 
Grade 
… 
 
 
 
 
Events with onset date after crossover will be excluded 
 
 
 


 
88 of 164 
Listing 12.2.2.10 Treatment-related grade 3-4 adverse events. Worst grade by cycle 
Arm 
Patient id. 
Cycle 
SOC Name 
Preferred term 
Grade 
… 
 
 
 
 
 
Events with onset date after crossover will be excluded 
 
Listing 12.2.2.11 Adverse Events grade 3-4 regardless of relationship. Worst grade by 
patient 
Arm 
Patient id. 
SOC Name 
Preferred term 
Grade 
… 
 
 
 
 
Events with onset date after crossover will be excluded 
 
Listing 12.2.2.12 Adverse Events grade 3-4 regardless of relationship. Worst grade by cycle 
Arm 
Patient id. 
Cycle 
SOC Name 
Preferred term 
Grade 
… 
 
 
 
 
 
Events with onset date after crossover will be excluded 
 
Listing 12.2.2.13 Treatment-related grade 3-4 adverse events in “All Crossover Patients” 
population. Worst grade by patient 
Arm 
Patient id. 
SOC Name 
Preferred term 
Grade 
… 
 
 
 
 
 
Listing 12.2.2.14 Adverse Events grade 3-4 regardless of relationship in “All Crossover 
Patients” population. Worst grade by patient 
Arm 
Patient id. 
SOC Name 
Preferred term 
Grade 
… 
 
 
 
 
 
At the time of the analysis, if appropriate, grouping of similar or clinically related items 
will be made. 
 
12.3 Serious Adverse Events and deaths.  
12.3.1 Serious Adverse Events 
Listing 12.3.1.1 SAEs 
Arm 
Patient 
id. 
Cycle Preferred  
term code 
Adverse 
event 
reported 
(verbatim) 
Status Grade Relationship Onset 
date 
Resolved 
date 
Action 
Serious 
Criteria 
… 
 
 
  
 
 
 
 
 
 
 
 
SAEs narratives of pharmacovigilance DB will be provided by the pharmacovigilance 
department. 
 
 


 
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12.3.2 Deaths 
 
Table 12.3.2.1 Cause of death 
Reason* 
Arm A 
Arm B 
N 
% 
N 
% 
Malignant disease 
 
 
 
 
Treatment-related adverse event  
 
 
 
 
Other  
 
 
 
 
Total 
 
 
 
 
(*) Denominator=Number of patients who died 
 
Listing 12.3.2.2 Deaths 
Arm 
Patient 
id. 
Death 
date Cause Comments 
Autopsy 
Autopsy 
report 
available 
Number of 
cycles 
administered 
Last 
infusion 
date  
Time on 
treatment* 
Time from 
Last 
dose** 
… 
 
 
 
 
 
 
 
 
 
 
(*)Time on treatment: defined as last infusion date plus 30 days, or date of death or subsequent therapy (whichever comes 
first) minus first infusion date.  (**)Time from last dose defined as death date minus last infusion date.  
 
Listing 12.3.2.3 Deaths due to AEs 
Arm 
Patient 
id.  
Cycle 
Preferred  
term code 
Adverse event 
reported 
(verbatim) 
Grade 
Relationship 
Onset 
date  
Resolved date 
Action 
… 
 
 
  
 
 
 
 
 
* AEs with Seriousness=Death 


 
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12.4 Clinical laboratory evaluation 
12.4.1 Hematological abnormalities 
Hematological toxicities classified according to the NCI-CTC will be calculated for all 
cycles. The worst grade reached by each patient during treatment will be also calculated. 
If serious toxicities happen, special follow-up, with descriptives and graphs (boxplots, line 
plots) will be made to find out the pattern of thrombocytopenia and neutropenia within and 
between the different cycles. 
Table 12.4.1.1 Hematological abnormalities during treatment, worst grade per patient 
 
Arm A 
Arm B 
N 
Grade  
1 
… 
Grade  
4 
All* 
N 
Grade  
1 
… 
Grade  
4 
All* 
 
N 
N 
% 
… 
N 
% 
N 
% 
 
N 
% 
… 
N 
% 
N 
% 
Leukopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thrombocytopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neutropenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lymphopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(*) Any grade. Events with onset date after crossover will be excluded 
 
Table 12.4.1.2 Hematological abnormalities during treatment, worst grade per cycle 
 
Arm A 
Arm B 
N 
Grade  
1 
… 
Grade  
4 
All* 
N 
Grade  
1 
… 
Grade  
4 
All* 
 
N 
N 
% 
… 
N 
% 
N 
% 
 
N 
% 
… 
N 
% 
N 
% 
Leukopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thrombocytopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neutropenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lymphopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(*) Any grade. Events with onset date after crossover will be excluded 
 
Table 12.4.1.3 Hematological abnormalities in during treatment in the “All Crossover 
Patients” population, worst grade per patient 
 
Arm B, before crossover 
Arm B, after crossover to Arm A 
N 
Grade  
1 
… 
Grade  
4 
All* 
N 
Grade  
1 
… 
Grade  
4 
All* 
 
N 
N 
% 
… 
N 
% 
N 
% 
 
N 
% 
… 
N 
% 
N 
% 
Leukopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thrombocytopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neutropenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lymphopenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(*) Any grade 
 
Listing 12.4.1.4 Grade 3-4 hematological abnormalities during treatment. Worst grade per 
patient 
Arm 
Patient id. 
Test 
Grade 
… 
 
 
 
Events with onset date after crossover will be excluded 


 
91 of 164 
Listing 12.4.1.5 Grade 3-4 hematological abnormalities during treatment. Worst grade per 
cycle 
Arm 
Patient id. 
Test 
Grade 
… 
 
 
 
Events with onset date after crossover will be excluded 
Listing 12.4.1.6 Hematological tests not assessed at any treatment visit per patient 
Arm 
Patient id. 
Lab. test 
… 
 
 
Listing 12.4.1.7 Hematological tests not assessed by patient and cycle 
Arm 
Patient id. 
Cycle 
Lab. test 
… 
 
 
 
Table 12.4.1.8 Platelets and RBC transfusions during the study 
 
Platelets (Units) 
Red Blood Cells (Units) 
Arm A 
Arm B 
Arm A 
Arm B 
 
 
N(%) 
N(%) 
N(%) 
N(%) 
Platelets (Units) 
0 transfusions 
 
 
 
 
1 transfusion 
 
 
 
 
… 
 
 
 
 
Median (range) 
 
 
 
 
Red Blood Cells (Units) 
 
0 transfusions 
 
 
 
 
1 transfusion 
 
 
 
 
… 
 
 
 
 
Median (range) 
 
 
 
 
Events with onset date after crossover will be excluded 
 
These tables will be complemented with plots for the median nadir of neutrophils (Figure 
12.4.1.9), platelets count (Figure 12.4.1.10) and hemoglobin values (Figure 12.4.1.11) by 
cycle along the treatment. Furthermore, if appropriate, graphs of the intercycle time course 
of neutropenia and thrombocytopenia will be provided. Eventually, graphs comparing the 
time course during the first and second cycle will be created.  
 
Listing 12.4.1.12 Grade 3-4 hematological abnormalities during treatment in the “All 
Crossover Patients” population. Worst grade per patient 
Arm 
Patient id. 
Test 
Grade 
… 
 
 
 
 
Listing 12.4.1.13 Grade 3-4 hematological abnormalities during treatment in the “All 
Crossover Patients” population. Worst grade per cycle 
Arm 
Patient id. 
Test 
Grade 
… 
 
 
 
 
 
 


 
92 of 164 
12.4.2 Biochemical abnormalities 
Grades of liver toxicity and intercycle pattern of creatinine, CPK, bilirubin, transaminases 
increase and alkaline phosphatase increase during a cycle will be calculated, as it is 
explained in the corresponding section for hematological toxicities. 
 
Table 12.4.2.1 Biochemical abnormalities during treatment, worst grade per patient 
 
Arm A 
Arm B 
N 
Grade  
1 
… 
Grade  
4 
All* 
N 
Grade  
1 
… 
Grade  
4 
All* 
 
N 
N 
% 
… 
N 
% 
N 
% 
 
N 
% 
… 
N 
% 
N 
% 
AST increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALT increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total bilirubin 
increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AP increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Creatinine increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CPK increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(*) Any grade. Events with onset date after crossover will be excluded 
 
Table 12.4.2.2 Biochemical abnormalities during treatment, worst grade per cycle 
 
Arm A 
Arm B 
N 
Grade  
1 
… 
Grade  
4 
All* 
N 
Grade  
1 
… 
Grade  
4 
All* 
 
N 
N 
% 
… 
N 
% 
N 
% 
 
N 
% 
… 
N 
% 
N 
% 
AST increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALT increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total bilirubin 
increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AP increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Creatinine increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CPK increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(*) Any grade. Events with onset date after crossover will be excluded 
 
Table 12.4.2.3 Biochemical abnormalities during treatment in the “All Crossover Patients” 
population, worst grade per patient 
 
Arm B, before crossover 
Arm B, after crossover to Arm A 
N 
Grade  
1 
… 
Grade  
4 
All* 
N 
Grade  
1 
… 
Grade  
4 
All* 
 
N 
N 
% 
… 
N 
% 
N 
% 
 
N 
% 
… 
N 
% 
N 
% 
AST increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALT increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total bilirubin 
increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AP increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Creatinine increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CPK increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(*) Any grade 
 
Listing 12.4.2.4 Grade 3-4 biochemical abnormalities during treatment. Worst grade per 
patient 
Arm 
Patient id. 
Test 
Grade 
… 
 
 
 
Events with onset date after crossover will be excluded 
 


 
93 of 164 
Listing 12.4.2.5 Grade 3-4 biochemical abnormalities during treatment. Worst grade per 
cycle 
Arm 
Patient id. 
Cycle 
Test 
Grade 
… 
 
 
 
 
Events with onset date after crossover will be excluded 
Listing 12.4.2.6 Biochemical tests not assessed at any treatment visit by patient 
Arm 
Patient id. 
Lab. test 
… 
 
 
Listing 12.4.2.7 Biochemical tests not assessed by patient and cycle 
Arm 
Patient id. 
Cycle 
Lab. test 
… 
 
 
 
 
These tables will be complemented with plots for the median peak of ALT (Figure12.4.2.8
), AST (Figure12.4.2.9) and CPK values (Figure12.4.2.10) by cycle along the treatment. If 
appropriate, graphs of the intercycle time course of ALT, AST and CPK will be provided.  
 
Listing 12.4.2.11 Grade 3-4 biochemical abnormalities during treatment in the “All 
Crossover Patients” population. Worst grade per patient 
Arm 
Patient id. 
Test 
Grade 
… 
 
 
 
 
Listing 12.4.2.12 Grade 3-4 biochemical abnormalities during treatment in the “All 
Crossover Patients” population. Worst grade per cycle 
Arm 
Patient id. 
Test 
Grade 
… 
 
 
 
 
12.4.3 Other metabolic parameters 
 
Table 12.4.3.1 Metabolic abnormalities during treatment, worst grade per patient 
 
Arm A 
Arm B 
N 
Grade  
1 
… 
Grade  
4 
All* 
N 
Grade  
1 
… 
Grade  
4 
All* 
 
N 
N 
% 
… 
N 
% 
N 
% 
 
N 
% 
… 
N 
% 
N 
% 
Hyperglycemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypoglycemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypoalbuminemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
…. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(*) Any grade. Events with onset date after crossover will be excluded 
 
Table 12.4.3.2 Metabolic abnormalities during treatment, worst grade per cycle 
 
Arm A 
Arm B 
N 
Grade  
1 
… 
Grade  
4 
All* 
N 
Grade  
1 
… 
Grade  
4 
All* 
 
N 
N 
% 
… 
N 
% 
N 
% 
 
N 
% 
… 
N 
% 
N 
% 
Hyperglycemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypoglycemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypoalbuminemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
…. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(*) Any grade. Events with onset date after crossover will be excluded 


 
94 of 164 
Table 12.4.3.3 Metabolic abnormalities during treatment in the “All Crossover Patients” 
population, worst grade per patient 
 
Arm B, before crossover 
Arm B, after crossover to Arm A 
N 
Grade  
1 
… 
Grade  
4 
All* 
N 
Grade  
1 
… 
Grade  
4 
All* 
 
N 
N 
% 
… 
N 
% 
N 
% 
 
N 
% 
… 
N 
% 
N 
% 
Hyperglycemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypoglycemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypoalbuminemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
…. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(*) Any grade 
 
Listing 12.4.3.4 Grade 3-4 metabolic abnormalities during treatment. Worst grade by 
patient 
Arm 
Patient id. 
Test 
Grade 
… 
 
 
 
Events with onset date after crossover will be excluded 
 
Listing 12.4.3.5 Grade 3-4 metabolic abnormalities during treatment. Worst grade by cycle 
Arm 
Patient id. 
Cycle 
Test 
Grade 
… 
 
 
 
 
Events with onset date after crossover will be excluded 
Listing 12.4.3.6 Metabolic tests not assessed at any treatment visit by patient 
Arm 
Patient id. 
Lab. test 
… 
 
 
Listing 12.4.3.7 Metabolic tests not assessed by patient and cycle 
Arm 
Patient id. 
Cycle 
Lab. test 
… 
 
 
 
 
Listing 12.4.3.8 Grade 3-4 metabolic abnormalities during treatment in the “All Crossover 
Patients” population. Worst grade per patient 
Arm 
Patient id. 
Test 
Grade 
… 
 
 
 
 
Listing 12.4.3.9 Grade 3-4 metabolic abnormalities during treatment in the “All Crossover 
Patients” population. Worst grade per cycle 
Arm 
Patient id. 
Test 
Grade 
… 
 
 
 
 
 
 


 
95 of 164 
12.4.4 Laboratory values over time 
In this section, grades 3-4 hematological and liver enzyme abnormalities will be displayed 
according to the cycle in which they occurred. 
Table 12.4.4.1 Evolution of hematological abnormalities from baseline by treatment arm, 
worst case per patient. 
 
Arm A 
Worst grade per patient 
Total 
0 
1 
… 
N 
% 
N 
% 
N 
% 
N 
% 
Baseline 
Neutropenia  
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
Thrombocytopenia 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
…. 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
                                 Arm B 
Neutropenia  
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
Thrombocytopenia  
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
… 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
Events with onset date after crossover will be excluded 
Table 12.4.4.2 Evolution of transaminase abnormalities from BL by treatment arm, worst 
case per patient. 
 
Arm A 
Worst grade per patient 
Total 
0 
1 
… 
N 
% 
N 
% 
N 
% 
N 
% 
Baseline 
AST increase 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
ALT increase 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
                                 Arm B 
AST increase 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
ALT increase 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
Events with onset date after crossover will be excluded 


 
96 of 164 
Table 12.4.4.3 Grade 3-4 laboratory abnormalities in the first cycle and in all other cycles 
Laboratory  
abnormalities 
Arm A 
Arm B 
Cycle 1 
Cycle>1 
Cycle 1 
Cycle>1 
No. 
cycles 
evaluated 
No. cycles 
grade 3-4 % 
No. 
cycles 
evaluated 
No. 
cycles 
grade 
3-4 
% No. cycles evaluated 
No. 
cycles 
grade 
3-4 
% 
No. 
cycles 
evaluated 
No. 
cycles 
grade 
3-4 
% 
Thrombocytopenia  
 
 
 
 
 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
 
 
 
 
 
 
AP  
 
 
 
 
 
 
 
 
 
 
 
 
Total bilirubin  
 
 
 
 
 
 
 
 
 
 
 
 
AST  
 
 
 
 
 
 
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
 
 
 
 
 
 
Events with onset date after crossover will be excluded 
 
Table 12.4.4.4 ALT time-course pattern 
Laboratory abnormalities 
Onset day  
grade 3-4 
Days in 
grade 3-4 
Day of recovery to 2.5 x ULN 
Days to recovery 
<=28 
29-35 
>35 
<=28 
29-35 
>35 
Arm A 
ALT 
 
 
 
 
 
 
 
 
Arm B 
ALT 
 
 
 
 
 
 
 
 
Events with onset date after crossover will be excluded 
 
Table 12.4.4.5 AST time-course pattern 
Laboratory abnormalities 
Onset day  
grade 3-4 
Days in 
grade 3-4 
Day of recovery to 2.5 x ULN 
Days to recovery 
<=28 
29-35 
>35 
<=28 
29-35 
>35 
Arm A 
AST 
 
 
 
 
 
 
 
 
Arm B 
AST 
 
 
 
 
 
 
 
 
Events with onset date after crossover will be excluded 
 
 
 


 
97 of 164 
12.5 Vital signs, physical findings, LVEF, ECG and other tests related to safety 
12.5.1 Vital signs and physical findings 
 
Table 12.5.1.1 ECOG performance status during the study 
(*) Worst ECOG PS of the cycle determinations. Results after crossover will be highlighted. 
 
Table 12.5.1.2 Weight by patient per cycle 
(*) % of changes respect to baseline Results after crossover will be highlighted. 
 
12.5.2 LVEF, ECG and other related tests 
Listing 12.5.2.1 LVEF evolution during the study. 
Arm 
Patient id. 
LVEF(%) 
Baseline* 
Minimum*  
End of treatment* 
 
 
 
 
 
All 
Median(Range) 
 
 
 
(*) LVEF (%) value and method 
Listing 12.5.2.2 Electrocardiogram results. Evolution during the study. 
Arm 
Patient id. 
Cycle 
ECG result 
… 
 
 
 
Results after crossover will be highlighted. 
Listing 12.5.2.3 Median change in LVEF. 
Arm 
Cycles 
LVEF 
 
Baseline 
XX 
 
Minimum 
YY 
 
End of treatment 
ZZ 
Listing 12.5.2.4 Troponin values. Evolution during the study. 
Arm 
Patient id. 
Cycle 
Infusion 
Value 
ULN 
… 
 
 
 
 
 
Results after crossover will be highlighted. 
 
 
  
Cycle/PS* 
  
0 
1 
2 
3 
.. 
.. 
.. 
Arm/Patient id. 
  
… 
 
 
 
 
. 
. 
. 
… 
 
 
 
 
. 
. 
. 
  
Cycle/Weight 
  
0 
(kg) 
1* 
(%) 
2* 
(%) 
3* 
(%) 
.. 
.. 
.. 
Arm/Patient id. 
  
… 
 
 
 
 
. 
. 
. 
 
 
 
 
 
 
 
 


 
98 of 164 
12.6 Concomitant therapy / procedures according to the ATC classification. 
Table 12.6.1 Concomitant medication during treatment (ATC1, ATC2 and ATC4 levels) 
Medication Term 
(ATC level 1 ) 
Medication Term 
(ATC level 2) 
Medication Term 
(ATC level 4) 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
 
 
 
X 
XX.X 
X 
XX.X 
X 
XX.X 
 
Table 12.6.2 Summary of concomitant medication during treatment 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
No. of systems at BL (ATC1 level) 
 
 
 
 
 
 
0 
1 
2 
 
 
 
 
 
 
 3 
 
 
 
 
 
 
Median (range) 
 
 
 
 
 
 
No. of indications at BL (ATC2 level) 
 
 
 
 
 
 
0 
1 
2 
 
 
 
 
 
 
 3 
 
 
 
 
 
 
Median (range) 
 
 
 
 
 
 
No. of agents at BL (ATC4 level) 
 
 
 
 
 
 
0 
1 
2 
 
 
 
 
 
 
 3 
 
 
 
 
 
 
Median (range) 
 
 
 
 
 
 
Listing  12.6.3 Patients on antiarrhythmics and/or known QT prolongation inducers 
treatment. 
Arm 
Patient 
id. 
Type 
Agent 
Route 
Dose 
Unit 
Start 
date 
Stop 
date 
Reason 
Indication 
… 
 
 
 
 
 
 
 
 
 
 
Listing  12.6.4 Patients with EPO or G-CSF. 
Arm 
Patient 
id. 
Type 
Agent 
Route 
Dose 
Unit 
Start 
date 
Stop 
date 
Reason 
Indication 
… 
 
 
 
 
 
 
 
 
 
 
Listing  12.6.5 Patients with any transfusion during treatment 
Arm 
Patient 
Cycle 
Date 
Specify (Nº units required) 
Reason 
… 
 
 
 
 
 
Taken from concomitant therapy dataset. 
Table 12.6.6 G-CSF, transfusions or EPO during treatment 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
G-CSF 
 
 
 
 
 
 
Platelets transfusions 
 
 
 
 
 
 
RBC transfusions 
 
 
 
 
 
 
EPO 
 
 
 
 
 
 
 


 
99 of 164 
Table 12.6.7 Subsequent therapy 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
Type 
 
 
 
 
 
 
  Chemotherapy 
 
 
 
 
 
 
   … 
 
 
 
 
 
 
Subsequent chemotherapy agents (ATC) 
 
 
 
 
 
 
  … 
 
 
 
 
 
 
   … 
 
 
 
 
 
 
 
Table 12.6.8 Time to subsequent therapy or death 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Time to subsequent therapy or 
death 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
Kaplan-Meier plot will be also shown (Figure 12.6.8)  
 
12.7 Safety analysis in special subgroups 
Table 12.7.1 Worst grade 3-4 by patient in special subgroups (Gender) 
Events 
Arm A 
Arm B 
Male 
Female 
Male 
Female 
N 
Grade 3-4 
% 
N 
Grade 
3-4 
% 
N 
Grade 
3-4 
% 
N 
Grade 
3-4 
% 
Thrombocytopenia  
 
 
 
 
 
 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
 
 
 
 
 
 
AP  
 
 
 
 
 
 
 
 
 
 
 
 
Total bilirubin  
 
 
 
 
 
 
 
 
 
 
 
 
AST  
 
 
 
 
 
 
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
 
 
 
 
 
 
(*)Any treatment-related toxicity present in >=5% of patients in any group 
 


 
100 of 164 
Table 12.7.2 Worst grade 3-4 by patient in special subgroups (Age) 
Events 
Arm A 
Arm B 
<65 years old 
…** 
<65 years old 
…** 
N 
Grade 3-4 
% 
N 
Grade 
3-4 
% 
N 
Grade 
3-4 
% 
N 
Grade 
3-4 
% 
Thrombocytopenia  
 
 
 
 
 
 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
 
 
 
 
 
 
AP  
 
 
 
 
 
 
 
 
 
 
 
 
Total bilirubin  
 
 
 
 
 
 
 
 
 
 
 
 
AST  
 
 
 
 
 
 
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
 
 
 
 
 
 
(*)Any treatment-related toxicity present in >=5% of patients in any group 
(**) Age 65-74, Age 75-84, Age ≥85. If there is a group of age with less than 5% of patients, it could be join with the 
previous/next group of age. 
 
Table 12.7.3 Worst grade 3-4 by patient in special subgroups (BMI) 
Events 
Arm A 
Arm B 
<30 
≥30 
<30 
≥30 
N 
Grade 3-4 
% 
N 
Grade 
3-4 
% 
N 
Grade 
3-4 
% 
N 
Grade 
3-4 
% 
Thrombocytopenia  
 
 
 
 
 
 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
 
 
 
 
 
 
AP  
 
 
 
 
 
 
 
 
 
 
 
 
Total bilirubin  
 
 
 
 
 
 
 
 
 
 
 
 
AST  
 
 
 
 
 
 
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
 
 
 
 
 
 
(*)Any treatment-related toxicity present in >=5% of patients in any group 
 
 
 


 
101 of 164 
12.8 Time to PS (ECOG) deterioration as index of QoL 
 
Table 12.8.1 Time to PS (ECOG) deterioration 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Time to first PS (ECOG) 
deterioration 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
Kaplan-Meier plot will be also shown (Figure 12.8.1)  
Time to PS value 2 or worse in patients with PS 0 or 1 at baseline will be assessed 


 
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APPENDIX II 
13 DB Listings 
 
CRF Listings. 
 
-Listing 13.1.1: Cover 
-Listing 13.1.2: Study registration 
-Listing 13.1.3: Demography 
-Listing 13.1.4: Pregnancy test 
-Listing 13.1.5: Prior history 
-Listing 13.1.6: Multiple myeloma history 
-Listing 13.1.7: Prior radiotherapy 
-Listing 13.1.8: Prior anticancer therapy 
-Listing 13.1.9: Prophylactic medication 
-Listing 13.1.10: Drug administration 
-Listing 13.1.11: Hematology laboratory values 
-Listing 13.1.12: Biochemical laboratory values 
-Listing 13.1.13: Coagulation laboratory values 
-Listing 13.1.14: Physical examination 
-Listing 13.1.15: Performance status 
-Listing 13.1.16: Vital signs 
-Listing 13.1.17: Electrocardiogram 
-Listing 13.1.18: LVEF 
-Listing 13.1.19: MM protein measurements 
-Listing 13.1.20: Bone marrow assessment 
-Listing 13.1.21: Tumor evaluation 
-Listing 13.1.22: Adverse events (including signs and symptoms) 
-Listing 13.1.23: Concomitant therapy/procedures 
-Listing 13.1.24: Overall response assessment by cycle 
-Listing 13.1.25: Best overall response 
-Listing 13.1.26: End of treatment 
-Listing 13.1.27: Follow up 
-Listing 13.1.28: Death report form 
-Listing 13.1.29: Off study 
-Listing 13.1.30: Signature report 
-Listing 13.1.31: Investigator comments 
 
External review listings 
 
-Listing 13.1.32: MM protein measurement review 
-Listing 13.1.33: Bone marrow assessment review 
-Listing 13.1.34: Tumor evaluation review 
-Listing 13.1.35: External response review 


 
103 of 164 
14 References 
 
1. O’Brien P, Fleming T. A multiple testing procedure for clinical trials. Biometrics 
1979; 35, 549-556. 
2. Robins JM, Tsiatis AA. Correcting for non-compliance in randomized trials using 
rank preserving structural failure time models. Commun Statist Theory Meth. 
1991;20(8):2609-31. 
3. Turnbull B. The empirical distribution function with arbitrary grouped, censored 
and truncated data. J R Stat Soc Ser B 1976; 38:290–295 
4. SAS OnlineDoc, V9.  
5. Parmar M. Machin D. Survival analysis. A practical approach. Wiley, Chichester, 
1995.  
6. Robins JM, Finkelstein DM: Correcting for noncompliance and dependent 
censoring in an AIDS Clinical Trial with inverse probability of censoring weighted 
(IPCW) log-rank tests. Biometrics 56:779-788, 2000. 
7. Latimer NR, Abrams KR, Lambert PC, Crowther MJ, Wailoo AJ, Morden JP, 
Akehurst RL, Campbell MJ. Adjusting survival time estimates to account for 
treatment switching in randomized controlled trials--an economic evaluation 
context: methods, limitations, and recommendations. Med Decis Making 
2014;34(3):387-402. 


 
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15  Revision History 
 
From Statistical Analysis Plan v5.0 to v6.0: 
This amendment of the Statistical Analysis Plan (SAP) is intended to incorporate an 
additional overall survival sensitivity analysis in order to better characterize the impact of 
crossover in arm B. The addition of this new analysis was consulted and agreed with the 
EMA Product Team Members in a clarification meeting that took place on 12th of June of 
2017. 
The nature of these analyses is supportive for the secondary analyses of overall survival 
already described in previous versions of the SAP. 
 
Rational of changes: 
In order to improve the characterisation of the actual impact of crossover in those patients 
who switched from DXM (Arm B) to plitidepsin plus DXM (Arm A), an analysis based on 
the two-stage method proposed by Latimer et al. (7) is performed.  
Briefly, the two-stage estimation is a method that provides a good fit to the treatment 
change mechanics often observed in oncology. Usually, switching is only permitted after 
disease progression, but this is likely to occur shortly afterwards. In that case, disease 
progression can be used as a secondary baseline for patients in the control group. Fitting a 
Weibull model would be expected to produce a reasonable estimate of the effect resulting 
from switching to the experimental treatment, provided that 1) the model fits the data, 2) 
“no unmeasured confounders” are present at the secondary baseline, and 3) switching 
occurs soon after the secondary baseline. The resulting acceleration factor associated with 
treatment change could then be used to “shrink” survival times in switching patients to 
derive a counterfactual survival dataset upon which standard survival analysis could be 
undertaken. 
 
CHANGES: 
 
Included changes are highlighted in Italic Bold. 
 
PAGE 16-17: Section 6.2.3 Secondary analyses – Overall survival 
 
Original text: 
 
It is anticipated that an indeterminate number of patients in the control arm will switch 
treatment after progression to plitidepsin plus dexamethasone. This could cause the size of 
the effect on OS to be difficult to interpret. Consequently, if the OS results show to be 
substantially influenced by crossover, the Sponsor will study the estimated effect of 
crossover in a first sensitivity analysis excluding the patients who crossed over and a 
second analysis censoring survival at the time of crossover. Estimates of the unbiased effect 
in survival will be studied by means of, rank preserving structural failure time (RPSFT) 


 
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models for correcting for treatment changes (2) and by the inverse probability of censoring 
weighting (IPCW) method (6). 
The following time-dependent covariates will be included in the IPCW analysis: ECOG, 
Body Surface Area (BSA), m-protein value (serum/urine), number of adverse events 
grade≥3, bone marrow plasma cells, creatinine, LDH, hemoglobin and corrected serum 
calcium. Also, baseline covariates such us gender, age, MM type (i.e.: IgG, IgA, light chain 
myeloma, non-secretory), number of prior lines of anticancer treatment, status (relapsed vs. 
relapsed/refractory), refractory status to bortezomib, lenalidomide/thalidomide prior 
therapy, refractory status to last prior therapy, refractory status to IMiD therapy, refractory 
status to PIs therapy, genetic risk, previous SCT, time from diagnosis to randomization, 
time from last progression before randomization, International Staging System, Durie-
Salmon stage, presence of plasmacytomas, presence of lytic lesions, number of 
plasmacytomas, sum of the dimensions of plamacytomas,  will be included. 
 
Changes to: 
It is anticipated that an indeterminate number of patients in the control arm will switch 
treatment after progression to plitidepsin plus dexamethasone. This could cause the size of 
the effect on OS to be difficult to interpret. Consequently, if the OS results show to be 
substantially influenced by crossover, the Sponsor will study the estimated effect of 
crossover in a first sensitivity analysis excluding the patients who crossed over and a 
second analysis censoring survival at the time of crossover. Estimates of the unbiased effect 
in survival will be studied by means of, rank preserving structural failure time (RPSFT) 
models for correcting for treatment changes (2), and by the inverse probability of censoring 
weighting (IPCW) method (6) and by means of the two-stage method proposed by Latimer 
et al. (7) in order to try to control any bias caused by treatment crossover. 
The following time-dependent covariates will be included in the IPCW analysis: ECOG, 
Body Surface Area (BSA), m-protein value (serum/urine), number of adverse events 
grade≥3, bone marrow plasma cells, creatinine, LDH, hemoglobin and corrected serum 
calcium. Also, baseline covariates such us gender, age, MM type (i.e.: IgG, IgA, light chain 
myeloma, non-secretory), number of prior lines of anticancer treatment, status (relapsed vs. 
relapsed/refractory), refractory status to bortezomib, lenalidomide/thalidomide prior 
therapy, refractory status to last prior therapy, refractory status to IMiD therapy, refractory 
status to PIs therapy, genetic risk, previous SCT, time from diagnosis to randomization, 
time from last progression before randomization, International Staging System, Durie-
Salmon stage, presence of plasmacytomas, presence of lytic lesions, number of 
plasmacytomas, sum of the dimensions of plamacytomas,  will be included. 
 
PAGE 49, section 11.3.4.1 OS analyses 
 
ADDED 
 
Table 11.3.4.1.11 OS (“All Randomized Patients” population and Two-stage method) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  


 
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Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.4.1.11). 
 
A forest plot (Figure 11.3.4.1.12)  with the summary of hazard ratios for OS in the different 
analysis populations will be shown to check the consistency across the different 
measurements. 
 
Supportive analyses needed to adjust OS by crossover by the two-stage method 
 
Table 11.3.4.1.13 Logistic regression (Crossover patients vs no crossover patients) 
Analysis of Maximum Likelihood Estimates* 
Variable Label 
Variable 
values 
DF 
Parameter 
Estimate 
Standard 
Error 
Chi-
Square 
Pr > ChiSq 
Odds 
Ratio 
95% Odds 
Ratio 
Confidence 
Limits 
 
 
 
 
 
 
 
 
 
* Logistic regression 
See list of covariates in section 6.2.3 
 
Table 11.3.4.1.14 PFS (Crossover patients vs no crossover patients) 
  
Crossover 
No crossover  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
Kaplan-Meier plot will be also shown (Figure 11.3.4.1.14). 
 
Table 11.3.4.1.15 Post progression survival (Weibull adjustment) 
Analysis of Maximum Likelihood Parameter Estimates 
Parameter 
 
DF 
Estimate 
Standard 
Error 
95% Confidence Limits 
Chi-Square 
Pr > ChiSq 
Intercept 
 
 
 
 
 
 
 
 
Treatment arm 
- 
 
 
 
 
 
 
 
Treatment arm 
Crossover 
 
 
 
 
 
 
 
Scale 
 
 
 
 
 
 
 
 
Weibull Shape 
 
 
 
 
 
 
 
 
 
PAGE 103, section 14 References 
 
ADDED 
 
1. Latimer NR, Abrams KR, Lambert PC, Crowther MJ, Wailoo AJ, Morden JP, 
Akehurst RL, Campbell MJ. Adjusting survival time estimates to account for 
treatment switching in randomized controlled trials--an economic evaluation 
context: methods, limitations, and recommendations. Med Decis Making 
2014;34(3):387-402. 


 
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From Statistical Analysis Plan v4.0 to v5.0: 
This amendment of the Statistical Analysis Plan (SAP) is intended to incorporate some 
additional analysis and clarifications requested during the pre-submission meetings on  
(22Apr2016), (27Jun2016) and (30Jun2016), by the EMA Product Team Members, and the 
CHMP Rapporteur and CHMP Co-Rapporteur appointed for the evaluation of the 
Marketing Authorization Application of plitidepsin in multiple myeloma in relation with 
the clinical part of the dossier. 
The nature of these analyses is supportive for the main and secondary analyses already 
described in previous versions of the SAP. 
 
Rational of changes: 
A comparison of the baseline characteristics in patients with Crossover vs. No crossover 
has been requested to rule out that patients with crossover can have a better prognosis than 
patients without crossover. Analysis will be added in section 11. 
A description of patients with crossover will be provided in order to confirm if PD prior to 
crossover was seen. Supplementary statistics of the time (in months) from study initiation 
to crossover will also be included. 
After discussion with the agencies personnel who will be involved in the assessment of the 
centralized procedure for Aplidin, the sensitivity analysis of PFS taking into account the 
confirmation of PD has been pointed out as a key sensitivity analysis to put in context the 
results of Admyre. Thus, not only the univariate analysis of PFS with confirmation of PD 
by IA, IRC but also subgroup analysis, and analysis of other secondary endpoints like DR 
using this second algorithm for determination of PD will be added to the set of sensitivity 
analyses.   
In line with the discussion on the management of patients with or without confirmation of 
PD, a measure of the time from randomization to treatment failure that leads to the need of 
a further treatment regimen (regardless the method of PD detection or the components of 
the PD) could by the Time to first subsequent therapy or death. This will be included as 
supportive analysis. 
An analysis of the median time window between the first PD and its confirmation in a 
second assessment has been requested to rule out that confirmation of PD could have been 
advanced or delayed in any of the treatment groups. 
Multivariate analyses of PFS by IRC (adding region as a covariate) have been added to 
check if there are differences in the main efficacy endpoint between different 
continents/geographical areas. 
Since the clinical benefit in terms of objective response is measured in different studies and 
along the different response criteria versions with and without taking into account the MR, 
a sensitivity analysis of response and its duration will be performed taking into account 
response equal PR or better. In addition, time to response with and without MR will be 
added. 


 
109 of 164 
The SAP includes different secondary analyses of OS taking into account a potential effect 
of crossover. It has been hypothesized that patients without crossover or subsequent 
therapies could have a worse prognosis. Analyses will be carried out to investigate the 
isolated effect of study treatments in survival in the population of patient without 
subsequent therapy. 
Supportive analysis to describe potential effects of the study drugs in QoL has been 
requested. Since patient reported outcome questionnaires have not been collected in this 
study, an indirect measure like time to first performance status deterioration have been 
added. 
 
CHANGES: 
 
Included changes are highlighted in Italic Bold. 
 
PAGE 5: ABBREVIATIONS AND GLOSSARY 
 
ADDED 
 
CHMP 
Committee for Medicinal Products for Human Use 
… 
 
EMA 
European Medicines Agency 
… 
 
QoL 
Quality of Life 
 
PAGE 17: Section 6.2.3 Secondary analyses – Overall survival 
ADDED 
An analysis will be carried out in the subpopulation of patients without crossover or 
subsequent therapy in order to investigate the isolated effect of study treatments in survival 
in this subpopulation. It will be also carried out in the subpopulation of patients without 
crossover or subsequent therapy and with event in the primary analysis of PFS by IRC. 
 
PAGE 17: Section 6.2.3 Secondary analyses – Response rate 
ADDED 
A supportive analysis of response rate will be performed taking into account PR or better 
as best overall response based on the IMWG criteria. 
 
PAGE 17: Section 6.2.3 Secondary analyses – Duration of response 
ADDED 
DR requiring confirmation of PD for determination of PFS will be analyzed according to 
the Kaplan-Meier method and compared between treatment groups using the log-rank test. 
DR for patients who have PR or better as best overall response based on the IMWG criteria 
will be calculated as a supportive analysis. 


 
110 of 164 
 
PAGE 17: Section 6.2.3 Secondary analyses – Time to response 
ADDED 
Time to response 
Time to response will be analyzed according to the Kaplan-Meier method and compared 
between treatment groups using the log-rank test. 
Time to response for patients who have PR or better as best overall response based on the 
IMWG criteria will be also calculated as a supportive analysis. 
 
PAGE 17: Section 6.2.3 Secondary analyses – Analysis of crossover 
ADDED 
A comparison of the baseline characteristics in patients with Crossover vs No crossover 
will be done to rule out that patients with crossover can have a better prognosis than 
patients without crossover.  
A listing of patients with crossover will be provided in order to confirm if PD was seen 
before crossover and if this PD was confirmed. 
Statistics of the time (in months) from study initiation to crossover will also be included. 
 
PAGE 18: Section 6.2.3 Secondary analyses – Symmetry evaluations 
ADDED 
An analysis of the median time window between the first documentation of PD and PD 
confirmation in a second assessment will be done to rule out that confirmation of PD could 
have been advanced or delayed in any of the treatment groups. 
 
PAGE 18: Section 6.2.3 Secondary analyses – Analysis of prognostic factors, subgroup 
analysis and multivariate analyses 
ADDED 
…. 
The analyses above will be also performed for the sensitivity analysis of PFS with 
confirmation of PD by IRC and IA. 
In addition, and in order to check if there are differences in the main efficacy endpoint 
between different continents/geographical areas, multivariate analyses of PFS by IRC, 
adding region as a covariate, will be performed. The variable “region” will be created 
with four categories (Europe, Asia, Oceania, and USA) and then three Cox regressions will 
be performed.  
1) 
PFS by IRC with arm, region and interaction term.  
2) 
PFS by IRC with arm and region as main effects. 


 
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3) 
Full model selected in the multivariate analysis of PFS by IRC, including region as 
variable. 
 
PAGE 21: Section 8.3 Subsequent therapy 
ADDED 
Time to first subsequent therapy or death will be analyzed as a measure of the time from 
randomization to treatment failure that leads to the need of a further treatment regimen 
(regardless the method of PD detection or the components of the PD). 
 
PAGE 23: Section 8.13 Analyses of performance status as a index of quality of life 
ADDED 
8.13 Analyses of performance status as a index of quality of life 
Since patient reported outcome questionnaires have not been collected  in this study, 
indirect measures of improvement like time to first performance status deterioration will be 
analyzed according to the Kaplan-Meier method  
 
PAGE 28: Section 11.1.1 Patient characteristics at baseline 
ADDED 
Table 11.1.1.4 Baseline characteristics comparison by treatment arm 
Variable** 
Value 
N 
Arm A 
Arm B 
p-value* 
Sex 
F 
XXX 
XX (XX.X%) 
XX (XX.X%) 
X.XXXX 
M 
XXX 
XX (XX.X%) 
XX (XX.X%) 
 
Age 
Median(range) XXX 
XX.X (XX-XX) 
XX.X (XX-XX) 
X.XXXX 
… 
 
 
 
 
 
(*)Fisher’s exact test (categorical variables); Mann-Whitney-Wilcoxon (continuous variables) 
(**)Sex, age, region, PS (ECOG), BSA, Durie Salmon stage, International Staging System, Secretory/Non-secretory, MM 
type, time from diagnosis, time from last PD, number of prior lines, status to prior therapy, status to prior bortezomib 
therapy, status to prior thalidomide/lenalidomide therapy, status to prior IMiD therapy, status to prior PIs therapy, stem 
cell transplantation, plasma cells, hemoglobin, creatinine, calcium, genetic risk, lytic lesions and plasmacytomas. 
 
PAGE 46, section 11.3.3 Sensitivity analyses of PFS 
 
ADDED 
Table 11.3.3.10 Time to PD confirmation (Independent Review Assessment and “All 
Randomized Patients” population) 
 
Arm A 
Arm B 
p-value 
Median 
95% CI 
Median 
95% CI 
Time to PD 
confirmation 
(days) 
 
 
 
 
 
 
 


 
112 of 164 
 
Table 11.3.3.11 Time to PD confirmation (Investigator Assessment and “All Randomized 
Patients” population) 
 
Arm A 
Arm B 
p-value 
Median 
95% CI 
Median 
95% CI 
Time to PD 
confirmation 
(days) 
 
 
 
 
 
 
 
 
 
 


 
113 of 164 
PAGE 49, section 11.3.4.1 OS analyses 
 
ADDED 
 
Table 11.3.4.1.9 OS (Subpopulation without crossover or subsequent therapy) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.4.1.9). 
 
Table 11.3.4.1.10 OS (Subpopulation of patients with event in the primary analysis and 
without crossover or subsequent therapy) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.4.1.10). 
 
 
PAGE 51, section 11.3.4.2 Response rate by independent review committee 
 
ADDED 
 
Table 11.3.4.2.8 Response rate estimates without MR by IMWG (Independent Review 
assessment and “All Randomized Patients” population) 
 
Arm A 
Arm B 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Response rate 
 
 
 
 
 
 
Binomial estimates and 95% exact confidence interval 
 
Table 11.3.4.2.9 Response rate comparison without MR by IMWG (Independent Review 
assessment and “All Randomized Patients” population) 
Response rate 
Arm A 
Arm B 
Fisher exact test 
(p-value) 
N 
% 
N 
% 
sCR+CR+VGPR+PR 
 
 
 
 
 
MR+SD+PD+UK* 
 
 
 
 
 (*) Including NE and insufficient data available. 
 
Table 11.3.4.2.10 Response rate estimates without MR by IMWG (Independent Review 
assessment and “All Evaluable Patients” population) 
 
Arm A 
Arm B 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Response rate 
 
 
 
 
 
 


 
114 of 164 
Binomial estimates and 95% exact confidence interval 
 
Table 11.3.4.2.11 Response rate comparison without MR by IMWG (Independent Review 
assessment and “All Evaluable Patients” population) 
Response rate 
Arm A 
Arm B 
Fisher exact test 
(p-value) 
N 
% 
N 
% 
sCR+CR+VGPR+PR 
 
 
 
 
 
MR+SD+PD 
 
 
 
 
 
Table 11.3.4.2.12 Median Time to Response (Independent Review assessment) 
 
Arm A 
Arm B 
Median 
95% CI  
Median 
95% CI  
Time to response* 
 
 
 
 
 (*)sCR, CR, VGPR, PR or MR 
 
Table 11.3.4.2.13 Median Time to Response without MR  (Independent Review 
assessment) 
 
Arm A 
Arm B 
Median 
95% CI  
Median 
95% CI  
Time to response* 
 
 
 
 
 (*)sCR, CR, VGPR or PR 
 
PAGE 53, section 11.3.4.3 Response rate by investigator assessment 
 
ADDED 
 
Table 11.3.4.3.7 Response rate estimates without MR by IMWG (Investigator assessment 
and “All Randomized Patients” population) 
 
Arm A 
Arm B 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Response rate 
 
 
 
 
 
 
Binomial estimates and 95% exact confidence interval 
 
Table 11.3.4.3.8 Response rate comparison without MR by IMWG (Investigator assessment 
and “All Randomized Patients” population) 
Response rate 
Arm A 
Arm B 
Fisher exact test 
(p-value) 
N 
% 
N 
% 
sCR+CR+VGPR+PR 
 
 
 
 
 
MR+SD+PD+UK* 
 
 
 
 
 (*) Including NE and insufficient data available. 
 
Table 11.3.4.3.9 Response rate estimates without MR by IMWG (Investigator assessment 
and “All Evaluable Patients” population) 
 
Arm A 
Arm B 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Response rate 
 
 
 
 
 
 
Binomial estimates and 95% exact confidence interval 
 
 
 


 
115 of 164 
Table 11.3.4.3.10 Response rate comparison without MR by IMWG (Investigator 
assessment and “All Evaluable Patients” population) 
Response rate 
Arm A 
Arm B 
Fisher exact test 
(p-value) 
N 
% 
N 
% 
sCR+CR+VGPR+PR 
 
 
 
 
 
MR+SD+PD 
 
 
 
 
 
Table 11.3.4.3.11 Median Time to Response (Investigator assessment) 
 
Arm A 
Arm B 
Median 
95% CI  
Median 
95% CI  
Time to response* 
 
 
 
 
 (*)sCR, CR, VGPR, PR or MR 
 
Table 11.3.4.3.12 Median Time to Response without MR  (Investigator assessment) 
 
Arm A 
Arm B 
Median 
95% CI  
Median 
95% CI  
Time to response* 
 
 
 
 
 (*)sCR, CR, VGPR or PR 
 
PAGE 54, section 11.3.4.4 Duration of response 
 
ADDED 
 
Table 11.3.4.4.3 DR without MR (Independent Review assessment and “All Responder 
Patients” population) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median DR 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
DR at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.4.4.3)  
 
Table 11.3.4.4.4 DR without MR (Investigator assessment and “All Responder Patients” 
population) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median DR 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
DR at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.4.4.4)  
 
 
 


 
116 of 164 
Table 11.3.4.4.5 DR with PD confirmation (Independent Review assessment and “All 
Responder Patients” population) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median DR 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
DR at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.4.4.5)  
 
Table 11.3.4.4.6 DR with PD confirmation (Investigator assessment and “All Responder 
Patients” population) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median DR 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
DR at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.4.4.6) 
 
PAGE 56, section 11.3.4.5 Analysis of crossover 
 
ADDED 
Listing 11.3.4.5.4 Best response and PFS before in crossover patients. 
Patient 
id. 
Independent review assessment 
Investigator assessment 
Best 
response 
PFS 
PFS event 
PD 
confirmation 
Best 
response 
PFS 
PFS event 
PD 
confirmation 
… 
 
 
 
 
 
 
 
 
 
Table 11.3.4.5.5 Time to crossover  
 
N 
Median 
Min 
Max 
Time to crossover (months) 
 
 
 
 
 
Table 11.3.4.5.6 Baseline characteristics comparison patients without crossover vs 
crossover 
Variable** 
Value 
N 
Without Crossover 
Crossover 
p-value* 
Sex 
F 
XXX 
XX (XX.X%) 
XX (XX.X%) 
X.XXXX 
M 
XXX 
XX (XX.X%) 
XX (XX.X%) 
 
Age 
Median(range) XXX 
XX.X (XX-XX) 
XX.X (XX-XX) 
X.XXXX 
… 
 
 
 
 
 
(*)Fisher’s exact test (categorical variables); Mann-Whitney-Wilcoxon (continuous variables) 
(**)Sex, age, PS (ECOG), BSA, Durie Salmon stage, International Staging System, Secretory/Non-secretory, MM type, 
time from diagnosis, time from last PD, number of prior lines, status to prior therapy, status to prior bortezomib therapy, 
status to prior thalidomide/lenalidomide therapy, status to prior IMiD therapy, status to prior PIs therapy, stem cell 
transplantation, plasma cells, hemoglobin, creatinine, calcium, genetic risk, lytic lesions and plasmacytomas. 
 
 
 


 
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PAGE 59, section 11.3.4.8 Univariate analyses 
 
ADDED 
 
Table 11.4.3.8.7 Univariate analysis of PFS with PD confirmation (Independent Review 
assessment and “All Randomized Patients” population) 
 
Arm A 
Arm B 
 
Prognostic factors** 
Median 
(months) 
Lower 
95% 
Confidence 
Limit 
Upper 
95% 
Confidence 
Limit 
Median 
(months) 
Lower 
95% 
Confidence 
Limit 
Upper 
95% 
Confidence 
Limit 
 
p-value* 
Gender 
 
 
 
 
 
 
 
Age 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 (*) Cox regression. (**) See covariate listing in section 6.2.3. A forest plot with the summary of HR will be also shown 
(Figure 11.3.4.8.7)  
 
 
PAGE 61, section 11.3.4.9 Multivariate analyses 
 
ADDED 
 
Table 11.3.4.9.6 Multivariate analysis of PFS by region (Independent Review assessment 
and “All Randomized Patients” population) 
Analysis of Maximum Likelihood Estimates* 
Variable Label 
Variable 
values 
DF 
Parameter 
Estimate 
Standard 
Error 
Chi-
Square 
Pr > ChiSq 
Hazard 
Ratio 
95% Hazard 
Ratio 
Confidence 
Limits 
 
 
 
 
 
 
 
 
 
* Cox regression 
See list of covariates in section 6.2.3 
 
Table 11.3.4.9.7 Multivariate analysis of PFS with PD confirmation (Independent Review 
assessment and “All Randomized Patients” population) 
Analysis of Maximum Likelihood Estimates* 
Variable Label 
Variable 
values 
DF 
Parameter 
Estimate 
Standard 
Error 
Chi-
Square 
Pr > ChiSq 
Hazard 
Ratio 
95% Hazard 
Ratio 
Confidence 
Limits 
 
 
 
 
 
 
 
 
 
* Cox regression 
See list of covariates in section 6.2.3 
 
 
PAGE 102, section 12.6 Concomitant therapy / procedures according to the ATC 
classification 
 
ADDED 
 
Table 12.6.8 Time to subsequent therapy or death 


 
118 of 164 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Time to subsequent therapy or 
death 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
Kaplan-Meier plot will be also shown (Figure 12.6.8)  
 
PAGE 104 Section 12.8 Time to PS (ECOG) deterioration as index of QoL 
 
ADDED 
 
12.8 Time to PS (ECOG) deterioration as index of QoL 
 
Table 12.8.1 Time to PS (ECOG) deterioration 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Time to first PS (ECOG) 
deterioration 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
Kaplan-Meier plot will be also shown (Figure 12.8.1) 
Time to PS value 2 or worse in patients with PS 0 or 1 at baseline will be assessed. 
 
 


 
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From Statistical Analysis Plan v3.0 to v4.0: 
 
Rational of changes: 
According to EMA guideline “E7 Geriatric Studies”, the sponsor has decided to update the 
SAP to fulfil these requirements. Geriatric patients can respond differently from younger 
patients to drug therapy, therefore supportive and exploratory age subgroup analyses have 
been included in this amendment.   
In order to characterize the efficacy of Aplidin plus dexamethasone in elderly population, 
subgroups analyses by age have been added in the efficacy and safety sections. 
In addition, other sentitivity analyses for the main endpoint comparison of the study and 
description of censoring reasons for OS have been added in order to get a better 
understanding of the results. Clarification regarding evaluability has been done in order to 
make clearer how patients are classified as Evaluable for efficacy. 
New exploratory efficacy analyses have been added according to the refractory status to 
prior therapies such as bortezomib, lenalidomide/thalidomide, last prior therapy, IMiD 
therapy and PIs therapy and according to the genetic risk. 
Minor corrections and analysis clarifications have been added. 
 
CHANGES: 
 
Included changes are highlighted in Italic Bold. 
 
PAGE 5: ABBREVIATIONS AND GLOSSARY 
 
ADDED 
 
IMiD 
Immunomodulatory Drug 
… 
 
IPCW 
Inverse Probability of Censoring Weighting 
… 
 
PIs 
Proteasome Inhibitors 
… 
 
RPSFT 
Rank Preserving Structural Failure Time 
 
 
PAGE 10: Section 4.1 Analysis sets definitions 
 
Original text: 
“All Evaluable Patients” analysis set is defined as all randomized patients who have 
completed at least one full cycle of treatment or have received two incomplete cycles 
followed by at least one response assessment not less than eight weeks (± one week) after 


 
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treatment onset. Patients withdrawn from the study due to early disease progression or 
treatment-related toxicity will be considered as “early progression” or “treatment failure”, 
respectively. … 
Changes to: 
“All Evaluable Patients” analysis set is defined as all randomized patients who have 
completed at least one full cycle of treatment or have received two incomplete cycles 
followed by at least one response assessment not less than eight weeks (± one week) after 
treatment onset. Patients withdrawn from the study due to early disease progression or 
treatment-related toxicity will be considered as “early progression” or “treatment failure”, 
respectively, even though they have not received a full cycle. ... 
 
PAGE 13: Section 6.1.2 Final analyses - Primary Endpoint. 
Original text: 
Progression-free survival (PFS) is defined as the time from the date of randomization to 
the date of documented progressive disease (PD) by IMWG criteria or death (regardless of 
the cause of death). If the patient receives further antitumor therapy before PD and within 
the timeframe expected for first follow-up, PFS will be censored on the date of the 
last disease assessment prior to the administration of this antitumor therapy. If the patient is 
lost to follow-up for the assessment of progression, or has more than one missing follow-up 
between the date of last tumor assessment and the date of progression, death or further 
antitumor therapy, the PFS will be censored at the date of last valid tumor assessment 
before the missing evaluations. 
An external review committee blinded to treatment arm will assign the objective response 
and a progression or censoring date for each patient based on laboratory data, radiologic 
and bone marrow assessments when required and evaluation of all relevant clinical 
information; then, this information will be merged with the date of death from the death 
report forms for the calculation of PFS. Patients with missing IRC evaluations will have 
their PFS censored at randomization date. 
 
Changes to: 
Progression-free survival (PFS) is defined as the time from the date of randomization to 
the date of documented progressive disease (PD) by IMWG criteria or death (regardless of 
the cause of death). If the patient receives further antitumor therapy before PD and within 
the timeframe expected for first follow-up, PFS will be censored on the date of the 
last disease assessment prior to the administration of this antitumor therapy. If the patient is 
lost to follow-up for the assessment of progression, or has more than one missing follow-up 
between the date of last tumor assessment and the date of progression, death or further 
antitumor therapy, the PFS will be censored at the date of last valid tumor assessment 
before the missing evaluations. 
An external review committee blinded to treatment arm will assign the objective response 
and a progression or censoring date for each patient based on laboratory data, radiologic 
and bone marrow assessments when required and evaluation of all relevant clinical 


 
121 of 164 
information; then, this information will be merged with the date of death from the death 
report forms and with further antitumor therapy data for the calculation of PFS. Patients 
with missing IRC evaluations will have their PFS censored at randomization date. 
 
PAGE 15: Section 6.1.2 Final analyses. Subsection Sensitivity analyses of PFS. 
Original text: 
In the first sensitivity analysis, the midpoint of the last two assessment dates on or prior to 
the documented disease progression will be used to impute the actual date of the disease 
progression. For patients without documented disease progression, the PFS will be 
censored at the date of last disease assessment.  
Changed to: 
In the first sensitivity analysis, the midpoint of the last two assessment dates on or prior to 
the documented disease progression will be used to impute the actual date of the disease 
progression. Those patients who have disease progression in the first assessment, the 
midpoint of randomization date and the documented disease progression will be used. 
Those patients who die, the midpoint between last disease assessment without PD and the 
date of death will be used. For patients without documented disease progression, the PFS 
will be censored at the date of last disease assessment following the same rules than in 
the main analysis. 
 
PAGE 15: Section 6.1.2 Final analyses – Sensitivity analyses of PFS 
 
ADDED 
A sensitivity analysis of PFS in the “All Evaluable Patients” population according to 
IRC and investigator assessment will be performed in order to present the results in the 
population described in the protocol. 
Due to the variability of the protein used for the disease assessment, a sensitivity analysis 
of PFS requiring the confirmation of the disease progression by IRC assessment will be 
performed. Patients who dies within the timeframe expected for the confirmation of PD, 
will be considered as PD confirmed by death. Those patients without confirmation of PD 
with a second disease assessment due to crossover, further antitumor therapy, lost to 
follow-up or other reason, will be censored. The same censoring rules described above 
for PFS calculation will be considered. 
 
PAGE 16: Section 6.2.3 Secondary analyses – Overall survival 
 
Original text: 
It is anticipated that an indeterminate number of patients in the control arm will switch 
treatment after progression to plitidepsin plus dexamethasone. This could cause the size of 
the effect on OS to be difficult to interpret. Consequently, if the OS results show to be 
substantially influenced by crossover, the Sponsor will study the estimated effect of 


 
122 of 164 
crossover by means of,  rank preserving structural failure time models for correcting for 
treatment changes (2) and by the inverse probability of censoring weighting method (6) in 
order to try to control any bias caused by treatment crossover. 
 
Changes to: 
 
It is anticipated that an indeterminate number of patients in the control arm will switch 
treatment after progression to plitidepsin plus dexamethasone. This could cause the size of 
the effect on OS to be difficult to interpret. Consequently, if the OS results show to be 
substantially influenced by crossover, the Sponsor will study the estimated effect of 
crossover in a first sensitivity analysis excluding the patients who crossed over and a 
second analysis censoring survival at the time of crossover. Estimates of the unbiased 
effect in survival will be studied by means of,  rank preserving structural failure time 
(RPSFT) models for correcting for treatment changes (2) and by the inverse probability of 
censoring weighting (IPCW) method (6) in order to try to control any bias caused by 
treatment crossover.  
 
ADDED 
 
The following time-dependent covariates will be included in the IPCW analysis: ECOG, 
Body Surface Area (BSA), m-protein value (serum/urine), number of adverse events 
grade≥3, bone marrow plasma cells, creatinine, LDH, hemoglobin and corrected serum 
calcium. Also, baseline covariates such us gender, age, MM type (i.e.: IgG, IgA, light 
chain myeloma, non-secretory), number of prior lines of anticancer treatment, status 
(relapsed 
vs. 
relapsed/refractory), 
refractory 
status 
to 
bortezomib, 
lenalidomide/thalidomide prior therapy, refractory status to last prior therapy, refractory 
status to IMiD therapy, refractory status to PIs therapy, genetic risk, previous SCT, time 
from diagnosis to randomization, time from last progression before randomization, 
International Staging System, Durie-Salmon stage, presence of plasmacytomas, presence 
of lytic lesions, number of plasmacytomas, sum of the dimensions of plamacytomas, will 
be included. 
 
ADDED 
The reasons for censoring of OS will be shown using counts and percentages.  
 
PAGE 17: Section 6.2.3 Secondary analyses – Multivariate analyses 
Original title: 
Multivariate analyses 
Changes to: 
Analysis of prognostic factors, subgroup analysis and multivariate analyses 
Original text: 


 
123 of 164 
Cox proportional hazard models for PFS and OS and logistic regression models for RR will 
include the following prognostic factors: Gender, age, baseline ECOG, Body Surface Area 
(BSA), MM type (i.e.: IgG, IgA, light chain myeloma, non-secretory), number of prior lines 
of anticancer treatment, status (relapsed vs. relapsed/refractory), previous SCT, time from 
diagnosis to randomization, time from last progression before randomization, International 
Staging System, Durie-Salmon stage, bone marrow plasma cells, creatinine (≥2 mg/dl vs. < 
2 mg/dl), LDH, hemoglobin and corrected serum calcium (>11.5 mg/100ml vs. ≤11.5 
mg/100ml). Further covariates may be included in the analyses according to the 
oncologist’s criteria.  
Changed to: 
Univariate evaluation of the influence of different prognostic factors on the main 
efficacy endpoints will be performed by using the following covariates: Gender, age, 
baseline ECOG, Body Surface Area (BSA), MM type (i.e.: IgG, IgA, light chain 
myeloma, non-secretory), number of prior lines of anticancer treatment, status (relapsed 
vs. relapsed/refractory) refractory status to bortezomib, lenalidomide/thalidomide prior 
therapy, refractory status to last prior therapy, refractory status to IMiD therapy, 
refractory status to PIs therapy, genetic risk, previous SCT, time from diagnosis to 
randomization, time from last progression before randomization, International Staging 
System, Durie-Salmon stage, bone marrow plasma cells, bone lytic lesions (Y/N), 
plasmacytomas at baseline (Y/N), number of lesions at baseline, sum of the dimensions 
of plamacytomas, creatinine (≥2 mg/dl vs. < 2 mg/dl), LDH, hemoglobin and corrected 
serum calcium (>11.5 mg/100ml vs. ≤11.5 mg/100ml). 
Exploratory subgroup analyses will be performed by means of logistic regression, 
Kaplan-Meier analysis and Cox regression. The different subgroup analyses will be 
summarized by means of Forest plots. 
Cox proportional hazard models for PFS and OS and logistic regression models for RR will 
include the following prognostic factors: Gender, age, baseline ECOG, Body Surface Area 
(BSA), MM type (i.e.: IgG, IgA, light chain myeloma, non-secretory), number of prior 
lines of anticancer treatment, status (relapsed vs. relapsed/refractory), previous SCT, 
time from diagnosis to randomization, time from last progression before randomization, 
International Staging System, Durie-Salmon stage, bone marrow plasma cells, creatinine 
(≥2 mg/dl vs. < 2 mg/dl), LDH, hemoglobin and corrected serum calcium (>11.5 
mg/100ml vs. ≤11.5 mg/100ml). Further covariates may be included in the analyses 
according to the oncologist’s criteria.  specified for the univariate analysis. More relevant 
and explanatory covariates from the univariate analysis will be included in the 
multivariate analyses.   
 
PAGE 17: Section 6.2.3 Secondary analyses – Symmetry evaluations 
TITLE ADDED: 
Wilcoxon test will be used to compare time to disease assessments between treatment arms. 
Moreover, Kaplan-Meier curves of the time from randomization to first and second disease 
assessment will be plotted. 
Sensitivity analyses of PFS. 


 
124 of 164 
For the three sensitivity analyses using imputation methods for the date of progression, 
similar unstratified log-rank test as for the key primary PFS analysis will be performed, 
based on the imputed data sets. 
 
PAGE 20: Section 8.7 Subgroup analyses 
Original text: 
No specific subgroup analysis is planned for efficacy. However, the influence of the study 
strata and other prognostic factors on the efficacy endpoints will be studied in the 
multivariate analysis. 
Changes to: 
Analysis of efficacy profile by age in order to characterize a potential benefit of the drug 
in elderly population is planned. Exploratory efficacy subgroup analyses according to 
genetic risk the refractory status to prior therapies such as bortezomib, 
lenalidomide/thalidomide, last prior therapy, IMiD therapy and PIs are planned. No 
other specific subgroup analysis is planned for efficacy. However, the influence of the 
study strata and other prognostic factors on the efficacy endpoints will be studied in the 
multivariate analysis. 
 
PAGE 29: Section 9. STATISTICAL SOFTWARE 
Original text: 
EAST v5.2 has been used to calculate sample size. SAS v9 (4) will be used for all statistical 
analysis outputs. 
 
Changes to: 
EAST v5.2 has been used to calculate sample size. SAS v9 (4) will be used for all statistical 
analysis outputs. Stata v14 or greater will be used for the analysis of crossover by RPSFT 
method. 
 
PAGE 22: Section 10.1. Patient dispositions 
Original text: 
Main characteristics concerning inclusion in the study, withdrawal from the study and 
protocol deviations will be displayed in this section. 
 
Changes to: 
Main characteristics concerning inclusion in the study, patient crossover from arm B to 
arm A, withdrawal from the study and protocol deviations will be displayed in this section. 
 
 
 


 
125 of 164 
ADDED 
 
Listing 10.1.2a Patients assigned to the wrong stratum by mistake 
Patient id. 
Assigned stratum by randomization 
Actual stratification values 
… 
 
 
 
Listing 10.1.2b Comparison of Durie-Salmon at IVRS and baseline value 
Patient id. 
Durie-Salmon value at IVRS 
Actual Durie-Salmon value 
… 
 
 
 
Listing 10.1.2c Comparison of ECOG PS at IVRS and baseline value 
Patient id. 
PS ECOG value at 
screening  
PS ECOG value at IVRS 
Last ECOG before start of 
study treatment 
… 
 
 
 
 
Table 10.1.5 Last cycle in Arm A before crossover 
Last cycle before crossover 
Crossover patients 
N 
% 
Cycle 1 
X 
XX.X 
Cycle 2 
 
 
… 
 
 
Total 
 
 
 
 
PAGE 24: Table 10.2.5 Reasons for treatment discontinuation by cycles received 
 
Footnote has been added. 
Original table: 
Reason 
Arm A 
Arm B 
Total 
Last cycle 
Last cycle 
Last cycle 
1 2 
… 
Total 
1 
2 
… 
Total 
1 
2 
… 
Total 
Progressive disease 
 
 
 
 
 
 
 
 
 
 
 
 
Toxicity 
 
 
 
 
 
 
 
 
 
 
 
 
Patient refusal 
 
 
 
 
 
 
 
 
 
 
 
 
Investigator decision 
 
 
 
 
 
 
 
 
 
 
 
 
Death (due to toxicity)* 
 
 
 
 
 
 
 
 
 
 
 
 
Death (non-treatment-related)** 
 
 
 
 
 
 
 
 
 
 
 
 
Other *** 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
(*) Cause of death = Toxicity (study drug related) (**) Cause of death = Malignant disease or Other (***) Specify (see 
listing 10.2.6) 
 
 


 
126 of 164 
Changes to: 
Reason 
Arm A 
Arm B 
Total 
Last cycle 
Last cycle 
Last cycle 
1 2 …**** 
Total 
1 
2 
… 
Total 
1 
2 
… 
Total 
Progressive disease 
 
 
 
 
 
 
 
 
 
 
 
 
Toxicity 
 
 
 
 
 
 
 
 
 
 
 
 
Patient refusal 
 
 
 
 
 
 
 
 
 
 
 
 
Investigator decision 
 
 
 
 
 
 
 
 
 
 
 
 
Death (due to toxicity)* 
 
 
 
 
 
 
 
 
 
 
 
 
Death (non-treatment-related)** 
 
 
 
 
 
 
 
 
 
 
 
 
Other *** 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
(*) Cause of death = Toxicity (study drug related) (**) Cause of death = Malignant disease or Other (***) Specify (see 
listing 10.2.6) (****) Cycles > % will be grouped as 6-10, 10-20 and >20. 
 
PAGE 24: Listing 10.2.7 Treatment discontinuation due to AEs 
 
FOOTNOTE ADDED: 
 
Action taken: study drug withdrawal 
 
 
PAGE 25: Table 11.1.1.3 Baseline characteristics: Age grouped 
 
Original table: 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
18-XX 
X 
XX.X 
X 
XX.X 
X 
XX.X 
XX-YY 
 
 
 
 
 
 
≥65 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
Changes to: 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
18-64 
X 
XX.X 
X 
XX.X 
X 
XX.X 
65-74 
 
 
 
 
 
 
75-84 
 
 
 
 
 
 
≥85 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
PAGE 25: Table 11.1.2.2 Time from last PD/relapse by dose 
 
DELETED: 
Table 11.1.2.2 Time from last PD/relapse by dose 
 
 
 


 
127 of 164 
PAGE 25: Section 11.1.2. Disease at diagnosis, time from diagnosis and current 
disease 
 
ADDED: 
Table 11.1.2. 7 Genetic risks at diagnosis. 
Genetic Risks* 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
High risk 
X 
XX.X 
X 
XX.X 
X 
XX.X 
Intermediate risk 
 
 
 
 
 
 
Good prognostic 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
(*)Patients will be classified in “high risk”, “intermediate risk” or “good prognosis” according to their genetic results 
(cytogenetic or FISH) at by clinical review. Further details in section 11.3.7. 
 
Tables will be renumbered accordingly. 
 
PAGE 25: Table 11.1.2. Disease at diagnosis, time from diagnosis and current disease 
 
Original table: 
Table 11.1.2.7 Baseline characteristics: MM protein measurements (Serum) 
 
Arm A 
Arm B 
Total 
N Median 
Min 
Max 
N 
Median Min 
Max 
N 
Median 
Min 
Max 
Total Ig G (mg/dL) 
X 
X.X 
X.X 
X.X 
X 
X.X 
X.X 
X.X 
X 
X.X 
X.X 
X.X 
Total Ig A (mg/dL) 
 
 
 
 
 
 
 
 
 
 
 
 
Total Ig M (mg/dL) 
 
 
 
 
 
 
 
 
 
 
 
 
Table 11.1.2.8 Baseline characteristics: MM protein measurements (Serum) 
 
Arm A 
Arm B 
Total 
N 
Median 
Min 
Max 
N 
Median Min 
Max 
N 
Median 
Min 
Max 
M-
spike(SPE)(g/dL) 
X 
X.X 
X.X 
X.X 
X 
X.X 
X.X X.X 
X 
X.X 
X.X 
X.X 
Kappa (mg/L) 
 
 
 
 
 
 
 
 
 
 
 
 
Lambda (mg/L) 
 
 
 
 
 
 
 
 
 
 
 
 
sFLC ratio 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 11.1.2.9 Baseline characteristics: MM protein type 
Arm 
Patient id. 
Serum / Urine 
Type 
… 
 
 
 
Table 11.1.2.10 Baseline characteristics: MM protein measurements (24h Urine analysis) 
 
Arm A 
Arm B 
Total 
N 
Median 
Min 
Max 
N 
Median 
Min 
Max 
N 
Median 
Min 
Max 
Protein -24h urine 
(mg/24 h) 
X 
X.X 
X.X 
X.X 
X 
X.X 
X.X 
X.X 
X 
X.X 
X.X 
X.X 
Urine M-spike 
(UPE) (Bence 
Jones) (g/24 hrs) 
 
 
 
 
 
 
 
 
 
 
 
 
Urine M-protein 
(Bence Jones) 
(mg/L) 
 
 
 
 
 
 
 
 
 
 
 
 
Kappa (mg/L) 
 
 
 
 
 
 
 
 
 
 
 
 
Lambda (mg/L) 
 
 
 
 
 
 
 
 
 
 
 
 


 
128 of 164 
Table 11.1.2.11 Baseline characteristics: Immunofixation urine 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
Positive 
X 
XX.X 
X 
XX.X 
X 
XX.X 
Negative 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Table 11.1.2.12  Baseline characteristics: Non-secretory myeloma 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
Yes 
X 
XX.X 
X 
XX.X 
X 
XX.X 
No 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
Changes to: 
Table 11.1.2.8 Baseline characteristics: MM protein measurements (Serum*) 
 
Arm A 
Arm B 
Total 
N Median 
Min 
Max 
N 
Median Min 
Max 
N 
Median 
Min 
Max 
Total Ig G (mg/dL) 
X 
X.X 
X.X 
X.X 
X 
X.X 
X.X 
X.X 
X 
X.X 
X.X 
X.X 
Total Ig A (mg/dL) 
 
 
 
 
 
 
 
 
 
 
 
 
Total Ig M (mg/dL) 
 
 
 
 
 
 
 
 
 
 
 
 
* Based on central lab assessments. 
Table 11.1.2.9 Baseline characteristics: MM protein measurements (Serum*) 
 
Arm A 
Arm B 
Total 
N 
Median 
Min 
Max 
N 
Median Min 
Max 
N 
Median 
Min 
Max 
M-
spike(SPE)(g/dL) 
X 
X.X 
X.X 
X.X 
X 
X.X 
X.X X.X 
X 
X.X 
X.X 
X.X 
Kappa (mg/L) 
 
 
 
 
 
 
 
 
 
 
 
 
Lambda (mg/L) 
 
 
 
 
 
 
 
 
 
 
 
 
sFLC ratio 
 
 
 
 
 
 
 
 
 
 
 
 
* Based on central lab assessments. 
Listing 11.1.2.10 Baseline characteristics: MM protein type*  
Arm 
Patient id. 
Serum / Urine 
Type 
… 
 
 
 
* Based on central lab assessments. 
 
 


 
129 of 164 
Table 11.1.2.11 Baseline characteristics: MM protein measurements (24h Urine analysis*) 
 
Arm A 
Arm B 
Total 
N 
Median 
Min 
Max 
N 
Median 
Min 
Max 
N 
Median 
Min 
Max 
Protein -24h urine 
(mg/24 h) 
X 
X.X 
X.X 
X.X 
X 
X.X 
X.X 
X.X 
X 
X.X 
X.X 
X.X 
Urine M-spike 
(UPE) (Bence 
Jones) (g/24 hrs) 
 
 
 
 
 
 
 
 
 
 
 
 
Urine M-protein 
(Bence Jones) 
(mg/L) 
 
 
 
 
 
 
 
 
 
 
 
 
Kappa (mg/L) 
 
 
 
 
 
 
 
 
 
 
 
 
Lambda (mg/L) 
 
 
 
 
 
 
 
 
 
 
 
 
* Based on central lab assessments. 
Table 11.1.2.12 Baseline characteristics: Immunofixation urine* 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
Positive 
X 
XX.X 
X 
XX.X 
X 
XX.X 
Negative 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
* Based on central lab assessments. 
Table 11.1.2.13  Baseline characteristics: Non-secretory myeloma* 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
Yes 
X 
XX.X 
X 
XX.X 
X 
XX.X 
No 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
* Based on central lab assessments. 
 
ADDED 
Table 11.1.2.16  Genetic risks at baseline. 
Genetic Risks* 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
High risk 
X 
XX.X 
X 
XX.X 
X 
XX.X 
Intermediate risk 
 
 
 
 
 
 
Good prognostic 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
(*)Patients will be classified in “high risk”, “intermediate risk” or “good prognosis” according to their genetic results 
(cytogenetic or FISH) at by clinical review. Further details in Section 11.3.7. 
 
 
 
 


 
130 of 164 
PAGE 28 Section 11.1.3 Skeletal sites involved at baseline 
 
Original listing: 
Listing 11.1.3.1 Baseline characteristics: Skeletal/soft tissue evaluation 
Arm 
Patient 
id. 
No lesion / NA 
Type 
Anatomic 
localization 
Method 
Measurements 
for soft tissue 
lesions (mm) 
Diffuse 
osteoporosis 
… 
 
 
 
 
 
XXX x XXX 
 
 
Changes to: 
Listing 11.1.3.1 Baseline characteristics: Skeletal/soft tissue evaluation 
Arm 
Patient 
id. 
Date of 
assessment 
No lesion / 
NA 
Type 
Anatomic 
localization 
Method 
Measurements 
for soft tissue 
lesions (mm) 
Diffuse 
osteoporosis 
… 
 
 
 
 
 
 
XXX x XXX  
 
ADDED 
Table 11.1.3.3 Baseline characteristics: Number of lesions 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
 Plasmacytoma 
X 
XX.X 
X 
XX.X 
X 
XX.X 
     1 
 
 
 
 
 
 
     2 
 
 
 
 
 
 
… 
 
 
 
 
 
 
Bone (Lytic lesion) 
 
 
 
 
 
 
     1 
 
 
 
 
 
 
     2 
 
 
 
 
 
 
… 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
Table 11.1.3.4 Baseline characteristics: Sum of plasmacytomas dimensions 
 
 
N 
Median 
Min 
Max 
Sum of plamacytomas product of 
diameters 
Arm A 
 
 
 
 
Arm B 
 
 
 
 
Total 
 
 
 
 
 
 
 
 


 
131 of 164 
PAGE 28: Section 11.1.4 Prior anticancer therapy 
 
ADDED 
Table 11.1.4.2 Number of patients with prior radiotherapy 
Prior radiotherapy 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
Yes 
X 
XX.X 
X 
XX.X 
X 
XX.X 
No 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Table 11.1.4.6 Status regarding response to bortezomib therapy 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
Relapsed* 
X 
XX.X 
X 
XX.X 
X 
XX.X 
Relapsed/Refractory** 
 
 
 
 
 
 
Refractory*** 
 
 
 
 
 
 
(*)Relapsed myeloma: at least one prior  bortezomib regimen, and not meeting criteria for relapsed and refractory / 
refractory myeloma. 
(**) Relapsed/refractory myeloma: relapse of disease while on salvage therapy, or progression within 60 days of last 
bortezomib therapy.  
(***)Refractory myeloma: non responder to last bortezomib therapy.  
 
Table 11.1.4.7 Status regarding response to lenalidomide therapy 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
Relapsed* 
X 
XX.X 
X 
XX.X 
X 
XX.X 
Relapsed/Refractory** 
 
 
 
 
 
 
Refractory*** 
 
 
 
 
 
 
(*)Relapsed myeloma: at least one prior  lenalidomide regimen, and not meeting criteria for relapsed and refractory / 
refractory  myeloma. 
(**) Relapsed/refractory myeloma:  relapse of disease while on salvage therapy, or progression within 60 days of last 
lenalidomide therapy.  
(***)Refractory myeloma: non responder to last lenalidomide therapy.  
 
Table 11.1.4.8 Status regarding response to thalidomide therapy 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
Relapsed* 
X 
XX.X 
X 
XX.X 
X 
XX.X 
Relapsed/Refractory** 
 
 
 
 
 
 
Refractory*** 
 
 
 
 
 
 
(*)Relapsed myeloma: at least one prior thalidomide regimen, and not meeting criteria for relapsed and refractory / 
refractory myeloma. 
(**) Relapsed/refractory myeloma: relapse of disease while on salvage therapy, or progression within 60 days of last 
thalidomide therapy.  
(***)Refractory myeloma: non responder to last thalidomide therapy.  
 
 


 
132 of 164 
Table 11.1.4.9 Status regarding response to bortezomib, lenalidomide/thalidomide 
therapy 
(*) 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
Resistant or refractory to 
lenalidomide/thalidomide and 
bortezomib therapies * 
X 
XX.X 
X 
XX.X 
X 
XX.X 
Resistant or refractory to 
lenalidomide/thalidomide therapy 
but not refractory to bortezomib ** 
 
 
 
 
 
 
Resistant or refractory to bortezomib 
therapy but not refractory to 
lenalidomide and thalidomide *** 
 
 
 
 
 
 
Other than the above 
 
 
 
 
 
 
 (*) Resistant or refractory myeloma: non responder or relapse of disease while on salvage therapy, or progression 
within 60 days of therapy.  
Table 11.1.4.10 Status regarding response to last therapy 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
Relapsed* 
X 
XX.X 
X 
XX.X 
X 
XX.X 
Relapsed/Refractory** 
 
 
 
 
 
 
Refractory*** 
 
 
 
 
 
 
(*)Relapsed myeloma: at least one prior regimen, and not meeting criteria for relapsed and refractory / refractory 
myeloma. 
(**) Relapsed/refractory myeloma: relapse of disease while on salvage therapy, or progression within 60 days of last 
therapy.  
(***)Refractory myeloma: non responder to last therapy.  
Table 11.1.4.11 Status regarding response to IMiD therapy 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
Relapsed* 
X 
XX.X 
X 
XX.X 
X 
XX.X 
Relapsed/Refractory** 
 
 
 
 
 
 
Refractory*** 
 
 
 
 
 
 
(*)Relapsed myeloma: at least one prior IMiD regimen, and not meeting criteria for relapsed and refractory / 
refractory myeloma. 
(**) Relapsed/refractory myeloma: relapse of disease while on salvage therapy, or progression within 60 days of IMiD 
therapy.  
(***)Refractory myeloma: non responder to IMiD therapy.  
Table 11.1.4.12 Status regarding response to PIs therapy 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
Relapsed* 
X 
XX.X 
X 
XX.X 
X 
XX.X 
Relapsed/Refractory** 
 
 
 
 
 
 
Refractory*** 
 
 
 
 
 
 
(*)Relapsed myeloma: at least one prior PIs regimen, and not meeting criteria for relapsed and refractory / refractory 
myeloma. 
(**) Relapsed/refractory myeloma: relapse of disease while on salvage therapy, or progression within 60 days of PIs 
therapy.  
(***)Refractory myeloma: non responder to PIs therapy.  
 
Consequently, the rest of the tables have been renumbered. 
 
 
 


 
133 of 164 
FOOTNOTE ADDED: 
 
Table 11.1.4.13 TTP to last prior anticancer therapy 
 
*In case of non-PD to last therapy, TTP will be calculated until the date of informed consent 
 
Original table: 
Table 11.1.4.8 Prior stem cell transplantation 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
0 
X 
XX.X 
X 
XX.X 
X 
XX.X 
1 
 
 
 
 
 
 
≥2 
 
 
 
 
 
 
Type 
N 
% 
N 
% 
N 
% 
Autologous 
X 
XX.X 
X 
XX.X 
X 
XX.X 
Allogeneic 
 
 
 
 
 
 
 
Changes to: 
Table 11.1.4.16 Prior stem cell transplantation 
 
Arm A 
Arm B 
Total 
N 
% 
N 
% 
N 
% 
0 
X 
XX.X 
X 
XX.X 
X 
XX.X 
1 
 
 
 
 
 
 
≥2 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
Type 
N 
% 
N 
% 
N 
% 
Autologous 
X 
XX.X 
X 
XX.X 
X 
XX.X 
Allogeneic 
 
 
 
 
 
 
 
 
PAGE 30: Table 11.1.6.5 Baseline characteristics: Left Ventricular Ejection Fraction 
(LVEF) 
 
Original table: 
Arm 
Patient id. 
Cycle 
Date 
LVEF (%) 
Institutional normal range (%) 
Method 
… 
 
 
 
 
 
 
 
Changes to: 
Arm 
Patient 
id. 
Not 
done 
Date 
LVEF (%) 
Interpretation 
Institutional normal range 
(%) 
Method 
… 
 
 
 
 
 
 
 
 
 
 


 
134 of 164 
PAGE 32: Table 11.1.8.2 Biochemical values at baseline 
 
Original table: 
 
Arm A 
Arm B 
Total 
Median (range) 
Median (range) 
Median (range) 
AST (xULN) 
 
 
 
ALT (xULN) 
 
 
 
Total bilirubin (xULN) 
 
 
 
Direct bilirubin (xULN) 
 
 
 
AP (xULN) 
 
 
 
Creatinine (xULN) 
 
 
 
Cr. Clearance (Calculated) (ml/min) 
 
 
 
Cr. Clearance (Measured) (ml/min) 
 
 
 
CPK (xULN) 
 
 
 
CPK MB (IU/L) 
 
 
 
Cardiac Troponin I (ng/ml) 
 
 
 
Total proteins (g/dL) 
 
 
 
Albumin (g/dL) 
 
 
 
Uric acid (mg/dL) 
 
 
 
LDH (xULN) 
 
 
 
Beta-2-microglobulin (mg/L) 
 
 
 
 
Changes to: 
 
Arm A 
Arm B 
Total 
Median (range) 
Median (range) 
Median (range) 
AST (xULN) 
 
 
 
ALT (xULN) 
 
 
 
Total bilirubin (xULN) 
 
 
 
Direct bilirubin (xULN) 
 
 
 
AP (xULN) 
 
 
 
Creatinine (xULN) 
 
 
 
Cr. Clearance (Calculated) (ml/min) 
 
 
 
Cr. Clearance (Measured) (ml/min)* 
 
 
 
CPK (xULN) 
 
 
 
CPK MB (IU/L) 
 
 
 
Cardiac Troponin I (ng/ml) 
 
 
 
Total proteins (g/dL) 
 
 
 
Albumin (g/dL) 
 
 
 
Uric acid (mg/dL) 
 
 
 
LDH (xULN) 
 
 
 
Beta-2-microglobulin (mg/L) 
 
 
 
(*)If available 
 
PAGE 32: Listing 11.1.8.3 Biochemical tests not assessed at baseline 
 
FOOTNOTE ADDED 
*CPKMB to be assessed as missing only if CPK>ULN 
 
 
 


 
135 of 164 
PAGE 32: Listing 11.1.8.4 Biochemical abnormalities at baseline. Grade ≥ 2 
 
Original table: 
Arm 
Patient id 
Parameter 
Value 
Grade 
… 
 
 
 
 
 
Changes to: 
Arm 
Patient id 
Parameter 
Value 
xULN 
Grade 
… 
 
 
 
 
 
 
PAGE 33: Listing 11.1.9.4 Metabolic abnormalities at baseline. Grade ≥ 2 
 
Original table: 
Arm 
Patient id 
Parameter 
Value 
Grade 
… 
 
 
 
 
 
Changes to: 
Arm 
Patient id 
Parameter 
Value 
xULN 
Grade 
… 
 
 
 
 
 
 
 
PAGE 35: Section 11.3.2 Supportive PFS analyses 
 
Original text: 
In the ‘time-to-event variables’, the unstratified and stratified log-rank test will be used to 
evaluate the differences between treatment arms and the median values of time-dependent 
parameters. Their fixed-time estimations will be analyzed according to the Kaplan-Meier 
method. Median follow-up assessments will be calculated using the Kaplan-Meier method 
reversing the censoring values (5). 
 
Changes to: 
In the ‘time-to-event variables’, the unstratified and stratified log-rank test will be used to 
evaluate the differences between treatment arms and the median values of time-dependent 
parameters. Their fixed-time estimations will be analyzed according to the Kaplan-Meier 
method. Median follow-up assessments will be calculated using the Kaplan-Meier method 
reversing the censoring values (5). Whenever it is not specified, the unstratified test is 
used. 
 
FOOTNOTE ADDED: 
 
Table 11.3.2.4  PFS – Concordance between Independent Review assessment and 
Investigator assessment ( “All Randomized Patients” population) 
 
XX, YY, ZZ = Patients evaluable for both Independent review assessment and investigator assessment 
 
 
 
 


 
136 of 164 
PAGE 37: Section 11.3.3 Sensitivity analyses of PFS 
 
Original titles: 
 
Table 11.3.3.1 PFS (first imputation of PD dates) (Independent Review assessment and 
“All Randomized Patients” population) 
 
Table 11.3.3.2 PFS (second imputation of PD dates) (Independent Review assessment and 
“All Randomized Patients” population) 
 
Table 11.3.3.3 PFS (third imputation of PD dates)  (Independent Review assessment and 
“All Randomized Patients” population) 
 
 
Changes to: 
 
Table 11.3.3.1 PFS (first midpoint imputation method of PD dates) (Independent Review 
assessment and “All Randomized Patients” population) 
 
Table 11.3.3.2 PFS (second weeks from randomization imputation method of PD dates) 
(Independent Review assessment and “All Randomized Patients” population) 
 
Table 11.3.3.3 PFS (third missing assessment imputation method of PD dates)  
(Independent Review assessment and “All Randomized Patients” population) 
 
 
ADDED 
Table 11.3.3.6 PFS (Independent Review assessment and “All Evaluable Patients” 
population) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.3.6)  
Table 11.3.3.7 PFS (Investigator Assessment and “All Evaluable Patients” population) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.3.7)  


 
137 of 164 
Table 11.3.3.8 PFS with confirmation of PD (Independent Review assessment and “All 
Randomized Patients” population) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.3.8)  
Table 11.3.3.9 PFS with confirmation of PD (Investigator Assessment and “All 
Randomized Patients” population) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.3.9)  
 
 
PAGE 38: Section 11.3.4.1 OS analyses 
 
ADDED 
Table 11.3.4.1.3 OS (“All Randomized Patients” population excluding crossover patients) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.4.1.3). 
 
Table 11.3.4.1.4 OS (“All Randomized Patients” population censoring crossover patients 
at cross-over date) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.4.1.4). 
 
 
 


 
138 of 164 
Table 11.3.4.1.5 OS (“All Randomized Patients” population and IPCW method) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.4.1.5). 
 
Table 11.3.4.1.6 OS (“All Randomized Patients” population and RPSFT method) 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.4.1.6). 
 
Table 11.3.4.1.8 OS – Reason of censoring (“All Randomized Patients” population)  
Reason of censoring 
Arm A 
Arm B 
N 
% 
N 
% 
Alive 
 
 
 
 
Lost to follow-up 
 
 
 
 
Withdrawal of consent 
 
 
 
 
 
 
PAGE 39: Section 11.3.4.2 Response rate by independent review committee 
 
ADDED 
 
Table 12.1.2.2.1 Response rate by IMWG at early futility analysis (Independent Review 
assessment and “All Evaluable Patients” population) 
Response 
Arm A 
Arm B 
N 
% 
N 
% 
sCR  
 
 
 
 
CR  
 
 
 
 
VGPR 
 
 
 
 
PR 
 
 
 
 
MR 
 
 
 
 
SD 
 
 
 
 
PD 
 
 
 
 
 
 
 
 


 
139 of 164 
PAGE 42: Section 11.3.4.7 Symmetry of evaluations 
 
ADDED 
 
Table 12.1.2.2.2  Time to first assessment 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median to first assessment 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
Kaplan-Meier plot will be also shown (Figure 11.3.4.7.2)  
 
Table 12.1.2.2.3  Time to second assessment 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median second assessment 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
Kaplan-Meier plot will be also shown (Figure 11.3.4.7.3)  
 
 
Page 43: New section 11.3.4.8 Univariate analyses 
 
ADDED 
15.1.1.1 Univariate analyses 
Table 11.3.4.8.1 Univariate analysis of PFS (Independent Review assessment and “All 
Randomized Patients” population) 
 
Arm A 
Arm B 
 
Prognostic 
factors** 
Median 
(months) 
Lower 
95% 
Confidence 
Limit 
Upper 
95% 
Confidence 
Limit 
Median 
(months) 
Lower 
95% 
Confidence 
Limit 
Upper 
95% 
Confidenc
e 
Limit 
 
p-
value* 
Gender 
 
 
 
 
 
 
 
Age 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
(*) Cox regression. (**) See covariate listing in section 6.2.3. A forest plot with the summary of HR will be also shown 
(Figure 11.3.4.8.1)  
 
Table 11.3.4.8.2 Univariate analysis of PFS (Investigator  Assessment and “All 
Randomized Patients” population) 
 
Arm A 
Arm B 
 
Prognostic 
factors** 
Median 
(months) 
Lower 
95% 
Confidence 
Limit 
Upper 
95% 
Confidence 
Limit 
Median 
(months) 
Lower 
95% 
Confidence 
Limit 
Upper 
95% 
Confidenc
e 
Limit 
 
p-
value* 
Gender 
 
 
 
 
 
 
 
Age 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
(*) Cox regression. (**) See covariate listing in section 6.2.3. A forest plot with the summary of HR will be also shown 
(Figure 11.3.4.8.2)  


 
140 of 164 
 
Table 11.3.4.8.3 Univariate analysis of OS (Independent Review assessment and “All 
Randomized Patients” population) 
 
Arm A 
Arm B 
 
Prognostic 
factors** 
Median 
(months) 
Lower 
95% 
Confidence 
Limit 
Upper 
95% 
Confidence 
Limit 
Median 
(months) 
Lower 
95% 
Confidence 
Limit 
Upper 
95% 
Confidenc
e 
Limit 
 
p-
value* 
Gender 
 
 
 
 
 
 
 
Age 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
(*) Cox regression. (**) See covariate listing in section 6.2.3. A forest plot with the summary of HR will be also shown 
(Figure 11.3.4.8.3)  
 
Table 11.3.4.8.4 Univariate analysis of OS  (Investigator  Assessment and “All 
Randomized Patients” population) 
 
Arm A 
Arm B 
 
Prognostic 
factors** 
Median 
(months) 
Lower 
95% 
Confidence 
Limit 
Upper 
95% 
Confidence 
Limit 
Median 
(months) 
Lower 
95% 
Confidence 
Limit 
Upper 
95% 
Confidenc
e 
Limit 
 
p-
value* 
Gender 
 
 
 
 
 
 
 
Age 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
(*) Cox regression. (**) See covariate listing in section 6.2.3. A forest plot with the summary of HR will be also shown 
(Figure 11.3.4.8.4)  
 
Table11.3.4.8.5 Univariate analysis of RR (Independent Review assessment and “All 
Randomized Patients” population) 
 
Arm A 
 
Arm B 
 
 
Prognostic factors** N 
RR 
Propor
tion  
(%) 
95% 
CI 
 
N 
RR 
Propor
tion  
(%) 
95% 
CI 
 
 
p-
value* 
Gender 
 
 
 
 
 
 
 
 
 
Age 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
(*) Logistic regression. (**) See covariate listing in section 6.2.3. A forest plot with the summary of ORR confidence 
intervals will be also shown (Figure 11.3.4.8.5)  
 
Table 11.3.4.8.6 Univariate analysis of RR  (Investigator  Assessment and “All 
Randomized Patients” population) 
 
Arm A 
 
Arm B 
 
 
Prognostic factors** N 
RR 
Propor
tion  
(%) 
95% 
CI 
 
N 
RR 
Propor
tion  
(%) 
95% 
CI 
 
 
p-
value* 
Gender 
 
 
 
 
 
 
 
 
 
Age 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
(*) Logistic regression. (**) See covariate listing in section 6.2.3. A forest plot with the summary of ORR confidence 
intervals will be also shown (Figure 11.3.4.8.6)  
 
Rest of sections and tables have been renumbered. 


 
141 of 164 
 
Page 43: Section 11.3.4.8 Multivariate analyses 
 
This section was renumbered to 11.3.4.9.  
 
FOOTNOTE ADDED 
 
In tables 11.3.4.9.1, 11.3.4.9.2 and 11.3.4.9.5: 
 
* Cox regression 
 
In tables 11.3.4.9.3 and 11.3.4.9.4: 
 
* Logistic regression 
 
 
PAGE 44: Section 11.3.6 Efficacy analysis by age 
 
ADDED 
 
11.3.6 Efficacy analysis by age 
If there is a group of patients with scarce percentage of patients (i.e.5%), it will be joined 
to the nearest group of age. Age ≥ 85 to Age 75-84, age 75-84 to age 65-74 and age 65-74 
to age 18-64 
Table 11.3.6.1PFS (Independent Review assessment and “All Randomized Patients” 
population) by age 
Age 
 
Arm A 
Arm B 
Parameter 
p-value 
Age 18-64  
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Age 65-74 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Age 75-84 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Age ≥85 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.6.1a/b/c/d)  


 
142 of 164 
Table 11.3.6.2PFS (Investigator Assessment and “All Randomized Patients” population) 
by age 
Age 
 
Arm A 
Arm B 
Parameter 
p-value 
Age 18-64  
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Age 65-74 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Age 75-84 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Age ≥85 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.6.2a/b/c/d)  
Table 11.3.6.3OS (“All Randomized Patients” population) by age 
Age 
  
Arm A 
Arm B  
Parameter 
p-value 
Age 18-64 
 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
Age 65-74 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
 
Age 75-84 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
 
Age ≥85 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 


 
143 of 164 
OS at 24 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.6.3a/b/c/d). 
 
Table 11.3.6.4Response rate by IMWG (Independent Review assessment and “All 
Randomized Patients” population) by age 
Age 
Response 
Arm A 
Arm B 
N 
% 
N 
% 
 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 
Age 18-64 
PR 
 
 
 
 
 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 
Age 65-74 
PR 
 
 
 
 
 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 
 
PR 
 
 
 
 
Age 75-84 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 
Age ≥85 
PR 
 
 
 
 
 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 (*) Including NE and insufficient data available. 
 
Table 11.3.6.5Response rate estimates by IMWG (Independent Review assessment and 
“All Randomized Patients” population) by age 
Age 
 
Arm A 
Arm B 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Age 18-64 
Response 
rate 
 
 
 
 
 
 
Age 65-74 
Response 
rate 
 
 
 
 
 
 
Age 75-84 
Response 
rate 
 
 
 
 
 
 
Age ≥85 
Response 
rate 
 
 
 
 
 
 
Binomial exact estimator and 95% confidence interval 
 
11.3.7 Efficacy analysis based on genetic risks 
 


 
144 of 164 
Patients will be classified in “high risk”, “intermediate risk” or “good prognosis” 
according to their genetic results (cytogenetic or FISH) at diagnosis or study entry.  
 
Patients with translocations such as t(4;14), t(14;16), t(14;20), del 17, del 13 or single 
alterations such as +1q or +1p will be classified as “high risk”; patients with 
translocations such as t(11;14), t(6;14) or other will be classified “intermediate risk”; 
and finally, those patients with single alterations of trisomies 3, 5, 6, 9, 11, 15, 19 or 21 
will be classified as “good prognosis”. This classification will be done by clinical review. 
 
 
Table 11.3.7.1 PFS (Independent Review assessment and “All Randomized Patients” 
population) by genetic risks 
Cytogenetic profile 
 
Arm A 
Arm B 
Parameter 
p-value 
High risk 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Intermediate risk 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Good prognosis 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.7.1a/b/c)  
 
 
 


 
145 of 164 
Table 11.3.7.2 OS (“All Randomized Patients” population) by genetic risks 
Cytogenetic profile 
  
Arm A 
Arm B  
Parameter 
p-value 
High risk 
 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
Intermediate risk 
 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
 
Good prognosis 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.7.2a/b/c). 
 
Table 11.3.7.3 Response rate by IMWG (Independent Review assessment and “All 
Randomized Patients” population) by genetic risks 
Cytogenetic profile 
Response 
Arm A 
Arm B 
N 
% 
N 
% 
 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 
High risk 
PR 
 
 
 
 
 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 
Intermediate risk 
PR 
 
 
 
 
 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 
 
PR 
 
 
 
 
Good prognosis 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 


 
146 of 164 
 
Unknown* 
 
 
 
 
 (*) Including NE and insufficient data available. 
 
Table 11.3.7.4 Response rate estimates by IMWG (Independent Review assessment and 
“All Randomized Patients” population) by genetic risks 
Cytogenetic 
profile 
Arm A 
Arm B 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
High risk 
 
 
 
 
 
 
Intermediate 
risk 
 
 
 
 
 
 
Good prognosis  
 
 
 
 
 
Binomial exact estimator and 95% confidence interval 
 
11.3.8 Efficacy analysis in patients resistant or refractory to last 
lenalidomide/thalidomide or last bortezomib therapy 
 
Patients will be classified in four groups according to their response to prior 
lenalidomide/thalidomide or bortezomib therapies.  
 
-Resistant or refractory to lenalidomide/thalidomide and bortezomib therapies 
-Resistant or refractory to lenalidomide/thalidomide therapy but not refractory to 
bortezomib 
-Resistant or refractory to bortezomib therapy but not refractory to lenalidomide and 
thalidomide 
-Other than the above  
 
 
 


 
147 of 164 
Table 11.3.8.1 PFS (Independent Review assessment and “All Randomized Patients” 
population) by lenalidomide/thalidomide or bortezomib prior therapies 
Prior therapies 
 
Arm A 
Arm B 
Parameter 
p-value 
Resistant or refractory to 
lenalidomide/thalidomide 
and bortezomib therapies 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Resistant or refractory to 
lenalidomide/thalidomide 
therapy but not 
refractory to bortezomib 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Resistant or refractory to 
bortezomib therapy but 
not refractory to 
lenalidomide and 
thalidomide 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Other than the above 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.8.1a/b/c/d)  
 
Table 11.3.8.2 OS (“All Randomized Patients” population) by lenalidomide/thalidomide 
or bortezomib prior therapies 
Prior therapies 
  
Arm A 
Arm B  
Parameter 
p-value 
Resistant or refractory to 
lenalidomide/thalidomide 
and bortezomib therapies 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
Resistant or refractory to 
lenalidomide/thalidomide 
therapy but not 
refractory to bortezomib 
 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
 
Resistant or refractory to 
bortezomib therapy but 
not refractory to 
lenalidomide and 
thalidomide 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
 
Other than the above 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  


 
148 of 164 
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.8.2a/b/c/d). 
 
Table 11.3.8.3 Response rate by IMWG (Independent Review assessment and “All 
Randomized Patients” population) by lenalidomide/thalidomide or bortezomib prior 
therapies 
Prior therapies 
 
Response 
Arm A 
Arm B 
N 
% 
N 
% 
 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 
Resistant or refractory to 
lenalidomide/thalidomide and bortezomib 
therapies 
PR 
 
 
 
 
 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
Resistant or refractory to 
lenalidomide/thalidomide therapy but not 
refractory to bortezomib 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 
 
PR 
 
 
 
 
 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 
 
PR 
 
 
 
 
Resistant or refractory to bortezomib 
therapy but not refractory to 
lenalidomide and thalidomide 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 
 
PR 
 
 
 
 
Other than the above 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 (*) Including NE and insufficient data available. 
 
 
 


 
149 of 164 
Table 11.3.8.4 Response rate estimates by IMWG (Independent Review assessment and 
“All Randomized Patients” population) by lenalidomide/thalidomide or bortezomib prior 
therapies 
Prior therapies 
Arm A 
Arm B 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Resistant or refractory to 
lenalidomide/thalidomide 
and bortezomib therapies 
 
 
 
 
 
 
Resistant or refractory to 
lenalidomide/thalidomide 
therapy but not 
refractory to bortezomib 
 
 
 
 
 
 
Resistant or refractory to 
bortezomib therapy but 
not refractory to 
lenalidomide and 
thalidomide 
 
 
 
 
 
 
Other than the above 
 
 
 
 
 
 
Binomial exact estimator and 95% confidence interval 
 
11.3.9 Efficacy analysis in patients refractory to last prior therapy 
 
Patients will be classified as refractory to last prior therapy or other.  
 
Table 11.3.9.1 PFS (Independent Review assessment and “All Randomized Patients” 
population) by refractory patients to last prior therapy 
Prior therapy 
 
Arm A 
Arm B 
Parameter 
p-value 
Refractory to last prior 
therapy 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Other 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.9.1a/b)  
 
Table 11.3.9.2 OS (“All Randomized Patients” population) by refractory patients to last 
prior therapy 
Prior therapy 
  
Arm A 
Arm B  
Parameter 
p-value 
Refractory to last prior 
therapy 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 


 
150 of 164 
OS at 24 months 
 
 
Diff: 
 
 
Other 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.9.2a/b). 
 
Table 11.3.9.3 Response rate by IMWG (Independent Review assessment and “All 
Randomized Patients” population) by refractory patients to last prior therapy 
Prior therapy 
 
Response 
Arm A 
Arm B 
N 
% 
N 
% 
 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 
Refractory to last prior therapy 
PR 
 
 
 
 
 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 
 
PR 
 
 
 
 
Other 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 (*) Including NE and insufficient data available. 
 
Table 11.3.9.4 Response rate estimates by IMWG (Independent Review assessment and 
“All Randomized Patients” population) by refractory patients to last prior therapy 
Prior therapy 
Arm A 
Arm B 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Refractory to last prior 
therapy 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
Binomial exact estimator and 95% confidence interval 
 
 
11.3.10 Efficacy analysis in patients exposed to IMiD therapies 
 
Patients who were exposed to IMiD therapies (pomalidomide, thalidomide or 
lenalidomide) will be classified as responders or refractory  
 
 


 
151 of 164 
Table 11.3.10.1 PFS (Independent Review assessment and “All Randomized Patients” 
population) in patients exposed to IMiD 
Prior therapy 
 
Arm A 
Arm B 
Parameter 
p-value 
Refractory to IMiD 
therapy 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Responders 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.9.1a/b)  
 
Table 11.3.10.2 OS (“All Randomized Patients” population) in patients exposed to IMiD 
Prior therapy 
  
Arm A 
Arm B  
Parameter 
p-value 
Refractory to IMiD 
therapy 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
 
Responders 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.9.2a/b). 
 
Table 11.3.10.3 Response rate by IMWG (Independent Review assessment and “All 
Randomized Patients” population) in patients exposed to IMiD 
Prior therapy 
 
Response 
Arm A 
Arm B 
N 
% 
N 
% 
 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 
Refractory to IMiD therapy 
PR 
 
 
 
 
 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 


 
152 of 164 
 
PR 
 
 
 
 
Responders 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 (*) Including NE and insufficient data available. 
 
Table 11.3.10.4 Response rate estimates by IMWG (Independent Review assessment and 
“All Randomized Patients” population) in patients exposed to IMiD 
Prior therapy 
Arm A 
Arm B 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Refractory to IMiD 
therapy 
 
 
 
 
 
 
Responders 
 
 
 
 
 
 
Binomial exact estimator and 95% confidence interval 
 
11.3.11 Efficacy analysis in patients exposed to PIs therapies 
 
Patients who were exposed to PIs therapies (bortezomib or carfilzomib) will be classified 
as responders or refractory  
 
 
Table 11.3.11.1 PFS (Independent Review assessment and “All Randomized Patients” 
population) in patients exposed to PIs 
Prior therapy 
 
Arm A 
Arm B 
Parameter 
p-value 
Refractory to PIs 
therapy 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Responders 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.9.1a/b)  
 
Table 11.3.11.2 OS (“All Randomized Patients” population) in patients exposed to PIs 
Prior therapy 
  
Arm A 
Arm B  
Parameter 
p-value 
Refractory to PIs 
therapy 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 


 
153 of 164 
 
Responders 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median OS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
OS at 12 months 
 
 
Diff: 
 
OS at 24 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.9.2a/b). 
 
Table 11.3.11.3 Response rate by IMWG (Independent Review assessment and “All 
Randomized Patients” population) in patients exposed to PIs 
Prior therapy 
 
Response 
Arm A 
Arm B 
N 
% 
N 
% 
 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 
Refractory to PIs therapy 
PR 
 
 
 
 
 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 
sCR  
 
 
 
 
 
CR  
 
 
 
 
 
VGPR 
 
 
 
 
 
PR 
 
 
 
 
Responders 
MR 
 
 
 
 
 
SD 
 
 
 
 
 
PD 
 
 
 
 
 
Unknown* 
 
 
 
 
 (*) Including NE and insufficient data available. 
 
Table 11.3.11.4 Response rate estimates by IMWG (Independent Review assessment and 
“All Randomized Patients” population) in patients exposed to PIs 
Prior therapy 
Arm A 
Arm B 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Proportion 
Lower 95% 
limit 
Upper 95% 
limit 
Refractory to PIs 
therapy 
 
 
 
 
 
 
Responders 
 
 
 
 
 
 
Binomial exact estimator and 95% confidence interval 
 
 
 


 
154 of 164 
PAGE 45: Section 12.1.1 Treatment administration 
 
Original footnote table 12.1.1.1: 
 
NA: Not applicable. If appropriate, the dose intensity of plitidepsin and dexamethasone will be calculated in those patients 
who crossover to the Arm B. 
 
Changes to: 
 
NA: Not applicable. If appropriate, the dose intensity of plitidepsin and dexamethasone will be calculated in those 
patients who crossover to the Arm B. Cycles after crossover will be excluded. 
 
ADDED 
 
Table 12.1.1.2 Number of cycles administered and dose intensity after crossover 
 
After crossover 
No. of cycles administered per patient 
N 
% 
1 
 
 
2 
 
 
3 
 
 
… 
 
 
Median (range) 
 
 Time on treatment (weeks) 
Median  
Range 
 
Plitidepsin cumulative dose (mg/m²) 
 
Median 
Range 
Plitidepsin dose intensity (mg/m²/wk) 
 
Median 
Range 
Plitidepsin relative dose intensity (%)  
 
Median 
Range 
Dexamethasone cumulative dose (mg) 
 
Median 
Range 
Dexamethasone dose intensity (mg/wk) 
 
Median 
Range 
Dexamethasone relative dose intensity (%)  
 
Median 
 
Range 
 
PAGE 45: Section 12.1 Extent of exposure 
 
FOOTNOTES ADDED 
 
The following footnote has been added in listing 12.1.2.1.1, 12.1.2.2.3, 12.1.3.1.1, 12.1.3.2, 
12.1.4.1.1, 12.1.4.4, 12.1.5.1. 
 
Results after crossover will be highlighted 
 


 
155 of 164 
The following footnote has been added in tables 12.1.2.1.2, 12.1.2.1.3, 12.1.2.1.4, 
12.1.2.2.1, 12.1.2.2.2, 12.1.3.1.2, 12.1.3.1.3, 12.1.3.1.4, 12.1.4.2, 12.1.4.3. 
 
Cycles after crossover will be excluded 
 
PAGE 54: Listing 12.1.6.1 Patients and cycles without prophylactic medication 
administration 
 
Original table: 
 
Patient id. 
Cycle 
Infusion 
Prophylactic medication 
not taken* 
Reason 
… 
 
 
 
 
(*) Ondansetron, diphenhydramine or ranitidine. 
 
 
Changes to: 
Arm 
Patient id. 
Cycle 
Infusion 
Prophylactic 
medication not 
taken* 
Reason 
 
… 
 
 
 
 
(*) Ondansetron, diphenhydramine or ranitidine. 
 
 
PAGE 54: Section 12.2 Averse Events (AEs) 
 
FOOTNOTE ADDED 
 
The following footnote has been added in tables and listings 12.2.2.1, 12.2.2.2, 12.2.2.3, 
12.2.2.4, 12.2...2.6, 12.2.2.7, 12.2.2.9, 12.2.2.10, 12.2.2.11, 12.2.2.12. 
 
Events with onset date after crossover will be excluded 
 
Original footnote: 
Tables 12.2.2.5 and 12.2.2.8. 
 
(*)All toxicities with onset date ≥ administration date after crossover (**) Any grade.  
 
Changes to: 
 
(*)All events with onset date ≥ administration date after crossover (**) Any grade.  
 
 
ADDED 
 
Listing 12.2.2.13 Treatment-related grade 3-4 adverse events in “All Crossover Patients” 
population. Worst grade by patient 
Arm 
Patient id. 
SOC Name 
Preferred term 
Grade 
… 
 
 
 
 
 


 
156 of 164 
Listing 12.2.2.14 Adverse Events grade 3-4 regardless of relationship in “All Crossover 
Patients” population. Worst grade by patient 
Arm 
Patient id. 
SOC Name 
Preferred term 
Grade 
… 
 
 
 
 
 
 
PAGE 58: Listing 12.3.2.3 Deaths due to AEs 
 
ADDED: 
* AEs with Seriousness=Death …. 
 
PAGE 56: Section 12.4 Clinical laboratory evaluation 
 
FOOTNOTE ADDED 
 
The following footnote has been added in tables and listings 12.4.1.1, 12.4.1.2,  12.4.1.4, 
12.4.1.5 12.4.1.8, 12.4.2.1, 12.4.2.2, 12.4.2.4, 12.4.2.5, 12.4.3.1, 12.4.3.2, 12.4.3.4, 
12.4.3.5, 12.4.4.1, 12.4.4.2, 12.4.4.3, 12.4.4.4, 12.4.4.5. 
 
Events with onset date after crossover will be excluded 
 
ADDED 
 
Listing 12.4.1.12 Grade 3-4 hematological abnormalities during treatment in the “All 
Crossover Patients” population. Worst grade per patient 
Arm 
Patient id. 
Test 
Grade 
… 
 
 
 
 
Listing 12.4.1.13 Grade 3-4 hematological abnormalities during treatment in the “All 
Crossover Patients” population. Worst grade per cycle 
Arm 
Patient id. 
Test 
Grade 
… 
 
 
 
 
Listing 12.4.2.11Grade 3-4 biochemical abnormalities during treatment in the “All 
Crossover Patients” population. Worst grade per patient 
Arm 
Patient id. 
Test 
Grade 
… 
 
 
 
 
Listing 12.4.2.12 Grade 3-4 biochemical abnormalities during treatment in the “All 
Crossover Patients” population. Worst grade per cycle 
Arm 
Patient id. 
Test 
Grade 
… 
 
 
 
 
Listing 12.4.3.8 Grade 3-4 metabolic abnormalities during treatment in the “All Crossover 
Patients” population. Worst grade per patient 
Arm 
Patient id. 
Test 
Grade 
… 
 
 
 
 
Listing 12.4.3.9 Grade 3-4 metabolic abnormalities during treatment in the “All Crossover 
Patients” population. Worst grade per cycle 


 
157 of 164 
Arm 
Patient id. 
Test 
Grade 
… 
 
 
 
 
PAGE 61: Section 12.5 Vital signs, physical findings, LVEF, ECG and other tests 
related to safety 
 
FOOTNOTE ADDED 
 
The following footnote has been added in tables 12.5.1.1, 12.5.1.2, 12.5.2.2 and 12.5.2.4. 
 
Results after crossover will be highlighted 
 
 
PAGE 68: Table 12.7.2 Worst grade 3-4 by patient in special subgroups (Age) 
 
Original table: 
 
Events 
Arm A 
Arm B 
<65 years old 
≥65 years old 
<65 years old 
≥65 years old 
N 
Grade 3-4 
% 
N 
Grade 
3-4 
% 
N 
Grade 
3-4 
% 
N 
Grade 
3-4 
% 
Thrombocytopenia  
 
 
 
 
 
 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
 
 
 
 
 
 
AP  
 
 
 
 
 
 
 
 
 
 
 
 
Total bilirubin  
 
 
 
 
 
 
 
 
 
 
 
 
AST  
 
 
 
 
 
 
 
 
 
 
 
 
ALT  
 
 
 
 
 
 
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
 
 
 
 
 
 
(*)Any treatment-related toxicity present in >=5% of patients in any group 
 
Changes to: 
 
Events 
Arm A 
Arm B 
<65 years old 
…** 
<65 years old 
…** 
N 
Grade 3-4 
% 
N 
Grade 
3-4 
% 
N 
Grade 
3-4 
% 
N 
Grade 
3-4 
% 
Thrombocytopenia  
 
 
 
 
 
 
 
 
 
 
 
 
Neutropenia  
 
 
 
 
 
 
 
 
 
 
 
 
AP  
 
 
 
 
 
 
 
 
 
 
 
 
Total bilirubin  
 
 
 
 
 
 
 
 
 
 
 
 
AST  
 
 
 
 
 
 
 
 
 
 
 
 


 
158 of 164 
Events 
Arm A 
Arm B 
<65 years old 
…** 
<65 years old 
…** 
N 
Grade 3-4 
% 
N 
Grade 
3-4 
% 
N 
Grade 
3-4 
% 
N 
Grade 
3-4 
% 
ALT  
 
 
 
 
 
 
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
 
 
 
 
 
 
(*)Any treatment-related toxicity present in >=5% of patients in any group 
(**) Age 65-74, Age 75-84, Age ≥85. If there is a group of age with less than 5% of patients, it could be join with the 
previous/next group of age. 
 
 
PAGE 85: Section 13 DB Listings 
 
ADDED: 
 
Listing 13.31 Investigator comments 
 
Rest of listings were renumbered accordingly.


 
159 of 164 
From Statistical Analysis Plan v2.0 to v3.0: 
A new “substantial” protocol amendment was included; therefore, the Statistical Analysis 
Plan v2.0 was changed in accordance with the new version of the protocol as follows: 
 
 In accordance with the correction in the bibliography in Appendix 5 of the protocol 
regarding the IMWG Response Criteria for Multiple Myeloma, progressive disease 
does not have to be confirmed with a second assessment. Sections of Sensitivity 
analyses have been modified accordingly. 
 A new substudy to assess the potential effect of plitidepsin on the QTc interval of 
patients enrolled in clinical trial APL-C-001-09 will be performed. Reference to a 
separate SAP for the substudy has been added.  
 A new method to estimate and control the effect of crossover in OS has been added. 
 Other minor corrections have also been done. 
 
 
CHANGES: 
 
Included changes are highlighted in Italic Bold. 
 
PAGE 14: Section 6.1.2 Final Analyses – Primary endpoint 
 
DELETED: 
Those patients in the control arm (Arm B) who crossed over to the combination 
arm (Arm A) before a proper confirmation of progressive disease by IMWG will 
be censored at the date of first drug administration of the combination arm for the 
primary analysis of PFS in the control arm. 
 
PAGE 15: Section 6.1.2 Final Analyses – Sensitivity analyses 
 
DELETED: 
In the third sensitivity analysis, disease progression will be assumed for the first 
missing scheduled assessment following the last evaluation without progression. 
In addition, two other sensitivity analyses of PFS will be done. The first one will 
be done using the IRC progression or censoring date for those patients who were 
crossed over without a proper confirmation of progressive disease. The second 
one will be done using the first documented progressive disease, even if it was not 
properly confirmed with a second determination. 
 
PAGE 16: Section 6.2.3 Secondary analyses – Overall survival 
 


 
160 of 164 
ADDED: 
It is anticipated that an indeterminate number of patients in the control arm will 
switch treatment after progression to plitidepsin plus dexamethasone. This could 
cause the size of the effect on OS to be difficult to interpret. Consequently, if the OS 
results show to be substantially influenced by crossover, the Sponsor will study the 
estimated effect of crossover by means of rank preserving structural failure time 
models for correcting for treatment changes (2) and by the inverse probability of 
censoring weighting method (6) in order to try to control any bias caused by 
treatment crossover. 
 
PAGE 21: Section 8.12 Analyses of the effects of plitidepsin on the QTc interval 
ADDED: 
8.12 Analyses of the effects of plitidepsin on the QTc interval 
A substudy will be conducted to assess the potential effects of plitidepsin on the 
QTc interval of patients with relapsed/refractory multiple myeloma enrolled in 
clinical trial APL-C-001-09. These analyses will be specified in a separate 
document. 
 
PAGE 30: Mock table 11.1.6.5 
 
CHANGES: 
Original title: 
Listing 11.1.6.5 Baseline characteristics: Left Ventricular Ejection Fraction (LVEF) 
Arm 
Patient id. 
Cycle 
Date 
LVEF (%) 
Institutional normal range (%) 
Method 
… 
 
 
 
 
 
 
 
Changes to: 
Table 11.1.6.5 Baseline characteristics: Left Ventricular Ejection Fraction (LVEF) 
Arm 
Patient id. 
Cycle 
Date 
LVEF (%) 
Institutional normal range (%) 
Method 
… 
 
 
 
 
 
 
 
PAGE 32: Mock table 11.1.8.2 
 
CHANGES: 
Original table: 
 
Table 11.1.8.2 Biochemical values at baseline 
 
Arm A 
Arm B 
Total 
Median (range) 
Median (range) 
Median (range) 
AST (IU/L) 
 
 
 
ALT (IU/L) 
 
 
 
Total bilirubin (mg/dL) 
 
 
 
Direct bilirubin (mg/dL) 
 
 
 


 
161 of 164 
AP (IU/L) 
 
 
 
Creatinine (mg/dL) 
 
 
 
Cr. Clearance (Calculated) (ml/min) 
 
 
 
Cr. Clearance (Measured) (ml/min) 
 
 
 
CPK (IU/L) 
 
 
 
CPK MB (IU/L) 
 
 
 
Cardiac Troponin I (ng/ml) 
 
 
 
Total proteins (g/dL) 
 
 
 
Albumin (g/dL) 
 
 
 
Uric acid (mg/dL) 
 
 
 
LDH (IU/L) 
 
 
 
Beta-2-microglobulin (mg/L) 
 
 
 
 
Changes to: 
 
Table 11.1.8.2 Biochemical values at baseline 
 
Arm A 
Arm B 
Total 
Median (range) 
Median (range) 
Median (range) 
AST (xULN) 
 
 
 
ALT (xULN) 
 
 
 
Total bilirubin (xULN) 
 
 
 
Direct bilirubin (xULN) 
 
 
 
AP (xULN) 
 
 
 
Creatinine (xULN) 
 
 
 
Cr. Clearance (Calculated) (ml/min) 
 
 
 
Cr. Clearance (Measured) (ml/min) 
 
 
 
CPK (xULN) 
 
 
 
CPK MB (IU/L) 
 
 
 
Cardiac Troponin I (ng/ml) 
 
 
 
Total proteins (g/dL) 
 
 
 
Albumin (g/dL) 
 
 
 
Uric acid (mg/dL) 
 
 
 
LDH (xULN) 
 
 
 
Beta-2-microglobulin (mg/L) 
 
 
 
 
 
PAGE 37: Mock tables 11.3.3.6 and 11.3.3.7 
 
DELETED: 
 
Table 11.3.3.6 PFS (Independent Review assessment and “All Randomized 
Patients” population) without censoring those patients who were crossed over 
without a proper confirmation of progressive disease. 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.3.6). 
 
Table 11.3.3.7 PFS (Investigator assessment and “All Randomized Patients” 
population) using the first documented progressive disease even if it was not 


 
162 of 164 
properly confirmed. 
  
Arm A 
Arm B  
Parameter 
p-value 
N 
 
 
  
  
Events 
 
 
  
  
Censored 
 
 
  
  
Median PFS 
 
 
Log-Rank:  
HR (95% CI) : 
LR:  
HR: 
PFS at 6 months 
 
 
Diff: 
 
Kaplan-Meier plot will be also shown (Figure 11.3.3.7). 
 
 
PAGE 45: Mock listing 12.1.2.1.1 
 
DELETED COLUMN: 
Listing 12.1.2.1.1 Delays 
Arm 
Patient 
id. 
Cycle 
Day 
Agent 
Previous 
cycle 
Previous 
cycle 
start date 
Delayed 
cycle 
Delayed 
cycle 
start 
date 
Dose 
Delay 
calculated. 
(days) 
Reason 
for dose 
delay 
Dose 
Delay 
Spec. 
… 
 
 
 
 
 
 
 
 
 
 
 
 
PAGE 47: Mock table 12.1.2.2.2 
 
DELETED: 
 
Table 12.1.2.2.2 Dose reduction in cycles delayed 
 
Reduction 
Reduction 
Yes 
No 
Yes 
No 
N 
% 
N 
% 
N 
% 
N 
% 
 
Arm A 
 
Cycle 2 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
Cycle nth 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
Arm B 
 
Cycle 2 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
Cycle nth 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
PAGE 60: Mock table 12.4.4.2 
 
CHANGES: 
Original table: 
Table 12.4.4.2 Evolution of transaminases abnormalities from BL by treatment arm, 
worst case per patient. 
 
Arm A 
Worst grade per patient 
Total 
0 
1 
… 
N 
% 
N 
% 
N 
% 
N 
% 
Basel
ine 
AST increase  
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 


 
163 of 164 
ALT increase 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
…. 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
                                 Arm B 
AST increase  
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
ALT increase 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
… 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
 
 
Changes to: 
Table 12.4.4.2 Evolution of transaminase abnormalities from BL by treatment arm, 
worst case per patient. 
 
 
Arm A 
Worst grade per patient 
Total 
0 
1 
… 
N 
% 
N 
% 
N 
% 
N 
% 
Baseline 
AST increase 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
ALT increase 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
                                 Arm B 
AST increase 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
ALT increase 
Grade 0 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
 
 
PAGE 66: Listing 13.1.13 
 
CHANGES: 
Original title:  
 
 
-Listing 13.1.13: Other metabolic laboratory values 
 
Changes to: 
 
 
-Listing 13.1.13: Coagulation laboratory values 
 
 
PAGE 67: Section 14: References 


 
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ADDED: 
6. Robins JM, Finkelstein DM: Correcting for noncompliance and dependent 
censoring in an AIDS Clinical Trial with inverse probability of censoring 
weighted (IPCW) log-rank tests. Biometrics 56:779-788, 2000.