Clinical trial NCT03450057
Conditions: Relapsed/Refractory Multiple Myeloma
Keywords: Multiple Myeloma MM Relapsed Refractory
Sponsor: Hellenic Society of Hematology
Start date: 2018-02-15; Completion date: 2021-03-22
Enrollment: 38 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study was to evaluate the effects of daratumumab with dexamethasone (DaraD) in subjects with relapsed or refractory multiple myeloma and renal impairment.

Detailed description:
This was a multicenter, single arm, open-label phase 2 study. 38 subjects were enrolled to receive daratumumab and dexamethasone. Treatment cycles had a duration of 28 days. Subjects received treatment until either disease progression, death, unacceptable toxicity or for a maximum of 30 months. Drug administration and follow-up visits occurred more frequently for early cycles (weekly for the first 8 weeks, every two weeks for weeks 9-24 and then every 4 weeks). Disease evaluations occurred monthly and involved mainly measurements of myeloma proteins. Other assessments included bone marrow examinations, skeletal surveys, assessment of extramedullary plasmacytomas, and measurements of serum calcium corrected for albumin, and β2- microglobulin and albumin.

Arms: arm 1: Daratumumab was given at a dose of 16 mg/kg administered as an intravenous (IV) infusion at weekly intervals (QW) for 8 weeks, then every 2 weeks (Q2W) for an additional 16 weeks, then every 4 weeks (Q4W) thereafter. Dexamethasone was administered according to the standard recommended dose of 40 mg (20 mg for patients \> 75 years of age) orally once daily on Days 1, 8, 15, and 22 of each 28-day treatment cycle.
Interventions: intervention 1: Daratumumab with dexamethasone
Intervention descriptions: intervention 1: Daratumumab:

Daratumumab was given at a dose of 16 mg/kg administered as an intravenous (IV) infusion at weekly intervals (QW) for 8 weeks, then every 2 weeks (Q2W) for an additional 16 weeks, then every 4 weeks (Q4W) thereafter. Subjects received pre-infusion medications before infusions to mitigate potential infused-related reactions (IRRs).

Dexamethasone:

Dexamethasone was administered at 40 mg (20 mg for patients \>75 years of age) orally, once daily on Days 1, 8, 15, and 22 of each 28-day treatment cycle.

Protocol documents:
Prot_000.pdf: 
EudraCT No: 2017-003950-18 
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Protocol No: ΕΑΕ-2017/ΜΜ02                                                                                                                                8 June 2020 
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Protocol title 
 
Efficacy of Daratumumab in Patients with Relapsed/Refractory 
Myeloma with Renal Impairment 
 
The DARE study 
 
Protocol Identifying Number: ΕΑΕ-2017/ΜΜ02 
ΕudraCT Number: 2017-003950-18 
 
 
Sponsor:  
Hellenic Society of Hematology 
27 Kifisias Ave, 11523, Athens  
Tel: +30- 210 7211806 , fax:+30- 210 6466288  
Email: info@eae.gr, infohaema@eae.gr  
Sponsor representative: Prof. Meletios Athanasios Dimopoulos  
 
Co-ordinating Investigator:  
Associate Prof. Efstathios Kastritis  
Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of 
Medicine, Athens - Greece 
   
Scientific Co-ordinating Investigator:  
Prof. Meletios Athanasios Dimopoulos 
Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of 
Medicine, Athens - Greece 
 
Study & Sponsor Status / financing: This is a Non-commercial, Sponsor/Investigator Initiated 
Study. Janssen Pharmaceuticals will provide the investigational medicinal product at no expense and 
financially support this research study. 
 
Protocol Version Number:  v 5.0 
 
Dated: 08 June 2020 


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CONTENTS 
PROTOCOL AMENDMENTS ............................................................................................... 8 
LIST OF ABBREVIATIONS ................................................................................................ 17 
STATEMENT OF COMPLIANCE ....................................................................................... 18 
PROTOCOL SUMMARY .................................................................................................... 18 
KEY ROLES ....................................................................................................................... 21 
1. BACKGROUND AND RATIONALE................................................................................ 22 
1.1 
MULTIPLE MYELOMA ............................................................................................ 22 
1.2 
DARATUMUMAB .................................................................................................... 23 
1.3 
RENAL IMPAIRMENT IN MYELOMA ...................................................................... 24 
1.4 
RATIONALE ............................................................................................................ 26 
2. POTENTIAL RISKS AND BENEFITS ............................................................................. 26 
2.1 
KNOWN POTENTIAL RISKS .................................................................................. 26 
2.2 KNOWN POTENTIAL BENEFITS ................................................................................ 28 
3. OBJECTIVES AND PURPOSE ...................................................................................... 29 
3.1 
PRIMARY OBJECTIVE ............................................................................................ 29 
3.2 
SECONDARY OBJECTIVES ................................................................................... 29 
4. STUDY DESIGN AND STUDY END POINTS ................................................................. 29 
4.1 
DESCRIPTION OF THE STUDY DESIGN ............................................................... 29 
4.1.1 PRIMARY ENDPOINT ............................................................................................. 30 
4.1.2 SECONDARY ENDPOINTS ..................................................................................... 30 
5.  
STUDY ENROLLMENT AND WITHDRAWAL ......................................................... 30 
5.1 
PARTICIPANT INCLUSION CRITERIA ................................................................... 30 
5.2 
PARTICIPANT EXCLUSION CRITERIA .................................................................. 31 
5.3 
PARTICIPANT WITHDRAWAL OR TERMINATION ................................................ 33 
5.3.1 REASONS FOR WITHDRAWAL OR TERMINATION .............................................. 33 


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5.3.2 HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION .................... 33 
5.4 
PREMATURE TERMINATION OR SUSPENSION OF STUDY ................................ 33 
6. STUDY TREATMENT ..................................................................................................... 34 
6.1 
STUDY TREATMENTS AND CONTROL DESCRIPTION ........................................ 34 
6.1.1 FORMULATION, APPEARANCE, PACKAGING, AND LABELING ........................ 34 
6.1.2 PRODUCT STORAGE AND STABILITY ................................................................. 34 
6.1.3 PREPARATION ....................................................................................................... 34 
6.1.4 DOSING AND ADMINISTRATION ........................................................................... 35 
6.1.5 DOSE ADJUSTMENTS/MODIFICATIONS/DELAYS ............................................... 35 
6.1.6 DURATION OF THERAPY ....................................................................................... 37 
6.2 
STUDY TREATMENT ACCOUNTABILITY PROCEDURES .................................... 37 
7. STUDY PROCEDURES AND SCHEDULE ..................................................................... 37 
7.1 
STUDY PROCEDURES/EVALUATIONS ................................................................. 37 
7.1.1 EFFICACY ASSESSMENTS .................................................................................... 37 
7.1.1.1 SERUM AND URINE SAMPLE COLLECTION FOR M-PROTEIN ASSESSMENT 
BY PEP AND IFE ............................................................................................................... 40 
7.1.1.2 FREE LIGHT CHAIN (FLC) PROTEIN ASSESSMENT .......................................... 41 
7.1.1.3 PLASMA CELL COUNT IN BONE MARROW BY LOCAL ASSESSMENT............ 41 
7.1.1.4 ASSESSMENT OF SOFT TISSUE PLASMACYTOMA (STP) ................................ 41 
7.1.1.5 SKELETAL SURVEY .............................................................................................. 42 
7.1.1.6 MINIMAL RESIDUAL DISEASE (MRD) BY MEANS OF NEXT GENERATION 
FLOW CYTOMETRY (EUROFLOW PROTOCOL). ............................................................ 42 
7.1.1.7 CORRECTED CALCIUM ........................................................................................ 42 
7.1.1.8 CYTOGENETICS BY MEANS OF FLUORESCENCE IN SITU HYBRIDIZATION 
(FISH) 42 
7.1.1.9 EGFR CALCULATION ........................................................................................... 42 
7.1.2 SAFETY ASSESSMENTS ....................................................................................... 43 
7.1.2.1 ADVERSE EVENTS ................................................................................................ 43 


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7.1.2.2 CLINICAL LABORATORY TESTS ......................................................................... 43 
7.1.2.3 VITAL SIGNS .......................................................................................................... 43 
7.1.2.4 PHYSICAL EXAMINATION .................................................................................... 44 
7.1.2.5 ECOG PERFORMANCE STATUS .......................................................................... 44 
7.1.2.6 CARDIAC ASSESSMENTS .................................................................................... 44 
7.1.3 HEPATITIS B VIRUS (HBV) SEROLOGY ................................................................. 44 
7.1.4 HBV DNA TESTS ...................................................................................................... 44 
7.2 
STUDY SCHEDULE ................................................................................................. 44 
7.2.1 SCREENING ............................................................................................................ 45 
7.2.2 TREATMENT PERIOD ............................................................................................. 47 
7.2.3 FOLLOW-UP PERIOD ............................................................................................. 47 
TABLE 7.2 – SCHEDULE OF EVENTS .............................................................................. 48 
7.3 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES ............... 51 
7.3.1 PRECAUTIONARY MEDICATIONS, TREATMENTS, AND PROCEDURES ........... 51 
7.3.2 PROHIBITED MEDICATIONS, TREATMENTS AND PROCEDURES ..................... 51 
7.3.3 RESCUE MEDICATIONS, TREATMENTS AND PROCEDURES ............................ 51 
7.3.3.1 HEMODIALYSIS ..................................................................................................... 51 
7.3.4 PARTICIPANT ACCESS TO STUDY TREATMENT AT STUDY CLOSURE ........... 51 
8. SAFETY MONITORING AND REPORTING ................................................................... 52 
8.1 
ADVERSE EVENTS ................................................................................................. 52 
8.1.1 ADVERSE EVENT DEFINITION .............................................................................. 52 
8.1.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) .......................................... 52 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT ......................................................... 53 
8.2.1 SEVERITY OF EVENT ............................................................................................. 53 
8.2.2 RELATIONSHIP TO STUDY TREATMENT(S) ........................................................ 53 
8.2.3 EXPECTEDNESS .................................................................................................... 54 


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8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP
 
54 
8.4 
REPORTING PROCEDURES .................................................................................. 54 
8.4.1 ADVERSE EVENT REPORTING ............................................................................. 54 
8.4.2 SERIOUS ADVERSE EVENT REPORTING ............................................................ 54 
8.4.3 EVENTS OF SPECIAL INTEREST .......................................................................... 55 
8.4.4 PREGNANCY .......................................................................................................... 55 
8.4.5 PRODUCT QUALITY COMPLAINTS ....................................................................... 56 
8.4.6 ANNUAL SAFETY REPORT ................................................................................... 56 
8.5 
SAFETY OVERSIGHT ............................................................................................. 56 
9.  CLINICAL MONITORING .............................................................................................. 56 
10. 
STATISTICAL CONSIDERATIONS ......................................................................... 56 
10.1 
STATISTICAL AND ANALYTICAL PLANS ............................................................. 56 
10.2 
STATISTICAL HYPOTHESES ................................................................................. 57 
10.3 
ANALYSIS DATASETS ........................................................................................... 57 
10.4 
DESCRIPTION OF STATISTICAL METHODS ........................................................ 57 
10.4.1 GENERAL APPROACH .......................................................................................... 57 
10.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) ..................................... 57 
10.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S).................................................. 58 
10.4.4 SAFETY ANALYSES ............................................................................................... 59 
10.4.5 BASELINE DESCRIPTIVE STATISTICS ................................................................. 60 
10.4.6 TREATMENTS (STUDY TREATMENT, CONCOMITANT THERAPIES) ................. 60 
10.4.7 PLANNED INTERIM ANALYSES ............................................................................ 61 
10.4.7.1 SAFETY REVIEW ................................................................................................. 61 
10.4.7.2 EFFICACY REVIEW ............................................................................................. 61 
10.4.8 ADDITIONAL SUB-GROUP ANALYSES ................................................................ 61 
10.4.9 MULTIPLE COMPARISON/MULTIPLICITY............................................................. 61 


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10.4.10 EXPLORATORY ANALYSES ................................................................................ 61 
10.5 
SAMPLE SIZE ......................................................................................................... 62 
10.6 
MEASURES TO MINIMIZE BIAS ............................................................................. 62 
10.6.1 ENROLMENT/MASKING PROCEDURES ............................................................... 62 
10.6.2 BLINDING - UNBLINDING ...................................................................................... 62 
11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA / DOCUMENTS ....... 62 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL ............................................... 63 
13. 
ETHICS/PROTECTION HUMAN OF SUBJECTS .................................................... 63 
13.1  ETHICAL STANDARDS .......................................................................................... 63 
13.2 
INSTITUTIONAL REVIEW BOARD (IRB)/INDEPENDENT ETHICS COMMITTEE 
(IEC) AND COMPETENT AUTHORITY .............................................................................. 63 
13.3 
INFORMED CONSENT PROCESS .......................................................................... 63 
13.3.1CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS ................................................................................................................. 63 
13.3.2 CONSENT PROCEDURES AND DOCUMENTATION ............................................. 64 
13.4 
PARTICIPANT AND DATA CONFIDENTIALITY ..................................................... 64 
13.5 
INSURANCE ............................................................................................................ 64 
14. DATA HANDLING AND RECORD KEEPING .............................................................. 65 
14.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES .......................... 65 
14.2 
STUDY RECORDS RETENTION ............................................................................. 65 
14.3 
PROTOCOL DEVIATIONS ...................................................................................... 66 
14.4 
PUBLICATION AND DATA SHARING POLICY ...................................................... 66 
14.5 
END OF STUDY REPORT ....................................................................................... 66 
15. STUDY ADMINISTRATION .......................................................................................... 67 
15.1 
STUDY LEADERSHIP ............................................................................................. 67 
16. CONFLICT OF INTEREST (COI) POLICY .................................................................... 67 
17. REFERENCES ............................................................................................................. 68 


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APPENDIX ......................................................................................................................... 70 
APPENDIX 1 – PREPARATION OF DARATUMUMAB ...................................................... 70 
APPENDIX 2 – GUIDELINES FOR ADMINISTRATING DARATUMUMAB ........................ 71 
APPENDIX 3A – THE INTERNATIONAL STAGING SYSTEM (ISS) FOR MULTIPLE 
MYELOMA ......................................................................................................................... 73 
APPENDIX 3B – THE REVISED INTERNATIONAL STAGING SYSTEM (ISS) FOR 
MULTIPLE MYELOMA ....................................................................................................... 73 
APPENDIX 4 – MODIFIED INTERNATIONAL MYELOMA WORKING GROUP (IMWG) 
UNIFORM RESPONSE CRITERIA FOR MULTIPLE MYELOMA ....................................... 74 
APPENDIX 5 – IMWG RENAL RESPONSE CRITERIA AND SIMPLIFIED RENAL 
RESPONSE CRITERIA ...................................................................................................... 76 
APPENDIX 6 – ECOG PERFORMANCE STATUS SCALE ................................................ 77 
APPENDIX 7 - REFERENCE CHARTS FOR THE CLASSIFICATION OF ASTHMA ......... 78 
APPENDIX 8 – JSH GUIDELINES FOR THE MANAGEMENT OF HEPATITIS B VIRUS 
INFECTION ........................................................................................................................ 79 
APPENDIX 9 – SIGNATURES ........................................................................................... 82 
 
 
 


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PROTOCOL AMENDMENTS 
 
Protocol Version  
Issue Date 
Original Protocol 
13 Oct 2017 
Amendment 1 
15 Mar 2018 
Amendment 2 
13 Jul 2018 
Amendment 3 
09 Jul 2019 
Amendment 4 
08 Jun 2020 
 
Amendments below are listed beginning with the most recent amendment. 
Amendment 4 (08 JUNE 2020) 
 
This amendment is considered substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union. 
The overall reason for the amendment: To update the protocol regarding the overall duration of the study, 
from 30 to 37 months. 
Applicable Section(s) 
Description of Change(s) 
Rationale: The enrolment period is changed from 18 to 24 months, and the total study duration from 30 to 
37 months. 
Protocol summary 
Section 4.1 
Section 6.1.6 
Section 7.2.2 
The sections were updated accordingly. 
Rationale: To update the known potential risks of daratumumab administration according to the most 
recent risk language of the drug. 
Section 2.1 
Text was updated accordingly. 
 
Amendment 3 (09 JULY 2019) 
 
This amendment is considered substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union. 
The overall reason for the amendment: To update the protocol based on new guidelines regarding the risk 
of HBV reactivation, give clarifications regarding the subject population, and provide additional 
recommendations on handling daratumumab delays and toxicities. 


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Applicable Section(s) 
Description of Change(s) 
Rationale: The sections below were revised following the new guidelines on patient screening for HBV. 
Section 5.1 
 
 
 
 
 
Section 5.2 
 
 
Section 7.1.3 and 7.1.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 7.2 
 
 
Section 7.3.1 
 
 
 
 
 
 
 
 
 
 
The following sentence was added to provide 
guidance regarding the contraception of the female 
partner of a male patient: 
“The additional contraception of female partners of 
childbearing potential should also be considered” 
 
Additional information was provided on the 
eligibility criteria of the subject population. 
 
The section of Study Procedures/Evaluations was 
amended with two paragraphs, as follows: 
7.1.3 HBV Serology 
All subjects will be tested locally for hepatitis B 
surface antigen (HBsAg), hepatitis B surface antibody
(Anti-HBs), and hepatitis B core antibody (Anti-HBc)
at Screening.  Additionally, subjects ongoing in the 
Treatment Phase who are within 6 months of starting 
study treatment when Protocol Amendment 3 is 
implemented will be required to have HBV serology 
performed locally upon signing the updated ICF. 
HBV serology is not required at Screening or for 
subjects ongoing in the Treatment Phase who are 
within 6 months of starting study treatment if this was
performed as part of standard of care within 3 months 
prior to first dose. 
 
HBV DNA Tests:  
Subjects who are positive for Anti-HBc or Anti-HBs 
will undergo testing for hepatitis B DNA by PCR. 
Subjects with serologic findings suggestive of HBV 
vaccination (Anti-HBs positivity as the only serologic
marker) and a known history of prior HBV 
vaccination do not need to be tested for HBV DNA 
by PCR. During and following study treatment, 
subjects who have history of HBV infection will be 
closely monitored for clinical and laboratory signs of 
reactivation of HBV as specified in the Time and 
Events Schedule (Table 7.2).  Where required by 
local law, the results of HBV testing may be reported 
to the local health authorities. 
 
The schedule of events was updated according to the 
guidelines discussed in the main body. 
 
Two paragraphs were added regarding management 
of Hepatitis B Virus Reactivation: 
 
Primary antiviral prophylaxis is permitted as per local
standard of care.  Per protocol, HBV DNA testing by 
PCR is mandatory for subjects at risk for HBV 
reactivation (see Section 7.1.4). 
For subjects who are diagnosed with HBV 
reactivation while on treatment, study treatment 
should be interrupted until the infection is adequately 
controlled. If the benefits outweigh the risks, study 


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Appendix 2 
 
Appendix 8 
 
treatment may be resumed with concomitant antiviral 
prophylaxis as per local standard of care. Consult a 
liver disease specialist as clinically indicated. 
 
A paragraph was added regarding primary antiviral 
prophylaxis for HBV reactivation 
Appendix 8 was added to provide additional 
information on HBV management.  
Applicable Section(s) 
Description of Change(s) 
Rationale: The list of known potential risks associated with daratumumab was updated according to the 
latest data. 
Section 2.1 
 
The section was updated accordingly. 
Applicable Section(s) 
Description of Change(s) 
Rationale: The sections below were revised in order to clarify the eligibility criteria. 
Sections 5.1 and 5.2 
 
Eligibility criteria were amended in order to clarify 
that patients who undergo intraperitoneal dialysis 
can be included, and patients with Amyloidosis 
shall be excluded. 
Applicable Section(s) 
Description of Change(s) 
Rationale: The sections below were revised in order to provide recommendations on toxicity management 
and delays/missed doses of daratumumab. 
Section 6.1.5 
 
The section regarding daratumumab dose 
modifications/delays was amended with:  
• specific information on how to handle particular 
toxicities; 
• a table with the respective dose delay/resumption 
schedule;  
• a paragraph regarding interruption of missed 
doses.  
Applicable Section(s) 
Description of Change(s) 
Rationale: The schedule of events was updated in order to specify that β2 microglobulins and LDH 
assessment will only be performed at screening. 
Table 7.2 
 
The schedule of events was updated accordingly.  
Applicable Section(s) 
Description of Change(s) 
Rationale: More details and clarification on Safety events of special interest events 
Section 8.4.3 
Events of Special Interest  
 
Safety events of special interest include, but are not limited 
to: 
• Secondary Primary Malignancies  
• Infusion Related Reactions 
• Medication Error, intercepted medication error or 
potential medication error (with or without patient 
exposure to IMP, e.g., product name confusion, 
product label confusion, intercepted prescribing or 
dispensing errors)  
• Abuse/Misuse/Overdose  
• Occupational Exposure  


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• Drug-Drug Interaction  
• Suspected Transmission of Infectious Agents  
• Exposure from breastfeeding 
• Unexpected therapeutic benefit or clinical benefit 
• Inadvertent or accidental exposure 
Applicable Section(s) 
Description of Change(s) 
Rationale: The sections below were revised in order to provide information on the Revised International 
Staging System for Multiple Myeloma. 
Appendix 3 
 
A table explaining the different stages and the 
respective requirements was added. 
Applicable Section(s) 
Description of Change(s) 
Rationale: Minor corrections/updates 
All over the protocol 
 
Minor corrections for typographic errors, total 
number of participating Sites, title and address 
updates were performed throughout the protocol. 
Amendment 2 (13 JULY 2018) 
The overall reason for the amendment: To update the protocol based on Italian health authority 
recommendations. 
Applicable Section(s) 
Description of Change(s) 
Rationale: The below sections were revised following the request of the Italian health authority, 
regarding the addition of a formal Interim Safety review by the Sponsor for the assessment of the study 
treatment safety profile in the population under evaluation. 
Section 10.4.7 Planned Interim Analyses 
 
 
 
 
10.4.7.1 Safety Review 
 
 
Clarifications were provided regarding planned 
interim analysis: No formal interim analysis for 
efficacy is planned but an in interim analysis 
for safety will be performed. 
 
The paragraph was amended as follows: The 
Sponsor Scientific Committee will perform an 
overall evaluation of the safety data when 19 
patients (50%) have received at least 1 dose of 
daratumumab. If a safety signal is identified 
and the Sponsor Scientific Committee 
determines that the safety profile of the study 
treatment is unfavorable, the recruitment of the 
rest of the subjects will be interrupted and the 
study may be stopped due to safety concerns. 
In the event of such a study termination all 
current subjects that are receiving 
daratumumab treatment may receive 
subsequent alternative treatment outside of the 
study as per the investigator's judgement and 
routine practice. More details on the Interim 
Safety Review will be provided in the 
Statistical Analysis Plan for this study. 
Amendment 1 (15 MAR 2018) 
This amendment is considered substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union. 


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The overall reason for the amendment: To clarify the below listed sections of the protocol and align it with 
other protocols of daratumumab studies 
Applicable Sections 
Description of Changes 
Rationale: To change the meaning of the abbreviation SD from Standard Deviation which is used twice in 
the text, to Stable disease which is recurrent, so to avoid confusion. 
List of Abbreviations 
Change of the meaning of the abbreviation SD from 
Standard Deviation  to Stable disease 
Rationale: To reconcile inclusion criteria in the summary with inclusion criteria in main body (section 5.1) 
Protocol Summary: Population; Section 5.1: 
Inclusion criteria 
.Inclusion criteria were updated as per main text 
Rationale: To describe more clearly the current approval status of the study drug with respect to the 
population included in the study so as not to confuse that daratumumab is not approved for the RRMM 
population. 
Section 1.2: Introduction; section 2.1: Known 
potential risks 
The text was amended to: "Daratumumab in 
combination with dexamethasone is not approved for 
the indication under study.” in Section 1.2 and the 
approval status of daratumumab with respect to the 
patient population (MM patients with renal 
impairment) is described in section 2.1: 
“Daratumumab is approved for the treatment of MM, 
yet data on the treatment of patients with renal 
impairment are very limited” 
Rationale: Update of the known potential risks for Daratumumab according to the updated risk language for 
the drug 
Section 2.1: Known potential risks 
Pulmonary edema was added to the uncommon 
Adverse Events and Difficulty with blood testing and 
IAT was removed. 
The IRR sub-section text was amended to: “Of the 
820 subjects who received daratumumab in the 
monotherapy and combination Studies, IRRs were 
reported in approximately half (48%) of subjects. 
The most common IRRs were cough (10%), 
dyspnoea (9%), chills (6%), throat irritation (6%), 
nasal congestion (5%), bronchospasm (5%), nausea 
(5%), and vomiting (5%). Grade 3 IRRs were 
reported in 6% of subjects. No Grade 4 IRRs were 
reported. For the majority of subjects (378 of 392; 
96%) an IRR occurred with the first infusion” as per 
IB language. 
Rationale: To clarify the characteristics of the population included in the study 
Section 4.1 Description of the Study Design 
Rephrased sentence to: “This is a multicenter, Phase 
2, single arm, open-label study evaluating 
daratumumab with dexamethasone (DaraD) in 
subjects with RRMM who have received at least two 
prior lines of treatment, with both bortezomib- and 
lenalidomide-based regimens and have renal 
impairment.” 
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Section 5.1: Participant Inclusion Criteria 
Criterion 3 was rephrased to depict that subjects 
must have documented multiple myeloma 
Measurable disease has been registered as a separate 
criterion (Criterion 6) 
Rationale: To specify that patients with active hepatitis A are also excluded and to update the COPD/asthma  
and cardiac disease exclusion criteria as per other daratumumab protocols 
Section 5.2 Participant Exclusion Criteria 
Active Hepatitis A is added to the exclusion criteria. 
COPD/asthma exclusion criterion has been updated.  
Cardiac disease exclusion criterion has been updated 
to clarify that uncontrolled cardiac arrhythmias are 
excluded. 
Rationale: To include recurrent Grade 3 IIRs in the reasons for withdrawing daratumumab as per Appendix 
2 guidelines 
Section 5.3.1 Reasons for Withdrawal or 
Termination 
A grade 3 IRR recurring 3 times during one infusion 
was added to the list of reasons to withdraw 
daratumumab 
Rationale: To remove pregnancy as a definite drug discontinuation criterion as per the latest daratumumab 
safety update 
Section 5.3.1 Reasons for Withdrawal or 
Termination 
Pregnancy was removed from the list 
Rationale: To clarify that dose adjustment or modification is not allowed for daratumumab 
Section 6.1.5 Dose 
Adjustments/Modifications/Delays 
The text “No dose adjustment or modification is 
permitted for daratumumab” was added 
Rational: To clarify when the assessments are to be performed and reconcile this table (Table 7.1) with the 
Schedule of Events (Table 7.2) 
Table 7.1 – Disease assessments 
Text was added specifying that IFE will be 
performed as needed to confirm CR (instead of 
disease progression) and that sFLC will be 
performed as needed to confirm sCR and on Day 1 
of each cycle only for patients that have no 
measurable M-protein by PEP. The text in the MRD 
section was replaced for clarity. 
Rational: To clarify: 1) that cardiac imaging assessments (MUGA or ECHO)  are acceptable if they are 
performed within 42 days from C1D1 and 2) that MUGA will be performed if ECHO is not available 
Section 7.1.2.6: Cardiac assessments, Section 7.2.1: 
Screening, Section 7.2: Schedule of Events 
Section 7.1.2.6: Text was amended to: “A 2-
dimensional echocardiogram (or if not available a 
MUGA scan) and an electrocardiogram will be 
performed at screening or within 42 days of Cycle 1 
Day 1. Echo (or MUGA) may be repeated  
throughout the study as clinically indicated”; Section 
7.2.1: cardiac assessments was added to the exams 
that can be performed within 42 days from C1D1 and 
MUGA was added to the list f Screening assessments 
as an alternative to ECHO; Schedule of Events: 
footnote was added clarifying that cardiac ECHO or 
MUGA are acceptable within 42 days from C1D1 


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Rationale: To clarify that skeletal survey assessments are acceptable if they are performed within 42 days of 
C1D1 same as with STPs 
Section 7.1.1.5 Skeletal survey, Section 7.2.1 
Screening 
Text was added clarifying that any imaging 
assessments already completed during the regular 
work-up of the patient within 42 days prior to start of 
treatment can be considered as the baseline images. 
Rationale: To clarify that eGFR will be used for assessment of renal function instead of Creatinine 
Clearance 
Section 7.2.1 and Table 7.2 
Creatinine clearance was replaced with eGFR 
Rationale: To include the FEV1 test in the screening assessments for subjects with known or suspected 
COPD as per updated exclusion criterion 
Section 7.2.1 and Table 7.2 
FEV1 test  for subjects with known or suspected 
COPD was added 
Rational: To clarify the circumstance under which use of corticosteroids other than dexamethasone is 
allowed. 
Section 7.3.2 Prohibited Medications, Treatments 
and Procedures, Section 6.1.4: Dosing and 
administration 
Text was added specifying that concomitant 
corticosteroids other than dexamethasone are allowed 
as pre- and post-infusion medications as well. In 
section 6.1.4 the phrase “on the days that 
dexamethasone dosing is concurrent” was added to 
specify the instructions for dexamethasone 
administration 
Rational: To provide instructions for the treatment of patients that require hemodialysis 
Section 7.3.3 Rescue Medications, Treatments and 
Procedures 
Section was added instructing that daratumumab 
should be administered on the day with the 
maximum distance from the subsequent dialysis 
Rational: Adaptation of the pregnancy section as per the latest risk language to reflect that continuation of 
treatment with daratumumab will be assessed by the investigator after consultations with Sponsor and 
subject. 


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Section: 8.4.4 Reporting of Pregnancy 
The Section was amended to: A female patient will 
be instructed to immediately inform the investigator 
if she becomes pregnant during the study. The 
investigator shall report all pregnancies within 24 
hours to the sponsor using the Pregnancy Reporting 
Form. Monitoring of the patient should continue 
until conclusion of the pregnancy. Pregnancies 
occurring up to 90 days after the completion of the 
study medication must also be reported to the 
investigator.  
There are no human or animal data to assess the risk 
of daratumumab use during pregnancy. IgG1 
monoclonal antibodies are known to cross the 
placenta after the first trimester of pregnancy. 
Therefore, daratumumab should not be used during 
pregnancy unless the benefit of treatment to the 
woman is considered to outweigh the potential risks 
to the fetus. The investigator will therefore inform 
the subject of the potential risks to the fetus and 
discuss with the Sponsor as well as the subject if it is 
in the subject’s best interest to continue or stop 
treatment with daratumumab. 
The effect of daratumumab on sperm is unknown. 
Therefore, pregnancy occurring in the partner of a 
male patient participating in the study should also be 
reported by the investigator within 24 hours of 
awareness to the sponsor by using the Pregnancy 
Reporting Form 
Rational: To clarify PQC reporting procedure 
Section 8.4.5 Product Quality Complaints 
Text was removed so as not to confuse that PQCs 
will be reported as SAEs ( i.e. with SAE form) 
Text was added in order to clarify that PQCs will be 
reported using the PQC form. 
Rational: To reconcile the pre-infusion drug administration guideline with study-specific procedures 
(dexamethasone as pre-infusion medication) 
Appendix 2 
20 mg dexamethasone was added in the pre-infusion 
medications paragraph 
Rational: To include guidelines for Prophylaxis against febrile episodes and healthcare related infections 
Appendix 2 
Text was added proposing the use of prophylactic 
levofloxacin: “Prophylactic use of antibiotics is 
highly recommended due to the susceptibility of 
multiple myeloma patients to infections. 
Prophylactic administration of levofloxacin (500 mg 
P.O. daily; dose adjusted for renal function) during 
the first 3 cycles of treatment is recommended as it 
has shown to significantly reduce febrile episodes 
and deaths without increasing healthcare associated 
infections or carriage of key nosocomial pathogens” 
Rational: To update the modified IMWG criteria to the most recent version 


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Appendix 4 
Instructions were included for measuring STP size 
“≥50% increase from nadir in SPD7 of >1 lesion, or 
≥50% increase in the longest diameter of a previous 
lesion >1 cm in the short axis” and the definition of 
STP was added in the footnote “SPD = sum of the 
products of the maximal perpendicular diameters of 
measured lesions” 
In note 4, the symbol for larger (>) was changed to 
larger or equal (≥).  
Rationale: Added Appendix 7 to provide guidelines for classification of asthma as persistent asthma is an 
exclusion criterion 
Appendix 7 
New section was added 
Rationale: Minor errors were noted. 
Throughout the protocol 
Minor grammatical, formatting, or spelling changes 
were made 
 
 
 
 
 


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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
CKD 
Chronic Kidney Disease 
CMP 
Clinical Monitoring Plan 
CA 
Competent Authority 
CR 
Complete Response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DoR 
Duration of Response 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
FAS 
Full Analysis Set 
FDA 
Federal Drug Administration 
FISH 
Fluorescent In Situ Hybridization 
IAT 
Indirect Antiglobulin Test  
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IMiD 
Immunomodulatory Drug 
IMWG 
International Myeloma Working Group 
IRB 
Institutional Review Board 
IRR 
Infusion Related Reaction 
ISS 
International Staging System 
MM 
Multiple Myeloma 
M-protein 
Monoclonal Paraprotein 
MRD 
Minimum Residual Disease 
TNT 
Time to Next Therapy 
MR 
Minimal Response 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PI 
Proteasome Inhibitor 
PomDex 
Pomalidomide + Dexamethasone 
PPS 
Per Protocol Set 
PQC 
Product Quality Complaint   
PR 
Partial Response 
SAE 
Serious Adverse Event 
sCR 
Stringent Complete Response 
SD 
Stable Disease 
sFLC 
Serum Free Light Chain 
sIFE 
Serum Immunofixation 
sPEP 
Serum Protein Electrophoresis 
STP 
Soft Tissue Plasmacytoma 
uIFE 
Urine Immunofixation 
uPEP 
Urine Protein Electrophoresis 
VGPR 
Very Good Partial Response 
WOCBP 
Women OF Childbearing Potential 


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STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with the Declaration of Helsinki, the Guideline for Good 
Clinical Practice of the international conference on Harmonization (ICH E6) and all applicable laws 
and regulations. The Principal Investigators will assure that no deviation from, or changes to the 
protocol will take place without prior agreement from the sponsor and documented approval from the 
accredited Independent Ethics Committee (IEC) and/or Competent Authority (CA), except where 
necessary to eliminate an immediate hazard to the trial participants. 
PROTOCOL SUMMARY 
Study Title: 
Efficacy of Daratumumab in Patients with Relapsed/Refractory Myeloma 
with Renal Impairment   
Methods: 
This is a multicenter, single arm, open-label phase 2 study.  
Approximately 38 subjects will be enrolled to receive daratumumab + 
dexamethasone. Treatment cycles have a duration of 28 days. Subjects will 
receive treatment until disease progression or unacceptable toxicity. Drug 
administration and follow-up visits will occur more frequently for early 
cycles (weekly for the first 8 weeks, every two weeks for weeks 9-24 and 
then every 4 weeks). Disease evaluations will occur monthly and consist 
mainly of measurements of myeloma proteins. Other assessments may 
include bone marrow examinations, skeletal surveys, assessment of 
extramedullary plasmacytomas, and measurements of serum calcium 
corrected for albumin, and β2- microglobulin and albumin.  
Assessment of myeloma response and disease progression will be conducted 
in accordance with the modified International Myeloma Working Group 
(IMWG) response criteria.  
Assessment of renal response will be conducted in accordance with the  
International Myeloma Working Group (IMWG) renal response criteria.  
Survival status and data of subsequent anti-myeloma treatment will be 
collected post-treatment. 
Objectives: 
 
The primary objective of this study is to evaluate progression free survival 
(PFS) in patients with relapsed/refractory MM (RRMM) with renal 
impairment (RI).  
The secondary objectives are the following: 
• 
To evaluate Overall Response Rates (ORR) 
• 
To evaluate Renal Response Rates (RRR)  
• 
To evaluate duration of response (DoR) in patients with RI. 
• 
To evaluate time to next therapy (TNT). 
• 
To evaluate Overall Survival (OS). 
• 
To assess the safety and tolerability of daratumumab with 
dexamethasone in patients with RRMM and RI. 
Endpoints 
Primary endpoint: Progression-free survival 
Secondary Endpoints: 
• 
Overall response rate 
• 
Renal Response Rates (RRR) 
• 
Duration of response 
• 
Time to next therapy 
• 
Overall survival 
• 
Safety (adverse events) 
 
 


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Population: 
Inclusion criteria: 
1. Males and females at least 18 years of age. 
2. Voluntary written informed consent before performance of any study-
related procedure. 
3. Subject must have documented multiple myeloma as defined by the 
criteria below:  
Monoclonal plasma cells in the bone marrow ≥ 10% or presence of a 
biopsy proven plasmacytoma.  
AND any or more of the following myeloma defining events: 
• 
Evidence of end organ damage that can be attributed to the 
underlying plasma cell 
proliferative disorder, specifically: 
• Hypercalcaemia: serum calcium >0.25 mmol/L (>1 
mg/dL) higher than the 
upper limit of normal or >2.75 mmol/L (>11 mg/dL) 
• Renal insufficiency: creatinine clearance <40 mL per min 
or serum creatinine >177 μmol/L (>2 mg/dL) 
• Anaemia: haemoglobin value of >20 g/L below the lower 
limit of normal, or a 
haemoglobin value <100 g/L 
• Bone lesions: one or more osteolytic lesions on skeletal 
radiography, CT, or PET-CT 
• 
Any one or more of the following biomarkers of malignancy: 
• Clonal bone marrow plasma cell percentage ≥60% 
• Involved:uninvolved serum free light chain ratio ≥100 
• >1 focal lesions on MRI studies 
4. Prior treatment with at least two lines of treatment that included both 
bortezomib- and lenalidomide-based regimens.  
5. Documented evidence of progressive disease (PD) as defined by the 
modified IMWG criteria (see Appendix 4)  on or after the last regimen if 
the patient responded to previous regimens. 
6. Subjects must have measurable disease as defined by any of the 
following:  
• 
Serum monoclonal paraprotein (M-protein) level  ≥ 1.0 g/dL 
(except for IgA subtype: ≥ 0.5 g/dL) or urine M-protein level 
≥ 200 mg/24 hours; or  
• 
Light chain multiple myeloma: Serum immunoglobulin free 
light chain ≥ 10 mg/dL (100 mg/L) and abnormal serum 
immunoglobulin kappa lambda free-light-chain ratio.  
 
7. Renal impairment defined as eGFR < 30 ml/min/1.73 m2 (calculated with 
the CKD-EPI formula, see section 7.1.1.9) or in need for dialysis. 
Patients who undergo intraperitoneal dialysis may also be included. 
8. Eastern Cooperative Oncology Group (ECOG) performance status score 
of ≤ 2. 
9. Willingness and ability to participate in study procedures. 


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10. Reproductive Status 
a) Women of childbearing potential (WOCBP) must have two negative 
serum or urine pregnancy tests, one 10-14 days prior to start of the 
study drug and one within 24 hours prior to the start of study drug. 
Females are not of reproductive potential if they have been in natural 
menopause for at least 24 consecutive months, or have had a 
hysterectomy and/or bilateral oophorectomy. 
b) Women must not be breastfeeding. 
c) WOCBP must agree to follow instructions for methods of 
contraception for 4 weeks before the start of treatment with study 
drugs, for the duration of treatment with study drugs, and for 3 
months after cessation of study treatment. 
d) Males who are sexually active must always use a latex or synthetic 
condom during any sexual contact with females of reproductive 
potential, even if they have undergone a successful vasectomy. They 
must also agree to follow instructions for methods of contraception 
for 4 weeks before the start of treatment with study drugs, for the 
duration of treatment with study drugs, and for a total of 90 days 
post-treatment completion. The additional contraception of female 
partners of childbearing potential should also be considered. 
e) Male patients must not donate sperm for up to 90 days post treatment 
completion. 
f) Female patients must not donate eggs for up to 90 days post treatment 
completion. 
g) Azoospermic males and WOCBP who are not heterosexually active 
are exempt from contraceptive requirements. However, WOCBP will 
still undergo pregnancy testing as described in this section. 
 
Phase: 
II 
Number of Sites 
enrolling 
participants: 
The study will be conducted at 6 sites located in Greece and 2 sites located 
in Italy.  
Description of 
Study Treatment: 
Daratumumab will be given at a dose of 16 mg/kg administered as an 
intravenous (IV) infusion at weekly intervals (QW) for 8 weeks, then every 
2 weeks (Q2W) for an additional 16 weeks, then every 4 weeks (Q4W) 
thereafter. Dexamethasone will be administered according to standard 
clinical practice. The recommended dose of dexamethasone is 40 mg (20 mg 
for patients ˃ 75 years of age) orally once daily on Days 1, 8, 15 and 22 of 
each 28-day treatment cycle. 
Participant 
Duration: 
Subjects will receive treatment until disease progression or unacceptable 
toxicity. Survival status and data of subsequent anti-myeloma treatment will 
be collected post-treatment. 
Study Duration: 
The maximum duration of the study is 37 months considering an accrual 
period of 24 months and a follow-up of the last patient for 13 months. 
 
 
 


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Key roles  
 
Sponsor’s Representative 
Prof. Meletios Athanasios Dimopoulos 
27 Kifisias Ave, 11523, Athens  
Tel: +30- 210 7211806 , fax:+30- 210 6466288  
Email: info@eae.gr ,  infohaema@eae.gr 
Co-ordinating Investigator 
Associate Prof. Efstathios Kastritis 
Department of Clinical Therapeutics, University of Athens School 
of Medicine, Alexandra General Hospital of Athens 
Address: 80 Vas. Sofias Ave & Lourou Str., Athens 11528, Greece 
Phone number: +30 213-2162846 
Email: ekastritis@gmail.com, ekastritis@med.uoa.gr 
Scientific Co-ordinating 
Investigator 
Prof. Meletios Athanasios Dimopoulos 
Department of Clinical Therapeutics, University of Athens School 
of Medicine, Alexandra General Hospital of Athens 
Address: 80 Vas. Sofias Ave & Lourou Str., Athens 11528, Greece 
Phone number: +30 213-2162540 
Email: mdimop@med.uoa.gr  
Scientific Committee 
Associate Prof. Efstathios Kastritis  
Prof. Meletios Athanasios Dimopoulos 
Prof. Evangelos Terpos 
E-mail: eterpos@med.uoa.gr,  eterpos@hotmail.com  
Study Manager 
Anna Papadopoulou 
Project Manager 
Health Data Specialists 
Address: 22 Katehaki Ave, 115 25 – Athens, Greece 
Phone number: + 30 210-6997247 
Email: a.papadopoulou@heads-research.com   
Study Statistician 
Giorgos Cheliotis 
Biometrics Program Manager 
Health Data Specialists 
Address: 22 Katehaki Ave, 115 25 – Athens, Greece 
Phone number: + 30 210-6997247 
Email: g.cheliotis@heads-research.com  
CRO 
Health Data Specialists SA 
Spaces – Dublin 
South Docklands 
77 Sir John Rogerson’s Quay Ireland  
Email: info@heads-research.com  
 
 
 


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1. Background and Rationale  
 
1.1 
Multiple Myeloma  
Multiple myeloma (MM) is a malignant plasma cell disorder that is characterized by the production of 
monoclonal immunoglobulin in the majority of patients and invasion of adjacent bone tissue. Common 
manifestations include bone pain, renal insufficiency, hypercalcemia, anemia and recurrent infections. 
Based on 2009-2013 cases and deaths in the United States, the number of new cases of myeloma was 
6.5 per 100,000 men and women per year. The number of deaths was 3.3 per 100,000 men and women 
per year. In 2013, there were an estimated 95,688 people living with myeloma in the U.S. 
Approximately 30, 300 people in the US are expected to receive a new diagnosis of MM in 2016 (1.8% 
of all new cancer cases) and 12, 650 are expected to die from MM. 
A hallmark feature of multiple myeloma is the production of abnormal antibodies or M-proteins. The 
M-protein produced by the malignant plasma cells is an IgG in about 50%-54% of myeloma patients 
and an IgA in about 20%. Of patients producing either IgG or IgA, 40% also have Bence Jones 
proteinuria, i.e. the presence of free monoclonal kappa (κ) or lambda (λ) light chains in urine. In 15 to 
20% of patients, plasma cells secrete only light chain protein (light chain myeloma)1. 
MM is characterized by osteolytic lesions, usually in the pelvis, spine, ribs, and skull. Lesions are caused 
by expanding plasmacytomas or by cytokines secreted by myeloma cells that activate osteoclasts and 
suppress osteoblasts. Increased bone loss may also lead to hypercalcemia. Solitary extraosseous 
plasmacytomas are unusual but may occur in any tissue, especially in the upper respiratory tract. In 
many patients, renal failure is present at diagnosis or develops during the course of the disorder and is 
caused by the deposition of light chains in the distal tubules or by hypercalcemia. Patients also often 
develop anemia due to kidney disease or suppression of erythropoiesis by cancer cells but sometimes 
also due to iron deficiency. These signs and symptoms are commonly denoted as CRAB (Calcium 
elevation, Renal dysfunction, Anemia, Bone destruction). 
The terms used to define patient populations studied in clinical trials have been standardized based on 
the American Society of Hematology–FDA panel on endpoints in myeloma 2: 
• 
Refractory myeloma: Disease that is nonresponsive while on primary or salvage therapy, or 
progresses within 60 days of last therapy. Nonresponsive disease is defined as either failure to 
achieve minimal response (MR) or development of progressive disease (PD) while on therapy. 
o Relapsed and refractory myeloma: Disease that is nonresponsive while on salvage therapy, or 
progresses within 60 days of the last therapy in patients who had achieved MR or better at some 
point previously before progressing in their disease course. 
o Primary refractory myeloma: Disease that is nonresponsive in patients who have never achieved 
a MR or better with any therapy. 
• 
Relapsed myeloma: Previously treated myeloma that progresses and requires the initiation of 
salvage therapy but does not meet criteria for either “primary refractory myeloma” or “relapsed-
and-refractory myeloma” categories. 
Currently approved treatments for patients with relapsed/refractory MM include proteasome inhibitors 
(PI) (e.g., bortezomib, carfilzomib), immunomodulatory drugs (thalidomide, lenalidomide, or 
pomalidomide), 
histone 
deacetylase 
inhibitors 
and 
monoclonal 
antibodies 
(elotuzumab, 
daratumumab)3. However, there is no cure, and current therapies only slow disease progression, prolong 
survival, and reduce symptoms. Although recent advances in the development of targeted therapeutics 


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and stem cell transplantation have improved overall and event-free survival, the great majority of 
patients with myeloma will relapse and experience disease progression. 
1.2 
Daratumumab 
Daratumumab is a human IgGκ monoclonal antibody that targets CD38, an important immunotherapy 
target due to its high expression on malignant plasma cells and low expression on other normal 
lymphoid and myeloid cells, as well as its being an important modulator of intracellular signaling. 
The main anti-myeloma effect of daratumumab is attributed to its antibody-dependent cellular 
cytotoxicity and complement-dependent cytotoxicity4. An additional mode of action appears to be the 
induction of apoptosis via FcR-mediated crosslinking 5. Further experiments using a Burkitt’s 
lymphoma (Daudi) cell line mixed with human macrophages in the presence of daratumumab showed 
daratumumab-specific antibody-dependent cellular phagocytosis that resulted in a 50% reduction in 
tumor cells. Dose-dependent daratumumab-specific phagocytosis was also observed with patient-
derived MM cell lines transduced with CD386. See the investigator’s brochure for more details. 
Daratumumab in combination with dexamethasone is not approved for the indication under study. In 
November 2015, daratumumab (DARZALEX®) as monotherapy was approved by the U.S. Food and 
Drug Administration (FDA) for the treatment of patients with multiple myeloma who have received at 
least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug 
(IMiD), or who are double-refractory to a PI and an immunomodulatory agent. This indication was 
approved under accelerated approval based on the results of the pivotal open-label Phase 2 MMY2002 
(SIRIUS) study in which treatment with single-agent daratumumab resulted in an Overall Response 
Rate (ORR) of 29.2 percent (95% CI; 20.8, 38.9). Median duration of response was 7.4 months (95% 
CI, 5.5-not estimable). Ninety-five percent of patients in the study were double refractory to a PI and 
IMiD and patients had received a median of five prior lines of therapy. No patients discontinued 
treatment due to infusion-related reactions (IRR) and 4.7 percent of patients discontinued treatment due 
to adverse events (AEs), none of which were considered drug-related. Stringent complete response 
(sCR) was reported in 2.8 percent of patients, very good partial response (VGPR) in 9.4 percent of 
patients, and partial response (PR) in 17 percent of patients. The most common adverse events, which 
occurred in more than 20 percent of patients, were fatigue, anemia, nausea, thrombocytopenia, back 
pain, neutropenia and cough7.  
These results were supported by those of the Phase 1/2 GEN501 study, which confirmed daratumumab 
as an effective single-agent treatment option for patients with relapsed and refractory myeloma, 
especially those with disease that is otherwise resistant to other treatments or those who have 
unacceptable side effects from other treatments. Daratumumab had an acceptable safety profile, with 
infusion-related reactions of grade 1 and 2 across the two dose cohorts (except for one patient with 
infusion-related reactions of grade 3), including mild and transient bronchospasm, headache, dyspnea, 
and fever. Most events occurred during the first infusion, and no patient discontinued treatment because 
of an infusion-related reaction. Daratumumab demonstrated a 36 percent ORR in patients treated with 
a 16 mg/kg dose, with responses improving (or “deepening”) over time8. 
In May 2016, the European Commission granted approval of daratumumab for the monotherapy of 
adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a PI and an 
IMiD and who demonstrated disease progression on the last therapy.  
The FDA (in November 2016) and the European Commission (in April 2017) have granted approval of 
daratumumab in combination with lenalidomide (an immunomodulatory agent) and dexamethasone, or 


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bortezomib (a proteasome inhibitor [PI]) and dexamethasone, for the treatment of patients with multiple 
myeloma who have received at least one prior therapy, based on data from two Phase 3 studies: 
MMY3003 and MMY3004. 
The MMY3003 (POLLUX) trial is a Phase 3, multinational, open-label, randomized, multicenter, 
active-controlled study of 569 patients with multiple myeloma who have received a median of one prior 
line of therapy. Patients were randomized to receive either daratumumab combined with lenalidomide 
and dexamethasone (DARA-LEN-DEX), or lenalidomide and dexamethasone alone (LEN-DEX). 
Participants were treated until disease progression, unacceptable toxicity or if they had other reasons to 
discontinue the study. The trial was unblinded after meeting its primary endpoint of improved 
Progression Free Survival (PFS) in a pre-planned interim analysis. In fact, the DARA-LEN-DEX 
combination achieved a 63 percent reduction in the risk of disease progression or death (PFS) compared 
to LEN-DEX alone (Hazard Ratio [HR] = 0.37; 95 percent CI, 0.27-0.52; p<0.0001). Additionally, 
daratumumab significantly increased the overall response rate (ORR) [93 percent vs. 76 percent, 
p<0.0001] and doubled the rate of complete responses (CR) or better [43 percent vs. 19 percent, 
p<0.0001], as well as the rate of very good partial responses (VGPR) or better [76 percent vs. 44 percent, 
p<0.0001]. Overall, the safety of the daratumumab combination therapy was consistent with the known 
safety profile of daratumumab monotherapy and lenalidomide plus dexamethasone, respectively. 
Daratumumab-associated infusion-related reactions (48 percent of patients) were mostly Grade 1/2 
(Grade 3/4: 5 percent/0 percent), and most (92 percent) occurred during the first infusion9. 
MMY3004 (CASTOR) is a Phase 3, multinational, open-label, randomized, multicenter, active-
controlled study that enrolled 490 patients with multiple myeloma who received a median of two prior 
lines of therapy. Thirty-three percent of patients were refractory to an immunomodulatory agent, and 
32 percent were refractory to their last line of prior therapy. Patients were randomized to receive either 
daratumumab combined with subcutaneous bortezomib and dexamethasone (DAR-BOR-DEX) 
(n=251) or bortezomib and dexamethasone alone (BOR-DEX) (n=247). Participants were treated with 
daratumumab until disease progression or unacceptable toxicity. The DAR-BOR-DEX combination 
demonstrated a 61 percent reduction in the risk of disease progression or death (PFS) compared to 
bortezomib and dexamethasone alone (Hazard Ratio (HR) = 0.39; 95 percent CI (0.28-0.53), p<0.0001). 
As in the POLLUX study, daratumumab significantly increased the overall response rate (ORR) [83 
percent vs. 63 percent, p<0.0001] and doubled CR or better rates [19 percent vs. 9 percent, p<0.0012], 
including doubling rates of VGPR rates [59 percent vs. 29 percent, p<0.0001]10. 
An ongoing 4-arm, multicenter, Phase 1b study is currently evaluating the safety and efficacy of 
daratumumab combined with pomalidomide plus dexamethasone. The study has so far concluded that 
the addition of daratumumab was well tolerated and did not result in additional toxicities except for 
infusion reactions. Deep and durable responses were observed quickly along with a high response rate11.  
1.3 
Renal Impairment in Myeloma  
About 20-40% of patients with multiple myeloma (MM) will present with some degree of renal 
impairment (RI) and about 25% of patients will experience RI later on, during the course of their 
disease. Moderate and severe RI is associated with poorer overall survival (OS) and higher risk of early 
death. Outcomes have however improved with the introduction of novel agents. Many patients can 
achieve a recovery of their renal function with the prompt initiation of the appropriate anti-myeloma 
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The older IMWG criteria MM had set a sCr level of 2 mg/dl as the cut-off value to define symptomatic 
MM due to RI12. Patients may however already have renal disease due to their monoclonal gammopathy 
and creatinine is not sensitive in detecting early-stage RI. More sensitive tools could allow early RI 
detection and assessment of the probability of renal function restoration (Kastritis, Terpos et al. 2013). 
Estimated glomerular filtration rate (eGFR) is more reliable and accurate. A decrease of eGFR by ≥ 
35% within 1 year, without other identifiable cause, is an indication for therapy13. The use of eGFR is 
recommended when renal function remains rather stable. Tools like RIFLE (risk, injury, failure, loss 
and end-stage kidney disease) and Acute Kidney Injury Network (AKIN) criteria are more sensitive for 
the evaluation of AKI, but data in MM patients is limited14.  
Treatment of MM aims at symptomatic improvement including renal function restoration. 
Normalization of sCr or eGFR increase by at least one or two CKD stages have been used as 
measures of renal response 12,15-17.  The 2016 IMWG consensus recommends using the Chronic 
Kidney Disease Epidemiology Collaboration preferably or the MDRD or CKD-EPI formulae 12,15. 
The recommended first choice regime in newly diagnosed MM patients incorporates a bortezomib-
dexamethasone backbone, which seems to achieve the higher and most rapid rates of renal recovery, 
with or without a third active agent. Thalidomide and lenalidomide are alternative options in selected 
patients. New drugs are additional treatment options for patients with relapsed or refractory disease, 
including carfilzomib, pomalidomide and monoclonal antibodies, but still data are limited in patients 
with RI. High dose therapy with autologous stem cell transplantation should be offered in otherwise 
eligible patients, despite RI, even if dialysis is required. The role of high cut-off hemodialysis 
membranes is still under investigation and more data are needed before these are incorporated in 
everyday clinical practice. 
Renal recovery rates are lower in patients with RRMM compared to newly diagnosed (NDMM) 
patients. In patients with RRMM and RI, the use of IMiDs (lenalidomide, pomalidomide) or other 
agents, (carfilzomib, elotuzumab, daratumumab) may be considered if resistance to bortezomib has 
been established. Pomalidomide seems to have a favorable safety profile in patients with RI but data on 
renal recovery are yet to be presented. The choice depends on previous lines of therapy and potential 
sensitivity/resistance. Regarding the role of carfilzomib, although the pharmacokinetics indicate that 
the drug can be used without dose adjustments (Badros, Vij et al. 2013), there is insufficient data on the 
efficacy in terms of renal recovery and safety in patients with severe RI. Elotuzumab is a potential 
alternative and safe option but more data is required on safety and efficacy and any potential to reverse 
RI. Panobinostat should be given in combination with bortezomib and dexamethasone and only in 
patients naïve or sensitive to prior bortezomib, however, there are no data for patients with RI.   
For patients with relapsed/refractory MM who present with new onset or pre-existing MM-related 
renal dysfunction, the treatment  options may be quite limited especially if they have been exposed or 
are refractory to proteasome inhibitors and IMiDs. Daratumumab may be the major treatment option 
for such patients, however, there are limited data for the efficacy and safety of daratumumab in 
patients with severe renal dysfunction. As a monoclonal antibody, the clearance of daratumumab is 
not involving the kidneys and the degree of renal dysfunction is not expected to alter PKs or PDs of 
the drug.  
No formal studies of daratumumab in patients with renal impairment have been conducted. As an IgG1қ 
monoclonal antibody, renal excretion metabolism of intact daratumumab is unlikely to represent major 
elimination route. A population PK analysis was performed based on pre-existing renal function data 
in patients receiving daratumumab, including 71 with normal renal function (creatinine clearance 


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[CRCL] ≥ 90 mL/min), 78 with mild renal impairment (CRCL < 90 and ≥ 60 mL/min), 68 with moderate 
renal impairment (CRCL < 60 and ≥ 30 mL/min), and 6 with severe renal impairment or end stage renal 
disease (CRCL< 30 mL/min). No clinically important differences in exposure to daratumumab were 
observed between patients with renal impairment and those with normal renal function. Thus, based on 
this population pharmacokinetic (PK) analysis18 no dosage adjustment is necessary for patients with 
renal impairment. 
Combining the efficacy of daratumumab in patients with relapsed refractory MM, and the lack of effect 
of renal dysfunction on daratumumab PKs, it is expected that daratumumab with dexamethasone is 
going to be a safe and effective therapy for patients with relapsed/refractory MM and renal impairment.  
1.4 
Rationale  
Daratumumab has proven efficacy in patients with relapsed or refractory myeloma, independently of 
prior exposure to bortezomib (or other PIs), IMiDs (thalidomide, lenalidomide or pomalidomide) or 
alkylating agents7,19. Single agent daratumumab has also shown to induce rapid myeloma responses, 
with a median time to at least PR of 0.9 months (1 cycle of therapy). Thus it is expected that 
daratumumab will be able to induce rapid responses in a significant proportion of heavily pretreated 
patients with relapsed or refractory which will have been exposed to bortezomib and lenalidomide and 
who will have renal dysfunction with a eGFR< 30 ml/min/1.73 m2, which defines severe renal 
impairment. It has been shown that rapid myeloma response is the stronger predictor of a subsequent 
renal function improvement and renal response.   
2. Potential risks and benefits  
2.1 
Known potential risks  
o Daratumumab 
As of 15 November 2019, approximately 5528 clinical trial patients with multiple myeloma and various 
other conditions have been treated with daratumumab intravenous or subcutaneous, alone or in 
combination with other therapies. Daratumumab is approved for the treatment of MM, yet data on the 
treatment of patients with renal impairment are very limited; moreover, not all the possible side effects 
and risks related to daratumumab are known and new side effects may occur. The following side effects 
are observed when daratumumab was given via an intravenous infusion for patients with multiple 
myeloma, either alone or in combination with other drugs: 
• 
Very common (more than 1 in 10 patients) 
o Infusion related reaction (see below) 
o Infection of the upper respiratory tract such as nose, sinuses throat or upper airway 
o Infection of the lower airway (bronchitis) 
o Infection of the lung (pneumonia) 
o Low platelets 
o Low red blood cells 
o Low white blood cells (including neutrophils and lymphocytes) 
o Decreased appetite 
o Abnormal sensation including numbness/tingling of hands, feet or limbs (neuropathy, 
paresthesia) 
o Headache 
o High blood pressure 


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o Cough 
o Shortness of breath, including wheezing 
o Constipation 
o Diarrhea 
o Nausea 
o Vomiting 
o Muscle spasms 
o Swelling of hands, feet or limbs 
o Fatigue, or lack of energy 
o Fever 
o Back pain 
o Sleeplessness (insomnia) 
o Joint pain 
• 
Common (1 to 10 in 100 patients) 
o Urinary tract infection 
o Flu like symptoms 
o Shingles (Herpes Zoster) 
o Sepsis (a life-threatening condition that arises when the body’s response to an infection injures 
its own tissues and organs  
o High blood glucose levels 
o Low blood calcium levels 
o Loss of body fluids, also known as dehydration 
o Irregular heartbeat 
o Chills 
o Low oxygen in the body 
o Swelling of the throat 
o Fluid in lungs (pulmonary edema) 
o Dizziness 
o Inflammation of the pancreas 
o Rash, itchy skin 
o Muscular pain in the chest 
• 
Uncommon (1 to 10 in 1,000 patients) 
o Liver infection (hepatitis) in those patients who are carriers of the hepatitis B virus 
o Interference with pre-transfusion blood testing (See Blood Type and IAT, in section 7.2.1) 
 
• 
Infusion–related reactions (IRR) 
Signs and symptoms of infusion-related reactions may include respiratory symptoms, such as stuffy 
nose, cough, throat irritation, as well as chills, vomiting and nausea. Less common symptoms are having 
trouble breathing (wheezing), runny nose, fever, chest discomfort, itching of the skin, low blood 
pressure or high blood pressure and fluid in the lungs (pulmonary edema). Most of the observed 
infusion-related reactions so far were mild or moderate, and ended by temporarily stopping the infusion 
and giving medicines to treat the side effect. Severe reactions have occurred, including narrowing and 
obstruction of the respiratory airway (bronchospasm), low oxygen, shortness of breath, high blood 
pressure, swelling in the throat and fluid in the lungs (pulmonary edema). See Appendix 2 for 
information regarding the management of IRRs and recommendations concerning the use of pre- and 
post-infusion medication. 


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o Dexamethasone  
Dexamethasone is a synthetic pregnane corticosteroid and derivative of cortisol (hydrocortisone) and is 
also known as 1-dehydro-9α-fluoro-16α-methylhydrocortisone or as 9α-fluoro-11β,17α,21-trihydroxy-
16α-methylpregna-1,4-diene-3,20-dione. 
The following events are observed when dexamethasone was given via an intravenous infusion or 
orally, either alone or in combination with other drugs: 
Gastrointestinal: 
Nausea, 
vomiting, 
anorexia, 
increased 
appetite, 
weight 
gain, 
aggravation of peptic ulcers. 
Dermatologic: Rash, skin atrophy, facial hair growth, acne, facial erythema, ecchymoses. 
Genitourinary: Menstrual changes (amenorrhea, menstrual irregularities). 
Neurological: Insomnia, euphoria, headache, vertigo, psychosis, depression, seizures, muscle 
weakness. 
Cardiovascular: Fluid retention and edema, hypertension; rarely, thrombophlebitis. 
Ocular: Cataracts, increased intraocular pressure, exophthalmos. 
Metabolic: Hyperglycemia, decreased glucose tolerance, aggravation or precipitation of diabetes 
mellitus, 
adrenal 
suppression 
(with 
Cushingoid 
features), 
hypokalemia. 
Hematologic: Leukocytosis. 
Other: 
Osteoporosis 
(and 
resulting 
back 
pain), 
appearance 
of 
serious 
infections 
including 
herpes 
zoster, 
varicella 
zoster, 
fungal 
infections, 
Pneumocystis 
carinii, 
tuberculosis; 
muscle 
wasting; 
delayed 
wound 
healing; 
suppression 
of 
reactions 
to 
skin tests. 
 
 
2.2 Known Potential Benefits 
The prognosis of multiple myeloma patients who become refractory to lenalidomide and bortezomib is 
very poor, indicating the need for new therapeutic strategies for these patients. Daratumumab has 
already shown marked activity as a monotherapy in heavily pre-treated patients. Its Breakthrough 
Therapy Designation from the FDA for patients who have been exposed to lenalidomide and 
bortezomib, highlights the potential clinical benefit of daratumumab therapy for the treatment of 
patients with relapsed/refractory multiple myeloma. The presence of sever renal dysfunction is an 
additional adverse feature of myeloma and requires immediate management, with effective, rapidly 
acting therapy. In this context daratumumab offers the most active therapy that is available for patients 
who have already been exposed and are relapsed or refractory to proteasome inhibitors and IMIDs and 
who present with severe renal impairment. Daratumumab has additional advantages related to the lack 
of effect of the degree of renal dysfunction or dialysis to PKs and pharmacodynamics of the monoclonal 
antibody. Thus, daratumumab with dexamethasone is likely to provide significant clinical benefit to 
subjects with relapsed or refractory multiple myeloma and renal impairment. 
  


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3. Objectives and Purpose  
The purpose of this study is to evaluate the effects of daratumumab with dexamethasone in subjects 
with relapsed or refractory multiple myeloma and renal impairment. 
3.1 
Primary objective 
The primary objective of this study is to evaluate progression free survival (PFS) in subjects with 
relapsed or refractory multiple myeloma and renal impairment treated with daratumumab and 
dexamethasone. 
3.2 
Secondary objectives 
The secondary objectives of the study are the following: 
• 
To evaluate Overall Response Rates (ORR) 
• 
To evaluate Renal Response Rates (RRR)  
• 
To evaluate duration of response (DoR)  in patients with RI. 
• 
To evaluate time to next therapy (TNT). 
• 
To evaluate Overall Survival (OS). 
• 
To assess the safety and tolerability of Daratumumab with dexamethasone in patients with 
RRMM and RI. 
 
 
 
 
4. Study Design and Study End points  
 
4.1 
Description of the Study Design 
This is a multicenter, Phase 2, single arm, open-label study evaluating daratumumab with 
dexamethasone (DaraD) in subjects with relapsed or refractory multiple myeloma who have received 
at least two prior lines of treatment, with both bortezomib- and lenalidomide-based regimens and have 
renal impairment. 
Approximately 38 subjects located in approximately 5 centers in Greece and 2 centers in Italy will 
receive daratumumab with dexamethasone. Treatment cycles have a duration of 28 days: 
Daratumumab will be given at a dose of 16 mg/kg administered as an intravenous (IV) infusion at 
weekly intervals (QW) for 8 weeks, then every 2 weeks (Q2W) for an additional 16 weeks, then every 
4 weeks (Q4W) thereafter. Subjects will receive pre-infusion medications before infusions to mitigate 
potential infusion reactions.  
Dexamethasone will be administered according to standard clinical practice and at a recommended 
total dose of 40 mg weekly (20 mg weekly for patients >75 years of age).  
Subjects will receive treatment until disease progression or unacceptable toxicity. 
Drug administration and follow-up visits will occur more frequently for early cycles (e.g., weekly or 
bi-weekly) (see Table 7.2). Disease evaluations will occur monthly and consist mainly of 
measurements of myeloma proteins and renal function indices. Other parameters may include bone 


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marrow examinations, skeletal surveys, assessment of extramedullary plasmacytomas, and 
measurements of serum calcium corrected for albumin, and β2-microglobulin and albumin.  
Assessment of myeloma response and disease progression will be conducted in accordance with the 
modified International Myeloma Working Group (IMWG) response criteria (see Appendix 4).  
Assessment of renal response will be conducted in accordance with the International Myeloma Working 
Group (IMWG) response criteria (see Appendix 5).  
Survival status and data of subsequent anti-myeloma treatment will be collected post-treatment. 
The maximum duration of the study is of 37 months considering an accrual period of 24 months and a 
follow-up of the last patient of 13 months. 
4.1.1 Primary Endpoint 
• 
Progression-free survival 
4.1.2 Secondary Endpoints 
• 
Overall response rate 
• 
Renal Response rate 
• 
Duration of response 
• 
Time to next therapy 
• 
Overall survival 
• 
Safety (adverse events) 
5.  
Study enrollment and withdrawal  
All criteria MUST be met to be included in the study. 
5.1 
Participant Inclusion Criteria 
1. Males and females at least 18 years of age. 
2. Voluntary written informed consent before performance of any study-related procedure. 
3. Subject must have documented multiple myeloma as defined by the criteria below:  
Monoclonal plasma cells in the bone marrow ≥ 10% or presence of a biopsy proven plasmacytoma.  
AND any or more of the following myeloma defining events: 
• 
Evidence of end organ damage that can be attributed to the underlying plasma cell 
proliferative disorder, specifically: 
• Hypercalcaemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the 
upper limit of normal or >2.75 mmol/L (>11 mg/dL) 
• Renal insufficiency: creatinine clearance <40 mL per min or serum creatinine >177 
μmol/L (>2 mg/dL) 
• Anaemia: haemoglobin value of >20 g/L below the lower limit of normal, or a 
haemoglobin value <100 g/L 
• Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-
CT 
• 
Any one or more of the following biomarkers of malignancy: 
• Clonal bone marrow plasma cell percentage ≥60% 
• Involved:uninvolved serum free light chain ratio ≥100 
• >1 focal lesions on MRI studies 


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4. Prior treatment with at least two lines of treatment that included both bortezomib- and lenalidomide-
based regimens.  
5. Documented evidence of progressive disease (PD) as defined by the modified IMWG criteria (see 
Appendix 4)  on or after the last regimen if the patient responded to previous regimens. 
6. Subjects must have measurable disease as defined by any of the following:  
• 
Serum monoclonal paraprotein (M-protein) level  ≥ 1.0 g/dL (except for IgA subtype: 
≥ 0.5 g/dL) or urine M-protein level ≥ 200 mg/24 hours; or  
• 
Light chain multiple myeloma: Serum immunoglobulin free light chain ≥ 10 mg/dL 
(100 mg/L) and abnormal serum immunoglobulin kappa lambda free-light-chain ratio.  
7. Renal impairment defined as eGFR < 30 ml/min/1.73 m2 (calculated with the CKD-EPI formula, 
see section 7.1.1.9) or in need for dialysis. Patients who undergo intraperitoneal dialysis may also 
be included. 
8. Eastern Cooperative Oncology Group (ECOG) performance status score of ≤ 2. 
9. Willingness and ability to participate in study procedures. 
10. Reproductive Status 
a) Women of childbearing potential (WOCBP) must have two negative serum or urine pregnancy 
tests, one 10-14 days prior to start of the study drug and one within 24 hours prior to the start 
of study drug. Females are not of reproductive potential if they have been in natural menopause 
for at least 24 consecutive months, or have had a hysterectomy and/or bilateral oophorectomy. 
b) Women must not be breastfeeding. 
c) WOCBP must agree to follow instructions for methods of contraception for 4 weeks before the 
start of treatment with study drugs, for the duration of treatment with study drugs, and for 3 
months after cessation of study treatment. 
d) Males who are sexually active must always use a latex or synthetic condom during any sexual 
contact with females of reproductive potential, even if they have undergone a successful 
vasectomy. They must also agree to follow instructions for methods of contraception for 4 
weeks before the start of treatment with study drugs, for the duration of treatment with study 
drugs, and for a total of 3 months post-treatment completion. 
e) Male patients must not donate sperm for up to 90 days post treatment completion. 
f) Female patients must not donate eggs for up to 90 days post treatment completion. 
g) Azoospermic males and WOCBP who are not heterosexually active are exempt from 
contraceptive requirements. However, WOCBP will still undergo pregnancy testing as 
described in this section. 
Highly effective methods of contraception have a failure rate of < 1% when used consistently and 
correctly. Subjects must agree to the use of two methods of contraception, with one method being 
highly effective (tubal ligation, intrauterine device [IUD], hormonal [birth control pills, injections, 
hormonal patches, vaginal rings or implants] or partner’s vasectomy) and the other method being 
additionally effective (male latex or synthetic condom, diaphragm, or cervical cap). 
5.2 
Participant Exclusion Criteria 
1. Previous therapy with daratumumab or other anti-CD38 therapy.  
2. Anti-myeloma treatment within 2 weeks prior to Cycle 1, Day 1.  
3. Cumulative dose of corticosteroids greater than or equal to the equivalent of 140mg prednisone for 
≥ 4 days  or a dose of corticosteroids greater than or equal to the equivalent of 40 mg/day of  
dexamethasone for ≥ 4 days within the 2-week period prior to Cycle 1, Day 1.  


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4. Previous allogenic stem cell transplant; or Autologous Stem Cell Transplantation (ASCT) within 
12 weeks before Cycle 1, Day 1.  
5. Clinical signs of meningeal involvement of multiple myeloma.  
6. Subject has either of the following: 
a. Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 
second (FEV1) <50% of predicted normal. Note that FEV1 testing is required for subjects 
suspected of having COPD and subjects must be excluded if FEV1 <50% of predicted 
normal. 
b. Known moderate or severe persistent asthma (see Appendix 7), within 2 years from C1D1, 
or currently has uncontrolled asthma of any classification. Note that subjects who currently 
have controlled intermittent asthma or controlled mild persistent asthma are allowed to 
participate in the study. 
7. Clinically significant cardiac disease, including:  
a) Myocardial infarction within 1 year, or unstable or uncontrolled condition (e.g., unstable 
angina, congestive heart failure, New York Heart Association Class III-IV).  
b) Uncontrolled cardiac arrhythmia (CTCAE Grade 2 or higher) (atrial fibrillation with controlled 
ventricular rate is allowed) or clinically significant ECG abnormalities.  
c) ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) >470 msec.  
8. Any of the following: 
a. Known active hepatitis A 
b. Patient is seropositive for hepatitis B (defined by a positive test for hepatitis B surface 
antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative 
but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to 
hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase 
chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who 
are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings 
suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a 
known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR. 
 
c.  Known to be seropositive for hepatitis C (except in the setting of a sustained virologic 
response [SVR], defined as aviremia at least 12 weeks after completion of antiviral 
therapy). 
9. Known to be seropositive for human immunodeficiency virus (HIV). 
10. Amyloidosis, or any prior or concurrent malignancy, except for the following: 
a) Adequately treated basal cell or squamous cell skin cancer. 
b) Any cancer (other than in-situ) from which the subject has been disease-free for 3 years prior 
to study entry. 
11. Any of the following laboratory test results during Screening:  
a) Absolute neutrophil count ≤ 1.0 × 109/L; 
b) Hemoglobin level ≤ 7.5 g/dL (≤ 4.65 mmol/L);  
c) Platelet count < 75 × 109/L in patients in whom < 50% of bone marrow nucleated cells are 
plasma cells and < 50x109/L in patients in whom more than 50% of bone marrow nucleated 
cells are plasma cells;  
d) Alanine aminotransferase level ≥ 2.5 times the upper limit of normal (ULN);  
12. Pregnant or nursing women. 
 
 


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5.3 
Participant Withdrawal or termination 
5.3.1 Reasons for Withdrawal or Termination 
Every patient has the right to discontinue study participation at any time, for any reason, and every 
patient may be discontinued from the study for any reason beneficial to his/her wellbeing.  
Subjects MUST discontinue investigational product for any of the following reasons: 
o Withdrawal of informed consent. 
o Any adverse event (AE), laboratory abnormality or intercurrent illness that, in the opinion 
of the investigator, indicates that continued participation in the study is not in the best 
interest of the subject. 
o Progressive Disease. 
o Grade 4 Infusion Related Reactions (IRR) to daratumumab or in case of 3 recurrences of a 
≥ Grade 3 IRR during one infusion (see Appendix 2). 
o When the study ends/is terminated. 
5.3.2 Handling of Participant Withdrawals or Termination 
All patients, except those who withdraw consent, will be followed up according to the study procedures. 
Subjects should be encouraged to continue participation in the trial until determination of disease 
progression. Those who discontinue study therapy before progression should allow the collection of 
necessary laboratory results until disease progression criteria are fulfilled. If the study drug is 
discontinued prior to disease progression, the reason for the discontinuation must be documented in the 
eCRF. 
If lost to follow-up, the investigator should contact the patient or a relative by telephone followed by 
registered mail or through a personal visit to establish as completely as possible the reason for the 
withdrawal. 
5.4 
Premature Termination or Suspension of Study 
The study can be terminated for any reason and at any time by the Sponsor. Should this be necessary, 
the patient should be seen as soon as possible and treated as a prematurely withdrawn patient. All 
measures will be adopted to ensure the safeguarding of the patient’s interests. 
 
 
 
 
 


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6. Study Treatment  
 
6.1 
Study treatments and Control Description 
 
6.1.1 Formulation, Appearance, Packaging, and Labeling 
This is an open-label study. Daratumumab is considered investigational treatment and will be supplied 
free of charge by the sponsor. Dexamethasone will be obtained by the Sponsor according to specific 
regulatory requirements. All study treatments used in this study, along with their packaging and 
labeling, have been approved by local Health Authorities.  
Investigational Medicinal Products (IMP): 
• 
Daratumumab (Darzalex®) 
Daratumumab 20 mg/mL concentrate for solution for infusion. The solution is colorless to yellow. 
Each 20 mL vial contains 400 mg of daratumumab (20 mg daratumumab per mL). 
• 
Dexamethasone  
Dexamethasone vials or tablets of various strengths and packaging configuration for oral 
administration. 
6.1.2 Product Storage and Stability 
Investigational treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designees have 
access. Upon receipt, all investigational treatment should be stored according to the instructions 
specified on the labels. Clinical supplies are to be dispensed only in accordance with the protocol. 
Medication labels will be in the local language and comply with the legal requirements of each country.  
Daratumumab vials should be stored at 2°-8° C in its original package to protect from light. 
After dilution, unless the method of opening/dilution precludes the risk of microbial contamination, the 
product should be used immediately. If not used immediately, in-use storage times and conditions are 
the responsibility of the user and should be no more than 24 hours at refrigerated conditions (2°-8° C) 
protected from light, followed by 15 hours (including infusion time) at room temperature (15°-25° C) 
and room light (see Appendix 1). 
Dexamethasone does not require any special storage conditions. 
6.1.3 Preparation 
Daratumumab is to be prepared according to the instructions in Appendix 1. 
 
 
 


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6.1.4 Dosing and Administration 
Daratumumab  
Daratumumab will be given at a dose of 16 mg/kg administered as an intravenous (IV) infusion at 
weekly intervals (QW) for 8 weeks, then every 2 weeks (Q2W) for an additional 16 weeks, then every 
4 weeks (Q4W) thereafter.  
See Appendix 2 for guidelines for the intravenous infusion of daratumumab and for pre-infusion and 
post-infusion medications to be given to mitigate potential infusion reactions.  
Infusion-related reactions (IRRs) have been reported in approximately half of all patients treated with 
daratumumab. Patients should therefore be monitored throughout the infusion and the post-infusion 
period. The majority of IRRs occurred at the first infusion and were Grade 1-2. Four percent of all 
patients had an IRR at more than one infusion. Severe reactions have occurred, including bronchospasm, 
hypoxia, dyspnoea, hypertension, laryngeal oedema and pulmonary oedema. Symptoms predominantly 
included nasal congestion, cough, throat irritation, chills, vomiting and nausea.  Less common 
symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, and hypotension. 
Patients should be pre-medicated with antihistamines, antipyretics and corticosteroids to reduce the risk 
of IRRs, as per local practice. 
See the Summary of Product Characteristics for more details about daratumumab. 
Dexamethasone 
The recommended dose of dexamethasone is 40 mg (20 mg for patients ˃ 75 years of age) orally  once 
daily on Days 1, 8, 15 and 22 of each 28-day treatment cycle. On the days that dexamethasone dosing 
is concurrent with the daratumumab administration, dexamethasone will be administered at a dose of 
40 mg IV or PO prior to the daratumumab infusion (IV: approximately 1 hour before, PO: 1-3 hours 
before) and will serve as both the pre-medication and the therapeutic dose (i.e. no other corticosteroids 
can administered as pre-medication on the days that dexamethasone dosing is concurrent).  
See the Summary of Product Characteristics for more details about dexamethasone. 
6.1.5 Dose Adjustments/Modifications/Delays 
➢ Daratumumab 
No dose adjustment or modification is permitted for daratumumab. Infusion reactions may lead to the 
interruption of IV daratumumab administration. Pre-infusion medications should be administered to 
reduce the risk of infusion-related reactions (IRRs) prior to treatment. 
For IRRs of any grade/severity, immediately interrupt daratumumab infusion and manage 
symptoms.The management of IRRs may further require reduction in the rate of infusion, or treatment 
discontinuation of daratumumab as outlined below. 
• Grade 1-2 (mild to moderate): Once the patient’s condition is stable, the infusion should be resumed 
at no more than half the rate at which the IRR occurred. If the patient does not experience any further 
IRR symptoms, infusion rate escalation may be resumed at increments and intervals as clinically 
appropriate up to the maximum rate of 200 mL/hour. 


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• Grade 3 (severe): Once reaction symptoms resolve, restarting of the infusion may be considered at 
no more than half the rate at which the reaction occurred. If the patient does not experience additional 
symptoms, infusion rate escalation may be resumed at increments and intervals as appropriate. The 
procedure above should be repeated in the event of recurrence of Grade 3 symptoms. Permanently 
discontinue daratumumab if the patient experiences a ≥ Grade 3 infusion-related symptom at the 
subsequent infusion. 
• Grade 4 (life threatening): Permanently discontinue daratumumab treatment. 
See Appendix 2 for further guidelines concerning the administration of daratumumab. 
See the Summary of Product Characteristics for more details about daratumumab 
Daratumumab Toxicity Management 
In the event of one of the following toxicities the infusion should be held to allow for recovery. The 
criteria for a dose delay are: 
• 
Grade 4 hematologic toxicity, except for Grade 4 lymphopenia 
• 
Grade 3 or higher thrombocytopenia 
• 
Febrile neutropenia 
• 
Neutropenia with infection, of any grade 
• 
Grade 3 or higher non-hematologic toxicities with the following exceptions: 
- 
Grade 3 nausea that responds to antiemetic treatment within 7 days 
- 
Grade 3 vomiting that responds to antiemetic treatment within 7 days 
- 
Grade 3 diarrhea that responds to antidiarrheal treatment within 7 days 
- 
Grade 3 fatigue that was present at baseline or that lasts for <7 days after the last 
administration of daratumumab 
- 
Grade 3 asthenia that was present at baseline or that lasts for <7 days after the last 
administration of daratumumab 
Daratumumab treatment should be resumed when the toxicity has resolved to Grade 2. If daratumumab 
administration does not commence within the prespecified window (Table 6.1) of the scheduled 
administration date, then the dose will be considered a missed dose. Administration may resume at the 
next planned dosing date. A missed dose will not be made up. 
TABLE 6.1: DARATUMUMAB-RELATED TOXICITY MANAGEMENT DOSE 
DELAY/RESUMPTION SCHEDULE 
Cycle 
Frequency 
Resumption window 
Cycles 1 and 2 
Weekly (QW) 
>3 days next planned weekly dosing date 
Cycles 3 to 6 
Biweekly (Q2W) 
>7 days next planned biweekly dosing date 
Cycles 7 on 
Every 4 weeks (Q4W) 
>14 days next planned every 4 weeks dosing date 
Any dose hold of more than 28 days due to toxicity will result in permanent discontinuation of 
daratumumab. Dose holds of more than 28 days for other reasons should be discussed with the Sponsor. 
Interruption of Missed Doses 
A daratumumab dose held for more than 3 days from the per-protocol administration date for any reason 
other than toxicities suspected to be related to daratumumab should be brought to the attention of the 
sponsor at the earliest possible time. Subjects missing ≥3 consecutive planned doses of daratumumab 


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for reasons other than toxicity should be withdrawn from treatment, unless, upon consultation with the 
sponsor and the review of safety and efficacy, continuation is agreed upon. 
➢ Dexamethasone 
Instructions for dose modifications of dexamethasone are shown in the table below: 
Dyspepsia = Grade 1-2  
Maintain dose and treat with histamine (H2) blockers or 
equivalent. Decrease by one dose level if symptoms persist. 
Dyspepsia ≥ 3 
Interrupt dose until symptoms are controlled. Add H2 blocker 
or equivalent and decrease one dose level when dose restarted. 
Edema ≥ Grade 3 
Use diuretics as needed and decrease dose by one dose level. 
Confusion or mood alteration ≥ Grade 2 
Interrupt dose until symptoms resolve. When dose restarted 
decrease dose by one dose level. 
Muscle weakness ≥ Grade 2 
Interrupt dose until muscle weakness ≤ Grade 1. Restart with 
dose decreased by one level. 
Hyperglycemia ≥ Grade 3 
Decrease dose by one dose level. Treat with insulin or oral 
hypoglycemic agents as needed 
Acute pancreatitis 
Discontinue patient from dexamethasone treatment regimen. 
Other ≥ Grade 3 dexamethasone-related 
adverse events 
Stop dexamethasone dosing until adverse event resolves to ≤ 
Grade 2. Resume with dose reduced by one level. 
Dexamethasone dose reduction levels: 
Dose reduction levels (≤ 75 years of age): Starting dose 40 mg; dose level -1 20 mg; dose level-2 10 mg on Days 1, 8, 15 and 22 of each 28-
day treatment cycle. 
Dose reduction levels (> 75 years of age): Starting dose 20 mg; dose level -1 12 mg; dose level-2 8 mg on Days 1, 8, 15 and 22 of each 28-
day treatment cycle. 
If recovery from toxicities is prolonged beyond 14 days, then the dose of dexamethasone will be decreased by one dose level. 
6.1.6 Duration of Therapy 
Treatment with study drug continues until disease progression, unacceptable toxicity (adverse event 
related to study drug), or the subject meets other criteria for discontinuation of study drug outlined in 
Section 5.3 and for a maximum period of 37 months. 
6.2 
Study treatment Accountability Procedures 
The investigator, or a pharmacist or other appropriate individual who is designated by the investigator, 
will maintain accurate records of the product’s delivery to the trial site, the inventory at the site, the use 
by each patient, and the return to the sponsor or alternative disposition of unused product(s). Monitoring 
of drug accountability will be performed by the field monitor during the study conduct and a copy of 
the final drug accountability and reconciliation log will be provided by the investigator(s) at the 
completion of the trial.  
 
7. Study procedures and Schedule  
 
7.1 
Study Procedures/Evaluations 
 
7.1.1 Efficacy Assessments 
The primary endpoint of this study is Progression Free Survival (PFS). Secondary efficacy endpoints 
are Overall Survival (OS), Overall Response Rate (ORR), Renal Response Rate (RRR), duration of 
response and time to next therapy. 


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Response or disease progression will be assessed by the Investigator based on the analysis of serum and 
urine protein electrophoresis (sPEP and uPEP), serum and urine immunofixation (sIFE, uIFE), serum 
free light chain protein (sFLC), imaging and bone marrow assessments as per IMWG guidelines (see 
Appendix 4). If the patient does not have documented disease progression as defined in Appendix 4 at 
the time of study drug discontinuation, then tumor assessments must continue to be performed 
according to the same schedule shown in Table 7.2 until disease progression even if a subsequent anti-
myeloma treatment is started prior to disease progression.   
Assessment of renal response will be conducted in accordance with the International Myeloma Working 
Group (IMWG) response criteria, based on eGFR calculated by the CKD-EPI formula.  
All study assessments and laboratory tests will be performed according to standard clinical practice and 
as clinically indicated. 
Assessments performed at external laboratories may be accepted as per institutional practice. 
Disease assessments are shown in Table 7.1. 
 
 


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Table 7.1 – Disease assessments 
M-protein by electrophoresis 
Serum (sPEP), Urine (uPEP) 
 
Screening and baseline 
Day one of each cycle 
End of treatment 
Post-treatment follow-up every 4 weeks 
As needed to confirm disease progression 
 
M-protein by immunofixation 
Serum (sIFE), Urine (uIFE) 
 
Screening and baseline 
End of treatment 
Post-treatment follow-up every 4 weeks 
As needed to confirm CR (when PEP is 0 or non-quantifiable) 
 
Serum free light chain sFLC 
Screening and baseline 
Day one of each cycle (for patients that have no measurable serum 
or urine M-protein)  
As needed to confirm sCR 
End of treatment 
Post-treatment follow-up every 4 weeks 
As needed to confirm disease progression 
 
Clinical 
assessment 
of 
soft 
tissue 
plasmacytoma (STP) 
Screening and baseline 
Day one of each cycle 
End of treatment 
Post-treatment follow-up every 4 weeks 
As needed to confirm disease progression 
CT/MRI assessment of STP 
If present or suspected, at screening and as clinically indicated. 
 
Plasma cell count in bone marrow 
At screening and during the study as clinically indicated to 
substantiate CR and PD for patients with non-measurable disease 
by M protein in serum and urine as well as by FLC. 
 
Skeletal survey by X-ray and/or CT/MRI 
At screening and as clinically indicated, CT/MRI in case of newly 
symptomatic areas with no X-ray finding. 
 
Serum Creatinine (for patients not on 
dialysis)  
Screening and baseline 
Weekly in the first two cycles then every two weeks for cycles 3-
6 and then on day one of each cycle 
End of treatment 
Post-treatment follow-up every 4 weeks 
 
Corrected calcium 
Screening and baseline 
Day one of each cycle 
End of treatment 
Post-treatment follow-up every 4 weeks 
As needed to confirm disease progression 
 
MRD by means of EuroFlow next 
generation cytometry 
If required for confirmation of sCR, upon confirmed CR/sCR and 
thereafter every 6 months as long as CR/sCR is maintained. 
 
Confirmation of response 
Based on IMWG criteria, response must be confirmed for all categories other than SD in order to rule 
out errors. A consecutive assessment can be performed at any time and confirmation should be obtained 
by M-protein assessments. 


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• 
Bone marrow assessments do not need to be repeated, but at least one bone marrow assessment 
is required to substantiate a CR. 
• 
If imaging studies were done, they need to rule out new lytic bone lesions. 
• 
Should confirmation assessments reveal a better category (e.g. VGPR after PR), the response 
category of the previous assessment will be considered as confirmed (PR). 
• 
Should confirmation assessments reveal a worse category, (e.g. VGPR after CR), the response 
category of the subsequent assessment will be considered as confirmed (VGPR). 
• 
Should repeated measurements of a variable result in more values, the worst assessment is to 
be considered. 
Laboratory confirmation of progressive disease 
A diagnosis of PD requires confirmation if determined based on M-protein measurement. Confirmation 
of an increase in M-protein or FLC should be obtained as soon as possible. 
Sponsor confirmation of progressive disease 
A diagnosis of progressive disease (that is also confirmed with a consecutive assessment if based on 
M-protein/serum FLC levels) must be reported, via email, to the sponsor’s Medical Reviewer within 1 
working day using the Progressive Disease Notification Form together with all supporting 
documentation for the diagnosis. The Medical Reviewer will check that the investigator’s assessment 
of PD is in line with the IMWG criteria and will provide a confirmation on the same form and return it 
via email to the site. In the case that the investigator’s assessment is not deemed in line with the IWMG 
criteria, the Medical Reviewer will provide comments in the relevant section of the notification form 
and may also contact the investigator to discuss the subject further. 
Study treatment discontinuation and start of subsequent anti-myeloma therapy should occur only after 
sponsor confirmation of PD. 
7.1.1.1 Serum and urine sample collection for M-protein 
assessment by PEP and IFE 
Response to treatment is based on M-protein levels in serum and urine. Two methods may be used: 
• 
Protein electrophoresis (PEP) provides quantitative measurements. 
• 
Immunofixation (IFE) provides qualitative measurements (present/absent). It is a more 
sensitive method than PEP and is used to confirm the absence of M-protein by PEP (CR). 
➢ Serum and urine immunofixation is required at baseline and to confirm CR regardless of whether 
measurable M-protein was present at baseline. 
➢ Subjects with measurable disease in sPEP will be assessed for response based on sPEP and not by 
the serum FLC assay. 
➢ Subjects with measurable disease in both sPEP and uPEP will be assessed for response based on 
these two tests and not by the serum FLC assay. 
Blood (serum) and 24-h urine for M-protein assessment will be collected as indicated in Table 7-2.  
Analysis by IFE will be done for all patients at screening and baseline, and thereafter only in case of 
disappearance of M-protein by PEP. 


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All samples (blood, urine, bone marrow, etc.) are collected and analyzed according to standard clinical 
practice. 
7.1.1.2 Free Light Chain (FLC) protein assessment 
The serum FLC assay measures free kappa light chain (0.33-1.94 mg/dL or 3.3-19.4 mg/L) and free 
lambda light chain (0.57-2.63 mg/dL or 5.7-26.3 mg/L). The FLC ratio is defined as the kappa serum 
level divided by the lambda serum level. Lambda is the involved light chain if FLC ratio < 0.26. Kappa 
is the involved light chain if FLC ratio of > 1.65. 
The FLC ratio is considered Normal if FLC ratio is within 0.26-1.65, and Abnormal if FLC ratio is 
<0.26 or >1.65. 
FLC serves to monitor disease status when serum M-protein or urine M-protein or both assessed by 
PEP is/are non-measurable (i.e., serum M-protein < 0.5 g/dL (5 g/L) or urine M-protein < 200 mg (0.2 
g) per 24 hours) and to identify sCR if CR criteria are met. 
Blood (serum) for FLC assessment will be collected as indicated in Table 7-2. FLC will be analyzed 
only when serum M-protein or urine M-protein or both assessed by PEP is/are non-measurable and to 
identify sCR.  
7.1.1.3 Plasma cell count in bone marrow by local assessment 
A bone marrow (BM) aspirate/biopsy for plasma cell quantification will be collected as indicated in 
Table 7-2 and the percentage of plasma cells will be determined by using cytological/histological 
examination. Either BM aspirate or biopsy can be used for this assessment, but the same method should 
be used throughout the trial.  
A bone marrow aspirate and/or biopsy should be performed for every patient at screening. As the 
procedure is invasive, post-baseline assessments should be performed for confirmation of CR/sCR or, 
if clinically indicated, at time of suspected disease progression or end of treatment. 
7.1.1.4 Assessment of Soft Tissue Plasmacytoma (STP) 
Clinical assessment by investigator 
The investigator should perform a clinical exam to assess the presence of STP at screening and baseline, 
on day one of each cycle, at end of treatment and during post-treatment follow-up. 
If suspicion of a STP, not present at screening, arises during the study, a CT or MRI must be performed 
immediately. 
• 
CT/MRI  
o Screening: A CT/MRI will be performed at screening within 21 days prior to start of study 
treatment if there is evidence of presence of an STP from the clinical examination or 
documented presence from previous imaging assessments. Any imaging assessments 
already completed during the regular work-up of the patient within 42 days prior to start of 
treatment can be considered as the baseline images. 
o Post-baseline: Assessments should be performed using the same imaging technique used at 
baseline. 


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− 
If STP is present at baseline, a CT/MRI should be performed every 12 weeks (+/- 
7 days) until disease progression. 
− 
If STP is not present at baseline, but there is a suspicion of STP and/or disease 
progression (based on clinical exam or symptoms) a CT/MRI should be performed 
promptly to confirm suspicion. 
Lesion size will be measured as the sum of the products of the longest diameters and longest 
perpendicular diameter for all measurable lesions. 
All tumor measurements must be made in millimeters. Measurable disease are lesions that can be 
accurately measured in 2 dimensions and both diameters must be ≥ 20 mm when evaluated by standard 
CT scanning or ≥ 10 mm when evaluated by spiral CT scanning or MRI.  
7.1.1.5 Skeletal survey 
A skeletal survey is to be performed by conventional radiography for osteolytic disease within 21 days 
prior to Cycle 1 Day 1 in all subjects. The survey will be performed during the study if clinically 
indicated. Use of conventional or low dose CT scan (i.e., of the spine) or MRI is acceptable. If imaging 
is performed on treatment for assessment of progression, the same imaging technique as the one used 
at screening must be used. The number and location of skeletal lesions and whether they are lytic should 
be recorded on the eCRF. On-treatment survey should record whether there is an increase in the number 
or size of lytic lesions. Any imaging assessments already completed during the regular work-up of the 
patient within 42 days prior to start of treatment can be considered as the baseline images. 
7.1.1.6 Minimal residual disease (MRD) by means of next 
generation flow cytometry (EuroFlow protocol). 
The EuroFlow-International Myeloma Foundation (IMF) next generation flow MRD approach provides 
a fast, highly applicable, ultrasensitive, standardized and accurate approach for the assessment of MRD 
in bone marrow samples from MM patients. MRD will be analyzed upon confirmed complete response 
and every 6 months thereafter until progression. 
7.1.1.7 Corrected calcium 
Corrected calcium in serum for determination of hypercalcemia as part of response assessment will be 
evaluated on day one of each cycle until disease progression using the following formula: 
Corrected Calcium, mg/dL = (0.8 x [Normal Albumin, g/dL - Subject’s Albumin, g/dL] + Serum Ca, 
mg/dL 
7.1.1.8 Cytogenetics by means of fluorescence in situ hybridization 
(FISH) 
A cytogenetic analysis of bone marrow cells will be performed at screening through fluorescence in 
situ hybridization according to standard clinical practice for del17p, t(4;14) and t(14;16). 
7.1.1.9 eGFR calculation 
The calculation of eGFR will be based on the CKD-EPI formula as follow 21:  


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7.1.2 Safety assessments 
Safety evaluations include assessments of Adverse Events (AE), clinical laboratory tests, vital sign 
measurements, physical examination, assessment of ECOG performance status, cardiac imaging 
(screening) and ECG. 
7.1.2.1 Adverse events 
Monitoring for adverse events will take place continuously throughout the study, starting from informed 
consent until 30 days after last study treatment. See Section 8 for details. 
7.1.2.2 Clinical laboratory tests 
Laboratory assessments to be performed according to standard clinical practice and medicinal products’ 
SPCs are listed below. See Table 7.2 for a schedule of assessments. 
• 
Hematology: CBC, Differential (absolute counts: lymphocytes, monocytes, neutrophils, 
eosinophils, basophils), platelets. 
• 
Clinical chemistry: sodium, potassium, total protein, albumin, alkaline phosphatase, GT, 
Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), total bilirubin, BUN, 
creatinine, glucose, eGFR based on CKD-EPI (see section 7.1.1.9). 
• 
Urine or Serum Pregnancy test in women who can be pregnant 
• 
Serum β 2-microglobulin, LDH 
7.1.2.3 Vital signs 
Vital signs (body temperature, seated blood pressure and heart rate) will be recorded as outlined in 
Table 7.2. Blood pressure and heart rate should be measured after the subject has been seated quietly 
for at least 5 minutes prior to dosing.  
Vital signs will be monitored also prior to, during and after the daratumumab infusion period. 


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7.1.2.4 Physical examination 
Physical examinations will be performed according to the visit schedule outlined in Table 7-2. A full 
physical examination will be performed at screening visit, whereas targeted exams will occur during 
the treatment and post-treatment periods according to the Investigator’s observations and/or subject 
complaints on new or changed conditions. 
Significant findings that were present prior to the signing of informed consent must be included in the 
Medical History eCRF page. Significant new findings that begin or worsen after informed consent must 
be recorded on the Adverse Event page of the eCRF. 
7.1.2.5 ECOG performance status 
Eastern Cooperative Oncology Group (ECOG) performance status will be evaluated as indicated in 
Table 7.2 using the criteria described in Appendix 6. The assessment should be completed prior to any 
study-related procedures or assessments. 
7.1.2.6 Cardiac assessments 
A 2-dimensional echocardiogram (or if not available a MUGA scan) and an electrocardiogram will be 
performed at screening or within 42 days of Cycle 1 Day 1. Echo (or MUGA) may be repeated  
throughout the study as clinically indicated. 
7.1.3 Hepatitis B Virus (HBV) Serology 
All subjects will be tested locally for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody 
(Anti-HBs), and hepatitis B core antibody (Anti-HBc) at Screening. Additionally, subjects ongoing in 
the Treatment Phase who are within 6 months of starting study treatment when Protocol Amendment 3 
is implemented will be required to have HBV serology performed locally upon signing the updated ICF. 
HBV serology is not required at Screening or for subjects ongoing in the Treatment Phase who are 
within 6 months of starting study treatment if this was performed as part of standard of care within 3 
months prior to first dose. 
7.1.4 HBV DNA Tests 
Subjects who are positive for Anti-HBc or Anti-HBs will undergo testing for hepatitis B DNA by PCR. 
Subjects with serologic findings suggestive of HBV vaccination (Anti-HBs positivity as the only 
serologic marker) and a known history of prior HBV vaccination do not need to be tested for HBV 
DNA by PCR. During and following study treatment, subjects who have history of HBV infection will 
be closely monitored for clinical and laboratory signs of reactivation of HBV as specified in the Time 
and Events Schedule (Table 7.2). Where required by local law, the results of HBV testing may be 
reported to the local health authorities. 
 
7.2 
Study schedule 
Table 7.2 lists all of the assessments and indicates the visits when they are performed. See Section 7.1 
for details concerning each assessment. All data obtained from these assessments must be supported in 
the patient’s source documentation. Baseline is defined as Cycle 1 Day 1 (C1D1) prior to start of study 


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treatment. For assessments that are not performed on C1D1, the screening results will be considered as 
baseline. 
Post-baseline disease evaluations may be conducted ± 3 days from the scheduled (based on C1D1) visit 
date, if necessary. At the following visit, the subject should return to the originally planned schedule. 
7.2.1 Screening 
Following signature of the Informed Consent Form (ICF), screening assessments will be performed 
within 21 days prior to Cycle 1 Day 1, with the exception of radiological assessments and cardiac echo 
for which results obtained within 42 days of C1D1 are also acceptable.  
A patient who has a laboratory result that does not satisfy eligibility criteria may have the test repeated 
when the investigator believes the re-test result is likely to be within the acceptable range to satisfy the 
entrance criteria, but should be completed within the 21 day screening window. If the bone marrow 
sample collected at screening (aspirate) is inadequate for genetic assessments (fluorescent in situ 
hybridization) (FISH) and/or evaluation of percentage of plasma cells, it should be repeated within the 
21 day screening window. Results from the skeletal survey or the radiologic assessments for 
Extramedullary Plasmacytomas, which have been performed as routine follow up within 42 days before 
C1D1, may be used without these tests being repeated. 
Patients who sign an informed consent but fail to be started on treatment for any reason will be 
considered screening failures. The reason for not starting the study treatment will be entered in the 
eCRF. The demographic information, informed consent, and Inclusion/Exclusion pages must also be 
completed for screening failure patients. No other data will be entered into the clinical database unless 
the patient experienced a Serious Adverse Event during the Screening Phase. 
Patients who fail to meet any of the inclusion and exclusion criteria will be considered screening failures 
and may be rescreened if their condition changes. Rescreening must be discussed with and approved by 
the sponsor on a case-by-case basis. Subjects who are deemed eligible for rescreening must sign a new 
ICF. 
Patient demographics and other baseline characteristics 
The following data is to be recorded on the eCRF during the screening period: 
• 
Demography (year of birth, age in years, sex, information on childbearing status of female patients, 
race, ethnicity). 
• 
Medical history / current medical conditions. 
• 
Diagnosis of Multiple Myeloma and extent of the disease (including staging at study entry, ISS 
and revised-ISS). Staging of MM should be done according the International Staging System (ISS) 
and the Revised-ISS (see Appendix 3). 
• 
Bone marrow aspirate/biopsy for cytogenetics (FISH). 
• 
All prior anti-neoplastic therapies including surgical interventions and chemo-, biologic-, 
immunologic- and radiation-therapies and stem cell transplants provided as treatment for MM. 
• 
All concomitant medications and significant non-drug therapies including transfusions of blood 
products administered within 14 days prior to first dose. 
• 
The following assessments must be performed and recorded for all patients: 
o Complete physical examination including height and weight. 
o Vital signs (temperature, heart rate, diastolic and systolic blood pressure) 


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o Eastern Cooperative Oncology Group (ECOG) performance status 
o Electrocardiogram 
o Cardiac imaging (ECHO or  MUGA) 
o FEV1 in subjects with known or suspected COPD 
o Serum pregnancy test performed in WOCBP (two pregnancy tests, one 10-14 days prior 
to start of study drug and one within 24 hours prior to start of study drug. Urine tests must 
have a sensitivity ≥ 25 mIU/mL). 
o Local laboratory evaluations (hematology, clinical chemistry, eGFR). 
• 
Disease assessments 
o In serum: 
• 
M-protein by PEP and IFE 
• 
FLC protein assessment 
• 
corrected calcium 
• 
serum Creatinine / eGFR  
o In urine (24-h urine collection required): 
• 
M-protein by PEP and IFE; 
o Local plasma cell count in bone marrow 
o Clinical and CT/MRI assessment of soft tissue plasmacytomas (STP) 
o Local full body skeletal survey by X-ray and/or CT/MRI 
o Blood type, Rh, and Indirect Antiglobulin Test (IAT) 
 
Blood Type and IAT 
Blood type, Rh, and IAT will be done before the first dose of daratumumab. Subject RBC phenotyping 
(standard or extended) is an alternative option to the IAT test, if locally required. Either method must 
be completed prior to first daratumumab infusion. 
Daratumumab interferes with the IAT, which is a routine pre-transfusion test performed to identify a 
patient’s antibodies to minor antigens so that suitable donor blood can be given for transfusion. 
Daratumumab does not interfere with ABO/RhD typing. CD38 is expressed at very low levels on 
erythrocytes. Daratumumab binds to the CD38 on erythrocytes, which results in a positive IAT (Indirect 
Antiglobulin or Coombs Test). This positive result masks the detection of antibodies to minor antigens 
and may prevent or delay blood banks from issuing donor blood for transfusion. This effect occurs 
during daratumumab treatment and for up to 6 months after treatment ends. Subjects will receive a 
patient identification wallet card for the study that includes the blood profile (ABO, Rh, and IAT or 
phenotyping) determined before the first infusion of daratumumab along with information on the IAT 
interference for healthcare providers/blood banks. Subjects are to carry this card throughout the 
treatment period and for at least 6 months after treatment ends. Blood banks can eliminate the 
daratumumab interference with IAT by treating reagent RBCs with dithiothreitol (DTT) 22-23 
Possible methods for blood banks to provide safe RBCs for transfusion to subjects receiving 
daratumumab include: 
• 
Providing ABO/RhD compatible, phenotypically (standard or extended phenotyping) or 
genotypically matched units, and 
• 
Providing ABO/RhD compatible, K-negative units after ruling out or identifying 
alloantibodies using DTT-treated reagent RBCs. 


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Uncrossmatched, ABO/RhD compatible RBC units should be administered if transfusion is needed 
emergently as per local blood bank practice. 
Despite daratumumab binding to CD38 on erythrocytes, no indication of clinically significant 
hemolysis has been observed in daratumumab studies. For additional details, refer to the Daratumumab 
IB. 
In case of an urgent need for a blood transfusion, a blood sample should be obtained before the first 
infusion of daratumumab and the subject’s blood type (ABO, Rh, and IAT) determined. Subjects should 
be provided a blood type card, which they will carry with them throughout the treatment period. 
7.2.2 Treatment Period 
Up to 38 patients will be treated in 28-day cycles until disease progression, unacceptable toxicity, death, 
or discontinuation from the study treatment due to other reason (see Section 5.4.1). A 24-month accrual 
period is planned for the study and the last patient enrolled will be followed up for a maximum of 13 
months. The entire study will therefore have a total maximum duration of 37 months. See Table 7.2 
for the assessment schedule, Section 7.1 for details about assessments and Section 6.1 for information 
about treatment. The general visit window during the treatment period is +/- 3 days. 
End of Treatment Visit 
An  End-of- Treatment Visit will take place 4 weeks after the last dose of study treatment, or as soon as 
possible before  the  start  of  subsequent  therapy, unless  the subject  withdraws  consent  for  study 
participation  or  is  lost  to  follow  up. Every effort  should  be  made  to  conduct  the End-of-Treatment  
Visit  before  the  subject starts  subsequent  treatment.  
7.2.3 Follow-up Period 
Post-treatment follow-up 
Patients who discontinue treatment for reasons other than documented disease progression, death, lost 
to follow-up, or withdrawal of consent should continue to be followed for response assessments every 
4 weeks as in Table 7.2. The reason for completion/discontinuation should be recorded on the eCRF. 
If a patient starts new anti-neoplastic therapy prior to disease progression, every attempt should be made 
to perform tumor evaluations until documented disease progression. In addition, all new anti-neoplastic 
therapy administered starting from the last dose of the study treatment until death, lost to follow-up, or 
withdrawal of consent will be recorded in the eCRF. 
Survival follow-up 
Subjects will be followed every 12 weeks, or more frequently, after disease progression for survival 
and subsequent myeloma therapy until the end of study. 


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Table 7.2 – Schedule of Events 
Day of Cycle (28-days) 
Screening
^ 
Treatment: visit window during the treatment period is +/- 3 days 
End of treatment EOT8 
Post treatment FU 
Every 4 weeks5 
Survival follow-up 
Every 12 weeks 
Cycles 1 and 2 
Cycles 3-6 
Cycles 7 and beyond 
-21 to 1 
1 BL 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
Demographic/baseline 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inc./Exc. criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MM diagnosis/history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
International Staging 
System (ISS) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cytogenetics (FISH) at 
study entry  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
 
Physical examination 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
 
Weight 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
 
Performance status 
(ECOG) 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Adverse Events 
Continuously from ICF until 30 days after last study treatment 
Treatment related 
SAEs 
Concomitant medication, 
transfusions 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Cardiac imaging:  ECHO 
or MUGA9 
X 
As clinically indicated 
FEV1*** 
X 
 
ECG 
X 
As clinically indicated 
Lab Assessments* 
 
Blood type assessment 
and indirect antiglobulin 
results0  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
Clinical chemistry 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
eGFR 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
Pregnancy test1 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Day of Cycle (28-days) 
Screening
^ 
Treatment: visit window during the treatment period is +/- 3 days 
End of treatment EOT8 
Post treatment FU 
Every 4 weeks5 
Survival follow-up 
Every 12 weeks 
Cycles 1 and 2 
Cycles 3-6 
Cycles 7 and beyond 
-21 to 1 
1 BL 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
Serum β2-microglobulin, 
LDH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B serology10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV-DNA PCR testing11 
X 
Every 12 weeks (window ±7 days) 
X 
Every 12 
weeks 
for up to 
6 months 
after the 
last dose 
of study 
treatment 
 
Efficacy Assessments 
 
Efficacy / Disease Assessment required to confirm response or disease progression should be performed as soon as possible after response or disease progression is suspected – see Section 7.1 for details) 
sPEP, uPEP2 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
sIFE, uIFE3 
X 
X 
 
 
. 
X 
 
 
X 
 
 
 
X 
X 
 
To confirm CR regardless of whether measurable M-protein was present at baseline. See Section 7.1.1.1 
 
 
sFLC assay, κ/λ ratio4 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Analyzed only when serum M-protein or urine M-protein or both assessed by PEP is/are non-measurable and to identify sCR in 
case CR criteria are met. See Section 7.1.1.2 
 
 
 
 
 
 
 
Plasma cell count in bone 
marrow 
X 
Plasma cell count during the study as clinically indicated to qualify for CR and PD for patients with non-measurable disease by M protein in serum and urine as 
well as by FLC. See Section 7.1.1.3 
 
MRD 
 
As per institution’s practice at complete response or better and thereafter every 6 months as long as CR/sCR is maintained through EuroFlow cytometry. See 
Section 7.1.1.6 
 
Corrected calcium6 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Skeletal survey7,9 
X 
As clinically indicated; CT/MRI in case of newly symptomatic areas with no X-ray finding. See Section 7.1.1.6 
 
Assessment of 
extramedullary soft tissue 
plasmacytoma 
X 
Clinical assessment on day one of each cycle at the End of treatment and at Post treatment follow-up every 4 weeks. CT or MRI at screening only if there are STP 
findings during the clinical assessment or documented evidence from previous imaging assessments and as clinically indicated. See Section 7.1.1.4 
 
Response assessment by 
Investigator 
 
C2D1 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Treatment  
 
Daratumumab 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
Dexamethasone 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
40 mg (20 mg for patients ˃ 75 years of age) orally, weekly 
 
 
 


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Day of Cycle (28-days) 
Screening
^ 
Treatment: visit window during the treatment period is +/- 3 days 
End of treatment EOT8 
Post treatment FU 
Every 4 weeks5 
Survival follow-up 
Every 12 weeks 
Cycles 1 and 2 
Cycles 3-6 
Cycles 7 and beyond 
-21 to 1 
1 BL 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
Other anti-neoplastic 
therapies  
 
Not permitted 
X 
X 
X 
Survival follow-up 
 
 
 
 
X 
^ The majority of screening assessments are to be performed within 21 days from the date of ICF signature until C1D1. See Section 7.2.1 for details. 
0 i In addition to ABO and Rh blood typing, indirect antiglobulin test (also known as indirect Coombs test) will be performed; it is recommended that the subject carries a card with the blood antigen profile at all times 
during the study. 
1 Women of childbearing potential (WOCBP) must have two negative serum or urine pregnancy tests, one 10-14 days prior to start of the study drug and one within 24 hours prior to the start of study drug. 
2M protein by electrophoresis in serum (sPEP) and urine (uPEP). Serum on Day 1 of each cycle until disease progression. 24-hour urine sample can be collected within ± 7 days of visit.  
3M protein by immunofixation in serum (sIFE) and urine (uIFE).  
4Free light chain protein assessment (sFLC) 
5 Patients who discontinue treatment for reasons other than disease progression, death, lost to follow-up, or withdrawal of consent should continue to be followed for response assessments every 4 weeks. 
6  Corrected calcium will be also performed as clinically indicated to confirm disease progression. 
7 As per institution’s practice 
 8 End of treatment visit should take place 4 weeks after the last dose of the study treatment or as soon as possible before the start of subsequent therapy. 
 9 If performed within 42 days from C1D1 are acceptable  
10 Local testing for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (Anti-HBs), and hepatitis B core antibody (Anti-HBc). Refer to Sections 7.1.3.  
11 For subjects with serologic evidence of resolved HBV infection (i.e., positive Anti-HBs or positive Anti-HBc) at Screening, HBV DNA testing by PCR must be performed locally. Refer to Section 7.1.4.** Unless 
otherwise stated, all blood and urine samples must be obtained before administration of study treatment. 
*** Subjects with known or suspected COPD must have an FEV test during Screening 
 
 


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7.3 
Concomitant Medications, Treatments, and Procedures  
All concomitant prescription medications taken during study participation will be recorded on the 
eCRF. For this protocol, a prescription medication is defined as a medication that can be prescribed 
only by a properly authorized/licensed clinician. Medications to be reported in the eCRF are 
concomitant prescription medications, over-the-counter medications and non-prescription medications. 
7.3.1 Precautionary Medications, Treatments, and Procedures 
See Appendix 2 for recommended pre-infusion medication. 
Management of Hepatitis B Virus Reactivation 
Primary antiviral prophylaxis is permitted as per local standard of care.  Per protocol, HBV DNA testing 
by PCR is mandatory for subjects at risk for HBV reactivation (see Section 7.1.4). 
For subjects who are diagnosed with HBV reactivation while on treatment, study treatment should be 
interrupted until the infection is adequately controlled. If the benefits outweigh the risks, study treatment 
may be resumed with concomitant antiviral prophylaxis as per local standard of care. Consult a liver 
disease specialist as clinically indicated. 
7.3.2 Prohibited Medications, Treatments and Procedures 
Any systemic, anti-myeloma therapy other than daratumumab and dexamethasone are prohibited while 
on study therapy. Concomitant steroids, other than weekly dexamethasone (see Section 6) are 
prohibited unless used to treat an adverse event and as pre- and post-infusion medication (see Section 
6 and Appendix 2). 
No interaction studies have been performed with daratumumab. Guidelines for the selection and use of 
other concomitant medications should be derived from dexamethasone prescribing information. 
7.3.3 Rescue Medications, Treatments and Procedures 
See Appendix 2 for guidelines for managing infusion-related reactions. 
7.3.3.1 Hemodialysis 
For patients in need of hemodialysis, daratumumab should be administered on the day with the 
maximum distance from the subsequent hemodialysis. 
7.3.4 Participant Access to Study Treatment at Study Closure 
Patients will be provided with study treatment until disease progression, death, lost to follow-up, or 
withdrawal of consent. The sponsor may terminate access to study drug if the study is terminated due 
to safety concerns.  
 
 


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8. Safety Monitoring and Reporting  
 
8.1 
Adverse events  
8.1.1 Adverse event definition   
According to the International Conference on Harmonization (ICH), an AE is any untoward medical 
occurrence in a patient or clinical investigation subject administered a pharmaceutical product and 
which does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. Pre-existing conditions that worsen during a study against the baseline conditions 
are to be reported as AEs.  
The occurrence of adverse events should be sought by non-directive questioning of the patient during 
screening, after signing informed consent, and at each visit during the study. Adverse events also may 
be detected when they are volunteered by the patient or through physical examination, laboratory test, 
or other assessments. 
Laboratory abnormalities that constitute an Adverse Event should be recorded on the Adverse Event 
page of the eCRF. Whenever possible, a diagnosis rather than a symptom should be provided (e.g. 
anemia instead of low hemoglobin).  
8.1.2 Definition of Serious Adverse Events (SAE) 
An AE or suspected adverse reaction is considered "serious" if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: death, a life-threatening adverse event, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or 
substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth 
defect.  
The term "life-threatening" in the definition of "serious" refers to an 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. 
Important medical events that may not result in death, be life-threatening, or require hospitalization may 
be considered serious when, based upon appropriate medical judgment, may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
Events not considered being SAEs are hospitalizations for: a standard procedure for therapy 
administration, routine treatment or monitoring of the study indication, hospitalization or prolongation 
of hospitalization for technical/practical or social reasons in absence of an AE, a procedure which is 
planned. A prolongation of such a hospitalization for a complication remains a reportable SAE. 
 
 


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8.2 
Classification of an Adverse Event 
8.2.1 Severity of Event 
Intensity: all AEs will be graded according to the Common Terminology Criteria for AEs (CTCAE 
version 4.03) as follows (a semi-colon indicates ‘or’ within the description of the grade): 
• 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• 
Grade 2: Moderate; minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental activities of daily living. 
• 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. 
• 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
• 
Grade 5: Death related to AE. 
 
 
 
8.2.2 Relationship to Study Treatment(s) 
For all collected AEs, the clinician who examines and evaluates the participant will determine the AE’s 
causality based on temporal relationship and his/her clinical judgment. The degree of certainty about 
causality will be graded using the categories below.  
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test result, 
occurs in a plausible time relationship to drug administration and cannot be explained by concurrent 
disease or other drugs or chemicals. The response to withdrawal of the drug (dechallenge) should be 
clinically plausible. The event must be pharmacologically or phenomenologically definitive, with use 
of a satisfactory rechallenge procedure if necessary.  
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of 
other factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within 
a reasonable time after administration of the drug, is unlikely to be attributed to concurrent disease or 
other drugs or chemicals, and follows a clinically reasonable response on withdrawal (dechallenge). 
Rechallenge information is not required to fulfil this definition. 
• 
Possibly Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other factors 
may have contributed to the event (e.g., the participant’s clinical condition, other concomitant events). 
Although an AE may rate only as “possibly related” soon after discovery, it can be flagged as requiring 
more information and later be upgraded to “probably related” or “definitely related,” as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to drug administration makes a causal relationship improbable (e.g., the event did 
not occur within a reasonable time after administration of the trial medication) and in which other drugs 
or chemicals or underlying disease provide plausible explanations (e.g., the participant’s clinical 
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• 
Not Related – The AE is completely independent of study drug administration, and/or evidence 
exists that the event is definitely related to another etiology. There must be an alternative, definitive 
etiology documented by the clinician.] 
8.2.3 Expectedness  
The Sponsor will be responsible for determining whether an AE is expected or unexpected. An AE will 
be considered unexpected if the nature, severity, or frequency of the event is not consistent with the 
applicable product information (e.g. Investigator’s Brochure or Summary of Product Characteristics 
(SPC) of the study agents.  
8.3 
Time Period and Frequency for Event Assessment and 
Follow-Up 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits and 
interviews of a study participant presenting for medical care, or upon review by a study monitor. All 
AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
eCRF. Information to be collected includes event description, time of onset, clinician’s assessment of 
severity, relationship to study product (assessed only by those with the training and authority to make 
a diagnosis), and time of resolution/stabilization of the event. All AEs occurring while on study must 
be documented appropriately regardless of relationship. All AEs will be followed to adequate 
resolution.  
Any medical condition that is present at the time that the participant signs the ICF will be considered 
as baseline condition and not reported as an AE. However, if the study participant’s condition 
deteriorates in severity and frequency at any time during the study, it will be recorded as an AE. 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode.  
The Investigator will record all reportable events with start dates occurring any time after informed 
consent is obtained until 30 days (both AEs and SAEs) after the last day of study treatment. At each 
study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit. Events 
will be followed for outcome information until resolution or stabilization. 
8.4 
Reporting Procedures 
8.4.1 Adverse Event Reporting  
All identified non-serious AEs (related and unrelated) must be recorded and described on the non-
serious AE page of the eCRF. 
8.4.2 Serious Adverse Event Reporting  
Every SAE, regardless of suspected causality, occurring after the patient has provided main informed 
consent and until at least 30 days after the patient has stopped study treatment must be reported to the 
Sponsor within 24 hours of site awareness. 
Any SAE experienced after this 30-day period should only be reported to the Sponsor if the investigator 
suspects a causal relationship to the study treatment. Recurrent episodes, complications, or progression 


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of the initial SAE must be reported as follow-up to the original episode within 24 hours of the 
investigator receiving the follow-up information. 
Information about all SAEs will be recorded on the Serious Adverse Event Report Form. 
All SAEs will be followed until satisfactory resolution or until the site investigator deems the event to 
be chronic or the adherence to be stable. Other supporting documentation of the event may be requested 
by the study sponsor and should be provided as soon as possible. The study sponsor will be responsible 
for notifying Health Authorities of any unexpected fatal or life-threatening suspected adverse reaction 
as soon as possible but in no case later than 7 calendar days after the sponsor's initial receipt of the 
information. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to the 
competent authorities and relevant ethics committees in accordance with Directive 2001/20/EC or as 
per national regulatory requirements in participating countries. 
8.4.3 Events of Special Interest  
Safety events of special interest include, but are not limited to: 
● 
Secondary Primary Malignancies  
● 
Infusion Related Reactions 
● 
Medication Error, intercepted medication error or potential medication error (with or without 
patient exposure to IMP, e.g., product name confusion, product label confusion, intercepted 
prescribing or dispensing errors)  
● 
Abuse/Misuse/Overdose  
● 
Occupational Exposure  
● 
Drug-Drug Interaction  
● 
Suspected Transmission of Infectious Agents  
● 
Exposure from breastfeeding 
● 
Unexpected therapeutic benefit or clinical benefit 
● 
Inadvertent or accidental exposure 
All events of special interest should be especially monitored and reported to the sponsor as SAEs and 
within 24 hours of site awareness, even if considered non-serious and regardless whether or not an 
(S)AE occurred. All of the events of special interest should be recorded on the eCRF.     
8.4.4 Pregnancy  
A female patient will be instructed immediately to inform the investigator if she becomes pregnant 
during the study. The investigator shall report all pregnancies within 24 hours to the sponsor using the 
Pregnancy Reporting Form. Monitoring of the patient should continue until conclusion of the 
pregnancy. Pregnancies occurring up to 90 days after the completion of the study medication must also 
be reported to the investigator.  
There are no human or animal data to assess the risk of daratumumab use during pregnancy. IgG1 
monoclonal antibodies are known to cross the placenta after the first trimester of pregnancy. Therefore, 
daratumumab should not be used during pregnancy unless the benefit of treatment to the woman is 
considered to outweigh the potential risks to the fetus. The investigator will therefore inform the subject 
of the potential risks to the fetus and discuss with the Sponsor as well as the subject if it is in the subject’s 
best interest to continue or stop treatment with daratumumab. 


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The effect of daratumumab on sperm is unknown. Therefore, pregnancy occurring in the partner of a 
male patient participating in the study should also be reported by the investigator within 24 hours of 
awareness to the sponsor by using the Pregnancy Reporting Form.. 
8.4.5 Product Quality Complaints  
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, i.e. any dissatisfaction relative to the identity, quality, durability, 
or reliability of a product, including its labeling or package integrity. A PQC may have an effect on the 
safety and efficacy of the product; therefore the timely, accurate, and complete reporting and analysis 
of PQC information are crucial for the protection of subjects, Investigators, and the Sponsor. 
All PQCs must be reported to the Sponsor using the PQC form  within 24 hours upon awareness, 
regardless if the relevant defect is combined with a (S)AE or not. Where possible, a sample of the 
suspected product should be maintained for further investigation if requested by the Sponsor. 
8.4.6 Annual Safety Report  
An Annual Safety Report will be submitted to the Competent Authorities and Ethics Committees once 
a year, according to the relevant local regulations. 
 
 
8.5 
Safety Oversight 
Safety data will be reviewed by the study Scientific Committee approximately every 6 months (after 
first randomized patient started study treatment). 
9.  Clinical Monitoring  
Clinical site monitoring will conducted to ensure that the rights and well-being of human subjects are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of the 
trial complies with the currently approved protocol, with GCP, and with applicable regulatory 
requirements.  
Monitoring for this study will be performed by a Contract Research Organization (CRO).  
Details of clinical site monitoring are documented in a Clinical Monitoring Plan (CMP). The CMP 
describes in detail who will conduct the monitoring, at what frequency monitoring will be done, at what 
level of detail monitoring will be performed, and the distribution of monitoring reports.  
Independent audits may be conducted to ensure monitoring practices are performed consistently across 
all participating sites and that monitors are following the CMP.  
10. 
Statistical considerations  
10.1 Statistical and Analytical Plans 
The primary analysis will be performed when the targeted number of events required for the primary 
analysis has been reached. 


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10.2 Statistical Hypotheses 
The primary efficacy endpoint is PFS as assessed by the Investigator. 
The expected median PFS with daratumumab treatment in the SIRIUS study was 5.6 months in the 
patients who received daratumumab at the dose of 16 mg/kg.  
In order to test at α=0.05 the null hypothesis that the PFS is less than 3 months versus the alternative 
hypothesis that PFS is at least 5 months with a power of 90%, 34patients must be  included in the study. 
This calculation assumes exponential survival curves, an accrual time of 18 months and a length of 
follow up period of 30 months. Assuming a drop-out rate of about 10%, 38 patients are needed.  
The distribution of PFS will be estimated using the Kaplan-Meier method. The median PFS along with 
95% confidence intervals will be presented (see Section 10.4.2). 
The analysis will be performed when at least 20 PFS events have been documented. 
10.3 Analysis Datasets 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been assigned 
according to the intent to treat principle. 
 
Per Protocol Set 
The Per-Protocol Set (PPS) consists of a subset of patients in the FAS who received at least one dose 
of the study drug and had no major protocol deviation. Protocol deviations leading to exclusion from 
the PPS will be defined in the Statistical Analysis Plan. 
Safety Set 
The Safety Set consists of all patients who received at least one dose of study treatment. Patients who 
have been randomized and did not take at least one dose of study treatment will not be included in the 
safety set. Patients will be analyzed according to the study treatment they actually received. 
10.4 Description of Statistical Methods 
10.4.1 General Approach 
All data collected in this study will be listed and summarized as appropriate as described below. Data 
from all sites will be pooled and summarized. 
Continuous data will be summarized by mean, standard deviation, median, first and third quartiles, 
minimum and maximum. Categorical data will be presented by absolute and relative frequencies (n and 
%) or contingency tables. 
One-sided alpha level 0.025 will be considered. No alpha level adjustment will be carried out for 
primary and secondary outcome variables. 
10.4.2 Analysis of the Primary Efficacy endpoint(s) 


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The efficacy analysis will be performed based on the FAS as primary analysis and on the PPS as 
supportive analysis. 
Progression Free Survival (PFS) 
Progression free survival is defined as the time, in months, from treatment initiation (Cycle 1 , day 1) 
to the date of the first documented disease progression or death due to any cause, whichever comes first. 
Clinical deterioration will not be considered progression. For subjects who neither progress nor die, the 
survival time will be censored at the date of their last disease assessment. For subjects who start a new 
anti-tumor treatment, survival time will be censored at the date of the start of the new treatment.  
The PFS function will be estimated using the Kaplan-Meier product-limit method. Median and two-
sided confidence intervals (CI) for median PFS will be computed by and Kaplan-Meier plots of PFS 
will be presented. 
Absolute frequencies and proportions of patients with disease progression or all-cause death will also 
be provided. 
10.4.3 Analysis of the Secondary Endpoint(s) 
All secondary efficacy analyses will be performed based on the FAS. 
Overall Response Rate (ORR) 
Overall response rate is defined as the proportion enrolled subjects who achieve a best response of 
partial response (PR) or better using the Modified criteria of the International Myeloma Working Group 
(IMWG) (see Appendix 4) as their best overall response. 
The response rate, along with its exact two-sided 95% CI, will be computed. 
Renal Response Rate (RRR) 
Renal Response Rate is defined as the proportion enrolled subjects who achieve a best response of renal 
partial response (PRRenal) or better using the criteria of the International Myeloma Working Group 
(IMWG) (see Appendix 5). 
Duration of Response (DoR) 
Duration of response will be restricted to the subjects that achieve a best objective response of PR or 
better. It is measured from the time, in months, that the criteria for objective response are first met until 
the date of a progression event (according to the primary definition of PFS). A subject with objective 
response who does not have a progression event will be censored at the same time they were censored 
under the primary definition of PFS. 
The DoR function will be estimated using the Kaplan-Meier product-limit method. Median and two-
sided confidence intervals for median duration of response will be computed and Kaplan-Meier plots 
of DoR will be presented. 
Time to Next Therapy (TNT) 
Time to next therapy will be defined as the time, in months, from Cycle 1 Day 1 to the date to next anti-
neoplastic therapy or death from any cause, whichever comes first. For subjects who neither start a new 


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anti-neoplastic therapy nor die, survival time will be censored at the date of their last available follow-
up assessment.  
Time to next therapy will be calculated using a log-rank test procedure. The TNT function will be 
estimated using the Kaplan-Meier product-limit method. Median and two-sided confidence intervals 
for median TNT will be computed. Kaplan-Meier plots of TNT will be presented. 
Overall Survival (OS) 
Overall survival is defined as the time, in months, from the first dose of therapy to the date of death 
from any cause. If a patient is not known to have died, survival time will be censored at the date of last 
contact (“last known date alive”). 
Overall survival will be estimated using the Kaplan-Meier product-limit method. Median and 
corresponding two-sided 95% confidence intervals will be computed. Kaplan-Meier plots of OS will be 
presented. 
10.4.4 Safety Analyses 
Safety analyses will be conducted on the Safety Set and will be reported. 
Adverse events 
AEs will be assessed according to the Common Terminology Criteria for AEs (CTCAE version 4.03). 
The incidence of AEs will be tabulated by MedDRA System Organ Class and Preferred Term. The 
incidence of AEs will also be summarized by system organ class, preferred term and severity (based on 
CTCAE grades). 
The same analysis will be repeated for SAEs regardless of drug relationship, for drug related SAEs, 
AEs with CTCAE grade 3 or 4 and for drug related AEs. AEs for which relationship to study drug is 
not specified will be considered treatment-related. 
Deaths reportable as SAEs will be listed by patient and tabulated by type of AE. 
Laboratory parameters 
Categorization of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 or according to normal ranges for 
those parameters without available CTCAE grading. The calculation of CTCAE grades will be purely 
based on the observed laboratory values, clinical assessments will not be taken into account. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 will not 
be used. 
For laboratory tests where grades are not defined by CTCAE v4.03, results will be graded by the 
low/normal/high (low and high) classifications based on laboratory normal ranges. 
The following by-treatment summaries will be generated separately for hematology, biochemistry and 
urinary laboratory tests: 
• 
Worst post-baseline CTCAE grade (regardless of the baseline status). Each patient will be 
counted only once for the worst grade observed post-baseline. 


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• 
Shift tables using CTCAE grades to compare baseline to the worst on-treatment value. 
• 
Shift tables using the low/normal/high/ (low and high) classification to compare baseline to the 
worst on-treatment value, for laboratory tests where CTCAE grades are not defined. 
Listings of all laboratory data with values flagged to show the corresponding CTCAE grades and the 
classifications relative to the laboratory normal ranges will also be generated. 
Other safety data 
ECGs, vital signs and ECOG PS will be listed and summarized. 
ECG 
• 
Shift table baseline to worst on-treatment result 
• 
Listing of ECG evaluations for all patients with at least one abnormality 
• 
Change from baseline QTcF 
Vital signs 
• 
Table with descriptive statistics at baseline, one or several post-baseline time points and change 
from baseline to this/these post-baseline time points 
ECOG PS 
• 
Shift tables comparing the baseline PS with the worst post-baseline result  
10.4.5 Baseline Descriptive Statistics 
All data about patient demographics and baseline characteristics will be summarized on the FAS, 
overall, by means of summary descriptive statistics. 
A complete description of patient disposition will be provided, specifying the number of enrolled 
patients, number of patients at each visit, completed and discontinued patients, and the reason for the 
discontinuation. 
The analysis populations will be described and the reasons for excluding the patient from any analysis 
set will be provided with the number of protocol violators per each criterion. 
Medical history data will be presented by MedDRA System Organ Class and Preferred Term. 
10.4.6 Treatments (study treatment, concomitant therapies) 
The Safety set will be used for the following analyses. 
Investigational treatment 
Duration of study treatment, cumulative dose, average daily dose, actual dose intensity and relative dose 
intensity of each of the components of study treatment will be summarized and for every 28-day cycle. 
The number of patients with dose changes/interruptions will be, along with the reasons for the dose 
change/interruptions. 
 


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Concomitant treatments 
Concomitant medications or procedures and significant non-drug therapies taken concurrently with the 
study treatment will be listed and summarized by WHO Anatomical Therapeutic Chemical (ATC) 
Class, Preferred Term. These summaries will include medications starting on or after the start of study 
treatment (defined as cycle 1 day 1) or medications starting prior to the start of study treatment and 
continuing after the start of study treatment. Any prior medication or significant non-drug therapy 
starting and ending prior to the start of study treatment will be listed. 
For the analyses of transfusions, only transfusions received after start of study treatment and up to 30 
days after last dose will be considered. The number of patients with transfusions and number of 
transfusions per patient will be analyzed. 
10.4.7 Planned Interim Analyses  
No formal interim analysis for efficacy is planned. An interim analysis for safety will be performed as 
described below. 
10.4.7.1 Safety Review 
The Sponsor Scientific Committee will perform an overall evaluation of the safety data when 19 patients 
(50%) have received at least 1 dose of daratumumab. If a safety signal is identified and the Sponsor 
Scientific Committee determines that the safety profile of the study treatment is unfavorable, the 
recruitment of the rest of the subjects will be interrupted and the study may be stopped due to safety 
concerns. In the event of such a study termination all current subjects that are receiving daratumumab 
treatment may receive subsequent alternative treatment outside of the study as per the investigator's 
judgement and routine practice. More details on the Interim Safety Review will be provided in the 
Statistical Analysis Plan for this study. 
10.4.7.2 Efficacy Review 
No formal efficacy review is planned. 
 
10.4.8 Additional Sub-group Analyses 
Additional sub-group analyses will be detailed in the Statistical Analysis Plan. 
10.4.9 Multiple Comparison/Multiplicity 
Unless stated otherwise, one-sided alpha level 0.025 will be considered. No alpha level adjustment will 
be carried out for primary and secondary endpoints. 
10.4.10 Exploratory Analyses 
Additional exploratory analyses will be detailed in the Statistical Analysis Plan. 
 
 


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10.5 Sample Size 
The calculations were based on previous data for daratumumab in patients with relapse or refractory 
myeloma. The median PFS with daratumumab treatment in the SIRIUS study was 5.6 months in patients 
who received daratumumab at the dose of 16 mg/kg.  
In order to test at α=0.05 the null hypothesis that the PFS is less than 3 months versus the alternative 
hypothesis that PFS is at least 5 months with a power of 90%, 34 patients must be  included in the study. 
This calculation assumes exponential survival curves, an accrual time of 18 months and a length of 
follow up period of 30 months. Assuming a drop-out rate of about 10%, 38 patients are needed.  
Sample size was computed by “SWOG One arm survival sample size and power” 
(www.swogstat.org/stat/public/one_survival.htm) 
10.6 Measures to Minimize Bias 
10.6.1 Enrolment/Masking procedures 
Patient numbering 
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned when the 
patient is first enrolled for screening and is retained as the primary identifier for the patient throughout 
his/her entire participation in the trial. The coordinating investigator or designated staff will assign the 
subject number. Once assigned, the Subject No. must not be reused for any other subject and the Subject 
No. for that individual must not be changed. If the patient fails to enroll for any reason, the reason will 
be entered into the Screening Disposition page 
10.6.2 Blinding - Unblinding 
Since this is an open-label study, the treatment will be open to patients, investigator staff, and personnel 
performing the assessments. 
11. 
Source Documents and Access to source data / documents  
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with ICH E6 and regulatory and institutional requirements for the protection of 
confidentiality of participants. Each site will permit authorized representatives of Regulatory Agencies 
to examine (and when permitted by applicable law, to copy) clinical records for the purposes of quality 
assurance reviews, audits, and evaluation of the study safety, progress, and data validity.  
Source data are all information, original records of clinical findings, observations, or other activities in 
a clinical trial necessary for the reconstruction and evaluation of the trial. Examples of these original 
documents and data records include, but are not limited to, hospital records, clinical and office charts, 
laboratory notes, memoranda, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and participant files and records kept at 
the pharmacy, at the laboratories, and medical-technical departments involved in the clinical trial.  
The eCRF will not be the only record of the patient’s participation in the study in order to ensure that 
anyone who accessed the patient’s medical record would have adequate knowledge that the patient is 
participating in the trial. 


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Inclusion/Exclusion Criteria Source Documentation Requirements 
The minimum source documentation requirements for the Inclusion/Exclusion criteria that specify a 
need for documented medical history (see Section 5.1 and Section 5.2) are the following: 
• 
Referral letter from treating physician 
• 
Complete history of medical notes at the site 
• 
Discharge summaries 
12. 
Quality Assurance and Quality Control  
Following written SOPs, the monitors will verify that the clinical trial is conducted and data are 
generated, documented (recorded), and reported in compliance with the protocol, GCP, and the 
applicable regulatory requirements [e.g., Good Laboratory Practices (GLP), Good Manufacturing 
Practices (GMP)].  
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory 
authorities. 
13. 
Ethics/Protection Human of Subjects  
13.1  Ethical standards 
This clinical study shall be implemented and reported in accordance with the ICH Guidelines for Good 
Clinical Practice, all applicable local regulations and with the ethical principles laid down in the 
Declaration of Helsinki. 
13.2 Institutional Review Board (IRB)/independent Ethics 
Committee (IEC) and competent authority 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the relevant IRB/EC and Competent Authority (CA) for review and approval. Approval of 
both the protocol and the consent form must be obtained before any participant is enrolled. Any 
amendment to the protocol will require review and approval by the IRB/EC and or CA before the 
changes are implemented to the study. All changes to the consent form will be IRB/EC and/or CA 
approved; a determination will be made regarding whether previously consented participants need to 
be re-consented.  
13.3 Informed Consent Process  
13.3.1Consent/Assent and other Informational Documents 
Provided to Participants 
Consent forms describing in detail the study agent, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to enrolment in the trial 
and before any study related procedure takes place.  
 
 


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13.3.2 Consent Procedures and Documentation 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Extensive discussion of risks and 
possible benefits of participation will be provided to the participants and their families. Consent forms 
will be IRB/EC-approved and the participant will be asked to read and review the document. The 
investigator will explain the research study to the participant and answer any questions that may arise. 
All participants will receive a verbal explanation in terms suited to their comprehension of the purposes, 
procedures, and potential risks of the study and of their rights as research participants. Participants will 
have the opportunity to carefully review the written consent form and ask questions prior to signing. 
The participants should have the opportunity to discuss the study with their surrogates or think about it 
prior to agreeing to participate. The participant will sign the informed consent document prior to any 
procedures being done specifically for the study. The participants may withdraw consent at any time 
throughout the course of the trial. A copy of the informed consent document will be given to the 
participants for their records. The rights and welfare of the participants will be protected by emphasizing 
to them that the quality of their medical care will not be adversely affected if they decline to participate 
in this study. 
13.4 Participant and data Confidentiality  
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor and their representatives. This confidentiality is extended to cover testing of biological samples 
and genetic tests in addition to the clinical information relating to participants. Therefore, the study 
protocol, documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized third party without 
prior written approval of the sponsor. 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB/EC or 
pharmaceutical company supplying study product(s) may inspect all documents and records required to 
be maintained by the investigator, including but not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for the participants in this study. The clinical study site will permit 
access to such records.  
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by local IRB/EC and Institutional regulations.  
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
not include the participant’s contact details or identifying information. Rather, individual participants 
and their research data will be identified by a unique study identification number. The study data entry 
and study management systems used by clinical sites will be secured and password protected. 
13.5 Insurance  
Prior to the start of the trial, the sponsor will ensure that adequate insurance for patients is in place 
covering losses due to death or injury resulting from the trial, in accordance with applicable laws and 
regulations in each country where the trial is conducted. In addition, the sponsor will ensure that 
adequate insurance is in place for both investigator(s) and sponsor to cover liability pertaining to death 
or injury resulting from the trial. The Investigator(s) will remain responsible towards the sponsor of any 
fault or misconduct regarding the performance of the Study. 


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14. Data Handling and Record Keeping  
14.1 Data Collection and Management Responsibilities  
• 
Data collection 
Designated investigator staff will enter the data required by the protocol into the eCRF using fully 
validated software that conforms to 21 CFR Part 11 requirements. Designated investigator site staff will 
not be given access to the Electronic Data Capture (EDC) system until they are trained.  
Web-based software will be used and no installation procedure is needed. Each site will be authorized 
by the Administrator to access the eCRF. Each site-qualified personnel will be allowed to access the 
eCRF by means of a ‘login mask’ requiring User ID and Password and may read, modify and update 
only the information he/she previously reported. Each page reports site code and patient code. 
On-line validation programs will check for data discrepancies and, by generating appropriate error 
messages, allow the data to be confirmed or corrected before transfer to the CRO working on behalf of 
the Sponsor. The Investigator will certify that the data entered into the eCRF is complete and accurate.  
After database lock, the investigator will receive a CD-ROM of patient data for archiving at the 
investigational site. 
• 
Database management and quality control 
The CRO working on behalf of the Sponsor will review the data entered into the eCRF by 
investigational staff for completeness and accuracy and instruct site personnel to make any necessary 
corrections or additions. The Data Manager will perform the cleaning session by reviewing the warning 
messages raised by on-line checks and by running post-entry checks by means of validation programs 
and data listings specific for the study. If clarifications are needed, the Data Manager will raise queries 
by means of data query forms through the web application. Designated investigator site staff will be 
required to respond to queries and the Data Manager will make the correction to the database according 
to the responses. 
Data collection and query flows as well as the on-line and off-line checks are detailed in the Data 
Management Plan and Data Validation documents. 
Concomitant medications and prior medications entered into the database will be coded using the World 
Health Organization (WHO) Drug Reference List, which employs the Anatomical Therapeutic 
Chemical (ATC) classification system. Medical history/current medical conditions and adverse events 
will be coded using the Medical dictionary for regulatory activities (MedDRA). 
Data about the study drug are tracked using the eCRF. The system is supplied by CRO, who also 
manages the database. 
The occurrence of any protocol deviations will be checked and the database will be locked and made 
available for data analysis after these actions have been completed and the database has been declared 
complete and accurate.  
14.2 Study Records Retention  
The investigator/institution should maintain the trial documents as specified in Essential Documents for 
the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable regulations and/or 


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guidelines. The investigator/institution should take measures to prevent accidental or premature 
destruction of these documents.  
Essential documents (written and electronic) should be retained for a period of not less than twenty five 
(25) years from the completion of the study unless the Sponsor provides written permission to dispose 
of them or, requires their retention for an additional period of time because of applicable laws, 
regulations and/or guidelines. The subjects’ medical files will be archived in accordance with the 
national laws. 
14.3 Protocol Deviations  
A protocol deviation is any noncompliance with the clinical trial protocol or GCP requirements. The 
noncompliance may be on the part of the participant, the investigator, or the study site staff. As a result 
of deviations, corrective actions are to be developed by the site and implemented promptly.  
These practices are consistent with ICH E6:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
It is the responsibility of the site to use continuous vigilance to identify and report deviations. All 
deviations must be addressed in study source documents. 
14.4 Publication and Data Sharing Policy 
This study will ensure that the public has access to the published results of the research.  
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted a 
clinical trials registration policy as a condition for publication. The ICMJE defines a clinical trial as any 
research project that prospectively assigns human subjects to intervention or concurrent comparison or 
control groups to study the cause-and-effect relationship between a medical intervention and a health 
outcome. Medical interventions include drugs, surgical procedures, devices, behavioral treatments, 
process-of-care changes, and the like. Health outcomes include any biomedical or health-related 
measures obtained in patients or participants, including pharmacokinetic measures and adverse events. 
The ICMJE policy requires that all clinical trials be registered in a public trials registry such as 
ClinicalTrials.gov, which is sponsored by the National Library of Medicine. Other biomedical journals 
are considering adopting similar policies. 
14.5 End of study report 
The sponsor will notify the accredited Ethics Committee and the Competent Authority for the end of 
study within a period of 90 days. The end of the study is defined as the last patient’s last visit. In case 
the study is ended prematurely, the sponsor will notify the accredited Ethics Committee and the 
Competent Authority within 15 days, including the reasons for the premature termination. 
The sponsor will submit the clinical study report with the final results of the study to the accredited 
Ethics Committee and the Competent Authority within one year after the end of study. 
 


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15. Study Administration  
15.1 Study Leadership 
The Scientific Committee will govern the conduct of the study and will be composed of the Sponsor 
Representative, the Co-ordinating Investigator and the Scientific Co-Ordinating Investigator. The 
Scientific Committee will meet in person at least annually. 
16. Conflict of Interest (COI) Policy  
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical. Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the trial. The study leadership has established policies 
and procedures for all study group members to disclose all conflicts of interest and will establish a 
mechanism for the management of all reported dualities of interest. Financial disclosures shall be 
provided by study personnel who are directly involved in the treatment or evaluation of patients at the 
site - prior to study start. 
 
 


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17. References   
1. 
Palumbo A, Anderson K. Multiple myeloma. N Engl J Med. 2011;364(11):1046-1060. 
2. 
Rajkumar SV, Harousseau JL, Durie B, et al. Consensus recommendations for the uniform 
reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 
2011;117(18):4691-4695. 
3. 
Laubach J, Garderet L, Mahindra A, et al. Management of relapsed multiple myeloma: 
recommendations of the International Myeloma Working Group. Leukemia. 2016;30(5):1005-1017. 
4. 
Phipps C, Chen Y, Gopalakrishnan S, Tan D. Daratumumab and its potential in the treatment 
of multiple myeloma: overview of the preclinical and clinical development. Ther Adv Hematol. 
2015;6(3):120-127. 
5. 
Overdijk MB, Jansen JH, Nederend M, et al. The Therapeutic CD38 Monoclonal Antibody 
Daratumumab Induces Programmed Cell Death via Fcgamma Receptor-Mediated Cross-Linking. J 
Immunol. 2016;197(3):807-813. 
6. 
Overdijk MB, Verploegen S, Ortiz Buijsse A, et al. Crosstalk between human IgG isotypes 
and murine effector cells. J Immunol. 2012;189(7):3430-3438. 
7. 
Lonial S, Weiss BM, Usmani SZ, et al. Daratumumab monotherapy in patients with 
treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 
2016;387(10027):1551-1560. 
8. 
Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with Daratumumab 
Monotherapy in Multiple Myeloma. N Engl J Med. 2015;373(13):1207-1219. 
9. 
Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, Lenalidomide, and Dexamethasone 
for Multiple Myeloma. N Engl J Med. 2016;375(14):1319-1331. 
10. 
Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, Bortezomib, and 
Dexamethasone for Multiple Myeloma. N Engl J Med. 2016;375(8):754-766. 
11. 
Chari A, Lonial S, Suvannasankha A, et al. Open-Label, Multicenter, Phase 1b Study of 
Daratumumab in Combination with Pomalidomide and Dexamethasone in Patients with at Least 2 
Lines of Prior Therapy and Relapsed or Relapsed and Refractory Multiple Myeloma. Blood. 
2015;126(23):508-508. 
12. 
Dimopoulos MA, Terpos E, Chanan-Khan A, et al. Renal impairment in patients with 
multiple myeloma: a consensus statement on behalf of the International Myeloma Working Group. J 
Clin Oncol. 2010;28(33):4976-4984. 
13. 
Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group 
updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538-548. 
14. 
Shi H, Zhang W, Li X, Ren H, Pan X, Chen N. Application of RIFLE criteria in patients with 
multiple myeloma with acute kidney injury: a 15-year retrospective, single center, cohort study. Leuk 
Lymphoma. 2014;55(5):1076-1082. 


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15. 
Dimopoulos MA, Sonneveld P, Leung N, et al. International Myeloma Working Group 
Recommendations for the Diagnosis and Management of Myeloma-Related Renal Impairment. J Clin 
Oncol. 2016. 
16. 
Ludwig H, Adam Z, Hajek R, et al. Light chain-induced acute renal failure can be reversed by 
bortezomib-doxorubicin-dexamethasone in multiple myeloma: results of a phase II study. J Clin 
Oncol. 2010;28(30):4635-4641. 
17. 
Dimopoulos MA, Roussou M, Gkotzamanidou M, et al. The role of novel agents on the 
reversibility of renal impairment in newly diagnosed symptomatic patients with multiple myeloma. 
Leukemia. 2013;27(2):423-429. 
18. 
Clemens PL, Yan X, Lokhorst HM, et al. Pharmacokinetics of Daratumumab Following 
Intravenous Infusion in Relapsed or Refractory Multiple Myeloma After Prior Proteasome Inhibitor 
and Immunomodulatory Drug Treatment. Clin Pharmacokinet. 2016. 
19. 
Usmani SZ, Weiss BM, Plesner T, et al. Clinical efficacy of daratumumab monotherapy in 
patients with heavily pretreated relapsed or refractory multiple myeloma. Blood. 2016;128(1):37-44. 
20. 
McCudden C, Axel AE, Slaets D, et al. Monitoring multiple myeloma patients treated with 
daratumumab: teasing out monoclonal antibody interference. Clin Chem Lab Med. 2016;54(6):1095-
1104. 
21. 
Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration 
rate. Ann Intern Med. 2009;150(9):604-612. 
22. 
Chapuy CI, Aguad MD, Nicholson RT, et al. International validation of a dithiothreitol 
(DTT)-based method to resolve the daratumumab interference with blood compatibility testing. 
Transfusion. 2016;56(12):2964-2972. 
23. 
Chapuy CI, Nicholson RT, Aguad MD, et al. Resolving the daratumumab interference with 
blood compatibility testing. Transfusion. 2015;55(6 Pt 2):1545-1554. 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX 
 
Appendix 1 – Preparation of Daratumumab 
 
This medicinal product is for single-use only. 
Prepare the solution for infusion using aseptic technique as follows: 
• 
Calculate the dose (mg), total volume (mL) of DARZALEX solution required and the number of 
DARZALEX vials needed based on patient weight. 
• 
Check that the DARZALEX solution is colorless to yellow. Do not use if opaque particles, 
discoloration or other foreign particles are present. 
• 
Using aseptic technique, remove a volume of 0.9% Sodium Chloride from the infusion 
bag/container that is equal to the required volume of DARZALEX solution. 
• 
Withdraw the necessary amount of DARZALEX solution and dilute to the appropriate volume by 
adding to an infusion bag/container containing 0.9% Sodium Chloride. Infusion bags/containers 
must be made of polyvinylchloride (PVC), polypropylene (PP), 13 polyethylene (PE) or polyolefin 
blend (PP+PE). Dilute under appropriate aseptic conditions. Discard any unused portion left in the 
vial. 
• 
Gently invert the bag/container to mix the solution. Do not shake. 
• 
Visually inspect parenteral medicinal products for particulate matter and discoloration prior to 
administration. The diluted solution may develop very small, translucent to white proteinaceous 
particles, as daratumumab is a protein. Do not use if visibly opaque particles, discoloration or 
foreign particles are observed. 
• 
Since DARZALEX does not contain a preservative, diluted solutions should be administered 
within 15 hours (including infusion time) at room temperature (15°C - 25°C) and in room light. 
• 
If not used immediately, the diluted solution can be stored prior to administration for up to 24 hours 
at refrigerated conditions (2°C - 8°C) and protected from light. Do not freeze. 
• 
Administer the diluted solution by intravenous infusion using an infusion set fitted with a flow 
regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) 
filter (pore size 0.22 or 0.2 micrometer). Polyurethane (PU), polybutadiene (PBD), PVC, PP or PE 
administration sets must be used. 
• 
Do not infuse DARZALEX concomitantly in the same intravenous line with other agents. 
• 
Do not store any unused portion of the infusion solution for reuse. Any unused product or waste 
material should be disposed of in accordance with local requirements. 
 
 
 
 
 
 


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Appendix 2 – Guidelines for Administrating Daratumumab 
 
Following dilution, daratumumab infusion should be intravenously administered at the appropriate 
initial infusion rate, as presented in the table below. Incremental escalation of the infusion rate should 
be considered only if the previous infusion of daratumumab was well tolerated. 
Infusion rates for daratumumab 
 
Dilution 
volume 
Initial infusion rate 
(first hour) 
Increments of infusion 
ratea 
Maximum infusion 
rate 
First 
infusion 
1,000mL 
50 mL/hour 
50 mL/hour every hour 
200 mL/hour 
Second 
infusion b 
500 mL 
50 mL/hour 
50 mL/hour every hour 
200 mL/hour 
Subsequent 
infusionsc 
500 mL 
100 mL/hour 
50 mL/hour every hour 
200 mL/hour 
a  Incremental escalation of the infusion rate should be considered only in the absence of infusion reactions. 
b  A dilution volume of 500 mL should be used only if there were no ≥ Grade 1 IRRs during the first 3 hours of the first 
infusion. Otherwise, continue to use a dilution volume of 1000 mL and instructions for the first infusion. 
 c A modified initial rate for subsequent infusions (i.e. third infusion onwards) should only be used only if there were no 
≥ Grade 1 IRRs during a final infusion rate of ≥ 100 mL/hr in the first two infusions. Otherwise, use instructions for the second 
infusion. 
 
Management of infusion-related reactions 
Pre-infusion medications should be administered to reduce the risk of infusion-related reactions (IRRs) 
prior to treatment with DARZALEX. 
For IRRs of any grade/severity, immediately interrupt the DARZALEX infusion and manage 
symptoms. 
Management of IRRs may further require reduction in the rate of infusion, or treatment discontinuation 
of DARZALEX as outlined below. 
• 
Grade 1-2 (mild to moderate): Once the patient’s condition is stable, the infusion should be 
resumed at no more than half the rate at which the IRR occurred. If the patient does not 
experience any further IRR symptoms, infusion rate escalation may be resumed at increments 
and intervals as clinically appropriate up to a maximum rate of 200 mL/hour (Table above). 
• 
Grade 3 (severe): If the intensity of the IRR decreases to Grade 2 or lower, restarting of the 
infusion may be considered at no more than half the rate at which the reaction occurred. If the 
patient does not experience additional symptoms, infusion rate escalation may be resumed at 
increments and intervals as appropriate (Table above). The procedure above should be repeated 
in the event of recurrence of Grade 3 symptoms. Permanently discontinue DARZALEX if the 
patient experiences a ≥ Grade 3 infusion-related symptom at the subsequent infusion. 
• 
Grade 4 (life threatening): Permanently discontinue DARZALEX treatment. 
 
Recommended concomitant medications 
Pre-infusion medication 
Pre-infusion medications should be administered to reduce the risk of IRRs to all patients approximately 
1-3 hour prior to every infusion of DARZALEX as follows: 
• 
intravenous corticosteroid (dexamethasone 20 mg, methylprednisolone 100 mg , or equivalent 
dose of an intermediate-acting or long-acting corticosteroid) ) plus 
• 
oral antipyretics (paracetamol 650 to 1,000 mg), plus 
• 
oral or intravenous antihistamine (diphenhydramine 25 to 50 mg or equivalent). 
 
Post-infusion medication 
For the prevention of delayed IRRs, oral corticosteroid (20 mg methylprednisolone or equivalent dose 
of a corticosteroid in accordance with local standards) should be administered on each of the two days 
following all infusions (beginning the day after the infusion). 
Additionally, for patients with a history of obstructive pulmonary disorder, the use of post-infusion 
medications including short and long acting bronchodilators, and inhaled corticosteroids should be 


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considered. Following the first four infusions, if the patient experiences no major IRRs, these inhaled 
post-infusion medications may be discontinued at the discretion of the physician. 
 
Prophylaxis for herpes zoster virus reactivation 
Anti-viral prophylaxis should be considered for the prevention of herpes zoster virus reactivation. 
 
Infection Prophylaxis: Prophylactic use of antibiotics is highly recommended due to the 
susceptibility of multiple myeloma patients to infections. Prophylactic administration of levofloxacin 
(500 mg P.O. daily; dose adjusted for renal function) during the first 3 cycles of treatment is 
recommended as it has shown to significantly reduce febrile episodes and deaths without increasing 
healthcare associated infections or carriage of key nosocomial pathogens. 
HBV prophylaxis: Primary antiviral prophylaxis for HBV reactivation is permitted as per local 
standard of care.  Please refer to Section 7.1.4 for more details about the management of HBV 
reactivation 
 
Source: Drayson, Mark T et al "Tackling Early Morbidity and Mortality in Myeloma (TEAMM): Assessing the 
Benefit of Antibiotic Prophylaxis and Its Effect on Healthcare Associated Infections in 977 Patients." Blood 
130.Suppl 1 (2017):903 
 
 


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Appendix 3a – The International Staging System (ISS) for Multiple 
Myeloma 
 
Stage 
Criteria 
Median Survival 
(Months) 
Stage 1 
Serum β 2-microglobulin < 3.5 mg/L 
Serum albumin ≥ 3.5 g/dL 
62 
Stage 2 
Not stage I or III 
(There are two categories for stage II) 
 
serum β2-microglobulin < 3.5 mg/L but serum albumin < 
3.5 g/dL OR 
 
β2-microglobulin 3.5 to < 5.5 mg/L irrespective of the 
serum albumin level 
44 
Stage 3 
Serum β2-microglobulin ≥ 5.5 mg/L 
29 
Greipp PR, San Miguel JF, Brian GM et al. International Staging System for Multiple Myeloma. J Clin 
Oncology 2005 23:3412-3420. 
 
 
Appendix 3b – The Revised International Staging System (ISS) for 
Multiple Myeloma 
 
Stage 
Criteria 
Median Survival 
(Months) 
Stage 1 
ISS stage I and standard-risk CA by iFISH  
and normal LDH 
Not reached 
Stage 2 
Not R-ISS stage I or III 
83 
Stage 3 
ISS stage III and either high-risk CA by iFISH 
or high LDH 
43 
Abbreviations: ISS: International Staging System, CA: chromosomal abnormalities, LDH: lactate 
dehydrogenase; R-ISS, revised International Staging System. 
 
Chromosomal abnormalities detected by iFISH:  
High risk: del(17p), and/or translocation t(4;14), and/or translocation t(14;16) 
Standard risk: No high-risk CA 
 
LDH: 
Normal: Serum LDH < the upper limit of normal 
High: Serum LDH > the upper limit of normal 
 
Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised International Staging System for Multiple 
Myeloma: A Report From International Myeloma Working Group. J Clin Oncology 2015 33(26):  
2863–2869 
 
 


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Appendix 4 – Modified International Myeloma Working Group 
(IMWG) Uniform Response Criteria for Multiple Myeloma 
 
Response 
IMWG criteria 
Stringent 
complete response 
(sCR) 
CR as defined below plus normal FLC ratio and absence of clonal cells in bone 
marrow1 by immunohistochemistry or immunofluorescence.2 
Complete 
response (CR) 
Negative immunofixation on serum and urine and disappearance of any soft 
tissue plasmacytomas and < 5% plasma cells in bone marrow.1 
Very good partial 
response (VGPR) 
Serum and urine M-protein detectable by immunofixation but not on 
electrophoresis or > 90% reduction in serum M-protein plus urine M-protein 
level < 100 mg/24 h 
Partial response 
(PR) 
> 50% reduction of serum M-protein and reduction in 24 hours urinary M-
protein by >90% or to < 200 mg/24 h. 
If serum and urine M-protein are unmeasurable,3 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 not measurable, and serum free light assay is 
also not measureable, > 50% reduction in plasma cells is required in place of M-
protein, provided baseline bone marrow plasma cell percentage was > 30%. 
In addition to the above listed criteria, if present at baseline, a > 50% reduction 
in the size of soft tissue plasmacytomas is also required. 
Minor (Minimal) 
Response (MR) 
25-49% reduction of serum M-protein and reduction in 24-hour urine M-protein 
by 50-89%, which still exceeds 200 mg per 24 hours. In addition, if present at 
baseline, 25-49% reduction in the size of soft tissue plasmacytomas is also 
required. No increase in the size or number of lytic bone lesions (development 
of compression fracture does not exclude response). 
No change/Stable 
disease (SD) 
Not meeting criteria for CR, VGPR, PR, or progressive disease. 
Progressive 
disease (PD)3 
Any of the following: 
• 
Increase of > 25% from lowest response value in any one or more of the 
following: 
o 
Serum M-component and/or (the absolute increase must be > 0.5 g/dL)4  
o 
Urine M-component and/or (the absolute increase must be > 200 mg/24 
h) 
o 
Only in patients without measurable serum and urine M-protein levels; 
the difference between involved and uninvolved FLC levels. The 
absolute increase must be > 10 mg/dL 
o 
Bone marrow plasma cell percentage; the absolute percentage must be 
> 10%5 
• 
Definite development of new bone lesions or soft tissue plasmacytomas or 
definite increase in the size of existing bone lesions or soft tissue 
plasmacytomas (≥50% increase from nadir in SPD7 of >1 lesion, or ≥50% 
increase in the longest diameter of a previous lesion >1 cm in the short axis). 
• 
Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL or 
2.87 mmol/L) that can be attributed solely to the plasma cell proliferative 
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Relapse 
Clinical relapse requires one or more of: 
Direct indicators of increasing disease and/or end organ dysfunction (CRAB 
features).4 It is not used in calculation of time to progression or progression-
free survival but is listed here as something that can be reported optionally or 
for use in clinical practice 
• 
Development of new soft tissue plasmacytomas or bone lesions 
• 
Definite increase in the size of existing plasmacytomas or bone lesions. 
A definite increase is defined as a 50% (and at least 1 cm) increase as 
measured serially by the sum of the products of the cross-diameters of 
the measurable lesion 
• 
Hypercalcemia (> 11.5 mg/dL) [2.87 mmol/L] 
• 
Decrease in hemoglobin of > 2 g/dL [1.24 mmol/L] 
• 
Rise in serum creatinine by 2 mg/dL or more [177 μmol/L or more] 
Relapse from CR3 
(To be used only if 
the 
end 
point 
studied is DFS)6  
Any one or more of the following: 
• 
Reappearance of serum or urine M-protein by immunofixation or 
electrophoresis 
• 
Development of > 5% plasma cells in the bone marrow5 
• 
Appearance of any other sign of progression (i.e., new plasmacytoma, 
lytic bone lesion, or hypercalcemia) 
Note: A 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. 
1 Confirmation with repeat bone marrow biopsy not needed. 
2 Presence/absence of clonal cells is based upon the kappa/lambda ratio. An abnormal kappa/lambda 
ratio by immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells 
for analysis. An abnormal ratio reflecting presence of an abnormal clone is kappa/lambda of > 4:1 or < 
1:2. 
3 All relapse categories require two consecutive assessments made at any time before classification as 
relapse or disease progression and/or the institution of any new therapy. In the IMWG criteria, CR 
patients must also meet the criteria for progressive disease shown here to be classified as progressive 
disease for the purposes of calculating time to progression and progression-free survival. The definitions 
of relapse, clinical relapse and relapse from CR are not to be used in calculation of time to progression 
or progression-free survival. 
4 For progressive disease, serum M-component increases of ≥1 gm/dL are sufficient to define relapse if 
starting M-component is ≥5 g/dL. 
5 Relapse from CR has the 5% cut-off versus 10% for other categories of relapse. 
6 For purposes of calculating time to progression and progression-free survival, CR patients should also 
be evaluated using criteria listed above for progressive disease. 
7 SPD = sum of the products of the maximal perpendicular diameters of measured lesions 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 5 – IMWG Renal Response Criteria and simplified renal 
response criteria  
 
Criteria for the Definition of Renal Response to Antimyeloma Therapy 
Renal Response 
 
Baseline eGFR, 
mL/min/1.73 m2* 
Best eGFR  Response 
mL/min/1.73 m2 
Complete response  
 
<50 
≥60 
Partial response  
 
< 15 
30-59 
Minor response  
<15 
15-29 
15-29 
30-59 
Abbreviations: CrCl, creatinine clearance; eGFR, estimate glomerular filtration rate. 
*eGFR is based on the Modification of Diet in Renal Disease formula, or the Chronic Kidney 
Disease Epidemiology Collaboration equation. 
 
 
Simplified criteria Renal Response criteria 
 
• 
Patients who presented with stage 5 RI (eGFR < 15 ml/min/1.73 m2)should double their eGFR 
and improve to at least stage 4  
 
• 
Patients with stage 4 (eGFR 15-29 ml/min/1.73 m2), increase their eGFR by at least 50% and 
improve to at least stage 3 (GFR ≥ 60 mL/min/1.73 m2)  
 
• 
Patients with stage 3 (eGFR 30-59 ml/min/1.73 m2), increase their eGFR by at least 50% and 
improve to at least stage 2 (GFR ≥ 60 mL/min/1.73 m2)  
 
 


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Appendix 6 – ECOG Performance Status Scale 
 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light housework, office 
work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair. 
5 
Dead 
 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-
655, 1982. 
Credit to: the Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 7 - Reference Charts for the Classification of Asthma  
 
Adapted from 2007 NHLBI Guidelines for the Diagnosis and Treatment of Asthma Expert Panel 
Report 3) 
Components of SEVERITY 
Classification of Asthma Severity (Youths  ≥ 12 years of age and adults) 
Intermittent 
Persistent 
Mild 
Moderate 
Severe 
Impairment 
 
Normal 
FEV1/FVC: 
 
8-19 yr       85% 
20-39 yr.    80% 
40-59 yr.    75% 
60-80 yr     70% 
Symptoms 
≤ 2 days/week 
> 2 days/week 
but not daily 
Daily 
Throughout the 
day 
Nighttime 
awakenings 
≤ 2x/month 
3–4x/month 
> 1x/week but not 
nightly 
Often 7x/week 
Short-acting 
beta2-agonist 
use for symptom 
control  
≤ 2 days/week 
> 2 days/week 
but not > 
1x/day 
Daily 
Several times a 
day 
Interference with 
normal activity 
None  
Minor 
limitation 
Some limitation  
Extremely 
limited 
Lung function 
• Normal 
FEV1 
between 
exacerbatio
ns 
• FEV1 > 
80% 
predicted 
• FEV1/FVC 
normal 
• 
FEV1 
≥80% 
predicted 
• 
FEV1/FV
C normal 
• 
60%<FEV1<80% 
predicted 
• 
FEV1/FVC 
reduced >5% 
• 
FEV1<60% 
predicted 
• 
FEV1/FVC 
reduced 
>5% 
Risk 
Exacerbation 
requiring oral 
systemic 
corticosteroids 
0-1x/year  
≥2x/year  
Consider severity and interval since last exacerbation. Frequency and severity 
may fluctuate over time for patients in any severity category 
Relative annual risk of exacerbations may be related to FEV1 
 
 
 


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Appendix 8 – JSH Guidelines for the Management of Hepatitis B 
Virus Infection 
 
Figure: Guidelines for the prevention of hepatitis B virus reactivation in patients receiving immunosuppressive 
therapy or chemotherapy. 
Addendum: Caution is required when administering powerful chemotherapeutic agents for 
hematological malignancies, as during or following completion of treatment some HBsAg positive or 
negative patients will develop hepatitis B due to reactivation of HBV, and some of these will go on to 
suffer fulminant hepatitis. Consideration should also be given to the possibility of HBV reactivation in 
association with standard chemotherapy for hematological malignancies or solid cancers, and 
immunosuppressive therapy for autoimmune diseases, such as rheumatic and collagen diseases. The 
incidences of HBV reactivation, hepatitis and fulminant hepatitis associated with standard 
chemotherapy and immunosuppressive therapy are not known, and there is a lack of evidence on which 
to base guidelines. Furthermore, prevention of fulminant hepatitis is not guaranteed with NA therapy. 
 
NB 1) HBV carriers and patients with resolved hepatitis B should be screened prior to 
immunosuppressive therapy or chemotherapy. First HBsAg testing should be performed to determine 
whether they are an HBV carrier. HBsAg negative patients should be tested for anti-HBc antibody and 
anti-HBs antibody, to conﬁrm past infection. Highly sensitive testing methods should be used for 
measurements of HBsAg, anti-HBc antibody and anti-HBs antibody. 
NB 2) A hepatologist should be consulted concerning HBsAg positive patients. A hepatologist should 
preferably be consulted for all patients administered NAs. 
NB 3) In some patients undergoing retreatment who did not undergo testing for anti-HBc or HBs 
antibody at the time of their initial chemotherapy, and in patients who have already commenced 


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immunosuppressive therapy, antibody titers may be low, in which case measurement of HBV DNA 
levels is preferable. 
NB 4) Patients with resolved HBV infection should be screened using real-time PCR measurement of 
HBV DNA levels. 
 
NB 5) 
a. Caution is required when treating patients with resolved HBV infection with rituximab + 
corticosteroid or ﬂudarabine chemotherapy, or when they undergo hematopoietic stem cell 
transplantation, as these patients are at high risk of HBV reactivation. HBV DNA levels should 
be monitored on a monthly basis during treatment, and for at least 12 months afterward. Long-
term monitoring is required for hematopoietic stem cell transplant recipients. 
b. Although the incidence is low, there is a risk of HBV reactivation with standard 
chemotherapy regimens. HBV DNA levels should be measured every 1–3 months, with the 
interval and duration tailored to the individual therapy regimen. It is best to err on the side of 
caution with patients undergoing treatment for hematological malignancies. 
c. There is also a risk of HBV reactivation associated with immunosuppressive therapy using 
corticosteroids, 
immunosuppressant 
agents, 
or 
molecular 
targeted 
therapy 
with 
immunosuppressant or immunomodulator activity. HBV DNA levels should be monitored on 
a monthly basis in patients on immunosuppressive therapy for at least 6 months after 
commencement or alteration (including cessation) of treatment. After 6 months, the interval 
and duration should be tailored to the individual therapy regimen. 
NB 6) Administration should be commenced as soon as possible, before commencement of 
immunosuppressive therapy or chemotherapy. 
NB 7) Administration should be commenced as soon as the HBV DNA levels exceed 2.1 log copies/mL, 
during or after immunosuppressive therapy or chemotherapy. If this occurs during treatment, it is 
preferable to consult with a hepatologist, and not immediately cease the immunosuppressant or 
antineoplastic agent with immunosuppressive activity. 
NB 8) Entecavir is the recommended NA. 
NB 9) Cessation of NA therapy can be considered if the following criteria are met. 
In patients who were HBsAg positive at the time of screening, when the criteria for cessation of NA 
therapy in cases with chronic hepatitis B are met. 
In patients who were anti-HBc antibody and/or anti-HBs antibody positive at the time of screening: 
1 NA therapy has been continued for at least 12 months after completion of immunosuppressive 
therapy or chemotherapy. 
2 ALT (GPT) levels have been normalized during this period (excluding causes of elevated 
ALT levels other than HBV). 
3 negative conversion of HBV DNA has occurred during this period. 


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NB 10) Patients should be carefully monitored, including measurement of HBV DNA levels, for at least 
12 months following completion of NA therapy. Monitoring methods depend on package inserts of each 
NA. NA therapy should be immediately resumed if HBV-DNA levels exceed 2.1 log copies/mL during 
monitoring period 
 
Source: Hepatology Research 2014;44(Suppl. 1): 1–58 
 
 


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Appendix 9 – Signatures 
 
I. 
SPONSOR’S SIGNATURE  
Study title: Efficacy of Daratumumab in Patients with Relapsed/Refractory Myeloma with Renal 
Impairment   
Protocol No: EAE-2017/MM02 
Version: 5.0 
Date: 08 June 2020 
 
Sponsor representative: 
 
 
 
Signature: 
 
 
 
………………..………………………….. 
 
 
 
 
 …………………… 
 
Prof. Meletios Athanasios Dimopoulos 
Hellenic Society of Hematology 27 Kifisias 
Ave, 11523, Athens 
 
Date (DD Mmm YYYY) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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II. CO-ORDINATING INVESTIGATORS SIGNATURE 
Study title: Efficacy of Daratumumab in Patients with Relapsed/Refractory Myeloma with Renal 
Impairment   
Protocol No: EAE-2017/MM02 
Version: 5.0 
Date: 08 June 2020 
 
I have read all pages of this clinical study protocol and I agree that it contains all the information 
required to conduct this study. 
 
Signature: 
 
 
………………..………………………….. 
 
 
 
 …………………… 
 
Associate Prof. Efstathios Kastritis  
Department of Clinical Therapeutics,  
National and Kapodistrian University of Athens 
School of Medicine, Athens - Greece 
 
Date (DD Mmm YYYY) 
 
 
 
 


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III. SCIENTIFIC CO-ORDINATING INVESTIGATORS SIGNATURE 
Study title: Efficacy of Daratumumab in Patients with Relapsed/Refractory Myeloma with Renal 
Impairment   
Protocol No: EAE-2017/MM02 
Version: 5.0 
Date: 08 June 2020 
 
I have read all pages of this clinical study protocol and I agree that it contains all the information 
required to conduct this study. 
 
Signature: 
 
 
………………..………………………….. 
 
 
 
 …………………… 
 
Prof. Meletios Athanasios Dimopoulos 
Department of Clinical Therapeutics,  
National and Kapodistrian University of Athens 
School of Medicine, Athens - Greece 
 
 
Date (DD Mmm YYYY) 
 
 
 
 
 


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IV. NATIONAL  CO-ORDINATING INVESTIGATOR SIGNATURE 
Study title: Efficacy of Daratumumab in Patients with Relapsed/Refractory Myeloma with Renal 
Impairment   
Protocol No: EAE-2017/MM02 
Version: 5.0 
Date: 08 June 2020 
 
I have read all pages of this clinical study protocol and I agree that it contains all the information 
required to conduct this study. 
 
Signature: 
 
 
………………..………………………….. 
 
 
 
 …………………… 
 
Associate Prof. Efstathios Kastritis  
Department of Clinical Therapeutics,  
National and Kapodistrian University of Athens 
School of Medicine, Athens - Greece 
 
Date (DD Mmm YYYY) 
 
 
 
 


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V. PRINCIPAL INVESTIGATOR SIGNATURE 
Study title: Efficacy of Daratumumab in Patients with Relapsed/Refractory Myeloma with Renal 
Impairment   
Protocol No: EAE-2017/MM02 
Version: 5.0 
Date: 08 June 2020 
 
I have read all pages of this clinical study protocol and agree to conduct the study as outlined in the 
protocol and to comply with all the terms and conditions set out therein. I confirm that I will conduct 
the study in accordance with ICH GCP guidelines and applicable local regulations. I will also ensure 
that Sub-investigator(s) and other relevant members of my staff have access to copies of this protocol 
and the ICH GCP guidelines to enable them to work in accordance with the provisions of these 
documents. 
Principal Investigator: 
 
 
Signature: 
 
<Insert name and qualifications of the Investigator> 
 
Printed Name: 
Date (DD Mmm YYYY) 
 
Address: 
 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 


Health Data Specialists 
DARE  ( ΕΑΕ-2017/ΜΜ02  )- Statistical Analysis Plan 
Version:  1.0 EN 
Author: GC, Reviewer: MS, Quality Assurance: GK  
Date: 02-02-2018 
 
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Document Approvals 
Role 
Name/Title/Location© 
Signature 
Date 
 
 
 
 
Chief Scientific Officer 
George Kouvatseas 
Partner-Chief Scientific Officer 
HeaDS Ltd. 
 
 


Health Data Specialists 
DARE  ( ΕΑΕ-2017/ΜΜ02  )- Statistical Analysis Plan 
Version:  1.0 EN 
Author: GC, Reviewer: MS, Quality Assurance: GK  
Date: 02-02-2018 
 
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Document History 
Version 
Date 
Comments 
Revised section(s) if applicable 
1.0 
02-02-2018 
First Version 
 
 
 
Distribution List 
Company 
Name 
E-Mail Address 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table of Contents 
  
1. 
Scope of the Document .......................................................................................................................................................... 8 
2. 
General Analysis Framework ................................................................................................................................................ 8 
2.1 
Databases ............................................................................................................................................................................... 8 
3. 
Intended Users ....................................................................................................................................................................... 8 
4. 
Short Trial Description .......................................................................................................................................................... 9 
5. 
SAP Development Parameters ............................................................................................................................................. 12 
5.1.1 
SAP Development Team ..................................................................................................................................................... 12 
5.1.2 
SAP Life Cycle Responsibility Task Matrix ....................................................................................................................... 12 
6. 
Study Objectives .................................................................................................................................................................. 12 
6.1.1 
Study Population & Number of participating Sites ............................................................................................................. 12 
6.1.2 
Study Drug and Dosing ....................................................................................................................................................... 13 
6.2 
Study Design ....................................................................................................................................................................... 13 
6.3 
Study Flowchart ................................................................................................................................................................... 14 
6.4 
Study Primary and Secondary Objectives............................................................................................................................ 16 
6.4.1 
Study Primary and Secondary Endpoints ............................................................................................................................ 16 
6.4.2 
Sample Size and Power Calculations ................................................................................................................................... 16 
6.5 
Population of Analysis Sets ................................................................................................................................................. 17 
6.5.1 
Full Analysis Set (FAS) ....................................................................................................................................................... 17 
6.5.2 
Per Protocol Analysis Set (PPS) .......................................................................................................................................... 17 
6.5.3 
Safety Set ............................................................................................................................................................................. 17 
6.5.4 
Subgroups ............................................................................................................................................................................ 17 
6.5.5 
Interim Analysis .................................................................................................................................................................. 18 
6.6 
Statistical Methodology ....................................................................................................................................................... 18 
6.6.1 
Methods of Statistical Analyses ........................................................................................................................................... 18 
6.6.1.1 
Patient-Reported Outcome (PRO) Measurements ............................................................................................................ 19 
6.6.1.2 
Statistical tests .................................................................................................................................................................. 19 
6.6.1.3 
Primary Endpoint Analysis ............................................................................................................................................... 20 
6.6.1.4 
Secondary Endpoint Analysis ........................................................................................................................................... 20 


Health Data Specialists 
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Date: 02-02-2018 
 
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6.6.1.5 
Safety Analysis ................................................................................................................................................................. 21 
6.6.1.6 
Treatments (study treatment, concomitant therapies) ....................................................................................................... 22 
6.6.1.7 
Planned Data Displays ...................................................................................................................................................... 23 
6.7 
References ........................................................................................................................................................................... 25 
APPENDIX 1 ..................................................................................................................................................................................... 26 
APPENDIX 2 ..................................................................................................................................................................................... 27 
 
 
List of Tables 
 
Table 1 Schedule of Events ............................................................................................................................................................... 14 
Table 2: Descriptive Analysis of Continuous Variables ................................................................................................................... 23 
Table 3: Descriptive Analysis of Categorical Variables ................................................................................................................... 24 
Table 4. Test statistics for categorical variables ............................................................................................................................... 24 
Table 5. Test statistics for continuous variables – T-test/Mann-Whitney ......................................................................................... 24 
Table 6. Modified International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma .............. 26 
Table 7. IMWG Renal Response Criteria ......................................................................................................................................... 27 
Table 8. Simplified renal response criteria ....................................................................................................................................... 28 
 
 
List of Figures 
 
No table of figures entries found.


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 General Info 
 
 Trial Name 
DARE  
 Study Code 
 ΕΑΕ-2017/ΜΜ02   
 Document Name 
STATISTICAL ANALYSIS PLAN 
 
 Production 
 Date 
 Responsible 
 
02-02-2018 
George Cheliotis 
 Last Mutation 
 Date 
 Responsible 
 
Not Applicable 
 
 Current Version 
Vers. 1.0 
 Status 
Final Document 
 Number of Pages 
 28 
 Owner Organization 
 
 Producer Organization 
HeaDS 
 Goal/Contents 
Description of the listings, tables, graphics and statistical analyses of the 
study 
 


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List of Abbreviations 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Chemical 
CI  
Confidence interval  
CKD 
Chronic Kidney Disease 
CSR  
Clinical Study Report  
CTCAE 
Common Terminology Criteria for Adverse Events 
DaraD 
Daratumumab with Dexamethasone 
DMP 
Data Management Plan 
DoR 
Duration of Response 
eCRF 
electronic Case Report Form  
EDC 
Electronic Data Capture 
EoT 
End of Treatment  
FAS 
Full Analysis Set 
IMWG 
 International Myeloma Working Group 
IV 
Intra-Venus 
MM 
Multiple Myeloma  
M-protein 
Serum monoclonal paraprotein 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PFS 
Progression Free Survival 
PPS 
Per Protocol Set 
PRO 
Patient Reported Outcome 
PRRenal 
Partial Renal Response 
PT 
Preferred Term 
QW 
weekly intervals 
Q2W 
every 2 weeks 
Q4W 
every 4 weeks 
RI 
Renal Impairment  
RRR 
Renal Response Rate 
RRMM 
Replaced/Refractory Multiple  Myeloma 
SAE  
Serious Adverse Event  
SAP 
Statistical Analysis Plan 


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SD  
Standard Deviation  
SOC 
System Organ Class 
SOP  
Standard Operating Procedure  
TNT 
Time to Next Therapy  
WOCBP 
Women of childbearing potential 
 
 


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1. Scope of the Document 
This document describes the listings, tables, graphics and statistical analyses of the DARE study (“Efficacy 
of Daratumumab in Patients with Relapsed/Refractory Myeloma with Renal Impairment.”) which are to be 
performed for the full reporting according to the protocol. All analyses are based on the outline given in the 
statistical section of the protocol. 
2. General Analysis Framework 
Data will be entered electronically on the electronic Case Report Form (eCRF) by the investigator or 
authorized personnel in the participating sites via an electronic data capture (EDC) platform using a web-
based secure server. 
In case of incomplete dates, imputations will be applied as specified in the Data Management Plan (DMP). 
For the calculation of durations, the imputed date will be used. In listings, the incomplete date will be 
presented. In case further pre-processing to create derived variables is required these derived variables will 
be contained in the analysis datasets, rather than creating them within the reporting programs. 
2.1 Databases 
Extracts of the data base will be used regularly to facilitate the program writing. The data extracts will be transferred 
to the analysis environment and will be used as the basis for the analysis.  
3. Intended Users 
Intended users are HeaDS’ staff and any external persons or agencies who need to understand the trial 
Statistical Analysis framework. In particular the following HeaDS’ personnel will use the Statistical 
Analysis Plan (SAP): 
1. The project manager in order to monitor operational execution and control project issues (e.g. capacity).  
2. The data manager in order to perform all the preventive and corrective actions. 
3. The clinical programmer in order to develop the data validation and statistical analysis program. 
4. The trial statistician in order to perform the statistical analysis. 


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4. Short Trial Description 
 
Study Title: 
Efficacy of Daratumumab in Patients with Relapsed/Refractory Myeloma 
with Renal Impairment   
Methods: 
This is a multicenter, single arm, open-label phase 2 study.  
Approximately 38 subjects will be enrolled to receive daratumumab + 
dexamethasone. Treatment cycles haveduration is 28 days. Subjects will 
receive treatment until disease progression or unacceptable toxicity. Drug 
administration and follow-up visits will occur more frequently for early 
cycles (weekly for the first 8 weeks, every two weeks for weeks 9-24 and 
then every 4 weeks). Disease evaluations will occur monthly and consist 
mainly of measurements of myeloma proteins. Other assessments may 
include bone marrow examinations, skeletal surveys, assessment of 
extramedullary plasmacytomas, and measurements of serum calcium 
corrected for albumin, and β2- microglobulin and albumin.  
Assessment of myeloma response and disease progression will be 
conducted in accordance with the modified International Myeloma 
Working Group (IMWG) response criteria.  
Assessment of renal response will be conducted in accordance with the 
IMWG response criteria.  
Survival status and data of subsequent antimyeloma treatment will be 
collected post-treatment. 
Objectives: 
 
The primary objective of this study is to evaluate progression free survival 
(PFS) in patients with relapsed/refractory MM (RRMM)with renal 
impairment (RI).  
The secondary objectives are the following: 
• To evaluate Overall Response Rates (ORR) 
• To evaluate Renal Response Rates (RRR)  
• To evaluate duration of response in patients with RI. 
• To evaluate time to next therapy. 
• To evaluate Overall Survival (OS). 
• To assess the safety and tolerability of Daratumumab with 
dexamethasone in patients with RRMM and RI. 
Endpoints 
Primary endpoint: Progression-free survival 
Secondary Endpoints: 
• Overall response rate 
• Renal Response Rates (RRR) 
• Duration of response 
• Time to next therapy 
• Overall survival 
• Safety; adverse events (AE) 
Population: 
About 38 patients will be enrolled. Main inclusion criteria are the 
following: 
1. Males and females at least 18 years of age. 
2. Voluntary written informed consent before performance of any study-
related procedure  
3. Myeloma requiring systemic therapy  


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4. Myeloma relapsing after, or refractory to, two or more different prior 
therapies, including immunomodulatory agents, proteasome inhibitors 
and chemotherapy with alkylating agents. Subject must have 
documented relapsed or refractory MMas defined by the criteria 
below:  
a) Monoclonal plasma cells in bone marrow ≥ 10% or presence of a 
biopsy proven plasmacytoma.  
b) Measurable disease as defined by any of the following:  
• Serum monoclonal paraprotein (M-protein) level ≥ 1.0 g/dL 
(except for IgA subtype: ≥ 0.5 g/dL) or urine M-protein level ≥ 
200 mg/24 hours; or  
• Light chain multiple myeloma: Serum immunoglobulin free 
light chain ≥ 10 mg/dL and abnormal serum immunoglobulin 
kappa lambda free-light-chain ratio.  
5. An eGFR < 30 ml/min/1.73 m2 (CKD-EPI formula) or in need for 
dialysis  
6. Eastern Cooperative Oncology Group performance-status  score of 2 
or less 
7. Life expectancy of at least 3 months 
8. Women of childbearing potential (WOCBP) must have two negative 
serum or urine pregnancy tests, one 10-14 days prior to start of the 
study drugs and one within 24 hours prior to the start of study drugs. 
Women must not be breastfeeding. WOCBP must agree to follow 
instructions for methods of contraception for 4 weeks before the start 
of treatment with study drugs, for the duration of treatment with study 
drugs, and for a total of 3 months after cessation of daratumumab 
treatment. Males who are sexually active with WOCBP must always 
use a latex or synthetic condom during any sexual contact with 
females of reproductive potential, even if they have undergone a 
successful vasectomy. 
 
Phase: 
II 
Number of Sites 
enrolling 
participants: 
The study will be conducted at approximately 5 sites located in Greece 
and approximately 2 sites located in Italy.  
Description of 
Study Treatment: 
Daratumumab will be given at a dose of 16 mg/kg administered as an 
intravenous (IV) infusion at weekly intervals (QW) for 8 weeks, then 
every 2 weeks (Q2W) for an additional 16 weeks, then every 4 weeks 
(Q4W) thereafter. Dexamethasone will be administered according to 
standard clinical practice. The recommended dose of dexamethasone is 40 
mg (20 mg for patients ˃ 75 years of age) orally once daily on Days 1, 8, 
15 and 22 of each 28-day treatment cycle. 
Participant 
Subjects will receive treatment until disease progression or unacceptable 


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Duration: 
toxicity. Survival status and data of subsequent antimyeloma treatment 
will be collected post-treatment. 
Study Duration: 
The maximum duration of the study is of 30 months considering an 
accrual period of 18 months and a follow-up of the last patient for 12 
months. 
 


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5. SAP Development Parameters  
 
5.1.1 SAP Development Team 
The document was developed according to the SOP: “ST-SOP-13-v1-Statistical Analysis Plan”. It was 
authored by the trial statistician and reviewed by the project manager. Quality assurance was the 
responsibility of the Chief Scientific Officer. 
5.1.2 SAP Life Cycle Responsibility Task Matrix  
The following matrix describes the roles and responsibilities related to the use, update, improvement and 
reproducibility of the SAP. 
Task 
Frequency 
Owner 
Approval 
Version Control 
ad hoc 
Trial Statistician 
Project Manager 
Amendments  
ad hoc 
Trial Statistician 
Sponsor 
Interaction With Other 
Documents  
ad hoc 
Project Manager 
Clinical Operations Manager & Quality 
Assurance 
Interaction With Other 
Trials  
ad hoc 
Project Manager 
Clinical Operations Manager & Quality 
Assurance 
Quality Assurance 
ad hoc 
Clinical Operations Manager & 
Quality Assurance 
Chief Scientific Officer 
SAP deviations 
ad hoc 
Trial Statistician 
Project Manager / Chief Scientific Officer 
/ Sponsor 
 
6. Study Objectives 
 
6.1.1 Study Population & Number of participating Sites 
About 38 patients will be enrolled.  The study will be conducted at approximately 5 sites located in Greece 
and approximately 2 sites located in Italy.  
Main inclusion criteria are the following: 
1. Males and females at least 18 years of age. 
2. Voluntary written informed consent before performance of any study-related procedure  
3. Myeloma requiring systemic therapy  
4. Myeloma relapsing after, or refractory to, two or more different prior therapies, including 
immunomodulatory agents, proteasome inhibitors and chemotherapy with alkylating agents. Subject 
must have documented relapsed or refractory multiple myeloma as defined by the criteria below:  
c) Monoclonal plasma cells in bone marrow ≥ 10% or presence of a biopsy proven plasmacytoma.  
d) Measurable disease as defined by any of the following:  
• Serum monoclonal paraprotein (M-protein) level ≥ 1.0 g/dL (except for IgA subtype: ≥ 0.5 g/dL) 
or urine M-protein level ≥ 200 mg/24 hours; or  


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• Light chain multiple myeloma: Serum immunoglobulin free light chain ≥ 10 mg/dL and abnormal 
serum immunoglobulin kappa lambda free-light-chain ratio.  
5. An eGFR < 30 ml/min/1.73 m2 (CKD-EPI formula) or in need for dialysis  
6. Eastern Cooperative Oncology Group performance-status  score of 2 or less 
7. Life expectancy of at least 3 months 
8. Women of childbearing potential (WOCBP) must have two negative serum or urine pregnancy tests, one 
10-14 days prior to start of the study drugs and one within 24 hours prior to the start of study drugs. 
Women must not be breastfeeding. WOCBP must agree to follow instructions for methods of 
contraception for 4 weeks before the start of treatment with study drugs, for the duration of treatment 
with study drugs, and for a total of 3 months after cessation of daratumumab treatment. Males who are 
sexually active with WOCBP must always use a latex or synthetic condom during any sexual contact 
with females of reproductive potential, even if they have undergone a successful vasectomy. 
6.1.2 Study Drug and Dosing  
Daratumumab will be given at a dose of 16 mg/kg administered as an intravenous (IV) infusion at weekly 
intervals (QW) for 8 weeks, then every 2 weeks (Q2W) for an additional 16 weeks, then every 4 weeks 
(Q4W) thereafter. Dexamethasone will be administered according to standard clinical practice. The 
recommended dose of dexamethasone is 40 mg (20 mg for patients ˃ 75 years of age) orally once daily on 
Days 1, 8, 15 and 22 of each 28-day treatment cycle.  
6.2 Study Design 
This is a multicenter, Phase 2, single arm, open-label study evaluating daratumumab with dexamethasone 
(DaraD) in subjects with relapsed or refractory multiple myeloma who have received at least one prior 
treatment and have failed both lenalidomide and bortezomib and have renal impairment. 
Approximately 38 subjects located in approximately 5 centers in Greece and 2 centers in Italy will receive 
DaraD. Treatment cycles have duration of 28 days: 
Daratumumab will be given at a dose of 16 mg/kg administered as an intravenous (IV) infusion at QW for 8 
weeks, then every 2 weeks (Q2W) for an additional 16 weeks, then every 4 weeks (Q4W) thereafter. 
Subjects will receive pre-infusion medications before infusions to mitigate potential infusion reactions.  
Dexamethasone will be administered according to standard clinical practice and at a recommended total 
dose of 40 mg weekly (20 mg weekly for patients >75 years of age).  
Subjects will receive treatment until disease progression or unacceptable toxicity. 
Drug administration and follow-up visits will occur more frequently for early cycles (e.g., weekly or bi-
weekly) (see Table 1). Disease evaluations will occur monthly and consist mainly of measurements of 
myeloma proteins and renal function indices. Other parameters may include bone marrow examinations, 
skeletal surveys, assessment of extra medullary plasmacytomas, and measurements of serum calcium 
corrected for albumin, and β2- microglobulin and albumin.  


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Assessment of myeloma response and disease progression will be conducted in accordance with the 
International Myeloma Working Group (IMWG) response criteria.  
Assessment of renal response will be conducted in accordance with the International Myeloma Working 
Group (IMWG) response criteria (see APPENDIX 2).  
Survival status and data of subsequent antimyeloma treatment will be collected post-treatment. 
The maximum duration of the study is of 30 months considering an accrual period of 18 months and a 
follow-up of the last patient of 12 months.   
6.3 Study Flowchart 
This interventional study records data available in the following visits. 
Table 1 Schedule of Events 
Day of Cycle (28-days) 
Screening
^ 
Treatment: visit window during the treatment period is +/- 3 days 
End of treatment EOT8 
Post treatment FU 
Every 4 weeks5 
Survival follow-up 
Every 12 weeks 
Cycles 1 and 2 
Cycles 3-6 
Cycles 7 and beyond 
-21 to 1 
1 
BL 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
Demographic/baseline 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inc./Exc. criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MM diagnosis/history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
International Staging 
System (ISS) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cytogenetics (FISH) at 
study entry  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
 
Physical examination 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
 
Weight 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
 
Performance status 
(ECOG) 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Adverse Events 
Continuously until 30 days after last study treatment 
Treatment 
related SAEs 
Concomitant 
medication, 
transfusions 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Cardiac imaging 
MUGA/ECHO 
X 
As clinically indicated 
 
ECG 
X 
As clinically indicated 
 
Lab Assessments* 
 
Blood type assessment 
and indirect 
antiglobulin results0  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
Clinical chemistry 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 


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Day of Cycle (28-days) 
Screening
^ 
Treatment: visit window during the treatment period is +/- 3 days 
End of treatment EOT8 
Post treatment FU 
Every 4 weeks5 
Survival follow-up 
Every 12 weeks 
Cycles 1 and 2 
Cycles 3-6 
Cycles 7 and beyond 
-21 to 1 
1 
BL 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
Creatinine clearance 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
Pregnancy test1 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum β2-
microglobulin, LDH 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Efficacy Assessments 
 
Efficacy / Disease Assessment required to confirm response or disease progression should be performed as soon as possible after response or disease 
progression is suspected – see Protocol; Section 7.1 for details) 
sPEP, uPEP2 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
sIFE, uIFE3 
X 
X 
 
 
. 
X 
 
 
X 
 
 
 
X 
X 
 
To confirm CR regardless of whether measurable M-protein was present at baseline. See 
Protocol; Section 7.1.1.1 
 
 
sFLC assay, κ/λ ratio4 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Analyzed only when serum M-protein or urine M-protein or both assessed by PEP is/are 
non-measurable and to identify sCR in case CR criteria are met. See Protocol;  Section 
7.1.1.2 
 
 
 
 
 
 
 
Plasma cell count in 
bone marrow 
X 
Plasma cell count during the study as clinically indicated to qualify for CR; and PD for patients with non-
measurable disease by M protein in serum and urine as well as by FLC. See Protocol; Section 7.1.1.4 
 
MRD 
 
As per institution’s practice at complete response and thereafter as clinically indicated through EuroFlow cytometry. 
See Protocol; Section 7.1.1.6 
 
Corrected calcium6 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Skeletal survey7 
X 
As clinically indicated; CT/MRI in case of newly symptomatic areas with no X-ray finding. See Protocol; Section 
7.1.1.6 
 
Assessment of 
extramedullary soft 
tissue plasmacytoma 
X 
Clinical assessment on day one of each cycle at the End of treatment and at Post treatment follow-up every 4 weeks. 
CT or MRI at screening only if there are STP findings during the clinical assessment or documented evidence from 
previous imaging assessments and as clinically indicated. See Protocol; Section 7.1.1.4 
 
Response assessment 
by Investigator 
 
C2D1 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Treatment  
 
Daratumumab 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
Dexamethasone 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
40 mg (20 mg for patients ˃ 75 years of age) orally, weekly 
 
 
 
Other anti-neoplastic 
therapies  
 
Not permitted 
X 
X 
X 
Survival follow-up 
 
 
 
 
X 
^ The majority of screening assessments are to be performed within 21 days from the date of ICF signature until C1D1. See Protocol; Section 7.2.1 for details. 
0 i In addition to ABO and Rh blood typing, indirect antiglobulin test (also known as indirect Coombs test) will be performed; it is recommended that the subject 
carries a card with the blood antigen profile at all times during the study. 
1 Women of childbearing potential (WOCBP) must have two negative serum or urine pregnancy tests, one 10-14 days prior to start of the study drug and one 
within 24 hours prior to the start of study drug.2M protein by electrophoresis in serum (sPEP) and urine (uPEP). Serum on Day 1 of each cycle until disease 
progression. 24-hour urine sample can be collected within ± 7 days of visit.  
3M protein by immunofixation in serum (sIFE) and urine (uIFE). 4Free light chain protein assessment (sFLC) 
5 Patients who discontinue treatment for reasons other than disease progression, death, lost to follow-up, or withdrawal of consent should continue to be followed 
for response assessments every 4 weeks. 
6  Corrected calcium will be also performed as clinically indicated to confirm disease progression. 
7 As per institution’s practice 8 End of treatment visit should take place 4 weeks after the last dose of the study treatment or as soon as possible before the start of 
subsequent therapy. 
* Unless otherwise stated, all blood and urine samples must be obtained before administration of study treatment. 
 


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6.4 Study Primary and Secondary Objectives  
The purpose of this study is to evaluate the effects of daratumumab with dexamethasone in subjects with 
relapsed or refractory multiple myeloma and renal impairment. 
Primary objective(s) 
The primary objective of this study is to evaluate progression free survival (PFS) in subjects with relapsed or 
refractory multiple myeloma and renal impairment treated with daratumumab and dexamethasone. 
Secondary objective(s) 
The secondary objectives of the study are the following: 
• To evaluate Overall Response Rates (ORR) 
• To evaluate Renal Response Rates (RRR)  
• To evaluate duration of response in patients with RI. 
• To evaluate time to next therapy. 
• To evaluate Overall Survival (OS). 
• To assess the safety and tolerability of Daratumumab with dexamethasone in patients with RRMM 
and RI. 
 
6.4.1 Study Primary and Secondary Endpoints 
Primary endpoint: 
• Progression-free survival 
Secondary endpoints 
• Overall response rate 
• Renal Response rate 
• Duration of response 
• Time to next therapy 
• Overall survival 
• Safety (adverse events) 
 
6.4.2 Sample Size and Power Calculations 
The calculations were based on previous data for daratumumab in patients with relapse or refractory 
myeloma. The median Progression Free Survival (PFS) with daratumumab treatment in the SIRIUS study 
was 5.6 months in patients who received daratumumab at the dose of 16 mg/kg.  


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In order to test at α=0.05 the null hypothesis that the PFS is less than 3 months versus the alternative 
hypothesis that PFS is at least 5 months with a power of 90%, 34 patients must be included in the study. 
This calculation assumes exponential survival curves, an accrual time of 18 months and a length of follow 
up period of 30 months. Assuming a drop-out rate of about 10%, 38 patients are needed.  
Sample 
size 
was 
computed 
by 
“SWOG 
One 
arm 
survival 
sample 
size 
and 
power” 
(www.swogstat.org/stat/public/one_survival.htm) 
6.5 Population of Analysis Sets 
6.5.1 Full Analysis Set (FAS)  
The FAS comprises all patients to whom study treatment has been assigned according to the intent to treat 
principle.  
6.5.2 Per Protocol Analysis Set (PPS) 
The PPS consists of a subset of patients in the FAS who received at least one dose of the study drug and had 
no major protocol deviation. Protocol deviations leading to exclusion from the PPS will be defined in the 
Statistical Analysis Plan. 
6.5.3 Safety Set 
The Safety Set consists of all patients who received at least one dose of study treatment. Patients who have 
been randomized and did not take at least one dose of study treatment will not be included in the safety set. 
Patients will be analyzed according to the study treatment they actually received.  
6.5.4 Subgroups 
In this study, no sub group analysis was planned to be performed within the primary and secondary 
endpoints analysis. However, it is considered necessary to further examine the data that will be collected, in 
order to provide insights for this non-in depth investigated population. Hence, additional subgroup and 
exploratory analyses will be performed (see 6.6). The following subgroups will be used for the additional 
analyses: 
• ISS stage at the time of diagnosis 
• Revised ISS stage at the time of diagnosis 
• eGFR (< 15 vs ≥15 at baseline) 
• Patients with at least one eGFR>30 measurement over the whole observation period vs patient 
without such a measurement   
• ECG (normal vs at least one abnormality) 
• Prior treatments (2-5 treatments vs >5 treatments) 
• LDH () 
• FISH risk (low risk, standard risk, intermediate risk & high risk) (1) 
• Age at diagnosis (<60 vs. ≥60). 
• MRD negativity (negative vs. positive). 


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6.5.5 Interim Analysis 
N/A 
6.6 Statistical Methodology  
All statistical analyses will be performed using SAS® version 9.4 (64-bit) or later, a validated statistical 
software package, (SAS Institute, Inc., Cary, NC, USA).  
Data from all sites will be pooled and summarized. Continuous data will be summarized by mean, standard 
deviation (SD), median, first and third quartiles, minimum and maximum. Categorical data will be presented 
by absolute and relative frequencies (n and %) or contingency tables. 
One-sided alpha level 0.025 will be considered. No alpha level adjustment will be carried out for primary 
and secondary outcome variables. 
The primary efficacy endpoint is PFS for patients, who received daratumumab at the dose of 16 mg/kg,  as 
assessed by the Investigator. The distribution of PFS will be estimated using the Kaplan-Meier method. The 
median PFS along with 95% confidence intervals will be presented (see Section 6.6.1.3). The analysis will 
be performed when at least 20 PFS events have been documented. 
6.6.1 Methods of Statistical Analyses  
All data regarding patient demographics and baseline characteristics will be summarized on the FAS, 
overall, by means of summary descriptive statistics. 
A complete description of patient disposition will be provided, specifying the number of enrolled patients, 
number of patients at each visit, completed and discontinued patients, and the reason for the discontinuation. 
The analysis populations will be described and the reasons for excluding the patient from any analysis set 
will be provided with the number of protocol violators per each criterion. 
Medical history data will be presented by MedDRA System Organ Class and Preferred Term. 
Descriptive statistical analysis will be performed for all study data and epidemiological methods will be 
applied. Continuous variables will be summarized with the use of descriptive statistical measures [mean 
value, standard deviation (SD), median and range] (Table 2). Categorical/distinct variables will be displayed 
as frequency tables (N, %) (Table 3), by group.  
Additional sub-group analyses will be performed. The basic demographic characteristics, the primary and 
the secondary endpoints will be summarized by group. Between groups comparisons will be performed. The 
sub groups that will be used are derived based on known risk factors that are associated either with the MM 
or with the RR. Hence, all the endpoints will be analyzed in the following subgroups: 


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• ISS stage at the time of diagnosis 
• Revised ISS stage at the time of diagnosis 
• ECG (normal vs at least one abnormality) 
• Prior treatments (2-5 treatments vs >5 treatments) 
• LDH () 
• FISH risk (low risk, standard risk, intermediate risk & high risk) (1) 
• Age >60 vs ≤60 
• MRD negativity (negative vs. positive). 
 
Additional exploratory analyses will be performed, in order: 
•  To compare the PFS, the OS, the ORR and the number of prior treatments at baseline (2-5 
treatments vs >5 treatments) between patients with eGFR < 15 vs ≥15 at baseline.  
• To compare the PFS, the OS, the ORR and the number of prior treatments at baseline (2-5 treatments 
vs >5 treatments) between patients with at least one eGFR>30 measurement over the whole 
observation period vs patient without such a measurement   
• To compare the PFS, the OS, the ORR and the number of prior treatments at baseline (2-5 treatments 
vs >5 treatments) between patients with observed renal response and patients without renal response 
• To evaluate if the FISH risk and renal response, measured as RRR are correlated. 
• To evaluate if the FISH risk and renal response, using as cut-off point the eGFR>30, are correlated. 
• To evaluate if the FISH risk and Prior treatments (2-5 treatments vs >5 treatments) are correlated 
 
6.6.1.1 Patient-Reported Outcome (PRO) Measurements 
No PROs will be used.  
6.6.1.2 Statistical tests 
Association between categorical variables will be assessed using either chi-square test (χ2), Fisher exact test 
or McNemar test, as appropriate (Table 4). Furthermore, in order to examine the differences in thevalues of 
continuous variables at different time periods, Wilcoxon signed rank test for related samples and U-Mann 
Whitney test for independent samples will be used (Table 5). 
Medical history and safety will be coded by MedDRA (the most updated version available) while  System 
Organ Class (SOC) and Preferred Term (PT) will be tabulated in frequency tables (N, %). 
Concomitant medication(s) will be coded through the ATC Drug Classification dictionary by WHO 
Collaborating Centre for Drug Statistics Methodology in terms of therapeutic subgroup, chemical subgroup 
and chemical substance and will be presented in frequency tables. 
 


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6.6.1.3 Primary Endpoint Analysis 
The efficacy analysis will be performed based on the FAS as primary analysis and on the PPS as supportive 
analysis. 
Progression Free Survival (PFS) 
PFS is defined as the time, in months, from treatment initiation (Cycle 1 , day 1) to the date of the first 
documented tumor progression or death due to any cause, whichever comes first. Clinical deterioration will 
not be considered progression. For subjects who neither progress nor die, the survival time will be censored 
at the date of their last tumor assessment. For subjects who start a new anti-tumor treatment, survival time 
will be censored at the date of the start of the new treatment.  
The PFS function will be estimated using the Kaplan-Meier product-limit method. Median and two-sided 
confidence intervals (CI) for median PFS will be computed by and Kaplan-Meier plots of PFS will be 
presented. 
Absolute frequencies and proportions of patients with tumor progression or all-cause death will also be 
provided. 
6.6.1.4 Secondary Endpoint Analysis 
All secondary efficacy analyses will be performed based on the FAS. 
Overall Response Rate (ORR) 
ORR is defined as the proportion enrolled subjects who achieve a best response of partial response (PR) or 
better using the Modified criteria of the IMWG ( 
Rajan, A. M., and S. V. Rajkumar. "Interpretation of cytogenetic results in multiple myeloma for clinical 
practice." Blood 
cancer 
journal 5.10 
(2015): 
e365.


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APPENDIX 1) as their best overall response. 
The response rate, along with its exact two-sided 95% CI, will be computed. 
Renal Response Rate (RRR) 
Rrr is defined as the proportion enrolled subjects who achieve a best response of renal partial renal response 
(PRRenal) or better using the criteria of the International Myeloma Working Group (IMWG) (APPENDIX 
2). 
Duration of Response (DoR) 
DoR will be restricted to the subjects that achieve a best objective response of PR or better. It is measured 
from the time, in months, that the criteria for objective response are first met until the date of a progression 
event (according to the primary definition of PFS). A subject with objective response who does not have a 
progression event will be censored at the same time they were censored under the primary definition of PFS. 
The DoR function will be estimated using the Kaplan-Meier product-limit method. Median and two-sided 
confidence intervals for median duration of response will be computed and Kaplan-Meier plots of DoR will 
be presented. 
Time to Next Therapy (TNT) 
TNT will be defined as the time, in months, from Cycle 1 Day 1 to the date to next anti-neoplastic therapy or 
death from any cause, whichever comes first. For subjects who neither start a new anti-neoplastic therapy 
nor die, survival time will be censored at the date of their last available follow-up assessment.  
Time to next therapy will be calculated using a log-rank test procedure. The TNT function will be estimated 
using the Kaplan-Meier product-limit method. Median and two-sided confidence intervals for median TNT 
will be computed. Kaplan-Meier plots of TNT will be presented. 
Overall Survival (OS) 
Overall survival is defined as the time, in months, from the first dose of therapy to the date of death from 
any cause. If a patient is not known to have died, survival time will be censored at the date of last contact 
(“last known date alive”). 
Overall survival will be estimated using the Kaplan-Meier product-limit method. Median and corresponding 
two-sided 95% confidence intervals will be computed. Kaplan-Meier plots of OS will be presented. 
6.6.1.5 Safety Analysis 
Safety analyses will be conducted on the Safety Set and will be reported. 
Adverse events 
AEs will be assessed according to the Common Terminology Criteria for AEs (CTCAE version 4.03). 


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The incidence of AEs will be tabulated by MedDRA System Organ Class and Preferred Term. The 
incidence of AEs will also be summarized by system organ class, preferred term and severity (based on 
CTCAE grades). 
The same analysis will be repeated for SAEs regardless of drug relationship, for drug related SAEs, AEs 
with CTCAE grade 3 or 4 and for drug related AEs. AEs for which relationship to study drug is not 
specified will be considered treatment-related. 
Deaths reportable as SAEs will be listed by patient and tabulated by type of AE. 
Laboratory parameters 
Categorization of laboratory values will be assigned programmatically as per NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03 or according to normal ranges for those parameters 
without available CTCAE grading. The calculation of CTCAE grades will be purely based on the observed 
laboratory values, clinical assessments will not be taken into account. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 will not be 
used. 
For laboratory tests where grades are not defined by CTCAE v4.03, results will be graded by the 
low/normal/high (low and high) classifications based on laboratory normal ranges. 
The following by-treatment summaries will be generated separately for hematology, biochemistry and 
urinary laboratory tests: 
• Worst post-baseline CTCAE grade (regardless of the baseline status). Each patient will be counted 
only once for the worst grade observed post-baseline. 
• Shift tables using CTCAE grades to compare baseline to the worst on-treatment value. 
• Shift tables using the low/normal/high/ (low and high) classification to compare baseline to the worst 
on-treatment value, for laboratory tests where CTCAE grades are not defined. 
Listings of all laboratory data with values flagged to show the corresponding CTCAE grades and the 
classifications relative to the laboratory normal ranges will also be generated. 
Other safety data 
ECGs, vital signs and ECOG PS will be listed and summarized. 
ECG 
• Shift table baseline to worst on-treatment result 
• Listing of ECG evaluations for all patients with at least one abnormality 
• Change from baseline QTcF 
Vital signs 


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• Table with descriptive statistics at baseline, one or several post-baseline time points and change from 
baseline to this/these post-baseline time points 
ECOG PS 
• Shift tables comparing the baseline PS with the worst post-baseline result  
6.6.1.6 Treatments (study treatment, concomitant therapies)  
The Safety set will be used for the following analyses. 
Investigational treatment 
Duration of study treatment, cumulative dose, average daily dose, actual dose intensity and relative dose 
intensity of each of the components of study treatment will be summarized and for every 28-day cycle. The 
number of patients with dose changes/interruptions will be, along with the reasons for the dose 
change/interruptions. 
Concomitant treatments 
Concomitant medications or procedures and significant non-drug therapies taken concurrently with the study 
treatment will be listed and summarized by WHO Anatomical Therapeutic Chemical (ATC) Class, Preferred 
Term. These summaries will include medications starting on or after the start of study treatment (defined as 
cycle 1 day 1) or medications starting prior to the start of study treatment and continuing after the start of 
study treatment. Any prior medication or significant non-drug therapy starting and ending prior to the start 
of study treatment will be listed. 
For the analyses of transfusions, only transfusions received after start of study treatment and up to 30 days 
after last dose will be considered. The number of patients with transfusions and number of transfusions per 
patient will be analyzed. 
  
6.6.1.7 Planned Data Displays 
Data displays below present an indicative list of templates for the tables and figures that will be produced.  
The following data displays are based on dummy data. 
 
Table 2: Descriptive Analysis of Continuous Variables 
 
Groups 
Group A 
Group B 
 
VAR1 
Mean 
 
 
SD 
 
 
Q1 
 


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median 
 
 
Q4 
 
 
Min 
 
 
Max 
 
 
N 
 
 
VAR2 
Mean 
 
 
SD 
 
 
Q1 
 
 
 
median 
 
 
 
Q4 
 
 
 
Min 
 
 
 
Max 
 
 
 
N 
 
 
 
… 
 
 
 
 


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Table 3: Descriptive Analysis of Categorical Variables 
 
Groups 
Group A 
Group B 
N 
% 
N 
% 
 
VAR1 
Level1 
 
 
 
 
 
Level2 
 
 
 
 
 
Level3 
 
 
 
 
 
VAR2 
Level1 
 
 
 
 
 
Level2 
 
 
 
 
… 
 
 
 
 
 
 
 
 
Table 4. Test statistics for categorical variables 
 
Cohort 
 
Cohort A 
Cohort B 
P-value 
N 
% 
95%  
CI 
N 
% 
95%  
CI 
 
 
VAR1 
Level1 
 
 
 
 
 
 
 
 
Level2 
 
 
 
 
 
 
 
Level3 
 
 
 
 
 
 
 
 
VAR2 
Level1 
 
 
 
 
 
 
 
 
Level2 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Table 5. Test statistics for continuous variables – T-test/Mann-Whitney 
 
Group 
Group A 
Group B 
 
VAR1 
Mean 
 
 
sd 
 
 
Q1 
 
 
median 
 
 
Q4 
 
 
Min 
 
 
Max 
 
 
N 
 


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P-value 
 
 
VAR2 
Mean 
 
 
sd 
 
 
Q1 
 
 
 
median 
 
 
 
Q4 
 
 
 
Min 
 
 
 
Max 
 
 
 
N 
 
 
P-value 
 
 
… 
 
 
 
 
6.7 References 
 
1. Rajan, A. M., and S. V. Rajkumar. "Interpretation of cytogenetic results in multiple myeloma for clinical 
practice." Blood cancer journal 5.10 (2015): e365.


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APPENDIX 1 
 
Table 6. Modified International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple 
Myeloma 
Response 
IMWG criteria 
Stringent complete 
response (sCR) 
CR as defined below plus normal FLC ratio and absence of clonal cells in bone 
marrow1 by immunohistochemistry or immunofluorescence.2 
Complete response 
(CR) 
Negative immunofixation on serum and urine and disappearance of any soft tissue 
plasmacytomas and < 5% plasma cells in bone marrow.1 
Very good partial 
response (VGPR) 
Serum and urine M-protein detectable by immunofixation but not on electrophoresis 
or > 90% reduction in serum M-protein plus urine M-protein level < 100 mg/24 h 
Partial response 
(PR) 
> 50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by 
>90% or to < 200 mg/24 h. 
If serum and urine M-protein are unmeasurable, 3 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 not measurable, and serum free light assay is also not 
measureable, > 50% reduction in plasma cells is required in place of M-protein, 
provided baseline bone marrow plasma cell percentage was > 30%. 
In addition to the above listed criteria, if present at baseline, a > 50% reduction in the 
size of soft tissue plasmacytomas is also required. 
Minor (Minimal) 
Response (MR) 
25-49% reduction of serum M-protein and reduction in 24-hour urine M-protein by 
50-89%, which still exceeds 200 mg per 24 hours. In addition, if present at baseline, 
25-49% reduction in the size of soft tissue plasmacytomas is also required. No 
increase in the size or number of lytic bone lesions (development of compression 
fracture does not exclude response). 
No change/Stable 
disease (SD) 
Not meeting criteria for CR, VGPR, PR, or progressive disease. 
Progressive disease 
(PD)3 
Any of the following: 
• Increase of > 25% from lowest response value in any one or more of the following: 
o Serum M-component and/or (the absolute increase must be > 0.5 g/dL)4  
o Urine M-component and/or (the absolute increase must be > 200 mg/24 h) 
o Only in patients without measurable serum and urine M-protein levels; the 
difference between involved and uninvolved FLC levels. The absolute increase 
must be > 10 mg/dL 
o Bone marrow plasma cell percentage; the absolute percentage must be > 10%5 
• 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/dL or 2.87 
mmol/L) that can be attributed solely to the plasma cell proliferative disorder 
Relapse 
Clinical relapse requires one or more of: 
Direct indicators of increasing disease and/or end organ dysfunction (CRAB 


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features).4 It is not used in calculation of time to progression or progression-free 
survival but is listed here as something that can be reported optionally or for use in 
clinical practice 
• 
Development of new soft tissue plasmacytomas or bone lesions 
• 
Definite increase in the size of existing plasmacytomas or bone lesions. A 
definite increase is defined as a 50% (and at least 1 cm) increase as measured 
serially by the sum of the products of the cross-diameters of the measurable 
lesion 
• 
Hypercalcemia (> 11.5 mg/dL) [2.87 mmol/L] 
• 
Decrease in hemoglobin of > 2 g/dL [1.24 mmol/L] 
• 
Rise in serum creatinine by 2 mg/dL or more [177 μmol/L or more] 
Relapse from CR3 
(To be used only if 
the 
end 
point 
studied is DFS)6  
Any one or more of the following: 
• 
Reappearance of serum or urine M-protein by immunofixation or 
electrophoresis 
• 
Development of > 5% plasma cells in the bone marrow5 
• 
Appearance of any other sign of progression (i.e., new plasmacytoma, lytic 
bone lesion, or hypercalcemia) 
 
 
 
 
 
 
APPENDIX 2 
 
 
Table 7. IMWG Renal Response Criteria 
Criteria for the Definition of Renal Response to Antimyeloma Therapy 
Renal Response 
 
Baseline eGFR, 
mL/min/1.73 m2* 
Best eGFR  Response 
mL/min/1.73 m2 
Complete response  
 
<50 
≥60 
Partial response  
 
< 15 
30-59 
Minor response  
<15 
15-29 
15-29 
30-59 
Abbreviations: CrCl, creatinine clearance; eGFR, estimate glomerular filtration rate. 
*eGFR is based on the Modification of Diet in Renal Disease formula, or the Chronic Kidney 
Disease Epidemiology Collaboration equation. 
 


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Table 8. Simplified renal response criteria 
Simplified criteria Renal Response criteria 
 
• 
Patients who presented with stage 5 RI (eGFR < 15 ml/min/1.73 m2)should 
double their eGFR and improve to at least stage 4  
 
• 
Patients with stage 4 (eGFR 15-29 ml/min/1.73 m2), increase their eGFR by at 
least 50% and improve to at least stage 3 (GFR ≥ 60 mL/min/1.73 m2)  
 
• 
Patients with stage 3 (eGFR 30-59 ml/min/1.73 m2), increase their eGFR by at 
least 50% and improve to at least stage 2 (GFR ≥ 60 mL/min/1.73 m2)