Conditions: Multiple Myeloma
Keywords: Untreated Multiple Myeloma daratumumab
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1085
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate if the addition of daratumumab to Bortezomib, Thalidomide and Dexamethasone will increase the stringent complete response rate after consolidation therapy and increase the progression free survival after daratumumab maintenance therapy in transplant eligible participants with previously untreated Multiple Myeloma.

Detailed description:
This is a randomized, open-label (identity of assigned treatment will be known to participants and study staff), 2-arm (2 treatment groups), multicenter study of daratumumab in participants diagnosed with previously untreated Multiple Myeloma who are eligible for high dose chemotherapy and autologous stem cell transplantation (transplantation of own bone marrow). Participants will be randomized (assigned by chance) to one of 2 treatment groups to either receive daratumumab plus bortezomib, thalidomide and dexamethasone or bortezomib, thalidomide and dexamethasone for induction (before transplantation) and consolidation (after transplantation) treatment. All responders will then be re-randomized (assigned by chance) to one of 2 treatment groups to receive maintenance treatment with daratumumab only or observation (no treatment). The study will include a 28-Day Screening Phase, a Treatment Phase of 6 treatment cycles (each cycle is 4 weeks in duration for total period of 30 weeks), and a Follow up Phase of 2 years. The total duration for each participant in the study will be approximately 138 weeks. The end of the study will occur approximately 5 years after the last participant is randomized in the second phase of the study. Disease assessments will be performed every 4 weeks in the first phase of the study and then every 8 weeks in the second phase of the study. Safety will be monitored throughout the study.

Arms:
arm 1: Bortezomib (VELCADE), Thalidomide, and Dexamethasone (VTD) arm 2: Bortezomib (VELCADE), Thalidomide, and Dexamethasone (VTD) plus daratumumab arm 3: Observation arm 4: daratumumab

Interventions: intervention 1: Bortezomib (VELCADE), Thalidomide, and Dexamethasone (VTD) intervention 2: Bortezomib, Thalidomide, Dexamethasone (VTD) + daratumumab intervention 3: Daratumumab
Intervention descriptions: intervention 1: Part 1: 4 Cycles of Bortezomib,Thalidomide and Dexamethasone induction therapy, followed by Autologous Stem Cell Transplantation, followed by 2 cycles of Bortezomib, Thalidomide and Dexamethasone consolidation intervention 2: Part 1: 4 Cycles of Bortezomib, Thalidomide and Dexamethasone plus daratumumab 16mg/kg induction therapy, followed by Autologous Stem Cell Transplantation, followed by 2 cycles of Bortezomib, Thalidomide and Dexamethasone plus daratumumab 16 mg/kg consolidation intervention 3: Daratumumab 16mg/kg every 8 weeks for 2 years

Protocol document:
Prot_000.pdf: 
 
 
 
Official Title of Study: 
 
Study of Daratumumab (JNJ-54767414 (HuMax® CD38) in Combination with Bortezomib 
(VELCADE), Thalidomide, and Dexamethasone (VTD) in the First Line Treatment of 
Transplant Eligible Subjects with Newly Diagnosed Multiple Myeloma. 
 
 
NCT Number: NCT02541383 
 
 
Document Date (Date in which document was last revised): 14 January 2021 


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Intergroupe Francophone du Myelome (IFM) 
 in Collaboration with  
Dutch-Belgian Cooperative Trial Group for Hematology Oncology (HOVON)  
And Janssen Research & Development 
 
Clinical Protocol 
 
Study of Daratumumab (JNJ-54767414 (HuMax® CD38) in Combination with Bortezomib 
(VELCADE), Thalidomide, and Dexamethasone (VTD) in the First Line Treatment of Transplant 
Eligible Subjects with Newly Diagnosed Multiple Myeloma. 
 
Protocol  IFM 2015-01 /HO131/54767414MMY3006; Phase 3 
Initial Version dated 14 January 2015 
AMENDMENT 1 dated 24 August 2015 
AMENDMENT 2 dated 21 March 2016 
AMENDMENT 3 dated 05 July 2019 
AMENDMENT 4 dated 14JAN2021 
 
JNJ-54767414 (daratumumab)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Status: 
Approved for Dossier Use 
Date: 
14 January 2021 
 


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Summary of protocol versions 
 
 
version  
date  
modifications  
initial version  
14/01/2015 
Amendment 1  
24/08/2015 
Main protocol changes:  
Inclusion criteria N°2 and exclusion N° 13 and 18 modified, precision on 
MRD evaluation, new CRAB criteria added, allowance of premedication 3 
hours before Dara and montelukast added, collect of AE during graft, 
details on sCR assessment. 
 
Amendment 2  
21/03/2016 
Main protocol changes: precision about MRD and response assessment 
during maintenance phase, inclusion criteria 2 and 5, exclusion criteria 
2/7/8. Precisions about vital signs and immunogenicity data, precision 
about montelukast for patient receiving daratumumab on part II only, 
precision of the delay between consolidation and maintenance phases.  
 
Amendment 3 
05/07/2019 
Main protocol changes:  
Precisions and clarifications added regarding EOT visit and FU visits (Pre-
PD/PD/Survival) procedures. 
Addition of IRR definition. 
Update of safety information in line with IB update (IB 15 and its 
addendum 1) 
Addition of recommendations already communicated to sites for Part I for 
harmonization purposes. 
Clarification regarding procedure in case of suspected daratumumab 
interference on SPEP and IFE.  
Clarification for recording the response to treatment. 
Clarification for recording any new malignancy event as an SAE. 
Clarifications regarding SAE declaration circuit. 
Changes in formulation/structure for accuracy and better understanding of 
protocol procedures. 
New MRD assessments during Pre-Progression Follow-up 
Changes in bisphosphonate therapy recommendations 
Change of IFM Director 
Amendment 4 
14/01/2021 
Modification of Pre-PD follow-up visit frequency 
IDMC meetings not needed after the unblinding of the data 
The interim analysis for PFS met the predefined boundary and turned into 
the final analysis of part 2 for PFS. Change in monitoring strategy: risk-
based approach with remote quality control of data/Risk-based monitoring 
Addition of analyses of screening aliquots using NGS methodology 


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Table of contents 
LIST OF IN-TEXT TABLES AND FIGURES ................................................................................................ 6 
SYNOPSIS .................................................................................................................................................... 7 
ABBREVIATIONS ...................................................................................................................................... 29 
1. 
INTRODUCTION................................................................................................................................ 32 
1.1. 
Background .................................................................................................................................... 32 
1.1.1. 
Multiple Myeloma ........................................................................................................................ 32 
1.1.2. 
Daratumumab ............................................................................................................................. 32 
1.1.3. 
Nonclinical Studies ..................................................................................................................... 33 
1.1.4. 
Clinical Studies ........................................................................................................................... 35 
1.2. 
Overall Rationale for the Study ...................................................................................................... 37 
2. 
OBJECTIVES AND HYPOTHESIS ................................................................................................... 41 
2.1. 
Objectives ...................................................................................................................................... 41 
2.2. 
Hypothesis ..................................................................................................................................... 42 
3. 
STUDY DESIGN AND RATIONALE ................................................................................................. 42 
3.1. 
Overview of Study Design .............................................................................................................. 42 
3.2. 
Study Design Rationale.................................................................................................................. 45 
4. 
SUBJECT POPULATION .................................................................................................................. 49 
4.1. 
Inclusion Criteria ............................................................................................................................ 50 
4.2. 
Exclusion Criteria ........................................................................................................................... 51 
4.3. 
Prohibitions and Restrictions ......................................................................................................... 54 
5. 
TREATMENT ALLOCATION AND BLINDING ................................................................................. 55 
6. 
DOSAGE AND ADMINISTRATION .................................................................................................. 56 
6.1. 
Daratumumab ................................................................................................................................ 57 
6.1.1. 
Daratumumab Preparation ......................................................................................................... 57 
6.1.2. 
Daratumumab Administration and Infusion Rate ........................................................................ 57 
6.1.3. 
Guidelines for Prevention and Management of Infusion Reactions ........................................... 58 
6.1.4. 
Management of Infusion-Related Reactions .............................................................................. 59 
6.2. 
Bortezomib, Thalidomide, and Dexamethasone (VTD) ................................................................. 60 
6.2.1. 
Dose Calculation of Bortezomib ................................................................................................. 60 
6.2.2. 
Bortezomib Administration .......................................................................................................... 60 
6.2.3. 
Thalidomide Administration ........................................................................................................ 61 
6.2.4. 
Dexamethasone Administration .................................................................................................. 61 
6.3. 
Dose Delays and Dose Modifications (General Principles) ........................................................... 61 
6.3.1. 
Cycle Delay ................................................................................................................................. 61 
6.3.2. 
Dose Modification Guidelines ..................................................................................................... 62 
6.3.3. 
Daratumumab Dose Modification ............................................................................................... 62 
6.3.4. 
Dose Reductions (Bortezomib, Thalidomide, and Dexamethasone) ......................................... 63 
7. 
TREATMENT COMPLIANCE ............................................................................................................ 69 
8. 
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 69 
8.1. 
Recommended Therapies .............................................................................................................. 69 
8.1.1. 
Prevention of Deep Venous Thrombosis .................................................................................... 69 
8.1.2. 
Therapy for Tumor Lysis Syndrome ........................................................................................... 69 


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8.1.3. 
Prophylaxis Against Pneumocystis carinii Pneumonia ............................................................... 69 
8.1.4. 
Prophylaxis for Herpes Zoster Reactivation ............................................................................... 70 
8.1.5. 
Bisphosphonate Therapy ............................................................................................................ 70 
8.1.6. 
Management of Hepatitis B Virus Reactivation .......................................................................... 70 
8.2. 
Permitted Therapies ....................................................................................................................... 70 
8.3. 
Prohibited Therapies ...................................................................................................................... 71 
9. 
STUDY EVALUATIONS .................................................................................................................... 71 
9.1. 
Study Procedures ........................................................................................................................... 71 
9.1.1. 
Overview ..................................................................................................................................... 71 
9.1.2. 
Screening Phase ........................................................................................................................ 72 
9.1.3. 
Treatment Phase ........................................................................................................................ 72 
9.1.4. 
Follow-Up Phase ........................................................................................................................ 76 
9.2. 
Safety Evaluations ......................................................................................................................... 77 
9.3. 
Immunogenicity Evaluations .......................................................................................................... 80 
9.3.1. 
Immunogenicity Assessments .................................................................................................... 80 
9.3.2. 
Analytical Procedures ................................................................................................................. 80 
9.4. 
Biomarker Evaluations ................................................................................................................... 81 
9.5. 
Sample Collection and Handling .................................................................................................... 82 
9.6. 
Efficacy ........................................................................................................................................... 82 
9.6.1. 
Evaluations ................................................................................................................................. 82 
9.6.2. 
Central Confirmation of stringent Complete Response (sCR).................................................... 84 
9.6.3. 
Myeloma Protein Measurements in Serum and Urine ................................................................ 85 
9.6.4. 
Albumin and Serum Calcium Corrected for Albumin .................................................................. 85 
9.6.5. 
Bone Marrow Examination.......................................................................................................... 86 
9.6.6. 
Assessment of Lytic Disease ...................................................................................................... 86 
9.6.7. 
Documentation of Extramedullary Plasmacytomas .................................................................... 87 
9.7. 
Patient Reported Outcomes ........................................................................................................... 87 
9.8. 
Medical Resource Utilization .......................................................................................................... 88 
10. 
SUBJECT COMPLETION/WITHDRAWAL ....................................................................................... 88 
10.1. 
Completion ..................................................................................................................................... 88 
10.2. 
Discontinuation of Study Treatment ............................................................................................... 88 
10.3. 
Withdrawal From the Study ............................................................................................................ 89 
11. 
STATISTICAL METHODS ................................................................................................................. 90 
11.1. 
Subject Information ........................................................................................................................ 90 
11.2. 
Sample Size Determination ........................................................................................................... 90 
11.3. 
Efficacy Analyses ........................................................................................................................... 90 
11.3.1. 
Endpoints .................................................................................................................................... 91 
11.3.2. 
Efficacy Analysis for Induction/ASCT/Consolidation Phase ....................................................... 92 
11.3.3. 
Efficacy Analysis for Maintenance Phase................................................................................... 93 
11.3.4. 
Other Efficacy Analyses.............................................................................................................. 94 
11.4. 
Daratumumab Immunogenicity Analyses ...................................................................................... 94 
11.5. 
Biomarker Analysis ........................................................................................................................ 94 
11.6. 
Patient Reported Outcomes ........................................................................................................... 95 
11.7. 
Safety Analyses ............................................................................................................................. 95 
11.8. 
Interim Analysis .............................................................................................................................. 96 
11.9. 
Independent Data Monitoring Committee ...................................................................................... 96 
12. 
ADVERSE EVENT REPORTING ...................................................................................................... 97 
12.1. 
Definitions ...................................................................................................................................... 97 
12.1.1. 
Adverse Event Definitions and Classifications ........................................................................... 97 
12.1.2. 
Attribution Definitions .................................................................................................................. 98 
12.1.3. 
Severity Criteria .......................................................................................................................... 99 
12.2. 
Special Reporting Situations .......................................................................................................... 99 
12.3. 
Procedures ................................................................................................................................... 100 
12.3.1. 
All Adverse Events .................................................................................................................... 100 


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12.3.2. 
Serious Adverse Events ........................................................................................................... 102 
12.3.3. 
Pregnancy ................................................................................................................................. 103 
12.4. 
Contacting Sponsor ...................................................................................................................... 103 
13. 
PRODUCT QUALITY COMPLAINT HANDLING ............................................................................ 103 
13.1. 
Procedures ................................................................................................................................... 103 
13.2. 
Contacting Janssen Regarding Product Quality .......................................................................... 104 
14. 
DARATUMUMAB INFORMATION .................................................................................................. 104 
14.1. 
Physical Description of Daratumumab ......................................................................................... 104 
14.2. 
Packaging .................................................................................................................................... 104 
14.3. 
Labeling ........................................................................................................................................ 104 
14.4. 
Preparation, Handling, and Storage ............................................................................................. 104 
14.5. 
Drug Accountability ...................................................................................................................... 104 
15. 
STUDY-SPECIFIC MATERIALS ..................................................................................................... 105 
16. 
ETHICAL ASPECTS ....................................................................................................................... 105 
16.1. 
Study-Specific Design Considerations ......................................................................................... 105 
16.2. 
Regulatory Ethics Compliance ..................................................................................................... 106 
16.2.1. 
Investigator Responsibilities ..................................................................................................... 106 
16.2.2. 
Independent Ethics Committee or Institutional Review Board ................................................. 106 
16.2.3. 
Informed Consent ..................................................................................................................... 107 
16.2.4. 
Privacy of Personal Data .......................................................................................................... 108 
16.2.5. 
Long-Term Retention of Samples for Additional Future Research .......................................... 109 
17. 
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 109 
17.1. 
Protocol Amendments .................................................................................................................. 109 
17.2. 
Regulatory Documentation .......................................................................................................... 110 
17.2.1. 
Regulatory Approval/Notification .............................................................................................. 110 
17.2.2. 
Required Prestudy Documentation ........................................................................................... 110 
17.3. 
Subject Identification, Enrollment, and Screening Logs .............................................................. 111 
17.4. 
Source Documentation................................................................................................................. 111 
17.5. 
Case Report Form Completion .................................................................................................... 111 
17.6. 
Data Quality Assurance/Quality Control ...................................................................................... 112 
17.7. 
Record Retention ......................................................................................................................... 112 
17.8. 
Monitoring .................................................................................................................................... 113 
17.9. 
Study Completion/Termination ..................................................................................................... 114 
17.9.1. 
Study Completion ..................................................................................................................... 114 
17.9.2. 
Study Termination ..................................................................................................................... 114 
17.10. On-Site Audits .............................................................................................................................. 114 
17.11. Use of Information and Publication .............................................................................................. 114 
REFERENCES .......................................................................................................................................... 117 
ATTACHMENT 1:  DIAGNOSTIC CRITERIA FOR MULTIPLE MYELOMA ........................................... 121 
ATTACHMENT 2: ECOG PERFORMANCE STATUS SCALE ............................................................... 122 
ATTACHMENT 3: CALCULATED CREATININE CLEARANCE (COCKCROFT & GAULT 
FORMULA) ...................................................................................................................................... 123 
ATTACHMENT 4: SERUM CALCIUM CORRECTED FOR ALBUMIN ................................................... 124 
ATTACHMENT 5: ASTHMA GUIDELINES ............................................................................................. 125 
ATTACHMENT 6: CONVERSION TABLE FOR GLUCOCORTICOSTEROID DOSE ............................ 127 
ATTACHMENT 7: BODY SURFACE AREA CALCULATION ................................................................. 128 


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INVESTIGATOR AGREEMENT ............................................................................................................... 129 
LAST PAGE .............................................................................................................................................. 130 
 
LIST OF IN-TEXT TABLES AND FIGURES 
TABLES 
Table 1. 
TIME AND EVENTS SCHEDULE: INDUCTION AND CONSOLIDATION PHASES ............... 18 
Table 2. 
TIME AND EVENTS SCHEDULE: STUDY DRUG DOSING, INDUCTION AND 
CONSOLIDATION PHASES .................................................................................................... 20 
Table 3. 
TIME AND EVENTS SCHEDULE: MAINTENANCE PHASE ................................................... 21 
Table 3 A. TIME AND EVENTS SCHEDULE (BIOMARKER SAMPLES): INDUCTION AND 
CONSOLIDATION PHASES…………………………………………………………………………………..….25 
Table 3 B. TIME AND EVENTS SCHEDULE (BIOMARKER SAMPLES): MAINTENANCE 
PHASE…………………………………………………………………………………………………………….…26 
Table 3 C. TIME AND EVENTS SCHEDULE (BIOMARKER SAMPLES): Pre-PD FU phase………….….27 
Table 4: 
Daratumumab Single-Agent Studies GEN501 and MMY2002 ................................................. 35 
Table 5: 
Daratumumab Combination Studies GEN503 and MMY1001 ................................................. 36 
Table 6: 
Part 2 (Maintenance Phase) Stratification Factors ................................................................... 56 
Table 7: 
Re-treatment criteria before the start of each cyclea ................................................................ 62 
Table 8: 
Daratumumab-Related Toxicity Management .......................................................................... 63 
Table 9: 
Dose Modification for Bortezomib ............................................................................................. 64 
Table 10: Dose Reduction for Thalidomide .............................................................................................. 64 
Table 11: Dose Reductions for Dexamethasone ...................................................................................... 64 
Table 12:  Dose Modification Guidelines for Bortezomib, Dexamethasone and Thalidomide .................. 65 
Table 13: International Uniform Response Criteria Consensus Recommendations ................................ 83 
 
FIGURES 
Figure 1: 
Daratumumab-Enhanced Multiple Myeloma Cell Killing by Key Multiple Myeloma 
Chemotherapeutic Agents ........................................................................................................ 34 
Figure 2: 
Dose-dependent Lysis of Multiple Myeloma cells in Triple Chemotherapy Treatments ........... 34 
Figure 3:  Study MMY3006 Study Scheme ............................................................................................... 44 
Figure 4: 
Study GEN501 8 and 16 mg/kg Dose Levels - Observed Trough Concentration vs. 
90% Target Suppression Concentration ................................................................................... 48 


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SYNOPSIS 
Study of Daratumumab (JNJ-54767414 (HuMax® CD38) in Combination with Bortezomib 
(VELCADE), Thalidomide, and Dexamethasone (VTD) in the First Line Treatment of Transplant 
Eligible Subjects with Newly Diagnosed Multiple Myeloma 
EudraCT Number: 2014-004781-15 
Daratumumab is a human IgG1ĸ monoclonal antibody (mAb) that binds with high affinity to a unique 
epitope on CD38, a transmembrane glycoprotein. It is a targeted immunotherapy directed towards tumor 
cells that express high levels of CD38, such as plasma cells from patients with multiple myeloma. This 
target is distinct from those of other approved agents for multiple myeloma therapy. 
OBJECTIVES AND HYPOTHESIS 
Primary Objectives:  
• 
The primary objective in Part 1 is to determine if the addition of daratumumab to VTD will increase 
the proportion of subjects achieving stringent complete response (sCR) post completion of 
consolidation therapy compared with VTD alone. 
• 
The primary objective in Part 2 is to determine if the use of daratumumab as single agent in 
maintenance compared to observation only will increase progression-free survival (PFS) when used 
after autologous stem cell transplant and consolidation therapy. 
Secondary Objectives: 
In Part 1, major secondary efficacy objectives are to determine if the addition of daratumumab to VTD will 
improve: 
− 
Progression-free survival (PFS) from first randomization 
− 
Time to progression (TTP) from first randomization 
− 
Complete response (CR) rate by the end of ASCT/consolidation 
− 
Minimal residual disease (MRD) negative rate by the end of ASCT/consolidation 
− 
Post-induction stringent complete response (sCR) rate 
− 
Progression-free survival after next line of therapy (PFS2) 
− 
Post-induction overall response rate (ORR) and rate of very good partial response (VGPR) or 
better 
− 
Overall survival (OS) 
− 
Duration of CR and sCR 
In Part 2, major secondary efficacy objectives are to determine if the addition of daratumumab to VTD will 
improve the assessment during maintenance of: 
− 
Time to progression 
− 
CR rate 
− 
MRD negative rate 
− 
PFS2 
− 
Rate of improved response 


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− 
Rate of MRD negative conversion 
− 
ORR 
− 
OS 
Other secondary objectives throughout the study are: 
− 
To evaluate quality of life and health economic/resource utilization 
− 
To assess immunogenicity of daratumumab 
− 
To assess safety and tolerability of daratumumab in combination with VTD 
− 
Rate of MRD conversion during Pre-PD Follow-Up.  
Exploratory Objectives: 
• 
To evaluate daratumumab’s impact on response and resistance to treatment 
Hypothesis 
As this study integrates induction therapy as well as post-transplant consolidation and maintenance therapy 
into a single, 2-stage randomization design to address 2 distinct questions about the effectiveness of 
daratumumab treatment during induction/consolidation and maintenance, there are two primary hypotheses 
for this study: 
Hypothesis for Induction/Consolidation: first randomization 
Addition of daratumumab to VTD improves post-consolidation sCR rate compared with VTD alone. 
Hypothesis for Maintenance: second randomization 
Daratumumab maintenance after ASCT prolongs PFS compared with observation. 
OVERVIEW OF STUDY DESIGN 
This is a randomized, open-label, active control, parallel group, multicenter, Phase 3 study in subjects with 
previously untreated multiple myeloma. The planned number of subjects to be treated in this study is as 
follows: 
1080 subjects (540/arm) for first randomization (induction)  
Approximately 800 subjects (400/arm) of the initial 1080 subjects will be randomized to maintenance. The 
actual accrual into the Maintenance Phase may be greater than 800 if a higher-than-expected proportion of 
subjects in the induction/consolidation stage achieve response and are randomized in the Maintenance 
Phase. 
The study will consist of 3 phases. The Screening Phase will extend up to 28 days prior to Cycle 1, Day 1. 
The Treatment Phase will be conducted in 2 parts, as described below, and will extend from Cycle 1 Day 1 
until treatment discontinuation due to progressive disease, unacceptable toxicity, ineligibility for second 
randomization, or 2 years of maintenance therapy/observation. The Follow-up (FU) Phase will extend from 
treatment discontinuation until death, lost to follow-up, withdrawal of consent, or study end, whichever 
occurs first. 
The 2 parts in the Treatment Phase are described below. 
Part 1: Induction/ASCT/Consolidation Phase (1:1 Randomization)  
Arm A: VTD induction therapy (4 cycles), followed by ASCT, followed by 2 cycles of VTD consolidation 


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Arm B: VTD plus daratumumab induction therapy (4 cycles), followed by ASCT, followed by 2 cycles of 
VTD plus daratumumab consolidation 
The consolidation phase of treatment will begin approximately 30 days after ASCT, when the subject has 
recovered sufficiently and engraftment is complete. Response will be evaluated at Day 100 post ASCT. 
Part 2: Maintenance Phase (1:1 Re-randomization of subjects achieving at least a PR after consolidation) 
Subjects with at least a PR will be randomized after determination of response at approximately Day 100 
after ASCT, and will enter the Maintenance Phase upon completion of consolidation therapy.  
Arm A: Observation only until documented disease progression (limited to 2 years maximum duration) 
Arm B: Daratumumab monotherapy until documented disease progression (limited to 2 years maximum 
duration) 
Subjects who are not randomized in Part 2 will enter in the Follow-up Phase and will be followed until 
disease progression, death or lost to follow up, withdrawal of consent or study end even if they receive 
subsequent anticancer treatments. 
 
 
 
 


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In Arm B, daratumumab (16 mg/kg) will be administered by intravenous (IV) infusion once every week for 
8 weeks (VTD Induction Cycle 1-2), then once every 2 weeks for 8 weeks (VTD Induction Cycle 3-4), and 
following ASCT once every 2 weeks for 8 weeks (VTD consolidation Cycle 5-6). Following subsequent re 
randomization, subjects assigned to the maintenance Arm B will receive daratumumab (16 mg/kg) once 
every 8 weeks until documented disease progression (limited to a maximum duration of 2 years). 
Permuted block randomization will be implemented in this study. Subjects will be stratified at first 
randomization by site affiliation (IFM or HOVON), International Staging System stage I, II, or III (β-2 
microglobulin and albumin) and by cytogenetics (standard risk or high risk as defined by presence of del17p 
or t(4;14), as centrally confirmed during screening). 
Response will be assessed 100 days after ASCT and eligibility for the second randomization will be 
determined. Subjects will be stratified at the second randomization by type of induction treatment (VTD 
+/- daratumumab) and by depth of response to induction/consolidation therapy (as determined by MRD 
status and post-consolidation response).  
Assessment of tumor response and disease progression will be conducted in accordance with the 
International Myeloma Working Group (IMWG) response criteria. An assessment of MRD will be 
conducted using flow cytometry and NGS on bone marrow aspirates for all patients in 
induction/consolidation phases and for patients who achieve at least VGPR in maintenance phase. Safety 
evaluations will include adverse event monitoring, physical examinations, electrocardiogram monitoring 
(ECGs), clinical laboratory parameters (hematology and chemistry), vital sign measurements, and Eastern 
Cooperative Oncology Group (ECOG) performance status.  
Two primary analyses are planned. The first primary analysis, with a purpose to evaluate response by 
measuring the stringent complete response (sCR) rate, will be performed after all subjects have completed 
the Day 100 post-ASCT response evaluation or have been discontinued from study treatment by this 
timepoint. The second primary analysis, for PFS, will be performed when approximately 390 PFS events 
have been observed. An interim analysis is planned for the maintenance stage after 273 (70%) PFS events 
are observed in the population of subjects who are re-randomized. In case the Interim analysis for PFS 
meets the pre-defined boundary, this Interim analysis reflects the primary analysis for PFS. No PFS analysis 
at 390 PFS events will be done. The next pre-planned analysis in that case will be the final data cutoff at 
the end of study, when approximately 350 subjects have died, or approximately 5 years after the last subject 
is randomized in the second randomization, whichever comes first.  
 
 


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SUBJECT POPULATION 
Inclusion Criteria 
Each potential subject must satisfy all of the following criteria to be enrolled in the study.  
1. 
Subject must be between 18 and 65 years of age. 
2. 
Subject must have documented multiple myeloma satisfying the CRAB or biomarkers of 
malignancy criteria (see Attachment 1) and measurable disease as defined by: 
• 
Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy proven 
plasmacytoma AND any one or more of the following myeloma defining events: 
− Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than ULN or 
>2.75 mmol/L (>11 mg/dL) 
− Renal insufficiency: creatinine clearance <40mL/min or serum creatinine 
>177 µmol/L (>2 mg/dL) 
− Anemia: hemoglobin >2 g/dL below the lower limit of normal or hemoglobin 
<10 g/dL 
− Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-
CT 
− Clonal bone marrow plasma cell percentage ≥60% 
− Involved: uninvolved serum free light chain ratio ≥100 
− >1 focal lesion on MRI studies 
• 
Measurable disease as defined by any of the following: 
− IgG multiple myeloma: Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL 
or urine M-protein level ≥200 mg/24 hours; or 
− IgA, IgE, IgD, or IgM multiple myeloma: serum M-protein level ≥0.5 g/dL or urine 
M-protein level ≥200 mg/24 hours; or 
− IgD multiple myeloma: serum M-protein level <0.5 g/dL and Serum 
immunoglobulin free light chain ≥10 mg/dL and abnormal serum immunoglobulin 
kappa lambda free light chain ratio; or  
− Light chain multiple myeloma without measurable disease in the serum or the urine: 
Serum immunoglobulin free light chain ≥10 mg/dL and abnormal serum 
immunoglobulin kappa lambda free light chain ratio 
3. 
Newly diagnosed subjects eligible for high dose therapy and autologous stem cell 
transplantation.  
4. 
Subject must have an ECOG performance status score of 0, 1, or 2 (see Attachment 2). 
 
 


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5. 
Subject must have pretreatment clinical laboratory values meeting the following criteria during 
the Screening Phase (Lab tests should be repeated if done more than 15 days before C1D1): 
a) hemoglobin 7.5 g/dL (5 mmol/L; prior red blood cell [RBC] transfusion or 
recombinant human erythropoietin use is permitted); 
b) absolute neutrophil count (ANC) 1.0 x 109/L (GCSF use is permitted); 
c) AST ≤2.5 x upper limit of normal (ULN); 
d) ALT ≤2.5 x ULN; 
e) total bilirubin ≤1.5 x ULN (except in subjects with congenital bilirubinemia, such as 
Gilbert syndrome, direct bilirubin ≤1.5 x ULN); 
f) calculated creatinine clearance 40 mL/min/1.73 m2 (see Attachment 3); 
g) corrected serum calcium ≤14 mg/dL (<3.5 mmol/L); or free ionized calcium 
≤6.5 mg/dL (≤1.6 mmol/L) (see Attachment 4); 
h) platelet count 70 x 109/L for subjects in whom <50% of bone marrow nucleated cells 
are plasma cells; otherwise platelet count >50x109/L (transfusions are not permitted to 
achieve this minimum platelet count). 
6. 
Women who are partners of men and of childbearing potential must be practicing one of the 
following methods of birth control: subcutaneous hormonal implant, levonorgestrel-releasing 
intra-uterine system, medroxyprogesterone acetate depot, tubal sterilization, ovulation 
inhibitory progesterone only pills, or sexual intercourse with a vasectomized male partner 
(vasectomy must be confirmed by 2 negative semen analyses). Or women will commit to 
absolute and continuous abstinence confirmed to her physician on a monthly basis. 
Childbearing potential is defined in Section 9.1.2. Contraception will start 4 weeks before the 
start of therapy, during therapy including dose interruptions, for 4 weeks after discontinuation 
of thalidomide and for 4 months after discontinuation of daratumumab. 
7. 
A woman of childbearing potential must have 2 negative serum or urine pregnancy tests at 
Screening, first within 10 to 14 days prior to dosing and the second within 24 hours prior to 
dosing.  
8. 
Each subject (or their legally acceptable representative) must sign an informed consent form 
(ICF) indicating that he or she understands the purpose of and procedures required for the study 
and are willing to participate in the study. Subject must be willing and able to adhere to the 
prohibitions and restrictions specified in this protocol. 
 
 


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Exclusion Criteria 
Any potential subject who meets any of the following criteria will be excluded from participating in the 
study.  
1. 
Subject has received daratumumab or other anti-CD38 therapies previously. 
2. 
Subject has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined 
significance, smoldering multiple myeloma, or solitary plasmacytoma. Monoclonal 
gammopathy of undetermined significance is defined by presence of serum M-protein <3 g/dL; 
absence of lytic bone lesions, anemia, hypercalcemia, and renal insufficiency related to the M-
protein; and (if determined) proportion of plasma cells in the bone marrow of 10% or less (Kyle 
200325). Smoldering multiple myeloma is defined as asymptomatic multiple myeloma with 
absence of related organ or tissue impairment (ROTI) end organ damage (Kyle 200325, Kyle 
200726). 
3. 
Subject has a diagnosis of Waldenström’s macroglobulinemia, or other conditions in which IgM 
M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions. 
4. 
Subject has prior or current systemic therapy or SCT for any plasma cell dyscrasia, with the 
exception of an emergency use of a short course (equivalent of dexamethasone 40 mg/day for 
a maximum 4 days) of corticosteroids before treatment. 
5. 
Subject has peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
Version 4. 
6. 
Subject has had any prior or concurrent invasive malignancy (other than multiple myeloma) 
within 10 years of study start except adequately treated basal cell or squamous cell carcinoma 
of the skin, carcinoma in situ of the cervix, localized prostate adenocarcinoma diagnosed ≥3 
years and without evidence of biochemical failure, or other cancer for which the subject has 
undergone potentially curative therapy and has no evidence of that disease for ≥10 years. 
7. 
Subject has had radiation therapy within 14 days of C1D1. 
8. 
Subject has had plasmapheresis within 28 days of C1D1. 
9. 
Subject is exhibiting clinical signs of meningeal involvement of multiple myeloma. 
10. 
a) 
Subject has known chronic obstructive pulmonary disease (COPD) with a Forced 
Expiratory Volume in 1 second (FEV1) < 50% of predicted normal. Note that FEV1testing is 
required for patients suspected of having COPD and subjects must be excluded if FEV1 <50% 
of predicted normal. 
b) 
Subject has known moderate or severe persistent asthma within the past 2 years (see 
Attachment 5), or currently has uncontrolled asthma of any classification. (Note that subjects 
who currently have controlled intermittent asthma or controlled mild persistent asthma are 
allowed in the study). 
11. 
Subject is known to be seropositive for history of human immunodeficiency virus (HIV) or 
known to have active hepatitis B or hepatitis C. 
12. 
Subject has any concurrent medical or psychiatric condition or disease (eg, active systemic 
infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to 
interfere with the study procedures or results, or that in the opinion of the investigator, would 
constitute a hazard for participating in this study. 


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13. 
Subject has clinically significant cardiac disease, including: 
• 
myocardial infarction within 1 year before randomization, or an unstable or 
uncontrolled disease/condition related to or affecting cardiac function (eg, unstable 
angina, congestive heart failure, New York Heart Association Class III-IV 
• 
uncontrolled cardiac arrhythmia (NCI CTCAE Version 4 Grade ≥2) or clinically 
significant ECG abnormalities 
• 
screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s 
formula (QTcF) >470 msec 
14. 
Subject has known allergies, hypersensitivity, or intolerance to boron or mannitol, 
corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to the 
Investigator's Brochure), or known sensitivity to mammalian-derived products. 
Or subject has known hypersensitivity to thalidomide. 
15. 
Subject has plasma cell leukemia (according to WHO criterion: ≥20% of cells in the peripheral 
blood with an absolute plasma cell count of more than 2 × 109/L) or POEMS syndrome 
(polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes). 
16. 
Subject is known or suspected of not being able to comply with the study protocol (eg, because 
of alcoholism, drug dependency, or psychological disorder). Subject has any condition for 
which, in the opinion of the investigator, participation would not be in the best interest of the 
subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-
specified assessments. 
17. 
Subject is a woman who is pregnant, or breast-feeding, or planning to become pregnant while 
enrolled in this study or within 4 months after the last dose of any component of the treatment 
regimen. Or, subject is a man who plans to father a child while enrolled in this study or within 
4 months after the last dose of any component of the treatment regimen. 
18. 
Subject has had major surgery within 2 weeks before randomization or will not have fully 
recovered from surgery, or has surgery planned during the time the subject is expected to 
participate in the study. Kyphoplasty or Vertebroplasty is not considered major surgery. 
19. 
Subject has received an investigational drug (including investigational vaccines) or used an 
invasive investigational medical device within 4 weeks before randomization or is currently 
enrolled in an interventional investigational study. 
20. 
Subject has contraindications to the use of any components of the backbone treatment regimens, 
per local prescribing information. 
21. 
Incidence of gastrointestinal disease that may significantly alter the absorption of oral drugs. 
22. 
Subjects unable or unwilling to undergo antithrombotic prophylactic treatment. 
 
 
 


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DOSAGE AND ADMINISTRATION 
Daratumumab (16mg/kg) will be administered by intravenous (IV) infusion once every week for 8 weeks 
(VTD induction Cycle 1-2), then every 2 weeks for the remaining induction cycles and consolidation cycles 
based on treatment assignment. Following subsequent re randomization, subjects assigned to the 
daratumumab maintenance arm will receive daratumumab (16mg/kg) once every 8 weeks until documented 
disease progression (limited to a maximum duration of 2 years). 
Subjects will receive 1.3 mg/m2 bortezomib as a SC injection twice a week (Days 1, 4, 8, and 11) for four 
28-day induction cycles (Cycles 1 to 4), and two consolidation cycles (Cycles 5 and 6), with an option to 
change the schedule from twice a week to once a week, should toxicity be encountered. Cycles will remain 
28 days in length regardless of injection interval. 
Thalidomide will be administered PO at 100 mg daily for 4 x28 day induction cycles and 2 x 28 day 
consolidation cycles. Thalidomide should be taken as a single dose at bedtime, to reduce the impact of 
somnolence. Thalidomide can be taken with or without food. 
Dexamethasone will be administered on scheduled days as indicated in the Time and Events Schedule at 
40 mg during Cycles 1 and 2. In Cycles 3 and 4, dexamethasone will be administered at 40 mg on Days 1-
2 and 20 mg on subsequent dosing days. Dexamethasone 20 mg will be administered in Cycles 5 and 6. On 
daratumumab infusion days, in the induction/consolidation phase, dexamethasone may be administered 
intravenously 1 hour before the daratumumab infusion. On days when daratumumab is not administered, 
dexamethasone is administered PO. Dexamethasone tablets are to be taken with or immediately after a meal 
or snack, preferably in the morning.  
In the maintenance phase, dexamethasone 20 mg will be administered as pre-medication on daratumumab 
infusion days. 
SAFETY EVALUATIONS 
Safety evaluations will include adverse event monitoring, physical examinations, electrocardiogram 
(ECGs) monitoring, clinical laboratory parameters (hematology and chemistry), vital sign measurements, 
and ECOG performance status. 
BIOMARKER EVALUATIONS 
Biomarkers for MMY3006 will focus on the evaluation of MRD in bone marrow aspirates and on the 
assessment of clinical efficacy in high-risk molecular subgroups.  
IMMUNOGENICITY EVALUATIONS 
Samples to assess the generation of antibodies to daratumumab (immunogenicity) and associated serum 
daratumumab concentration levels will be obtained from all subjects according to the Time and Events 
Schedule. 
EFFICACY EVALUATIONS 
Assessment of tumor response and disease progression will be conducted in accordance with the IMWG 
response criteria. Efficacy evaluations will include measurements of tumor burden/residual disease, 
myeloma proteins, bone marrow examinations, skeletal surveys, extramedullary plasmacytomas, and serum 
calcium corrected for albumin. 
 
 


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STATISTICAL METHODS 
Sample Size 
The sample size of this study takes into consideration the statistical power for the primary comparisons in 
both stages of the study. For Part 2 (maintenance phase), it is assumed that median PFS from the second 
randomization is 45 months for observation, and daratumumab maintenance will decrease the risk of 
progression or death by 25% (HR=0.75; estimated median PFS of 60 months for daratumumab 
maintenance). To achieve 80% power with a significance level of 0.05, 390 PFS events are needed. 
Assuming a 36 months accrual and 45 months of additional follow-up, approximately 800 subjects 
(400/arm) will be randomized in the second randomization (daratumumab maintenance vs. observation).  
Assuming that 75% of subjects in the induction/ASCT/consolidation stage are eligible to be randomized 
for maintenance, which takes into account the expected response rate as well as potential dropouts, 1080 
subjects (540/arm) will be randomized in the first randomization (daratumumab in combination with VTD 
induction/ASCT/VTD consolidation vs. VTD induction/ASCT/VTD consolidation). This sample size 
would provide at least over 85% power to detect an improvement in sCR rate from 25% to 35% at a 2-sided 
α of 0.05. 
Analysis Population 
Analysis of primary and secondary efficacy variables will be based on the intent-to-treat (ITT) population, 
which includes all subjects randomized in the first randomization. In addition, maintenance-specific 
analyses will use the maintenance-specific intent-to-treat population (ITT-m), which will include all 
subjects who are randomized in the second randomization. 
All safety analyses will be based on the safety analysis set. The safety population will be defined separately 
for the induction/ASCT/consolidation and maintenance stages. These populations will include all subjects 
randomized at each stage who received at least 1 dose of study drugs at the respective stage. 
Efficacy Analyses 
The primary comparison of the 2 randomized induction/consolidation treatments will be made with respect 
to sCR rate using the Cochran-Mantel-Haenszel chi square test in the ITT population. A Mantel-Haenszel 
odds ratio, along with its 2-sided 95% confidence interval, will be calculated. All binary secondary 
endpoints for the induction/ASCT/consolidation stage will be analyzed similarly as the primary endpoint 
(sCR rate). 
The statistical comparison between the 2 induction regimens with respect to PFS from the first 
randomization will need to take into consideration subsequent maintenance assignment (daratumumab 
maintenance or observation). A usual “as-randomized”-type of intent-to-treat analysis that compares the 2 
induction treatments with respect to PFS without considering maintenance treatment has been shown to 
produce potentially biased estimates of treatment effects. As such, 2 appropriate intent-to-treat (ITT)-type 
of induction comparisons of particular interest, 1 specific to each maintenance treatment (daratumumab 
maintenance or observation), will be conducted:  
• 
daratumumab+VTD (D-VTD) induction/consolidation followed by daratumumab maintenance vs. 
VTD induction/consolidation followed by daratumumab maintenance, and 
• 
daratumumab+VTD (D-VTD) induction/consolidation followed by observation vs. VTD 
induction/consolidation followed by observation 
For each of the 2 comparisons, the analysis will include any subjects who are randomized in the first 
randomization and are then subsequently randomized to the specific maintenance treatment as well as those 
subjects who are randomized in the first randomization but are not randomized in the second randomization. 
A stratified Cox regression analysis with inverse probability weighting will be performed (Lokhnygina 
200730), which yields unbiased estimates of treatment effects and maintains Type I error rate. The overall 


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comparison of induction treatments will be made treating these 2 comparisons as 2 strata with the variance 
estimated using the robust variance estimator (the sandwich estimate). These 3 comparisons will all be 
tested with the significance level of 0.05 (2-sided) following the closed testing procedure. Essentially, the 
statistical significance is established for each of the 2 maintenance-specific comparisons if both itself and 
the overall induction comparison are significant at the 2-sided level of 0.05. Other time-to-event endpoints, 
except for duration of response, will be analyzed similarly. Duration of response will be presented 
descriptively using the weighted Kaplan-Meier estimates by Miyahara and Wahed 201036. 
The primary comparison of the 2 randomized maintenance treatments (daratumumab maintenance and 
observation) will be made with respect to PFS from the second randomization using a stratified log-rank 
test in the ITT-m population. The Kaplan-Meier method will be used to estimate the distribution of PFS 
from the second randomization for each treatment. The treatment effect (hazard ratio) and its 2-sided 95% 
confidence intervals are to be estimated using a stratified Cox regression model with maintenance treatment 
as the sole explanatory variable. In addition, the interaction between induction/consolidation and 
maintenance will be tested at a 2-sided significance level of 0.05 by a stratified Cox regression model that 
includes the interaction term between maintenance treatment and induction/consolidation treatment. All 
secondary time-to-event endpoints in the maintenance stage will be analyzed similarly as for the primary 
endpoint (PFS from the second randomization). 
The comparison of the 2 randomized maintenance arms on binary secondary endpoints will be made using 
the Cochran-Mantel-Haenszel chi square test in the population of all subjects that are randomized in the 
second randomization. The observed rate of the binary outcome will be provided along its 2-sided 95% CIs. 
A Mantel-Haenszel odds ratio, along with its 2-sided 95% confidence interval, will be calculated. 
Safety Analyses 
In general, adverse events that occurred during the induction/consolidation and maintenance stages will be 
summarized separately. Treatment-emergent adverse events for each stage will be defined as events that 
occur or worsen after administration of the first dose of during that stage and through 30 days after the last 
dose of study drug in that stage and before the next phase of treatment begins. Adverse events will be 
summarized by system organ class and preferred terms, NCI toxicity grade, and by action taken with study 
treatment.  
Summaries, listings, datasets, or subject narratives will be provided, as appropriate, for those subjects who 
die, who discontinue treatment due to an adverse event, or who experience a severe or a serious adverse 
event. These will be provided using the same formats as those used for adverse events. 
 


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Table 1. 
TIME AND EVENTS SCHEDULE: INDUCTION AND CONSOLIDATION PHASES 
Notes 
Screening 
Phase 
Induction 
Treatment 
(Cycles 1-4) 
ASCT 
Consolidation 
Treatment  
(Cycles 5-6) 
Day 100 
post ASCT 
within 28 days 
before 
randomization 
D1 
D28 
(refer to 
Section 
9.1.3) 
D1 
proceed to 
Table 3 
Study treatment should be initiated within 3 days after randomization. Induction and consolidation cycles are approximately 28 days in duration. Treatment will be for a 
maximum of 4 induction cycles and 2 consolidation cycles. The start of each cycle may occur ±3 days of the scheduled day in order to accommodate the schedule of the 
site or subject. Details of ASCT will be collected as per Section 9.1.3. 
Procedures 
Informed consent 
ICF must be signed before any study-related procedures are 
performed. 
X 
 
 
 
 
Eligibility criteria 
 
X 
 
 
 
 
X 
Demography/ 
Medical History 
 
X 
 
 
 
 
 
Height 
 
X 
 
 
 
 
 
Chest X-ray 
May be  performed within 42 days before randomization 
X 
 
 
 
 
 
FEV1test 
Subjects with COPD or asthma, FEV1 should be measured 
X 
 
 
 
 
 
ECOG 
X 
C4 
 
X 
12-lead ECG 
Acceptable for screening if performed as part of SOC within 
42 days before randomization 
X 
C4 
 
 
X 
Physical exam 
Including neurological exam 
X 
Symptom and disease directed exam as clinically indicated 
Vital signs, weight 
X 
Please see Table 2 for details. 
Blood type and IAT 
results 
Includes ABO, Rh, and IAT results. Provide results on wallet 
card. 
C1D1 
predose 
 
 
 
 
Laboratory Assessments 
Pregnancy test 
For women of childbearing potential only. During screening, within 10-14 days prior to first dose and again within 24 hrs prior to first dose. During 
study, weekly during Cycle 1 and then monthly in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles. 
Please refer to Section 9.2 for details. 
 
Hematology 
Local lab. Testing have to be performed within the 2 weeks 
before C1D1 
X 
Please see Table 2 for details. 
Serum chemistry 
Local lab. Testing have to be performed within the 2 weeks 
before C1D1 
X 
Please see Table 2 for details. 
Daratumumab 
immunogenicity and 
serum 
concentration 
For all subjects: Sample to be taken prior to treatment on 
C1D1.  
Following daratumumab administration If an infusion reaction 
occurs, obtain unscheduled blood sample as soon as 
possible. Samples to be sent to central laboratory. 
C1D1 
predose 
 
 
 
 


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Notes 
Screening 
Phase 
Induction 
Treatment 
(Cycles 1-4) 
ASCT 
Consolidation 
Treatment  
(Cycles 5-6) 
Day 100 
post ASCT 
within 28 days 
before 
randomization 
D1 
D28 
(refer to 
Section 
9.1.3) 
D1 
proceed to 
Table 3 
Disease Evaluations: Every effort should be made to conduct disease evaluations as per schedule (window ±3 days). Refer to Section 9.6 for details on efficacy evaluations. Response 
assessment for primary efficacy endpoints should occur as close to Day 100 post-ASCT as possible (window up to Day 114 post ASCT). 
Cytogenetics/FISH 
(stratification) 
For screening (up to 42 days before randomization) 
A core biopsy and aspirate is strongly preferred for screening 
and to confirm response (sCR). If not available, morphologic 
review of the aspirate smear is acceptable. 
Flow cytometry should be systematically performed at Day 
100 to evaluate sCR. 
X 
 
 
 
 
 
Bone Marrow Exam 
Myeloma disease 
evaluation 
X 
 
 
 
C4 
 
 
 
 
X 
 
Serum disease 
evaluations (SPEP) 
Blood sample to be sent to central laboratory. IFE and FLC 
when CR is suspected or maintained. FLC every cycle for 
subjects with light chain myeloma. Not required C1D1. 
X 
X 
C4 
 
X 
X 
Quantitative Ig 
Blood. Central lab 
X 
 
C4 
 
 
X 
Urine disease 
evaluations (UPEP) 
24H Urine. Sample to be sent to central laboratory. IFE when 
CR is suspected or maintained. Not required C1D1. 
X 
X 
C4 
 
X 
X 
β2-microglobulin 
Central lab. 
X 
 
 
 
 
 
Calcium 
Local lab. 
X 
X 
C4 
 
X 
X 
Albumin 
Local.and central lab 
X 
X 
C4 
 
X 
X 
Assessment of lytic 
disease 
Acceptable for screening if performed as part of SOC within 
42 days before randomization 
X 
As clinically indicated 
Extramedullary 
plasmacytomas 
Subjects with history of plasmacytoma; acceptable for 
screening if performed as part of SOC within 42 days before 
randomization 
X 
 If applicable, by physical exam every 4 wks, by radiologic exam (if required) 
every 12 wks 
Patient Reported 
Outcome 
EORTC-QLQ-30 and EQ-5D-5L at each specified visit. To be 
completed before any other study procedures are performed. 
X 
C4 
 
X 
Ongoing Subject Review 
Adverse Events 
See Section 12 for detailed instructions. 
continuous from the time of signing of ICF until 30 days after last dose of last study drug 
Concomitant 
Medications 
See Section 8 for detailed instructions. 
continuous from the time of signing of ICF until 30 days after last dose of last study drug 
 
 
 


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Table 2. 
TIME AND EVENTS SCHEDULE: STUDY DRUG DOSING, INDUCTION AND CONSOLIDATION PHASES 
Study Day 
Notes 
Week 1 
Week 2 
Week 3 
Week 4 
D1 
D2 
D4 
D8 
D9 
D11 
D15 
D16 
D22 
D23 
D28 
Cycles are 4 weeks (28 days) in duration and are based on the administration of VELCADE. Treatment will be for 4 x 28 days induction cycles and following ASCT 2x consolidation cycles.The 
start of each cycle may occur ±3 days of the scheduled day in order to accommodate the schedule of the site or subject. On dosing days where the chemotherapy combination products are 
given with daratumumab, study treatment should be administered in the following order (when more than 1 component is scheduled): dexamethasone, daratumumab, bortezomib and thalidomide 
(at bed time). 
Hematology 
Local lab. Testing may be performed up to 2 days before 
infusion. Results of hematology tests must be evaluated 
before treatment. Perform at additional timepoints, as 
clinically indicated. 
X 
 
 
C1-
C2 
 
 
X 
 
C1-C2 
 
 
Clinical 
Chemistry 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
If weight changes by more than 10% from baseline, the dose 
of all study treatments will be re-calculated 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
For Arm A: to be measured at the beginning of the visit. 
For Arm B: Vital signs (blood pressure, temperature, pulse) 
measured in sitting position. On Cycle 1 Day 1: immediately 
before the start of dara infusion; at 0.5, 1, 1.5, 2, 3.5 hrs after 
the start of the infusion; at end of infusion; and 0.5, 1hr after 
end of infusion. For all other infusions, vital signs will be 
measured immediately before infusion start and at end of 
dara infusion. 
X 
 
 
C1-
C2 
 
 
X 
 
C1-
C2 
 
 
Diary review 
Accountability/exposure check 
X 
 
 
 
 
 
 
 
 
 
 
Pre-infusion Medications, Arm B only 
Antihistamine 
Administer not more than 3 hours before dara infusion. 
Paracetamol or acetaminophen 650-1000 mg. H1  receptor 
antagonist (dosing according to institutional standard) ;  
10mg of montelukast is required prior to cycle 1 day 1 of 
Daratumumab and is optional before all other doses 
X 
 
 
C1-C2 
 
 
X 
 
C1-C2 
 
 
Paracetamol 
X 
 
 
C1-C2 
 
 
X 
 
C1-C2 
 
 
Montelukast 
X 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration, Arm A and Arm B 
Dexamethasone 
Administer 1 hr before dara infusion. Dexamethasone 40mg 
in C1 and C2. In C3 and C4, dexamethasone 40mg on D1 
and D2, dexamethasone 20mg on subsequent dosing days. 
Dexamethasone 20mg in C5 and C6. Also serves as pre-
infusion medication for daratumumab. 
X 
X 
 
X 
X 
 
X 
X 
C1-
C2 
C1-
C2 
 
Bortezomib 
Administer by SC injection. Dose may be delayed up to 48 
hrs, however subsequent doses must be adjusted as all 
VELCADE doses must be at least 72 hrs apart. Doses that 
need to be withheld are skipped and will not be made up later 
in the cycle. 
X 
 
X 
X 
 
X 
 
 
 
 
 
Thalidomide 
Dispense on Day 1 for self-administration. 
100 mg every day at bedtime. 
Study Drug Administration, Arm B Only 


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Daratumumab 
Refer to IP manual for recommendations on daratumumab 
infusion rate. Skip if infusion cannot be given within 1 wk. 
X 
 
 
C1-
C2 
 
 
X 
 
C1-
C2 
 
 
 
Table 3. 
TIME AND EVENTS SCHEDULE: MAINTENANCE PHASE 
 
 
Notes 
Maintenance Treatment Phase (Weeks) 
EOT 
Pre-PD 
FU 
PD  
Survival 
FU 
1 
9 
17 25 33 41 49 52 57 65 73 81 89 97 
105 
 
Repeat Day 100 post -ASCT assessments if they were not done within 14 days of Week 1 of the Maintenance Phase. Study treatment 
should be initiated within 10 days after randomization. Week 1 corresponds to date of first daratumumab maintenance infusion for 
subjects in Arm B and randomization date for subjects in Arm A. The start of each cycle/visit may occur ±3 weeks of the scheduled day 
 
This visit 
may occur 
±3 weeks 
of the 
scheduled 
day 
 
This visit 
may occur 
±3 weeks 
of the 
scheduled 
day 
 
Procedures 
 
 
2nd randomization 
within 10 days of Wk1D1 of 
Maintenance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
8wks and 
16wks post 
PD 
Then every 4 
months 
12-lead ECG 
 
As clinically indicated 
 
 
 
 
Physical exam 
 
Symptom and disease directed exam as clinically indicated 
 
 
 
Weight 
If a subject’s weight changes 
>10% from baseline, the 
dose of all study drug will be 
re-calculated 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Vital signs 
For Arm A: to be measured 
at the beginning of the visit. 
For Arm B: Vital signs (blood 
pressure, temperature, 
pulse) measured in sitting 
position. For 1st infusion: 
immediately before the start 
of dara infusion; at 0.5, 1, 
1.5, 2, 3.5 hrs after the start 
of the infusion; at end of 
infusion; and 0.5, 1hr after 
end of infusion. For all other 
infusions, vital signs will be 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 


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Notes 
Maintenance Treatment Phase (Weeks) 
EOT 
Pre-PD 
FU 
PD  
Survival 
FU 
1 
9 
17 25 33 41 49 52 57 65 73 81 89 97 
105 
measured immediately 
before infusion start and at 
end of dara infusion. 
Assessment of 
lytic disease, and 
extramedullary 
plasmacytomas 
Same type of imaging as 
done for screening 
procedures for lytic disease. 
Same method of 
assessment done at 
screening for extramedullary 
plasmacytomas (if 
applicable) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
Study Drug Administration (Arm B only, following second randomization) 
 
 
Daratumumab  
 
 
 
Administer premedications 
as per Section 6.1.3 
10mg of montelukast is 
required prior to 1st infusion 
of dara if patient was in VTD 
Arm during Part 1 and is 
optional before all other 
doses. 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Laboratory Assessments 
 
 
Pregnancy test 
Women of childbearing 
potential in Arm B only 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
x 
 
 
 
Hematology 
For Arm A: at the time of the 
visit. 
For Arm B: Testing may be 
performed up to 2 days 
before infusion days. Results 
of hematology tests must be 
evaluated before each study 
drug administration. Perform 
at additional timepoints, as 
clinically indicated. To be 
done by local lab. 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Serum chemistry 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 


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Notes 
Maintenance Treatment Phase (Weeks) 
EOT 
Pre-PD 
FU 
PD  
Survival 
FU 
1 
9 
17 25 33 41 49 52 57 65 73 81 89 97 
105 
Daratumumab 
immunogenicity 
and serum 
concentration 
 
To be taken from all pts  
For Arm B: to be taken 
predose if it falls on a dara 
dosing day. 
.Samples to be sent to 
central laboratory. 
In addition, following 
administration of 
daratumumab if an infusion 
reaction occurs, obtain 
unscheduled blood sample 
as soon as possible.  
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Randomiza
tion #1 or 
#2 Arm B 
patients 
only:  8wks 
post last 
dose of 
dara 
 
 
 
 
 
Disease Evaluations: Every effort should be made to conduct disease evaluations as per schedule (window ±3 days). Refer to Section 9.2 for details on efficacy 
evaluations. 
 
 
Serum disease 
evaluations 
(SPEP) 
IFE and FLC when CR is 
suspected or maintained. 
FLC every cycle for subjects 
with light chain myeloma. 
Central lab. 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Q12wk until 
PD  
X 
 
Quantitative Ig 
Central lab. 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
 
X 
 
Urine disease 
evaluations 
(UPEP) 
IFE when CR is suspected 
or maintained. Central lab. 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Q12wk until 
PD  
X 
 
Calcium,  
Local lab. 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Q12wk until 
PD  
 
 
Albumin 
Local & Central Lab 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Q12wk until 
PD 
 
 
Bone Marrow 
aspirate/biopsy for 
myeloma disease 
evaluation 
A core biopsy and aspirate is 
strongly preferred to confirm 
response (sCR). If not 
available, morphologic 
review of the aspirate smear 
is acceptable. This is done 
by the local laboratory. 
An aspirate for Flow 
Cytometry/MRD should be 
systematically performed 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X (please 
refer to 
table 3C)  
 
 


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Notes 
Maintenance Treatment Phase (Weeks) 
EOT 
Pre-PD 
FU 
PD  
Survival 
FU 
1 
9 
17 25 33 41 49 52 57 65 73 81 89 97 
105 
and sent to the central lab 
whenever it will be 
necessary to evaluate sCR. 
Assessment of 
lytic disease 
 See Section 9.6.6 for 
detailed instructions. 
As clinically indicated 
 
 
 
 
Extramedullary 
plasmacytomas 
Subjects with history of 
plasmacytoma 
(cf. § 9.6.7) 
 If applicable, by physical exam every 4 wks, by radiologic exam (if required) every 12 wks 
X 
X 
 
 
PRO 
EORTC-QLQ-30 and EQ-
5D-5L at each specified visit. 
To be completed before any 
other study procedures are 
performed. 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
8wks and 
16wks post 
PD 
 
 
Follow-up Assessments (after PD), every 4 months 
 
 
Second primary 
malignancies 
 
<-----------------------------------------------------------------X---------------------------------------------------------> 
 
PFS2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Anticancer 
Therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Survival 
 
<-----------------------------------------------------------------X--------------------------------------------------------> 
 
X 
 
X 
 
Ongoing Subject Review 
 
 
Adverse Events 
See Section 12 for detailed 
instructions. 
<--------------------------------X- until 30 days post last protocol regimen dose or last visit for OBS arm-------------------------------> 
 
 
Concomitant 
Medications 
See Section 8 for detailed 
instructions. 
<--------------------------------X- until 30 days post last protocol regimen dose or last visit for OBS arm ------------------------------> 
 
 
 
Abbreviations: AE=adverse event; C=cycle; COPD=chronic obstructive pulmonary disease; CR=complete response; ECOG=Eastern Cooperative Oncology Group; D=day; 
Dara=daratumumab; ECG=electrocardiogram; EOT= End-of-Treatment visit to be performed for all arms; FEV1= Forced Expiratory Volume (in 1 second); FFPE=formalin-fixed 
paraffin embedded; FLC=free light chain; FU: follow-up; ICF=informed consent form; IP=investigational product; MRD=minimal residual disease; MRI=magnetic resonance imaging; 
PBMC= peripheral blood mononuclear cell ; PK=pharmacokinetics; PD= disease progression; PRO=patient reported outcome; SAE=serious adverse event; SOC=standard of care; 
SPEP=serum M-protein quantitation by electrophoresis; UPEP=urine M-protein quantitation by electrophoresis;  Wk=week 


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Table 3 A. TIME AND EVENTS SCHEDULE (BIOMARKER SAMPLES): INDUCTION AND CONSOLIDATION PHASES 
Sample 
 
 
 
 
 
Notes 
Test 
Screening 
Phase 
Induction 
Treatment 
(Cycles 1-4) 
ASCT 
Consolidation 
Treatment  
(Cycles 5-6) 
Day 100 
post 
ASCT 
within 28 
days before 
randomization 
D1 
D28 
D1 
Biomarker laboratory assessments 
Bone marrow 
aspirate/biopsy 
 
 
 
 
For screening (up to 42 days 
before randomization) 
 
For response/MRD analysis 
fresh bone marrow aspirate is 
required. Flow Cytometry 
should be systematically 
performed at Day 100 to 
evaluate sCR. 
 
All samples for analysis to be 
sent to central laboratory 
 
MRD (Next Gen Seq) 
 
X 
 
 
C4 
 
 
 
X 
 
Response/MRD (Centralised 
flow)  
 
 
 
C4 
 
 
 
X 
 
 
Immuno phenotyping/Flow 
(HOVON pts only) 
 
X 
 
 
 
 
X 
 
Sequencing (DNA/RNA) 
 
X 
 
 
 
 
 
Whole blood  
Central lab.HOVON pts Only 
 
Immunophenotyping (HOVON 
pts only 
 
X 
 
C1 
 
 
X 
Whole blood  
Central lab, processed to 
plasma/PBMC’s 
Biomarkers 
 
X 
 
 
 
 
X 
 
 
 


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Table 3 B. 
TIME AND EVENTS SCHEDULE (BIOMARKER SAMPLES): MAINTENANCE PHASE 
 
Notes 
Maintenance Treatment Phase (Weeks) 
FU 
PD 
1 
9 
17 25 
33 
41 49 
52 
57 65 73 81 89 97 
105 
 Week 1 corresponds to date of first daratumumab maintenance infusion for subjects in Arm B and randomization date for subjects in Arm A. The start of each cycle/visit may occur 
±3 weeks of the scheduled day 
 
Biomarker laboratory assessments 
 
Bone marrow aspirate 
for MRD (NGS & Flow 
cytometry in selected 
pts) 
For Response/MRD 
(Centralised flow) fresh bone 
marrow aspirate is required.   
Flow Cytometry should be 
systematically performed for 
patients who achieve at least 
VGPR or whenever it will be 
necessary to evaluate sCR. 
 All samples for analysis to be 
sent to central laboratory 
 
 
 
X(at least VGPR) 
 
 
 
X(at least VGPR) 
 
 
 
 
 
 
X(at least VGPR) 
X (please refer 
to table 3 C) 
 
 
 
   
Immunophenotyping/bio-
markers 
Bone marrow aspirate,Central 
lab. (HOVON pts only) 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
Cytogenetics 
(FISH/DNA/RNA 
Analysis) 
Bone marrow aspirate/biopsy 
(Central Lab) 
 
 
 
 
 
 
X 
Blood samples 
immunophenotyping/ 
biomarkers 
Central lab.(HOVON pts only) 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 


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Table 3 C. 
TIME AND EVENTS SCHEDULE (BIOMARKER SAMPLES): Pre-PD FU phase  
 
 
 


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Notes 
Pre-PD FU Phase (at some timepoint after the end of maintenance 
phase*)  
At 1 year* 
At 2 years* 
At 3 years* 
 
Biomarker laboratory assessments 
Bone marrow 
aspirate for MRD 
(NGS & Flow 
cytometry in MRD 
negative patients 
after week 105 or 
last MRD 
assessment since 
D100)  
 An aspirate for Flow 
Cytometry/MRD 
should be 
systematically 
performed and sent to 
the central lab  
X 
X 
X 
*The Pre-PD follow up visit closest to this sampling timepoint can be used for MRD sampling. 
 
 


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ABBREVIATIONS 
ANC 
Absolute Neutrophil Count 
ADCC 
antibody-dependent cell-mediated cytotoxicity 
ADCP 
antibody-dependent cellular phagocytosis 
AE 
adverse event 
ALT 
ALanine aminotransferase 
ANC 
absolute neutrophil count 
ASA 
AcetylSalicylic Acid 
ASCO 
American Society of Clinical Oncology 
ASCT 
Autologous Stem Cell Transplantation 
AST 
alanine aspartate transferase 
AUC(0-t) 
area under the serum concentration versus time curve between time zero and a defined time point t 
BFU-E 
Blast Forming Unit – Erythrocyte 
BM-MNC 
bone marrow mononuclear cell 
BSA 
body surface area 
BUCY 
Busulfan n –cyclophosphamide 
BUMEL 
busulfan + melphalan 
BUN 
Blood urea nitrogen 
CDC 
complement-dependent cytotoxicity 
CFU GM 
Colony Forming Unitt-Granulocyte Macrofage 
CI 
confidence Interval 
CIP 
complement inhibitory proteins 
CL 
Total systemic clearance of drug after IV administration 
CL/F 
Apparent systemic clearance of drug after extravascular administration 
Cmax 
Maximum observed Concentration 
Cmin 
Minimum observed Concentration 
CNV 
Copy number variation 
COPD 
chronic obstructive pulmonary disease 
CR 
Complete Response 
CRAB 
hyperCalcemia Renal Insufficiency Anemia Bone lesions 
CT 
Computed Tomography 
Dara 
Daratumumab 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
D-VTD 
daratumumab+VTD 
DVD 
doxorubicin+VELCADE+dexamethasone 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
eDC 
electronic Data Capture 
EOT 
end-of-Treatment 
FEV1 
Forced Expiratory Volume (in 1 second) 
FFPE 
formalin-fixed paraffin embedded 
FLC 
Free Light Chain 
FU 
Follow-up 
G-CSF 
granulocyte colony stimulating factor 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
HDT-ASCT 
high dose therapy and autologous stem cell transplant 
HOVON 
Haemato Oncology Foundation for Adults in the Netherlands 
HIV 
Human Immunodeficiency Virus 
HR 
hazard ratio 
IAT 
Indirect Antiglobulin Test (also known as indirect Coombs test) 
ICA 
Isotype Control Antibody 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 


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IEC 
Independent Ethics Committee 
IFE 
Immunofixation  
IFM 
Intergroupe Francophone du Myelome 
IHC 
ImmunoHistoChemistry 
IL 
InterLeukin 
IMiD 
immunomodulatory agent 
IMWG 
International Myeloma Working Group 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
intention to treat 
ITT-m 
maintenance specific intention to treat 
ISS 
International Staging System 
IV 
Intravenous 
IWRS 
interactive web-based randomization system 
LDH  
lactic acid dehydrogenase 
LMWH 
Low Molecular Weight Heparin 
mAb 
monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEL 140 
Melphalan 140 mg/m² 
MGUS 
Monoclonal Gammopathy of Undetermined Significance 
MM 
Multiple Myeloma 
MoA 
mechanism of action 
M protein 
monoclonal paraprotein 
MP 
Melphalan+Prednisone 
MR 
Minimal Response 
MRD 
Minimal Residual Disease 
MRI 
Magnetic Resonance Imaging 
MTD 
maximum-tolerated dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
nCR 
near CR 
NK 
Natural Killer cell 
ORR 
overall response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PBSC 
peripheral blood stem cells 
PCA 
Progenitor Cell Assay 
PCP 
pneumocystis carinii pneumonia 
PD 
progressive disease 
PET 
Positron emission tomography 
PFS 
Pre-PD FU 
progression-free survival 
Pre-Progression Follow-Up 
PK 
Pharmacokinetics 
PI 
proteasome inhibitor 
PO 
Per Os 
POEMS 
polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes 
Pom-dex 
Pomalidomide-dexamethasone 
PQC 
product quality complaint 
PR 
Partial Response 
PRO 
patient reported outcome 
QD 
every day 
QIgs 
quantitative immunoglobulins 
QTcF 
QT interval corrected by Fridericia’s formula 
RBC 
red blood cell 
Rd / RVD 
lenalidomide (Revlimid) + dexamethasone / Revlimid + VELCADE + dexamethasone 
ROTI 
related organ or tissue impairment 
SAE 
serious adverse event 
SC 
Subcutaneous 
sCR 
stringent Complete Response 


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SCT 
Stem Cell Transplantation 
SD 
Stable Disease 
SNP 
Single Nucleotide Polymorphisms 
SOC 
standard of care 
SPEP 
Serum M-protein ElectroPhoresis 
t1/2 
half-life 
TBI 
Total Boby Irradiation 
TD 
Thalidomide + dexamethasone 
TTP 
time to progression 
ULN 
upper limit of normal  
UPEP 
24-hour urine M-protein quantitation by electrophoresis 
V 
volume of distribution 
VAD 
vincristine+doxorubicin+dexamethasone 
VCD 
VELCADE + cyclophosphamide + dexamethasone 
VD 
VELCADE (bortezomib) + dexamethasone 
VGPR 
very good partial response 
VMP 
VELCADE + melphalan + prednisone 
Vss/F 
Apparent volume of distribution at steady-state 
VTD 
VELCADE (bortezomib) +thalidomide+dexamethasone 
WHO 
World Health Organization 
Wk 
Week 
 
 
 
 


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1. 
INTRODUCTION  
1.1. 
Background 
1.1.1. 
Multiple Myeloma 
Multiple myeloma is a malignant disorder of the plasma cells, characterized by uncontrolled and 
progressive proliferation of a plasma cell clone. The proliferating multiple myeloma cells displace 
the normal bone marrow, leading to dysfunction in normal hematopoietic tissue and destruction of 
the normal bone marrow architecture, which is reflected by clinical findings such as anemia, 
paraprotein in serum or urine, and bone resorption seen as diffuse osteoporosis or lytic lesions 
shown in radiographs (Kyle 200325).  
Treatment choices for multiple myeloma vary with the aggressiveness of the disease and related 
prognostic factors (Palumbo 201145). Newly diagnosed patients in good physical health with active 
disease will generally receive high-dose chemotherapy with autologous stem cell transplantation 
(ASCT) (Attal 19961, Child 200310). Eligibility for ASCT is established primarily by age and 
comorbidities (Harousseau 200921). For patients in whom transplantation is not an option, 
treatment traditionally consists of systemic chemotherapy, with adjunctive use of radiation or 
surgery in selected cases associated with extramedullary disease (Engelhardt 201414, NCCN 
201340, Palumbo 200946, Smith 200553). 
The therapeutic landscape of multiple myeloma has changed markedly in the past decade with the 
introduction of the novel immunomodulatory agents, thalidomide, lenalidomide, and 
pomalidomide, as well as proteasome inhibitors, bortezomib (VELCADE®) and carfilzomib. New 
approaches to therapy that incorporate these agents have produced significantly higher response 
rates and improved duration of both progression-free survival (PFS) and overall survival (OS) in 
the context of randomized, controlled studies. Collectively, novel therapies for multiple myeloma 
have been associated with substantial improvements in patient outcome (Kumar 2012b24).  
1.1.2. 
Daratumumab 
Daratumumab is a human IgG1ĸ monoclonal antibody (mAb) that binds with high affinity to a 
unique epitope on CD38, a transmembrane glycoprotein. It is a targeted immunotherapy directed 
towards tumor cells that express high levels of CD38, such as plasma cells from patients with 
multiple myeloma. This target is distinct from those of other approved agents for multiple 
myeloma therapy. 
Based on preclinical data, daratumumab may utilize multiple effector cell functions, resulting in 
immune mediated killing of tumor cells. In ex vivo experiments utilizing human bone marrow 
stromal cells co-cultured with primary multiple myeloma cells, complement-dependent 
cytotoxicity (CDC) occurs rapidly and demonstrates maximal myeloma cell killing by 
daratumumab within 1 hour of antibody-mediated activation of the complement proteins (de Weers 
201111). Daratumumab-induced antibody-dependent cell-mediated cytotoxicity (ADCC) is slower 
in its action, with maximal ADCC by daratumumab observed at 4 hours in vitro (de Weers 201111). 
Daratumumab has also been shown to induce antibody-dependent cellular phagocytosis (ADCP) 


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in the presence of macrophages within 4 hours in vitro (Overdijk 201342). The precise role of some 
or all of these effector functions in reducing tumor burden in patients is unknown. 
1.1.3. 
Nonclinical Studies 
Two ex vivo studies evaluated the effects of combining daratumumab with chemotherapeutic 
agents and immunomodulator agents that are currently used for the treatment of multiple myeloma. 
In the first study (GMB3003-069), a combination of lenalidomide and daratumumab against 
multiple myeloma was evaluated (data on file). Daratumumab-dependent cell-mediated 
cytotoxicity of purified primary multiple myeloma cells and the patient-derived multiple myeloma 
cell line UM-9 killing was significantly augmented by lenalidomide pretreatment of peripheral 
blood mononuclear cells (PBMC) from healthy donors (effector cells). Synergy was demonstrated 
between lenalidomide and daratumumab-induced ADCC in bone marrow mononuclear cells of 
subjects with multiple myeloma. Daratumumab-induced ADCC of UM-9 cells was significantly 
up-regulated in PBMCs that were derived from 3 subjects with multiple myeloma during 
lenalidomide treatment. From this study, it is concluded that lenalidomide and daratumumab 
enhance killing of multiple myeloma cells ex vivo via ADCC.  
In a second study (GMB3003-070), the potential benefit of combining daratumumab with multi-
drug chemotherapy regimens was evaluated in fresh tumor cells from subjects with multiple 
myeloma (data on file). Lysis of primary tumor cells was measured directly in bone marrow 
mononuclear cell (BM-MNC) isolates obtained from subjects with multiple myeloma. Synergistic 
tumor cell lysis was demonstrated when daratumumab was combined with lenalidomide and/or 
bortezomib, even in samples from subjects that were refractory to lenalidomide and bortezomib 
treatment. Treatment of BM-MNC with lenalidomide or bortezomib resulted in 10% and 18% 
lysis, respectively. A combination of lenalidomide and bortezomib resulted in 25% lysis of BM-
MNC. When daratumumab was added to either lenalidomide or bortezomib, a 2-fold increase in 
lysis was observed compared with lenalidomide or bortezomib alone. When daratumumab was 
added to combinations of dexamethasone, lenalidomide and bortezomib or to bortezomib, 
prednisone, and dexamethasone, the cell lysis was significantly increased (p<0.001) compared 
with the triple combination alone (no daratumumab) (van der Veer 2011b57). Refer to Figure 1 and 
Figure 2. 
 


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Figure 1: 
Daratumumab-Enhanced Multiple Myeloma Cell Killing by Key Multiple Myeloma 
Chemotherapeutic Agents 
 
Figure 2: 
Dose-dependent Lysis of Multiple Myeloma cells in Triple Chemotherapy Treatments 
 
In toxicology studies in cynomolgus monkeys and chimpanzees, the major observed toxicities 
were cytokine release syndrome and thrombocytopenia. A minor decrease in red blood parameters 
was also observed. Cytokine release was seen only following the first dose and was markedly 
reduced following implementation of a 10 mg predose of daratumumab. The effect on platelets 
and red cells was reversible. 
To assess the effect of daratumumab on hematopoietic progenitor cells, colony forming units – 
granulocyte-macrophage (CFU-GM) and blast forming units – erythrocyte (BFU-E) were counted 
in a progenitor cell assay (PCA). Using fresh or thawed unselected mobilized blood progenitor 
cells, CFU-GM and BFU-E in plates including DARA or isotype-control antibody (ICA) at 


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500ng/ml were not significantly different from control plates. At 3 weeks post-SCT, NK cells were 
a median of 30% of mononuclear cells and actively lysed a median of 75% of target cells with 
DARA compared to ICA (P < 0.05). (personal communication, Raymond Comenzo). 
1.1.4. 
Clinical Studies 
1.1.4.1. 
Single-Agent Daratumumab Studies (GEN501 and MMY2002) 
Two single-agent studies with daratumumab are ongoing (Studies GEN501 and MMY2002; Table 
4). Seventy-seven (77) subjects have been treated in Parts 1 and 2 of Study GEN501 with doses 
ranging from ≤1 mg/kg to 24 mg/kg, and 124 subjects have been treated in Study MMY2002.  
Table 4: 
Daratumumab Single-Agent Studies GEN501 and MMY2002 
Study Number 
Study Design 
Number of subjects Treated/ 
Treatment Regimen 
GEN501 
Open-label, Phase 1/2, first-in-human, 
single-agent study in subjects with 
multiple myeloma whose disease is 
relapsed or refractory to at least 2 prior 
lines of therapies 
 
Population was heavily treated with 
prior treatment, including ASCT, 
chemotherapy based regimens, IMiDs, 
and PIs 
Part 1 
n=32 total treated with daratumumab weekly 
 
0.005-1 mg/kg (n=17) 
2 mg/kg (n=3) 
4 mg/kg (n=3) 
8 mg/kg (n=3) 
16 mg/kg (n=3) 
24 mg/kg (n=3) 
Part 2 
n=51 total treated 
8 mg/kg (n=30) 
 
First dose, followed by a 3-
week resting period, 
followed by weekly doses 
for 7 weeks, then q2w for an 
additional 14 weeks, and 
monthly, until the subject 
experiences disease 
progression or 
unmanageable toxicity 
 
16 mg/kg (n=21) 
 
Weekly for 8 weeks, 
followed by q2w for an 
additional 16 weeks, and 
monthly, for up to 96 weeks, 
or until the subject 
experiences disease 
progression or 
unmanageable toxicity 
MMY2002 
Open-label, multicenter, 2-stage, Phase 
2 study of daratumumab for the 
treatment of subjects with multiple 
myeloma who have received at least 3 
prior lines of therapy including a PI and 
an IMiD or whose disease is double 
refractory to both a PI and an IMiD 
Part 1, Stage 1 (18 subjects randomized to 8mg/kg and 16 
subjects randomized to 16mg/kg): total of 34 subjects 
Part 1, Stage 2 (16mg/kg): total of 25 subjects 
Stage 2 (16mg/kg): total of 65 subjects 
ASCT=autologous stem cell transplant; IMiD= immunomodulatory agent; PI=proteasome inhibitor 
 
Among the 32 subjects treated in Part 1 of Study GEN501, the maximum tolerated dose (MTD) 
was not reached following intravenous (IV) infusions up to 24 mg/kg. Two subjects experienced 
dose-limiting toxicities (DLTs) in the lower dose cohorts (a subject in the 0.1-mg/kg group had 
Grade 3 anemia and Grade 4 thrombocytopenia, and a subject in the 1.0-mg/kg group had Grade 3 
aspartate aminotransferase increased).  


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Among the 51 subjects treated in Part 2 of Study GEN501, serious adverse events (SAEs) were 
reported in 37% of subjects (43% of subjects in the 8-mg/kg group and 29% of subjects in the 16 
mg/kg-group). The most frequently reported SAEs were pneumonia (6% subjects), and pyrexia 
(4% of subjects). 
Among the 34 subjects treated in Stage 1 of Study MMY2002, SAEs were reported in 27% of 
subjects (33% of subjects in the 8 mg/kg group, and 19% of subjects in the 16 mg/kg group). The 
most frequently reported SAE was renal failure acute (6% of subjects). 
1.1.4.2. 
Combination Daratumumab Studies 
One study of daratumumab in combination with lenalidomide and dexamethasone (Study 
GEN503), and 1 study of daratumumab in combination with various backbone treatment regimens 
(Study MMY1001) are ongoing.  
Table 5: 
Daratumumab Combination Studies GEN503 and MMY1001 
Study Number 
Study Design 
Treatment Regimen 
Status/Estimated 
Start Date 
 
Number of 
subjects 
Treated/Planned 
GEN503 
Open-label, Phase 1/2 multicenter, dose-
escalating study investigating the safety of 
daratumumab in combination with 
lenalidomide and dexamethasone in subjects 
with relapsed or refractory multiple 
myeloma 
Phase 1:  
2-16 mg/kg daratumumab, in 
combination with lenalidomide 
(25 mg daily Days 1-21 of 28 
days) and dexamethasone 
(40 mg weekly) 
Phase 1: Ongoing 
(n=13 subjects 
treated) 
 
2 mg/kg (n=3) 
4 mg/kg (n=3) 
8 mg/kg (n=4) 
16 mg/kg (n=3) 
Phase 2:  
16 mg/kg daratumumab, in 
combination with lenalidomide 
(25 mg daily Days 1-21 of 28 
days) and dexamethasone 
(40 mg weekly) 
Part 2: 
 n=18 subjects 
treated  
 
approximately 30 
subjects planned 
MMY1001 
Open-label, non-randomized, multicenter, 
Phase 1b study to evaluate the safety, 
tolerability, and dose regimen of 
daratumumab when administered in 
combination with various backbone 
treatment regimens for multiple myeloma in 
either the newly diagnosed or those who 
have received at least 2 prior therapies, 
depending on the backbone treatment 
regimen 
Daratumumab 16 mg/kg 
(initially, with possibility to de-
escalate, if necessary) 
The backbone regimens to be 
combined with daratumumab 
include bortezomib-
dexamethasone (VD), VMP, 
VTD, and pomalidomide-
dexamethasone 
n=19 subjects 
treated1 
VTD (n=6) 
VMP (n=6) 
Vd (n=1) 
Pom-dex (n=6) 
 
approximately 80 
subjects planned 
1. 
As of 18July2014 
Pom-dex=pomalidomide-dexamethasone; VMP-bortezomib-melphalan-prednisone; VTD=bortezomib-thalidomide-
dexamethasone 
 


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Based on preliminary efficacy data, 15 of 20 efficacy evaluable subjects in Study GEN503 have 
achieved a PR or better following treatment with daratumumab in combination with lenalidomide 
and dexamethasone. 
The safety profile observed in Study GEN503 is consistent with historical safety data for 
lenalidomide and dexamethasone. Doses ranged from 2 mg/kg to 16 mg/kg daratumumab, in 
combination with the approved doses of lenalidomide (25 mg daily Days 1-21 of 28 days) and 
dexamethasone (40 mg weekly). No dose-limiting toxicity (DLT) drug-related safety signals have 
been observed in this heavily pre-treated population of subjects with advanced multiple myeloma. 
The Part 2 daratumumab dose was determined to be 16 mg/kg. Across all dose cohorts in Part 1 
and in the 16 mg/kg expansion cohort for Part 2, the most frequently reported Grade 3 or higher 
AE was neutropenia (6 subjects), which is a known toxicity of lenalidomide. Eight serious adverse 
events (SAEs) have been reported. All SAEs were assessed by the investigator as not related to 
daratumumab. Four subjects experienced infusion related reactions during the first infusion of 
daratumumab. These events were determined by the investigator to be related to daratumumab. In 
all instances, daratumumab was interrupted temporarily and restarted without complication or 
further incident. 
In study MMY1001, preliminary safety is available from 6 subjects treated in the VTD + 
daratumumab cohort and 6 subjects treated in the VMP + daratumumab cohort. No serious AEs or 
dose-limiting toxicities have been reported in either cohort. Adverse events have been those 
expected for VTD or VMP alone; with the exception of infusion related reactions (Grade 1 or 
Grade 2) attributable to daratumumab. 
Planned Phase 3 combination studies include a Phase 3 study (MMY3003) comparing 
daratumumab, lenalidomide, and dexamethasone with Rd and a Phase 3 study (MMY3004) 
comparing daratumumab, bortezomib, and dexamethasone with Vd. Both studies are in patients 
with relapsed or refractory multiple myeloma and are planned to start in the second half of 2014. 
For the most comprehensive nonclinical and clinical information regarding daratumumab, refer to 
the latest version of the Investigator's Brochure for daratumumab. The term "sponsor" used 
throughout this document refers to the entities listed in the Contact Information page(s), which 
will be provided as a separate document. 
1.2. 
Overall Rationale for the Study 
Treatment choices for multiple myeloma vary with age, performance status, comorbidity, the 
aggressiveness of the disease, and related prognostic factors (Palumbo 201145). Newly diagnosed 
patients with multiple myeloma are typically categorized into 2 subpopulations usually defined by 
their age and suitability for the subsequent approach to treatment. Younger patients will typically 
receive an induction regimen followed by consolidation treatment with high-dose chemotherapy 
and ASCT. For those not considered suitable for high-dose chemotherapy and ASCT, longer-term 
treatment with multi-agent combinations including alkylators, high-dose steroids, and novel agents 
are currently considered as standards of care. 
Recent studies have indicated that multiple-drug combinations are superior over single- or double-
agent combinations in treating multiple myeloma (Cavo 20126, van der Veer 2011b57). In 


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particular, bortezomib-based treatment regimens have demonstrated significant improvements in 
response, PFS, and OS compared with non-bortezomib-based therapy, both in newly diagnosed 
transplant ineligible patients and those suitable for induction and transplant (Sonneveld 201354, 
Dimopoulos 200912). The addition of new drugs to available regimens, or combinations of new 
drugs, can improve clinical benefit because of the induction of a higher rate of initial complete 
responses (CRs), which then improves relapse-free survival and OS. Contingent on the premise 
that the combined agents have non-overlapping and synergistic mechanisms of actions (MoAs), 
the immediate and effective targeting of the tumors with multiple agents appears to be a successful 
strategy in improving the clinical outcome of multiple myeloma therapy. Such a strategy is in 
agreement with the emerging concept that the genetic signature of multiple myeloma, and 
consequently the patient’s susceptibility to a specific agent, will be highly heterogeneous, which 
may benefit from multi-drug combination therapies. Nevertheless, the CR rate of the best 
chemotherapeutic combinations is currently <50%, indicating that even multi-drug combinations 
cannot cure multiple myeloma, and all current combination therapies eventually induce drug 
resistance (Rosiñol 201251, Reeder 200950). 
In an ex vivo flow cytometry-based assay platform, addition of daratumumab to both bortezomib-
melphalan-prednisone 
(VMP) 
and 
lenalidomide-bortezomib-dexamethasone 
significantly 
increased the treatment effect by almost doubling the bone marrow mononuclear cells lysis levels 
(van der Veer 2011b57). Daratumumab’s immediate and effective cell mediated cytotoxic effects 
against multiple myeloma cells, combined with the observed remarkable synergy with 
lenalidomide-bortezomib (even among patients who are refractory to lenalidomide-bortezomib), 
may potentially improve the clinical outcome for patients with multiple myeloma when combined 
with these agents in combination regimens (van der Veer 2011b57). 
Induction Therapy in Transplant-eligible Patients 
Induction regimens for transplant-eligible patients are given with the intention of reducing the 
plasma cell disease burden and improving the depth of response. 
Response rates to induction therapy have been significantly increased by the use of novel 
agent-based combinations. VD, which is superior to the classical vincristine, Adriamycin and high-
dose dexamethasone (VAD) regimen, has become the backbone of induction therapy before ASCT 
(Harousseau 2010c19). The addition of another agent to the VD backbone to form a triple 
combination such as thalidomide (VTD), doxorubicin (DVD or PAD), lenalidomide (RVD), or 
cyclophosphamide (VCD), has yielded yet higher response rates in Phase II trials. Three 
prospective studies have already shown that VTD is superior to thalidomide and dexamethasone 
(TD) or VD. (Harousseau 2010b20, Cavo 20107, Rosiñol 201251, Moreau 2011b37). Overall, 
Bortezomib-based induction regimens have demonstrated significant improvements in response 
and PFS/OS in this induction setting compared with non-bortezomib-based induction and are 
generally well-tolerated, with a higher rate of peripheral neuropathy but no apparent increase in 
risk of death during induction (Sonneveld 201354). In newly diagnosed patients, bortezomib-
dexamethasone (VD) and bortezomib-thalidomide-dexamethasone (VTD) are now considered 
standard induction regimens for patients eligible for ASCT (Engelhardt 201414, Moreau 201338, 
NCCN 201340). 


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High Dose Chemotherapy and Stem Cell Rescue 
High dose chemotherapy for myeloma was introduced in the early 1980’s, after it was 
demonstrated that complete remissions could be induced in a substantial percentage of patients 
(McElwain 198334). The risks (morbidity and mortality) associated with such an approach were 
high, but were subsequently reduced by the application of autologous stem cell rescue. 
Bone marrow was the source of stem cells in the early studies, however peripheral blood stem cells 
(PBSC) are now used routinely as autologous rescue (Child 200310). Autologous SCT has now 
become the standard approach to improve or deepen response and can be considered a form of 
consolidation. However consolidation more routinely refers to a period of intensification therapy 
after ASCT. After attaining an optimal response from induction therapy, blood stem cells are 
mobilized in peripheral blood with the use of G-CSF with either cyclophosphamide or in some 
cases plerixafor (Mozobil) (Giralt 200916). They are then harvested by apheresis/ leukapheresis. 
Conditioning Therapy 
Patients are then given high dose therapy with melphalan, typically 100-200 mg/m2 over a period 
of 1 to 2 days followed by rescue using the previously collected stem cells.  Melphalan together 
with total body irradiation (MEL140  +  TBI), busulphan plus melphalan (BUMEL) and busulphan 
followed by cyclophosphamide (BUCY) are also potential options for conditioning therapy.  
Consolidation Therapy in Transplant-eligible Patients 
Post-transplant, patients are given a further short intense period of treatment in order to deepen the 
quality of the response obtained with induction therapy. This treatment is most commonly referred 
to as consolidation therapy.  
Upgraded rates of CR and CR-nCR, in the range between 10% and 30%, have been reported with 
post-ASCT use of bortezomib or lenalidomide as single agents (Mellqvist 200935, Attal 20092). 
VTD consolidation (2 cycles) following tandem ASCT was able to reduce the relapse rate and 
prolong PFS in the prospective trial conducted by the GIMEMA with VTD (Cavo 20126). In 
several of these studies, consolidation therapy with VTD yielded molecular remissions in up to 
60% of patients (Ladetto 201027, Terragna 201055). 
Moreover, in a recent retrospective analysis comparing VTD induction followed by single ASCT 
versus VTD induction, single ASCT and VTD consolidation (2 cycles), the IFM showed that the 
use of consolidation was associated with an improvement in response rates and PFS. (Leleu 
201329) 
The current IFM recommendations for the treatment of frontline MM in symptomatic patients 
eligible for high-dose therapy outside clinical trials comprise VTD induction (4 cycles), ASCT 
prepared by melphalan 200 mg/m2, followed by VTD consolidation (2 cycles).  
Maintenance Therapy  


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Maintaining response after successful induction, high dose chemotherapy with transplant and 
consolidation is an important goal in treating multiple myeloma. It is now accepted that patients 
who are on treatment for longer periods do better than those on short course treatments. 
To date, several groups in different countries have adopted a maintenance strategy in their 
protocols. In Germany patients are maintained with single agent thalidomide. Admittedly, there is 
no accepted standard for maintenance but an agreed need to do so. The major limitation is the 
toxicity of the commonly available drugs which are suitable for use long term. Thalidomide, as 
maintenance therapy after ASCT, has been investigated and has been shown to improve response 
quality and increased PFS (Ludwig 201231). However it has been associated with increased 
peripheral neuropathy and thromboembolisms (Palumbo 2008c44, Morgan 201239).  Similarly, 
lenalidomide, given as maintenance therapy after ASCT, has also been investigated in 2 
randomized, prospective trials (McCarthy 201232, Attal 20123). In a study of lenalidomide 
maintenance therapy, initiated at Day 100 after hematopoietic stem cell transplantation, 
lenalidomide treatment significantly improved time to disease progression and OS among patients 
with multiple myeloma; however, it was associated with more toxicity and second cancers. 
Summary 
Induction prior to and consolidation and maintenance following ACST is now emerging as a 
widely accepted treatment approach in newly diagnosed multiple myeloma patients who are 
deemed to be eligible for high dose therapy with autologous stem cell transplant.  
The clinical utility of improving the depth of response using consolidation therapy and preserving 
response in the long term using maintenance therapy has been demonstrated in a number of studies. 
However, multiple myeloma still remains incurable, and the agents currently available for long 
term therapy have a number of shortcomings in terms of safety and tolerability. 
Strategies directed at improving and maintaining response for longer periods of time and new 
treatment options directed at alternative mechanisms are urgently needed for patients with multiple 
myeloma.  
Daratumumab with its novel mechanism of action together and good profile of tolerability is 
ideally suited to being investigated as an adjunct to induction, consolidation and subsequent long 
term maintenance therapy 
The target population for this study is newly diagnosed subjects with a confirmed diagnosis of 
symptomatic multiple myeloma and measurable disease who are suitable for high dose treatment 
with ASCT. 
The safety profile of daratumumab to date, which does not appear to overlap with those known for 
approved agents, combined with its distinct MoA, suggest that the therapeutic profile of 
daratumumab combined with various backbone regimens may improve the treatment effect of 
these regimens. Additionally, daratumumab as a single agent may prolong the progression free 


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interval for these patients. The detailed rationale for the study design elements are provided in 
Section 3.2. 
2. 
OBJECTIVES AND HYPOTHESIS 
2.1. 
Objectives 
Primary Objective 
• 
The primary objective in Part 1 is to determine if the addition of daratumumab to VTD will 
increase the proportion of subjects achieving stringent complete response (sCR) post 
completion of consolidation therapy compared with VTD alone. 
• 
The primary objective in Part 2 is to determine if the use of daratumumab as single agent 
in maintenance compared to observation only will increase progression-free survival (PFS) 
when used after autologous stem cell transplant and consolidation therapy. 
Secondary Objectives 
In Part 1, major secondary efficacy objectives are to determine if the addition of daratumumab to 
VTD will improve: 
• 
Progression-free survival (PFS) from first randomization 
• 
Time to progression (TTP) from first randomization 
• 
Complete response (CR) rate by the end of ASCT/consolidation 
• 
Minimal residual disease (MRD) negative rate by the end of ASCT/consolidation 
• 
Post-induction stringent complete response (sCR) rate 
• 
Progression-free survival after next line of therapy (PFS2) 
• 
Post-induction overall response rate (ORR) and rate of very good partial response (VGPR) 
or better 
• 
Overall survival (OS) 
• 
Duration of CR and sCR 
 
In Part 2, major secondary efficacy objectives are to determine if the addition of daratumumab to 
VTD will improve the assessment during maintenance of: 
• 
Time to progression 
• 
CR rate 
• 
MRD negative rate 
• 
PFS2 
• 
Rate of improved response 
• 
Rate of MRD negative conversion 
• 
ORR 


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• 
OS 
 
Other secondary objectives throughout the study are: 
• 
To evaluate quality of life and health economic/resource utilization 
• 
To assess immunogenicity of daratumumab 
• 
To assess safety and tolerability of daratumumab in combination with VTD 
• 
Rate of MRD conversion during Pre-PD Follow-Up. 
Exploratory Objectives 
The exploratory objective is: 
• 
To evaluate daratumumab’s impact on response and resistance to treatment 
2.2. 
Hypothesis 
As this study integrates induction therapy as well as post-transplant consolidation and maintenance 
therapy into a single, 2-stage randomization design to address 2 distinct questions about the 
effectiveness of daratumumab treatment during induction/consolidation and maintenance, there 
are two primary hypotheses for this study: 
Hypothesis for Induction/Consolidation: first randomization 
• Addition of daratumumab to VTD improves post-consolidation sCR rate compared with VTD 
alone. 
Hypothesis for Maintenance: second randomization 
• Daratumumab maintenance after ASCT prolongs PFS compared with observation. 
3. 
STUDY DESIGN AND RATIONALE 
3.1. 
Overview of Study Design 
This is a randomized, open-label, active control, parallel group, multicenter, Phase 3 study in 
subjects with previously untreated multiple myeloma. The planned number of subjects to be treated 
in this study is as follows: 
• 
1080 subjects (540/arm) for first randomization (induction)  
• 
Approximately 800 subjects (400/arm) of the initial 1080 subjects will be randomized to 
maintenance. The actual accrual into the Maintenance Phase may be greater than 800 if a 
higher-than-expected proportion of subjects in the induction/consolidation stage achieve 
response and are randomized in the Maintenance Phase. 
The study will consist of 3 phases. The Screening Phase will extend up to 28 days prior to Cycle 1, 
Day 1. The Treatment Phase will be conducted in 2 parts, as described below, and will extend from 


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Cycle 1 Day 1 until treatment discontinuation due to progressive disease, unacceptable toxicity, 
ineligibility for second randomization, or 2 years of maintenance therapy/observation. The Follow-
up Phase will extend from treatment discontinuation until death, lost to follow-up, withdrawal of 
consent, or study end, whichever occurs first. 
The 2 parts in the Treatment Phase are described below. 
Part 1: Induction/ASCT/Consolidation Phase (1:1 Randomization)  
Arm A: VTD induction therapy (4 cycles), followed by ASCT, followed by 2 cycles of VTD 
consolidation 
Arm B: VTD plus daratumumab induction therapy (4 cycles), followed by ASCT, followed 
by 2 cycles of VTD plus daratumumab consolidation 
The consolidation phase of treatment will begin approximately 30 days after ASCT, when the 
subject has recovered sufficiently and engraftment is complete. Response will be evaluated at Day 
100 post ASCT. 
Part 2: Maintenance Phase (1:1 Re-randomization of subjects achieving at least a PR after 
consolidation) 
Subjects with at least a PR will be randomized after determination of response at approximately 
Day 100 after ASCT, and will enter the Maintenance Phase upon completion of consolidation 
therapy.  
Arm A: Observation only until documented disease progression (limited to 2 years maximum 
duration) 
Arm B: Daratumumab monotherapy until documented disease progression (limited to 2 years 
maximum duration) 
Subjects who are not randomized in Part 2 will enter in the Follow-up Phase and will be followed 
until disease progression, death or lost to follow up, withdrawal of consent or study end even if 
they receive subsequent anticancer treatments A schematic overview of the study is provided in 
Figure 3. 
 
 
 


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Figure 3:  
Study MMY3006 Study Scheme 
 
 
In Arm B, daratumumab (16 mg/kg) will be administered by intravenous (IV) infusion once every 
week for 8 weeks (VTD Induction Cycle 1-2), then once every 2 weeks for 8 weeks (VTD 
Induction Cycle 3-4), and following ASCT once every 2 weeks for 8 weeks (VTD consolidation 
Cycle 5-6). Following subsequent re randomization, subjects assigned to the maintenance Arm B 
will receive daratumumab (16 mg/kg) once every 8 weeks until documented disease progression 
(limited to a maximum duration of 2 years). 
Permuted block randomization will be implemented in this study. Subjects will be stratified at first 
randomization by site affiliation (IFM or HOVON), International Staging System stage I, II, or III 
(β-2 microglobulin and albumin) and by cytogenetics (standard risk or high risk as defined by 
presence of del17p or t(4;14), as centrally confirmed during screening) . 
Response will be assessed 100 days after ASCT and eligibility for the second randomization will 
be determined. Subjects will be stratified at the second randomization by type of induction 
treatment (VTD +/- daratumumab) and by depth of response to induction/consolidation therapy 
(as determined by MRD status and post-consolidation response). The stratification factors for the 
second randomization are presented in Table 6. 


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Assessment of tumor response and disease progression will be conducted in accordance with the 
International Myeloma Working Group (IMWG) response criteria. An assessment of MRD will 
be conducted using flow cytometry and next-generation sequencing on bone marrow aspirate for 
all patients in induction/consolidation phases and for patients who achieve at least VGPR in 
maintenance phase. MRD assessment will be performed also every year during Pre-PD FU if the 
MRD remains negative (after W105 of maintenance). Safety evaluations will include adverse event 
monitoring, physical examinations, electrocardiogram monitoring (ECGs), clinical laboratory 
parameters (hematology and chemistry), vital sign measurements, and Eastern Cooperative 
Oncology Group (ECOG) performance status.  
Two primary analyses are planned. The first primary analysis, with a purpose to evaluate response 
by measuring the stringent complete response (sCR) rate, will be performed after all subjects have 
completed the Day 100 post-ASCT response evaluation or have been discontinued from study 
treatment by this timepoint. The second primary analysis, for PFS, will be performed when 
approximately 390 PFS events have been observed. An interim analysis is planned for the 
maintenance stage after 273 (70%) PFS events are observed in the population of subjects who are 
re-randomized. In case the Interim analysis for PFS meets the pre-defined boundary, this Interim 
analysis reflects the primary analysis for PFS. No PFS analysis at 390 PFS events will be done. 
The next pre-planned analysis in that case will be the final data cutoff  
at the end of study, when approximately 350 subjects have died, or approximately 5 years after the 
last subject is randomized in the second randomization, whichever comes first. Investigators will 
be informed when the cutoffs are to occur. All available data prior to the time of a clinical cutoff 
will be included in each of the respective analyses.  
3.2. 
An Independent Data Monitoring Committee (IDMC) will be formed to 
review data including those from interim analyses of overall safety (please 
see Section 11.9). At the part 2 interim analysis, the primary endpoint was 
met, and the study data was unblinded. No new safety signals were 
observed. No further IDMC meetings will be scheduled. Safety data will be 
reviewed by regular Pharmacovigilance aggregate data review. Study 
Design Rationale 
Rationale for Study Design and Endpoints: 
The aim of the study is to demonstrate the clinical activity of daratumumab in the first instance by 
assessment of the level of response post consolidation therapy. Subsequent confirmation of the 
longer-term benefit of daratumumab treatment will be by long-term follow-up to assess PFS. 
Furthermore, the contribution of maintaining subjects on daratumumab monotherapy post 
consolidation as a maintenance therapy will also be explored.  
In order to facilitate this, a 2-stage randomization design will be used to evaluate the efficacy of 
daratumumab, both as part of the induction/consolidation regimen and as maintenance therapy 
after consolidation. In order to isolate the net contribution of the benefit of maintaining 
daratumumab post consolidation, those achieving a PR or better subjects will be re-randomized in 
a second stage to daratumumab monotherapy as maintenance treatment (for up to 2 years) or 


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observation. This will enable the net contribution of maintenance treatment to be isolated, while 
at the same time investigating continuous daratumumab therapy. 
This design is capable of evaluating various sequences of induction/ASCT/consolidation regimens 
(eg, daratumumab + SOC vs SOC) and maintenance therapies (eg, daratumumab maintenance vs 
observation) simultaneously in 1 study, and has been established as being more efficient than 
conventional development means of utilizing multiple studies or a factorial design.  
The post ASCT/consolidation assessment of sCR has the advantage that it is not influenced by 
maintenance treatment, and thus is an immediate measure of efficacy for the 
induction/consolidation regimens being compared in Part 1. It has also been well-established as 
being strongly correlated with long-term clinical outcomes including PFS and OS. A group of 
internationally renowned experts in the field of myeloma recommended that CR should be used as 
an appropriate surrogate endpoint for regulatory purposes in the newly diagnosed multiple 
myeloma setting (Rajkumar 201147). 
Rationale for Stringent Complete Response (sCR) 
Traditionally long- term outcomes have served as the principle means of measuring efficacy in 
multiple myeloma trials. However, as response rates, length of disease-free interval and 
corresponding OS rates improve, it becomes more and more difficult to demonstrate incremental 
benefit in a reasonable time frame. In the front line treatment of multiple myeloma the level of 
tumor burden reduction particularly the achievement of complete and very good partial responses, 
has emerged as a powerful predictive factor associated with a prolonged PFS and OS (van de Velde 
200756, Lahuerta 200828, Blade 20004, Harousseau 2009b18, Harousseau 2009a17,Chanan-Khan 
20108, Gay 201115). 
Furthermore, given that a VGPR or CR is now achievable in a vast majority of patients in the first-
line when the latest generation of therapies are used together with high dose therapy and 
autologous transplant, more stringent definitions of response are required in order to account for 
deeper levels of response up to and including the possibility of complete eradication of the plasma 
cell clone. 
A majority of the response definitions are based on serologic and cytologic results, in order to 
more carefully identify high-quality responses occurring beyond the CR level, the IMWG in 2006 
introduced the category of stringent complete response (sCR), as defined by a negative 
immunofixation plus normal free-light chain ratio and the absence of clonal bone marrow plasma 
cells by immunohistochemistry or immunofluorescence (Durie 200613). 
The predictive value of sCR was highlighted in a study by Kapoor et al that determined the 
maximal response rates achieved in 445 consecutive patients who underwent ASCT within 12 
months of diagnosis. The study identified patients who achieved varying degrees of CR; 109 of 
whom (25%) achieved a sCR after ASCT. In terms of outcome, the median OS rate from the time 
of transplantation for the patients who attained an sCR was not reached, this was in contrast to 
those patients achieving conventional CR, where the median OS was 81 months and for near CR 
(nCR) 60 months. Five-year OS rates for the 3 response categories were 80%, 53%, and 47% for 


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sCR, CR, and nCR, respectively. In terms of impact on time to progression, the TTP from ASCT 
of patients achieving an sCR was significantly longer (50 months) compared to the patients 
achieving CR or nCR (20 months and 19 months, respectively). On multivariable analysis, post 
ASCT response of sCR was found to be an independent prognostic factor for survival versus CR 
(HR=0.44; 95% CI, 0.25 to 0.80; p=0.008), in addition to proliferation rate, pre-ASCT 
cytogenetics, and performance status. In a landmark analysis, OS of subjects surviving at least 2 
years post-transplantation and achieving sCR was superior (median OS not reached) compared to 
the conventional CR group (median OS of 70 months) (p=0.007). (Kapoor 201323). 
Rationale for Daratumumab Dose Selection 
Based on pharmacokinetic (PK), clinical activity, and clinical safety data, the 16 mg/kg 
daratumumab dose was selected for this study.  
Target Saturation: Clinical PK data are available from Parts 1 and 2 of the ongoing Study 
GEN501. For the 8 and 16 mg/kg dose levels, the relationship between observed trough 
concentration and concentration associated with 90% target suppression is presented in Figure 4. 
The concentration associated with 90% target suppression was calculated using the principles of 
target mediated disposition. Specifically, the dashed lines represent the expected concentration 
when 90% of clearance related to target binding is inhibited 
 


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Figure 4: 
Study GEN501 8 and 16 mg/kg Dose Levels - Observed Trough Concentration vs. 90% Target 
Suppression Concentration 
 
 
 
 
8mg/kg: Observed trough concentration 
values below predicted 90% suppression 
throughout dosing 
 
 
 
 
 
 
 
 
 
 
16mg/kg: Observed trough concentration 
values at 90% suppression throughout 
dosing 
 
 
Following repeated doses of 8 mg/kg, observed trough concentrations are below those predicted 
for 90% suppression. However, following repeated doses of 16 mg/kg, the observed trough 
concentrations are similar to those predicted for 90% suppression. Therefore, the 16 mg/kg dose 
is the lowest dose that results in 90% target suppression at all timepoints. Following the initial 
weekly dosing period, the impact of target-mediated clearance will be decreased due to target 
suppression. Therefore, the frequency of dosing is decreased following long-term treatment. 
Clinical Activity Data: The rate and depth of clinical response is higher for the 16-mg/kg dose 
compared with the 8-mg/kg dose, based on data from Part 2 of Study GEN501 and from Study 
MMY2002 (both ongoing studies). Across the 2 studies, VGPRs were observed in 6 of 36 subjects 
treated at the 16-mg/kg dose, while no VGPR was observed in 48 subjects treated at the 8-mg/kg 
dose. In addition, in Part 1 of GEN501, 16 mg/kg was the lowest dose resulting in complete bone 
marrow clearance. 


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In Part 2 of Study GEN501, the ORRs (i.e., PR or greater) were reported in 3/30 (10%) subjects 
in the 8 mg/kg dose regimen and 7/20 (35%) subjects in 16 mg/kg dose regimen. For Study 
MMY2002, the unconfirmed ORRs for the 8 mg/kg and 16 mg/kg dose regimens were similar to 
those observed in GEN501. These data are still maturing. The preliminary data support that full 
target saturation at the 16 mg/kg dose is needed to achieve higher and deeper response rates. As 
these studies are ongoing, data are still emerging, and subject response may change as the data 
mature.  
Clinical Safety Data: In addition, the 16 mg/kg dose and schedule was shown to have an 
acceptable and manageable safety profile among the subjects for whom preliminary data were 
available in Studies GEN501 and MMY2002.  
Rationale for Immunogenicity Evaluations 
Immunogenicity to daratumumab is possible. Therefore, samples to determine the presence of 
antibodies to daratumumab (immunogenicity) will be collected from all subjects. All of the serum 
concentration assessments collected during the study will be used to interpret the immunogenicity 
data. The information from these samples and data from other studies will be used to determine 
the immunogenicity of daratumumab. 
Rationale for Biomarker Evaluations 
Biomarkers collected in this study will provide information about daratumumab in multiple 
myeloma and will focus on two key objectives: the evaluation of minimal residual disease (MRD) 
and the efficacy of daratumumab + VTD (compared to VTD) in high-risk molecular subgroups. In 
addition, exploratory studies may examine the effects of daratumumab + VTD on immune cell 
subpopulations following transplant.  
4. 
SUBJECT POPULATION 
Screening for eligible subjects will be performed within 28 days before administration of the study 
drug. The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
investigator should consult with the appropriate sponsor’s representative before enrolling a subject 
in the study. For a discussion of the statistical considerations of subject selection, refer to 
Section 11.2. 


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4.1. 
Inclusion Criteria 
Each potential subject must satisfy all of the following criteria to be enrolled in the study.  
1. 
Subject must be between 18 and 65 years of age. 
2. 
Subject must have documented multiple myeloma satisfying the CRAB or biomarkers 
of malignancy criteria (see Attachment 1) and measurable disease as defined by: 
• 
Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy 
proven plasmacytoma AND any one or more of the following myeloma defining 
events: 
− Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than ULN 
or >2.75 mmol/L (>11 mg/dL) 
− Renal insufficiency: creatinine clearance <40mL/min or serum creatinine 
>177 µmol/L (>2 mg/dL) 
− Anemia: hemoglobin >2 g/dL below the lower limit of normal or hemoglobin 
<10 g/dL 
− Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or 
PET-CT 
− Clonal bone marrow plasma cell percentage ≥60% 
− Involved: uninvolved serum free light chain ratio ≥100 
− >1 focal lesion on MRI studies 
• 
Measurable disease as defined by any of the following: 
− IgG multiple myeloma: Serum monoclonal paraprotein (M-protein) level 
≥1.0 g/dL or urine M-protein level ≥200 mg/24 hours; or 
− IgA, IgE, IgD, or IgM multiple myeloma: serum M-protein level ≥0.5 g/dL 
or urine M-protein level ≥200 mg/24 hours; or 
− IgD multiple myeloma : serum M-protein level <0.5 g/dL and Serum 
immunoglobulin free light chain ≥10 mg/dL and abnormal serum 
immunoglobulin kappa lambda free light chain ratio; or 
− Light chain multiple myeloma without measurable disease in the serum or 
the urine: Serum immunoglobulin free light chain ≥10 mg/dL and abnormal 
serum immunoglobulin kappa lambda free light chain ratio 
3. 
Newly diagnosed subjects eligible for high dose therapy and autologous stem cell 
transplantation.  
4. 
Subject must have an ECOG performance status score of 0, 1, or 2 (see Attachment 2). 


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5. 
Subject must have pretreatment clinical laboratory values meeting the following criteria 
during the Screening Phase (Lab tests should be repeated if done more than 15 days 
before C1D1): 
a) hemoglobin 7.5 g/dL ( mmol/L; prior red blood cell [RBC] transfusion or 
recombinant human erythropoietin use is permitted); 
b) absolute neutrophil count (ANC) 1.0 x 109/L (GCSF use is permitted); 
c) AST ≤2.5 x upper limit of normal (ULN); 
d) ALT ≤2.5 x ULN; 
e) total bilirubin ≤1.5 x ULN (except in subjects with congenital bilirubinemia, 
such as Gilbert syndrome, direct bilirubin ≤1.5 x ULN); 
f) calculated creatinine clearance 40 mL/min/1.73 m2 (see Attachment 3); 
g) corrected serum calcium ≤14 mg/dL (<3.5 mmol/L); or free ionized calcium 
≤6.5 mg/dL (≤1.6 mmol/L) (see Attachment 4); 
h) platelet count 70 x 109/L for subjects in whom <50% of bone marrow 
nucleated cells are plasma cells; otherwise platelet count >50x109/L 
(transfusions are not permitted to achieve this minimum platelet count). 
6. 
Women who are partners of men and of childbearing potential must be practicing one 
of the following methods of birth control: subcutaneous hormonal implant, 
levonorgestrel-releasing intra-uterine system, medroxyprogesterone acetate depot, 
tubal sterilization, ovulation inhibitory progesterone only pills, or sexual intercourse 
with a vasectomized male partner (vasectomy must be confirmed by 2 negative semen 
analyses). Or women will commit to absolute and continuous abstinence confirmed to 
her physician on a monthly basis. Childbearing potential is defined in Section 9.1.2. 
Contraception will start 4 weeks before the start of therapy, during therapy including 
dose interruptions, for 4 weeks after discontinuation of thalidomide and for 4 months 
after discontinuation of daratumumab. 
7. 
A woman of childbearing potential must have 2 negative serum or urine pregnancy tests 
at Screening, first within 10 to 14 days prior to dosing and the second within 24 hours 
prior to dosing.  
8. 
Each subject (or their legally acceptable representative) must sign an informed consent 
form (ICF) indicating that he or she understands the purpose of and procedures required 
for the study and are willing to participate in the study. Subject must be willing and able 
to adhere to the prohibitions and restrictions specified in this protocol. 
4.2. 
Exclusion Criteria 
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study.  


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1. 
Subject has received daratumumab or other anti-CD38 therapies previously. 
2. 
Subject has a diagnosis of primary amyloidosis, monoclonal gammopathy of 
undetermined significance, smoldering multiple myeloma, or solitary plasmacytoma. 
Monoclonal gammopathy of undetermined significance is defined by presence of serum 
M-protein <3 g/dL; absence of lytic bone lesions, anemia, hypercalcemia, and renal 
insufficiency related to the M-protein; and (if determined) proportion of plasma cells in 
the bone marrow of 10% or less (Kyle 200325). Smoldering multiple myeloma is defined 
as asymptomatic multiple myeloma with absence of related organ or tissue impairment 
(ROTI) end organ damage (Kyle 200325, Kyle 200726). 
3. 
Subject has a diagnosis of Waldenström’s macroglobulinemia, or other conditions in 
which IgM M-protein is present in the absence of a clonal plasma cell infiltration with 
lytic bone lesions. 
4. 
Subject has prior or current systemic therapy or SCT for any plasma cell dyscrasia, with 
the exception of an emergency use of a short course (equivalent of dexamethasone 
40 mg/day for a maximum 4 days) of corticosteroids before treatment. 
5. 
Subject has peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by 
the National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) Version 4. 
6. 
Subject has had any prior or concurrent invasive malignancy (other than multiple 
myeloma) within 10 years of study start except adequately treated basal cell or 
squamous cell carcinoma of the skin, carcinoma in situ of the cervix, localized prostate 
adenocarcinoma diagnosed ≥3 years and without evidence of biochemical failure, or 
other cancer for which the subject has undergone potentially curative therapy and has 
no evidence of that disease for ≥10 years. 
7. 
Subject has had radiation therapy within 14 days of C1D1. 
8. 
Subject has had plasmapheresis within 28 days of C1D1. 
9. 
Subject is exhibiting clinical signs of meningeal involvement of multiple myeloma. 
10. 
a) 
Subject has known chronic obstructive pulmonary disease (COPD) with an 
Forced Expiratory Volume in 1 second (FEV1) < 50% of predicted normal. Note that 
FEV1 testing is required for patients suspected of having COPD and subjects must be 
excluded if FEV1 <50% of predicted normal. 
b) 
Subject has known moderate or severe persistent asthma within the past 2 years 
(see Attachment 5), or currently has uncontrolled asthma of any classification. (Note 
that subjects who currently have controlled intermittent asthma or controlled mild 
persistent asthma are allowed in the study). 


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11. 
Subject is known to be seropositive for history of human immunodeficiency virus (HIV) 
or known to have active hepatitis B or hepatitis C. 
12. 
Subject has any concurrent medical or psychiatric condition or disease (eg, active 
systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) 
that is likely to interfere with the study procedures or results, or that in the opinion of 
the investigator, would constitute a hazard for participating in this study. 
13. 
Subject has clinically significant cardiac disease, including: 
• 
myocardial infarction within 1 year before randomization, or an unstable or 
uncontrolled disease/condition related to or affecting cardiac function (eg, 
unstable angina, congestive heart failure, New York Heart Association 
Class III-IV 
• 
uncontrolled cardiac arrhythmia (NCI CTCAE Version 4 Grade ≥2) or clinically 
significant ECG abnormalities 
• 
screening 12-lead ECG showing a baseline QT interval as corrected by 
Fridericia’s formula (QTcF) >470 msec 
14. 
Subject has known allergies, hypersensitivity, or intolerance to boron or mannitol, 
corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to 
the Investigator's Brochure), or known sensitivity to mammalian-derived products. 
Or subject has known hypersensitivity to thalidomide. 
15. 
Subject has plasma cell leukemia (according to WHO criterion: ≥20% of cells in the 
peripheral blood with an absolute plasma cell count of more than 2 × 109/L) or POEMS 
syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and 
skin changes). 
16. 
Subject is known or suspected of not being able to comply with the study protocol (eg, 
because of alcoholism, drug dependency, or psychological disorder). Subject has any 
condition for which, in the opinion of the investigator, participation would not be in the 
best interest of the subject (eg, compromise the well-being) or that could prevent, limit, 
or confound the protocol-specified assessments. 
17. 
Subject is a woman who is pregnant, or breast-feeding, or planning to become pregnant 
while enrolled in this study or within 4 months after the last dose of any component of 
the treatment regimen. Or, subject is a man who plans to father a child while enrolled 
in this study or within 4 months after the last dose of any component of the treatment 
regimen. 
18. 
Subject has had major surgery within 2 weeks before randomization or will not have 
fully recovered from surgery, or has surgery planned during the time the subject is 
expected to participate in the study. Kyphoplasty or Vertebroplasty are not considered 
major surgery. 
19. 
Subject has received an investigational drug (including investigational vaccines) or 
used an invasive investigational medical device within 4 weeks before randomization 
or is currently enrolled in an interventional investigational study. 


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20. 
Subject has contraindications to the use of any components of the backbone treatment 
regimens, per local prescribing information. 
21. 
Incidence of gastrointestinal disease that may significantly alter the absorption of oral 
drugs. 
22. 
Subjects unable or unwilling to undergo antithrombotic prophylactic treatment. 
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
Section 17.4 describes the required documentation to support meeting the enrollment criteria. 
Subjects who fail to meet the inclusion and exclusion criteria (i.e., screen failures) 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 determined to be eligible for the study after 
rescreening must sign a new ICF and then will be assigned a new Screening number. 
4.3. 
Prohibitions and Restrictions 
Potential subjects must be willing and able to adhere to the following prohibitions and restrictions 
during the course of the study to be eligible for participation: 
1. 
A woman of childbearing potential must remain on a highly effective method of birth 
control (see inclusion criteria). Guidelines presented in the Celgene thalidomide 
pregnancy prevention program must be followed. Contraception must begin 4 weeks 
before initiating treatment with thalidomide or daratumumab, during therapy, during 
dose interruptions and continuing for 4 weeks after discontinuation of thalidomide and 
for 4 months following discontinuation of daratumumab. Reliable contraception is 
indicated even where there has been a history of infertility, unless due to hysterectomy. 
2. 
Serum (urine in the case where serum is not possible in a timely manner) pregnancy test 
to be performed for all women of childbearing potential regularly during the study, at 4 
weeks following the last dose of thalidomide, at the End-of-Treatment Visit, and at 4 
months after the last dose of daratumumab. In addition, a pregnancy test may be done 
at any time during the study at the discretion of the investigator if a subject misses a 
period or has unusual menstrual bleeding. 
3. 
A man who has not had a vasectomy and who is sexually active with a woman of 
childbearing potential must agree to use a barrier method of birth control eg, condom 
with spermicidal foam/gel/film/cream/suppository, and all men must also not donate 
sperm during the study, for 1 week after discontinuation of thalidomide and for 4 months 
following discontinuation of daratumumab. The exception to this restriction is that if 
the subject’s female partner is surgically sterile, a second method of birth control is not 
required. 
4. 
 Daratumumab Interference with Indirect Antiglobulin Test (IAT) results  


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Daratumumab interferes with the Indirect Antiglobulin Test (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 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) 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 IAT interference by treating reagent RBCs with dithiothreitol (DTT) 
(Chapuy 2015). 
Possible methods for blood banks to provide safe RBCs for transfusion to subjects 
receiving daratumumab include: 
a) Providing ABO/RhD compatible, phenotypically (standard or extended 
phenotyping prior to daratumumab administration) or genotypically matched 
units 
b) Providing ABO/RhD compatible, K-negative units after ruling out or identifying 
alloantibodies using DTT-treated reagent RBCs 
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 Investigator's Brochure. 
5. 
TREATMENT ALLOCATION AND BLINDING 
Subjects will be assigned in a randomized manner to receive either 16 mg/kg daratumumab in 
combination with VTD or VTD alone as induction and consolidation therapy. Subjects who 
successfully completed consolidation with a response of PR or better according to the IMWG 
criteria will be assigned a second time in a randomized manner to receive daratumumab alone or 
observation until documented progression of disease (limited to a maximum duration of 2 years). 
Permuted block randomization will be implemented in this study. 
Subjects will be stratified at first randomization by site affiliation (IFM or HOVON), International 
Staging System stage I, II, or III (β-2 microglobulin and albumin) and by cytogenetics (standard 
risk or high risk as defined by presence of del17p or t(4;14), as centrally confirmed during 


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screening). Subjects will be stratified at the second randomization by type of induction treatment 
and by depth of response to induction/consolidation therapy (as determined by MRD status and 
post-consolidation response). For stratification purposes, if cytogenetic results are not available 
(i.e., due to technical reasons), the subject will be assumed to have normal cytogenetics and if 
MRD status is not available the subject will be assumed to be MRD positive. The stratification 
factors for the second randomization are presented in Table 6. 
Table 6: 
Part 2 (Maintenance Phase) Stratification Factors 
Randomized to VTD arm the induction/ASCT/consolidation phase 
MRD Status 
IMWG Response 
sCR 
CR 
VGPR 
PR 
Negative 
Stratum 1 
Stratum 1 
Stratum 1 
NA 
Positive 
Stratum 2 
Stratum 3 
Stratum 3 
Stratum 4 
Randomized to VTD+dara arm the induction/ASCT/consolidation phase 
 
MRD Status 
IMWG Response 
sCR 
CR 
VGPR 
PR 
Negative 
Stratum 5 
Stratum 5 
Stratum 5 
NA 
Positive 
Stratum 6 
Stratum 7 
Stratum 7 
Stratum 8 
CR=complete response; IMWG=International Myeloma Working Group; MRD=minimum residual disease; 
PR=partial response; sCR=stringent complete response; VGPR=very good partial response 
 
The investigator will screen and if eligible randomize each subject using an interactive web-based 
randomization system (IWRS). Each subject will be assigned a unique subject number.  
This is an open-label study. Subjects and sites will not be blinded to treatment assignment. 
6. 
DOSAGE AND ADMINISTRATION 
In this protocol, daratumumab is the investigational product. Daratumumab is to be administered 
as described in the Time and Events Schedule. On dosing days where the chemotherapy 
combination products are given with daratumumab, dexamethasone should be administered 1 hour 
before the daratumumab infusion, bortezomib should be administered after the end of the 
daratumumab infusion and thalidomide should be taken as a single dose at bedtime.  
Detailed information on the composition of daratumumab can be found in the Investigational 
Product (IP) Manual. All drugs to be used in this study should only be handled by staff specially 
trained in the safe handling of them. The cytotoxic drugs should be handled and prepared with 
caution, and the use of gloves and other appropriate protective clothing is recommended. The 
pharmacist or person authorized to dispense bortezomib and daratumumab will prepare these drugs 
under aseptic conditions. 
The cycle of VTD is approximately 28 days (4 weeks) in duration, and treatment will be for a 
maximum of 4 induction cycles and 2 consolidation cycles. The cycles during the maintenance 
period are approximately 8 weeks in duration, and treatment will continue until disease progression 
with a limit of up to 2 years.  


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The start of each cycle may occur ±3 days (induction/consolidation phases) and ± 3 weeks 
(maintenance phase) of the scheduled day in order to accommodate the schedule of the site or 
subject. Subjects will be treated for the allowed maximal treatment period or until disease 
progression, unacceptable toxicity, or other reasons as listed in Section 10.2. 
6.1. 
Daratumumab 
6.1.1. 
Daratumumab Preparation 
The infusion solution will be prepared on the day of the planned infusion. Detailed instructions for 
preparation and administration of daratumumab will be supplied in the IP Manual or equivalent 
document. 
6.1.2. 
Daratumumab Administration and Infusion Rate 
Daratumumab (16mg/kg) will be administered by intravenous (IV) infusion once every week for 
8 weeks (VTD induction Cycle 1-2), then every 2 weeks for the remaining induction cycles and 
consolidation cycles based on treatment assignment. Following second randomization, subjects 
assigned to the daratumumab maintenance arm will receive daratumumab (16mg/kg) once every 
8 weeks until documented disease progression (limited to a maximum duration of 2 years). 
Each subject’s dose will be calculated based on the subject’s weight and rounded to the nearest 
kilogram. There is no cap on the absolute dose allowed, as long as the dose does not exceed 
16 mg/kg. If a subject’s weight changes by more than 10% from baseline, the dose of daratumumab 
will be re-calculated. For recommendations on daratumumab infusion rate, please refer to the IP 
Manual. All infusions will be performed as outpatient visits. Subjects will receive preinfusion 
medications and postinfusion medications as outlined in Section 6.1.3. 
As noted Table 2, vital signs should be monitored extensively on Cycle 1 Day 1 before, during, 
and after the first infusion of daratumumab immediately before the start of dara infusion; at 0.5, 1, 
1.5, 2, 3.5 hours after the start of the infusion; at end of infusion; and 0.5, 1 hour after end of 
infusion. For all other infusions, vital signs should be measured immediately before the start of 
infusion and at the end of the infusion. If a subject experiences any significant medical event, then 
the investigator should assess whether the subject should stay overnight for observation. 
As noted Table 3, vital signs should be monitored extensively on week 1 for the 1st administration 
of daratumumab in Part 2 for patients who were randomized in VTD Arm in Part 1; immediately 
before the start of dara infusion; at 0.5, 1, 1.5, 2, 3.5 hours after the start of the infusion; at end of 
infusion; and 0.5, 1 hour after end of infusion. 
 
 


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6.1.3. 
Guidelines for Prevention and Management of Infusion Reactions 
6.1.3.1. 
Preinfusion Medication  
Preinfusion medications for subjects receiving daratumumab in either part 1 or part 2 of the study 
and will be administered as described in the Time and Events Schedules.  
On daratumumab infusion days, subjects will receive the following medications prior to infusion: 
• 
Paracetamol (acetaminophen) 650-1000 mg IV or orally (PO) up to 3 hours prior to 
daratumumab infusion 
• 
An antihistamine (H1  receptor antagonist according to institutional standard ) up to 3 hours 
prior to infusion  
• 
Montelukast should be given up to 3 hours prior to daratumumab administration. 
For Part 1, 10mg is required on Cycle 1 Day 1 and optional for all other doses of 
daratumumab.  
For Part 2, for first administration, 10mg is required on Week 1 infusion and optional for all 
other doses of daratumumab. 
• 
Dexamethasone 40 mg IV or PO on Cycles 1 and 2 on infusion days. In Cycles 3 and 4, 
Dexamethasone 40 mg IV or PO on Day 1 and 20 mg IV or PO for subsequent dosing days. 
For Part 1, Dexamethasone, as study treatment, should be administered 1 hour before 
daratumumab infusion. 
For Part 2, Dexamethasone, as premedication, should be administered up to 3 hours prior to 
daratumumab infusion. 
If necessary, all PO preinfusion medications may be administered outside of the clinic on the day 
of the infusion, provided they are taken up to 3 hours before the infusion. 
6.1.3.2. 
Postinfusion Medication 
For subjects with higher risk of respiratory complications (eg, subjects who have a FEV1 <80%), 
patients with mild asthma or mild COPD, the following postinfusion medications should be 
considered: 
• 
Antihistamine  
• 
Short-acting β2 adrenergic receptor agonist such as salbutamol  
• 
Control medications for lung disease (eg, inhaled corticosteroids ± long-acting β2 
adrenergic receptor agonists for subjects with asthma; long-acting bronchodilators such as 
tiotropium or salmeterol ± inhaled corticosteroids for subjects with COPD) 
In addition, these at-risk subjects may be hospitalized for monitoring for up to 2 nights after an 
infusion. If subjects are hospitalized, then their FEV1 should be measured before discharge. If these 
subjects are not hospitalized, then a follow up telephone call should be made to monitor their 
condition within 48 hours after all infusions. If the subject has not experienced a significant 
medical event but is hospitalized overnight only for observation, then the hospitalization should 


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not be reported as a serious adverse event. Investigators may prescribe bronchodilators, 
antihistamines, and corticosteroids that are deemed necessary to provide adequate supportive care 
in the event a bronchospasm occurs after subjects are released from the hospital/clinic. If, after 4 
full doses, an at-risk subject experiences no major infusion-related reactions, then these 
postinfusion medications may be stopped at the investigator’s discretion. 
6.1.4. 
Management of Infusion-Related Reactions 
Subjects should be carefully observed during daratumumab infusions. Particular caution should be 
taken for the first infusion of daratumumab which may occur at the start of either part 1 or part 2 
of the study depending on the treatment assignment. 
Trained study staff at the clinic should be prepared to intervene in case of any infusion reactions 
occurring, and resources necessary for resuscitation (eg, agents such as epinephrine and 
aerosolized bronchodilator, also medical equipment such as oxygen tanks, , and a defibrillator) 
must be available. Attention to staffing should be considered when multiple subjects will be dosed 
at the same time.  
If an infusion-related reaction develops, then the infusion should be paused. Subjects who 
experience adverse events during the infusion must be treated according to the investigator’s 
judgment and best clinical practice. The following guidelines may apply: 
• 
Subjects should be treated with acetaminophen, antihistamine, or corticosteroids. 
Intravenous saline may be indicated. For bronchospasm, urticaria, or dyspnea, subjects may 
require antihistamines, oxygen, corticosteroids, or bronchodilators. For hypotension, 
subjects may require vasopressors. 
• 
In the event of a life-threatening infusion-related reaction (which may include pulmonary 
or cardiac events), or anaphylactic reaction, daratumumab should be discontinued and no 
additional daratumumab should be administered to the subject. Aggressive symptomatic 
treatment should be applied.  
If an infusion is paused, then a longer-than-anticipated infusion time may occur. Overnight stays 
at the hospital because of slow infusion times should not be reported as a serious adverse event. 
However, if the underlying cause of the delayed infusion time is an adverse event or serious 
adverse event, then that should be reported as such. 
6.1.4.1. 
Infusion-Related Events of Grade 1 or Grade 2 
If the investigator assesses an adverse event to be related to the daratumumab infusion, then the 
infusion should be paused. When the subject’s condition is stable, the infusion may be restarted at 
the investigator’s discretion. Upon restart, the infusion rate should be half of that used before the 
interruption. Subsequently, the infusion rate may be increased at the investigator’s discretion.  
If the subject experiences a Grade 2 or higher event of laryngeal edema or a Grade 2 or higher 
event of bronchospasm that does not respond to systemic therapy and does not resolve within 
6 hours from the onset, then the subject must be withdrawn from treatment. 


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6.1.4.2. 
Infusion-Related Reactions (IRR) of Grade 3 or Higher 
For infusion-related adverse events that are Grade 4, the infusion should be stopped and treatment 
with daratumumab will be discontinued for that subject. 
For infusion-related adverse events that are Grade 3, the daratumumab infusion must be stopped, 
and the subject must be observed carefully until the resolution of the adverse event or until the 
intensity of the event decreases to Grade 1, at which point the infusion may be restarted at the 
investigator’s discretion. Upon restart, the infusion rate should be half of that used before the 
interruption. Subsequently, the infusion rate may be increased at the investigator’s discretion. 
If the intensity of the adverse event returns to Grade 3 after restart of the infusion, then the 
procedure described in this section may be repeated at the investigator’s discretion. Should the 
intensity of the adverse event increase to Grade 3 for a third time, then treatment with 
daratumumab will be discontinued for that subject. An IRR is defined as any adverse event (AE) 
occurring during or within the 24 hours after the Daratumumab infusion and assessed as related to 
Daratumumab infusion. 
6.2. 
Bortezomib, Thalidomide, and Dexamethasone (VTD) 
Sites will use commercially available chemotherapy treatments for administration in this study 
unless otherwise communicated. Before administering, refer to the currently approved package 
inserts for complete prescribing information. 
6.2.1. 
Dose Calculation of Bortezomib 
The amount (in mg) of bortezomib to be administered will be determined by BSA, which will be 
calculated according to a standard nomogram (Attachment 7). The total calculated dose of 
bortezomib may be rounded to the nearest decimal point (eg, a calculated dose of 2.47 mg can be 
rounded to 2.5 mg). On treatment days when both bortezomib and daratumumab are administered, 
bortezomib must be administered after the end of the daratumumab infusion. 
6.2.2. 
Bortezomib Administration  
Subjects will receive 1.3 mg/m2 bortezomib as a SC injection twice a week (Days 1, 4, 8, and 11) 
for four 28-day induction cycles (Cycles 1 to 4), and two consolidation cycles (Cycles 5 and 6), 
with an option to change the schedule from twice a week to once a week, should toxicity be 
encountered. Cycles will remain 28 days in length regardless of injection interval. 
Bortezomib will be supplied in sterile, single-use vials containing 3.5 mg of bortezomib. For SC 
administration, each vial of bortezomib for Injection should be reconstituted within 8 hours before 
dosing with 1.4 mL of normal (0.9%) saline (sodium chloride for injection) so that the reconstituted 
solution contains bortezomib at a concentration of 2.5 mg/mL. If a subject’s weight changes by 
more than 10% from baseline, the dose of bortezomib will be re-calculated. 
Bortezomib may be administered IV if injection site reactions are encountered. Please refer to local 
prescribing information for further details on either SC or IV administration. 


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6.2.3. 
Thalidomide Administration 
Thalidomide will be administered PO at 100 mg daily for 4 x28 days induction cycles and 2 x 28 
days consolidation cycles. Thalidomide should be taken as a single dose at bedtime, to reduce the 
impact of somnolence. Thalidomide can be taken with or without food. Breaking or dividing 
thalidomide is strongly discouraged. 
Thalidomide dose may be reduced, or the treatment schedule may be modified for the management 
of the study drug-related toxicities.  
 
6.2.4. 
Dexamethasone Administration 
Dexamethasone will be administered on scheduled days as indicated in the Time and Events 
Schedule at 40 mg during Cycles 1 and 2. In Cycles 3 and 4, dexamethasone will be administered 
at 40 mg on Days 1-2 and 20 mg on subsequent dosing days. Dexamethasone 20 mg will be 
administered in Cycles 5 and 6. On daratumumab infusion days, in the induction/consolidation 
phase, dexamethasone may be administered intravenously 1 hour before the daratumumab 
infusion. On days when daratumumab is not administered, dexamethasone is administered PO. 
Dexamethasone tablets are to be taken with or immediately after a meal or snack, preferably in the 
morning. 
In the maintenance phase, dexamethasone 20 mg will be administered as pre-medication on 
daratumumab infusion days up to 3 hours prior to infusion. 
Dexamethasone dose may be reduced, or the treatment schedule may be modified for the 
management of the study drug-related toxicities.  
6.3. 
Dose Delays and Dose Modifications (General Principles) 
6.3.1. 
Cycle Delay 
On the first day of each new treatment cycle and before each daratumumab dose, the subject will 
be evaluated by the treating physician for possible toxicities that may have occurred after the 
previous dose(s). Toxicities are to be assessed according to NCI CTCAE, Version 4. Dose 
modifications or delays will be made based on the toxicity experienced during the previous cycle 
of therapy or newly encountered on Day 1 of a cycle. For any neurological deficits that develop, 
it is strongly recommended that these be evaluated by the same physician who performed the 
neurological assessment at baseline. The parameters in Table 7 must be met on the first day of a 
new cycle (i.e., the following represent baseline inclusion criteria levels): 


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Table 7: 
Re-treatment criteria before the start of each cyclea 
Laboratory parameter 
Requirements before each study agent administration 
ANC 
1.0 x 109/L with or without neutrophil growth factors 
Platelet count 
70 x 109/L with or without platelet transfusions, thrombopoietic cytokines, or 
both 
Hemoglobin 
7.5 g/dL (≥4.96 mmol/L) with or without transfusion, erythropoietin, or both  
Other clinically significant 
toxicitya 
Recovery to Grade  1 or baseline, unless described otherwise in the dose 
modification guidelines 
a 
Refer to Section 0 for management of neurotoxicity. 
 
If the above parameters are not met during the induction/consolidation phase, the start of the next 
cycle will be held for a minimum of 1 week and a maximum of 28 days until recovery to the 
specified levels. During the cycle delay, daratumumab, bortezomib, dexamethasone and 
thalidomide, (all applicable) must be held. If there is a delay in the start of a new cycle (i.e., none 
of the study medications are given during this period) for more than 28 days due to insufficient 
recovery from toxicity, subjects will discontinue taking the study drugs permanently (unless 
Sponsor approves continuation) and have procedures performed as outlined in Section 10.2.  
If the above parameters are not met during the maintenance phase, the start of the next cycle will 
be held for a minimum of 3 weeks and a maximum of 28 days until recovery to the specified levels. 
 
6.3.2. 
Dose Modification Guidelines 
Toxicities should be attributed, whenever possible, to a specific study drug so that dose 
modifications can be made rationally. Reduction of a single agent and not others is appropriate if 
toxicity is considered to be related primarily to 1 of the agents. If multiple toxicities are attributed 
to an individual study drug, dose adjustment should be made according to the guidelines for the 
most severe toxicity. Please refer to the tables below for dose reduction steps and dose modification 
guidelines.  
Once dose reduction for a medication has been implemented, unless otherwise stated specifically 
in the table below, dose re-escalation should not occur, unless in the judgment of the investigator 
there is clinical benefit and a reasonable and acceptable risk profile. 
6.3.3. 
Daratumumab Dose Modification 
Individual dose modification of daratumumab is not permitted, but dose delay is recommended as 
the primary method for managing daratumumab-related toxicities.  
6.3.3.1. 
Daratumumab-Related Toxicity Management 
Refer to Section 6.1.3 for details on management of infusion-related reactions. If any of the 
following criteria are met and the event cannot be ascribed to bortezomib or thalidomide, the 
daratumumab infusion must be held to allow for recovery from toxicity. The criteria for a dose 
delay are: 


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• 
Grade 4 hematologic toxicity 
• 
Grade 3 thrombocytopenia with bleeding 
• 
Febrile neutropenia  
• 
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 
If daratumumab administration does not commence within the prespecified window (Table 8) of 
the scheduled administration date, then the dose will be considered a missed dose. Administration 
may resume at the next planned dosing date. 
Table 8: 
Daratumumab-Related Toxicity Management 
Frequency 
Dose Missed 
Dosing Resumption 
Weekly  
>3 days 
next planned weekly dosing date 
Every 2 weeks 
>7 days 
next planned every-2-weeks dosing date 
Every 4 weeks 
>21 days 
next planned every-four-weeks dosing date 
Every 8 weeks 
>28 days 
next planned every-8-weeks dosing date 
 
A missed dose will not be made up. If a dose is delayed, then the dates of all subsequent doses 
must be adjusted during the study Part 1. Any adverse event deemed to be related to daratumumab 
that requires a dose hold of more than 28 days will result in permanent discontinuation of 
daratumumab (unless Sponsor approves continuation).  
6.3.3.2. 
Daratumumab Interruption or Missed Doses 
A daratumumab dose that is held for more than the permitted time (Table 8) 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’s study team at the earliest possible time. Subjects 
whose dose was delayed for more than 28 days should be withdrawn from study treatment, unless, 
upon consultation with the sponsor and the review of safety and efficacy, continuation is agreed 
upon. 
6.3.4. 
Dose Reductions (Bortezomib, Thalidomide, and Dexamethasone) 
Bortezomib will be modified or discontinued according to the guidelines presented in Table 9. 


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Table 9: 
Dose Modification for Bortezomib 
Starting Dose 
First Dose Reduction 
Second Dose Reduction 
Third Dose Reduction 
Bortezomib 1.3 mg/m2 on 
Days 1, 4, 8, 11 
Bortezomib 1.3 mg/m2 on 
Days 1, 8 
Bortezomib 1.0 mg/m2 on 
Days 1, 8 
Discontinue bortezomib 
 
Thalidomide will be reduced or discontinued according to the guidelines presented in Table 10. 
Table 10: 
Dose Reduction for Thalidomide 
  
Starting Dose  
First Dose Reduction 
Second Dose Reduction 
Third Dose Reduction 
100 mg QD 
50 mg QD 
50 mg every second day  
Discontinue thalidomide 
QD=every day 
 
Dexamethasone will be reduced or discontinued according to the guidelines presented in Table 11. 
Table 11: 
Dose Reductions for Dexamethasone 
First Dose Reduction 
Second Dose Reduction 
Third Dose Reduction 
Reduce dexamethasone by 50% from 
previous dose 
Skip dexamethasone on days when 
daratumumab is not given. 
Discontinue dexamethasone 
 
If reduction of dexamethasone dose occurs prior to Week 2 of Cycle 3, dose of dexamethasone 
from Week 2 of Cycle 3 onwards should also be reduced by 50% (ie. 10mg instead of 20mg). Dose 
Modification Guidelines for Bortezomib, Thalidomide and Dexamethasone. 
Dose modification guidelines for bortezomib, thalidomide and, dexamethasone are provided in 
Table 12.  


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Table 12:  
Dose Modification Guidelines for Bortezomib, Dexamethasone and Thalidomide 
 
 
Body System 
NCI-CTC Adverse Event 
and or Symptom and 
Category 
Bortezomib 
Thalidomide 
Dexamethasone 
Allergic reactions 
Allergic reaction or 
hypersensitivity 
Grade 2 OR 3 
Hold all therapy. 
If the toxicity resolves to  Grade 1, restart study drug(s). Modify/reduce by 1 dose level the suspected medication(s) AND 
implement appropriate anti-allergic prophylaxis therapy. 
If the reaction was anaphylactic in nature, do not resume any of the suspected study drug(s). 
NOTE: If the reaction was cutaneous in nature, refer to the cutaneous category below. 
Allergic reaction or 
hypersensitivity 
Grade 4 
Discontinue study drug(s). 
Constitutional 
Fluid Retention (i.e., edema) 
>Grade 3 (limiting function 
and unresponsive to therapy 
or anasarca) 
 
 
Administer diuretics as needed and decrease 
dexamethasone or prednisone dose by 1 dose 
level; if edema persists despite above measures, 
decrease dose another dose-level. 
Discontinue dexamethasone or prednisone and do 
not resume if symptoms persist despite second 
reduction. 
Fatiguea  
 Grade 3 (i.e., severe 
fatigue interfering with 
activities of daily living) 
 
Reduce dose of Thalidomide by 1 
dose level. If symptoms persist, 
modify bortezomib also by 1 dose 
level. 
 
a Determine if fatigue is possibly not medication-related but due to an underlying cause (eg, infection, progression of disease, diarrhea, 
anemia, depression) and treat these symptoms/causes as appropriate. 
Cutaneous 
Non-blistering rash 
Grade 2 
Hold thalidomide and bortezomib therapies. Begin treatment with 
antihistamines and/or low-dose steroids as per institutional practice. 
If the toxicity resolves to  Grade 1, restart thalidomide and bortezomib 
modified/reduced by 1 dose level 
 
Non-blistering rash 
 Grade 3 or 4  
Hold thalidomide and bortezomib therapies. Begin treatment with 
antihistamines and/or low-dose steroids as per institutional practice. 
If the toxicity resolves to  Grade 1, restart bortezomib (only) modified/ 
reduced by 1 dose level and continue antihistamines and/or low-dose 
steroids as per institutional practice. If no further symptoms are seen, then 
restart thalidomide at 1 dose reduction level.  
If toxicity recurs despite above measure, discontinue bortezomib and/or 
thalidomide permanently, as appropriate.  
 
Desquamating (blistering) 
rash- 
any grade or erythema 
multiform  Grade 3 
Discontinue thalidomide AND bortezomib permanently. 
Hold other therapies. Begin treatment with antihistamines and/or low-dose steroids as per institutional practice. 
If the toxicity resolves to  Grade 1, restart other medications.  
 
 
 
 
 


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Body System 
NCI-CTC Adverse Event 
and or Symptom and 
Category 
Bortezomib 
Thalidomide 
Dexamethasone 
Gastrointestinal 
Constipationb 
Requiring manual extraction. 
 Grade 3 
Hold bortezomib and thalidomide. 
Upon recovery to  Grade 1, restart bortezomib and thalidomide modified/ 
reduced by 1 dose level. 
 
Diarrheac 
 Grade 3 
Hold bortezomib and consider loperamide therapy. 
Upon recovery to  Grade 1, restart bortezomib modified/reduced by 1 dose 
level. 
 
Dyspepsia, gastric or 
duodenal ulcer, gastritis 
Grade 1-2 (requiring medical 
management) 
 
 
Treat with histamine-2 blockers, sucralfate, or 
omeprazole.  
If symptoms persist despite above measures, 
decrease dexamethasone or prednisone dose by 1 
dose level. 
Dyspepsia, gastric or 
duodenal ulcer, gastritis 
 Grade 3 (requiring 
hospitalization or surgery) 
 
 
Hold dexamethasone and consider treatment with 
histamine-2 blockers, sucralfate, or omeprazole. 
Restart dexamethasone or prednisone reduced by 
1 dose level if symptoms are adequately 
controlled.  
If symptoms persist despite above measures, 
discontinue dexamethasone or prednisone and do 
not resume. 
b Prior to dose reduction of medications, consider/eliminate other possible causes of constipation.  
c  Prior to dose reduction of medications, consider/eliminate other possible causes (i.e., bacterial or viral infections) of diarrhea.  
Hematologicald 
Neutropenia 
Grade 3 (without 
complications) 
 
No dose reduction required of either bortezomib or thalidomide. Consider 
treatment with G-CSF. 
 
Neutropenia associated with 
fever (38.5ºC): Grade 3 
or neutropenia Grade 4 
Hold therapy with all drugs until recovery to baseline OR  Grade 2. 
Upon recovery, restart thalidomide reduced by 1 dose level. Maintain 
bortezomib at current dose and consider G-CSF support. 
If recurrence is seen, modify/reduce bortezomib by 1 dose level. 
 
Thrombocytopenia 
Grade 3 (without 
complications) 
No dose reduction required for either bortezomib or thalidomide. 
 
 
Platelet count <25,000/L 
(i.e., Grade 4) or Grade 3 
thrombocytopenia with 
bleeding 
Hold therapy with all drugs until recovery to baseline OR  Grade 2. 
Upon recovery, restart thalidomide at current dose and bortezomib 
modified/reduced by 1 dose level. If recurrence is seen, reduce thalidomide 
by 1 dose-level and bortezomib by 1 further dose-level. 
 
Infection 
Herpes Zostere activation or 
reactivation 
ANY grade 
Hold ALL therapies until lesions are dry. If not already underway, begin antiviral treatment 
Once the infection is resolved all medications can be restarted without a dose reduction; however, continued antiviral 
prophylaxis is required. 


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Body System 
NCI-CTC Adverse Event 
and or Symptom and 
Category 
Bortezomib 
Thalidomide 
Dexamethasone 
Musculoskeletal 
Muscle weakness >Grade 2 
(symptomatic and interfering 
with function +/- interfering 
with activities of daily 
living) 
 
 
Decrease dexamethasone dose by 1 dose level. If 
weakness persists despite above measures, 
decrease dose by 1 further dose level. If 
symptoms still persist, discontinue and do not 
resume if symptoms persist. 
d In the event of concurrent neutropenia and thrombocytopenia, please refer to the recommendation provided for thrombocytopenia in which it is recommended to first dose reduce 
bortezomib and then thalidomide. 
e In the event that a subject is already receiving antiviral treatment at the time of the Herpes Zoster activation, consider switching to or adding another antiviral agent. 
Metabolic 
Hyperglycemia 
 Grade 3 
 
 
Treatment with insulin or oral hypoglycemics. If 
uncontrolled despite above measures, decrease 
dose by 1 dose level until levels are satisfactory. 
Neurologicalf 
Somnolence 
 Grade 3  
 
Reduce thalidomide by 1 dose level. 
If symptoms persist, reduce by a 
further dose level. If then unresolved, 
discontinue thalidomide. 
 
Peripheral Neuropathy (Sensory or Motor) and/or 
Neuropathic Pain 
Grade 1 (paresthesias  
and/or loss of reflexes) 
without pain or loss of 
function 
No action required. 
 
Grade 1 with pain or 
Grade 2 (interfering 
with function but not 
with activities of daily 
living) 
Modify/reduce bortezomib and thalidomide by 1 dose level. 
 
Grade 2 with pain or 
Grade 3 (interfering 
with activities of daily 
living) 
Hold bortezomib until toxicity resolves to <Grade 2. When toxicity 
resolves, reinitiate with a reduction in dose level and schedule (i.e. modify 
by 2 dose levels 
Discontinue thalidomide permanently. 
 
Grade 4 (permanent 
sensory loss that 
interferes with 
function) 
Discontinue bortezomib and thalidomide permanently. 
 
 
f The neurotoxicity-directed questionnaire is a useful tool for determining the presence and intensity of neuropathic pain and/or peripheral neuropathy from the subject’s perspective. 
Neuropathic symptoms are more prominent than abnormalities on the clinical examination. After the subject completes the neurotoxicity directed questionnaire, the questionnaire 
should be reviewed to assist with the evaluation of the onset and intensity of peripheral neuropathy and other neurotoxicities that may require intervention or dose modification. 
 


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Body System 
NCI-CTC Adverse Event 
and or Symptom and 
Category 
Bortezomib 
Thalidomide 
Dexamethasone 
Neuro-
psychological  
Confusion or mood alteration 
>Grade 2 (interfering with 
function +/- interfering with 
activities of daily living) 
 
 
Hold dexamethasone until symptoms resolve.  
Restart with 1 dose level reduction.  
If symptoms persist despite above measures, 
discontinue dexamethasone and do not resume. 
Thromboembolic 
Venous and /or pulmonary 
thrombo-embolism 
 Grade 3 [Deep vein 
thrombosis or cardiac 
thrombosis intervention 
indicate; eg: anticoagulation, 
lysis, filter, invasive 
procedure.] 
 
Stop thalidomide until toxicity 
resolves and, if not already given, 
start anticoagulation therapy. 
Restart thalidomide at  
1 dose level lower after adequate 
anticoagulation, 
Stop until toxicity resolves and, if not already 
given, start anticoagulation therapy. 
Restart dexamethasone or prednisone at full dose 
after adequate anticoagulation, 
Renal Impairment 
 
 
 
 
Other toxicities 
 
Any reported  
 Grade 3 
Determine attribution of the toxicity and hold the therapy (ies) as appropriate. 
If toxicity resolves to  Grade 1, resume therapy with 1 level of dose modification/reduction. 
 


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7. 
TREATMENT COMPLIANCE 
Daratumumab and the components of the backbone regimens will be administered by qualified 
site staff, and the details of each administration will be recorded in the electronic case report form 
(eCRF). Subjects will be provided with a diary to record intake of thalidomide and dexamethasone. 
Additional details are provided in the IP Manual. 
8. 
PRESTUDY AND CONCOMITANT THERAPY 
Throughout the study, investigators may prescribe any concomitant medications or treatments 
deemed necessary to provide adequate supportive care except for those listed in Section 8.3. The 
sponsor must be notified in advance (or as soon as possible thereafter) of any instances in which 
prohibited therapies are administered.  
Routine systemic use of the following concomitant medications will be collected in the eCRF and 
recorded in the source documents beginning with signing of the ICF to 30 days after the last dose 
of the last study treatment or until the start of subsequent anticancer treatment, if earlier: growth 
factors, transfusions, anti-infectives (antibacterials, antivirals, and antimycotics), steroids, anti-
arrhythmics and other cardiac supportive therapy, anti-epileptics, centrally acting psychiatric 
medication, anti-histamines and other medications targeting postinfusion systemic reactions, 
bisphosphonates, and any anticancer therapy (including radiation). During the transplant period 
(that is to say the period from the first day of hospitalization to the day before C5D1) only the 
concomitant treatments used to treat AE specified in Section 9.1.3. will have to be recorded. 
Concomitant medications to manage AEs and SAEs will be recorded as per Section 12.3.1. 
8.1. 
Recommended Therapies 
8.1.1. 
Prevention of Deep Venous Thrombosis 
All subjects who receive thalidomide are required to receive prophylactic anti-thrombotic 
treatment, including low-molecular-weight heparin and aspirin (acetylsalicylic acid). It is 
mandatory that every subject receives 1 of these 2 prophylactic measures (either aspirin at a 
minimum of 100 mg PO per day or daily subcutaneous low molecular weight heparin injections, 
per investigator preference). 
8.1.2. 
Therapy for Tumor Lysis Syndrome 
Subjects should be monitored for symptoms of tumor lysis syndrome. Management of tumor lysis 
syndrome, including dehydration and abnormal laboratory test results such as hyperkalemia, 
hyperuricemia, and hypocalcemia, is highly recommended. It is also recommended that high-risk 
subjects, i.e., those with a high tumor burden, be treated prophylactically in accordance with local 
standards (eg, rehydration; diuretics; allopurinol 300 mg daily and medication to increase urate 
excretion). Subjects are to be provided prophylactic therapy to manage infusion reactions during 
the Treatment Phase, as described in Section 6.1.3.1. 
8.1.3. 
Prophylaxis Against Pneumocystis carinii Pneumonia 
Pneumocystis carinii pneumonia (PCP) prophylaxis should be considered, as per institutional 
guidelines. 


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8.1.4. 
Prophylaxis for Herpes Zoster Reactivation 
Prophylaxis for herpes zoster reactivation is recommended during the Treatment Phase. 
Acceptable antiviral therapy includes acyclovir (eg, 400 mg given orally 3 times a day, or 
800 mg given orally 2 times a day or per institutional standards), famcyclovir (eg, 125 mg given 
3 days orally, twice a day or per institutional standards), or valacyclovir (eg, 500 mg given 
orally, twice a day or per institutional standards), initiated within 1 week of the first dose and 
continue for 3 months following treatment. 
8.1.5. 
Bisphosphonate Therapy 
Bisphosphonate therapy is recommended to be continued per treatment guidelines (NCCN 2013). 
Commercially available IV bisphosphonates (pamidronate and zoledronic acid) are preferred when 
available, and should be used according to the manufacturer’s recommendations, as described in 
the prescribing information, for subjects with osteolytic or osteopenic myelomatous bone disease. 
Oral bisphosphonates may be used as alternatives if IV bisphosphonates are not available at the 
study site. 
Subjects who are currently using bisphosphonate therapy when they enter the study should 
continue the same treatment. If clinically indicated, subjects may initiate bisphosphonate therapy 
as soon as possible during Screening and no later than the end of Cycle 1.  After Cycle 1, 
investigators could prescribe bisphosphonates to subjects who have not received it before, as per 
investigator judgment but only after checking if there is no disease progression. 
 
Management of Hepatitis B Virus Reactivation 
For patients with positive HBV serology, clinical and laboratory monitoring of signs of 
inactivation should be performed during treatment and for at least six (6) months after stopping 
treatment with daratumumab. A consultation with a doctor specializing in the treatment of HBV 
infections should be considered, if necessary. 
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.  
 
8.2. 
Permitted Therapies 
Subjects are to receive full supportive care during the study. The following medications and 
supportive therapies are examples of support therapies that may be used during the study: 
• 
Colony stimulating factors, erythropoietin, and transfusion of platelets and red cells. 
Erythropoietic agents may increase thromboembolic risk; if administered, subjects should 
be instructed to seek medical care if they develop symptoms of thromboembolism such as 
shortness of breath, chest pain, arm or leg swelling. Particularly, a hemoglobin 
concentration above 12g/dl should lead to discontinuation of erythropoietic agents. 


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• 
Loperamide is recommended for the treatment of diarrhea, starting at the time of the first 
watery stool. The loperamide dose and regimen is according to institutional guidelines. 
Prophylactic loperamide is not recommended 
• 
It is important to prevent constipation (eg, adequate hydration, high-fiber diet, and stool 
softeners if needed) 
• 
Adequate hydration is recommended for prevention of myeloma-related kidney disease 
• 
Prophylactic antiemetics, with the exception of corticosteroids 
• 
An emergency short course of corticosteroid (equivalent of dexamethasone 40 mg/day for 
a maximum 4 days) is permitted before treatment. 
8.3. 
Prohibited Therapies 
Concomitant administration of any other antineoplastic therapy for the intention of treating 
multiple myeloma not defined in the study protocol is prohibited, including medications that target 
CD38. Continuation of daratumumab and components of the VTD regimen during or after 
emergency orthopedic surgery or radiotherapy because of the subject’s benefit may occur only in 
the absence of disease progression and after consultation with and approval by the sponsor. Such 
emergency radiotherapy may consist of localized radiotherapy for pain control or for stabilization 
of an extensive bone lesion at high risk of pathologic fracture or damage to surrounding tissues in 
a subject in whom delay of systemic therapy is not appropriate. Such radiotherapy is to occur 
within the first 2 cycles of treatment and the absence of evidence of disease progression is to be 
reviewed and approved by the sponsor. 
Concomitant administration of investigational agents is prohibited. Administration of 
commercially available agents with activity against or under investigation for multiple myeloma, 
including systemic corticosteroids (>10 mg prednisone per day or equivalent) (other than those 
given for infusion-related reactions as described in Section 6.1.3.2) should be avoided. 
Nonsteroidal anti-inflammatory agents should be avoided to prevent myeloma-related kidney 
disease.  
Typically, IV contrast is NOT used in computed tomography (CT) scanning of the subjects with 
secretory multiple myeloma because of the risk to the kidney. If administration of IV contrast is 
necessary, then adequate precautions including hydration are indicated. The sponsor must be 
notified in advance (or as soon as possible thereafter) of any instances in which prohibited 
therapies are administered. 
9. 
STUDY EVALUATIONS 
9.1. 
Study Procedures 
9.1.1. 
Overview 
The Time and Events Schedules summarize the frequency and timing of assessments applicable to 
this study. Study assessments will be performed only after written informed consent is obtained. 
Every effort should be made to keep subjects on the study schedule as planned from Cycle 1 Day 
1. At each visit, study assessments should be completed before the administration of any treatment. 


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Any missed visits, tests not performed, or examinations that are not conducted must be reported 
as such in the eCRF. 
All visit-specific PRO assessments should preferably be conducted/completed before any tests, 
procedures, or other consultations for that visit to prevent influencing subject perceptions. Refer 
to Section 9.7 for details. 
Urine and blood collections should be kept as close to the specified time as possible. Other 
measurements may be done earlier than specified, if needed. Additional pregnancy tests may be 
performed, as determined necessary by the investigator or required by local regulation, to establish 
the absence of pregnancy at any time during the subject's participation in the study. 
The total blood volume for the study is estimated at approximately 50 mL during screening, 
400 mL in Part 1 (Induction/ASCT/Consolidation Phase), and approximately 500 mL in Part 2 (2-
year Maintenance Phase). This includes laboratory assessments associated with safety, efficacy, 
and pharmacokinetic evaluations, as well as scientific research samples. Repeat or unscheduled 
samples may be taken for safety reasons upon investigator judgment, in case of disease 
progression, or for technical issues with the samples. 
9.1.2. 
Screening Phase 
The signed ICF must be obtained before any study-specific procedures are performed. The 
Screening Phase begins when the first screening assessment is conducted. During the Screening 
Phase, eligibility criteria will be reviewed, and a complete clinical evaluation will be performed as 
specified in the Time and Events Schedule. Screening procedures will be performed within 28 
days before Cycle 1 Day 1; however, results of tests such as skeletal survey, radiologic tests (eg, 
magnetic resonance imaging [MRI]) to document baseline size of known or suspected 
extramedullary plasmacytomas; ECG; chest x rays; or bone marrow aspirate/biopsy) performed 
up to 6 weeks (42 days) before randomization as routine standard of care for the subject’s disease 
can be used.  
A negative pregnancy test for women of childbearing potential must be documented within 10 to 
14 days and again within 24 hours before the first dose of any component of the treatment regimen.  
If approved by the sponsor, subjects who are screen failures may be rescreened if their condition 
changes (see Section 4.2 for details). 
9.1.3. 
Treatment Phase 
Details of the procedures performed during the Treatment Phase are outlined in the Time and 
Events Schedules.  
The study treatment should be initiated within 3 days after the first randomization. 
The Treatment Phase begins on Cycle 1 Day 1 and continues until disease progression, completion 
of the planned maintenance treatment duration for a maximum of 2 years, or for the other reasons 
outlined in Section 10.2. Subjects will be closely monitored for adverse events, laboratory 


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abnormalities, and clinical response. Clinical evaluations and laboratory studies may be repeated 
more frequently, if clinically indicated. If disease progression is diagnosed, then the subject will 
discontinue the study drugs, complete the End-of-Treatment Visit, and enter the Follow-up Phase. 
Study Part 1 
Induction Treatment 
Subjects will receive up to 4 x 28 days cycles of VTD induction therapy as described in Section 6.2. 
Subjects in Arm B will receive daratumumab in addition to VTD as described in Section 6.1. 
Efficacy will be assessed at the start of each cycle. 
Post Induction Efficacy Assessment (end of Cycle 4)  
A bone marrow biopsy/aspirate (preferably both but morphologic review of the aspirate smear may 
be done if a core biopsy is not available) will be performed at the end of Cycle 4 to determine the 
plasma cell burden. The time window for this assessment is +/-3 days. As long as disease 
progression is not observed, subjects may proceed to stem cell mobilization. Subjects who cannot 
proceed to stem cell mobilization at this timepoint, based on investigator discretion or institutional 
practice, will be withdrawn from treatment. Subjects with disease progression will also be 
withdrawn from treatment. These subjects will enter in the follow-up phase.  
Mobilization and Harvesting Stem Cells 
Stem cell mobilization will be performed using cyclophosphamide (recommended dose of 3 g/m2) 
and G-CSF (recommended dose of 10 microg/kg/day until the last day of the collection for a 
maximum of 10 days) after Cycle 4 and stem cells will be harvested based on response to 
mobilization.  
The use of Plerixafor is permitted per institutional practice in case of failure. 
It is recommended not to exceed a maximum of 4 weeks after the end of Cycle 4 to start the 
mobilization. 
In case of subsequent of failure with Plerixafor bone marrow harvest may be performed.  
Sufficient stem cells should be harvested to enable multiple transplants in accordance with 
institutional standards. 
An assessment of the efficiency of mobilization/harvesting will be recorded in the eCRF (please 
see Section 9.2). During the transplant period (that is to say the period from the first day of 
hospitalization to the day before C5D1), neutropenia and thrombocytopenia resulting from bone 
marrow aplasia will not be recorded as AEs in the eCRF. Only the following have to be recorded 
in the eCRF:  
- any evolution of ongoing AE 
- any new AE related, or that appears to be related, to Daratumumab 


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- any new infection from at least grade 3 
- any new oral mucositis from at least grade 3. 
 
It is recommended not to exceed a maximum of 4-8 weeks between the mobilization and the start 
of melphalan. 
 
Conditioning (melphalan) 
Subjects will receive melphalan 200mg/m2 as conditioning therapy over a period of 24 to 48 hours.  
 
Transplant 
Subjects will have a single re-infusion of stem cells 24-48 hours after high dose melphalan 
(+ permitted tolerance) 
Engraftment/Recovery (Day 1-60 post ASCT) 
Subjects will be monitored for successful engraftment; support therapy will be administered 
according to institutional/study group standards. 
Consolidation (30-60 days) 
Consolidation therapy may commence when engraftment (ANC > 0.5x109/L and platelets 
>20x109/L without transfusion) is complete and when in the opinion of the investigator the subject 
is fit enough to tolerate subsequent systemic therapy (30-60 days post ASCT).  
Subjects will receive a further 2 x 28-day cycles of VTD as described in Section 6.2. Subjects 
randomly assigned to Arm B will receive daratumumab as described in Section 6.1. 
Efficacy will be assessed at the start of each cycle. 
Post consolidation efficacy assessment (Day 100 post ASCT)  
Subjects will be assessed for efficacy for the primary endpoint at Day 100 post ASCT. If subjects 
are still receiving consolidation therapy at Day 100, the assessment of efficacy should be 
performed immediately upon completion of consolidation therapy. The time window for this 
assessment is +/- 3 days from Day 100 or from end of consolidation therapy, as applicable. 
Study Part 2 
Randomization to Maintenance/Observation Phase (continuing from end of last 
consolidation cycle, 50 days)  
Subjects who complete consolidation and attain a minimum of a partial response or better 
according to the IMWG criteria will be eligible for re-randomization to either daratumumab 


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maintenance or observation. Subjects who are not eligible for re-randomization will enter the 
Follow-up Phase. 
The maximum time period between the end of the last consolidation cycle and second 
randomization should be no more than 50 days. Any assigned treatment should be initiated no later 
than 10 days after the second randomization in to part 2 of the study.  
Maintenance phase 
Subjects are randomly assigned to Arm A (observation) or Arm B (they will receive daratumumab 
as described in Section 6.1). 
All subjects will be assessed for efficacy every 8 weeks after re-randomization, additional 
assessments of MRD status will also be performed for patients who achieve at least VGPR (weeks 
25, 52, 105 or whenever it will be necessary). 
End-of-Treatment Visit (EOT) 
Subjects will be treated for the maximal allowed treatment duration (or until disease progression, 
unacceptable toxicity, or for the other reasons outlined in Section 10.2). Unless a subject withdraws 
consent for study participation, is lost to follow-up, or dies, an End-of-Treatment Visit is to be 
scheduled within 30 days after the last dose of all components of the treatment regimen have been 
discontinued, or within 30 days after the last observation visit (for subject in Arm A) or as soon as 
possible before the start of subsequent therapy.  
Every effort should be made to conduct the End-of-Treatment Visit before the subject starts 
subsequent therapy.  
Adverse events and concomitant therapies that occur within 30 days after the last visit (last dose 
of any component of the treatment regimen or the last observation visit) must be collected. 
Additional information on reporting of adverse events can be found in Section 12. 
During the EOT visit, a complete evaluation should be performed: 
• Hematology/Serum chemistry (local laboratory),  
• Disease evaluation (central laboratory),  
• Bone marrow examination (myelogram and MRD assessment (if applicable)) 
• Assessment of lytic disease (same type of imaging as performed for screening procedures), 
if applicable.  
• Extramedullary plasmacytoma assessment (same type of evaluation as performed for 
screening visit and/or during study treatment) if applicable 
• Adverse event 


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• Concomitant medication 
 
9.1.4. 
Follow-Up Phase 
The Follow-up Phase will begin once a subject permanently discontinues treatment with study 
medications, except for subjects randomized to Arm A (observation) in the Maintenance Phase. 
These subjects will enter the Follow-up Phase 2 years after the second randomization or upon 
disease progression, withdrawal of consent, or start of new anticancer therapy, whichever is 
earliest.  
For all subjects who complete or discontinue study drug without disease progression (Pre-PD), 
disease evaluations should continue to be performed every 12 weeks as specified in the Time and 
Events Schedules until documented disease progression.  
Pre-PD Follow-Up (FU) visits need to be scheduled as indicated below:  
First Pre-PD FU visit:  
• if patient is on treatment arm: 8 weeks after the last dose of any component of the treatment 
regimen  
• if patient is on Observation arm: 8 weeks after the last Maintenance/Observation phase 
visit  
The second and subsequent Pre-PD Follow-up visits will be performed every 12 weeks until 
documented disease progression. 
MRD assessment will be performed also every year during Pre-PD FU if the MRD remains 
negative (after W105 of maintenance/Observation visit  or the last MRD assessment since D100 
). Thereafter subsequent anticancer treatment and response to treatment including date of 
subsequent progression (PFS2) will be recorded and survival status will be obtained.  
In case the patient starts a new line of therapy without disease progression, Follow-Up visits will 
be performed every 12 weeks until disease progression, lost to follow-up or death. The assessments 
done will be as details below in the Survival Follow-up visits. 
If disease progression occurs, Survival Follow-up visits will be planned: 
• Survival Follow-Up 1 visit will be performed 8 weeks after PD: Patient reported outcome 
(EORTCQLQ-C30 and EQ-5D-5L) must be completed 
• Survival Follow-Up 2 visit will be performed 16 weeks after PD: Patient reported outcome 
(EORTCQLQ-C30 and EQ-5D-5L) must be completed  
• Subsequent Survival Follow-up visits will be performed every 4 months 


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In accordance with the 2011 IMWG consensus recommendations for the purposes of the study a 
line of therapy is defined as one or more cycles of a planned treatment program. The planned 
treatment approach of induction therapy followed by autologous stem cell transplantation, 
consolidation, and where applicable maintenance is considered one line of therapy. 
 A new line of therapy starts when a planned course of therapy is modified to include other 
treatment agents (alone or in combination) as a result of a disease progression, relapse, or toxicity. 
(Rajkumar, 201147). 
If the information is obtained via telephone contact, written documentation of the communication 
must be available for review in the source documents. If the subject has died, the date and cause 
of death will be collected and documented in the eCRF. Follow-up of subject data will continue 
until 350 subjects have died, or for a maximum of 5 years after the last subject is randomized in 
Part 2 for the maintenance phase, which will be considered the end of the study. 
9.2. 
Safety Evaluations 
Safety and tolerability is a secondary objective of this study, the study will be conducted under the 
supervision of an IDMC (refer to Section 11.9) until the unblinding of data. Safety evaluations 
will include adverse event monitoring, physical examinations, electrocardiogram (ECGs) 
monitoring, clinical laboratory parameters (hematology and chemistry), vital sign measurements, 
and ECOG performance status. All toxicities will be graded according to the NCI-CTCAE Version 
4. Any clinically relevant changes occurring during the study must be recorded in the Adverse 
Event eCRF page. Any clinically significant abnormalities persisting at the end of the study/early 
withdrawal will be followed by the investigator until resolution or until a clinically stable endpoint 
is reached.  
Based on the previous human experience with daratumumab, in vitro studies, and animal 
toxicological 
findings, 
infusion-related 
reactions/allergic 
reactions, 
hemolysis, 
and 
thrombocytopenia will be closely monitored. As a biologic agent, immunogenicity also will be 
monitored. Any of the safety monitoring assessments may be performed more frequently, and 
adverse events should be evaluated by the investigator according to the standard practice, if 
clinically indicated. 
Adverse Events 
Adverse events (with the exception of progression of multiple myeloma) will be reported by the 
subject (or, when appropriate, by a caregiver, surrogate, or the subject's legally acceptable 
representative) from the time a signed and dated informed consent is obtained until 30 days 
following the last dose of any component of the treatment regimen, except for subjects randomized 
to Arm A (observation) in the Maintenance Phase. For these subjects, adverse events will be 
collected for 2 years after the second randomization, or upon disease progression, withdrawal of 
consent, or start of new anticancer therapy (whichever occurs first), even though no study drug is 
being administered. Adverse events will be followed by the investigator as specified in Section 12 
Adverse Event Reporting.  
For AE reporting during the transplant period, please see Section 9.1.3. 


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Infusion Related Reaction (IRR) 
An IRR is defined as any adverse event (AE) occurring during or within the 24 hours after the 
Daratumumab infusion and assessed as related to Daratumumab infusion. 
Clinical Laboratory Tests  
Blood samples for serum chemistry and hematology will be collected. The investigator must 
review the laboratory report, document this review, and record any clinically relevant changes 
occurring during the study in the Adverse Event eCRF page. The laboratory reports must be filed 
with the source documents. 
The following tests will be performed by the local laboratory, unless otherwise specified: 
• 
Hematology Panel 
-hemoglobin 
-absolute neutrophil count 
-white blood cell (WBC) count 
-absolute lymphocyte count 
- platelet count 
 
• 
Serum Chemistry Panel 
During induction and consolidation cycles: 
-urea 
-alkaline phosphatase 
-creatinine 
-lactic acid dehydrogenase (LDH) 
-glucose 
-uric acid 
-AST 
-total and direct bilirubin 
-ALT 
-total protein 
 
 
During maintenance cycles: 
 
-AST 
-urea 
-ALT 
-creatinine 
-total and direct bilirubin 
 
 
 
 
• 
Other Laboratory Tests 
-Serum pregnancy test: Women of childbearing potential only. Urine pregnancy test allowed 
if results from a serum pregnancy test will not be promptly available. Thalidomide is 
contraindicated for use during pregnancy, as even a single dose can induce a high frequency 
of severe and life-threatening birth defects. Guidelines presented in the Celgene thalidomide 
pregnancy prevention program must be followed. If pregnancy does occur, then study 
treatment should be discontinued immediately, and the subject should be referred to an 
obstetrician experienced in reproductive toxicity for further evaluation and counseling. 
-Calcium and albumin adjusted calcium: These parameters will be part of the efficacy 
evaluations as specified in Section 9.6.4. Albumin will be analyzed by the central and local 
laboratories. Measurement of calcium and albumin should follow the schedule for disease 
assessments. Measurement of free ionized calcium is an acceptable alternative to corrected 
serum calcium for determining hypercalcemia. 
 


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Daratumumab Interference with Indirect Antiglobulin Test (IAT) results  
Daratumumab interferes with the Indirect Antiglobulin Test (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 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) 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 IAT interference by treating 
reagent RBCs with dithiothreitol (DTT) (Chapuy 2015). 
Possible methods for blood banks to provide safe RBCs for transfusion to subjects receiving 
daratumumab include: 
a) Providing ABO/RhD compatible, phenotypically (standard or extended phenotyping prior 
to daratumumab administration) or genotypically matched units 
b) Providing ABO/RhD compatible, K-negative units after ruling out or identifying 
alloantibodies using DTT-treated reagent RBCs 
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 Investigator's Brochure. 
Stem Cell Harvest: For subjects who receive ASCT, record number of CD34+ cells collected, 
agents used for mobilization, and hematopoietic engraftment information. 
Pulmonary Function Test: Subjects with known or suspected COPD or asthma must have a FEV1 
test during screening. Refer to Section 6.1.3.2 for details on subjects with higher risk of respiratory 
complications. 
ECG: 12-lead ECGs will be performed as specified in the Time and Events Schedule. Whenever 
possible, ECGs should be taken immediately before chemistry and PK assessments. During the 
collection of ECGs, subjects should be in a quiet setting without distractions (eg, television, cell 
phones). Subjects should rest in a supine position for at least 5 minutes before ECG collection and 
should refrain from talking or moving arms or legs. If blood sampling or vital sign measurement 


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is scheduled for the same time point as ECG recording, then the procedures should be performed 
in the following order: ECG(s), vital signs, blood draw. 
Vital Signs: (pulse, temperature, blood pressure) will be performed as specified in the Time and 
Events Schedule. It is recommended that blood pressure and pulse measurements be preceded by 
at least 5 minutes of rest in a quiet setting without distractions (eg, television, cell phones). 
Physical Examination: A complete physical examination (including neurological examination) 
should be performed during the Screening Phase. Thereafter, only a symptom directed physical 
examination is required. Abnormalities will be recorded in the appropriate section of the eCRF. 
9.3. 
Immunogenicity Evaluations 
9.3.1. 
Immunogenicity Assessments 
Samples to assess the generation of antibodies to daratumumab (immunogenicity) and associated 
serum daratumumab concentration levels will be obtained from all subjects according to the Time 
and Events Schedule. At specified time points, venous blood samples (5 mL per sample) will be 
collected and the serum will be divided into 3 aliquots (1 aliquot for immunogenicity assessment, 
1 aliquot for serum daratumumab concentration, and 1 aliquot as a back-up).  Daratumumab 
concentration is evaluated at all immunogenicity time points to ensure appropriate interpretation 
of immunogenicity data and both analyses are performed on aliquots from the same blood draw; 
no additional sampling is required.  
Procedures for sample collection, preparation, identification, storage, and shipment will be 
provided in the Laboratory Manual or equivalent document. The exact dates and times of blood 
sampling must be recorded. Collected samples must be stored under the specified and controlled 
conditions for the temperatures indicated in the Laboratory Manual. Samples collected for 
determining immunogenicity/serum concentrations of daratumumab in this study may be retained 
to address questions about drug characteristics that may arise at a later time point. 
A blood sample should be drawn, if possible, for determination of antibodies to daratumumab any 
time an infusion reaction is observed or reported during the study. Daratumumab serum 
concentration will also be determined from the same infusion reaction sample for the purpose of 
interpreting immunogenicity data. These samples will be stored and evaluated if deemed 
necessary. If the infusion reaction results in treatment discontinuation, then subjects should 
undergo all scheduled safety and efficacy evaluations. Samples collected for the analysis of 
daratumumab immunogenicity/serum concentration may additionally be used to evaluate safety or 
efficacy aspects that address concerns arising during or after the study period or for the evaluation 
of relevant biomarkers by the sponsor or sponsor’s designee. 
9.3.2. 
Analytical Procedures 
Serum samples will be analyzed to assess the generation of antibodies to daratumumab and 
associated concentrations of daratumumab using validated immunoassay methods by or under the 
supervision of the sponsor’s bioanalytical facility. 


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For the immunogenicity assessments, serum samples will be screened for antibodies binding to 
daratumumab and serum titer will also be determined from confirmed positive samples. Other 
immunogenicity analyses (eg, assessment of neutralizing capabilities) may be performed to further 
characterize the immune responses that are generated. 
9.4. 
Biomarker Evaluations  
Biomarker analyses, including evaluation of MRD, are dependent upon the availability of 
appropriate biomarker assays and may be deferred or not performed if, during or at the end of the 
study, it becomes clear that the analysis will have no scientific value, or if there are not enough 
samples or not enough responders to allow for adequate biomarker evaluation. In the event the 
study is terminated early or shows poor clinical efficacy, completion of biomarker assessments is 
based on justification and intended utility of the data. Samples for biomarker evaluations will be 
collected as specified in the Time and Events Schedule.  
Biomarkers for MMY3006 will focus on the evaluation of MRD and immune profiling in bone 
marrow aspirates and on the assessment of clinical efficacy in high-risk molecular subgroups.  
The use of sensitive methodology to detect MRD following a clinical response is being adopted 
by myeloma researchers as a supplemental criterion to define CR (Paiva 201143). Monitoring MRD 
(clonal plasma cells still present in bone marrow) is important to detect residual disease after 
treatment and early relapse, to monitor the effects of treatment at low levels of disease, to measure 
the depth of response and how it correlates with outcome, and to continue to maintain a defined 
treatment. The most commonly used sensitive methods to monitor MRD include next generation 
sequencing (NGS), allele-specific oligonucleotide PCR, and multiparametric flow cytometry 
(Rawstron 201349, Sarasquete 200552). Markers used to monitor multiple myeloma MRD may 
include CD138/CD38/CD45/CD56 and kappa/lambda light chains.  
Residual disease would be indicated by the presence of clonal plasma cells in a subject. MRD will 
be monitored by NGS and in selected patients, by flow cytometry using collected marrow aspirate 
samples.  
A portion of the baseline bone marrow aspirate will also be utilized for assessment of high-risk 
molecular subgroups by RNA/DNA sequencing of CD138+ MM cells. Specific high-risk markers 
to be analyzed may include t(4;14), t(14;16), 1q21, and del17p, as well as GEP-70 and other 
signatures associated with poor prognosis.  In addition, if feasible, a bone marrow aspirate will be 
collected at disease progression to monitor for mechanisms of resistance to daratumumab. 
Next-Generation Sequencing (NGS) Analyses will be performed on screening blood samples aliquots a 
posteriori, using the same methodology as the one used for MRD detection in bone marrow after 
treatment initiation.  
In addition to evaluating MRD and clinical efficacy in high-risk subgroups, biomarker assessments 
will also monitor changes in immune cell subpopulations after induction, transplant, and 
consolidation. The immune system related parameters to be analyzed may include the 
determination of the frequency and activity of immune effector cells including T cells (cytotoxic, 


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regulatory, memory T cells subsets), B cells, NK cells, myeloid derived suppressor cells (MDSC), 
macrophages, and dendritic cells, as these cells are involved in immune mediated tumor lysis. The 
initial values of all these parameters and the relative changes during therapy will be correlated with 
the quality and the duration of the clinical response. For these immune monitoring studies, flow 
cytometry or CyTOF may be performed. CyTOF uses transition element isotopes as labels for 
antibodies, thereby providing the opportunity to measure multiple markers simultaneously on 
every cell that is analyzed, with no requirements for compensation of spectral overlap. Samples 
may also be collected at time of relapse, to monitor changes in immune subpopulations that lead 
to resistance.  These immune profiles will be analysed for associations with clinical data (quality 
of response, MRD status and depth, PFS, OS) as well as with MM sequencing data. 
Other exploratory biomarker analyses may include assessment of copy number variation (CNV) 
and single nucleotide polymorphisms (SNP) in genes associated with daratumumab mechanism of 
action (CD38, complement inhibitory proteins CD46, CD55, CD59, complement, Fcgamma 
receptors, KIR, etc.). In addition, exploratory analyses may be performed to monitor complement 
proteins, cytokines indicative of immune response, and unbiased evaluation of protein. 
9.5. 
Sample Collection and Handling 
If blood samples are collected via an indwelling cannula, an appropriate amount (1 mL) of 
serosanguineous fluid slightly greater than the dead space volume of the lock will be removed 
from the cannula and discarded before each blood sample is taken. Refer to the Time and Events 
Schedule for the timing and frequency of all sample collections. 
For samples that will be sent to the central laboratory, sample dates and times must be recorded on 
the laboratory requisition form. Further instructions for the collection, handling, storage, and 
shipment of samples are found in the Laboratory Manual that will be provided. Collection, 
handling, storage, and shipment of samples must be under the specified, and where applicable, 
controlled temperature conditions as indicated in the Laboratory Manual. 
9.6. 
Efficacy 
9.6.1. 
Evaluations 
Assessment of tumor response and disease progression will be conducted in accordance with the 
IMWG response criteria. Efficacy evaluations will include measurements of tumor burden/residual 
disease, myeloma proteins, bone marrow examinations, skeletal surveys, extramedullary 
plasmacytomas, and serum calcium corrected for albumin. 
9.6.1.1. 
Response Categories 
Disease evaluations must be performed as outlined in the Time and Events Schedules on the 
scheduled assessment day (±3 days). Disease evaluations scheduled for treatment days should be 
collected before study drug is administered. Disease evaluations will be performed by a central 
laboratory (unless otherwise specified).  


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This study will use the IMWG consensus recommendations for multiple myeloma treatment 
response criteria (Durie 200713, Rajkumar 201147) presented in Table 13. For quantitative 
immunoglobulin at baseline, M-protein, and immunofixation measurements in serum and 24-hour 
urine, the investigator will use results provided by the central laboratory. 
For subjects with suspected daratumumab interference on SPEP and IFE, a reflex assay will be 
performed to distinguish daratumumab from any remaining endogenous M protein in the patient’s 
serum. Subjects with confirmed daratumumab interference who meet all other clinical criteria for 
CR or sCR will be considered CR/sCR. 
 
Table 13: 
International Uniform Response Criteria Consensus Recommendations 
Response  
Response Criteria 
Stringent complete 
Response (sCR) 
• 
CR as defined below, plus 
• 
Normal FLC ratio, and 
• 
Absence of clonal PCs by immunohistochemistry, immunofluorescencea or 2- to 4-color flow 
cytometry 
Complete 
response (CR)* 
• 
Negative immunofixation on the serum and urine, and 
• 
Disappearance of any soft tissue plasmacytomas, and 
• 
<5% PCs in bone marrow 
Very good partial 
Response 
(VGPR)* 
• 
Serum and urine M-component detectable by immunofixation but not on 
• 
electrophoresis, or 
• 
≥90% reduction in serum M-protein plus urine M-protein <100 mg/24 hours 
Partial response 
(PR) 
• 
≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to 
<200 mg/24 hours 
• 
If the serum and urine M-protein are not measurable, a decrease of ≥50% 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 measurable, 
≥50% reduction in bone marrow PCs is required in place of M-protein, provided baseline bone 
marrow plasma cell percentage was ≥30% 
• 
In addition to the above criteria, if present at baseline, a ≥50% reduction in the size of soft tissue 
plasmacytomas is also required. 
Stable disease 
(SD) 
• 
Not meeting criteria for CR, VGPR, PR, or progressive disease 
Progressive 
disease (PD)† 
Increase of 25% from lowest response value in any one of the following: 
• 
Serum M-component (absolute increase must be ≥0.5 g/dL),  
• 
Urine M-component (absolute increase must be ≥200 mg/24 hours),  
• 
Only in subjects without measurable serum and urine M-protein levels: the difference between 
involved and uninvolved FLC levels (absolute increase must be >10 mg/dL) 
• 
Only in subjects without measurable serum and urine M-protein levels and without measurable 
disease by FLC levels, bone marrow PC percentage (absolute percentage must be ≥10%) 
• 
Bone marrow plasma cell percentage: the absolute percentage must be >10% 
• 
Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the 
size of existing bone lesions or soft tissue plasmacytomas 
• 
Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that can be attributed 
solely to the PC proliferative disorder 
FLC = free light chain; PC = plasma cell 


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All response categories (CR, sCR, VGPR, PR, and PD) require 2 consecutive assessments made at any time before the 
institution of any new therapy; CR, sCR, VGPR, PR, and SD categories also require no known evidence of progressive or 
new bone lesions if radiographic studies were performed. VGPR and CR categories require serum and urine studies 
regardless of whether disease at baseline was measurable on serum, urine, both, or neither.  
Radiographic studies are not required to satisfy these response requirements. Bone marrow assessments need not be 
confirmed. For PD, serum M-component increases of more than or equal to 1 g/dL are sufficient to define relapse if starting 
M-component is ≥5 g/dL. 
*Clarifications to IMWG criteria for coding CR and VGPR in subjects in whom the only measurable disease is by serum FLC 
levels: CR in such subjects indicates a normal FLC ratio of 0.26 to 1.65 in addition to CR criteria listed above. VGPR in 
such subjects requires a >90% decrease in the difference between involved and uninvolved FLC levels. 
†Clarifications to IMWG criteria for coding PD: Bone marrow criteria for PD are to be used only in subjects without 
measurable disease by M protein and by FLC levels; “25% increase” refers to M protein, FLC, and bone marrow results, 
and does not refer to bone lesions, soft tissue plasmacytomas, or hypercalcemia and the “lowest response value” does not 
need to be a confirmed value.  
a Presence/absence of clonal cells is based upon the kappa/lambda ratio. An abnormal kappa/lambda ratio by 
immunohistochemistry 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. 
 
 
Clinical Relapse 
Clinical relapse is defined using the definition of clinical relapse in the IMWG criteria (Durie 200613, Rajkumar 201147). In 
the IMWG criteria, clinical relapse is defined as requiring one or more of the following direct indicators of increasing 
disease or end-organ dysfunction that are considered related to the underlying plasma cell proliferative disorder: 
1. Development of new soft tissue plasmacytomas or bone lesions on skeletal survey, magnetic resonance imaging, or other 
imaging 
2. 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 
3. Hypercalcemia (>11.5 mg/dL; >2.875mM/L) 
4. Decrease in hemoglobin of more than 2 g/dL (1.25 mM) or to less than 10 g/dL 
5. Rise in serum creatinine by more than or equal to 2 mg/dL (≥177 mM/L) 
6. Hyperviscosity 
In some subjects, bone pain may be the initial symptom of relapse in the absence of any of the above features. However, bone 
pain without imaging confirmation is not adequate to meet these criteria in studies. 
 
Disease progression must be consistently documented across clinical study sites using the criteria 
in Table 13. It is important that instances of disease progression be reported to the sponsor as soon 
as possible. 
Patients will continue in the last confirmed response category until there is confirmation of 
progression or improvement to a higher response status; patients cannot move to a lower response 
category. 
For continuation of treatment, the IMWG response will be determined on an ongoing basis by the 
investigator. For data analysis and reporting, however, the study team will use a validated 
computer algorithm that has been shown to provide consistent review of the data necessary to 
determine disease progression and response according to the IMWG criteria. 
Serum free light chain assay test results will be analyzed by the central laboratory for the 
assessment of sCR, according to the most recently published IMWG criteria (Durie 200713). 
Freelite ® or another validated assay will be utilized for this assessment.  
9.6.2. 
Central Confirmation of stringent Complete Response (sCR) 
Subjects who are believed have attained a stringent Complete Response (sCR) will have this 
confirmed centrally by a minimum of 4 color flow cytometry. A fresh bone marrow aspirate is 


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required for flow cytometry as outlined in the Time and Events Schedules or whenever it will be 
required to assess sCR. 
9.6.3. 
Myeloma Protein Measurements in Serum and Urine 
Blood and 24-hour urine samples for M-protein measurements will be sent to and analyzed by a 
central laboratory. Only 1 serum and one 24-hour urine sample per time point are required by the 
central laboratory to perform the following tests. 
• 
Serum quantitative immunoglobulins (QIgs) 
− 
All subjects will be evaluated for IgG, IgA, IgM and IgE at Screening. During the study, 
subjects with IgD or IgE disease will be evaluated for IgG, IgA, IgM and IgE and subjects 
with IgG, IgA, or IgM disease will be evaluated for IgG, IgA, and IgM 
• 
Serum M-protein quantitation by electrophoresis (SPEP) 
• 
Serum immunofixation at screening and thereafter when M-protein is non-quantifiable up 
to confirmation of CR 
• 
24-hour urine M-protein quantitation by electrophoresis (UPEP) 
• 
Urine immunofixation at screening and thereafter when a M-protein is non-quantifiable up 
to confirmation of CR 
• 
Free light chain assessment for subjects with light chain only myeloma and IgD myeloma 
(IgD<0,5g/dL at screening); also for all subjects to confirm sCR 
Blood and 24-hour urine samples will be collected as specified in the Time and Events Schedule 
until the development of confirmed disease progression. Disease progression based on 1 of the 
laboratory tests alone must be confirmed by at least 1 repeat investigation performed 1 to 3 weeks 
later. Disease evaluations will continue beyond relapse from CR until disease progression is 
confirmed. Serum and urine immunofixation test will be performed at screening and thereafter 
when serum or 24-hour urine M-protein electrophoresis [by SPEP or UPEP] is negative or non-
quantifiable. For subjects with light chain multiple myeloma, both serum and urine 
immunofixation test will be performed at every cycle.  
As an IgG1 kappa immunoglobulin, Daratumumab has been shown to interfere with serum protein 
electrophoresis (SPE) and immunofixation (IFE) (McCudden 201033). This detection of 
daratumumab can be mitigated through a reflex assay using the anti-idiotype antibody to bind 
daratumumab, shift it on SPE and IFE, and confirm interference.  This reflex assay will be 
implemented as part of response criteria.  For those subjects who meet all other clinical criteria for 
CR/sCR, with confirmed daratumumab interference on SPE/IFE, will be considered CR/sCR.   
9.6.4. 
Albumin and Serum Calcium Corrected for Albumin  
Blood samples for calculating serum calcium corrected for albumin will be collected and analyzed 
locally, as specified in the Time and Events Schedule until the development of confirmed disease 
progression. Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.8 
mmol/L) can indicate disease progression or relapse if it is not attributable to any other cause (see 
disease response criteria in Table 13). Calcium binds to albumin and only the unbound (free) 


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calcium is biologically active; therefore, the serum calcium level must be adjusted for abnormal 
albumin levels (“corrected serum calcium”). The formula for adjustment is presented in 
Attachment 4. 
Measurement of free ionized calcium is an acceptable alternative to corrected serum calcium for 
determining hypercalcemia. Free ionized calcium levels greater than the ULN (local laboratory 
reference ranges) are considered to be hypercalcemic for this study. 
9.6.4.1. 
β2-microglobulin and Albumin 
Blood samples for β2 microglobulin and albumin are to be collected at Screening and will be 
analyzed by the central laboratory. 
9.6.5. 
Bone Marrow Examination 
Bone marrow aspirate and/or biopsy will be performed at screening for clinical staging 
(morphology, cytogenetics, and immunohistochemistry [IHC] or immunofluorescence or flow 
cytometry), to establish baseline multiple myeloma clonality to monitor for MRD, and to perform 
molecular subtyping to monitor daratumumab activity in high-risk molecular subgroups. Clinical 
staging may be performed locally; however, a portion of the bone marrow aspirate/biopsy must be 
sent to the central lab for analysis of MRD and molecular subtyping. A fresh bone marrow aspirate 
at screening is required. A core bone marrow biopsy/aspirate will be performed to confirm sCR 
and CR. If a bone marrow core biopsy cannot be obtained or is not available, morphologic review 
of the bone marrow aspirate smear may be reviewed by the local laboratory for confirmation of 
CR. Bone marrow aspirates are acceptable for determination of relapse from CR (IHC or 
immunofluorescence) and to monitor for MRD. If feasible, a bone marrow aspirate may be 
collected from subjects at disease progression to evaluate mechanisms of daratumumab resistance.  
9.6.6. 
Assessment of Lytic Disease 
A complete skeletal survey (including skull, entire vertebral column, pelvis, chest, humeri, femora, 
and any other bones for which the investigator suspects involvement by disease) is to be performed 
and evaluated by the local laboratory by roentgenography (or the local standard of care imaging, 
eg, low-dose CT) during the Screening Phase. Please note that the same methodology used at 
Screening should be used throughout the study for comparison purposes. During the Treatment 
Phase and before disease progression is confirmed, imaging should be performed whenever 
clinically indicated based on symptoms, to document response or progression. Magnetic resonance 
imaging (MRI) or low-dose CT scan are acceptable methods for evaluation of bone disease, and 
may be included at the discretion of the investigator (see the disease response criteria in Table 13). 
If a radionucleotide bone scan was used at Screening in addition to the complete skeletal survey, 
then both methods must be used to document disease status. These tests must be performed at the 
same time. However, a radionucleotide bone scan does not replace a complete skeletal survey. 
Sometimes subjects present with disease progression manifested by symptoms of pain due to bone 
changes. Therefore, disease progression may be documented, in these cases, by skeletal survey or 
other radiographs, depending on the symptoms that the subject experiences. If the diagnosis of 
disease progression is obvious by radiographic investigations, then no repeat confirmatory x-rays 


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are necessary. In instances where changes may be more subtle, a repeat x-ray may be performed 
in 1 to 3 weeks per investigator discretion. 
9.6.7. 
Documentation of Extramedullary Plasmacytomas 
Sites of known extramedullary plasmacytomas must be documented during the Screening Phase. 
Clinical examination or MRI may be used to document extramedullary sites of disease. CT scan 
evaluations are an acceptable alternative if there is no contraindication to the use of intravenous 
contrast. Positron emission tomography (PET) scan or ultrasound tests are not acceptable to 
document the size of extramedullary plasmacytomas. 
Extramedullary plasmacytomas should be assessed for all subjects with a history of 
plasmacytomas or if clinically indicated at screening, by clinical examination or radiologic 
imaging. Assessment of measurable sites of extramedullary disease will be performed and 
evaluated locally every 4 weeks (by physical examination) for subjects with a history of 
plasmacytomas or as clinically indicated during treatment for other subjects until development of 
confirmed CR or confirmed disease progression. If assessment can only be performed 
radiologically, then evaluation of extramedullary plasmacytomas may be done every 12 weeks. 
For every subject, the methodology used for evaluation of each disease site should be consistent 
across all visits. Irradiated or excised lesions will be considered not measurable and will be 
monitored only for disease progression. 
To qualify for PR, the sum of products of the perpendicular diameters of the existing 
extramedullary plasmacytomas must have decreased by at least 50%, from the smallest measurable 
size during the study and new plasmacytomas must not have developed (see the disease response 
criteria in Table 13). To qualify for disease progression, either the sum of products of the 
perpendicular diameters of the existing extramedullary plasmacytomas must have increased by at 
least 50% or a new plasmacytoma must have developed. In the cases where not all existing 
extramedullary plasmacytomas are reported, but the sum of products of the perpendicular 
diameters of the reported plasmacytomas have increased by at least 50%, this will also qualify as 
disease progression. 
9.7. 
Patient Reported Outcomes 
It is anticipated that the addition of daratumumab will provide benefits in terms of symptom 
reduction, improved functioning, and improved utilities. To measure functional status, well-being, 
and symptoms, the EORTC QLQ-C30 and the EQ-5D-5L instruments will be used. Both 
questionnaires will be completed at the timepoints outlined in the Time and Events Schedule 
before any other study procedures scheduled for the same day. 
The EORTC QLQ-C30 includes 30 items resulting in 5 functional scales (physical functioning, 
role functioning, emotional functioning, cognitive functioning, and social functioning), 1 Global 
Health Status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items 
(dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The recall 
period is 1 week (the past week). The EORTC QLQ-C30 has been widely used among cancer 
patients. Scores are transformed to a 0 to 100 scale. Administration time is approximately 11 


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minutes. Reliability, validity, and clinically meaningful change have been demonstrated in patients 
with multiple myeloma (Wisloff 199657, Wisloff 199758). The focus of the PRO assessment will 
be the global health scale which is designated as a secondary endpoint.  The remaining domains 
are included as exploratory endpoints. 
The EQ-5D-5L is a generic measure of health status. For purposes of this study, the EQ-5D-5L 
will be used to generate utility scores for use in cost effective analyses. The EQ-5D-5L is a 5 item 
questionnaire that assesses 5 domains including mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression plus a visual analog scale rating “health today” with 
anchors ranging from 0 (worst imaginable health state) to 100 (best imaginable health state) 
(Herdman 201122). The scores for the 5 separate questions are categorical and are cannot be 
analyzed as cardinal numbers. However, the scores for the 5 dimensions are used to compute a 
single utility score ranging from zero (0.0) to 1 (1.0) representing the general health status of the 
individual. 
9.8. 
Medical Resource Utilization 
Medical resource utilization (MRU) data, principally number of hospitalizations and use of 
permitted therapies, will be derived from data reported in the eCRF for all subjects throughout the 
study. Hospitalization or prolongation of hospitalization related to Daratumumab administration 
reaction and/or SAE must to be reported in e-CRF.  
 
10. 
SUBJECT COMPLETION/WITHDRAWAL 
10.1. 
Completion 
A subject will be considered to have completed the study if he or she has finished all 
protocol-specified procedures before the end of the study, has not died, has not been lost to follow 
up, and has not withdrawn consent for study participation before the end of the study. 
10.2. 
Discontinuation of Study Treatment 
The Treatment Phase will be conducted in 2 parts and will extend from Cycle 1 Day 1 until 
treatment discontinuation due to progressive disease, unacceptable toxicity, ineligibility for second 
randomization, or 2 years of maintenance therapy/observation. The Follow-up Phase will extend 
from treatment discontinuation until death, loss to follow-up, withdrawal of consent, or study end, 
whichever occurs first. 
If a subject's study treatment must be discontinued before the end of the treatment regimen, this 
will not result in automatic withdrawal of the subject from the study. After treatment 
discontinuation, the subject will move into the Follow-up Phase. Follow-up visit assessments 
should continue as specified in the Time and Events Schedule. If study treatment is discontinued 
for a reason other than disease progression, then disease evaluations will continue to be performed 
as specified in the Time and Events Schedule. 
A subject's study treatment must be discontinued if: 


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• 
The investigator believes that for safety reasons (eg, adverse event) it is in the best interest 
of the subject to discontinue study treatment 
• 
The subject becomes pregnant  
• 
The subject (or the subject’s legally acceptable representative) withdraws consent for 
administration of study drug 
• 
The subject initiates treatment with a prohibited medication (Section 8.3) 
• 
The subject received concurrent (non-protocol) treatment for multiple myeloma 
• 
The subject experiences unacceptable toxicity, including infusion-related reactions 
described in Section 6.1.4 
• 
The subject’s dose is held for more than 28 days (unless Sponsor approves continuation) 
• 
The subject is not eligible for randomization to Part 2 
• 
The subject experiences disease progression (please see below). Relapse from CR is not 
considered as disease progression 
A subject who experiences a second primary malignancy, that can be treated by surgery alone may 
continue to receive the assigned study treatment and should continue to be followed for subsequent 
progression of multiple myeloma. 
Before subjects discontinue study treatment due to disease progression, sites will document 
disease progression (for example by completing a disease progression form or by contacting the 
IWRS) as soon as possible and within 48 hours. The study team will confirm that treatment should 
be discontinued. After confirmation from the study team, study treatment may be discontinued, 
and the subject entered to follow-up. 
The primary reason for discontinuation of study treatment is to be recorded in the eCRF. 
10.3. 
Withdrawal From the Study 
A subject will be withdrawn from the study for any of the following reasons: 
• 
Lost to follow-up 
• 
Withdrawal of consent for study participation 
• 
Death 
• 
Sponsor terminates the study 
• 
Screening failure 
If a subject is lost to follow-up, every reasonable effort must be made by the study site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal. The measures 
taken to follow up must be documented. 
When a subject withdraws consent for study participation before completing the study, the reason 
for withdrawal is to be documented in the eCRF and in the source document. Study drug assigned 
to the withdrawn subject may not be assigned to another subject. Subjects who withdraw will not 
be replaced.  


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Withdrawal From the Use of Samples in Future Research 
The subject may withdraw consent for use of samples for research (refer to Section 16.2.5). In 
such a case, samples will be destroyed after they are no longer needed for the clinical study. Details 
of the sample retention for research are presented in the main ICF. 
11. 
STATISTICAL METHODS 
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
in this section. 
11.1. 
Subject Information 
Analysis of primary and secondary efficacy variables will be based on the intent-to-treat (ITT) 
population, which includes all subjects randomized in the first randomization. In addition, 
maintenance-specific analyses will use the maintenance-specific intent-to-treat population 
(ITT-m), which will include all subjects who are randomized in the second randomization. 
All safety analyses will be based on the safety analysis set. The safety population will be defined 
separately for the induction/ASCT/consolidation and maintenance stages. These populations will 
include all subjects randomized at each stage who received at least 1 dose of study drugs at the 
respective stage. 
11.2. 
Sample Size Determination 
The sample size of this study takes into consideration the statistical power for the primary 
comparisons in both stages of the study. For Part 2 (maintenance phase), it is assumed that median 
PFS from the second randomization is 45 months for observation, and daratumumab maintenance 
will decrease the risk of progression or death by 25% (HR=0.75; estimated median PFS of 60 
months for daratumumab maintenance). To achieve 80% power with a significance level of 0.05, 
390 PFS events are needed. Assuming a 36 months accrual and 45 months of additional follow-
up, approximately 800 subjects (400/arm) will be randomized in the second randomization 
(daratumumab maintenance vs. observation).  
Assuming that 75% of subjects in the induction/ASCT/consolidation stage are eligible to be 
randomized for maintenance, which takes into account the expected response rate as well as 
potential dropouts, 1080 subjects (540/arm) will be randomized in the first randomization 
(daratumumab in combination with VTD induction/ASCT/VTD consolidation vs. VTD 
induction/ASCT/VTD consolidation). This sample size would provide at least over 85% power to 
detect an improvement in sCR rate from 25% to 35% at a 2-sided α of 0.05. 
11.3. 
Efficacy Analyses 
The study is designed to evaluate daratumumab treatment at 2 stages of first-line treatment, one 
concerning daratumumab in combination with VTD (D-VTD) as induction/consolidation, the 
other daratumumab maintenance, in ASCT-eligible myeloma subjects. Therefore, a separate Type 
I error rate (alpha) will be assigned at the level of 0.05 for each of the 2 distinct hypotheses of 
interest (induction/ASCT/consolidation, maintenance). 


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11.3.1. 
Endpoints 
Part 1: Induction/ASCT/Consolidation Phase 
Primary Endpoint 
Stringent Complete Response (sCR), by end of consolidation therapy, defined as the percentage 
of subjects achieving CR in addition to having a normal serum FLC ratio and an absence of clonal 
cells in bone marrow by immunohistochemistry, immunofluorescence or 2- to 4-color flow 
cytometry. Subjects who demonstrate all criteria for sCR, but have confirmed daratumumab 
interference on SPEP and IFE, will be considered sCR. 
Major Secondary Endpoints 
• 
PFS (from first randomization), defined as time from the initial randomization to either 
confirmed progressive disease (PD) per the IMWG criteria or death, whichever comes first. 
It is noted that the PFS events (PD or death) may include those that occur in the 
maintenance phase.  
• 
Time to progression (TTP) (from first randomization), defined as time from the initial 
randomization to confirmed progressive disease (PD) per the IMWG criteria, or death due 
to progressive disease, whichever occurs first. It is noted that the events (PD or death due 
to PD) may include those that occur in the maintenance phase. 
• 
Post-ASCT/ consolidation CR rate, defined as the proportion of subjects who have 
achieved CR or better by the end of consolidation per the IMWG criteria.  
• 
Post-ASCT/consolidation MRD negative rate, defined as the proportion of subjects who 
have achieved MRD negative status by the end of consolidation per the IMWG criteria. 
• 
Post-induction sCR rate, defined as the proportion of subjects who have achieved sCR prior 
to high-dose therapy/ASCT per the IMWG criteria.  
• 
PFS2 (from first randomization), defined as the time from initial randomization to time of 
subsequent progression on next line of therapy after disease progression on study treatment. 
• 
OS (from first randomization), measured from the date of initial randomization to the date 
of the subject’s death. If the subject is alive or the vital status is unknown, then the subject’s 
data will be censored at the date the subject was last known to be alive. 
 
Other Secondary Endpoints 
• 
Post-induction overall response rate (ORR) and rate of VGPR or better, defined as the 
proportions of subjects who have achieved PR or better by the end of induction per the 
IMWG criteria. 
• 
Duration of CR and sCR will be calculated from the date of the initial documentation of a 
CR or sCR to the date of the first documented evidence of relapse of CR or disease 
progression, as defined in the IMWG criteria, whichever occurs first. For subjects who have 
not relapsed nor progressed, data will be censored at the last disease evaluation. 
• 
Impact of D-VTD compared to VTD on patient-reported perception of global health 


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Part 2: Maintenance Phase 
Primary Endpoint 
Progression Free Survival (PFS) post completion of maintenance therapy, defined as the duration 
from the date of re-randomization to either progressive disease, according to the IMWG criteria, 
or death, whichever occurs first. 
Major Secondary Endpoints 
• 
TTP (from second randomization), defined as time from the second randomization to 
confirmed progressive disease (PD) per the IMWG criteria, or death due to progressive 
disease, whichever occurs first.  
• 
Overall CR rate, defined as the proportion of subjects who have achieved CR or better 
during the study per the IMWG criteria.  
• 
Overall MRD negative rate, defined as the proportion of subjects who have achieved MRD 
negative status by the end of study.  
• 
PFS2 (from second randomization), defined as the time from the second randomization to 
time of subsequent progression on next line of therapy after disease progression on study 
treatment. 
• 
OS (from second randomization), defined as the time from the second randomization to the 
date of death. 
 
Other Secondary Endpoints 
• 
Rate of improved response during maintenance, defined as the proportion of subjects who 
have achieved a better category of response during maintenance compared to the response 
status at the end of consolidation (up to the second randomization). This is to be evaluated 
among the group of subjects who not achieved sCR by the second randomization.  
• 
Rate of MRD negative conversion during maintenance, defined as the proportion of 
subjects who have achieved de novo MRD negative status during maintenance. 
• 
ORR rate, defined as the proportion of subjects who have achieved PR or better by the end 
of study.  
11.3.2. 
Efficacy Analysis for Induction/ASCT/Consolidation Phase 
The primary comparison of the 2 randomized induction/consolidation treatments will be made with 
respect to sCR rate using the Cochran-Mantel-Haenszel chi square test in the ITT population. A 
Mantel-Haenszel odds ratio, along with its 2-sided 95% confidence interval, will be calculated. 
All binary secondary endpoints for the induction/ASCT/consolidation stage will be analyzed 
similarly as the primary endpoint (sCR rate). 
The statistical comparison between the 2 induction regimens with respect to PFS from the first 
randomization will need to take into consideration subsequent maintenance assignment 
(daratumumab maintenance or observation). A usual “as-randomized”-type of intent-to-treat 


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analysis that compares the 2 induction treatments with respect to PFS without considering 
maintenance treatment has been shown to produce potentially biased estimates of treatment effects. 
As such, 2 appropriate intent-to-treat (ITT)-type of induction comparisons of particular interest, 1 
specific to each maintenance treatment (daratumumab maintenance or observation), will be 
conducted:  
• 
daratumumab+VTD (D-VTD) induction/consolidation followed by daratumumab 
maintenance vs. VTD induction/consolidation followed by daratumumab maintenance, and 
• 
daratumumab+VTD (D-VTD) induction/consolidation followed by observation vs. VTD 
induction/consolidation followed by observation 
For each of the 2 comparisons, the analysis will include any subjects who are randomized in the 
first randomization and are then subsequently randomized to the specific maintenance treatment 
as well as those subjects who are randomized in the first randomization but are not randomized in 
the second randomization. A stratified Cox regression analysis with inverse probability weighting 
will be performed (Lokhnygina 200730), which yields unbiased estimates of treatment effects and 
maintains Type I error rate. The overall comparison of induction treatments will be made treating 
these 2 comparisons as 2 strata with the variance estimated using the robust variance estimator (the 
sandwich estimate). These 3 comparisons will all be tested with the significance level of 0.05 (2-
sided) following the closed testing procedure. Essentially, the statistical significance is established 
for each of the 2 maintenance-specific comparisons if both itself and the overall induction 
comparison are significant at the 2-sided level of 0.05. Other time-to-event endpoints, except for 
duration of response, will be analyzed similarly. Duration of response will be presented 
descriptively using the weighted Kaplan-Meier estimates by Miyahara and Wahed 201036. 
11.3.3. 
Efficacy Analysis for Maintenance Phase 
The primary comparison of the 2 randomized maintenance treatments (daratumumab maintenance 
and observation) will be made with respect to PFS from the second randomization using a stratified 
log-rank test in the ITT-m population. The Kaplan-Meier method will be used to estimate the 
distribution of PFS from the second randomization for each treatment. The treatment effect (hazard 
ratio) and its 2-sided 95% confidence intervals are to be estimated using a stratified Cox regression 
model with maintenance treatment as the sole explanatory variable. In addition, the interaction 
between induction/consolidation and maintenance will be tested at a 2-sided significance level of 
0.05 by a stratified Cox regression model that includes the interaction term between maintenance 
treatment and induction/consolidation treatment. All secondary time-to-event endpoints in the 
maintenance stage will be analyzed similarly as for the primary endpoint (PFS from the second 
randomization). 
The comparison of the 2 randomized maintenance arms on binary secondary endpoints will be 
made using the Cochran-Mantel-Haenszel chi square test in the population of all subjects that are 
randomized in the second randomization. The observed rate of the binary outcome will be provided 
along its 2-sided 95% CIs. A Mantel-Haenszel odds ratio, along with its 2-sided 95% confidence 
interval, will be calculated. 


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11.3.4. 
Other Efficacy Analyses 
The 2-stage randomization design of this study allows comparison of all 4 sequences of 
induction/ASCT/consolidation and maintenance treatments: 
• 
D-VTD induction/consolidation followed by daratumumab maintenance  
• 
D-VTD induction/consolidation followed by observation 
• 
VTD induction/consolidation followed by daratumumab maintenance 
• 
VTD induction/consolidation followed by observation 
The distribution of PFS, TTP, and OS for these 4 sequences will be estimated using the weighted 
Kaplan-Meier estimates [Miyahara and Wahed 201036]. Pairwise comparisons of these 4 
comparisons will be made by a stratified Cox regression analysis with inverse probability 
weighting (Lokhnygina 200730), except for the 2 pairwise comparisons: D-VTD followed by 
daratumumab maintenance vs. D-VTD followed by observation, and VTD followed by 
daratumumab maintenance vs. VTD followed by observation, which reduces to the 2 maintenance 
comparisons specific to a particular induction regimen. 
11.4. 
Daratumumab Immunogenicity Analyses 
The incidence of antibodies to daratumumab (immunogenicity) will be summarized for all subjects 
who receive a dose of daratumumab and have appropriate samples for detection of antibodies to 
daratumumab. 
11.5. 
Biomarker Analysis 
Biomarker studies are designed to identify markers predictive of response (or resistance) to 
daratumumab. Analyses will be performed and stratified by clinical covariates or molecular 
subgroups using the appropriate statistical methods (eg, parametric or non-parametric, univariate 
or multivariate, analysis of variance, or survival analysis, depending on the endpoint). Correlation 
of baseline expression levels or changes in expression levels with response or time to-event 
endpoints will identify responsive (or resistant) subgroups in addition to genes and pathways 
attenuated following treatment with daratumumab. In order to remove any confounding influence 
of prognostic factors, any predictive biomarker identified in this study could be verified in a 
prospective clinical study with a control treatment arm. 
Any biomarker measures will be listed, tabulated, and where appropriate, plotted. Subjects will be 
grouped by prescribed dose. Complete responders will be utilized to investigate the prognostic 
effect of MRD on PFS. MRD analysis will include evaluation of data from other studies to 
determine if decreased MRD is seen with daratumumab + bortezomib based chemotherapy 
regimen compared with the bortezomib based chemotherapy alone.  
Results of biomarker and pharmacodynamic analyses may be presented in a separate report. 
Planned analyses are based on the availability of clinically valid assays and may be deferred if 
emerging study data show no likelihood of providing useful scientific information. 


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In addition, due to the small sample sizes of high-risk subgroups within the multiple myeloma 
patient population, a meta-analyses may be performed across daratumumab Phase 3 studies to 
evaluate clinical efficacy of daratumumab with standard of care agents in pre-specified subgroups 
of multiple myeloma patients. The meta-analysis protocol will pre-specify the objective of the 
meta-analysis, the criteria for inclusion and exclusion of studies, the hypotheses and endpoints, 
and statistical methods including a method for investigation of heterogeneity. This meta-analytic 
approach, supported by high-quality data from the individual trials, should be able to provide 
definitive evidence on the effectiveness of daratumumab in the subpopulation of multiple myeloma 
subjects with high-risk molecular abnormalities. In a similar fashion, a meta-analysis examining 
MRD negativity in daratumumab treated patients in frontline, newly diagnosed multiple myeloma 
(MMY3006, MMY3007, and MMY3008 studies) may also be performed. 
11.6. 
Patient Reported Outcomes 
EORTC QLQ-C30 domain scores will be summarized at each time point as indicated in the Time 
and Events Schedule. The relationship between clinical response and change in domain scores will 
be explored. EQ-5D-5L scores will be summarized at each time point. 
11.7. 
Safety Analyses 
Safety analyses will be conducted after 100 subjects have completed consolidation therapy and at 
6 monthly intervals under the direction of the independent monitoring committee (IDMC) until 
the unblinding of data. 
Adverse Events 
The verbatim terms used in the eCRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). In general, adverse events that 
occurred during the induction/consolidation and maintenance stages will be summarized 
separately. Treatment-emergent adverse events for each stage will be defined as events that occur 
or worsen after administration of the first dose of during that stage and through 30 days after the 
last dose of study drug in that stage and before the next phase of treatment begins. Adverse events 
will be summarized by system organ class and preferred terms, NCI toxicity grade, and by action 
taken with study treatment. 
Summaries, listings, datasets, or subject narratives will be provided, as appropriate, for those 
subjects who die, who discontinue treatment due to an adverse event, or who experience a severe 
or a serious adverse event. These will be provided using the same formats as those used for adverse 
events. 
Clinical Laboratory Tests 
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly 
abnormal results will be used in the summary of laboratory data. Descriptive statistics will be 
calculated for each laboratory analyte at baseline and for observed values and changes from 
baseline at each scheduled time point. Changes from baseline results will be presented in pre- 
versus post treatment cross-tabulations (with classes for below, within, and above normal ranges). 
Worst toxicity grade during treatment presented, according to NCI CTCAE Version 4. A listing 


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of subjects with any laboratory results outside the reference ranges will be provided. A listing of 
subjects with any markedly abnormal laboratory results will also be provided. 
Vital Signs 
Descriptive statistics of pulse, temperature, and blood pressure (systolic and diastolic) values and 
changes from baseline will be summarized at each scheduled time point. The percentage of 
subjects with values beyond clinically important limits will be summarized. 
Descriptive statistics for electrocardiogram data will be calculated at baseline and for observed 
values and changes from baseline at each scheduled time point. Frequency tabulations of the 
abnormalities will be made. 
11.8. 
Interim Analysis 
Two primary analyses are planned, one for each stage. The first primary analysis is specific to the 
induction/ASCT/consolidation stage, and its main purpose is to evaluate the effectiveness of the 2 
induction/consolidation treatments with respect to the stringent complete response (sCR) rate, 
which will be performed after all subjects have completed the induction/ASCT/consolidation 
treatment phase. No interim analysis is planned for Part 1. 
The second primary analysis is specific to the maintenance stage, and its main purpose is evaluate the 2 
maintenance arms with response for PFS, which will be performed when approximately 390 PFS events 
have been observed in the population of subjects who are re-randomized in the maintenance stage. An 
interim analysis is planned for the maintenance stage after 273 (70%) PFS events are observed in the 
population of subjects who are re-randomized. The significance level at this interim analysis will be 
determined based on the observed number of PFS events at the time of the analysis, using the O’Brien-
Fleming boundaries as implemented by the Lan-DeMets alpha spending method. Assuming 273 PFS events 
are observed, the alpha to be spent in this interim analysis will be 0.0147 (2-sided) and will be 0.0455 (2-
sided) for the final analyses. In case the Interim analysis for PFS meets the pre-defined boundary this interim 
analysis reflects the primary analysis for PFS. No PFS analysis at 390 PFS events will be done.  
 
11.9. 
Independent Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC) will be formed to review data including 
those from interim analyses of overall safety. The IDMC members will be independent of the trial 
and familiar with the methodology of hematological oncology trials. The IDMC will include a 
fixed number of permanent members with experience of clinical studies in hematological oncology 
including at least one statistician. They must be aware of the implications of the conclusions based 
on immature data and agree with the design and objectives of this protocol.  
The first IDMC meeting will take place after the first 100 subjects have completed consolidation 
therapy (first safety analysis) and subsequently approximately every six months - either face-to-
face or via teleconference – to review accrual, study conduct (including treatment withdrawals), 
patient safety (adverse events presented according to assigned treatment), and disease-related 
event until the unblinding of data.  In addition, the IDMC will evaluate efficacy and toxicity of the 


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peripheral stem cell mobilization. This will include data concerning stem cell yield and whether 
any additional agents were required for peripheral stem cell mobilization (for example plerixifor). 
Relevant safety data for review by the IDMC will include: 
• 
AEs (NCI-CTC AE version 4.0) and SAEs 
• 
AEs requiring dose reduction or modification 
• 
AEs associated with stem cell mobilization. 
After each meeting, the IDMC will provide the Study Steering Committee with its 
recommendation. At the part 2 interim analysis, the primary endpoint was met, and the study data 
was unblinded. No new safety signals were observed. No further IDMC meetings will be 
scheduled. Safety data will be reviewed by regular Pharmacovigilance aggregate data review. 
12. 
ADVERSE EVENT REPORTING 
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsors and are mandated by 
regulatory agencies worldwide. The sponsor and Janssen have established Standard Operating 
Procedures in conformity with regulatory requirements worldwide to ensure appropriate reporting 
of safety information; all clinical studies conducted by the sponsor, Janssen, or their affiliates will 
be conducted in accordance with those procedures. 
12.1. 
Definitions 
12.1.1. 
Adverse Event Definitions and Classifications 
Adverse Event 
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the interventions and/or treatment. An adverse event can therefore 
be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational or non-investigational) product, 
whether or not related to that medicinal (investigational or non-investigational) product (definition 
per International Conference on Harmonisation [ICH].) This includes any occurrence that is new 
in onset or aggravated in severity or frequency from the baseline condition, or abnormal results of 
diagnostic procedures, including laboratory test abnormalities. Note: The sponsor collects adverse 
events starting with the signing of the ICF (refer to Section 12.3.1 for time of last adverse event 
recording). 
Serious Adverse Event 
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose: 
• 
Results in death 


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• 
Is life-threatening 
 
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization* 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
• 
Is a suspected transmission of any infectious agent via a medicinal product 
• 
Is Medically Important** 
• 
Occurrence of any new malignancy, either solid cancer or hematological malignancy (that 
occurred after first dose taken of study treatment) 
* Overnight stays at the hospital because of slow infusion times should not be reported as a serious 
adverse event 
**Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be immediately 
life threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. These should 
usually be considered serious. 
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal 
relationship between the study drug and the event (eg, death from anaphylaxis), the event must be 
reported as a serious and unexpected suspected adverse reaction even if it is a component of the 
study endpoint (eg, all-cause mortality).  
Unlisted (Unexpected) Adverse Event/Reference Safety Information 
An adverse event is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For daratumumab, the expectedness of an adverse event will 
be determined by whether or not it is listed in the Investigator's Brochure.  
Adverse Event Associated With the Use of the Drug 
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely by the definitions listed in Section 12.1.2. 
An IRR is defined as any adverse event (AE) occurring during or within the 24 hours after the 
daratumumab infusion and assessed as related to daratumumab infusion. 
12.1.2. 
Attribution Definitions 
Not Related 
An adverse event that is not related to the use of the drug. 


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Doubtful 
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely. 
Possible 
An adverse event that might be due to the use of the drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded. 
Probable 
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant drug(s), 
concomitant disease(s). 
Very Likely 
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship in 
time is very suggestive (eg, it is confirmed by dechallenge and rechallenge). 
12.1.3. 
Severity Criteria  
The severity assessment for an adverse event or serious adverse event should be completed using 
the NCI CTCAE Version 4. Any adverse event or serious adverse event not listed in the 
NCI CTCAE Version 4 will be graded according to investigator clinical judgment by using the 
standard grades as follows: 
Grade 1 (Mild): Awareness of symptoms that are easily tolerated, causing minimal discomfort 
and not interfering with everyday activities. 
Grade 2 (Moderate): Sufficient discomfort is present to cause interference with normal activity. 
Grade 3 (Severe): Extreme distress, causing significant impairment of functioning or 
incapacitation. Prevents normal everyday activities. 
Grade 4: Life-threatening of disabling adverse event 
Grade 5: Death related to the adverse event 
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities). 
12.2. 
Special Reporting Situations 
Safety events of interest relating to study drug that may require expedited reporting or safety 
evaluation include, but are not limited to: 


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• 
Overdose of study drug. No MTD has been reached for daratumumab. However, if the dose 
exceeds the maximum tested dose of 24 mg/kg, then it will be considered as overdose in 
this study. 
• 
Suspected abuse/misuse of a study drug 
• 
Inadvertent or accidental exposure to study drug  
• 
Medication error involving daratumumab (with or without subject/patient exposure to 
daratumumab, eg, name confusion) 
• 
Any adverse event leading to treatment discontinuation and assessed as related to 
Daratumumab or any part of the VTD backbone regimen. 
• 
All events of secondary malignancies will be notified to sponsor as SAE. These events will 
be followed and reported to the sponsor throughout the study (including the Follow up 
phase). 
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the adverse event page of the 
eCRF. 
12.3. 
Procedures 
12.3.1. 
All Adverse Events 
All adverse events and special reporting situations, whether serious or non-serious, must be 
reported from the time a signed and dated ICF is obtained until 30 days after the last dose of any 
component of the treatment regimen, until the subject withdraws consent for study participation, 
or until the subject starts subsequent anticancer therapy. However, for subjects randomized to Arm 
A (observation) in the Maintenance Phase, adverse events will continue to be collected for 2 years 
after the second randomization, or upon disease progression, withdrawal of consent, death or start 
of new anticancer therapy (whichever occurs first in the Maintenance Phase), even though no study 
drug is being administered. The only exception is for subjects who have withdrawn informed 
consent for study participation or for subjects who have received additional treatment with 
therapeutic intent for multiple myeloma within 30 days after the last dose of any component of the 
treatment regimen.  
For subjects who have received additional treatment with therapeutic intent for multiple myeloma 
during the adverse event reporting period, only adverse events that are considered to be possibly, 
probably, or definitely related to study drug (Daratumumab) or any part of the VTD backbone 
treatment regimen must be reported (unless the subject has been withdrawn from the study).  
Serious adverse events, including those spontaneously reported to the investigator within 30 days 
of the last dose of any component of the treatment regimen, and those that are considered related 
to daratumumab occurring within the Follow-up Phase, must be reported using the Serious Adverse 
Event Form. The sponsor and Janssen will evaluate any safety information that is spontaneously 
reported by an investigator beyond the time frame specified in the protocol.  
Adverse Events, Serious Adverse Event, including pregnancy, will be followed by the investigator. 


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Disease progression should not be recorded as an adverse event or serious adverse event term; 
instead, signs and symptoms of clinical sequelae resulting from disease progression/lack of 
efficacy will be reported if they fulfill the serious adverse event definition (refer to Section 12.1.1). 
Death should not be recorded as an adverse event or serious adverse event, but as the outcome of 
an adverse event. The event that resulted in the death should be reported as a serious adverse event. 
During the mobilization and stem cell transplantation procedures, AEs related to the planned 
procedures need to be reported as AEs; any toxicity related to daratumumab exposure should be 
reported.  
During the transplant period (that is to say the period from the first day of ASCT hospitalization 
to the day before C5D1), neutropenia and thrombocytopenia resulting from bone marrow aplasia 
will not be recorded as AEs in the eCRF.   
 
Only the following have to be recorded in the eCRF: 
✓ any evolution of ongoing AE 
✓ any new AE related, or that appears to be related, to Daratumumab 
✓ any new infection from at least grade 3 
✓ any new oral mucositis from at least grade 3. 
All events that meet the definition of a serious adverse event will be reported as serious adverse 
events, regardless of whether they are protocol-specific assessments. 
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, 
must be recorded using medical terminology in the source document and the eCRF. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology 
(eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper 
respiratory infection"). Investigators must record in the eCRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions. 
The sponsor and Janssen assume responsibility for appropriate reporting of adverse events to the 
regulatory authorities. The sponsor and Janssen will also report to the investigator (and the head 
of the investigational institute where required) all serious adverse events that are unlisted 
(unexpected) and associated with the use of the study drug. The investigator (or sponsor where 
required) must report these events to the appropriate Independent Ethics Committee/Institutional 
Review Board (IEC/IRB) that approved the protocol unless otherwise required and documented 
by the IEC/IRB.  
Subjects (or their designees, if appropriate) must be provided with a "wallet (study) card" and 
instructed to carry this card with them for the duration of the study indicating the following:  
• 
Subject's name 
• 
Study number 


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• 
Investigator's name and 24-hour contact telephone number 
• 
Local sponsor's name and 24-hour contact telephone number  
• 
Statement, in the local language(s), that the subject is participating in a clinical study 
12.3.2. 
Serious Adverse Events 
All serious adverse events occurring during the study must be reported to the appropriate sponsor’s 
contact person by study-site personnel within 24 hours of their knowledge of the event.  
Information regarding serious adverse events will be transmitted to the sponsor and Janssen 
pharmacovigilance using the Serious Adverse Event Form, which must be completed and signed 
by a physician from the study site, and transmitted to the appropriate sponsor’s delegated contact 
person within 24 hours. The initial and follow-up reports of a serious adverse event should be made 
by facsimile (fax) and or e-Mail. The appropriate sponsor’s delegated contact person will review 
the SAE reports for completeness and accuracy before sending to Janssen Pharmacovigilance team 
within 24 hours from reception. 
All serious adverse events that have not resolved by the end of the study, or that have not resolved 
upon discontinuation of the subject's participation in the study, must be followed until any of the 
following occurs: 
• 
The event resolves 
• 
The event stabilizes 
• 
The event returns to baseline, if a baseline value/status is available 
• 
The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct 
• 
It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts) 
Suspected transmission of an infectious agent by a medicinal product will be reported as a serious 
adverse event. Any event requiring hospitalization (or prolongation of hospitalization) that occurs 
during the course of a subject's participation in a study must be reported as a serious adverse event, 
except hospitalizations for the following: 
• 
If the subject has not experienced a significant medical event but is hospitalized overnight 
only for observation following infusion of daratumumab, then the hospitalization should 
not be reported as a serious adverse event. 
• 
Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons 
such as pending placement in long-term care facility; elective procedures for a condition 
unrelated to multiple myeloma, respite care) 
• 
Surgery or procedure planned before entry into the study (must be documented in the 
eCRF). Note: Hospitalizations that were planned before the signing of the ICF; or 
hospitalizations due to planned mobilization and transplant, and where the underlying 


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condition for which the hospitalization was planned has not worsened, will not be 
considered serious adverse events. Any adverse event that results in a prolongation of the 
originally planned hospitalization is to be reported as a new serious adverse event. 
12.3.3. 
Pregnancy 
All initial reports of pregnancy must be reported to the appropriate sponsor’s contact person by the 
study-site personnel within 24 hours of their knowledge of the event using the appropriate 
pregnancy notification form. The appropriate sponsor’s delegated contact person will review the 
pregnancy reports for completeness and accuracy before sending to Janssen Pharmacovigilance 
team within 24 hours from reception. Abnormal pregnancy outcomes (eg, spontaneous abortion, 
stillbirth, and congenital anomaly) are considered serious adverse events and must be reported 
using the Serious Adverse Event Form. Any subject who becomes pregnant during the study must 
discontinue further study treatment and promptly be withdrawn from the study. The subject should 
be referred to a physician experienced in teratology for evaluation and advice. Investigators should 
follow the local label for guidance on subject education and ensure that all subjects adhere to the 
thalidomide pregnancy prevention program. Follow-up information regarding the outcome of the 
pregnancy and any postnatal sequelae in the infant will be required. 
The effect of the study drug on sperm is unknown, therefore pregnancies in partners of male subjects 
included in the study will be reported by the study-site personnel within 24 hours of their knowledge 
of the event using the appropriate pregnancy notification form. 
12.4. 
Contacting Sponsor 
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed on the Contact Information 
page(s), which will be provided as a separate document. 
13. 
PRODUCT QUALITY COMPLAINT HANDLING 
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 the study drug, including its labeling or package integrity. A PQC may 
have an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting 
and analysis of PQC information from studies are crucial for the protection of subjects, 
investigators, and the sponsor, and are mandated by regulatory agencies worldwide. Janssen, the 
manufacturer of daratumumab, has established procedures in conformity with regulatory 
requirements worldwide to ensure appropriate reporting of PQC information; all studies conducted 
by the sponsor or its affiliates will be conducted in accordance with those procedures. 
13.1. 
Procedures 
All initial PQCs must be reported to Janssen by the study-site personnel within 24 hours after being 
made aware of the event. If the defect is combined with a serious adverse event, then the study-
site personnel must report the PQC to Janssen according to the serious adverse event reporting 
timelines (refer to Section 12.3.2). A sample of the suspected product should be maintained for 
further investigation if requested by Janssen. 


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13.2. 
Contacting Janssen Regarding Product Quality 
Janssen, the manufacturer of the investigational product daratumumab, will list the names (and 
corresponding telephone numbers) of the individuals who should be contacted regarding product 
quality issues are listed on the Contact Information page(s), which will be provided as a separate 
document. 
14. 
DARATUMUMAB INFORMATION 
14.1. 
Physical Description of Daratumumab  
daratumumab supplied for this study is colorless to yellow liquid and sterile concentrate of 20 
mg/mL in a vial. It will be manufactured and provided under the responsibility of Janssen. Refer 
to the Investigator's Brochure for a list of excipients. 
14.2. 
Packaging 
Daratumumab will be supplied to the site/pharmacy in glass vials containing daratumumab at a 
concentration of 20 mg/mL. 
14.3. 
Labeling 
Daratumumab labels will contain information to meet the applicable regulatory requirements. Each 
vial will contain a study-specific label with a unique identification number. 
14.4. 
Preparation, Handling, and Storage 
All daratumumab vials must be stored in the original carton in a refrigerator ranging from 2°C to 
8°C and must not be utilized after the expiry date printed on the label. The product must be 
protected from light and must not be frozen. Daratumumab does not contain preservatives; 
therefore, any unused portion remaining in the vial must be discarded.  
Daratumumab will be diluted in a sterile, pyrogen-free physiological saline solution (0.9% NaCl) 
prior to IV administration. Refer to the IP manual for details regarding dose preparation, storage, 
and handling of diluted solutions. 
14.5. 
Drug Accountability 
The investigator is responsible for ensuring that all daratumumab received at the site is inventoried 
and accounted for throughout the study. The daratumumab administered to the subject must be 
documented on the drug accountability form. All daratumumab will be stored and disposed of 
according to the sponsor's instructions. Study-site personnel must not combine contents of the 
daratumumab containers, as outlined in the IP Manual. 
Daratumumab must be handled in strict accordance with the protocol and the container label and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused daratumumab must be available for verification by the sponsor's 
study site monitor during on-site monitoring visits. The return to Janssen of unused daratumumab 
will be documented on the IP destruction form. When the study site is an authorized destruction 
unit and daratumumab supplies are destroyed on-site, this must also be documented on the IP 


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destruction form. Potentially hazardous materials such as used ampules, needles, syringes and vials 
containing hazardous liquids, should be disposed of immediately in a safe manner and therefore 
will not be retained for drug accountability purposes.  
Daratumumab should be dispensed under the supervision of the investigator or a qualified member 
of the study-site personnel, or by a hospital/clinic pharmacist. Daratumumab will be supplied only 
to subjects participating in the study. Returned daratumumab must not be dispensed again, even to 
the same subject. Daratumumab may not be relabeled or reassigned for use by other subjects. The 
investigator agrees neither to dispense the daratumumab from, nor store it at, any site other than 
the study sites agreed upon with the sponsor. 
15. 
STUDY-SPECIFIC MATERIALS 
The investigator will be provided with the following supplies: 
• 
Study Protocol 
• 
Investigator’s Brochure 
• 
Investigational Product Manual 
• 
Laboratory Manual 
• 
Electronic data capture (eDC) Manual 
• 
Sample ICF 
• 
Subject diary for recording of post infusion medications self-administered at home 
16. 
ETHICAL ASPECTS 
16.1. 
Study-Specific Design Considerations 
The primary safety profile of daratumumab is consistent with infusion-related reactions. Based on 
the mode of action of daratumumab, a potential risk could be infection; therefore, the protocol 
requires the review of hematological laboratory results prior to daratumumab infusion. CD38 is 
distributed in erythrocytes and platelets. A significant reduction of platelets was reported in an 
animal study. In a human clinical study (Study GEN501), thrombocytopenia was also reported. 
However, safety laboratory monitoring did not show a clinically meaningful reduction of platelets. 
No bleeding events were observed. Anemia was also reported in Study GEN501. Free hemoglobin 
was mildly elevated, but other parameters did not support hemolysis. Routine safety laboratory 
measurement of RBCs and platelets will be closely monitored in this study. 
Potential subjects will be fully informed of the risks and requirements of the study and, during the 
study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential adverse events of the study, and provide their consent voluntarily will be enrolled. Note 


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that as specified in Section 16.2.3, a legally acceptable representative may provide consent on behalf 
of the subject. 
The total blood volume for the study is estimated at approximately 50 mL during screening, 
400 mL in Part 1 (Induction/ASCT/Consolidation Phase), and approximately 500 mL in Part 2 (2-
year Maintenance Phase). The total blood volume to be collected is considered to be acceptable for 
subjects participating in a cancer clinical study and reasonable over the time frame of the study. 
16.2. 
Regulatory Ethics Compliance 
16.2.1. 
Investigator Responsibilities 
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements. Good Clinical Practice is an international ethical and scientific 
quality standard for designing, conducting, recording, and reporting studies that involve the 
participation of human subjects. Compliance with this standard provides public assurance that the 
rights, safety, and well-being of study subjects are protected, consistent with the principles that 
originated in the Declaration of Helsinki, and that the study data are credible. 
16.2.2. 
Independent Ethics Committee or Institutional Review Board 
Before the start of the study, the investigator (or sponsor/sponsor representative where required) 
will provide the IEC/IRB with current and complete copies of the following documents (as 
required by local regulations): 
• 
Final protocol and, if applicable, amendments 
• 
Sponsor-approved ICF (and any other written materials to be provided to the subjects) 
• 
Investigator's Brochure (or equivalent information) and amendments/addenda 
• 
Sponsor-approved subject recruiting materials 
• 
Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable 
• 
Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB) 
• 
Information regarding funding, name of the sponsor, institutional affiliations, other 
potential conflicts of interest, and incentives for subjects 
• 
Any other documents that the IEC/IRB requests to fulfill its obligation 
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol, 
amendments (if any, excluding the ones that are purely administrative, with no consequences for 
subjects, data or study conduct), the ICF, applicable recruiting materials, and subject compensation 
programs, and the sponsor has received a copy of this approval. This approval letter must be dated 
and must clearly identify the IEC/IRB and the documents being approved. 


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During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate: 
• 
Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct) 
• 
Revision(s) to ICF and any other written materials to be provided to subjects 
• 
If applicable, new or revised subject recruiting materials approved by the sponsor 
• 
Revisions to compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable 
• 
New edition(s) of the Investigator's Brochure and amendments/addenda 
• 
Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually) 
• 
Reports of adverse events that are serious, unlisted/unexpected, and associated with the 
study drug 
• 
New information that may adversely affect the safety of the subjects or the conduct of the 
study 
• 
Deviations from or changes to the protocol to eliminate immediate hazards to the subjects 
• 
Report of deaths of subjects under the investigator's care 
• 
Notification if a new investigator is responsible for the study at the site 
• 
Development Safety Update Report and Line Listings, where applicable 
• 
Any other requirements of the IEC/IRB 
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of the 
change(s). 
Furthermore, where required, progress reports/written summaries of the trial status will be 
submitted to the IRB/IEC annually, or more frequently if requested. 
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about 
the study completion (if applicable, the notification will be submitted through the head of 
investigational institution).  
16.2.3. 
Informed Consent 
Each subject (or a legally acceptable representative) must give written consent according to local 
requirements after the nature of the study has been fully explained. The ICF(s) must be signed 
before performance of any study-related activity. The ICF(s) that is/are used must be approved by 
both the sponsor and by the reviewing IEC/IRB and be in a language that the subject can read and 
understand. The informed consent should be in accordance with principles that originated in the 


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Declaration of Helsinki, current ICH and GCP guidelines, applicable regulatory requirements, and 
sponsor policy. 
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects or their legally acceptable representatives the aims, 
methods, reasonably anticipated benefits, and potential hazards of the study, and any discomfort 
participation in the study may entail. Subjects will be informed that their participation is voluntary 
and that they may withdraw consent to participate at any time. They will be informed that choosing 
not to participate will not affect the care the subject will receive for the treatment of his or her 
disease. Subjects will be told that alternative treatments are available if they refuse to take part and 
that such refusal will not prejudice future treatment. Finally, they will be told that the investigator 
will maintain a subject identification register for the purposes of long-term follow up if needed 
and that their records may be accessed by health authorities and authorized sponsor personnel 
without violating the confidentiality of the subject, to the extent permitted by the applicable law(s) 
or regulations. By signing the ICF the subject or legally acceptable representative is authorizing 
such access, including permission to obtain information about his or her survival status, and agrees 
to allow his or her study physician to recontact the subject for the purpose of obtaining consent for 
additional safety evaluations, if needed, and subsequent disease-related treatments, or to obtain 
information about his or her survival status. 
The subject or legally acceptable representative will be given sufficient time to read the ICF and 
the opportunity to ask questions. After this explanation and before entry into the study, consent 
should be appropriately recorded by means of either the subject's or his or her legally acceptable 
representative's personally dated signature. After having obtained the consent, a copy of the ICF 
must be given to the subject. Where local regulations require, a separate ICF may be used for the 
required DNA component of the study. 
If the subject or legally acceptable representative is unable to read or write, an impartial witness 
should be present for the entire informed consent process (which includes reading and explaining 
all written information) and should personally date and sign the ICF after the oral consent of the 
subject or legally acceptable representative is obtained. 
16.2.4. 
Privacy of Personal Data 
The collection and processing of personal data from subjects enrolled in this study will be limited 
to those data that are necessary to fulfill the objectives of the study. These data must be collected 
and processed with adequate precautions to ensure confidentiality and compliance with applicable 
data privacy protection laws and regulations. Appropriate technical and organizational measures 
to protect the personal data against unauthorized disclosures or access, accidental or unlawful 
destruction, or accidental loss or alteration must be put in place. Sponsor personnel whose 
responsibilities require access to personal data agree to keep the identity of subjects confidential. 
The informed consent obtained from the subject (or his or her legally acceptable representative) 
includes explicit consent for the processing of personal data and for the investigator/institution to 
allow direct access to his or her original medical records (source data/documents) for study-related 


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monitoring, audit, IEC/IRB review, and regulatory inspection. This consent also addresses the 
transfer of the data to other entities and to other countries. 
The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps will 
be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations. 
Exploratory DNA, pharmacodynamic, biomarker, and immunogenicity research is not conducted 
under standards appropriate for the return of data to subjects. In addition, the sponsor cannot make 
decisions as to the significance of any findings resulting from exploratory research. Therefore, 
exploratory research data will not be returned to subjects or investigators, unless required by law 
or local regulations. Privacy and confidentiality of data generated in the future on stored samples 
will be protected by the same standards applicable to all other clinical data.] 
16.2.5. 
Long-Term Retention of Samples for Additional Future Research 
Samples collected in this study may be stored for up to 15 years (or according to local regulations) 
for additional research. Samples will only be used to understand daratumumab, to understand 
multiple myeloma, to understand differential drug responders, and to develop tests/assays related 
to daratumumab and multiple myeloma. The research may begin at any time during the study or 
the post-study storage period.  
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored for research (refer to Section 10.3). 
17. 
ADMINISTRATIVE REQUIREMENTS 
17.1. 
Protocol Amendments 
Neither the investigator nor the coordinating study group (HOVON) will modify this protocol 
without a formal amendment by the sponsor (IFM). All protocol amendments must be issued by 
the sponsor and signed and dated by the investigator. Protocol amendments must not be 
implemented without prior IEC/IRB approval, or when the relevant competent authority has raised 
any grounds for non-acceptance, except when necessary to eliminate immediate hazards to the 
subjects, in which case the amendment must be promptly submitted to the IEC/IRB and relevant 
competent authority. Documentation of amendment approval by the investigator and IEC/IRB 
must be provided to the sponsor. When the change(s) involves only logistic or administrative 
aspects of the study, the IRB (and IEC where required) only needs to be notified. 
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor representative 
(see Contact Information page(s) provided separately). Except in emergency situations, this 
contact should be made before implementing any departure from the protocol. In all cases, contact 
with the sponsor must be made as soon as possible to discuss the situation and agree on an 
appropriate course of action. The data recorded in the eCRF and source documents will reflect any 


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departure from the protocol, and the source documents will describe this departure and the 
circumstances requiring it. 
17.2. 
Regulatory Documentation 
17.2.1. 
Regulatory Approval/Notification 
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met. 
17.2.2. 
Required Prestudy Documentation 
The following documents must be provided to the sponsor before shipment of daratumumab to the 
study site: 
• 
Protocol and amendment(s), if any, signed and dated by the principal investigator 
• 
A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee. 
• 
Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or 
a member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study. 
• 
Regulatory authority approval or notification, if applicable 
• 
Signed and dated statement of investigator (eg, Form FDA 1572), if applicable 
• 
Documentation of investigator qualifications (eg, curriculum vitae) 
• 
Completed investigator financial disclosure form from the principal investigator, where 
required 
• 
Signed and dated clinical trial agreement, which includes the financial agreement 
• 
Any other documentation required by local regulations 
 
The following documents must be provided to the sponsor before enrollment of the first subject: 
• 
Completed investigator financial disclosure forms from all subinvestigators 
• 
Documentation of subinvestigator qualifications (eg, curriculum vitae) 
• 
Name and address of any local laboratory conducting tests for the study, and a dated copy 
of current laboratory normal ranges for these tests, if applicable 


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• 
Local laboratory documentation demonstrating competence and test reliability 
(eg, accreditation/license), if applicable 
17.3. 
Subject Identification, Enrollment, and Screening Logs 
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness. 
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification 
and date of birth. In cases where the subject is not randomized into the study, the date seen, and 
date of birth will be used. 
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study. 
17.4. 
Source Documentation 
At a minimum, source documentation must be available for the following to confirm data collected 
in the eCRF: subject identification, eligibility, and study identification; study discussion and date 
of signed informed consent; dates of visits; results of safety and efficacy parameters as required 
by the protocol; record of all adverse events and follow-up of adverse events; concomitant 
medication; drug receipt/dispensing/return records; study drug administration information; and 
date of study completion and reason for early discontinuation of study drug or withdrawal from 
the study, if applicable. In addition, the author of an entry in the source documents should be 
identifiable.  
At a minimum, the type and level of detail of source data available for a subject should be 
consistent with that commonly recorded at the study site as a basis for standard medical care. 
Specific details required as source data for the study will be reviewed with the investigator before 
the study and will be described in the monitoring guidelines (or another equivalent document).  
The minimum source documentation requirements for Section 4.1 and Section 4.2 that specify a 
need for documented medical history are as follows: 
• 
Referral letter from treating physician 
• 
Complete history of medical notes at the site 
• 
Discharge summaries 
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by subject interview or other protocol required assessment (eg, physical examination, 
laboratory assessment) and documented in the source documents. 
17.5. 
Case Report Form Completion 
Case report forms are provided for each subject in an electronic format.  


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Electronic Data Capture (eDC) will be used for this study. The study data will be transcribed by 
study-site personnel from the source documents onto an eCRF and transmitted in a secure manner 
to the sponsor within the timeframe agreed upon between the sponsor and the study site. The 
electronic file will be considered to be the eCRF. 
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the subject's source documentation. All data relating to the 
study must be recorded in eCRFs prepared by the sponsor. Data must be entered into eCRFs in 
English. Study site personnel must complete the eCRF as soon as possible after a subject visit, and 
the forms should be available for review at the next scheduled monitoring visit. 
All subjective measurements (eg, pain scale information or other questionnaires) will be completed 
by the same individual who made the initial baseline determinations whenever possible. The 
investigator must verify that all data entries in the eCRFs are accurate and correct. 
All eCRF entries, corrections, and alterations must be made by the investigator or other authorized 
study-site personnel. If necessary, queries will be generated in the eDC tool.  
If corrections to an eCRF are needed after the initial entry into the eCRF, this can be done in 3 
different ways: 
• 
Study site personnel can make corrections in the eDC tool at their own initiative or as a 
response to an auto query (generated by the eDC tool) 
• 
Study site manager can generate a query for resolution by the study-site personnel 
• 
Clinical data manager can generate a query for resolution by the study-site personnel 
17.6. 
Data Quality Assurance/Quality Control 
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, periodic monitoring visits by sponsor representatives, and 
direct transmission of clinical laboratory data from a central laboratory into the sponsor's data base. 
Written instructions will be provided for collection, handling, storage, and shipment of samples.  
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before 
the start of the study. The sponsor will review eCRFs for accuracy and completeness during on-
site monitoring visits and after transmission to the sponsor; any discrepancies will be resolved with 
the investigator or designee, as appropriate. After upload of the data into the study database they 
will be verified for accuracy and consistency with the data sources. 
17.7. 
Record Retention 
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRFs 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical 
Trial, and all study documents as specified by the applicable regulatory requirement(s). The 


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investigator/institution will take measures to prevent accidental or premature destruction of these 
documents. 
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents will be retained for a longer period 
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the 
responsibility of the sponsor to inform the investigator/institution as to when these documents no 
longer need to be retained. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will accept 
the responsibility. The sponsor must be notified in writing of the name and address of the new 
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents 
before having obtained written approval from the sponsor. 
If it becomes necessary for the sponsor, Janssen or the appropriate regulatory authority to review 
any documentation relating to this study, the investigator/institution must permit access to such 
reports. 
17.8. 
Monitoring 
Representatives working on behalf of the sponsor will use a combination of monitoring techniques, 
central, remote, and on-site monitoring to monitor this study.  On-site monitoring visits will be 
performed as frequently as necessary. The monitor will record dates of the on-site visits in a study 
site visit log that will be kept at the study site. The first post-initiation visit will be made as soon 
as possible after enrollment has begun. At these visits, the monitor will compare the data entered 
into the eCRF with the hospital or clinic records (source documents). The nature and location of 
all source documents will be identified to ensure that all sources of original data required to 
complete the eCRF are known to the sponsor and study-site personnel and are accessible for 
verification by the sponsor study-site contact. If electronic records are maintained at the study site, 
the method of verification must be discussed with the study-site personnel.  
Direct access to source documentation (medical records) must be allowed for the purpose of 
verifying that the data recorded in the eCRF are consistent with the original source data. Findings 
from this review of eCRFs and source documents will be discussed with the study-site personnel. 
The sponsor expects that, during monitoring visits, the relevant study-site personnel will be 
available, the source documentation will be accessible, and a suitable environment will be provided 
for review of study-related documents. The monitor will meet with the investigator on a regular 
basis during the study to provide feedback on the study conduct. 
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during these 
remote contacts, study-site personnel will be available to provide an update on the progress of the 
study at the site. 


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Central monitoring will take place for data identified by the sponsor as requiring central review. 
 
17.9. 
Study Completion/Termination 
17.9.1. 
Study Completion 
The study is considered completed 5 years after the last subject is randomized in Part 2 for the 
maintenance phase, or 350 subjects have died, whichever occurs first.  
17.9.2. 
Study Termination 
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been collected 
and a study-site closure visit has been performed. The investigator may initiate study-site closure 
at any time, provided there is reasonable cause and sufficient notice is given in advance of the 
intended termination.  
Reasons for the early closure of a study site by the sponsor or investigator may include but are not 
limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of subjects by the investigator 
 
• 
Discontinuation of further daratumumab development 
17.10. On-Site Audits 
Representatives of the sponsor and Janssen clinical quality assurance department may visit the 
study site at any time during or after completion of the study to conduct an audit of the study in 
compliance with regulatory guidelines and company policy. These audits will require access to all 
study records, including source documents, for inspection and comparison with the eCRFs. Subject 
privacy must, however, be respected. The investigator and study-site personnel are responsible for 
being present and available for consultation during routinely scheduled study-site audit visits 
conducted by the sponsor or its designees.  
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part 
of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has 
been contacted by a regulatory agency concerning an upcoming inspection. 
17.11. Use of Information and Publication 
All information, including but not limited to information regarding daratumumab or the sponsor's 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not 


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previously published, and any data, including exploratory biomarker research data, generated as a 
result of this study, are considered confidential and remain the sole property of the sponsor. The 
investigator agrees to maintain this information in confidence and use this information only to 
accomplish this study, and will not use it for other purposes without the sponsor's prior written 
consent. 
The investigator understands that the information developed in the study will be used by the 
sponsor and Janssen in connection with the continued development of daratumumab, and thus may 
be disclosed as required to other clinical investigators or regulatory agencies. To permit the 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the sponsor with all data obtained in the study. 
The results of the study will be reported in a Clinical Study Report generated by the sponsor or the 
sponsor’s delegate and will contain eCRF data from all study sites that participated in the study, 
and direct transmission of clinical laboratory data from a central laboratory into the sponsor's 
database. Recruitment performance or specific expertise related to the nature and the key 
assessment parameters of the study will be used to determine a coordinating investigator. Results 
of exploratory biomarker analyses performed after the Clinical Study Report has been issued will 
be reported in a separate report and will not require a revision of the Clinical Study Report. Study 
subject identifiers will not be used in publication of results. Any work created in connection with 
performance of the study and contained in the data that can benefit from copyright protection 
(except any publication by the investigator as provided for below) shall be the property of the 
sponsor as author and owner of copyright in such work. 
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data and 
information without approval from the investigator. The investigator has the right to publish study 
site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow for 
filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor will 
not mandate modifications to scientific content and does not have the right to suppress information. 
For multicenter study designs and substudy approaches, secondary results generally should not be 
published before the primary endpoints of a study have been published. Similarly, investigators 
will recognize the integrity of a multicenter study by not submitting for publication data derived 
from the individual study site until the combined results from the completed study have been 
submitted for publication, within 12 months of the availability of the final data (tables, listings, 
graphs), or the sponsor confirms there will be no multicenter study publication. Authorship of 
publications resulting from this study will be based on the guidelines on authorship, such as those 
described in the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, which 
state that the named authors must have made a significant contribution to the design of the study 


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or analysis and interpretation of the data, provided critical review of the paper, and given final 
approval of the final version. 
Registration of Clinical Studies and Disclosure of Results 
Where appropriate the study sponsor or Janssen LLC on behalf of the sponsor will register and 
disclose the existence of and the results of clinical studies as required by law. 


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17. Harousseau J-L, Attal M, and Avet-Loiseau H. The role of complete response in multiple myeloma. Blood 
2009;114:3139-3146. 
18. Harousseau J-L and Moreau P. Autologous Hematopoietic Stem-Cell Transplantation for Multiple Myeloma. 
N Engl J Med 2009;360:2645-54. 


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19. Harousseau J-L, Palumbo A, Richardson PG, et al. Superior outcomes associated with complete response in 
newly diagnosed multiple myeloma patients treated with non-intensive therapy; analysis of the Phase 3 VISTA 
study of bortezomib plus melphalan-prednisone versus melphalan-prednisone. Blood. 2010c;116(19):3743-50. 
20. Harousseau JL, Attal M, Avet-Loiseau H, et al. Bortezomib Plus Dexamethasone Is Superior to Vincristine 
Plus Doxorubicin Plus Dexamethasone As Induction Treatment Prior to Autologous Stem-Cell Transplantation 
in Newly Diagnosed Multiple Myeloma: Results of the IFM 2005-01 Phase III Trial. J Clin Oncol.2010b; 
28:4621-4629. 
21. Harousseau JL, Moreau P. Autologous hematopoietic stem-cell transplantation for multiple myeloma. N Engl J 
Med. 2009;360:2645–2654. 
22. Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level version of 
the EQ-5D (EQ-5D-5L). Qual Lif Res. 2011;20:1727-1736. 
23. Kapoor P, Kumar SK, Dispenzieri A, et al. Importance of Achieving Stringent Complete Response After 
Autologous Stem-Cell Transplantation in Multiple Myeloma. J Clin Oncol 2013;31:4529-4535. 
24. Kumar S, Flinn I, Richardson PG, et al. Randomized, multicenter, Phase 2 study (EVOLUTION) of 
combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated 
multiple myeloma. Blood. 2012b; 119:4375-4382. 
25. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. 
Mayo Clin Proc. 2003;78(1):21-33. 
26. Kyle RA, Remstein ED, Therneau TM, et al. Clinical course and prognosis of smoldering (asymptomatic) 
multiple myeloma. N Engl J Med. 2007;356(25):2582-2590. 
27. Ladetto M, Pagliano G, Ferrero S. Major Tumor Shrinking and Persistent Molecular Remissions After  
Consolidation With Bortezomib, Thalidomide, and Dexamethasone in Patients With Autografted Myeloma. J 
Clin Oncol. 2010; 28(12): 2077-84. 
28. Lahuerta JJ, Mateos MV, Martinez-Lopez J, et al. Influence of pre- and post-transplantation responses on 
outcome of patients with multiple myeloma: sequential improvement of response and achievement of complete 
response are associated with longer survival. J Clin Oncol 2008;26:5575-5782. 
29. Leleu X, Fouquet G, Hebraud B, et al. Consolidation with VTd significantly improves the complete remission 
rate and time to progression following VTd induction and single autologous stem cell transplantation in 
multiple myeloma. Leukemia 2013;27:2242-2244. 
30. Lokhnygina Y, Helterbrand JD. Cox regression methods for two-stage randomization designs. Biometrics 
2007; 63: 422-428. 
31. Ludwig H, Durie BM, McCarthy P, et al. IMWG consensus on maintenance therapy in multiple myeloma. 
Bloo 2012;119:3003-3015. 
32. McCarthy PL, Kouros O, Hofmeister CC. Lenalidomide after Stem-Cell Transplantation for Multiple 
Myeloma. N Engl J Med. 2012; 366: 1770-1781. 
33. McCudden 2010 McElwain TJ, Powles RL. High-dose intravenous Melphalan for plasma-cell leukaemia and 
myeloma.Lancet 1983; 2(8354): 822-824. 
34. McElwain TJ, Powles RL. High-dose intravenous Melphalan for plasma-cell leukaemia and myeloma.Lancet 
2(8354): 822-824, 1983 
35. Mellqvist U-H, Westin J, Gimsing P, et al. Improved Response Rate with Bortezomib Consolidation after High 
Dose Melphalan: First Results of a Nordic Myeloma Study Group Randomized Phase III Trial. Blood (ASH 
Annual Meeting Abstracts). 2009. 114: Abstract 530. 
36. Miyahara S and Wahed AS. Weighted Kaplan-Meier estimators for two-stage treatment regimes. Stat Methods 
2010;10:2581-91. 
37. Moreau P, Avet-Loiseau H, Facon T, et al. Bortezomib plus dexamethasone versus reduced-dose bortezomib, 
thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly 
diagnosed multiple myeloma. Blood. 2011b; 118(22): 5752-58. 


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38. Moreau P, San Miguel J, Ludwig H, et al. Multiple myeloma: ESMO clinical practice guidelines for diagnosis, 
treatment, and follow-up. Annals of Oncol 2013;24(Supplement 6):vi133-vi137. 
39. Morgan GJ, Walter MG, Faith ED. The role of maintenance thalidomide therapy in multiple myeloma: MRC 
Myeloma IX results and meta-analysis. Blood. 2012;119(1):7-15. 
40. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN 
Guidelines): Multiple Myeloma, version 2.2013. Fort Washington, PA: National Comprehensive Cancer 
Network.  
41. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol. 1982;5(6):649-655. 
42. Overdijk MB, Verploegen S, Bogels M, et al. Phagocytosis is a potent mechanism of action for the therapeutic 
human monoclonal antibody daratumumab in lymphoma and multiple myeloma. Submitted to Blood. 13 May 
2013. 
43. Paiva B, Martinez-Lopez J, Vidriales M-B, et al. Comparison of immunofixation, serum free light chain, and 
immunophenotyping for response evaluation and prognostication in multiple myeloma. J Clin Oncol 
2011;29:1627-1633. 
44. Palumbo A, Facon T, Sonneveld P, et al. Thalidomide for treatment of multiple myeloma: 10 Years later. 
Blood. 2008c;111(8):3968-3977. 
45. Palumbo A, Anderson K. Multiple myeloma. N Engl J Med. 2011;364(11):1046-1060. 
46. Palumbo A, Sezer O, Kyle R, et al. International Myeloma Working Group guidelines for the management of 
multiple myeloma patients ineligible for standard high-dose chemotherapy with autologous stem cell 
transplantation. Leukemia; 2009:23:1716-1730. 
47. Rajkumar SV, Harousseau J-L, Durie B, et al. Consensus recommendations for the uniform reporting of 
clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011; 114:4691-4695. 
48. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for 
the diagnosis of multiple myeloma. Lancet Oncol. 2014;15:e538-e548. 
49. Rawstron AC, Child JA, de Tute RM, et al. Minimal residual disease assessed by multiparameter flow 
cytometry in multiple myeloma:  impact on outcome in the Medical Research Council Myeloma IX Study.  J 
Clin Oncol. 2013;31(20):2540-7, doi: 10.1200/JCO.2012.46.2119. 
50. Reeder CB, Reece DE, Kukreti V, et al. Cyclophosphamide, bortezomib and dexamethasone induction for 
newly diagnosed multiple myeloma: high response rates in a Phase II  clinical trial. Leukemia. 2009;23:1337-
1341. 
51. Rosiñol L, Oriol A, Teruel AI, et al. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as 
induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. 
Blood. 2012;120(8);1589-1596. 
52. Sarasquete ME, Garcia-Sanz R, Gonzalez D, et al. Minimal residual disease monitoring in multiple myeloma: a 
comparison between allelic-specific oligonucleotide real-time quantitative polymerase chain reaction and flow 
cytometry. Haematologica 2005;90:1365-1372. 
53. Smith A, Wisloff F, Samson D. Guidelines on the diagnosis and management of multiple myeloma 2005. Br J 
Haematol. 2005;132:410-451. 
54. Sonneveld P, Goldschmidt LR, Blade J, et al. Bortezomib-Based Versus Non-bortezomib-Based Induction 
Treatment Before Autologous Stem-Cell Transplantation in Patients With Previously Untreated Multiple  
Myeloma: A Meta-Analysis of Phase III Randomized, Controlled Trials. J Clin Oncol. 2013. Epub ahead of 
print. 10.1200/JCO.2012.48.4626. 
55. Terragna C, Zamagni E, Petrucci MT, et al. Molecular remission after bortezomib-thalidomide dexamethasone 
compared with thalidomide dexamethasone as consolidation therapy after double autologous transplantation 
for multiple myeloma: results of a qualitative and quantitative analysis. Blood. (ASH Annual Meeting 
Abstracts). 2010;116:Abstract 861. 


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56. Van de Velde H, Liu X, Chen G, et al. Complete response correlates with long-term survival and progression-
free survival in high-dose therapy in multiple myeloma. Hematologica 2007;92:1399-1406. 
57. van der Veer M, de Weers M, van Kessel B. Towards effective immunotherapy of myeloma: enhanced 
elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody 
daratumumab. Haematol. 2011b:96(2):284-290. 
58. Wisloff F, Eika S, Hippe E, et al. Measurement of health-related quality of life in multiple myeloma. Nordic 
Myeloma Study Group. Br J Haematol. 1996;92:604-613. 
59. Wisloff F, Hjorth M. Health-related quality of life assessed before and during chemotherapy predicts for 
survival in multiple myeloma. Nordic Myeloma Study Group. Br J Haematol .1997;97:29-37. 
 


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ATTACHMENT 1:  DIAGNOSTIC CRITERIA FOR MULTIPLE MYELOMA 
 
Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary 
plasmacytoma1 AND any one or more of the following myeloma defining events:  
 
Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative 
disorder, specifically: 
• 
Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than ULN or 
>2.75 mmol/L (>11 mg/dL) 
• 
Renal insufficiency: creatinine clearance2 <40mL/min or serum creatinine 
>177 µmol/L (>2 mg/dL) 
• 
Anemia: hemoglobin >2 g/dL below the lower limit of normal or hemoglobin 
<10 g/dL 
• 
Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT3 
Any one or more of the following biomarkers of malignancy: 
• 
Clonal bone marrow plasma cell percentage1 ≥60% 
• 
Involved: uninvolved serum free light chain ratio4 ≥100 
• 
>1 focal lesion5 on MRI studies 
 
 
Footnotes: 
1. Clonality should be established by showing / light-chain restriction on flow cytometry, 
immunohistochemistry, or immunofluorescence. Bone marrow plasma cell percentage should 
preferably be estimated from a core biopsy specimen; in case of a disparity between the 
aspirate and the core biopsy, the highest value should be used.  
2. Measured or estimated by validated equations. 
3. If bone marrow has less than 10% clonal plasma cells, more than one bone lesion is required 
to distinguish from solitary plasmacytoma with minimal marrow involvement. 
4. These values are based on the serum Freelite assay (The Binding Site Group, Birmingham 
UK). The involved free light chain must be ≥100mg/L. 
5. Each focal lesion must be 5mm or more in size. 
 
Reference: Rajkumar 2014. 


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ATTACHMENT 2: ECOG PERFORMANCE STATUS SCALE 
Grade  ECOG Performance Status  
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair 
5 
Dead 
Reference:  Oken 198241 


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ATTACHMENT 3: CALCULATED CREATININE CLEARANCE (COCKCROFT & 
GAULT FORMULA) 
 
 
When serum creatinine is measured in µmol/L: 
 
Where Constant is 1.23 for men and 1.04 for women. 
 
 
 
 


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ATTACHMENT 4: SERUM CALCIUM CORRECTED FOR ALBUMIN 
 
If calcium is expressed in mg/dL and albumin is expressed in g/L: 
Corrected calcium (mg/L) =  
 
serum calcium (mg/L) + 0.8•(40 - serum albumin [g/L]) 
 
If calcium is expressed in mmol/L and albumin is expressed in g/L: 
Corrected calcium (mmol/L) =  
 
serum calcium (mmol/L) + 0.02•(40 - serum albumin [g/L]) 
 
Source: Burtis 19985 
 


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ATTACHMENT 5: ASTHMA GUIDELINES 
 
 


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ATTACHMENT 6: CONVERSION TABLE FOR GLUCOCORTICOSTEROID DOSE 
 
 
Generic Name 
Oral or Intravenous 
 
 Dose (mg) 
Dexamethasone 
0.75 
Methylprednisolone 
4 
Prednisolone 
5 
Prednisone 
5 
 


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ATTACHMENT 7: BODY SURFACE AREA CALCULATION 
 BSA should be calculated using the Mosteller Formula (shown below); however, the DuBois 
Formula can be used as an alternative. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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INVESTIGATOR AGREEMENT 
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will 
conduct the study as outlined herein. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who 
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed 
regarding the study drug, the conduct of the study, and the obligations of confidentiality. 
Coordinating Investigator (where required): 
 
Name (typed or printed): 
 
Institution and Address: 
 
 
 
 
 
 
 
Signature: 
 
Date: 
 
 
 
 
(Day Month Year) 
 
Principal (Site) Investigator: 
 
Name (typed or printed): 
 
Institution and Address: 
 
 
 
 
 
 
 
Telephone Number: 
 
Signature: 
 
Date: 
 
 
 
 
(Day Month Year) 
 
Sponsor's Responsible Medical Officer: 
 
Name (typed or printed): 
 
Institution: 
 
Signature: 
 
Date: 
 
 
 
 
(Day Month Year) 
 
Note: If the address or telephone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required. 
 
 
 
 


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PROTOCOL – SPONSOR VALIDATION FORM  
 
 
Intergroupe Francophone du Myelome (IFM) 
 in Collaboration with  
Dutch-Belgian Cooperative Trial Group for Hematology Oncology (HOVON)  
And Janssen Research & Development 
 
Clinical Protocol 
 
Study of Daratumumab (JNJ-54767414 (HuMax® CD38) in Combination with Bortezomib 
(VELCADE), Thalidomide, and Dexamethasone (VTD) in the First Line Treatment of Transplant 
Eligible Subjects with Newly Diagnosed Multiple Myeloma. 
 
Protocol  IFM 2015-01 /HO131/54767414MMY3006; Phase 3 
Initial Version dated 14 January 2015 
AMENDMENT 4 dated 14 January 2021 
 
JNJ-54767414 (daratumumab)  
 
 
 
 
 
Sponsor's Representatives 
Sign.:  __________________________________   date:  _________  
IFM 
             
 
 
 
 
 
 __________________________________  date:  _________  
 
 
 
 
 
 
 
 
 
LAST PAGE 

SAP_001.pdf: 
Official Title of Study: 
Study of Daratumumab (JNJ-54767414 (HuMax® CD38) in Combination with Bortezomib (VELCADE), 
Thalidomide, and Dexamethasone (VTD) in the First Line Treatment of Transplant Eligible Subjects 
with Newly Diagnosed Multiple Myeloma. 
 
 
NCT Number: NCT02541383 
 
 
Document Date (Date in which document was last revised): 16 September 2020 


CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved,  Date: 16 September 2020
Janssen Research & Development 
Statistical Analysis Plan (Part 2)
A Phase 3 Study of Daratumumab (JNJ-54767414 (HuMax® CD38) in Combination with 
Bortezomib (VELCADE), Thalidomide, and Dexamethasone (VTd) in the First Line Treatment of 
Transplant Eligible Subjects with Newly Diagnosed Multiple Myeloma
Protocol 54767414MMY3006; Phase 3
JNJ54767414  (daratumumab)
Status:
Approved
Date:
16 September 2020
Prepared by:
Janssen Research & Development, LLC
Document No.: EDMS-RIM-161303, 1.0
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.


JNJ54767414  (daratumumab)
Statistical Analysis Plan 54767414MMY3006 (Part 2)
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Status: Approved,  Date: 16 September 2020
TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................................2
LIST OF IN-TEXT TABLES ..........................................................................................................................4
LIST OF IN-TEXT FIGURES.........................................................................................................................4
ABBREVIATIONS.........................................................................................................................................5
1.
INTRODUCTION..................................................................................................................................6
1.1.
Trial Objectives.................................................................................................................................6
1.2.
Trial Design.......................................................................................................................................7
1.3.
Statistical Hypotheses for Trial Objectives .......................................................................................9
1.4.
Sample Size Justification..................................................................................................................9
1.5.
Randomization and Blinding.............................................................................................................9
2.
GENERAL ANALYSIS DEFINITIONS...............................................................................................10
2.1.
Visit Windows .................................................................................................................................10
2.2.
Pooling Algorithm for Analysis Centers ..........................................................................................10
2.3.
Analysis Sets ..................................................................................................................................10
2.4.
Definition of Subgroups ..................................................................................................................11
2.5.
Imputation of Missing Data.............................................................................................................12
2.5.1.
Adverse Event Start and End Date .............................................................................................12
2.5.2.
Concomitant Medication/Therapy Start and End Date................................................................13
2.5.3.
Subsequent Anti-cancer Therapy Start Date ..............................................................................13
2.6.
Other General Definitions ...............................................................................................................14
2.6.1.
Treatment Arms...........................................................................................................................14
2.6.2.
International Staging System (ISS) Staging................................................................................14
2.6.3.
Month and Year...........................................................................................................................14
2.6.4.
Maximum Date ............................................................................................................................14
2.6.5.
End of Follow-up and Duration of Follow-up...............................................................................14
2.6.6.
Relationship of Adverse Events to Study Medication .................................................................14
2.6.7.
General Analysis Specifications..................................................................................................14
3.
INTERIM ANALYSIS..........................................................................................................................15
4.
SUBJECT INFORMATION ................................................................................................................15
4.1.
Demographics and Baseline Characteristics..................................................................................15
4.2.
Disposition Information ...................................................................................................................15
4.3.
Treatment Compliance ...................................................................................................................16
4.4.
Extent of Exposure .........................................................................................................................16
4.5.
Protocol Deviations.........................................................................................................................16
4.6.
Concomitant Medications ...............................................................................................................16
4.7.
Subsequent Anticancer Therapies in Part 2...................................................................................16
5.
EFFICACY..........................................................................................................................................17
5.1.
Analysis Specifications ...................................................................................................................17
5.1.1.
Level of Significance ...................................................................................................................17
5.1.2.
Data Handling Rules ...................................................................................................................17
5.2.
Primary Efficacy Endpoint in Part 2................................................................................................18
5.2.1.
Definition .....................................................................................................................................18
5.2.2.
Analysis Methods ........................................................................................................................18
5.2.3.
Sensitivity and Supplementary Analysis .....................................................................................19
5.3.
Major Secondary Endpoints in Part 2.............................................................................................19


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5.3.1.
Time to Progression from 2nd Randomization .............................................................................19
5.3.1.1.
Definition ..................................................................................................................................19
5.3.1.2.
Analysis Methods .....................................................................................................................19
5.3.2.
Overall CR or better rate .............................................................................................................20
5.3.2.1.
Definition ..................................................................................................................................20
5.3.2.2.
Analysis Methods .....................................................................................................................20
5.3.3.
Overall MRD negative rate..........................................................................................................20
5.3.3.1.
Definition ..................................................................................................................................21
5.3.3.2.
Analysis Methods .....................................................................................................................21
5.3.4.
MRD Negative CR or Better Rate ...............................................................................................21
5.3.4.1.
Definition ..................................................................................................................................21
5.3.4.2.
Analysis Methods .....................................................................................................................22
5.3.5.
Progression-free Survival after next line of therapy (PFS2) from 2nd Randomization ................22
5.3.5.1.
Definition ..................................................................................................................................22
5.3.5.2.
Analysis Methods .....................................................................................................................23
5.3.6.
Overall Survival (OS) from 2nd Randomization ...........................................................................23
5.3.6.1.
Definition ..................................................................................................................................23
5.3.6.2.
Analysis Methods .....................................................................................................................23
5.4.
Other Secondary Endpoints in Part 2.............................................................................................23
5.4.1.
Rate of Improved Response During Maintenance......................................................................23
5.4.1.1.
Definition ..................................................................................................................................23
5.4.1.2.
Analysis Methods .....................................................................................................................24
5.4.2.
Rate of MRD Negative Conversion During Maintenance............................................................24
5.4.2.1.
Definition ..................................................................................................................................24
5.4.2.2.
Analysis Methods .....................................................................................................................24
5.4.3.
Rate of MRD Negative CR or Better Conversion During Maintenance ......................................24
5.4.3.1.
Definition ..................................................................................................................................24
5.4.3.2.
Analysis Methods .....................................................................................................................24
5.5.
Time to Subsequent Antimyeloma Treatment................................................................................24
5.5.1.1.
Definition ..................................................................................................................................24
5.5.1.2.
Analysis Methods .....................................................................................................................25
5.6.
Subgroup Analysis of Efficacy Endpoints in Part 2 ........................................................................25
6.
SAFETY..............................................................................................................................................25
6.1.
Adverse Events in Part 2 ................................................................................................................25
6.1.1.
Treatment Emergent Adverse Events.........................................................................................26
6.1.2.
Adverse Events of Clinical Interest .............................................................................................27
6.1.2.1
Infusion-Related Reactions .........................................................................................................27
6.1.2.2
Infections .....................................................................................................................................28
6.1.2.2.1 Infections/Infestations .................................................................................................................28
6.1.2.2.2 Opportunistic Infections...............................................................................................................28
6.1.2.3
Neutropenia.................................................................................................................................28
6.1.2.4
Thrombocytopenia.......................................................................................................................28
6.1.2.5
Hemorrhage ................................................................................................................................28
6.1.2.6
Peripheral neuropathies ..............................................................................................................28
6.1.2.7
Second Primary Malignancy .......................................................................................................28
6.2.
Deaths in Part 2..............................................................................................................................29
6.3.
Vital Signs.......................................................................................................................................29
6.4.
Clinical Laboratory Tests ................................................................................................................29
6.5.
Other Safety Parameters................................................................................................................29
6.5.1.
ECOG Performance Status.........................................................................................................29
7.
PHARMACOKINETICS/IMMUNOGENICITY/PHARMACODYNAMICS...........................................29
7.1.1.
Sampling Timepoints...................................................................................................................29
7.1.2.
Analysis Methods ........................................................................................................................30


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8.
BIOMARKER .....................................................................................................................................30
8.1.
Minimal Residual Disease (MRD)...................................................................................................30
8.1.1.
Sampling Timepoints...................................................................................................................30
8.1.2.
Analysis Methods ........................................................................................................................30
9.
PATIENT REPORTED OUTCOMES (PRO)......................................................................................30
9.1.1.
PRO Instruments.........................................................................................................................31
9.1.2.
Analysis Methods ........................................................................................................................31
REFERENCES ............................................................................................................................................33
ATTACHMENT 1:
PD AND RESPONSE ALGORITHM..........................................................................34
LIST OF IN-TEXT TABLES
Table 1:
Part 2 (Maintenance Phase) Stratification Factors......................................................................9
Table 2:
Subgroup Analyses for Efficacy and Safety Endpoints.............................................................11
Table 3:
PFS from 2nd Randomization Event and Censoring Method.....................................................18
Table 4:
PFS2 from 2nd Randomization Event and Censoring Method...................................................23
LIST OF IN-TEXT FIGURES
Figure 1:
Schematic Overview of the Study ...............................................................................................8


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Status: Approved,  Date: 16 September 2020
ABBREVIATIONS
AE
Adverse event
ALB
Albumin
ALKY
Alkylating agent
ASCT
Autologous stem cell transplant
B2MG
Beta2 microglobulin
CI
Confidence interval
CMH
Cochran-Mantel-Haenszel
CR
Complete response
DOR
Duration of response
DPS
Data presentation specifications
ECOG
European cooperative oncology group
EORTC
European Organization for Research and Treatment of Cancer
EQ-5D-5L
EuroQol Five Dimension Questionnaire
eCRF
Electronic case report form
GHS
Global health status
FLC
HEMAR
Free light chain
Health Economics/Market Access/Reimbursement
HRQoL
Health-related quality of life
ICH
International Conference on Harmonization
IMiD
Immunomodulatory drug
IMWG
International multiple myeloma working group
IRR
Infusion related reaction
ISS
International staging system
ITT
Intent-to-Treat
IWRS
Interactive web response system
LLN
Lower limit normal
MedDRA
Medical Dictionary for Regulatory Activities
MM
Multiple myeloma
MRD
Minimal residual disease
NCI CTC
National cancer institute common terminology criteria
NE
Not evaluable
ORR
Overall response rate
OS
Overall survival
PD
Progressive disease
PFS
Progression free survival
PI
Proteasome inhibitor
PR
Partial response
PRO
Patient reported outcome
PT
Preferred term
SAE
Serious adverse event
SAP
Statistical Analysis Plan
sCR
Stringent complete response
SD
Stable disease
SOC
System organ class
TEAE
Treatment-emergent adverse event
TTP
Time to disease progression
TTR
Time to response
ULN
Upper limit normal
VAS
Visual analog scale
VGPR 
Very good partial response
VTd
VELCADE (bortezomib) + thalidomide + dexamethasone 


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1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of the analysis set(s), derived variables and 
statistical methods for the primary analyses pertaining to Part 2 specified in the protocol 
54767414MMY3006.
Part 2 is defined as the study where subjects with at least a partial response by IMWG criteria after 
induction/ASCT/consolidation (Part1) are randomized to enter the Maintenance Phase:

Arm A: Observation only until documented disease progression (or a maximum of 2 years)

Arm B: Daratumumab monotherapy until documented disease progression (limited to 2 years maximum 
treatment duration)
1.1.
Trial Objectives
Primary Objective
The primary objective in Part 2 is to determine if the use of daratumumab as single agent in 
maintenance compared to observation only will increase progression-free survival (PFS) when used 
after autologous stem cell transplant and consolidation therapy.
Secondary Objectives
Major secondary efficacy objectives in Part 2 of the trial are:

Time to progression (TTP) from second randomization

Complete response (CR) or better rate

Stringent complete response (sCR) rate 

Rate of improved response

Minimal residual disease (MRD) negative CR or better rate

Minimal residual disease (MRD) negative rate

Rate of MRD negative CR or better conversion rate

Rate of MRD negative conversion

Progression-free survival after next line of therapy (PFS2) from second randomization

Overall survival (OS) from second randomization
Other secondary objectives are:

To evaluate health-related quality of life (HRQoL) and health economic/resource utilization

To assess immunogenicity of daratumumab

To assess safety and tolerability of daratumumab


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Exploratory Objectives
The exploratory objective of the study is to evaluate daratumumab’s impact on response and 
resistance to treatment. 
1.2.
Trial Design
This is a randomized, open-label, active control, parallel group, multicenter, Phase 3 study in subjects 
with previously untreated multiple myeloma. Out of 1080 subjects randomized in Part 1 
(Induction Phase) of the trial, approximately 800 subjects (400/arm) were supposed to be randomized 
in Part 2 (Maintenance Phase). The actual accrual into the Induction phase was 1085 subjects and is 
886 subjects in the Maintenance phase.
The Treatment Phase in Part 2 is described below and will extend from the second randomization 
after completion of consolidation treatment and determination of response (partial response [PR] or 
better) at approximately Day 100 after autologous stem cell transplant (ASCT) until the documented 
progressive disease (PD) or 2 years of maintenance therapy/observation, whichever occurs first. The 
Follow-up Phase will extend from treatment discontinuation or completion of observation period,
until death, loss to follow-up, withdrawal of consent, or study end, whichever occurs first.
Part 2: Maintenance Phase (1:1 Second randomization of subjects achieving at least a PR 
after consolidation)
After completion of consolidation and determination of response at approximately Day 100 after 
ASCT, subjects with at least a PR will be randomized to Arm A and Arm B in 1:1 manner. Subjects
will then enter the Maintenance Phase. Subjects who have not achieved at least a PR after the 
completion of consolidation treatment and therefore are not second randomized to Part2 will enter 
the Follow-up Phase for Part 1 and will be followed until disease progression or death, even if they 
receive subsequent treatment.

Arm A: Observation only until documented disease progression Arm B: Daratumumab monotherapy
(16 mg/kg once every 8 weeks) until documented disease progression (limited to 2 years maximum 
treatment duration). 
A schematic overview of the study is provided in Figure 1 below.


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Figure 1:
Schematic Overview of the Study
Response will be assessed approximately 100 days after ASCT and eligibility for the second 
randomization will be determined. Subjects will be stratified at the second randomization by type of 
induction treatment (VTd or VTd + daratumumab) and by depth of response to induction / ASCT /
consolidation therapy (as determined by MRD status and post-consolidation response, see table 1). 
Assessment of tumor response and disease progression will be conducted in accordance with the 
International Myeloma Working Group (IMWG) response criteria. An assessment of MRD will be 
conducted using next-generation sequencing and next generation flow cytometry on bone marrow 
aspirate from the subjects who achieve at least VGPR in maintenance phase. 
Safety evaluations will include adverse event monitoring, physical examinations, clinical laboratory 
parameters (hematology and chemistry), vital sign measurements, and Eastern Cooperative Oncology 
Group (ECOG) performance status. 
The primary analysis for Part 2, i.e. PFS, will be performed when approximately 390 PFS events have 
been observed among subjects randomized to Maintenance phase after the second randomization. In 
addition, an interim analysis is planned for Part 2 after approximately 273 (70%) PFS events are 
observed in the population of subjects who are second randomized to Maintenance phase.  After the 


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interim analysis, IDMC will make recommendations regarding the continuation of the study. The 
details will be provided in a separate IDMC charter.
A final data cutoff will occur at the end of study, when approximately 350 subjects have died, or 
approximately 5 years after the last subject is randomized in Part 2 to the Maintenance phase, 
whichever comes first. Investigators will be informed when the cutoffs are to occur. 
1.3.
Statistical Hypotheses for Trial Objectives
The statistical hypothesis in Part 2 of the trial is that daratumumab maintenance after ASCT prolongs 
PFS compared with observation.
1.4.
Sample Size Justification
For Part 2 (maintenance phase), it is assumed that median PFS from the second randomization is 
45 months for observation, and daratumumab maintenance will decrease the risk of progression or 
death by 25% (HR=0.75; estimated median PFS of 60 months for daratumumab maintenance). To 
achieve 80% power with a significance level of 0.05, 390 PFS events are needed. 
1.5.
Randomization and Blinding
Permuted block randomization will be implemented in this study.
At the second randomization, subjects will be stratified by type of induction treatment and by depth of 
response to induction/consolidation therapy (as determined by MRD status and post-consolidation 
response). The stratification factors for the second randomization are presented in Table 1. This is an 
open-label study. Subjects and sites will not be blinded to treatment assignment.
Table 1:
Part 2 (Maintenance Phase) Stratification Factors
Randomized to VTd arm in the induction/ASCT/consolidation phase
MRD* Status
IMWG Response
sCR
CR
VGPR
PR
Negative
Stratum 1
Stratum 1
Stratum 1
NA**
Positive
Stratum 2
Stratum 3
Stratum 3
Stratum 4
Randomized to VTd+dara arm in the induction/ASCT/consolidation phase
MRD* Status
IMWG Response
sCR
CR
VGPR
PR
Negative
Stratum 5
Stratum 5
Stratum 5
NA**
Positive
Stratum 6
Stratum 7
Stratum 7
Stratum 8
CR=complete response; IMWG=International Myeloma Working Group; MRD=minimum residual 
disease; PR=partial response; sCR=stringent complete response; VGPR=very good partial response
* MRD by Flow at 10-4 as a stratification factor recorded in the CRF.
** Six subjects were observed to be MRD negative with IMWG response of PR at Day 100 post-ASCT. 
These subjects were mapped to Stratum 4 or Stratum 8 due to the lack of specific stratum defined in the 
protocol for such subjects.


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2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Visit Windows
Analysis time points for Part 2 will be based on treatment phase (maintenance) and administrations 
instead of visits. 
Maintenance phase (8 weeks per administration):
The start date of the maintenance phase is the 2nd randomization date, and the end date of the 
maintenance phase is the start date of the follow-up phase - 1 day (if not available, use the 
maximum date defined in section 2.6.). 
Pre-maintenance baseline value:
For subjects who are randomized in the maintenance phase, the last non-missing observation on or 
before the date of second randomization or Week 1 visit date, whichever is later.
End of treatment (EOT):
a.
For subjects treated with Daratumumab maintenance treatment, within 30 days after 
the last dose of Daratumumab treatment has been discontinued or completed. 
b. For subjects assigned to observation maintenance arm, within 30 days after the last 
observation visit or as soon as possible before the start of subsequent therapy.  
Follow-up phase:
The follow-up phase will begin once a subject discontinues treatment with study medications, 
except for subjects randomized to Arm A (observation) in the maintenance phase. These subjects 
will enter the follow-up phase after end of treatment visit date in the maintenance phase, disease 
progression, start of new anticancer therapy, or end of maintenance phase due to any reasons, 
whichever is earliest.  
Relative day:
Assessments will be presented chronologically by administration day, study day, which are defined 
as the follows:
administration Day = assessment date – start date of the administration + 1
Study Day in the maintenance phase = assessment date – start date of the maintenance phase + 1.
2.2.
Pooling Algorithm for Analysis Centers
Data from all study centers will be pooled for analyses. 
2.3.
Analysis Sets
The following analysis sets are defined. 
ITT
o
Maintenance-specific Intent-to-treat (ITT-m) analysis set: includes all subjects 
randomized in the second randomization. Analyses for Part 2 maintenance comparison of 
demographics, baseline characteristics, baseline lab, and primary and secondary efficacy 
endpoints will be primarily analyzed based on this population.


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Safety
o
Maintenance-specific Safety (Safety-m) analysis set: includes all subjects randomized to 
Arm B (daratumumab) in the second randomization and have received at least 1 
administration of daratumumab and all subjects randomized to Arm A (observation) in the 
second randomization. This population will be used for all safety analyses for Part 2.
Immune response-evaluable
o
Maintenance-specific immune response-evaluable analysis set: includes all subjects 
who received at least 1 administration of daratumumab in either Part 1 or Part 2 
(maintenance phase) and had at least 1 immunogenicity sample obtained during Part 2 after 
the first administration.
Pharmacokinetic (PK)
o
Maintenance-specific PK-evaluable analysis set: includes all subjects who received at 
least 1 administration of daratumumab either in Part 1 or Part 2 (maintenance phase) and 
had at least 1 pharmacokinetic sample obtained during Part 2 after the first administration.
2.4.
Definition of Subgroups 
Subgroup analysis will be performed for the subgroups specified in Table 2.
Table 2:
Subgroup Analyses for Efficacy and Safety Endpoints
Subgroup
Definition
Analysis Type
Sex
Male, Female
E, S
Age
<50, 50-60, >60 
E, S
Site
IFM, Hovon
E, S
ISS staging 
I, II, and III
E 
Cytogenetics
high risk vs. standard risk 
E
Pre-maintenance baseline renal 
function (CrCl)
E: >90 mL/min; ≤90 mL/min; 
S:  ≤90, >90 mL/min
E, S
Pre-maintenance baseline renal 
function (CrCl) with adjustment for 
overweight subjects (BMI>30kg/m2)
≤90, >90 mL/min
S
Type of MM
IgG, Non-IgG 
E
Pre-maintenance baseline ECOG 
performance score
0, ≥1
E
Induction/ASCT/Consolidation 
treatment group
VTd, DVTd
E
MRD (Stratification factor)
MRD positive, MRD negative 
E
Response (Stratification factor)
VGPR or better vs PR
E
E: efficacy (PFS, Overall CR or better rate, Overall MRD negative rate); S: TEAE
Note: Age will be calculated based on the second randomization date and date of birth of the subject.
Subgroups that are not specified as pre-maintenance baseline will be based on the pre-induction baseline results.


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2.5.
Imputation of Missing Data
Unless specified otherwise, no data imputation will be applied for missing safety evaluations, and all 
available data for all subjects will be presented. For analysis and reporting purpose, missing/partial 
dates in medical history (date of initial MM diagnosis), adverse event (AE onset date; AE end date), 
concomitant therapies (start date; end date), and subsequent anti-cancer therapies (start date) will be 
imputed. 
2.5.1.
Adverse Event Start and End Date
Adverse Event Start Date
If the onset date of an adverse event is completely or partially missing, the following imputation rules 
will be used.

When month and year are presented and the day is missing:
o
If the onset month and year are the same as the month and year of second randomization
date, the day of second randomization date or the day-component of the AE end date 
(possibly imputed) is imputed, whichever is earlier; 
o
If the onset month and year are not the same as the month and year of second 
randomization date, the first day of the month is imputed.

When only a year of the onset date is present:
o
If the onset year is the same as the year of second randomization date:

If AE end date is available and is prior to second randomization date, the day and 
month of AE end date are imputed;

Otherwise, the day and month of second randomization date are imputed. 
o
If the onset year is different from the year of second randomization date, the 1st of January 
is imputed.

If the onset date is completely missing, the second randomization date is imputed as the onset 
date.
No imputation will be done for partial or missing AE onset time.


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Adverse Event End Date
If the end date of an adverse event is completely or partially missing, the following imputation rules 
will be used.

If month and year are present and the day of the month is missing, the last day of the month is 
imputed. 

If only a year is present, the 31st of December is used. 
After the imputation, if the imputed date is later than the date of death (if available) after imputation, 
the date of death will be used as the imputed date.
No imputation will be done for partial or missing AE end time.
2.5.2.
Concomitant Medication/Therapy Start and End Date
For concomitant medications/therapy, if the start or end date is completely missing, no imputation 
will be performed. If the start or end date is partially missing, the following imputation rules will be 
used. 

If only the day is missing, the 15th day of the month will be used. 

If both the day and month are missing, the 30th of June will be used.
If the medication/therapy was taken after second randomization, and the imputed start date is prior to 
second randomization date, further adjust the imputed start date as second randomization date. Also 
adjust the imputed medication/therapy end date so that it is on or after second randomization date.
2.5.3.
Subsequent Anti-cancer Therapy Start Date
If the start date of subsequent anti-cancer therapy is completely missing or the month is missing, no 
imputation will be performed. If only the day of subsequent therapy start date is missing, the 
following imputation rules will be applied:

If the month and year of the start date are the same as the month and year of the last dosing date
(for observational arm, end of treatment date in disposition or 2 years after second randomization
if end of treatment date in disposition is not available), the day of last dosing date or the 
day-component of the stop date of subsequent anti-cancer therapy will be imputed, whichever is 
earlier. 

If the month and year of the start date are not the same as the month and year of last dosing date
(for observational arm, end of treatment date in disposition or 2 years after second randomization
if end of treatment date in disposition is not available), the first day of the month will be imputed.


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2.6.
Other General Definitions
2.6.1.
Treatment Arms
Treatment arms for Part 2
maintenance phase are: Observation vs. Daratumumab. 
Induction-maintenance arms are: VTd-Observation, VTd-Daratumumab, DVTd-Observation, 
DVTd-Daratumumab.
2.6.2.
International Staging System (ISS) Staging
ISS stage is based on the combination of serum β2-microglobulin (B2MG) and serum albumin 
(ALB) at baseline for the induction phase.

Stage I: B2MG <3.5 mg/L and ALB ≥3.5 g/dL (≥35 g/L) 

Stage III: B2MG ≥5.5 mg/L

Stage II: neither I nor III
2.6.3.
Month and Year
One year equals to 365.25 days. One month equals to 365.25/12 days.
2.6.4.
Maximum Date
Maximum date is same as overall survival date.
2.6.5.
End of Follow-up and Duration of Follow-up
The end of follow-up is defined as the maximum date.
Duration of follow-up since second randomization (in months) equals the end of follow-up minus the 
second randomization date plus 1, divided by 365.25/12.
2.6.6.
Relationship of Adverse Events to Study Medication
For each adverse event, its relationship to study medication is determined by investigator and 
recorded on the eCRF. An adverse event is considered as related to study medication if the 
relationship is possible, probable or very likely.
2.6.7.
General Analysis Specifications
Categorical variables are to be summarized using frequency counts and percentages. Continuous 
variables are to be summarized by the following descriptive statistics: mean, standard deviation, 
median and range (minimum and maximum). 


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3.
INTERIM ANALYSIS 
The primary objective of Part 2 of the study is to evaluate the 2 maintenance arms with response for 
PFS, which will be performed when approximately 390 PFS events have been observed in the 
population of subjects who are second randomized in the maintenance phase. 
An interim analysis is planned for Part 2 of the study after 273 (70%) PFS events are observed in the 
population of subjects who are second randomized. The significance level at this interim analysis will 
be determined based on the observed number of PFS events at the time of the analysis, using the 
O’Brien-Fleming boundaries as implemented by the Lan-DeMets alpha spending method. If 273 PFS 
events are observed, the alpha to be spent in this interim analysis will be 0.0147 (2-sided) and will be 
0.0455 (2-sided) for the final analyses.
4.
SUBJECT INFORMATION
4.1.
Demographics and Baseline Characteristics
Demographics: age (continuous), age category (< 50 years, 50-60, and > 60 years), sex (male, female), 
height (cm), weight (kg) and ECOG performance status (0, >=1) at the pre-maintenance baseline will 
be summarized by induction-maintenance arms for ITT-m subjects.
Baseline disease characteristics such as, type of myeloma (heavy chain, light chain, biclonal),  type 
of measurable disease, free light chain (ratio K/L, dFLC), ISS staging (I, II, III), cytogenetics profile, 
time since initial diagnosis (months), serum M-protein, urine M-protein, number of lytic bone lesions 
(None, 1-3, 4-6, more than 7), plasmacytoma (Yes, No) presence of diffuse myeloma-related 
osteopenia (Yes, No), presence of evaluable bone marrow assessment (Yes, No), bone marrow % 
plasma cells (<10, 10 – ≤ 30, > 30), bone marrow cellularity (hypocellular, normocellular, moderately 
cellular, severely acellular, indeterminate) at the baseline of the first randomization will be 
summarized by induction-maintenance treatment arms for the ITT-m subjects. 
A summary for depth of response, including MRD status assessed by NGS method at pre-maintenance 
baseline will be summarized by induction-maintenance treatment arms.
A summary of hematology and chemistry laboratory values at pre-maintenance baseline will be 
provided.
General medical history will be summarized by body system and condition status as reported on eCRF 
for ITT-m subjects by maintenance treatment arms.
4.2.
Disposition Information
For Part 2, the number of subjects who completed, discontinued the maintenance treatment phase will 
be summarized for ITT-m analysis set by maintenance arms. The number of subjects that are 
randomized to daratumumab maintenance arm but were not treated along with the reasons will be 
presented. Subjects who discontinued the study along with the reasons reported for the 
discontinuation on the eCRF will also be summarized.


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4.3.
Treatment Compliance
Refer to Section 4.4.
4.4.
Extent of Exposure
Extent of exposure to daratumumab during the maintenance phase will be summarized and presented
by the induction-maintenance treatment arms based on the maintenance-specific safety analysis set
for the subjects that are randomized to Arm B (daratumumab). 
The number of daratumumab administrations (continuous and categorical variables) will be 
summarized. For subjects randomized to daratumumab maintenance arm, duration of study treatment
during the maintenance phase will be calculated as the number of days from the date of the first
administration of daratumumab during the maintenance phase to the date of the last administration of 
daratumumab. For subjects randomized to the observation maintenance arm, duration of study 
treatment will be calculated as the number of days from the date of second randomization to the end 
of treatment date.  Duration of study treatment will be summarized descriptively.
The total dose administered for daratumumab (mg/kg) will be summarized by descriptive statistics. 
The dose intensity, which is defined as the sum of total dose administered divided by the number of
treatment administrations, will be calculated for daratumumab and summarized by descriptive 
statistics. Relative dose intensity (%) is the ratio of total dose received and total planned dose, where 
total planned dose will be calculated as the planned dose level times the number of administrations.
Descriptive summary statistics will be presented for relative dose intensity.
4.5.
Protocol Deviations
The incidence of major protocol deviation during the maintenance phase of the study, together with 
the corresponding deviation terms will be summarized by maintenance treatment arms for the ITT-m
subjects. A listing of all major protocol deviations during the maintenance phase will be provided. In 
case COVID-19 pandemic leads to major protocol deviations those will be flagged as such.
4.6.
Concomitant Medications
Concomitant medications collected o n the CRF page during the maintenance phase of the study
will be summarized by
therapeutic class, pharmacologic class, and drug name for each
maintenance treatment arm. A similar summary will be provided for subjects randomized to Arm 
B (daratumumab) who received growth factor support, pre-infusion medication and post-infusion 
medication, respectively. Additionally, prophylactic antiviral medication use will be tabulated.
4.7.
Subsequent Anticancer Therapies in Part 2
Subsequent anticancer therapies during the maintenance phase will be tabulated by therapeutic class,
pharmacologic class, and drug name within each maintenance treatment arm for the ITT-m subjects.


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5.
EFFICACY
A validated computerized algorithm, which is based on the IMWG response criteria (Durie 2006, 
Rajkumar 2011), which has been used and validated by an independent review committee in study 
MMY2002, will be utilized to determine response and disease progression for each subject. As a
sensitivity analysis, investigator assessments of response and disease progression per the IMWG 
response criteria will also be performed.
5.1.
Analysis Specifications
5.1.1.
Level of Significance
All statistical hypothesis tests and 95% confidence interval presented will be 2-sided. The primary 
hypothesis will be tested at the 0.05 significance level (overall). The main purpose for Part 2 of the 
study is to evaluate the 2 maintenance arms with response for PFS, which will be performed when 
approximately 390 PFS events have been observed in the population of subjects who are second 
randomized in the maintenance phase. 
In Part 2, if the testing for the primary endpoint of PFS post-completion of maintenance therapy is
statistically significant, the following key secondary endpoints in Part 2 as given in the order below
will be sequentially tested. Each endpoint will be tested with an overall two-sided alpha of 0.05 by
utilizing a hierarchical testing approach as proposed by (Tang and Geller, 1999) that strongly
controls Type I error rate. The key secondary endpoints are ordered as follows:
1) TTP from second randomization
2) Overall CR or better rate 
3) Overall MRD negative CR or better rate
4) OS from second randomization
An interim analysis will be performed after 273 (70%) PFS events are observed in the ITT-m subjects. 
The significance level at this interim analysis will be determined based on the observed number of 
PFS events at the time of the analysis, using the O’Brien-Fleming boundaries as implemented by the 
Lan-DeMets alpha spending method. If 273 PFS events are observed, the alpha to be spent in this 
interim analysis will be 0.0147 (2-sided) and will be 0.0455 (2-sided) for the final analyses.
For OS, a modified linear alpha spending function will be used to determine the efficacy boundary. 
The alpha to be spent for OS at the time of interim efficacy analysis (i.e, 273 PFS events, which is 
70% of the total planned PFS events) is 0.0002 (2-sided). The final analysis of OS will occur when 
approximately 350 deaths have been recorded, or approximately 5 years after the last subject is second 
randomized to the Maintenance phase, whichever comes first. 
5.1.2.
Data Handling Rules
There is no imputation planned for missing efficacy endpoint values, except for missing MRD 
assessment results as such results will be considered as positive.


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5.2.
Primary Efficacy Endpoint in Part 2
The primary efficacy endpoint is the PFS.
5.2.1.
Definition
PFS is defined as the duration from the date of second randomization to progressive disease, 
according to the validated computerized algorithm based on the IMWG criteria, or death, whichever 
occurs first.
Determination of dates of PFS event from 2nd randomization and dates for censoring is summarized 
in Table 3 as follows.
Table 3:
PFS from 2nd Randomization Event and Censoring Method
Situation
Date of Progression or Censoring
Outcome
No post-second randomization disease
assessment
Second randomization
Censored
Disease progression
Earliest date that indicates disease 
progression
PFS event
Death in the absence of PD
Date of death
PFS event
Other (e.g., withdrawal of consent to study
participation, lost to follow-up, etc.)
Date of last disease assessment prior to
Other
Censored
5.2.2.
Analysis Methods
The primary comparison of the 2 randomized maintenance treatments (daratumumab maintenance 
and observation) will be made with respect to PFS from the second randomization using a stratified 
log-rank test in the ITT-m population. The Kaplan-Meier method will be used to estimate the 
distribution of PFS from the second randomization for each arm. The treatment effect (hazard ratio) 
and its 2-sided 95% confidence intervals will be estimated using a stratified Cox regression model 
with maintenance treatment as the sole explanatory variable. The stratification factors used in the 
analysis include type of induction treatment and depth of response to induction/consolidation therapy 
(Please refer to Table 1 for the stratification factors used for second randomization). 
In addition, the interaction between induction/consolidation and maintenance will be tested at a 
2-sided significance level of 0.05 by a stratified Cox regression model that includes the interaction 
term between maintenance treatment and induction/consolidation treatment. The stratification factor 
will only include the depth of response.
The comparison of the 2 randomized maintenance treatments will also be made with respect to PFS 
from the second randomization using a stratified log-rank test in the ITT-m analysis set separately by 
the induction treatment received (VTd or DVTd) by the subjects. The stratification factor will include 
the depth of response. The Kaplan-Meier method will be used to estimate the distribution of PFS from 


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the second randomization for each of the maintenance treatment arm and Kaplan-Meier plots will be 
created separately by the induction treatment received.
5.2.3.
Sensitivity and Supplementary Analysis
A sensitivity analysis of PFS from 2nd randomization based on investigator assessment of progressive 
disease as per the IMWG response criteria will be performed in a similar manner as described in
Section 5.2.2.
Another sensitivity analysis of PFS from 2nd randomization based on investigator assessment of PD 
as per the IMWG response criteria will be performed separately for each of the induction treatment 
received by the subjects.
Additionally, a sensitivity analysis of PFS from 2nd randomization by censoring data due to start of
subsequent anticancer therapy will be performed in a similar manner as described in Section 5.2.2.
Further, a sensitivity analysis of PFS derived from the algorithm by censoring for death or
progression after missing more than one evaluation will be performed in a similar
manner as
described in Section 5.2.2.
A supplementary analysis of PFS derived from the algorithm by censoring for death due to COVID-
19 for subjects, who have not developed a confirmed progressive disease, will be performed in a 
similar manner as described in Section 5.2.2.
A sensitivity analysis using unstratified log-rank test and unstratified Cox regression model will also 
be performed.
5.3.
Major Secondary Endpoints in Part 2
5.3.1.
Time to Progression from 2nd Randomization
5.3.1.1.
Definition
TTP from 2nd randomization is defined as the duration from the date of second randomization to
confirmed progressive disease, according to the validated computerized algorithm based on the
IMWG response criteria, or death due to progressive disease, whichever occurs first.
The censoring rules for TTP from second randomization will be similar to the ones applied for PFS 
from second randomization (please refer to Table 3), except that death not due to PD will be censored 
instead of considering that as an event for TTP. 
5.3.1.2.
Analysis Methods
TTP from 2nd randomization will be analyzed in a similar manner as PFS from 2nd randomization 
described in Section 5.2.2 based on the ITT-m population.


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Competing risk analysis will be performed for TTP as a sensitivity analysis by treating deaths not due 
to PD as competing events. The treatment effect (hazard ratio) and its 2-sided 95% confidence 
intervals will be estimated using a proportional sub-distribution hazards model with maintenance 
treatment as the sole explanatory variable. The stratification factors used in the analysis include type 
of induction treatment and depth of response to induction/consolidation therapy (Please refer to 
Table 1 for the stratification factors used for second randomization).
5.3.2.
Overall CR or better rate 
5.3.2.1.
Definition
All patients came to maintenance phase had PR or better at post-consolidation by investigator.  
Overall CR or better rate is defined as the percentage of ITT-m subjects who have achieved CR or 
better from post-consolidation onward per validated computerized algorithm based on the IMWG 
criteria. The response of CR or better must be achieved on or prior to the start of subsequent therapies.
Overall VGPR or better rate is defined as the percentage of ITT-m subjects who achieved the best 
response of VGPR or better from post-consolidation onward. The VGPR better status is assessed 
using the computerized algorithm based on the IMWG response criteria and must be achieved on or 
prior to start of subsequent therapies.
Further, additional analyses of overall CR or better rate at 1 year and 2 years will be conducted.  
Overall CR or better rate at 1 year (or 2 years) defines as the percentage of ITT-m subjects who 
achieved the best response of CR or better from post-consolidation onward to 1 year (or 2 years) after 
second randomization. The CR or better status is assessed using the computerized algorithm based 
on the IMWG response criteria and must be achieved on study treatment or on observation and on 
or prior to start of subsequent therapies with no progressive disease within 1 year (or 2 years) after 
second randomization.
5.3.2.2.
Analysis Methods
The comparison of the 2 randomized maintenance arms (observation vs. daratumumab) will be made 
with respect to CR or better rate using the stratified Cochran-Mantel-Haenszel (CMH) chi-square test 
in the ITT-m analysis set. A Mantel-Haenszel odds ratio, along with its 2-sided 95% confidence 
interval and the p-value from the CMH test will be reported. Stratification factors used in the analysis 
include the stratification factors used for the second randomization (Please refer to Table 1 for the 
stratification factors). 
CR or better rate at 1 year and 2 years will be analyzed in a similar manner to the analysis of overall 
CR or better rate as described above
5.3.3.
Overall MRD negative rate 
An assessment of MRD will be conducted using next generation flow cytometry (NGF) and next 
generation sequencing (NGS) on bone marrow aspirates for all subjects who achieve at least VGPR 
in maintenance phase. NGS will be performed on subjects with available sample with the clonoSEQ 


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MRD assay to detect malignant plasma cells and will be considered as the primary method of MRD 
assessment. The clonoSEQ assay and Euroflow based multiparametric flow cytometry assay both 
have a sensitivity of 1 cancer cell in the background of 100,000 white blood cells (<10-5) or greater
and will both be utilized in this study to assess MRD.
5.3.3.1.
Definition
Overall MRD negative rate is defined as the proportion of subjects who have achieved negative MRD 
status from post-consolidation onward. The MRD negativity must be achieved on or prior to the start 
of subsequent therapies. For analysis purpose, subjects in the ITT-m population without MRD
assessment will be considered as having positive MRD.
Additionally, analyses of overall MRD negativity rate at 1 year and 2 years will be performed.  It is
defined
as
the proportion
of subjects
who have achieved negative MRD status from 
post-consolidation onward to 1 year (or 2 years) after second randomization. The MRD negativity 
must be achieved on study treatment or on observation and on or prior to the start of subsequent 
therapies and the last MRD assessment within 1 year (or 2 years) after second randomization has to 
be negative. For analysis purpose, subjects in the ITT-m population without MRD assessment will
be considered as having positive MRD
5.3.3.2.
Analysis Methods
The MRD negative rate by using threshold of < 10-5 will be analyzed like the analysis of CR or better
rate as described in Section 5.3.2.2. MRD by flow is used as the primary analysis, while MRD by 
next generation sequencing (NGS) is used as the sensitivity analysis.
Overall MRD negativity rate at 1 year and 2 years will be analyzed in a similar manner to the analysis 
of overall MRD negativity rate as described above.
A sensitivity analysis of MRD negative rate by using threshold of <10-6will be performed in a similar 
manner as described above.
5.3.4.
MRD Negative CR or Better Rate
5.3.4.1.
Definition
MRD negative CR or better rate is defined as the proportion of subjects who achieved negative MRD 
(at 10-5 threshold value) and CR or better response per validated computerized algorithm based on 
the IMWG criteria from post-consolidation onward. The MRD negativity and CR or better response 
must be achieved on or prior to the start of subsequent therapies. For analysis purpose, subjects in the 
ITT-m population without MRD assessment will be considered as having positive MRD.
Further MRD negative CR or better rate at 1 year (or 2 years) defines as the proportion of subjects 
who achieved negative MRD (at 10-5 threshold value) and CR or better response per validated 
computerized algorithm based on the IMWG criteria from post-consolidation onward to 1 year (or 2 
years) after second randomization. The MRD negativity and CR or better response must be achieved 


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on study treatment or on observation and on or prior to the start of subsequent therapies and patient 
should not have progression disease within 1 year (or 2 years) after second randomization. The last 
MRD assessment within 1 year (or 2 years) after second randomization has to be negative. For
analysis purpose, subjects in the ITT-m population without MRD assessment will be considered as
having positive MRD.
5.3.4.2.
Analysis Methods
The comparison of the MRD negative CR or better rate between the 2 randomized maintenance arms 
(observation vs. daratumumab) will be made using the stratified CMH chi-square test in the ITT-m
analysis set. A Mantel-Haenszel odds ratio, along with its 2-sided 95% confidence interval and the 
p-value from the CMH test will be reported. Stratification factors used in the analysis include the 
stratification factors used for the second randomization (Please refer to Table 1 for the stratification 
factors). 
MRD negative CR or better rate at 1 year and 2 years will be analyzed in a similar manner to the 
analysis of MRD negative CR or better rate as described above.
5.3.5.
Progression-free Survival after next line of therapy (PFS2) from 2nd
Randomization
5.3.5.1.
Definition
Progression-free survival on next line of therapy (PFS2) from 2nd randomization is defined as:

The time from second randomization to the 2nd progression or death, whichever comes first.
The 2nd disease progression will be based on investigator judgment.

Any deaths are considered as PFS2 events. 

Subjects, who are alive and with no disease progression, will be censored at the last disease 
assessment. 

Subjects without any post-second randomization follow-up will be censored at the date of second 
randomization.

Otherwise, subject will be censored at the minimum of last disease assessment and last date of 
follow-up.
Determination of dates of PFS2 from 2nd randomization event and dates for censoring is summarized
in Table 4 as follows.


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Table 4:
PFS2 from 2nd Randomization Event and Censoring Method
Situation
Date of Progression or Censoring
Outcome
No post-second randomization 
disease assessment 
Second randomization
Censored
Alive and no disease progression
Date of last disease assessment 
Censored
Two disease progressions from two 
different lines of treatments or death 
Minimum of earliest date that indicates 
the 2nd progression and date of death
PFS2 event
Other
Minimum of last disease assessment and 
last date of follow-up
Censored
5.3.5.2.
Analysis Methods
PFS2 from 2nd randomization will be analyzed for the ITT-m population. The analysis like PFS from 
2nd randomization described in Section 5.2.2 will be performed. If the number of PFS2 events is less 
than 80, non-stratified analyses will be used.
5.3.6.
Overall Survival (OS) from 2nd Randomization
5.3.6.1.
Definition
Overall survival from 2nd randomization is measured from the date of second randomization to the 
date of death due to any cause. Subjects who are lost to follow-up will be censored at the time of lost 
to follow-up. Subjects who are still alive at the clinical cut-off date for the analysis will be censored 
at the last known alive date. The date of last known alive will be determined by the maximum 
collection/assessment date among the selected data domains within the clinical database.
5.3.6.2.
Analysis Methods
OS from 2nd randomization will be analyzed for the ITT-m population. The analysis like PFS from 
2nd randomization described in Section 5.2.2 will be performed. If the number of deaths is less than 
80, non-stratified analyses will be used.
5.4.
Other Secondary Endpoints in Part 2
5.4.1.
Rate of Improved Response During Maintenance
5.4.1.1.
Definition
Rate of improved response during maintenance is defined as the proportion of subjects who have 
achieved a better category of response as per the validated computerized algorithm based on IMWG 
criteria during maintenance compared to the response status at the end of consolidation (up to the 
second randomization). This will be evaluated among the group of subjects who achieved the 
response of PR, VGPR, and CR at the second randomization. The response has to be assessed on or 
before the start of the subsequent therapy.


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5.4.1.2.
Analysis Methods
The rate of improved response will be analyzed for ITT-m subjects in a similar manner to the analysis 
of CR or better rate as described in Section 5.3.2.2. Improvement in responses by one, two, and three 
categories with further clarification on the specific response improvements will also be presented in 
the summary.
5.4.2.
Rate of MRD Negative Conversion During Maintenance
5.4.2.1.
Definition
The rate of MRD negative conversion during maintenance is defined as the percentage of subjects 
who achieved de novo MRD negative status during maintenance among subjects with MRD positive 
measurement at Day 100 post-ASCT.
Subjects with missing MRD measurement at day 100 
post-ASCT will not be included
5.4.2.2.
Analysis Methods
The rate of MRD negative conversion during maintenance will be analyzed in a similar manner to the 
analysis of CR or better rate as described in Section 5.3.2.2. 
5.4.3.
Rate of MRD Negative CR or Better Conversion During Maintenance
5.4.3.1.
Definition
The rate of MRD negative CR or better conversion during maintenance is defined as the percentage 
of subjects who achieved de novo MRD negative and CR or better status during maintenance among 
subjects with post-consolidation response status worse than CR or a positive MRD measurement at 
Day 100 post-ASCT. Subjects with missing MRD measurement at day 100 post-ASCT will not be 
included
5.4.3.2.
Analysis Methods
The rate of MRD negative CR or better conversion during maintenance will be analyzed in a similar 
manner to the analysis of CR or better rate as described in Section 5.3.2.2. 
5.5.
Time to Subsequent Antimyeloma Treatment
5.5.1.1.
Definition
Time to subsequent antimyeloma treatment is defined as the time from second randomization to the
start of subsequent antimyeloma treatment. Death due to PD without start of subsequent therapy
will be considered as event. Subjects who withdrew consent to study or are lost to follow-up or die
due to causes other than disease progression will be censored at the date of death or the last date
known to be alive.


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5.5.1.2.
Analysis Methods
The Kaplan-Meier method will be used to estimate the distribution of time to subsequent antimyeloma 
treatment for the ITT-m population. Median time to subsequent antimyeloma treatment with 95% CI 
will be tabulated. In addition, a Kaplan-Meier curve for time to subsequent antimyeloma treatment 
will be plotted. The hazards ratio and its 95% CI will be obtained through a stratified Cox’s regression 
model with maintenance treatment as the sole explanatory variable. Treatment comparison will be 
made via a stratified log-rank test. The stratification factors used in the analysis include type of 
induction treatment and depth of response to induction/consolidation therapy (Please refer to Table 1
for the stratification factors used for second randomization). 
5.6.
Subgroup Analysis of Efficacy Endpoints in Part 2
For assessment of internal consistency and investigation of homogeneity of the treatment effect across 
subgroups, a subgroup analysis of the primary and secondary endpoints of PFS, overall CR or better 
rate, and overall MRD negative rate on pre-specified subgroups defined in Section 2.4 will be 
conducted. Subgroup analyses will be performed if data warrants such investigation. 
Forest plots of subgroup analysis of the given endpoints will be generated.  
6.
SAFETY
Key safety analyses will be summarized by the induction-maintenance treatment arms
(VTd-Observation, VTd-Daratumumab, DVTd-Observation, and DVTd-Daratumumab) and total 
columns for observation and Dara maintenance for subjects in maintenance-specific safety analysis 
set in Part 2.
6.1.
Adverse Events in Part 2
Unless otherwise specified, treatment-emergent adverse events are defined as follows:
Arm A (observation): Any AE with onset date and time on or after the date of second randomization 
through the day prior to start of subsequent therapy or end of observation date +30 days in the 
maintenance phase, whichever is earlier.  Adverse events start before second randomization and 
ongoing at second randomization with an improvement or no change in toxicity will not be considered 
as a treatment-emergent adverse event in part 2. 
Arm B (daratumumab): Any AE with onset date and time on or after the date of second randomization
through 30 days after the last study agent administration; or the day prior to start of subsequent
therapy, whichever is earlier; or any AE that is considered Dara related on or after second 
randomization.  Adverse events start before second randomization and ongoing at second 
randomization with an improvement or no change in toxicity will not be considered as a 
treatment-emergent adverse event in part 2.
AEs will be monitored throughout the study. All AEs will be recorded in standard medical 
terminology and graded according to the National Cancer Institute Common Terminology Criteria 


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for Adverse Events (NCI-CTCAE), most recent version. For AE reporting, the verbatim term used in 
the eCRF by investigators to identify adverse events will be coded using the latest version of Medical 
Dictionary for Regulatory Activities (MedDRA) coding dictionary. Unless otherwise specified, at 
each level of subject summarization in reporting the incidence of the AE, a subject is counted once if 
one or more events were recorded.  
Treatment-emergent adverse events will be summarized for induction-maintenance treatment arms in 
Part 2. An overview of TEAEs reported through the maintenance phase will be provided for each 
treatment arm. The overview will include summaries of subjects with TEAEs, with TEAEs related to 
study treatment, with TEAEs of maximum toxicity grade of 1 to 5, SAEs, TEAEs leading to 
discontinuation of study treatment (Arm B only).
TEAEs leading to discontinuation of study treatment are summarized for subjects having 
discontinued the study treatment due to adverse event(s) on the end of treatment CRF page. A 
summary of number of subjects who discontinued study treatment because of 1 or more TEAEs by 
MedDRA system-organ class and preferred term will be provided. 
6.1.1.
Treatment Emergent Adverse Events
The following summaries will be provided for all TEAEs: 

An overview of TEAE  

An overview of TEAE by subgroups specified in Section 2.4
In addition, the following summaries will be generated: 

TEAEs by system organ class (SOC) and preferred term (PT)

Most common (at least 10%) TEAEs by SOC, PT

TEAEs by SOC, PT by subgroups specified in Section 2.4

TEAEs by SOC, PT, and relationship to study drug (Arm B only)

TEAEs by SOC, PT, and worst grade


Serious TEAEs by SOC and PT

Most common (at least 0.6%) serious TEAEs by SOC, PT

Serious TEAEs by SOC, PT by subgroups specified in Section 2.4


Grade 3/4 TEAEs by SOC and PT

Most common (at least 1%) Grade 3/4 TEAEs by SOC, PT

Grade 3/4 TEAEs by SOC, PT by subgroups specified in Section 2.4


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The following summaries of treatment modifications (only in Arm B) due to TEAEs will be provided: 

Administration delay due to TEAE by PT and grade 3/4.

Infusion skipping due to TEAE by PT and grade 3/4.

Infusion interruption due to TEAE by PT and grade 3/4.
In addition, the following summaries will be generated: 

Treatment discontinuation (Arm B only) due to TEAEs by PT and grade ≥ 3.

TEAEs with outcome of death by PT and relationship to study medication
6.1.2.
Adverse Events of Clinical Interest
The adverse events of clinical interest would focus on below items (detail would be defined on the 
DPS or below sections),

Infusion related reactions (IRR)

Infections
o
Infections and Infestations 
o
Opportunistic infections

Hemorrhage events

Interferences for blood typing

Neutropenia events

Thrombocytopenia events

Second primary malignancies (SPM)
6.1.2.1
Infusion-Related Reactions 
Subjects with any IRR associated with daratumumab administration will be summarized by
MedDRA system-organ class and preferred term. The summaries will be presented by all grades,
Grade 3, 4, and 5. In addition, the total number of subjects with IRR in more than 1 infusion will be
reported. Additionally, the timing of IRR associated with daratumumab administration will be
evaluated through a summary of IRR by event onset time. IRRs leading to infusion modifications 
during infusion will be summarized by system-organ class and preferred term. The summaries will 
be presented by induction treatment arms for the subjects treated with daratumumab maintenance.  A 
summary of infusion related reaction at first Daratumumab maintenance infusion by infusion volume
will also be provided.


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A
listing of subjects with Grade 3 or higher treatment-emergent infusion-related reactions
associated with daratumumab administration will be provided. In addition, subjects with treatment-
emergent infusion-related reactions resulting in discontinuation of daratumumab will be listed. 
6.1.2.2
Infections
6.1.2.2.1 Infections/Infestations
Infections and infestations refer to adverse events with SOC of infections and infestations. A 
summary of number of subjects with 1 or more toxicity Grade 3 or 4 treatment-emergent infections 
and infestations by MedDRA preferred term and relationship to treatment will be provided.
Additional summary analyses may include by onset time (i.e., ≤ 6 months vs. 6-≤ 12 months vs. 12+
months from the date of second randomization).
6.1.2.2.2 Opportunistic Infections
Opportunistic Infections refer to adverse events with PT which would be defined on the DPS. The 
summaries will be presented by for grades and Grade 3 or 4 for each induction-maintenance treatment 
arm.
6.1.2.3
Neutropenia
Neutropenia refers to adverse events with PT which would be defined on the DPS. The summaries 
will be presented for all grades and Grade 3 or 4 for each induction-maintenance treatment arm.
6.1.2.4
Thrombocytopenia
Thrombocytopenia refers to adverse events with PT which would be defined on the DPS. The
summaries will be presented for all grades and Grade 3 or 4 for each induction-maintenance 
treatment arm.
6.1.2.5
Hemorrhage
Hemorrhage will be defined by Standardized MedDRA Queries (SMQ) with the first subcategory 
SMQ of hemorrhage terms (exclude laboratory terms). The summaries will be presented for all 
grades and Grade 3 or 4 for each induction-maintenance treatment arm.
6.1.2.6
Peripheral neuropathies
Peripheral neuropathies (PNs) refer to adverse events with high level term (HLT) of peripheral 
neuropathies NEC. Incidences of PNs will be summarized by MedDRA high level term and preferred 
term. 
The
summaries will be presented
for
all grades and grade
3 or
4 for
each 
induction-maintenance treatment arm.
6.1.2.7
Second Primary Malignancy
SPM data is collected from both the AE form and the SPM form. A listing of second primary 
malignancy (SPM) will be provided.  Second primary malignancies will be clinically reviewed and 


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categorized as cutaneous/non-invasive, non-cutaneous/invasive or hematologic malignancies, which 
will be summarized accordingly.
6.2.
Deaths in Part 2
The total number of subjects who died during the maintenance phase will be tabulated by induction-
maintenance treatment arm. The number of subjects who died within 30 days of end of treatment
(Arm A) or within 30 days of last dose of study maintenance treatment (Arm B) will be summarized 
for the Part 2 maintenance-specific safety subjects. The primary cause of death collected on eCRF 
page will also be summarized. If the primary cause of death reported is AE, the number of subjects 
who died due to at least one reasonably study drug related AE will be further reported. 
A listing of subjects who died after second randomization during maintenance phase will be provided. 
6.3.
Vital Signs
Vital signs including temperature (oC), systolic and diastolic blood pressure (mmHg) and pulse (beats 
per minute [bpm]) values will be descriptively summarized (mean, standard deviation, median, 
minimum and maximum) at each scheduled time point by induction-maintenance treatment arms 
using maintenance-specific safety set.
6.4.
Clinical Laboratory Tests
Treatment-emergent worst toxicity grade (NCI-CTAE version 4.03) during maintenance treatment
phase, defined as the worst toxicity grade observed for any laboratory parameter assessed on or after 
the second randomization, will be tabulated for applicable laboratory parameters for maintenance-
specific safety subjects for Part 2. Descriptive statistics for values and changes from pre-maintenance 
baseline for these laboratory parameters will be provided. In addition, shifts from pre-maintenance 
baseline toxicity grade to worst toxicity grade during maintenance treatment phase will be generated. 
6.5.
Other Safety Parameters
6.5.1.
ECOG Performance Status
Frequencies of ECOG performance status (0, >=1) over time during the maintenance treatment phase 
will be summarized for maintenance-specific safety subjects for Part 2. In addition, shift from pre-
maintenance baseline to worst score during maintenance treatment phase will be provided. 
7.
PHARMACOKINETICS/IMMUNOGENICITY/PHARMACODYNAMICS
Samples to assess the generation of antibodies to daratumumab (immunogenicity) and concentration 
of daratumumab will be obtained from subjects according to the Time and Events Schedule in the 
protocol.
7.1.1.
Sampling Timepoints
For subjects receiving daratumumab treatment, the daratumumab immunogenicity and concentration 
data for Part 2 analysis will be collected at the pre-dose of Week 1 and Week 52 of maintenance 


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treatment, and 8 weeks post last dose of Daratumumab and will be summarized using descriptive 
statistics.
7.1.2.
Analysis Methods
The incidence
of anti-daratumumab antibodies
will be summarized by
daratumumab 
induction/consolidation and maintenance treatments among immune response-evaluable analysis set 
in the maintenance subjects.
Concentration of daratumumab in serum will be summarized by daratumumab induction/
consolidation and maintenance treatments using pharmacokinetic-evaluable analysis set in the 
maintenance subjects. The summary will be descriptive including the mean, SD, coefficient of 
variation, median, range and geometric mean, at each assessment visit during the maintenance phase.
8.
BIOMARKER
Biomarker studies are designed to identify markers predictive of response (or resistance) to 
daratumumab. Planned analyses are based on the availability of clinically valid assays and may be 
deferred if emerging study data show no likelihood of providing useful scientific information. Results 
of biomarker analyses may be presented in a separate report.
Blood samples will be drawn from all subjects to better understand the mechanism of action and
mechanism of resistance of daratumumab and summarized as applicable.
8.1.
Minimal Residual Disease (MRD)
An assessment of MRD will be conducted using NGS and multiparametric flow cytometry on bone 
marrow aspirates for all subjects who achieve at least VGPR in maintenance phase.
8.1.1.
Sampling Timepoints
In Part 2, bone marrow aspirates will be analyzed by EuroFlow based multiparametric flow cytometry 
assay and NGS for MRD on Week 25, 52 and 105.
8.1.2.
Analysis Methods
Details on MRD negativity rate analyses are described in Section 5.3.3.2. 
9.
PATIENT REPORTED OUTCOMES (PRO)
It is anticipated that daratumumab will provide benefits in terms of symptom reduction, improved 
functioning, and improved utilities. To measure functional status, well-being, and symptoms, the 
EORTC QLQ-C30 and the EQ-5D-5L instruments will be used. Both questionnaires will be 
completed at the timepoints outlined in the Time and Events Schedule given in the protocol before 
any other study procedures scheduled for the same day.


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9.1.1.
PRO Instruments
The EORTC QLQ-C30 includes 30 items resulting in 5 functional scales (physical, role, emotional, 
cognitive, and social), 1 Global Health Status (GHS) scale, 3 symptom scales (fatigue, 
nausea/vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, 
diarrhea, and financial difficulties). The instrument contains 28 items using a Likert scale with 4 
response options: “Not at All,” “A Little,” “Quite a Bit,” and “Very Much” (scored 1 to 4). Two 
additional items use response options (1 to 7): 1 = Very Poor, to 7 = Excellent. All scale and item 
scores will be linearly transformed to be in the range from 0 to 100 according to the algorithm in 
EORTC QLQ-C30 scoring manual, version 3.0 (Fayers et al, 2001). A higher score represents a 
higher ("better") HRQoL, higher (“better”) level of functioning, or a higher ("worse") level of 
symptoms.
The EQ-5D-5L is a 5-item questionnaire that assesses 5 domains including mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression plus a visual analog scale (VAS) rating “health 
today” with anchors ranging from 0 (worst imaginable health state) to 100 (best imaginable health 
state). The scores for the 5 dimensions are used to compute a single utility score ranging from 0 to 1 
representing the general health status of the individual (but scoring by the UK algorithm allows for 
value less than 0).
The PRO includes the following:

Summary Scores
o
EORTC-QLQ-C30 functional scales (physical, role, emotional, cognitive, social), 
global health status (GHS) scale, symptom scales (pain, fatigue, nausea/vomiting)
o
EQ-5D-5L utility score

Single Item Scores
o
EORTC QLQ-C30 single symptom items 
o
EQ-5D-5L visual analog scale (VAS) 
9.1.2.
Analysis Methods
Compliance rates for completion of EORTC QLQ-C30 and EQ-5D-5L at each time point during the 
maintenance phase will be generated based on the actual number of subjects received PRO 
assessments over the number of expected.
EORTC QLQ-C30 domain scores (functional scales, GHS, symptom scales), and single symptom 
items will be descriptively summarized at each time point for ITT-m analysis set by maintenance 
treatment arms. Descriptive statistics will also be provided for change from pre-maintenance baseline 
in GHS score by the MRD negativity status.
EQ-5D-5L utility score and VAS will be descriptively summarized at each time point for ITT-m 
analysis set by maintenance treatment arms.


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A repeated measures mixed effects model analysis will be conducted estimating change from baseline 
(pre-maintenance) at each time point between two maintenance arms. ITT-m subjects who have a 
baseline value, last PRO assessment before second randomization, and at least one value from the 
maintenance phase are included in the analysis. Change from baseline will be fitted to a mixed effects 
model including subjects as a random effect, and baseline value, treatment group, time in month, 
treatment-by-time interaction, and stratification factors as fixed effects.
A distribution-based method will be used to define improvement/worsening in scores, i.e.,
half SD away from the mean score at baseline (pre-maintenance) combining both treatment groups.
Time to improvement will be summarized by using descriptive statistics such as mean, standard 
deviation (SD), median and range. Time to worsening will be estimated using Kaplan-Meier methods. 
The hazard ratio for Daratumumab relative to observation group and its associated 95% confidence 
interval (CI) will be calculated based on the stratified Cox proportional hazards model by the 
stratification factor at second randomization. Death due to disease progression will be considered as 
worsening. Subjects who have not met the definition of worsening will be censored at the last PRO 
assessment. Subjects without pre-maintenance baseline assessment or post pre-maintenance baseline 
assessment will be censored at date of second randomization.


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REFERENCES
Rajkumar SV, Harousseau J-L, Durie B, et al. Consensus recommendations for the uniform reporting of clinical trials: 
report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011; 4691-4695.
Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia 
2006; 20:1467–1473. Corrigenda/Erratum in: Leukemia. 2007; 21: 1134-1135.
Tang DI, Geller NL. Closed testing procedures for group sequential clinical trials with multiple endpoints. Biometrics. 
1999;55(4):1188-1192


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ATTACHMENT 1:
PD AND RESPONSE ALGORITHM
PD and Response Algorithm
54767414MMY3006
The issues addressed by the program are: 
1. Whether or not the disease progressed and date* of progression 
2. The date* of censoring for subjects whose disease never progressed
3. Reason(s) for PD
4. The date* and category of best and first response
5. Duration of response
* Day post-randomization for randomized subjects.  
1
Determination of PD and Relapse from CR
1.1
IMWG Criteria 
1.1.1 Progressive Disease
PD is to be used for calculation of time to disease progression and progression-free survival 
for all subjects including those experiencing CR.
PD is defined as satisfying any one of the criteria listed below. These are identical to the 
IMWG criteria as described in the protocol. Further explanations (noted in superscript) 
pertaining to particular PD criteria are provided in Section 1.2, Clarifications and 
Modifications. 
a.
Increase (1.2.2) of ≥25% in the level of serum M-protein and absolute increase (1.2.2)
must be ≥0.5 g/dL (5 g/L) (1.2.3; 1.2.4).
b. Increase (1.2.2, 1.2.18) of ≥25% in the 24-hour urinary light chain excretion (urine M-
protein) and absolute increase (1.2.2) must be ≥200 mg/24 hours (1.2.3).
c.
Only in subjects without measurable serum and urine M-protein levels:  increase 
(1.2.2) of ≥25% in the difference between involved and uninvolved FLC levels (1.2.20)
and absolute increase (1.2.2) must be >10 mg/dL (1.2.3).
d. Only in subjects without measurable serum and urine M-protein levels and without 
measurable disease by FLC levels: increase (1.2.2) of ≥25% in the level of bone 
marrow plasma cells percentage and absolute increase (1.2.2) must be ≥10% (1.2.3).
e.
Definite increase (1.2.8) in the size of existing bone lesions (1.2.9) or soft tissue 
plasmacytomas (1.2.9; 1.2.10).
f.
Definite development of new bone lesions (1.2.11) or soft tissue plasmacytomas (1.2.12, 
1.2.13).


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g. Development of hypercalcemia (1.2.14; 1.2.15; 1.2.16) (corrected serum calcium >2.875 
mmol/L or >11.5 mg/dL) that can be attributed solely to the PC proliferative 
disorder.
1.1.2 Relapse from CR 
Relapse from CR is to be used for calculation of disease-free survival for subjects 
experiencing CR.
Relapse from CR is defined as satisfying any one of the criteria listed below (a, b, or c). These 
are identical to the IMWG criteria as described in the protocols. Further explanations (noted 
in superscript) pertaining to particular relapse from CR criteria are provided in Section 1.2, 
Clarifications and Modifications. 
a.
Reappearance of serum or urinary M-protein by immunofixation or 
electrophoresis (1.2.3; 1.2.7).
b. Development of 5% plasma cells in the bone marrow.
c.
Appearance of any other sign of progression (i.e., new plasmacytomas, lytic bone 
lesion if the lesion is marked ‘relationship with the disease’, or hypercalcemia)
(1.2.11; 1.2.12; 1.2.13; 1.2.14; 1.2.15).
1.2
Clarifications and Modifications
In order to allow these rules to be applied consistently and to be programmed, the Sponsor 
has added certain clarifications and modifications for using the IMWG criteria. 
1.2.1
Measurable disease is defined in the protocol by at least one of the following 
measurement: (1) serum M-protein ≥ 1g/dL (≥ 10 g/L) or ≥ 0.5 g/dL (≥ 5 g/L) for subjects 
with IgA, IgD, IgE or IgM multiple myeloma; (2) urine M-protein ≥ 200 mg/24h; (3) serum 
FLC assay: involved FLC level ≥ 10 mg/dL (≥ 100 mg/L) provided serum FLC ratio is 
abnormal.
1.2.2
The reference point for calculating increase and % of increase for M-protein, FLC and 
bone marrow plasma cells will be the lowest response value and the “lowest response value” 
does not need to be a confirmed value. 
1.2.3
Requires 2 consecutive (i.e., no intermediate values that do not meet the definition of 
PD) assessments made at any time before the institution of any new therapy (i.e., subsequent 
anti-cancer therapy). If a subject has an unconfirmed PD followed by death due to PD within 
30 days of unconfirmed PD, or PD (the same parameter as of initial observed PD) observed 
within 4 weeks after start of subsequent anti-cancer therapy, the unconfirmed PD will be 
considered as PD.  
1.2.4
If nadir serum M-protein is ≥ 50g/L (≥5 g/dL), M-protein increases of ≥ 10g/L (1g/dL) 
is sufficient for progressive disease. It does not require meeting “increase of ≥ 25% in the 
level of serum M-protein”. 


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1.2.5
Any 2 consecutive increase of serum M-protein ≥5 g/L (≥0.5 g/dL) is consistent with 
progressive disease, assuming that increase of ≥25% is met or not applicable, even if the serum 
M-protein level is below measurable disease threshold.
1.2.6
The baseline value for assessing disease progression is the last pretreatment 
measurement (it applies to SPEP, UPEP, FLC, plasmacytomas and bone lesions except as
noticed in Section 1.2.10).  For example, if there is a screening value and a Cycle 1 Day 1 
value (prior to start of treatment) for M-protein, the program ignores the screening value and 
uses Cycle 1 Day 1 as the reference point for assessing PD for the first post-treatment results.
1.2.7
The program disregards serum M-protein and urine paraprotein measurements prior 
to Day 5 after dosing.  These tests are considered too soon after dosing to be regarded as 
legitimate on-treatment values. 
1.2.8
The program computes the date of progression as the earliest date of any of the tests 
listed in Section 1.1.1 (a, b, e, f or g for subjects with measurable serum or/and urine M-
protein; or a, b, c, e, f or g for subjects without measurable serum and urine M-protein) that 
indicate PD. Similarity, the program computes the date of relapse from CR as the earliest date 
of any of the tests listed in Section 1.1.2 (a, b, or c) that indicate relapse from CR. 
1.2.9
For PD due to bone lesions, the algorithm will rely on information collected on the 
eCRF regarding skeletal survey (i.e., increase in the size of lytic bone lesions or increase in 
the total number of lytic bone lesions if the lesion is marked ‘relationship with the disease’) 
and other radiology reports. At any time, study sites may report progressive disease based on 
an increase in the size or number of lytic bone lesions if the lesion is marked ‘relationship 
with the disease’.  The algorithm accepts this determination as definitive.
1.2.10 Plasmacytomas/bone lesions that are first reported during the first week on study are 
treated as baseline plasmacytomas/bone lesions. The rationale for this rule is that 
plasmacytomas/bone lesions take time to develop, so anything reported within 1 week of first 
dose almost certainly existed before the start of study drug.  In the case that no pre-treatment 
value for plasmacytomas/bone lesion is available, the first post-treatment value is used as 
baseline.  
1.2.11 For plasmacytomas, the Sponsor has defined “definite increase in size” as an increase 
of over 50% in the sum of the products of the two longest perpendicular diameters when 
available, using the smallest previous product as the reference point.
1.2.12 New post-baseline bone lesions are evidence of PD. If no baseline bone lesions are 
available, then any subsequent data that report a bone lesion will be considered as 
development of new bone lesions.
1.2.13 New post-baseline plasmacytomas are evidence of PD, even if the measurements are 
not available.  If no baseline plasmacytoma data are available, then any subsequent data that 


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report a plasmacytoma will be considered as a “new” plasmacytoma and will be considered 
as evidence of PD.
1.2.14 Hypercalcemia will be based on corrected calcium values as long as they are available 
(i.e., corrected calcium values are collected or serum calcium and albumin are collected).  If 
corrected calcium values are not available, free-ionized calcium values will be used if they 
are available.  Hypercalcemia based on free-ionized calcium will be defined as >1.5 mmol/L.
1.2.15 For subjects who have hypercalcemia at baseline, the program will never assess PD 
due to “development of hypercalcemia”.  A subject is considered to have hypercalcemia at 
baseline if he or she meets one of the following criteria:
a.
For subjects with corrected calcium values, any corrected calcium value >ULN 
which occurs on or before Day 4 (relative to first dose).
Note: if subject had central and local assessments done on the same day, the central 
record takes precedence.
b.
For subjects without corrected calcium values in all visits, but with free-
ionized calcium values on or before Day 4, any free-ionized calcium value 
>ULN which occurs on or before Day 4 (relative to first dose).  
1.2.16 For subjects with normal calcium at baseline, if the first PD criteria met is a post-
baseline hypercalcemic value, then the following programming algorithm will be applied:
a. The program will first search for evidence of progression in other parameters 
within the following 112 days. If PD is determined in other parameters within 
the following 112 days, then the subject is assessed as PD.  The date of PD is the 
date of the initial hypercalcemic value and hypercalcemia is indicated as the 
reason or one of the reasons for PD.   
b. If PD is not determined in other parameters within 112 days, the program will 
search for the next available corrected calcium/free-ionized calcium value.  If 
the second value also meets the criteria for hypercalcemia, the subject is assessed 
as PD.  The date of PD is the date of the initial hypercalcemic value and 
hypercalcemia is indicated as the reason or one of the reasons for PD.
c. If there is no more follow-up calcium value, then the subject is assessed as PD.
d. Any PD identified through a), b) or c) will be flagged and reviewed by clinical 
to ensure that hypercalcemia can be attributed solely to the plasma cell 
proliferative disorder. Hypercalcemia due to other reasons will not be considered 
as PD in the algorithm.
1.2.17 Descriptive (or non-numeric) results from bone marrow aspirate or bone marrow 
biopsy will be given a numeric interpretation based on the following conventions: 
a.
Percentage plasma cells reported as a range on the CRF page will be assigned the mean 
value (i.e., lower range plus upper range divide by 2) that will be analyzed by the 


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programming algorithm (e.g., an amount reported as 10-15% would be interpreted as 
12.5%).
b. Percent plasma cells reported as <x% will be interpreted as (x-1)% and percent plasma 
cells reported as >x% will be interpreted as x%.
c.
Other conventions include:
Reported as:
Interpreted as:
“Not significantly present”
4%
“Sheets of plasma cells not seen”
4%
1.2.18 Imputation of UPEP and SPEP values: If the serum immunofixation result is “Not 
Detected” and the SPEP value is missing or not done, then SPEP value is treated as 0.  If the 
urine immunofixation is “Not Detected” and the UPEP is missing or not done, then UPEP 
value is treated as 0.
1.2.19 a. Spurious UPEP values are not used in the determination.  Determination of a 
spurious value is as follows:  If at least 4 values exist in the neighborhood (+/- 178 days) of 
the value of interest, the mean and standard deviation of the values is computed (not including 
the value of interest in the calculation).  The value of interest is compared to the mean +/- 3 
standard deviations.  If the value < mean-3*standard deviation or the value > 
mean+3*standard deviation then the value is considered spurious.  The last two values 
available for a particular subject are never considered as spurious.  The baseline value for a 
subject is also never considered as spurious.
b. If the first PD criteria met is two consecutive UPEP values and subject has started 
subsequent anticancer therapy, this subject is assessed as PD and date of PD is the date of 
first UPEP assessment. Otherwise, if the first PD criteria met is two consecutive UPEP 
values and subject has not started subsequent anticancer therapy, then the following 
programming algorithm will be applied:
1) The program will first search for evidence of progression in other parameters 
within the following 178 days.  If PD is determined in other parameters within the 
following 178 days, then the subject is assessed as PD.  The date of PD is the date 
of the initial UPEP value.
2) If PD is not determined in other parameters within 178 days and no more UPEP 
values are available, then the subject is assessed as PD due to UPEP.
3)  Otherwise, the third UPEP value is considered.  If the third value meets the criteria 
for PD, the subject is assessed as PD due to UPEP.  If the third value does not meet 
the criteria for PD, but other parameters indicate PD within the next 178 days, the 
subject is assessed as PD due to UPEP at the time of the initial UPEP value.
4) Otherwise, the fourth UPEP value is considered.  If the fourth value meets the 
criteria for PD, the subject is assessed as PD due to UPEP.  If the fourth value does 
not meet the criteria for PD, the subject is not assessed as PD due to UPEP.  If no 
fourth UPEP value is available, the subject is not assessed as PD. 


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1.2.20 Difference between involved and uninvolved FLC level is defined as absolute value 
of kappa FLC level minus lambda FLC level in the serum.
1.2.21 Development of plasma cell leukemia is considered as disease progression. The date 
of PD is the date of event onset.


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2
Determination of Date of Censoring and Reason for PD
The date of last post-baseline efficacy measure is used as the censoring date for all subjects 
without progressive disease. Subjects that have no post-baseline efficacy data are censored at 
the date of randomization for randomized subjects.    
The reason(s) for PD is defined as the initial reason(s) that caused the program to indicate PD 
as well as any other criteria that were met by the time of confirmation of PD.  Indicator 
variables for each reason (SPEP, UPEP, FLC, bone marrow, bone lesion [increase in number, 
increase in size], extramedullary plasmacytoma [new extramedullary plasmacytoma, increase
in size], hypercalcemia and plasma cell leukemia) are created.
3
Determination of Response Category and Duration of Response
3.1
IMWG Criteria
According to IMWG criteria, response categories include complete response (CR), stringent 
complete response (sCR), very good partial response (VGPR), partial response (PR), stable 
disease (SD), and progressive disease (PD) (defined in Section 1).  Although minimal 
response (MR) is not officially a response category in the IMWG criteria, consensus 
recommendations state that for subjects with relapsed and /or refractory myeloma, MR should 
be reported separately in clinical trials. Categories of sCR, CR, VGPR, PR, and SD are 
determined using the IMWG criteria and MR adopted from the EBMT criteria for subjects 
with relapsed refractory myeloma as outlined below.
Further explanations (noted in superscript) pertaining to particular response criteria are 
provided in Section 3.2, Clarifications and Modifications.  The definition for duration of 
response is also covered in Section 3.2.18.
3.1.1
Definition of CR
Requires all of the following:
a.
Negative immunofixation of serum and urine (3.2.4; 3.2.5; 3.2.6; 3.2.19).
b. Disappearance of any soft tissue plasmacytomas.
c.
<5% plasma cells in the bone marrow (3.2.7).
3.1.2
Definition of sCR
Requires all of the following:
a.
CR as defined above.
b. Normal FLC ratio (3.2.5, 3.2.8).
c.
Absence of clonal bone marrow plasma cell (PCs)(3.2.21) by 2- to 4-color flow 
cytometry.
3.1.3
Definition of VGPR


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Requires any of the following:
a.
Serum and urine M-component detectable by immunofixation but not on 
electrophoresis (3.2.5; 3.2.11;3.2.12), or
b. ≥90% reduction (3.2.10) in serum M-protein plus urine M-protein <100 mg/24 hours 
(3.2.5; 3.2.11)
c.
If the serum and urine M-protein are not measurable, a reduction (3.2.10) of >90% 
in the difference between involved and uninvolved FLC levels (3.2.5; 3.2.13) is 
required.
d. In addition to the above criteria, if present at baseline, ≥50% reduction (3.2.10) in 
the size of soft tissue plasmacytomas is also required.
3.1.4
Definition of PR 
Requires all of the following:
a.
50% reduction (3.2.10) of serum M-protein (3.2.5) and reduction (3.2.10) in 24-hour 
urinary M-protein by 90% or to <200 mg/24 hours (3.2.5).
b. If the serum and urine M-protein are not measurable, a reduction (3.2.10) of ≥50% in 
the difference between involved and uninvolved FLC levels (3.2.5; 3.2.13) is required.
c.
In addition to the above criteria, if present at baseline, ≥50% reduction (3.2.10) in the 
size of soft tissue plasmacytomas is also required.
3.1.5
Definition of SD
Not meeting the criteria for sCR, CR, VGPR, PR, or PD.
3.2
Clarifications and Modifications
As was the case with PD, developing a program to assess response requires adding certain 
clarifications, minor modifications and additions to the IMWG criteria.
3.2.1
Only subjects with measurable disease at baseline are eligible for assessment of 
response (i.e., considered in the response-evaluable population).  Measurable disease is 
defined in Section 1.2.1; only legitimated on treatment serum M-protein and urine paraprotein 
measurements are used for assessment of response. The legitimated on treatment 
measurements is defined in Section 1.2.6.
3.2.2
CR, sCR, VGPR, PR, MR and SD response categories require no known evidence of 
progressive or new bone lesions if radiographic studies were performed. Once the program 
has determined PD for a subject, no subsequent response assessments are performed.  For 
example, a subject who progresses at week 6 cannot have a first response or best response that 
starts after week 6.


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3.2.3
Subjects with measurable disease (defined in Section 1.2.1) in serum (SPEP) and urine 
(UPEP) need to be followed by both SPEP and UPEP for response assessment and 
categorization; Except for assessment of CR or better, subjects with measurable disease 
restricted to the SPEP will need to be followed only by SPEP (i.e., urine M-protein need not 
show a reduction, but the available urine M-protein values must not meet the criteria for PD); 
correspondingly, subjects with measurable disease restricted to the UPEP will need to be 
followed only UPEP (i.e., serum M-protein need not show a reduction, but the available serum 
M-protein values must not meet the criteria for PD). For example, a subject who has baseline 
values of 0.1 g/dL of IgG M-protein and 300 mg/24 hrs. of urine paraprotein and who 
subsequently maintains values of 0.1 g/dL and 120 mg/24 hrs. will be regarded as achieving 
a PR; Subjects with measurable disease in either SPEP or UPEP or both will be assessed for 
response only based on these two tests and not by the FLC assay. 
3.2.4
To be considered CR, both serum and urine immunofixation must be carried out and 
be negative regardless of the size of baseline M-protein in the serum or urine; subjects with 
negative UPEP values pretreatment still require UPEP testing to confirm CR.
3.2.5
Requires 2 consecutive (i.e., no intermediate values that do not meet the definition of 
response) assessments made at any time before the institution of any new therapy (i.e., 
subsequent anti-cancer therapy).
3.2.6
For coding CR in subjects in whom the only measurable disease is by serum FLC 
levels: it requires a normal FLC ratio (Kappa/Lambda) in addition to CR criteria. However, a 
normal FLC ratio is not required if the involved FLC level decrease to below detectable level 
(Kappa<0.5 mg/L; or lambda<0.6 mg/L). The default reference range of 0.26 to 1.65 will be 
used to determine normal FLC ratio, if the reference range from central/local laboratory is not 
available.
3.2.7
If all criteria for confirmed CR were met, except that bone marrow aspirate and biopsy 
were not performed, and baseline bone marrow evaluation showed <5% plasma cells, then the 
algorithm accepts this as a CR.  If both bone marrow aspirate and bone marrow biopsy 
were 
performed at baseline, then both values must have <5% plasma cells for the rule to be 
applied.  For subjects without measurable disease at baseline or subjects whose baseline bone 
marrow plasma cells percentage is >5%, bone marrow confirmation is required for CR 
response. 
3.2.8
Normal FLC ratio is required for all subjects regardless of whether disease at baseline 
was measurable on serum, urine, both or neither. However, a normal FLC ratio is not required 
if the involved FLC level decrease to below detectable level (Kappa<0.5 mg/L; or lambda<0.6 
mg/L). The default reference range of 0.26 to 1.65 will be used to determine normal FLC ratio 
(Kappa/Lambda), if the reference range from central/local laboratory is not available.


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3.2.9
Presence/absence of clonal cells is based upon the kappa/lambda ratio. An abnormal 
kappa/lambda ratio by immunohistochemistry 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.
3.2.10 Reductions are based on changes from baseline.
3.2.11 VGPR categories require serum and urine studies regardless of whether disease at 
baseline was measurable on serum, urine, both or neither. For coding VGPR in subjects in 
whom the only measurable disease is by SPEP, it is not required that UPEP value must meet 
VGPR criteria, but UPEP test must be performed and not meeting PD criteria whenever SPEP 
meet VGPR criteria; correspondingly, for coding VGPR in subjects with measurable disease 
restricted to the UPEP, it is not required that SPEP value must meet VGPR criteria, but SPEP 
test must be performed and not meeting PD criteria whenever UPEP meet VGPR criteria.
3.2.12 Serum and urine M-protein via SPEP and UPEP must be reported as 0, not detected, 
or below level of quantification and positive serum or urine immunofixation.
3.2.13 Difference between involved and uninvolved FLC level is defined as absolute value 
of kappa FLC level minus lambda FLC level in the serum.
3.2.14 Skeletal survey is not required for assessment of response unless clinically indicated.  
However, if skeletal survey is performed, there should be no indication of disease progression 
before confirmation of response.
3.2.15 The date of first/best response is the earliest date that all available and required 
response criteria are met.  The date of serum immunofixation response is the initial date of 
response, not the date of confirmation.  The date of urine immunofixation response is the 
initial date of response, not the date of confirmation.  The latest date of response (date at which 
all criteria were met) among all the relevant response criteria will also be stored in the analysis 
dataset.
3.2.16 Duration of response (DOR) applies to subjects achieving at least PR by IMWG 
criteria and is measured from start of achieving PR (first observation of PR before 
confirmation) to the time of disease progression, with deaths owing to causes other than 
progression not counted but censored. DOR is derived as (date of PD or date of censoring –
date of first response + 1).
3.2.18 Occasionally, the results of the urine immunofixation and UPEP may conflict.  If the 
urine IFE is negative and the UPEP has any value less than 200 mg/24 hrs., the UPEP is 
disregarded and the urine results are treated as satisfying the requirement for a CR.  Similarly, 
if serum IFE becomes and remains negative, appearance of low level of paraprotein (0.5 g/dL 
or 5 g/L) in SPEP will be disregarded.
3.2.19 A DIRA result of NEGATIVE is treated as equivalent to a negative immunofixation 
of serum (SIFE) if it is associated with (IGG, Kappa). If SIFE is not done at the visit of DIRA 
result of NEGATIVE, then the baseline SIFE needs to be (IGG, Kappa) to be treated as 


JNJ54767414  (daratumumab)
Statistical Analysis Plan 54767414MMY3006 (Part 2)
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 16 September 2020
equivalent to a negative SIFE. If there is no repeat of the DIRA test, we consider a single 
DIRA test as equivalent of two consecutive immunofixation of serum tests if that indicates a 
CR. 
3.2.20 Subjects with at least one post-baseline disease assessment corresponding to the type 
of measurable disease at baseline and also not falling into any response category or 
progressive disease are assigned as response category- stable disease (SD).
3.2.21 Refers to <10-3 residual clonal plasma cells.
4
REFERENCES 
1. BGM Durie et al. International uniform response criteria for multiple myeloma. Leukemia 
2006
2. Rajkumar et al. Consensus recommendations for the uniform reporting of clinical trials: report 
of the International Myeloma Workshop Consensus Panel 1. Blood 2011