Conditions: Multiple Myeloma Chronic Kidney Disease
Keywords: myeloma multiple myeloma chronic kidney disease renal failure bortezomib Velcade thalidomide bendamustine dexamethasone serum free light chains proteosomal inhibition immunomodulatory
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 31
Healthy volunteers: no

Brief summary:
The purpose of this study is to compare the effectiveness of bortezomib versus thalidomide in reducing free light chains in the blood of myeloma patients. In addition participants will receive bendamustine (chemotherapy) and dexamethasone (steroids), which increase the effectiveness of both bortezomib and thalidomide. The trial will also study whether an earlier reduction of free light chains increases the chances of the kidneys recovering.

Detailed description:
Renal impairment is a life threatening condition of myeloma. 20-25% of patients will present at diagnosis with renal dysfunction. Outcome is poor due to high early mortality, with 28% of newly diagnosed myeloma patients in myeloma trials with renal failure not surviving beyond 100 days, compared with 10% overall.

This study aims to establish:

1. Whether proteosomal inhibition (bortezomib) or immunomodulatory (thalidomide) based therapy achieves threshold reduction of serum free light chains (sFLCs) in a significant majority of patients.
2. Whether sFLC response to the first 2 cycles (early responder) predicts haematological and renal response to the next 2 cycles of therapy.
3. An early time point for assessment of sFLC reduction as a biomarker for response.

Participants will be stratified by age and chronic kidney disease (CKD) stage to receive either bortezomib, bendamustine and dexamethasone (BBD) or thalidomide, bendamustine and dexamethasone (BTD).

Arms:
arm 1: Bortezomib, Bendamustine and Dexamethasone arm 2: Thalidomide, Bendamustine and Dexamethasone

Interventions: intervention 1: Bortezomib intervention 2: Thalidomide intervention 3: Bendamustine intervention 4: Dexamethasone
Intervention descriptions: intervention 1: 1.3 mg/m2 subcutaneously\* days 1, 4, 8 and 11 of each cycle. Number of cycles: Four 21 day cycles (participants not suitable for ASCT (autologous stem cell transplant) will continue up to 6 cycles on the treatment regimen to which they were randomised).

\*intravenous infusion available in case of patient intolerance to subcutaneous bortezomib intervention 2: 100 mg daily orally, preferably at night, days 1-21 of each cycle. Four 21 day cycles (participants not suitable for ASCT will continue up to 6 cycles on the treatment regimen to which they were randomised) intervention 3: 60 mg/m2 i.v. days 1 and 8 of each cycle. Four 21 day cycles (participants not suitable for ASCT will continue up to 6 cycles on the treatment regimen to which they were randomised) intervention 4: 40mg orally days 1-2, 4-5, 8-9 and 11-12 of each cycle

Protocol document:
Prot_SAP_000.pdf: 
 
OPTIMAL Protocol_V12.0_01Aug2017 
 
 Page 1 of 85 
Sponsor: Oxford University Hospitals NHS Foundation Trust 
OPTIMAL 
  
   
Confidentiality Statement 
Optimising Renal outcome in Myeloma renal failure 
A study of Thalidomide, Bendamustine and Dexamethasone (BTD) vs Bortezomib, Bendamustine 
and Dexamethasone (BBD) in patients with renal failure defined as a GFR below 30 mls/min 
PROTOCOL 
Version: 12.0 
Date: 01 Aug 2017 
EudraCT No.:  
2012-003947-31 
ISRCTN No.:  
32505664 
NCT No.: 
NCT02424851 
Ethics Ref No.: 
13-NE-0361 
Sponsor Protocol Ref.:  
26866138-MMY2070 
Chief Investigator: 
Dr. Karthik Ramasamy 
Sponsor: 
Oxford University Hospitals NHS Foundation Trust 
Funders: 
JANSSEN-Cilag Ltd and Bloodwise (formerly named Leukaemia and 
lymphoma Research)  
Chief Investigator Signature: 
Investigator’s Agreement: 
I have received and read the Summary of Product Characteristics (SmPC’s) for Bortezomib and Thalidomide. I have 
read the OPTIMAL Protocol Version 12.0, 01 August 2017 I agree to abide by all the provisions set forth herein. The 
study shall be conducted in accordance with the provisions of the current version of the Declaration of Helsinki, ICH-
GCP (UK 2006) and the Data Protection Act (1998). I agree to comply with all the regulations regarding clinical 
research that apply in the UK. I agree to ensure that the confidential information contained in this document will not 
be used for any purpose other than the evaluation and conduct of the clinical investigation without the prior written 
consent of the Sponsor Oxford University Hospitals NHS Foundation Trust. 
Name of Investigator (print): 
 
Signature of Investigator: 
 
Date: 
 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 2 of 84 
 
This document contains confidential information that must not be disclosed to anyone other than the Sponsor, the 
Investigator Team, host organisation, and members of the Research Ethics Committee and Competent Authority, 
unless authorised to do so. 
 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 3 of 84 
 
TABLE OF CONTENTS 
CONTACTS: ............................................................................................................................................................ 7 
1. SYNOPSIS ......................................................................................................................................................... 10 
2. ABBREVIATIONS ........................................................................................................................................... 13 
3. BACKGROUND AND RATIONALE ............................................................................................................. 15 
4. OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS .................................................................... 20 
5. TRIAL DESIGN ................................................................................................................................................ 21 
6. PARTICIPANT IDENTIFICATION .............................................................................................................. 23 
6.1. Trial Participants ................................................................................................................................ 23 
6.2. Inclusion Criteria ................................................................................................................................ 23 
6.3. Exclusion Criteria ............................................................................................................................... 24 
7. TRIAL PROCEDURES .................................................................................................................................... 25 
7.1. Recruitment ....................................................................................................................................... 25 
7.2. Informed Consent .............................................................................................................................. 25 
7.3. Screening and Eligibility ..................................................................................................................... 26 
7.3.1 Screening Logs ................................................................................................................................ 26 
7.3.2 Screening Assessments ................................................................................................................... 26 
7.4 Registration and Randomisation ........................................................................................................ 28 
7.4.1 Recruitment Logs ............................................................................................................................ 28 
7.4.2 Randomisation ................................................................................................................................ 28 
7.4.3 Participant Trial Card ...................................................................................................................... 28 
7.5 Treatment and Subsequent Assessments .......................................................................................... 29 
7.5.1 Treatment:Cycles 1-4 ...................................................................................................................... 29 
7.5.2 Treatment Cycles 5-6 ...................................................................................................................... 30 
7.6 1 Month Follow-up post Treatment ................................................................................................... 32 
7.7 12 Month Follow-up post Randomisation .......................................................................................... 33 
7.8. Withdrawal or Change of Status of Participants ............................................................................... 34 
7.8.1 Withdrawal ..................................................................................................................................... 34 
7.8.2 Loss to Follow Up ............................................................................................................................ 35 
7.8.3Participant Transfer ......................................................................................................................... 35 
7.9 Definition of End of Trial .................................................................................................................... 35 
8. LABORATORY AND SAMPLING ................................................................................................................ 36 
8.1 Local Clinical Laboratory Evaluations ................................................................................................. 36 
8.2 Central Laboratory Samples ............................................................................................................... 36 
8.2.1 Central Laboratory Samples (Birmingham): ................................................................................... 36 
8.2.2 Central Laboratory Samples (Oxford) ............................................................................................. 38 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 4 of 84 
 
8.2.3 Notifying Trial Office of Samples ..................................................................................................... 39 
8.3 Additional gifted samples ................................................................................................................... 39 
8.4 Availability and prioritisation of samples ........................................................................................... 40 
9. INVESTIGATIONAL MEDICINAL PRODUCTS (IMPs) ......................................................................... 40 
9.1 Trial Treatments ................................................................................................................................. 40 
9.1.1 Supportive Therapies ...................................................................................................................... 41 
9.2 Dose Modifications ............................................................................................................................. 42 
9.2.1 Thalidomide Dose Modification ..................................................................................................... 42 
9.2.2 Bortezomib Dose Modification ....................................................................................................... 42 
9.2.3 Bendamustine Dose Modification: ................................................................................................. 42 
9.2.4 Dexamethasone Dose Modification: .............................................................................................. 42 
9.3 Bortezomib Route of Administration ................................................................................................. 42 
9.4 Irradiated Blood Products .................................................................................................................. 43 
9.5 Labeling, Storage, Accountability and Ordering of Study Drugs ........................................................ 43 
9.5.1 Ordering of Study Drugs ................................................................................................................. 43 
9.5.2 Labeling of Study Drugs .................................................................................................................. 43 
9.5.3 Storage and Dispensing of Study Drugs .......................................................................................... 44 
9.5.4 Accountability of Study Drugs ........................................................................................................ 44 
9.5.5 Unavailability of Study drug ........................................................................................................... 44 
9.6. Participant Compliance and Treatment Diary Card(s) ...................................................................... 44 
9.7 Study Drug Destruction ...................................................................................................................... 45 
9.8 Concomitant Medication .................................................................................................................... 45 
9.9 Post-trial Treatment ........................................................................................................................... 45 
10. SAFETY REPORTING.................................................................................................................................. 46 
10.1 Definitions ........................................................................................................................................ 46 
10.2 Assessment of Causality ................................................................................................................... 47 
10.3 Assessment of Expectedness ............................................................................................................ 47 
10.4 Terminology and Assessment of Severity ........................................................................................ 47 
10.5 Reporting Non-Serious Adverse Events  ........................................................................................... 48 
10.6 Reporting Serious Adverse Events  ................................................................................................... 48 
10.7 Foreseeable Events that DO NOT require reporting as an SAE ........................................................ 49 
10.8. Foreseeable SAEs that DO require immediate reporting as SAEs ................................................... 50 
10.9 Procedures in Case of Pregnancy ..................................................................................................... 50 
10.9.1 Pregnancy Follow-Up Reports ...................................................................................................... 50 
10.9.2 SAEs During Pregnancy ................................................................................................................. 50 
10.9.3 Pregnancy Report Processing at Sponsor site .............................................................................. 51 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 5 of 84 
 
10.10 SUSAR Reporting ............................................................................................................................ 51 
10.11 Review of SAEs ............................................................................................................................... 51 
10.11.1 OPTIMAL Trial Office and Sponsor Responsibilities ................................................................... 51 
10.11.2 Development Safety Update Reports (DSURs) ........................................................................... 52 
10.11.3 Safety Reporting Responsibilities to Janssen-Cilag .................................................................... 52 
11. DATA AND SAFETY MONITORING COMMITTEE (DSMC) .............................................................. 52 
11.1 Primary Responsibilities of the DSMC .............................................................................................. 52 
11.2 Membership of the DSMC ................................................................................................................ 53 
12. TRIAL STEERING COMMITTEE (TSC) .................................................................................................. 53 
13. STATISTICS ................................................................................................................................................... 53 
13.1 Interim Analysis ................................................................................................................................ 54 
13.2 Final Analysis .................................................................................................................................... 54 
13.3 Patient Reported Outcomes ............................................................................................................. 54 
13.4 Termination of the Trial ................................................................................................................... 55 
13.5 Inclusion in Analysis.......................................................................................................................... 55 
14. DATA MANAGEMENT ................................................................................................................................ 55 
14.1 Source Data ...................................................................................................................................... 55 
14.2 Case Report Forms (CRF’s) and Data Recording  .............................................................................. 55 
14.3 Archiving ........................................................................................................................................... 57 
15. QUALITY ASSURANCE PROCEDURES ................................................................................................... 57 
16. SERIOUS BREACHES .................................................................................................................................. 57 
17. ETHICAL AND REGULATORY CONSIDERATIONS ............................................................................. 58 
17.1 Declaration of Helsinki ..................................................................................................................... 58 
17.2 ICH Guidelines for Good Clinical Practice ......................................................................................... 58 
17.3 Approvals .......................................................................................................................................... 58 
17.4 Reporting .......................................................................................................................................... 58 
17.5 Access to Data and Confidentiality ................................................................................................... 58 
17.6 Expenses and Benefits ...................................................................................................................... 59 
18. FINANCE AND INSURANCE ...................................................................................................................... 59 
18.1 Funding ............................................................................................................................................. 59 
18.2 Indemnity and Insurance .................................................................................................................. 59 
18.3 Publication Policy ............................................................................................................................. 59 
19. REFERENCES ................................................................................................................................................ 61 
Appendix A:  Schedule of Events .............................................................................................................. 64 
Appendix B:  ECOG Performance Status .................................................................................................. 66 
Appendix C: International Staging System (ISS) ....................................................................................... 67 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 6 of 84 
 
Appendix D: International Myeloma Working Group (IMWG) Uniform Response Criteria ..................... 68 
Appendix E: Quality of Life Questionnaire ............................................................................................... 70 
Appendix F: SAE Reporting Flow Chart ..................................................................................................... 73 
Appendix G: Definition of Women of Childbearing Potential .................................................................. 74 
Appendix H: Pregnancy Report Form A .................................................................................................... 75 
Appendix I: Pregnancy Report Form B ..................................................................................................... 76 
Appendix J: Flowchart for Bortezomib SC to IV switch ............................................................................ 81 
Appendix K: OPTIMAL Trial Schema ......................................................................................................... 84 
 
 
 
 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 7 of 84 
 
CONTACTS: 
 
Chief Investigator: 
Dr. Karthik Ramasamy 
Consultant Haematologist 
Oxford University Hospitals NHS Foundation 
Trust, Cancer Centre 
Churchill Hospital 
Old Road Headington 
OX3 7LE 
Tel:  01865 235882 
Fax: 01865 235260 
Email: kramasamy@nhs.net 
 
Sponsor: 
Oxford University Hospitals NHS Foundation 
Trust Research and Development Department 
Joint Research Office, Block 60  
Churchill Hospital  
Oxford OX3 7LE  
Tel: 01865 572237 
Fax: 01865 572242 
Peer review and 
endorsement: 
Bloodwise (formerly named Leukaemia and lymphoma Research) 
Funders: 
Janssen-Cilag Ltd 
50-100 Holmers Far Way 
High Wycombe 
Bucks 
HP12 4EG 
Bloodwise 39-40 Eagle Street 
London  
WC1R 4TH 
 
 
Collaborators: 
Professor Mark Drayson 
Director Clinical Immunology Service 
School of Immunity and Infection 
College of Medicine and Dentistry 
University of Birmingham 
Edgbaston, Birmingham 
B15 2TT 
Tel: 01214 144074 
Fax: 01214 143069 
Email: m.t.drayson@bham.ac.uk 
 
 
 
 
Collaborators: 
Prof Stephen Schey  
Consultant Haematologist 
Kings College Hospital 
London 
SE5 9RS 
Tel:  020 3299 4550 
Fax: 020 3299 4289 
Email : sschey@nhs.net 
 
 
 
 
 
 
 
 
              


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 8 of 84 
 
 
Professor Janet Dunn 
Prof. of Clinical Trials & Head of Cancer Trials 
Warwick Clinical Trials Unit (WCTU) 
Division of Health Sciences  
Warwick Medical School 
University of Warwick 
Coventry, CV4 7AL 
Tel: 02476 575847  
Fax: 02476 528375 
Email: j.a.dunn@warwick.ac.uk 
 
 
 
 
Statistician: 
Dr Gulnaz Iqbal 
Statistician 
Warwick Clinical Trials Unit (WCTU) 
Division of Health Sciences 
Warwick Medical School 
University of Warwick 
Coventry, CV4 7AL 
 
Tel: 02476 575847  
Fax: 02476 528375 
Email: g.iqbal@warwick.ac.uk 
 
 
 
 
Safety Data  
Monitoring  
Committee: 
Prof Kwee Yong 
Department of Haematology, UCLH  
1st Floor Central, 250 Euston Road, 
London  NW1 2PG 
 
 
Tel: 020 3447 8028 
Fax: 020 3447 9911 
Email: kwee.yong@ucl.ac.uk 
 
 
 
Dr Matthew Jenner 
Mailpoint 8, Level C 
Southampton General Hospital,  
Tremona Road, 
Southampton, SO16 6YD 
 
Tel: 023 8120 4438 
Email: Matthew.Jenner@uhs.nhs.uk 
 
 
 
 
Dr Matthew Streetly 
Department of Clinical Haematology 
4th floor, Southwark Wing 
Guy's Hospital 
Great Maze Pond 
London SE1 9RT 
Tel: 020 7188 2757  
Email:Matthew.Streetly@gstt.nhs.uk 
 
 
 
 
 
Trial Steering 
Group Chair: 
Professor Margaret Rees 
1 Hawthorn Rd  
West Newcastle upon Tyne 
Tyne and Wear  
NE3 4DN  
Clinical Trial 
Coordinator: 
 
Clinical Trial Coordinator 
Late Phase Haematology Research 
Team 
Churchill Hospital 
Headington 
Oxford, OX3 7LE 
Tel:  01865 223353 (Mon-Fri, 9am to 5pm) 
Email: optimal.trial@nhs.net 
 
  
For general queries, drug orders, supply of trial materials, collection of data and SAE reporting please 
contact the OPTIMAL Trial Coordinator 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 9 of 84 
 
Randomisation: 
 
Warwick Clinical Trials Unit  
(WCTU) 
The University of Warwick 
Gibbet Hill Road 
Coventry 
CV4 7AL 
Tel: 02476 150402 (Mon-Fri, 9am to 5pm) 
Fax: 02476 151586 
Central Laboratory 
(Birmingham): 
 
Clinical Immunology Laboratory 
University of Birmingham 
PO Box 1894 
Vincent Drive, 
Edgbaston 
Birmingham 
B15 2SZ 
Tel: 0121 414 4069  
Fax: 0121 414 3069 
 
Central Laboratory 
(Oxford): 
 
Molecular Haematology Lab 
Level 4 
John Radcliffe Hospital 
Headington  
Oxford 
OX3 9DU 
Tel: 01865 220381 
Email: maite.cabes@nhs.net 
 
Distributer for 
Bortezomib  
B&C 
Florence Brassart 
Watson & Crick Hill 
Rue Granbonpré,  
11 B-1348  
Mont-Saint-Guibert  
(Belgium) 
Tel:  +32 10 237 437 
Fax: +32 10 238 850 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RANDOMISATION 
To randomise a participant please contact Warwick Clinical Trials Unit:  
Tel: 02476 150402 (Mon-Fri, 9am to 5pm)* 
Fax: 02476 151586 (Mon-Fri, 9am to 5pm) 
* excluding public holidays or dates when notice has been given by the Trial Coordinator 
SAE REPORTING 
Please send all SAE Forms to OPTIMAL Trial Team within 24 hours of becoming aware of event: 
Email: OPTIMAL.trial@nhs.net (Mon-Fri, 9am to 5pm)* 
* excluding public holidays or dates when notice has been given by the Trial Coordinator) 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 10 of 84 
 
1. SYNOPSIS 
Background 
Renal impairment is a life threatening complication of myeloma. Up to 20-25% of patients will present at 
myeloma diagnosis with renal dysfunction. Outcome is poor as a result of a high early mortality, with 28% 
of newly diagnosed myeloma patients in myeloma trials with renal failure not surviving beyond 100 days 
compared with 10% overall. The MERIT trial and results of studies in Mayo Clinic and Birmingham show that 
within weeks of diagnosing myeloma with renal failure, treatment with dexamethasone alone or combined 
with bortezomib lowers serum free light chain (sFLC) levels by more than 50% in half of patients. 
Importantly, achieving lower sFLC levels in this early period is associated with a greater chance of being 
alive and dialysis free at 100 days. 
 
Aims 
1) Establish whether proteasomal inhibition (bortezomib) or immunomodulatory (thalidomide) based 
therapy achieves threshold reduction of sFLCs in a significant majority of patients. 
2) Establish whether sFLC response to the first two cycles (early responder) predict haematological and 
renal response to next two cycles of therapy. 
3) Establish an early time point for assessment of sFLC reduction as a biomarker for response. 
 
Methods 
In this Phase II trial, 120 newly diagnosed myeloma patients with eGFR less than 30mls/min will be 
randomised to receive a minimum of 4 cycles of either thalidomide or bortezomib; all participants will also 
receive bendamustine and dexamethasone in three weekly cycles. Randomisation will be stratified based 
on age and Chronic Kidney Disease staging. sFLC response to the first two cycles of therapy will be used as 
the primary endpoint. All other endpoints are secondary. Participants will be recruited from up to 20 sites 
across the UK.  
 
Retrospective analysis of 54 patients treated from 18 centres in 10 countries showed that bortezomib 
patients had a median sFLC reduction of 79% by day 12 compared to 66% in the thalidomide patients (35). 
A realistic difference between treatment arms can be detected by recruiting 60 patients in each arm. This 
will allow the detection of 23% differences in the percentage of patients achieving 50% reduction in sFLC 
between treatment arms, e.g. from 60% to 83%, with 80% power and a 5% 2-sided significance level.  
 
Use of research results 
The results of this trial will be used to show if bortezomib based induction is superior to thalidomide based 
induction for threshold sFLC reduction, which is important in light of NICE approval for bortezomib use 
upfront only in thalidomide contraindicated or intolerant patients. Early identification of poor responders 
based on sFLC response who may benefit from alternative therapy will be derived from this study to build a 
Phase III question. 
 
 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 11 of 84 
 
Trial Title 
Optimising Renal outcome in Myeloma renal failure - A study of Thalidomide, 
Bendamustine and Dexamethasone (BTD) vs Bortezomib, Bendamustine and 
Dexamethasone (BBD) in patients with renal failure defined as a GFR below 30 
mls/min 
 Short Title 
OPTIMAL 
Clinical Phase  
Phase ll 
Trial Design 
Randomised Control Phase II trial. Participants will be stratified by age and 
CKD disease stage to receive either bortezomib, bendamustine and 
dexamethasone (BBD) or thalidomide, bendamustine and dexamethosone 
(BTD) 
Trial Participants 
Newly diagnosed myeloma patients with eGFR less than 30mls/min presenting 
with renal failure 
 
Planned Sample Size 
 
120 
Treatment duration 
 
4-6 cycles 
Follow up duration 
Maximum 12 months post randomisation.  
 
Planned Trial Period 
 
3 years  6 months 
 
Objectives 
Outcome Measures/Endpoints 
Primary 
To compare serum free light chain 
response to two cycles of therapy 
with either  bortezomib (Arm A) or 
thalidomide (Arm B) 
 
To determine if myeloma response is 
associated with renal response at 
the end of cycle 4 (co-primary end 
point) 
 
Proportion of participants with 
response defined as >50% reduction 
from baseline in sFLC at week 6 (after 
receiving two cycles of therapy) 
 
Renal response at end of 4 cycles of 
therapy. Modified IMWG Uniform 
Criteria Of Response and Progression 
1998, 2006, 2011 
 
Secondary 
 
To assess whether sFLC response can 
predict overall response and 
correlation of sFLC with monoclonal 
protein in the urine 
 
Assess haematological and non–
haematological toxicity in both 
treatment arms  
 
Survival 
 
 
 
 
Compare change in renal function at 
the end of cycles 2 and 4 between 
the two treatment regimens 
 
To evaluate treatment effects on 
other patient reported outcomes 
sFLC response  at end of weeks 1, 2, 3, 
4, 5, 6, 9 and 12 of treatment with 
bortezomib (Arm A) or thalidomide 
(Arm B) 
 
Toxicity as defined by NCI CTCAE v4.0 
Haematological responses  
Adverse Events (NCI CTCAE v4.0) 
 
Overall survival from randomisation to 
end of study period (assessed at 1 
month post end of treatment and 12 
months post randomisation) 
 
Renal response at end of second and 
fourth cycles of therapy  as defined by 
IMWG renal response criteria 
 
Quality of life measured by EQ-5D (38) 
 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 12 of 84 
 
Investigational 
Medicinal Products 
(IMPs) 
Bortezomib 
Thalidomide 
 
Non Investigational 
Medicinal 
Product 
(nIMPs) 
Dexamethasone 
Bendamustine 
Treatment Regimens 
Four 21 day cycles (participants not suitable for ASCT will continue up to 6 
cycles on the treatment regimen to which they were randomised) 
 
Arm A (BBD)  
Bortezomib: 1.3 mg/m2 subcutaneously* days 1, 4, 8 and 11 of each cycle 
Bendamustine: 60 mg/m2 i.v. days 1 and 8 of each cycle 
Dexamethasone: 40 mg orally days 1-2, 4-5, 8-9 and 11-12 of each cycle 
The cycle is repeated every 3 weeks (21 days).  
 
For cycles 3-4 (and 5-6, where relevant) bortezomib may be given as 1.3 
mg/m2 weekly for 3 weeks in a 21 day cycle in combination with 
bendamustine and dexamethasone. 
*intravenous infusion available in case of participant intolerance to 
subcutaneous bortezomib (see Section 9.3) 
 
(Participants over 70 years of age and frail, as defined by having an ECOG 
score of > 1, the dose of dexamethasone will be reduced from 40 to 20 mg 
daily) 
 
Arm B (BTD) 
Thalidomide: 100 mg daily orally, preferably at night, days 1-21 of each cycle 
Bendamustine: 60 mg/m2 i.v. days 1 and 8 of each cycle 
Dexamethasone: 40 mg orally days 1-2, 4-5, 8-9 and 11-12 of each cycle 
The cycle is repeated every 3 weeks (21 days).  
 
(Participants > 70 years of age, frail ( ECOG >1) participants the dose of 
dexamethasone will be reduced from 40 to 20 mg daily) 
 
 
 
 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 13 of 84 
 
 
2. ABBREVIATIONS 
AE 
Adverse event 
ANC 
Absolute Neutrophil Count 
AP 
Anteroposterior 
AR  
Adverse reaction 
ASCT 
Autologous Stem Cell Transplant 
BBD 
Arm A of trial treatment: Bortezomib, bendamustine and dexamethasone 
BDD 
Bortezomib, doxorubicin and dexamethasone 
BTD 
Arm B of trial treatment: Thalidomide, bendamustine and dexamethasone 
CKD 
Chronic Kidney Disease 
CI 
Chief Investigator 
CR 
Complete Response 
CRD 
Cycolphosphamide, lenalidomide and dexamethasome 
CRDa 
Cycolphosphamide, lenalidomide and dexamethasome; attenuated 
CRF 
Case Report Form 
CT 
Clinical Trials 
CTA 
Clinical Trials Authorisation 
CTD 
Cyclophosphamide, thalidomide and dexamethasone 
CTDa 
Cyclophosphamide, thalidomide and dexamethasone; attenuated 
CTU 
Clinical Trials Unit 
DMC/DSMC 
Data Monitoring Committee / Data and Safety Monitoring Committee 
DoB 
Date of Birth 
DSUR 
Development Safety Update Report 
ECG 
Electrocardiogram 
FBC 
Full blood count 
FLC 
Free Light Chain 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
GP 
General Practitioner 
IB 
Investigators Brochure 
ICF 
Informed Consent Form 
ICH GCP 
International Conference on Harmonisation of technical requirements for registration 
of pharmaceuticals for human use  
IMP 
Investigational Medicinal Product 
IMWG 
International Myeloma Working Group criteria 
MDRD 
Modification in Diet in Renal Disease 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 14 of 84 
 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MR 
Minor Response 
MRD 
Minimal Residual Disease 
MTD 
Maximum Tolerated Dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events  
nIMP 
non-Investigational Medicinal Product 
ORR 
Overall Response Rate 
PA 
Posteroanterior  
PI 
Principal Investigator 
PIS 
Participant/ Patient Information Sheet 
PR 
Partial Response 
PRO 
Patient Reported Outcomes 
R&D 
NHS Trust R&D Department 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SDV 
Source Data Verification 
sFLC 
Serum Free Light Chain 
SIV 
Site Initiation Visit 
SmPC 
Summary of Medicinal Product Characteristics 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TMF 
Trial Master File 
TSC 
Trial Steering Committee 
TSG 
Trials Safety Group 
VAD 
Vincristine, Adriamycin and Dexamethasone 
VGPR 
Very Good Partial Response 
 
 
 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 15 of 84 
 
3. BACKGROUND AND RATIONALE 
Myeloma is a cancer of bone marrow plasma cells that causes 1) impaired red blood cell formation 
(haematopoiesis) and anaemia 2) renal failure 3) osteoporosis, lytic bone disease and skeletal fractures 4) 
immunosuppression and consequent infection. There are approximately 4,000 new UK cases of myeloma 
per annum (1) .The overall prevalence however is likely to be increasing given the recently published data 
demonstrating improved survival rates over the last decade (2, 3).  The median age at presentation is 
approximately 70 years while only 15% of patients are aged less than 60 years. Myeloma has a higher 
incidence in Afro-Caribbean ethnic groups compared to Caucasians, but there are few other distinctive 
epidemiological features. The majority of cases present de novo but it is now recognised that this is 
preceded by an asymptomatic monoclonal gammopathy of undetermined significance (MGUS) phase in 
virtually all patients (4).  
 
Renal impairment is a common and potentially serious complication of myeloma.  Up to 20-25% of patients 
will present at initial diagnosis with some degree of renal dysfunction (5), and it occurs in up to 50% of 
patients at some time during their disease (6). It is possible to reverse renal insufficiency in approximately 
half of patients (7) but half will have some degree of persistent renal impairment, and of these 2-12% will 
require renal replacement therapy. 
 
Renal failure occurs commonly in myeloma because of damage caused to renal tubules by free light chains, 
a process called cast nephropathy, or ’myeloma kidney’. The risk of renal damage is directly proportionate 
to the level of urinary free light chain excretion and not attributable to the light chain class or the presence 
or absence of whole M-proteins.  Only 2% of patients without urinary free light chain excretion have renal 
impairment but this percentage increases to 50% with increasing levels of urinary free light chain excretion 
(8). 
Over the past decade overall survival prospects for patients with multiple myeloma have considerably 
improved with projected median survivals of 6-7 years for patients in the high intensity arm of the most 
recent MRC trial Myeloma IX (9).  However the outcome for patients with multiple myeloma complicated 
by renal impairment lags behind the improved results seen for patients without significant renal 
impairment.  
This is mainly as a result of a high early death rate, with 28% of newly diagnosed myeloma patients in 
myeloma trials with renal failure not surviving beyond 100 days compared with 10% overall (10). It has 
been shown however that those surviving the first 60 days have similar overall survival to patients without 
renal failure. 
Some progress has been made since the early 1970s when median survival was 2 months for patients with 
a blood urea >13 mmol/l compared to 37 months for those with a urea <6.52 mmol/l. By 1998 Torra and 
Blade et al.  reported  further improvements with median survival of patients with renal impairment  
reaching 20-24 months (11).  Recent studies in 2009 reported by Kastritis et al. have shown that in the era 
of high dose steroid containing regimens, further improvements in survival have been achieved. In 
particular the use of high dose steroids, with or without novel agents, was shown in these studies to be 
associated with better rates of renal recovery and with reversal of dialysis dependency occurring in up to 
40% of patients compared to rates of only 10% seen up to the 1990s (12). 
It is therefore crucially important to take effective action to try and prevent renal failure, or if established, 
to reverse it as this will significantly improve long term prognosis (13).   


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 16 of 84 
 
MERIT (MyEloma Renal Impairment Trial) is a randomised controlled trial of adjunctive plasma exchange in 
patients with newly diagnosed multiple myeloma and acute renal failure from the Renal Association and 
the UK Myeloma Forum. In MERIT’s first 59 patients with newly diagnosed myeloma and serum creatinine 
>500µmol/L:- 
 
Median reduction in malignant serum free light chain (sFLC) levels by 2 weeks (usually 5 days) of 
dexamethasone alone (40 mg days 1-4 & 9-12) was: 69% (range: -78% to +99%);   
 
This reduction was greater in the patients who were alive and independent of dialysis at 100 days 
(median 76.5% versus 53.2% reduction). 
 
The 18 patients who were alive and dialysis independent at 100 days had lower sFLC levels 
(P=0.019) than the 34 patients who were dialysis dependent and the 7 who died 
 
It follows from the MERIT results that in treating patients with myeloma and renal impairment, regimens 
which give the greatest depth and speed of response should be chosen so that light chain production is 
reduced to the lowest level possible and as fast as possible. To ensure greatest tumour kill such regimens 
should be able to be given without significant dose reduction in this setting. They should be well tolerated 
with as few side effects as possible given the vulnerability of this patient group who often face problems 
with infection, fluid balance and metabolic issues. 
It has been shown that high dose steroid containing regimens are effective in rapidly killing myeloma cells 
and can safely be given without dose reduction in renal impairment (14). Analysis of sFLC responses in 
MERIT shows that this happens very quickly, mostly within 5 days in responding patients (15).  
However, the addition of an alkylator and a novel agent to high dose steroids will increase both the rate of 
response and also the proportion of patients achieving complete responses or very good partial responses. 
Bendamustine (γ-[1-methyl-5-bis(β-chloroethyl) -amino-benzimidazolyl-2]-butyric acid hydrochloride) has 
dual mechanism of action as an alkylating agent and antimetabolite (16). Bendamustine exhibits partial 
cross resistance to other alkylating agents and is effective in patients with relapsed myeloma. 
Bendamustine is metabolised to hydroxyl derivatives with rapid elimination by hepatic and renal excretion. 
Pharmacokinetic data available in myeloma patients with renal impairment shows no accumulation of drug 
in patients with end stage renal disease. Metabolites were present in the dialysate and only 5% of the 
administered dose detected in the urine (17). Up to 20% of administered bendamustine is renally 
eliminated within 24 hours of dosing, making this drug a potential therapeutic option for patients with 
renal impairment.  
The mechanism of action of bendamustine is through promoting myeloma cell apoptosis and cell cycle 
arrest. Caspase 3 activation is seen in myeloma cell lines treated with bendamustine, this would enhance 
synergy with other agents such as dexamethasone and thalidomide used in myeloma. Cell cycle arrest in G2 
phase is through inhibition of ATM and Chk2 and not ATR and CHk1, which markedly contrasts the 
mechanism of action in comparison to traditional alkylating agents (18). A phase III randomised trial was 
performed comparing bendamustine and prednisolone (BP, bendamustine dose 50 mg/m2 days 1-2 every 
cycle) with, the gold standard for myeloma, melphalan and prednisolone (MP). Although the overall 
response rate was comparable between 75% in the BP and 70% in the MP group, a significantly higher 
number of patients treated with BP achieved a complete remission than did patients receiving MP (32 vs. 
13%; P=0.007). A critical observation was, maximum response was achieved more rapidly in patients 
treated with BP compared to MP (6.8 vs. 8.7 cycles; P<0.02). Haematological toxicities were comparable 
between both groups (19). A dose escalation study of single agent bendamustine in 31 heavily pretreated 
myeloma patients (all were post autograft), confirmed efficacy and safety of this agent. Only one episode of 
febrile neutropaenia was observed at the maximum tolerated dose (MTD) of 100 mg/m2 (20). 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 17 of 84 
 
Melphalan is less suitable in renal failure as the manufacturer recommends that initial doses of melphalan 
should be reduced by 50% if the glomerular filtration rate (GFR) is <40-50 ml/min, and that melphalan 
should not be used in patients where the GFR is below 30 ml/min. Renal dosing of cyclophosphamide 
remains controversial. Cyclophosphamide pharmacokinetics assessed in groups of patients with CKD stages 
3, 4 and 5 after intravenous doses of 0.5 – 1 g/m2 showed significant reduction in clearance. 
Cyclophosphamide is dialysable which enhances clearance in Chronic Kidney Disease (CKD) stage 5 patients 
(21). The manufacturer says consistent advice about dosing in poor renal function cannot be given with 
available data.  
Thalidomide pharmacokinetics seem to be unaltered in patients with renal dysfunction (22). Less than 1% 
of thalidomide is excreted unchanged in the urine and it does not appear to be hepatically or renal 
metabolised to any large extent, appearing to undergo non-enzymatic hydrolysis in plasma to form multiple 
degradation products, which may be metabolically active. Manufacturers do not recommend dosage 
reduction, but caution in renal impairment is recommended. Although the clearance of thalidomide is 
increased during dialysis it appears not necessary to give a supplementary dose. A report of thalidomide 
use in 20 patients with renal impairment did not show any increase in toxicity (23). Extensive clinical 
experience has been gained with thalidomide in myeloma patients with renal impairment, with no added 
toxicity. 
Thalidomide, alkylator and steroid containing regimens have been shown to be associated with a high rate 
of complete response (CR) and very good partial response (VGPR) varying from 23 - 47% in patients with 
myeloma.  In MRC Myeloma IX Trial 555 patients received cyclophosphamide, thalidomide and 
dexamethasone (CTD) induction therapy giving 82.5% CR+VGPR+PR rates and 426 older patients received 
CTD attenuated (CTDa, dexamethasone reduced from 40 mg to 20 mg) giving 63.8% CR+VGPR+partial 
response (PR) rates(9, 24). sFLC response was not measured at early time intervals in Myeloma IX but it is 
expected that the responses were at least as good as for dexamethasone alone. Retrospective study in a 
select cohort of myeloma patients with CKD 4 and CKD 5 confirmed the safety of the combination of 
bendamustine (120 mg fixed dose), thalidomide and dexamethasone in this population. It was also 
observed that three out of four patients who were dialysis dependent became dialysis independent after 
therapy (25). Grade 3-4 neutropaenia was observed in 1/9 patients. This formed the rationale for 
investigating the efficacy of this combination in a larger cohort of myeloma patients (MUK one trial 
ISRCTN90889843). This trial will also identify the right dose of bendamustine in myeloma patients in 
combination with thalidomide and dexamethasone, including patients with a creatinine clearance of up to 
≥10 ml/min. 
Bortezomib has been shown in in vitro studies to be metabolised primarily through oxidative deboronation 
by the liver cytochrome P450 system. Early disposition kinetics of bortezomib in patients did not appear to 
be affected by creatinine clearance (range <30 ml/min to >80 ml/min) (bortezomib SPC). 
A number of studies have shown that bortezomib, either alone, or in combination with other agents, 
produces similar response rates in patients with renal impairment to patients with normal renal function, 
and can be safely delivered with no excess toxicity.  These include sub-analyses of patients with renal 
impairment in the SUMMIT, CREST and APEX studies (26, 27). Importantly bortezomib was shown to 
produce rapid response rates with time to first response being 1.4 months in patients receiving bortezomib, 
melphalan and prednisolone in the VISTA study compared to 3.5 months in those receiving melphalan and 
prednisolone alone (28). This has now become standard of care for elderly myeloma patients.   
Bendamustine and bortezomib in combination with steroids have been used both in newly diagnosed 
myeloma patients with renal impairment and in relapsed refractory myeloma patients. In the renal study, 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 18 of 84 
 
bendamustine dosing of 60 mg/m2 days 1 and 2 in combination with bortezomib was well tolerated with 
best  biochemical response reached in 11/18 patients by the end of 2 cycles of therapy (29). Berenson et al. 
performed a Phase I/II dose finding study of bendamustine in combination with bortezomib in 44 
relapsed/refractory patients and have not reached an MTD at 90 mg/m2 dose of bendamustine (30). 
Berdeja et al. performed a Phase II study of combination of bendamustine and bortezomib and 
dexamethasone in newly diagnosed patients with a fixed dose of bendamustine at 80 mg/m2 on days 1 and 
4 (31). During a planned interim analysis of 18 patients, this combination produced a high overall response 
rate (ORR) and the majority of non-haematological toxicity was considered to be bortezomib induced. They 
have now switched to weekly bortezomib scheduling and are accruing more patients in this study. Ludwig 
et al. have explored the combination of bendamustine with bortezomib in the relapsed refractory setting 
(32). Bendamustine administered at dose between 70 mg/m2 and 90 mg/m2 in combination with 
bortezomib was well tolerated with an overall response rate of 50% in this heavily pre-treated group of 
patients. The German investigators have previously investigated bendamustine combinational therapy in a 
sequential escalation study starting with bortezomib monotherapy and addition of dexamethasone 
followed by bendamustine (50 – 100 mg/m2) in non-responding patients. A total of 50 patients were 
evaluated with 7 patients requiring the bortezomib, dexamethasone, bendamustine (BBD) combination of 
which 6/7 achieved minor response (MR) or better, confirming the significant activity of this combination. 
Adverse effects were comparable between the three groups of patients (33). Only one patient in the BBD 
combination developed Grade 3-4 neutropaenia. These studies confirm the safety and efficacy of the 
combination of bortezomib, bendamustine and dexamethasone in myeloma patients. 
In summary 
The MERIT trial has shown that within two weeks of diagnosing myeloma with renal failure, 
dexamethasone alone can lower serum free light chain levels by more than 50% in more than half of 
patients. MERIT shows patients who are alive and dialysis free at 100 days (as compared to those dead or 
on dialysis) have lower levels of FLC at entry and greater reductions in free light chains in the first two 
weeks. Samples for FLC levels were obtained at 0, 5, 10, 16 & 100 days – only assessing response to 2 weeks 
dexamethasone (+/- plasma exchange) and not to subsequent cycles of chemotherapy, except for the much 
later 100 day sample. 
Thus MERIT does not provide evidence on how much subsequent FLC response there was to successive 
cycles of chemotherapy, correlated with renal recovery or how a 2 week FLC response to dexamethasone 
could predict subsequent FLC response to subsequent cycles of Vincristine, Adriamycin, Dexamethasone 
(VAD). 
OPTIMAL can answer these questions by examining individual patient FLC responses at 1, 2, 3, 4, 5, 6, 9, 
and 12 weeks.   
In MERIT median reduction in malignant serum free light chain (sFLC) levels by 2 weeks of dexamethasone 
alone (40 mg days 1-4 & 9-12; total 320 mg/cycle) was: 69% (range: -78% to +99%). In MRC Myeloma IX 
Trial 555 patients received Cyclophosphamide, Thalidomide and Dexamethasone (CTD) induction therapy 
giving 82.5% CR+VGPR+PR rates and 426 older patients received CTDa (dexamethasone reduced from 40 
mg to 20 mg; 160 mg/cycle) giving 63.8% CR+VGPR+PR rates. In OPTIMAL we expect half of patients to 
receive only 160 mg dexamethasone/cycle. sFLC response was not measured at early time intervals in 
Myeloma IX. Analysis of response to the first cycle of CTDa/Cyclophosphamide, lenalidomide and 
dexamethasone attenuated (CRDa) (for the first 92 patients in Myeloma XI trial) shows 65% of patients 
achieve a 75% reduction in malignant FLC and 70% patients achieve a 50% reduction in malignant FLC. 
These Myeloma XI patients were not in renal failure and so the serum half-life of FLC was a few hours. In 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 19 of 84 
 
OPTIMAL patients serum half-life of FLC will be a day or more because of reduced glomerular filtration. 
Accordingly the percentage of OPTIMAL patients achieving more than a 50% reduction in malignant FLC in 
response to first cycle of chemotherapy is expected to be significantly less than in Myeloma XI trial. 
In limited numbers of patients with newly diagnosed myeloma and renal failure the addition of bortezomib 
to dexamethasone has achieved rapid and good serum free light chain responses and internationally, 
bortezomib is considered a good therapeutic option for myeloma patients with renal failure.  Both BBD and 
BTD have been evaluated in small groups of myeloma patients demonstrating significant activity and safety 
(25, 29). Data for renal reversibility exists for dexamethasone, thalidomide and bortezomib. The rationale 
of adding an alkylator to the combination is the synergism with these agents exhibited in trials and rapid 
clinical responses obtained, which is critical for improving outcomes for myeloma patients with renal 
failure.  
Thus there is rationale for comparing the effectiveness of a thalidomide, dexamethasone, and 
bendamustine regimen with a bortezomib, dexamethasone and bendamustine regimen on the basis that 
both are effective and can be given to patients even with advanced renal impairment. 
We hypothesise:  
1) A significant difference in achieving a reduction in sFLC levels during the first two cycles of therapy when 
comparing thalidomide versus bortezomib in combination with bendamustine and dexamethasone.  
2) Light chain response at the end of two cycles predicts response to four cycles of therapy; allowing early 
identification of poor responders who may benefit from alternative therapy. 
OPTIMAL can test how often poor early response to the first two cycles of randomised treatment will 
always be followed by poor response to two further cycles of the same therapy.  
 
 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 20 of 84 
 
4. OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS 
Table 4.1: Objectives and Outcome Measures/Endpoints 
 
Objectives 
Outcome Measures/Endpoints  
 
Primary 
 
To compare serum free light chain response to 
two cycles of therapy with either bortezomib (Arm 
A) or thalidomide (Arm B)  
 
 
To determine if myeloma response is associated 
with renal response at the end of cycle 4 (co-
primary end point) 
 
Proportion of participants with response 
defined  as >50% reduction (from  
baseline) in sFLC at week 6 (after 
receiving two cycles of therapy) 
 
Renal response at end of 4 cycles of 
therapy. Modified IMWG Uniform 
Criteria Of Response and Progression 
1998, 2006, 2011 
 
 
Secondary 
 
Assess whether early sFLC response can predict 
overall response and correlation with monoclonal 
protein in the urine 
 
 
Assess haematological and non–haematological 
toxicity in both treatment arms 
 
 
Survival  
 
 
 
 
 
Compare change in renal function by the end of 
cycles 2 and 4 between the two treatment 
regimens 
 
To evaluate treatment effects on other patient 
reported outcomes 
 
sFLC  response at the end of weeks 1, 2, 
3, 4, 5, 6, 9, & 12 of treatment with 
bortezomib (Arm A) or thalidomide (Arm 
B) 
 
Toxicity as defined by (NCI CTCAE v4.0)  
Haematological responses 
Adverse Events (NCI CTCAE v4.0) 
 
Overall survival from randomisation to 
end of study period (overall survival will 
be assessed  at 1 month post end of 
treatment and 12 months post 
randomisation) 
 
Renal response at end of second and 
fourth cycles of therapy  as defined by 
IMWG renal response criteria 
 
Quality of life measured by validated 
(EQ-5D-3L) questionnaire (38) 
 
 
 
 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 21 of 84 
 
5. TRIAL DESIGN 
OPTIMAL is a prospective, multicentre, open label, randomised control trial. At enrolment participants are 
randomised to one of two treatment groups:  
Arm A: Bortezomib, Bendamustine and Dexamethasone (BBD) 
Arm B: Thalidomide, Bendamustine and Dexamethasone (BTD) 
 
The trial aims to recruit 120 participants from up to 20 sites across the UK. . Participants will be randomised 
to receive an average of 4 cycles of either bortezomib (Arm A) or thalidomide (Arm B); all participants will 
receive bendamustine and dexamethasone in three week cycles. Treatment period for participants 
receiving 4 cycles of therapy will be 12 weeks.  
Participants not considered suitable for autologous stem cell transplant (ASCT) may be given up to a further 
two cycles of treatment (up to 6 cycles in total) in their respective arms. Treatment period for participants 
receiving additional cycles 5 and 6 will be 15 and 18 weeks respectively.  
Assessments will be performed during treatment as per schedule summarized in Appendix A. These include 
local laboratory evaluations, concomitant medications, significant toxicity and adverse events. Central 
laboratory sampling will be performed at the end of each treatment cycle (weeks 1, 2, 3, 4, 5, 6,  9 and 12) 
for both Arm A and B. Participants undergoing additional cycles with have reduced assessments for cycles 5 
and 6 with no central sampling during treatment. 
All participants who have received at least 2 cycles of treatment will be followed up. Assessments and 
sampling will be performed at 1 month follow-up post end of treatment (approximately 30 days after last 
dose). Data will then be requested at 12 months post randomisation.  
Participants will also be asked to complete a validated Quality of Life Questionnaire (EQ-5D-3L) on day 1 of 
each treatment and at 1 month and 12 month follow up.  
Any research specific assessments and sampling should coincide with routine clinical appointments 
wherever possible. Data will be recorded on to trial specific CRF’s and entered onto a database.  
See protocol section 7 and Appendix A for full details and schedule of assessment and sampling.  
 
 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 22 of 84 
 
Figure 4.1 
Trial flow diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessed for eligibility (n=130) 
Excluded (n=10) 
Arm A (n=60) 
Bortezomib, Bendamustine, and 
Dexamethasone (BBD)   
Arm B (n=60) 
Thalidomide, Bendamustine, and 
Dexamethasone (BTD) 
Bortezomib 
vs 
Thalidomide 
SECONDARY ENDPOINTS 
at end of 4-6 cycles therapy or significant toxicity 
 Serum free light chain (sFLC) response 
 sFLC response prediction based on 1st and 2nd cycle response 
 Drug toxicity 
 Overall survival 
Follow-up to end of therapy (4-6 cycles) + ≤30 days 
All patients will be followed-up 12 months post randomisation 
 
Randomised (n=120) 
Consented 
PRIMARY ENDPOINT 
 Serum free light chains (sFLC) response to first 2 cycles of chemotherapy 
CO-PRIMARY END POINT 
Renal response at end of 4-6 cycles of therapy 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 23 of 84 
 
6. PARTICIPANT IDENTIFICATION 
6.1. Trial Participants 
Patients with newly diagnosed myeloma with renal impairment defined as <30 mls/min are eligible to be 
included in the trial if they meet the following criteria.  
6.2. Inclusion Criteria 
 
Participant is willing and able to give informed consent for participation in the trial. 
 
Male or female, aged 18 years or above. 
 
Patients attending NHS Haemato-oncology centres. 
 
Patients with newly diagnosed symptomatic myeloma. 
 
Glomerular Filtration Rate (GFR) <30 mls/min. 
 
Chronic kidney disease (CKD) staging is based on estimated or measured GFR. CKD stage 4 (15-29 
ml/min) and CKD stage 5 (<15 ml/min) are eligible to enter the study. It is expected centres will 
consider use of fluid resuscitation and pulsed dose of steroid therapy in this group of patients to 
salvage renal function prior to trial screening. 
 
A number of patients with newly diagnosed myeloma and renal failure will have a pre-existing 
medical condition (hypertension, diabetes etc.) causing renal damage. Where there is a medical 
condition (e.g. hypertension, diabetes) which may cause renal damage, there must have been a 
further decline (≥15 mls/min GFR) between previous steady state and the study screening.  
 
Female participants of childbearing potential and male patients whose partner is a woman of 
childbearing potential must be willing to use contraception in accordance with (and consent to) the 
Celgene-approved process for thalidomide and lenalidomide Risk Management and Pregnancy 
Prevention Programme. 
 
Women of childbearing potential must have a negative pregnancy test performed by a healthcare 
professional in accordance with the Celgene-approved process for thalidomide and lenalidomide 
Risk Management and Pregnancy Prevention. 
 
Free of prior malignancies for  2 years with exception of currently treated basal cell, squamous cell 
carcinoma of the skin, localised prostate cancer or carcinoma “in-situ” of the cervix or breast. 
 
In the Investigator’s opinion, is able and willing to comply with all trial requirements. 
 
Willing to allow his or her General Practitioner and consultant to be notified of participation in the 
trial. 
 
 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 24 of 84 
 
6.3. Exclusion Criteria 
The participant may not enter the trial if ANY of the following apply: 
 
Female participant who is pregnant, lactating or planning pregnancy during the course of the trial or 
the female partner of a male participant planning a pregnancy during the course of the trial or are 
unwilling or unable to take sufficient precautionary measures 
 
Aged <18 years. 
 
Known allergy to investigational drugs. 
 
Any other significant disease or disorder which, in the opinion of the Investigator, may either put 
the participants at risk because of participation in the trial, or may influence the result of the trial, or 
the participant’s ability to participate in the trial. 
 
Any of the following laboratory abnormalities: 
o Absolute neutrophil count (ANC) < 1.0 x109/L 
o Platelet count <75 x 109/L 
o Serum SGOT/AST or SGPT/ALT >3 x upper limit of normal. 
 Use of any standard/experimental anti-myeloma drug therapy excluding dexamethasone 14 days 
prior to trial entry. 
 CKD stages < 4. 
 Intention to use a physical method of serum free light chain removal such as plasma exchange or 
high cut off dialysis. 
 Grade 2 neuropathy or more (NCI CTCAE v 4.0) will preclude use of thalidomide and Bortezomib. 
 Participants who have participated in another research trial involving an investigational product in 
the past 12 weeks. 
 Contraindicated to receive either one of the study drugs, thalidomide or Bortezomib, based on the 
respective summary of product characteristics. 
 
Researchers will advise patients presenting with suspected myeloma and renal failure, that if they sign 
an OPTIMAL consent form, they will be screened for myeloma. Only once eligibility is confirmed, will 
they be randomised into the OPTIMAL trial.  
 
 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 25 of 84 
 
7. TRIAL PROCEDURES 
Any trial related assessments will be performed only after written informed consent is obtained. All 
screening study assessments must be completed before investigational product administration. The 
schedule of assessments is provided in Appendix A.  Every effort should be made to keep participants on 
the study schedule as planned. 
 
Any missed visits, or tests or assessments not completed, must be reported on the relevant CRF with the 
reason for the missing data. Any protocol deviations must be reported to Trial Coordinator and 
documented on relevant CRF. 
7.1. Recruitment 
Patients presenting or referred to the haematology departments at a study site with possible myeloma and 
renal failure will be reviewed by the site’s study investigators.  Potential participants will have the purpose 
of the trial explained to them. Written and verbal explanation of the Participant Information Sheet (PIS) will 
be presented to potential participants detailing no less than: the exact nature of the trial; what it will 
involve for the participant; the implications and constraints of the protocol; the known side effects and any 
risks involved in taking part. It will be clearly stated that the participant is free to withdraw from the trial at 
any time for any reason without prejudice to future care, and with no obligation to give the reason for 
withdrawal. It will be explained that there are a series of screening assessments that will be performed 
after consent is given (see Section 7.3), and screened potential participants may not necessarily be eligible 
for the trial. It  
The participant will be allowed a minimum 24 hours to consider the information, and given the opportunity 
to discuss with the investigator, their GP or any other individuals in order to decide whether they will 
participate in the trial. The PIS will contain local contact details for researchers and an independent contact 
7.2. Informed Consent 
Each participant must personally sign and date the current approved version of the Informed Consent Form 
(ICF) before any trial specific procedures are performed. The correct version number and date of the PIS 
provided should be added to the Consent Form.  
Informed consent should be obtained by the local investigator (PI). If the PI is delegating the responsibility 
to other suitably qualified individuals as documented on the Site Staff and Delegation Log, it remains the 
responsibility of the PI to ensure that the standard procedures for informed consent within a clinical trial 
are followed.  
The local investigator is responsible for ensuring that the participants understand the risks and benefits of 
the trial, answering any questions the participants may have throughout the study, and sharing any new 
information that may be relevant to the participant’s continued participation in the trial.  
It is recommended that consent is taken before local bone marrow assessments, to enable trial specific 
bone marrow aspirate samples to be taken at the same time as standard local bone marrow samples.   
As part of the consent process, participants will also be asked to gift bone marrow samples and any 
additional blood and urine samples for future ethically approved research. This is optional and is not 
required for participation in the study.  These samples should only be sent if a participant has consented, 
and a copy of the participant Informed Consent Form included with the sample and CRF.  


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 26 of 84 
 
Participants in the study will need to consent for their data to be held in a database for research purposes, 
and for their information to be accessed by relevant research staff for the purposes of this trial, including 
OPTIMAL Coordinating Centre, Sponsor and research staff at sites. This will be detailed in the PIS and 
Informed Consent Form. All data will be handled according to Data Protection Act (1998) (see section 17). 
Participants will be informed of their rights and ability to withdraw from the trial at any time and without 
giving a reason.  A participant can withdraw consent fully or from specific aspects. This will be recorded 
using the relevant CRF. A participant can withdraw from any further sample or data collection but any 
samples and data already taken can still be used in data analysis. This is because samples are anonymized 
and so it is not possible to arrange for destruction of any existing samples or data. However, if a participant 
withdraws consent, no further samples or data will be collected. This will be clearly explained in the 
Participant Information Sheet and Consent Form. 
Additionally, participants will be asked to record on the ICF whether they wish to receive a summary report 
of the study findings. When available the summary report will be provided by the OPTIMAL Trial Office to 
local study teams for dissemination to the relevant consenting participants.  
The original signed Consent Form should be retained by the trial site and filed in local site file. A copy of the 
signed Informed Consent form should be given to the participant, and a copy of the Participant Information 
Sheet and Consent Form added to the participant’s medical notes.  
Copies of Consent Forms will also be requested by OPTIMAL Trial Coordinating Office for monitoring 
purposes. Consent Forms will be stored separately to any study data or other personal data and will be 
transferred using secure methods only.  
Participants will be able to access the standard benefits locally available to all myeloma patients. No 
additional monetary payments as part of trial will be made. 
7.3. Screening and Eligibility 
7.3.1 Screening Logs 
Investigators will be expected to maintain a screening log of all potential participants at their site.  
Participants will not be registered at consent and therefore during screening potential participants should 
be identified by limited information only, including Initials and Date of Birth, as well as screening date and 
outcome of the screening process (e.g. enrolled into study, reason for ineligibility, or refused to 
participate).  
Screening logs will be requested from sites by the OPTIMAL Trial Team on a monthly basis. Copies of the 
screening logs should also be filed locally. 
 
7.3.2 Screening Assessments 
The following assessments will be carried out in order to establish eligibility for the trial.  
All screening study assessments must be completed before any investigational product is administered. 
 
The following screening procedures must be completed not more than 21 days before the day of 
randomisation. In addition clinical laboratory evaluations and screening central labs samples must be taken 
not more than 14 days before the day of starting treatment. Please refer to Appendix A. 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 27 of 84 
 
 
Medical History 
Detailed history of myeloma including; date of diagnosis, staging (International Staging System - - 
see Appendix C), and location(s) of bone disease as per standard of care. Detailed description of all 
prior and on-going diseases and disorders should be documented.   
 
Treatment History and Concomitant Medication(s) 
Details of treatment history and current concomitant medication including all medications, 
treatments and therapies used in the prior 4 weeks, as well as those currently being taken. 
 
Physical Examination 
Physical examination including assessment of ECOG performance status (refer to Appendix B for 
ECOG performance status), height and weight (to calculate drug dose), and baseline neuropathy.  
 
Skeletal Survey/MRI 
Skeletal survey (including spine) as per local standard of care, and MRI if clinically indicated. 
 
Chest X-ray and Electrocardiogram (ECG) 
A chest X-ray and ECG will be carried out during the screening process as per standard of care and 
any abnormalities recorded in the relevant CRF.  
 
Local Clinical Laboratory Evaluations (not more than 14 days before start of treatment ) 
 
Biochemistry: Sodium, Potassium, Total Protein, Albumin, Adjusted Calcium, 
Bicarbonate, Magnesium, Phosphate, Urea, Creatinine, LFTs, CRP, LDH, Uric acid, 
Glucose,  Creatinine Clearance  
 
Immunology: Beta-2 microglobulin, sFLC, paraprotein, quantitative immunoglobulins  
 
Haematology:  haemoglobin, haematocrit, bilirubin,  WBC, platelet count, neutrophils, 
lymphocytes and monocytes 
 
Bone marrow assessment: Bone marrow aspirate and trephine to confirm diagnosis of 
myeloma  
 
Urine Pregnancy Test: for women of child-bearing potential (WCP) (Appendix G)  
 
 Screening Central Laboratory Samples (not more than 14 days before start of treatment) ) 
The following samples should be collected and sent to central labs as detailed below:  
Screening Samples for Birmingham Central Labs: 
 
Bone marrow aspirate 2 ml (EDTA) * 
 
Blood 5 ml (EDTA)  
 
Blood 10 ml (clotted)  
Urine 20 ml (universal) - for inpatients undergoing 24 hour urine collection, please 
collect 20 ml aliquot sample in universal container 
Screening Samples for Oxford Central Labs: 
 
Bone marrow aspirate 5 ml (EDTA) * 
 
Bone marrow aspirate 2 unstained slides *  
*Bone marrow samples are optional gifted samples – for consenting participants only  
See Protocol Section 8 and ‘Central Laboratory Sample Handling Manual’ for further details on laboratory 
and sampling requirements and processes.  


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 28 of 84 
 
7.4 Registration and Randomisation  
7.4.1 Recruitment Logs 
 
Participants deemed eligible after screening will be registered on to the trial. Registered participants will be 
recorded on a recruitment log with information including Study ID, Date of Birth, Initials and hospital 
number as well as date of consent, date of randomisation and treatment allocation. No personal 
information which may identify the participant should be included on the recruitment log.   
7.4.2 Randomisation 
 
Randomisation will be performed by Warwick Clinical Trials Unit (CTU). A computer minimisation program 
will be used and participants will be stratified according to:  
1) Age (<=70 or >70 years).  
2) Chronic kidney disease (CKD) stage 4 or stage 5. 
To randomize a participant, researchers should ensure they have completed both the eligibility and 
randomisation forms and then contact Warwick CTU by phone or alternatively fax the randomisation form 
on the details below: 
 
  
  
 
 
 
Participant will be randomized to either group A or group B and assigned a unique Study ID. This 
information will be given over the phone and/or confirmed by email. This unique Study ID will become the 
primary way in which the participant will be identified for the duration of the study and should be included, 
together with initials and date of birth, on all relevant trial documentation and correspondence. 
 
7.4.3 Participant Trial Card 
After a participant has been randomized site staff should inform the participant of their treatment 
allocation as soon as they are able to and provide the participant with a completed Participant Trial Card 
including details of their treatment allocation and local site contact details. 
 
 
Warwick Clinical Trials Unit 
Tel: 02476 150402 (Mon-Fri, 9am to 5pm) 
Fax: 02476 151586 (Mon-Fri, 9am to 5pm) 
 
Please ensure you have completed the eligibility checklist 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 29 of 84 
 
7.5 Treatment and Subsequent Assessments 
7.5.1 Treatment: Cycles 1-4  
 
All participants will undergo the following assessments during treatment cycles 1-4 (as per schedule, 
summarised in Appendix A): 
 
Day 1 of Cycles 1-4: 
 
 
Physical Examination  
Weight and assessment of ECOG performance status (see Appendix B) 
 
 
Concomitant Medication 
Details of current concomitant medication including all medications, treatments and therapies will 
be collected throughout treatment cycle from day 1 and recorded on the relevant CRF. This 
includes any changes since previous trial visit. 
 
Quality of Life Questionnaire 
Participants will be asked to complete a validated Quality of Life Questionnaire (EQ-5D-3L) (see 
Appendix E) on day 1 of each cycle administered  
 
Local Clinical  Laboratory evaluations (see Appendix A) 
 
Biochemistry: Sodium, Potassium, Total Protein, Albumin, Adjusted Calcium, 
Bicarbonate, Magnesium, Phosphate, Urea, Creatinine, LFTs, CRP, LDH, Uric acid, 
Glucose,  Creatinine Clearance  
 
Immunology: Beta-2 microglobulin, sFLC, paraprotein, quantitative immunoglobulins  
 
Haematology:  haemoglobin, haematocrit, bilirubin,  WBC, platelet count, neutrophils, 
lymphocytes and monocytes 
 
Urine pregnancy test: For women of child-bearing potential (see Appendix G for a 
definition). To be carried out either the day before, or on day 1 of each cycle of 
treatment. 
 
Parenteral Drugs administered at local hospital 
Bortezomib (Arm A only) - days 1, 4, 8 and 11 of each cycle 
Bendamustine (Arm A and B) – days 1 and 8 of each cycle 
 
Drug Dispensing and Treatment Diary Card(s) 
Dexamethasone (Arm A and B) and thalidomide (Arm B) dispensed to participants 
Participants given relevant Participant Treatment Diary Card(s) for completion  
 
Adverse Event Reporting 
Details of Adverse Events will be collected throughout treatment cycle and recorded on relevant 
CRF. This includes any changes since previous trial visit. 
 
During Treatment Cycles 1-4: 
 
Concomitant Medications 
Any changes in concomitant medication including all medications, treatments and therapies will be 
collected throughout treatment cycle and recorded at end of cycle on the relevant CRF. 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 30 of 84 
 
 
Central Samples (Birmingham) will be collected to monitor changes in serum and urine 
paraprotein, sFLC levels and renal function at the end of weeks 1, 2, 3, 4, 5, 6, 9 and 12 
o Blood in EDTA 5ml 
o Blood clotted 10ml 
o Urine sample 20ml in universal container - for inpatients undergoing 24 hour urine 
collection, please collect 20 ml aliquot sample in universal container 
 
 
Parenteral Drugs administered at local hospital 
Bortezomib (Arm A only) - days 1, 4, 8 and 11 of each cycle 
Bendamustine (Arm A and B) – days 1 and 8 of each cycle 
 
Adverse Event Reporting 
Details of any Adverse Events should be collected throughout treatment cycle and recorded at the 
end of cycle on relevant CRF. This includes follow up information for previous Adverse Events. 
 
Samples should be sent in packaging provided together with a completed Birmingham Sample CRF form to: 
Clinical Immunology Service, PO Box 1894, Vincent Drive, Edgbaston, Birmingham, B15 2SZ 
See Protocol section 8 and ‘Central Laboratory Sample Handling Manual’ for further details on laboratory 
and sampling requirements and processes.  
 
End of Cycles of 1-4: 
 
Concomitant Medications 
Any changes in concomitant medication including all medications, treatments and therapies will be 
collected throughout treatment cycle and recorded at end of cycle on the relevant CRF. 
 
Drug Accountability and Collection of Treatment Diary Card(s) 
Collection of completed Participant Treatment Diary Card(s) for dexamethasone (Arms A and B) and 
thalidomide (Arm B) 
 
Adverse Event Reporting  
Details of any Adverse Events should be collected throughout treatment cycle and recorded on 
relevant CRF. This includes follow up information for previous Adverse Events. 
 
Survival 
 
Completion of Treatment Form CRF 
 
7.5.2 Treatment: Cycles 5 and 6  
 
Responding participants not considered suitable for autologous stem cell transplant (ASCT) may be given up 
to two further cycles of treatment in their respective arms. Participants receiving additional cycles will 
undergo the following reduced assessments (see Appendix A):  
 
 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 31 of 84 
 
Day 1 Cycles 5-6 
 
Physical examination  
Weight assessment of ECOG performance status (see Appendix B) 
 
Concomitant medication 
Details of current concomitant medication including all medications, treatments and therapies will 
be collected throughout treatment cycle from day 1 and recorded on the relevant CRF. This 
includes any changes since previous trial visit. 
 
Quality of Life Questionnaire 
Participants will be asked to complete a validated Quality of Life Questionnaire (EQ-5D-3L) (see 
Appendix E) on day 1 of each cycle administered  
 
 
Local Clinical  Laboratory evaluations (see Appendix A) 
 
Biochemistry: Sodium, Potassium, Total Protein, Albumin, Adjusted Calcium, 
Bicarbonate, Magnesium, Phosphate, Urea, Creatinine, LFTs, CRP, LDH, Uric acid, 
Glucose,  Creatinine Clearance  
 
Immunology: Beta-2 microglobulin, sFLC, paraprotein, quantitative immunoglobulins  
 
Haematology:  haemoglobin, haematocrit, bilirubin,  WBC, platelet count, neutrophils, 
lymphocytes and monocytes 
 
Urine pregnancy test: For women of child-bearing potential (WCP) (see Appendix G for 
definition). To be carried out either day before, or on day 1 of each cycle of treatment. 
 
 
Parenteral Drugs administered at local hospital 
Bortezomib (Arm A only) - days 1, 4, 8 and 11 of each cycle  
Bendamustine (Arm A and B) - days 1 and 8 of each cycle 
 
Drug Dispensing and Treatment Diary Card(s) 
Dexamethasone (Arm A and B) and thalidomide (Arm B) dispensed to participants 
Participants to be given relevant Participant Treatment Diary Card(s) for completion 
 
Adverse Event Reporting 
Details of Adverse Events will be collected throughout treatment cycle and recorded on relevant 
CRF. This includes any changes since previous trial visit. 
 
During Treatment Cycles 5-6 
 
Concomitant Medications 
Any changes in concomitant medication including all medications, treatments and therapies will be 
collected throughout treatment cycle and recorded at end of cycle on the relevant CRF. 
 
Parenteral Drugs administered at local hospital 
Bortezomib (Arm A only) - days 1, 4, 8 and 11 of each cycle 
Bendamustine (Arm A and B) - days 1, 4, 8 and 11 of each cycle 
 
Adverse Events Reporting 
Details of any Adverse Events should be collected throughout treatment cycle and recorded at the 
end of cycle on relevant CRF. This includes follow up information for previous Adverse Events. 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 32 of 84 
 
End of Cycles 5-6 
 
Concomitant Medications 
Any changes in concomitant medication including all medications, treatments and therapies will be 
collected throughout treatment cycle and recorded at end of cycle on the relevant CRF. 
 
Drug Accountability and Collection of Treatment Diary Card(s) 
Collection of completed Participant Treatment Diary Card(s) for dexamethasone (Arms A and B) and 
thalidomide (Arm B) 
 
Adverse Event Reporting  
Details of any Adverse Events should be collected throughout treatment cycle and recorded on 
relevant CRF. This includes follow up information for previous Adverse Events. 
 
Survival 
 
Completion of Treatment Form CRF 
Please note: NO Central Laboratory Samples required for participants undergoing treatment cycles 5-6. 
7.6 1 Month Follow-up post Treatment  
 
All participants completing at least 2 cycles of treatment will undergo the following assessments 
approximately 30 days after the final treatment or discontinuation of treatment (Appendix A): 
 
Physical examination  
Weight and assessment of ECOG performance status (see Appendix B) 
 
 
Drug Accountability and Collection of Treatment Diary Card(s)  
Collection of completed Participant Treatment Diary Card(s) for dexamethasone (Arm A and B) and 
thalidomide (Arm B) for last cycle of treatment 
 
Local Clinical Laboratory Evaluations  
 
Biochemistry: Sodium, Potassium, Total Protein, Albumin, Adjusted Calcium, 
Bicarbonate, Magnesium, Phosphate, Urea, Creatinine, LFTs, CRP, LDH, Uric acid, 
Glucose,  Creatinine Clearance  
 
Immunology: Beta-2 microglobulin, sFLC, paraprotein, quantitative immunoglobulins  
 
Haematology:  haemoglobin, haematocrit, bilirubin,  WBC, platelet count, neutrophils, 
lymphocytes and monocytes 
 
Bone marrow assessment: Bone marrow aspirate and trephine for response 
assessments 
 
Urine pregnancy test:  For women of child-bearing potential (WCP) (for definition of 
WCP see Appendix G) this final test should be performed 30 days after last dose of 
study drug 
 
 
 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 33 of 84 
 
 Central Laboratory Samples (Birmingham)  
 
Bone marrow aspirate 2 ml (EDTA) * 
 
Blood 5 ml (EDTA)  
 
Blood 10 ml (clotted)  
 
Urine 20 ml (universal) - for inpatients undergoing 24 hour urine collection, please 
collect 20 ml aliquot sample in universal container 
 Central Laboratory Samples (Oxford)  
 
Bone marrow aspirate 5 ml (EDTA) * 
 
Bone marrow aspirate 2 unstained slides *  
*Bone marrow sample are optional gifted samples – for consenting participants only  
 
 
Quality of Life Questionnaire 
Participants will be asked to complete a validated Quality of Life Questionnaire (EQ-5D-3L) 
(Appendix E) 
 
Adverse Events Reporting 
Details of any Adverse Events since end of last treatment cycle should be recorded on relevant CRF. 
This includes follow up information for any previous Adverse Events. 
 
Treatment Efficacy Information 
Assessment Response and Disease Progression: Serum paraprotein, serum FLCs, renal response and 
overall response will be assessed using  International Myeloma Working Group (IMWG) Uniform 
Response Criteria for Multiple Myeloma (36, 37) (See Appendix D) . Details on immunofixation and 
imaging (if clinically required). 
 
Survival 
 
See Protocol section 8 and ‘Central Laboratory Sample Handling Manual’ for further details on laboratory 
and sampling requirements and processes.  
       7.7 12 Month Follow-up post Randomisation  
Participants will undergo the following assessments approximately 12 months after randomisation (see 
Appendix A): 
 
 
Physical examination - Weight and assessment of ECOG performance status (see Appendix B) 
 
Disease status 
 
Local Clinical Laboratory Evaluations 
 
Biochemistry: Creatinine Clearance, eGFR only 
 
Clinical assessment 
 
Adverse Events Reporting - Details of any Adverse Events since last follow up visit should be 
recorded on relevant CRF. This includes follow up information for any previous Adverse Events. 
 
Summary of Treatment - Including hospital admission history since end of trial treatment and 
subsequent anti-myeloma treatment 
 
Survival 
If participant is unable or unwilling to attend clinical appointment, 12 month follow up can be completed 
using hospital notes, if participant has given consent.  


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 34 of 84 
 
7.8. Withdrawal or Change of Status of Participants 
7.8.1 Withdrawal 
Participants have the right to withdraw from any aspect of the trial at any time and without giving a reason. 
In addition, the Investigator may withdraw a participant from some or all aspects of the trial at any time if 
the Investigator considers it necessary for any reason including: 
 
 
Pregnancy – In the case of pregnancy in a female participant the participant must be withdrawn 
from trial treatment immediately (pregnancy is an exclusion criteria), and participant should remain 
on-study for follow-up, unless the participant or clinician specifically requests otherwise. Any 
pregnancy in female participants or female partners of male participants should be reported to the 
OPTIMAL Trial Office using SAE Reporting Form as an “other medically important event” and CRF 
Pregnancy Form A within 24 hours of awareness. Consent to follow-up of the pregnancy should be 
sought, and the outcome of the pregnancy reported to OPTIMAL Trial Office using CRF Pregnancy 
Form B. (See protocol Section 10 for further details of Safety Reporting).  
 
Physical clearance of free light chains - Participants undergoing either plasma exchange or high cut 
off dialysis must be withdrawn from study. 
 
Ineligibility either arising during the trial, or retrospectively after becoming aware of ineligibility  
 
Significant protocol deviation 
 
Significant non-compliance with treatment regimen or trial requirements. 
 
Significant toxicity 
 
Adverse event which requires discontinuation of the trial medication or results in inability to 
continue to comply with trial procedures. 
 
Disease progression which requires discontinuation of the trial medication or results in inability to 
continue to comply with trial procedures. 
 
Withdrawal of consent 
 
Loss to follow up  
Withdrawal can be from all aspects of the trial or from certain aspects only. For example, it may be 
necessary for a participant to discontinue with trial treatment but every effort should be made to keep 
participants on-study for follow-up and central laboratory sampling as per protocol, unless a participant or 
clinician explicitly requests otherwise.  
 
Sites should discuss any Withdrawals with Chief Investigator via OPTIMAL Trial Office prior to 
withdrawing a participant. 
 
After withdrawal has been discussed with the Chief Investigator, any change in status or withdrawal should 
be documented on the relevant Withdrawal CRF including reason(s) for withdrawal, and which specific 
aspects of the trial the participant is being withdrawn from.  Details of withdrawal should also be 
documented in the participant’s hospital notes.  
 
If a participant or clinician withdraws consent for further sampling, this should be recorded on the 
OPTIMAL Withdrawal Form and the OPTIMAL Trial Coordinator should be notified that no further samples 
will be taken for that participant. Sites must ensure all local staff are informed that no further sampling 
should be undertaken.  
 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 35 of 84 
 
If further sampling is not possible but consent has not specifically been withdrawn e.g. participant moves to 
palliative or residential care, this does not need to be recorded as a withdrawal but sites should notify the 
OPTIMAL Trial Coordinator that no further samples will be collected and note on relevant CRF’s. 
 
Sites should ensure all local site staff are informed of any withdrawals or change of status to ensure that no 
further sampling or follow up is undertaken for participants who have withdrawn consent. 
 
If a participant is withdrawn from further treatment but has completed at least 2 treatment cycles , the 
participant should be followed-up at approximately 30 days after their final treatment (as per the 1 month 
follow-up post treatment (see Section 7.6.) and at 12 months post-randomisation (see Section 7.7), unless 
the participant or clinician specifically requests otherwise.  
 
If a participant is withdrawn due to an adverse event, the Investigator should arrange for follow-up visits or 
telephone calls to take place until the adverse event has resolved or stabilised. 
 
Due to the sampling process and anonymising of data, it is not possible for participants to request that 
existing data or samples are destroyed and any existing data can be included in study analysis. However, if a 
participant withdraws consent, no further samples or data will be collected.  
 
7.8.2 Loss to Follow Up 
 
Every effort should be made to continue participant follow up as per protocol and ensure participant 
contact details are updated as required. If a participant is unable to be contacted for an extended period of 
time and follow-up not able to be completed, this should be recorded on the Withdrawal CRF as ‘Loss to 
Follow up’. It should also be documented in the participant’s hospital notes. 
 
7.8.3 Participant Transfer 
 
For participants moving from the area, every effort should be made for the participant to be followed-up at 
another participating trial site and for this trial site to take over responsibility for the participant. If the 
participant is happy to transfer to another site and continue follow up, the main trial contact at the current 
hospital should liaise with the OPTIMAL Trial Coordinator to identify a suitable receiving hospital (if 
possible) and facilitate the transfer. (participant names must be removed from any documentation). 
 
The contact at the current hospital should complete a Participant Transfer form and send to the OPTIMAL 
Trial Office prior to the participant transfer. Any data queries for the participant should be completed prior 
to transfer if possible. Copies of any relevant trial documentation including Informed Consent Form must 
be sent to the new hospital to complete the transfer and copies must be also retained at the original site 
for monitoring purposes. 
 
7.9 Definition of End of Trial 
The end of trial will be the date of the last 12 month follow-up visit of the last participant.   
All pregnancies during trial period will be followed to completion, if participant has given consent. 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 36 of 84 
 
8. LABORATORY AND SAMPLING 
8.1 Local Clinical Laboratory Evaluations  
The following routine local clinical laboratory evaluations will be performed as per schedule (Appendix A) 
and the data and results used for the purposes of this trial: 
 Biochemistry: Sodium, Potassium, Total Protein, Albumin, Adjusted Calcium, Bicarbonate, 
Magnesium, Phosphate, Urea, Creatinine, LFTs, CRP, LDH, Uric acid, Glucose,  Creatinine Clearance 
(Creatinine clearance in ml/min to be measured based on the following abbreviated MDRD equation 
: 186 x (Creat / 88.4)-1.154 x (Age)-0.203 x (0.742 if female) x (1.210 if black) using creatinine 
micromol/L. The calculator for this can be found at http://www.renal.org/egfrcalc/) 
 Immunology: Beta-2 microglobulin, sFLC, paraprotein, quantitative immunoglobulins  
 Haematology:  haemoglobin, haematocrit, bilirubin,  WBC, platelet count, neutrophils, lymphocytes 
and monocytes 
 Bone marrow assessment: Bone marrow aspirate and trephine to confirm diagnosis of myeloma 
and renal response  
 Urine pregnancy testing: For women of child-bearing potential (WCP) (see appendix G for 
definition) at screening, and again on the day of, or the day before, day 1 of each cycle. Final test 
should be done approximately 30 days after the last dose of study drug. 
8.2 Central Laboratory Samples 
The following research specific clinical laboratory evaluations should be performed as per schedule (see 
Appendix A and table 8.1). 
 
8.2.1 Central Laboratory Samples (Birmingham): 
 
 
Bone marrow aspirate (2ml EDTA) at screening, and 1 month post end of treatment (or 
discontinuation of treatment) * 
 
Blood and urine for central laboratory analysis of quantitative immunoglobulins, Beta-2 
microglobulin,  free light chains, immunofixation of serum and urine, paraprotein quantitation by 
densitometry at screening, at the end of weeks 1, 2, 3, 4, 5, 6, 9, & 12 of treatment and 1 month 
post end of treatment (or discontinuation of treatment);  
o Blood 5 ml (EDTA) 
o Blood 10 ml (clotted) 
o Urine 20 ml  in universal container - for inpatients  undergoing 24 hour urine collection, 
please collect 20 ml aliquot sample in universal container 
 
*Bone marrow samples are additional gifted samples – for consenting participants only. Local bone marrow 
assessments will be used to confirm diagnosis at screening.  
 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 37 of 84 
 
Blood and urine samples will be used in analysis of sFLC and renal response for primary and secondary 
endpoints.  Blood samples will be analysed to try and compare the rate of production and removal of light 
chains between treatments, which may help to guide treatment decisions. Urine samples will be used for 
the assessment of sFLC, paraprotein and immunoglobulins, and for measuring renal response using IMW 
consensus criteria. 
All samples should be accompanied by a Birmingham Central Sample CRF with a copy of the participant’s 
Informed Consent Form.   
 
Boxes/packaging will be sent to each site following site initiation. Please be aware that postage is not pre-
paid. Samples should be sent first class post on the day of collection to the following address: 
 
 
 
 
 
 
 
 
 
 
 
 
8.2.1.1 Sampling timing 
 
Samples should to be taken as close as possible to the end of the week (day 7 of each week) +/- 2 days is 
acceptable i.e. if end of treatment week 1 falls on a Sunday (day 7 of week 1), blood and urine samples may 
be taken on the previous Friday (day 5 of week 1) or following Monday or Tuesday (days 1 or 2 of week 2).  
 
If a participant’s treatment is delayed please keep to the specified sampling time-points calculating 
sampling from the start of treatment, and add in additional sample collections to cover all required time-
points. For example, if cycle 3 is delayed- take blood and urine samples at week 9 and 12 post start of 
treatment (regardless of where the participant is in their treatment schedule) and add in additional 
samples at the end of week 3 of cycle 3 and the end of week 3 of cycle 4. These should be recorded as 
“other” with details in the relevant sample CRF. 
 
If an on-treatment sample is missed, do not wait until the next time-point; take the missed sample as soon 
as possible and record the time-point (as ‘other’ with details) on the CRF (immunology sample analysis 
request form). 
 
 
 
Clinical Immunology Service, PO Box 1894,  
Vincent Drive, Edgbaston, Birmingham, B15 2SZ 
Fax: (0)121 414 3069 
Please include copies of completed Birmingham Sample CRF and signed 
participant Informed Consent Form 
Please refer to the “Central Laboratory Sample Handling Manual” for 
further details on preparation, logging and postage of Central Laboratory samples 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 38 of 84 
 
8.2.2 Central Laboratory Samples (Oxford) 
 
Bone marrow aspirate at screening and 1 month follow-up post end of treatment (or discontinuation of 
treatment): 
 
Bone marrow aspirate 5 ml (EDTA) * 
 
Two unstained slides of bone marrow aspirate. * 
 
*Bone marrow samples are additional gifted samples – for consenting participants only.  
 
All samples should be accompanied by an Oxford Central Sample CRF and a copy of the participant’s 
consent form. Consent Forms can be sent either by post or secured email using details below. If Consent 
Form is sent via post it must be sent separately to any trial data or documentation such as CRF. 
 
Boxes/packaging will be send to each site following site initiation. Please be aware that postage is not pre-
paid. Samples should be sent first class post on the day of collection. Please do not post bone marrow 
aspirate samples to Oxford on a Friday. If collection of bone marrow aspirate samples on a Friday is 
unavoidable, please refrigerate samples over the weekend and post on the following Monday.  
 
Samples should be sent first class post on the day of collection to the following address: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FAO Molecular Haematology Lab (OPTIMAL Trial) 
Level 4, Academic Centre 
John Radcliffe Hospital, Headley Way, Headington, Oxford,  
OX3 9DU 
Email: maite.cabes@nhs.net  
Please ensure you enclose copy of the Oxford Central Sample CRF and a copy of the 
participant’s consent form 
Please refer to the “Central Laboratory Sample Handling Manual” for further 
details on preparation, logging and postage of central laboratory samples 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 39 of 84 
 
Table 8.1 summarising sampling requirements at time points during study. 
 
Screening / 1 
month FU 
Treatment 
(each cycle) 
Documents 
Address 
BIRMINGHAM 
Bone marrow 
aspirate EDTA 
(2ml)  
Blood EDTA 5ml 
Blood (clotted) 
10ml 
Urine container 
20ml 
 
Blood EDTA 5ml 
Blood (clotted)  
10ml 
Urine container 
20ml   
Birmingham 
Central Sample 
Form (CRF 19) 
 
Copy of Consent 
Form required 
Send to: 
Clinical 
Immunology 
Service 
PO Box 1894 
Vincent Drive 
Edgbaston, 
Birmingham 
B15 2SZ 
OXFORD 
Bone marrow 
aspirate EDTA 
(5ml)  
2 x slides 
unstained bone 
marrow (slide 
box)  
 
 
--------------- 
Oxford Central 
Sample Form    
(CRF 18) 
 
Copy of Consent 
Form required 
Send to: 
FAO Maite Cabes 
Molecular 
Haematology Lab 
Level 4, John 
Radcliffe Hospital 
Headley Way, 
Headington 
Oxford, OX3 9DU 
 
 
8.2.3 Notifying Trial Office of Samples 
 
Please notify OPTIMAL Trial Office when samples are collected and sent using the contact details below: 
 
 
 
 
 
8.3 Additional gifted samples 
 
Bone marrow samples will be collected and sent to Central Laboratories in Oxford and Birmingham to be 
stored for future ethically approved research, if participant has consented. Participants will also be asked to 
consent for any remaining serum and urine samples obtained for this trial to be stored indefinitely and 
used for future ethically approved research.  Future research may include assessing percentage of myeloma 
Notifying OPTIMAL Trial Office of Samples  
Please notify OPTIMAL Trial Office when samples are collected and sent by sending 
OPTIMAL “Notification of Samples Form” 
Email: OPTIMAL.trial@nhs.net 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 40 of 84 
 
cells before treatment and at the end of treatment, including Minimum Residual Disease, morphology and 
MM FISH, and assessment of chromosomal and molecular difference before and after treatment 
For additional gifted samples stored at Oxford Central Laboratory, the CI will be responsible for the 
custodial arrangements. For additional gifted samples stored at Birmingham Central Laboratory, the 
Director Clinical Immunology Service will be responsible for the analysis of these samples and the storage 
of any remaining non-cellular samples at the end of the study. 
8.4 Availability and prioritisation of samples 
 
Central laboratory samples should be taken at the same time as routine local samples wherever possible. If 
this is not possible or there is insufficient sample, local samples should be prioritised and researchers 
should confirm with the participant and treating clinician that an additional research sample can be taken.  
It is recommended that during screening consent is taken before local bone marrow assessments, to enable 
trial specific bone marrow aspirate samples to be taken at the same time as standard local bone marrow 
samples.   
Research specific blood and urine samples should be prioritised research samples as these are required for 
primary and secondary endpoints. Bone marrow samples are additional gifted samples although every 
effort should be made to obtain these if possible, for consenting participants. 
 
 
9. INVESTIGATIONAL MEDICINAL PRODUCTS (IMPs) 
Bortezomib and thalidomide will be considered Investigational Medicinal Products (IMPs) in this trial. 
Bendamustine and dexamethasone will be considered non-Investigational Medicinal Products (nIMPs) in 
this trial  
Prior to Site Initiation Visit (SIV) each PI will be required to sign confirming their Trust’s compliance with the 
standard thalidomide Celgene pregnancy prevention programme.     
9.1 Trial Treatments  
Participants will be randomised to receive one of two treatment schedules: 
Arm A 
Bortezomib, Bendamustine and Dexamethasone (BBD) 
Participants > 70 years of age the dose of dexamethasone will be reduced from 40 mg to 20 mg daily 
Days 1, 4, 8 and 11 Bortezomib 1.3 mg/m2* subcutaneous **  
Days 1, 8  Bendamustine 60 mg/m2 intravenous infusion 
Days 1-2, 4-5, 8-9 and 11-12 Dexamethasone 40 mg daily orally 
The cycle is repeated every 3 weeks (21 days).  


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 41 of 84 
 
*For cycles 3-4 (and 5-6, where relevant) Bortezomib may be given as 1.3 mg/m2 weekly for 3 weeks in a 21 
day cycle in combination with Bendamustine and dexamethasone as per local practice.  The dosing regimen 
used must be documented in the CRF. 
**or intravenous infusion- see section 9.3 “route of Bortezomib administration”; if intravenous infusion is 
required due to participant intolerance of subcutaneous treatment, please contact the Chief Investigator 
and Trial Coordinator providing details for reasons for change. 
 
Arm B 
Thalidomide, Bendamustine and Dexamethasone (BTD)  
Participants > 70 years of age, the dose of dexamethasone will be reduced from 40 mg to 20 mg daily 
Days 1 to 21 Thalidomide 100 mg daily p.o. preferably at night 
Days 1, 8  Bendamustine 60 mg/m2 intravenous infusion 
Days 1-2, 4-5, 8-9 and 11-12 Dexamethasone 40 mg daily orally 
The cycle is repeated every 3 weeks (21 days).  
 
Total number of cycles (Arm A and B): All participants will receive four 21 day cycles. Autologous stem cell 
transplant (ASCT) as consolidation therapy is standard of care for <65 year old newly diagnosed patients. 
Participants not considered for ASCT, will continue on therapy in the form of BTD or BBD (based on their 
initial randomisation) up to a total of 6 cycles or significant toxicity. 
 
9.1.1 Supportive Therapies 
The following concomitant medications are permitted:  
 
Co-trimoxazole 480 mg - three times per week PO or alternative for PCP prophylaxis as per local 
institutional practice 
 
Omeprazole 20 mg - once daily PO whilst on dexamethasone 
 
Metoclopramide 10-20 mg-  three times per day PO as required and on days of Bendamustine 
 
Allopurinol 100 mg - orally daily 
 
Aciclovir 200 mg-  twice per day, orally 
 
Thromboprophylaxis must be initiated for all participants on the BTD treatment arm and may be required 
for participants on the BBD arm based on risk assessment – consider use of Aspirin or Warfarin orally as 
LMWH is contraindicated at GFR <30 mls /min. However, if renal recovery occurs, participants can be 
switched to LMWH subcutaneously based on local practice. 
 
The role of anti-bacterial prophylaxis is uncertain in these patients. Local protocols for antibiotic use 
should be adopted. 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 42 of 84 
 
9.2 Dose Modifications 
 
All dose reductions must be recorded in the relevant CRF. 
 
9.2.1 Thalidomide Dose Modification: 
Neuropathy: Thalidomide should be stopped or reduced if there are symptoms of progressive neuropathy 
causing functional disability.  If the drug is stopped, re-introducing thalidomide after a 2 week gap at 50 
mg/day with subsequent cautious dose escalation may be considered if symptoms permit. 
9.2.2 Bortezomib Dose Modification: 
Dose modifications for bortezomib will be based on the drug summary of product characteristics (SmPC).  
Dose reductions to 1.0 mg/m2 and 0.7 mg/m2 are permitted.  If further reductions are required the 
bortezomib treatment should be stopped and further treatment options discussed with the Chief 
Investigator. 
 
Dose reduction for neuropathy grade 2 with pain or grade 3 attributed to bortezomib should be reported as 
an SAE as detailed in Section 10.6. 
9.2.3 Bendamustine Dose Modification: 
 
Myelosuppression:  If the neutrophil count falls below 1.0 x 109/L with therapy, or platelets below 50 x 
109/L, bendamustine should be temporarily discontinued.  Start participants on G-CSF and platelet support 
until counts recover (Neutrophils > 1.0 x109/l and platelets >50 x 109/l); consider reintroducing 
bendamustine at 50% of original dose. If dose reduction is employed please record this on the relevant CRF. 
Renal Impairment:  a 50% dose reduction should be implemented for patient participants with a GFR of 
less than 10ml/min 
9.2.4 Dexamethasone Dose Modification: 
A dose reduction in dexamethasone should occur only for Grade 3 or 4 corticosteroid toxicities. 
Dexamethasone should be reduced to 20 mg per day if dose reduction is required. Further dose levels of 10 
mg daily and 5 mg daily can also be considered if there is on-going toxicity.  In exceptional circumstances, 
subjects may not tolerate sudden steroid withdrawal at the end of 4 days of dexamethasone therapy. In 
such an instance, and after the first cycle, a tapering regimen of dexamethasone (10 mg on day 5; 6 mg on 
day 6; 2 mg on day 7 then stop) can be prescribed. 
   9.3 Bortezomib Route of Administration  
A small proportion of participants on subcutaneous bortezomib experience local site reactions. If a Principal 
Investigator (PI) wishes to switch a participant from subcutaneous to intravenous injection, due to 
intolerance, it must be recorded as an Adverse Event in the CRF.  The PI should change the injection site at 
the next infusion and if the participant remains intolerant, record as an Adverse Event and contact the 
Chief Investigator (CI), via the Trial Coordinator, with all relevant information. The CI will review the 
information provided. If the Chief Investigator approves the switch, the Trial Coordinator will forward the 
recommendation to Janssen–Cilag Ltd for their approval. If approved, Janssen-Cilag will provide participant 
specific stock of the drug to the site pharmacy via B&C. If a route change is employed it must be recorded in 
the relevant CRF. jSee Appendix J for a flow chart summarising switch of route of administration. 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 43 of 84 
 
9.4 Irradiated Blood Products  
 
Bendamustine is a bifunctional agent with antimetabolite and alkylating agent properties.  It is mandatory 
that all participants treated in this trial receive irradiated blood products to prevent transfusion associated 
graft versus host disease. 
 
9.5 Labeling, Storage, Accountability and Ordering of Study Drugs 
9.5.1 Ordering of Study Drugs 
9.5.1.1 Bortezomib 
Upon site activation, the OPTIMAL Trial Office will inform B&C and confirm site set up for supply of 
bortezomib. The site pharmacist will need to order the initial supply of Bortezomib for subcutaneous 
administration. Site pharmacies should ensure they have sufficient stock of Bortezomib SC stored at site 
ready to be allocated at participant registration and randomisation. We recommend ordering sufficient 
drugs for the first cycle of treatment; one carton of Bortezomib SC (10 blistered vials, 3.5 mg each).  
Each site pharmacist will request supply of bortezomib by faxing or emailing the completed OPTIMAL Trial 
drug order form to the OPTIMAL Coordinating Team on the details below. The Trial Coordinator will review 
and approve the shipment to be released from B&C. Confirmation of shipment from B&C will be sent by 
email to site pharmacists and the Trial Coordinator. Please allow a minimum of 7 working days from order 
date for delivery.  
 
 
 
 
 
OPTIMAL Trial Office will request a monthly log of trial drug distribution from B&C for monitoring purposes. 
9.5.1.2 Bendamustine, Thalidomide, Dexamethasone 
 
Sites should obtain bendamustine, thalidomide and dexamethasone directly from local pharmacy stock in 
accordance with local procedures and guidelines. It is the responsibility of site pharmacies to ensure 
sufficient stock of bendamustine, thalidomide, dexamethasone is stored locally for participants on trial.  
 
9.5.2 Labeling of Study Drugs 
Bortezomib and thalidomide are registered as Investigational Medicinal Products (IMPs) in this trial.  B&C 
Group will distribute bortezomib centrally directly to trial sites with trial specific labels in accordance with 
current regulatory requirements.  
Thalidomide will be sourced locally at individual trial sites as per routine practice. Site pharmacists will be 
responsible for labeling thalidomide for trial use in accordance with regulation 46 SI2004/1031 and detailed 
Drug Ordering (Bortezomib) 
Please send completed OPTIMAL drug order form to OPTIMAL Trial Team: 
Email:OPTIMAL.trial@nhs.net 
 
Please allow a minimum of 7 working days from order date for delivery  


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 44 of 84 
 
guidance provided in Annex 13 of the EU Good Manufacturing Practice Guide. Sites will be provided with a 
label for use as part of the trial. 
Bendamustine and dexamethasone are registered as non-Investigational Medicinal Products (nIMPs) in this 
trial. Both bendamustine and dexamethasone will be sourced locally at individual trial sites as per routine 
practice and do not require labelling for trial use.   
 
9.5.3 Storage and Dispensing of Study Drugs  
Please refer to the current SmPCs for details of storage for unopened and reconstituted products. Sites 
should follow their own local SOPs for storage and temperature monitoring. Storage records for all trial 
drugs must be maintained and made available for review on request. Any temperature excursions whilst 
stored on site must be reported to the Sponsor (via the Trial Coordinator). Affected stock should be 
quarantined and must not be used until the affected stock is verified as suitable for use. The decision on 
suitability of IMP will be made by the drug provider and confirmed by the Trial Office to sites, ensuring the 
Sponsor is made aware. For further details on this please see the OPTIMAL Pharmacy Manual.   
The study drugs will be dispensed as per standard Clinical Trials procedures from the hospital pharmacy. It 
is not feasible to blind the randomisation as one treatment contains an intravenous component. 
 
9.5.4 Accountability of Study Drugs 
It is the responsibility of the local pharmacists to ensure full drug accountability records are maintained for 
all IMPs (bortezomib and thalidomide). For further details of requirements please refer to the Pharmacy 
Manual. Records of accountability may be requested by Sponsor or OPTIMAL Trial Coordinating Team for 
monitoring purposes. No pharmacy accountability of bendamustine and dexamethasone will be required 
for this trial, although participants will be required to complete Participant Treatment Diary Card(s) for 
dexamethasone and thalidomide assessing participant compliance (see Section 9.6).  
  
 
9.5.5 Unavailability of Study drug 
 
If due to unforeseen or exceptional circumstance a trial specific drug is not available, commercial stock can 
be used on the condition that it is confirmed that the trial specific and commercial stock are identical in 
terms of manufacturing and product quality. Sites must contact Sponsor and OPTIMAL Coordinating Team 
who will review the circumstances and use of commercial stock. This would need to be approved by CI and 
Sponsor prior to implementation. Both CI and Sponsor must be notified when trial stock is available for use 
again. The cost of this will be the responsibility of the individual host organisation. 
9.6. Participant Compliance and Treatment Diary Card(s) 
Bendamustine and bortezomib will be administered on site.  Any reasons for non-administration should be 
documented in the relevant CRF. Thalidomide and dexamethasone are dispensed to participants. 
Participants will be requested to return all empty, unused or part used thalidomide and/or dexamethasone 
medication and packaging from used medication at each visit to the researcher. The researcher will record 
any unused medication in the relevant CRF, prior to returning the drugs to pharmacy.  


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 45 of 84 
 
Participants will also be given a Participant Treatment Diary Card by the researcher to complete for each 
cycle of thalidomide and/or dexamethasone. This must be completed by the participant to confirm that all 
doses were taken and if any were missed to record the details and reason.  
Participants randomized to Arm A (bortezomib, bendamustine and dexamethasone) will only complete a 
Treatment Diary Card for dexamethasone. Participants randomized to Arm B (thalidomide, bendamustine 
and dexamethasone) will need to complete Treatment Diary Cards for both dexamethasone and 
thalidomide. 
The Treatment Diary Card(s) should be collected at the end of each cycle of treatment and returned to the 
OPTIMAL Trial Office with the accompanying Treatment CRF. Site staff should also retain a copy locally.  
9.7 Study Drug Destruction 
Destruction of any returned participant medication should be completed as per local procedures once 
accountability and compliance checks have been completed. Confirmation of destruction may be requested 
by OPTIMAL Trial Team for monitoring purposes. 
9.8 Concomitant Medication 
Details of any concomitant medication (any medication, other than the trial product, that is taken during 
the trial) should be recorded at trial entry (i.e. Screening) and then again on the first and last day of each 
treatment cycles.  
Any changes in concomitant medication during treatment cycles should be recorded at the end of week 3 
of each treatment cycle. Any changes in concomitant medication between trial visits (i.e. between 
Screening and first treatment cycle, or between two different treatment cycles) should be recorded on day 
of the next treatment cycle.   
If there has been no change in concomitant medication please state this clearly on relevant CRF. 
If any change influences the participant’s eligibility to continue in the trial, as per inclusion/exclusion 
criteria, the Chief Investigator and/or Trial Coordinator must be informed and any withdrawal documented 
on the relevant Withdrawal CRF (see section 7.8).  
9.9 Post-trial Treatment 
Participants will be deemed to have completed the trial when they have completed the 12 month follow-up 
post randomisation. Participants should discuss further treatment and continuing care with their clinician 
and clinical care team. 
 
Please refer to the “Pharmacy Manual” for further details on IMP and pharmacy 
related procedures and requirements. 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 46 of 84 
 
10. SAFETY REPORTING 
10.1 Definitions 
Adverse Event (AE) 
Any untoward medical occurrence in a participant to whom a medicinal product has been 
administered, including occurrences not necessarily caused by or related to that product. 
Adverse Reaction (AR) 
 
An untoward and unintended response in a participant to whom an investigational 
medicinal product has been administered, which is related to any dose administered to 
that participant. 
The phrase "response to an investigational medicinal product" means that a causal 
relationship between a trial medication and an AE is at least a reasonable possibility, i.e. 
the relationship cannot be ruled out. 
All cases judged by either the reporting medically qualified professional or the Sponsor as 
having a reasonable suspected causal relationship to the trial medication qualify as 
adverse reactions. 
Serious Adverse Event 
(SAE) 
A serious adverse event is any untoward medical occurrence that: 
 
results in death 
 
is life-threatening* 
 
requires inpatient hospitalisation or prolongation of existing hospitalisation** 
 
results in persistent or significant disability or incapacity 
 
consists of a congenital anomaly or birth defect. 
 
Other medically important event e.g. pregnancy (see section 9.6)*** 
*The term "life-threatening" refers to an event in which the participant was at risk of 
death at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe. 
** “Hospitalisation” is defined as an inpatient admission, regardless of length of stay, 
even if the hospitalisation is a precautionary measure for continued observation. 
Hospitalisations for a pre-existing condition (including elective procedures that have not 
worsened) do not constitute an SAE. 
*** “Other medically important events” may not be immediately life threatening or 
result in death or hospitalisation, but may also be considered serious if they jeopardise 
the participant or require an intervention to prevent one of the above consequences (e.g. 
suspected transmission of an infectious agent by a medicinal product is a serious event). 
Medical judgment should be exercised in deciding whether an AE/AR or other important 
medical event require expedited reporting. Any AE is considered serious if it is associated 
with clinical signs and symptoms judged by the investigator to have a significant clinical 
impact 
Serious 
Adverse 
Reaction (SAR) 
An adverse event that is both serious and, in the opinion of the reporting Investigator, 
believed with reasonable probability to be due to one of the trial treatments, based on 
the information provided. 
Suspected Unexpected 
Serious 
Adverse 
Reaction (SUSAR) 
A serious adverse reaction, the nature and severity of which is not consistent with the 
information about the medicinal product in question set out: 
 in the case of a product with a marketing authorisation, in the summary of product 
characteristics (SmPC) for that product (OPTIMAL Study) 
 in the case of any other investigational medicinal product, in the investigator’s 
brochure (IB) relating to the trial in question. 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 47 of 84 
 
NB: To avoid confusion or misunderstanding of the difference between the terms “serious” and “severe”, the 
following note of clarification is provided: “Severe” is often used to describe intensity of a specific event, 
which may be of relatively minor medical significance. “Seriousness” is the regulatory definition supplied 
above. 
Any pregnancy occurring during the clinical trial and the outcome of the pregnancy should be recorded and 
followed up for congenital abnormality or birth defect, at which point it would fall within the definition of 
“serious”. Please refer to Section 10.9 for procedures in the case of pregnancy. 
10.2 Assessment of Causality 
The relationship of each adverse event to the trial medication must be determined by a medically qualified 
individual according to the following definitions: 
Classification 
Definition 
Drug 
Related 
(Related) 
The adverse event follows a reasonable temporal sequence from trial 
medication administration. It cannot reasonably be attributed to any other 
cause. 
Not Drug Related 
(Unrelated) 
The adverse event is probably produced by the participant’s clinical state or 
by 
other 
modes 
of 
therapy 
administered 
to 
the 
participant. 
 
 
10.3 Assessment of Expectedness 
Expectedness will be determined using the current Summary of Product Characteristics (SmPC) for each 
drug. SmPC’s are also available using the following link:  http://www.medicines.org.uk/emc/   
It is the responsibility of the site staff to make sure the most recent version of the SmPC is used when 
assessing expectedness. Updated SmPC’s will be provided to sites by the Trial Office. 
If there are any updated SmPC’s for any of the trial drugs, the CI will review and assess whether there are 
any clinically significant changes. If there is a significant change on review by the CI, these will be submitted 
as a substantial amendment to regulatory authorities. If there is no significant change, these updated 
SmPC’s will be submitted with the next DSUR.  
     10.4 Terminology and Assessment of Severity 
An adverse event term must be provided for each serious adverse event or adverse reaction, preferably 
using the Short Name as listed in the Common Terminology Criteria for Adverse Events v4.03 (CTCAE).  
Severity of each Adverse Event or Reaction must be determined by using the Common Terminology Criteria 
for Adverse Events v4.03 (CTCAE) as a guideline, wherever possible. The criteria are available online at:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
 
In those cases where the CTCAE criteria do not apply, severity should be coded according to the following 
criteria: 1 = Mild 2 = Moderate 3 = Severe and recorded on CRF  
 
 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 48 of 84 
 
  10.5 Reporting Non-Serious Adverse Events  
All non-serious Adverse Events, whether expected or not, occurring during the time period from 
randomisation until the final study visit (12 months post-randomisation) that are observed by the 
Investigator, or reported by the participant, must be recorded on the relevant  CRF, whether or not 
attributed to trial medication. The following information should be recorded: description of event, date of 
onset and end date, severity, assessment of relatedness to trial medication and outcome. Follow-up 
information should be provided as necessary as soon as available. 
The severity of events will be assessed using the Common Terminology Criteria for Adverse Events V 4.03 
(CTCAE) as a guideline, wherever possible and using the following scale:  1 = mild, 2 = moderate, 3 = severe. 
The CTCAE criteria are available online at:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
AEs considered related to the trial medication as judged by a medically qualified investigator or the Sponsor 
must be followed up either until resolution, or until the event is considered stable. 
It will be left to the Investigator’s clinical judgment to decide whether or not an AE is of sufficient severity 
to require the participant’s removal from treatment.  A participant may also voluntarily withdraw from 
treatment due to what he or she perceives as an intolerable AE.  If either of these situations occurs, the 
participant should undergo an end of trial assessment and be given appropriate care under medical 
supervision until symptoms cease, or the condition becomes stable. The researcher should record details 
on the Withdrawal CRF and continue to follow-up the participant as per the trial protocol, unless 
specifically requested otherwise by the clinician or participant.  
10.6 Reporting Serious Adverse Events  
All SAEs must be reported immediately (within 24 hours of awareness) during the time period from 
randomisation to 30 days following last administration of IMP.  Please note: this period is 24 working hours 
so if a site becomes aware of an SAE on Friday it can be reported on the Monday, although it is advised to 
send as soon as possible. 
Each SAE must be reported on OPTIMAL SAE Reporting Form. When reporting an initial SAE the ‘initial’ box 
must be checked to indicate an initial report and the following minimum information is required:  
description of event, date of onset, severity, and assessment of causality and relatedness to trial 
medication.  A separate SAE Form should be used for each SAE. 
 
The SAE Form must be signed by the site Investigator (consultant name on the Site Signature and 
Delegation Log who is responsible for the participant’s care). The Investigator must assess the severity, 
causality and expectedness of the event. In the absence of the responsible investigator the form should be 
completed and signed by another suitably qualified member of the site trial team. The responsible 
investigator should subsequently check the SAE form, make changes as appropriate, sign and then send to 
the OPTIMAL Trial Coordinator as soon as possible by secured email using the details below: 
 
 
 
 
 
 
SAE REPORTING 
Please send all SAE Forms to OPTIMAL Trial Team within 24 hours of becoming aware of event: 
Email:OPTIMAL.trial@nhs.net 
(Mon-Fri, 9am to 5pm, excluding public holidays or dates when notice has been given by the Trial Coordinator) 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 49 of 84 
 
The OPTIMAL Trial Coordinator will confirm receipt of the SAE Reporting Form and provide a unique SAE 
Reference Number as confirmed by the Sponsor. This SAE reference number should be added to all SAE 
documentation and be quoted in all follow-up correspondence.  
 
 Follow-up information should be reported on a blank OPTIMAL SAE Reporting Form by ticking the box 
marked ‘follow-up’, including follow up information and an end date and outcome when known. 
Participants must be followed-up until clinical recovery is complete and laboratory results have returned to 
normal or baseline, or until the event has stabilised. 
  
Sites should refer to Safety Reporting guidance document provided by OPTIMAL Trial Office and contact CI 
or Trial Coordinator to discuss any queries or issues relating to AE’s or SAE’s. 
10.7 Foreseeable Events that DO NOT require reporting as an SAE 
The following table lists foreseeable events that fulfill the definition of an SAE related to myeloma and its 
treatment and but do not require expedited reporting as an SAE for this trial. 
Foreseeable SAE’s which do not require expedited reporting as an SAE for this trial must be recorded in the 
relevant section(s) of the CRF. 
Table 10.1. Forseeable Events that fulfill the definition of an SAE but do not require expedited reporting 
for this trial.  
Foreseeable Events that DO NOT require expedited reporting as an SAE for this trial 
These SAE’s should be recorded on relevant CRF. 
Disease progression  
Disease related deaths  
Routine treatment or monitoring of the studied indication not associated with any deterioration in 
myeloma condition  
Treatment, which was elective or pre-planned, for a pre-existing condition, not associated with any 
deterioration in myeloma condition 
Hospitalisation for palliative care  
Grade 1-4 haematological toxicity is an expected consequence of effective treatment, and is only required 
to be reported if it fulfills the criteria of an SAE as defined above (see  Section 9.1)  
Treatment (including hospitalisation, or extension of hospitalisation) for transfusions or pain relief  
Surgical interventions for skeletal related events, e.g. fixation of fractures, vertebroplasty  
Increased bone pain 
Febrile neutropaenia 
Alopecia 
 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 50 of 84 
 
10.8. Foreseeable SAEs that DO require immediate reporting as SAEs 
The following table lists foreseeable events that fulfill the definition of an SAE related to myeloma and its 
treatment which do require expedited reporting as an SAE for this trial. 
Foreseeable SAE’s which do require expedited reporting as an SAE for this trial must be reported on an SAE 
Reporting Form as per protocol (see section 10.6).  These should be reviewed and assessed for severity, 
relatedness and causality by a medically qualified person. 
Table 10.2. Forseeable Events that fulfill the definition of an SAE that do require expedited reporting for 
this trial.  
Foreseeable Events that DO require expedited reporting as an SAE for this trial 
These SAE’s should be reporting immediately using an SAE Reporting Form 
Hyperglycaemia  grade 3 or above 
Neuropathy grade 2 with pain or grade 3 
Venous thromboembolism  
New bone fractures or spinal cord compression during therapy  
Development of any grade 4 non-haematological toxicity (excluding alopecia) 
 
Sites should refer to the current Summary of Product Characteristics (SmPC) for each drug for more specific 
details and potential drug interactions. Please see the OPTIMAL Pharmacy Manual for further details. 
10.9 Procedures in Case of Pregnancy  
If a female participant or the partner of a male participant becomes pregnant at any time from the date of 
randomisation to 30 days after final study drug administration, the pregnancy must be reported to the 
OPTIMAL Trial Coordinator within the same timelines as an SAE and classified as an “other medically 
important event” on the SAE Reporting Form. Both a completed SAE Reporting Form and Pregnancy Report 
Form A CRF (Appendix H) must be submitted to the Trial Coordinator by secured email within 24 hours of 
awareness. The Investigator should seek consent to report information regarding the outcome of the 
pregnancy from the mother.  
10.9.1 Pregnancy Follow-Up Reports  
All pregnancies should be followed-up until an outcome is determined (if participant consent is given). 
Follow-up Pregnancy Report Form B CRF (Appendix I) must be submitted to the OPTIMAL Trial coordinator 
by secured email within 1 business day of learning of the outcome. Reports must include an evaluation of 
the possible relationship of the trial treatment to the pregnancy outcome.  
 10.9.2 SAEs During Pregnancy  
Any SAE occurring during pregnancy must be reported using the SAE Reporting Form, according to SAE 
reporting procedures detailed in Section 10.6.  


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 51 of 84 
 
10.9.3 Pregnancy Report Processing at Sponsor site  
The OPTIMAL Trial Coordinator will submit all Pregnancy Reports concerning participants or partners who 
have received or have been exposed to any IMPs to Janssen-Cilag (Bortezomib only) and the Sponsor 
Representative (Oxford University Hospitals NHS Foundation Trust R&D department) within 24 hours of 
awareness. The CI with the Sponsor will submit a report to the MHRA and REC should the pregnancy 
outcome meet the definition of a SUSAR. 
10.10 SUSAR Reporting 
All SUSARs will be reported by the CI to the relevant Competent Authority, REC and any other parties as 
applicable. For fatal and life-threatening SUSARS, this will be done no later than 7 calendar days after the 
Sponsor or delegate is first aware of the reaction. Any additional relevant information will be reported 
within 8 calendar days of the initial report.  All other SUSARs will be reported within 15 calendar days. 
Principal Investigators will be informed of all SUSARs for the relevant IMP for all studies with the same 
Sponsor, whether or not the event occurred in the current study. 
10.11 Review of SAEs  
10.11.1 OPTIMAL Trial Office and Sponsor Responsibilities 
The joint Oxford University Hospitals NHS Foundation Trust / University of Oxford Trials Safety Group (TSG) 
will conduct a review of all SAEs for the trial reported during the quarter and cumulatively. The aims of this 
committee include: 
 
To identify any trends, such as increases in un/expected events, and take appropriate action 
 
To seek additional advice or information from investigators where required 
 
To evaluate the risk of the trial continuing and take appropriate action where necessary 
 
The Trial Coordinator will forward all SAEs to the Chief Investigator and the Sponsor representative (Oxford 
University Hospitals NHS Foundation Trust R&D department) who will perform an initial check of the 
report, request any additional information, and ensure it is reviewed by the Sponsor’s medically qualified 
Medical Monitor, with oversight and input from the Chief Investigator. All SAEs will also be reviewed at the 
Trial Safety Group meeting.  
Additional and further information, including follow-up or corrections to the original case, will be requested 
from site staff by the Trial Coordinator as required and forwarded to the Chief Investigator and Sponsor 
Representative. 
Oxford University Hospitals NHS Foundation Trust is undertaking the duties of trial Sponsor and is 
responsible for the reporting of SUSARs and other SARs to the regulatory authorities (MHRA) and the 
research ethics committees as appropriate.  
 
The OPTIMAL Trial Office and Sponsor will keep all investigators informed of any safety issues that arise 
during the course of the trial. 
 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 52 of 84 
 
10.11.2 Development Safety Update Reports (DSURs) 
 
The CI will submit (in addition to the expedited reporting detailed above for SAE’s and SUSAR’s) 
Development Safety Update Report (DSUR’s) once a year throughout the clinical trial, or on request, to the 
Competent Authority (MHRA in the UK), Research Ethics Committee (REC), host NHS Trust and Sponsor. A 
copy will be sent to sites for filing locally in site files. 
 
10.11.3 Safety Reporting Responsibilities to Janssen-Cilag  
The Sponsor, Chief Investigator, or suitably delegated individuals, will submit to the identified 
representative of Janssen the following safety information for participants receiving bortezomib (Arm A): 
 
Copies of all SAEs reported during the study for participants randomized to receive bortezomib 
(Arm A) 
 
Details of all AE’s reported during the study for participants randomized to receive bortezomib 
(Arm A), provided annually and in a final report within 6 months of completion of  treatment of last 
participant  
 
Copies of annual trial specific Development Safety Update Reports (DSURs) sent to the Competent 
Authorities and Research Ethics Committees (following causality and expectedness assessments 
made as applicable for the current study sponsored by the institution and/or principal investigator); 
 
The Sponsor and Chief Investigator shall notify Janssen-Cilag immediately in case of a suspension of 
recruitment or premature cessation of the concerned clinical study because of a safety concern; 
preferably by means of a telephone contact with the Company Representative, alternatively by fax 
within 24 hours of the decision;  
11. DATA AND SAFETY MONITORING COMMITTEE (DSMC) 
A Data and Safety Monitoring Committee (DSMC) will remain in place throughout the study and hold a 
meeting at least once annually.   
11.1 Primary Responsibilities of the DSMC 
To safeguard the interests of trial participants, assess the safety and efficacy of the interventions during the 
trial, and monitor the overall conduct of the clinical trial. 
The DSMC remit will include making recommendations to the Trial Steering Committee (TSC) (see section 
12). The DSMC will receive and review the progress and accruing data of this trial and provide advice on the 
conduct of the trial to the TSC. The DSMC should inform the Chair of the TSC if, in their view: 
 
there are concerns about the safety of one or more of the treatment arms 
 
the results show a benefit of one treatment arm over another that is so large, and precise, that it is 
likely to convince a broad range of clinicians to change practice 
 
it is evident that if the trial continued it would fail to show a clear benefit for any treatment arm 
 
accrual is so low that it is unlikely that a sufficient number of participants would be recruited to 
provide meaningful results 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 53 of 84 
 
Interim analysis will take place after 60 participants (who have completed at least 2 cycles of treatment) 
have been recruited. During interim analysis, the DSMC will review the data unblinded to the treatment 
arms and may make recommendations to amend or terminate the trial if there are unacceptable toxicities 
or excess of events in one treatment arm. In addition, participant safety will be reviewed assessing the 
reported toxicity for the recruited cohort of participants. 
11.2 Membership of the DSMC 
 
The DSMC is an independent group consisting of clinicians and other appropriate professionals who have 
pertinent experience in the management of adult participants with haematological cancer, particularly 
participants diagnosed with multiple myeloma, as well as in the conduct and monitoring of randomised 
clinical trials. A DMC Charter outlines the roles and responsibilities of the DMC. Each member of the DSMC 
is expected to serve until a final assessment of safety data is completed.   
12. TRIAL STEERING COMMITTEE (TSC) 
A TSC comprising of an independent chair, the Chief Investigator, Trial Coordinator, representative of the 
Sponsor and at least one other clinician not directly associated with the trial, will remain in place 
throughout the study.  
The TSC will provide advice and oversight on trial management and any trial related issues. The roles and 
responsibilities of the TSC are outlined in the TSC charter.  
The TSC will consider the advice of the DSMC and may consider discontinuing the trial if the recruitment 
rate or data quality are unacceptable or if the trial compromises participant safety in any way. The TSC may 
also recommend that the trial stop early if the interim analyses (60 participants who have completed at 
least 2 cycles) showed differences between treatments in terms of efficacy. 
The TSC will meet at least once annually although may meet more frequently to discuss specific issues 
arising, or in e event of any concerns. 
13. STATISTICS 
Data presented in December 2011 at the American Society of Haematology conference from a single centre 
retrospective analysis of 112 patients presenting with renal impairment in Greece suggests that bortezomib 
(n=30 patients) containing regimens act more rapidly than thalidomide containing regimes (n=53 patients) 
with significant differences in response (83% vs 61%) (34). In addition, a retrospective analysis of 54 
patients not uniformly treated from 18 centres in 10 countries showed that 73% of patients demonstrated 
a reduction in sFLC over the course of treatment with 86.7% of these patients (i.e. 63% of all patients) 
demonstrating decreased sFLC levels by day 12 (35). Bortezomib patients had a median reduction of 79% by 
day 12 compared to 66% in the thalidomide patients. This was a retrospective audit and some patients may 
have received a combination of thalidomide and bortezomib. There were centres which also employed 
different types of high cut off dialysers and it is not yet clear if that plays an important role in reduction of 
sFLC. 
These data imply that a 35% difference between treatment arms may not be achieved. Recruiting 60 
patients in each arm can detect a more realistic lesser difference between treatment arms. This will allow 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 54 of 84 
 
the detection of 23% differences in the percentage of patients achieving >50% reduction in sFLC between 
treatment arms, e.g. from 60% to 83%, with 80% power and a 5% 2-sided significance level, assuming no 
drop-out. This will also allow the detection of 24% differences in the percentage of patients achieving >50% 
reduction in sFLC between treatment arms e.g. from 60% to 84%, with 80% power and a 5% 2-sided 
significance level, assuming 10% drop-outs. 
For the secondary endpoint of percentage reduction in sFLC, 55 patients on each arm would allow the 
detection of a standardised difference of 0.55 or greater with 80% power and a 5% 2-sided significance 
level. This is just looking at the results at one time point and we will also undertake longitudinal analysis for 
each patient to explore changes over time. These data will be logged in order to accommodate the 
expected extreme values. 
13.1 Interim Analysis 
There are no formal stopping rules for the trial since 120 participants are needed to be able to detect the 
23% expected difference between treatments. However an interim analysis is planned once the first 60 
participants have been randomised into the trial and completed at least 2 cycles of chemotherapy. The 
interim analysis will assess the proportion of participants achieving >50% reduction in sFLC following two 
cycles of chemotherapy in order to test the power calculation assumptions.  
In addition, participant safety will be reviewed assessing the reported toxicity for this first cohort of 60 
participants.  The DSMC will review the data unblinded to the treatment arms and may make 
recommendations to amend or terminate the trial if there are unacceptable toxicities or excess of events in 
one treatment arm.  
13.2 Final Analyses  
The proportion of participants achieving varying levels of sFLC response at the end of 2 cycles of treatment 
will be compared using a chi-squared test.  The secondary endpoints of sFLC response, renal response, 
toxicity and survival will be assessed once all participants have been followed up for at least 12 weeks (or 
until withdrawn).  
Survival will be calculated from the date of consent to the date of death within the first 12 weeks (or up to 
week 18 for those participants receiving cycles 5 & 6) , or censored as alive at 12 weeks if death occurred 
after this time or if no date of death was recorded. Kaplan-Meier curves will be compared across 
treatments and median survival will be estimated for each treatment group both unadjusted and adjusted 
for age and CKD 4/5.  
Prediction model for renal recovery based on sFLC response will be explored using multivariate techniques 
with adjustment for treatment, age, CKD 4/5 and other clinical factors as appropriate. 
13.3 Patient Reported Outcomes 
Patient Reported Outcomes will be measured using validated EuroQoL Quality of Life (EQ-5D-3L) Heath 
questionnaires (38). Participants will be asked to complete a questionnaire on day 1 of each treatment 
cycle and at 1 month and 12 month follow up visits. Summary statistics will be used to assess change from 
baseline to follow up. 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 55 of 84 
 
13.4 Termination of the Trial 
In the event that the trial is terminated early; all participants will be advised accordingly and local 
investigators should discuss with participants a return to standard NHS care.  
The trial will be terminated prematurely if: 
 
Mandated by the Research Ethics Committee 
 
Mandated by the Competent Authority (MHRA in UK)  
 
Following recommendations from the Data and Safety Monitoring Committee (DSMC) 
 
The interim analysis does not support the continuation of the study 
 
There are safety issues which cannot be resolved 
 
The study is unlikely to capture creditable data 
 
Funding for the trial ceases 
 
Withdrawal of Sponsorship or NHS permission 
 
The Sponsor, regulatory authorities, and site investigators will be advised and the requisite forms 
completed and submitted according to regulatory timelines. 
If the trial has been concluded or terminated early, the CI in conjunction with the Sponsor, must ensure the 
Research Ethics Committee and Competent Authority (MHRA in the UK) is notified in writing within 15 days 
of the decision.   Funders or any other relevant parties will also be notified in writing. 
13.5 Inclusion in Analysis 
Participants who fulfil the eligibility criteria, consent to take part in the study, are randomised, and receive 
at least two cycles of treatment will have their data included in the study analysis.  In the event that a 
participant has withdrawn from the trial, any existing data can be used in data analysis.  
14. DATA MANAGEMENT 
14.1 Source Data 
Source documents are where data is first recorded, and from which participants’ CRF data is obtained. 
These include, but are not limited to, hospital records (from which medical history and previous and 
concurrent medication may be summarised into the CRF), clinical and office charts, laboratory and 
pharmacy records, diaries, microfiches, radiographs, and correspondence. 
14.2 Case Report Forms (CRF’s) and Data Recording  
All trial data will be entered onto paper CRFs at sites and transferred to OPTIMAL Coordinating Centre 
where it will be entered into a validated database. Sites will not have access to the trial database and all 
data will be entered centrally at Oxford. Hardcopy copies of CRF’s will be filed securely at OPTIMAL Trial 
Coordinating Centre and electronic copies will also be taken. Every effort should be made to complete trial 
documentation as fully as possible and in accordance with the protocol. OPTIMAL Trial Coordinating team 
will contact sites to request any missing or additional information and this should be provided in a timely 
manner. 
 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 56 of 84 
 
At randomisation participants will be assigned a unique Study ID No. which will be used alongside 
Participant Initials and Date of Birth to identify the participant on all trial documentation.  Identifiable data 
will not be included in any trial documentation or the database. Sites should ensure that participant Study 
ID No. is clearly written on each page of each CRF and that separate CRF’s are secured so that it is clear 
which CRF relates to which participant. Sites should ensure copies of all CRF’s are taken before posting and 
filed locally to avoid any loss of data.  
 
Sites should send completed CRF’s via secure post to the OPTIMAL Coordinating Centre using the contact 
details below. Screening, Eligibility and Randomisation CRF’s should be sent immediately to OPTIMAL 
Coordinating Centre via secure email, with hardcopies to follow via post. Randomisation Forms should also 
be sent to Warwick CTU via fax, if not using telephone randomisation (see section 7.4).  Treatment CRF’s, 
including QoL questionnaire and Participant Treatment Diary Cards can be sent in batches via post to 
OPTIMAL Coordinating Centre, preferably at the end of each treatment cycle. 1 month Follow UP CRF’s, 
including QoL questionnaire and Participant Treatment Diary Cards, and 12 month Follow UP CRF should be 
sent via post to the Coordinating Centre upon completion of CRF.  
 
The relevant Central Laboratory Sampling CRF should be sent with the participant samples, and a copy also 
sent to OPTIMAL Coordinating Centre via post in batches. A copy of the participant Informed Consent Form 
must also be sent for both Oxford and Birmingham Central samples (see section 8)  
 
Adverse Events CRF’s can be sent in batches alongside associated CRF’s. Serious Adverse Event CRF’s must 
be sent immediately as per SAE Reporting procedures (see section 10.6).  
 
In the case of Participant Transfer, Death or Withdrawal (see section 7.8), sites should complete and send 
the relevant completed CRF via post to the Coordinating Centre as soon as they become aware of the 
change. If the Death may be related to an SAE sites should gather required information as soon as possible 
to complete the SAE and Death Form. Withdrawal Forms should be completed as soon as possible after a 
withdrawal decision has been made. 
 
Copies of Informed Consent Forms should be sent only via secure email address, or if sent via post should 
be sent separately to any study documentation to ensure anonymity. Original signed Consent Forms should 
be retained at sites. 
 
If frequent postage is an issue for sites, sites can email copies of CRF’s and send original copies in periodical 
batches.  This is excluding screening, eligibility and randomisation forms which must be sent prior to a 
participant entering the trial. 
 
 
 
 
 
 
 
 
 
 
Sending CRF’s and Documents 
OPTIMAL Coordinating Team 
Late Phase Haematology Research Team 
Churchill Hospital 
Headington 
Oxford, OX3 7LE 
 
Email: OPTIMAL.trial@nhs.net 
 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 57 of 84 
 
14.3 Archiving 
 
All trial documentation should be archived at site as per local NHS guidelines before being destroyed. 
OPTIMAL Trial Team will contact sites to arrange for the transfer of any relevant documentation relating to 
study close-down and archiving.  
15. QUALITY ASSURANCE PROCEDURES 
 
The trial will be conducted in accordance with the current approved protocol, ICH GCP, and all other 
relevant regulations and standard operating procedures.  
       15.1 Monitoring and Audit 
Sponsor representative monitors from Oxford University Hospitals NHS Foundation Trust and regulatory 
authority inspectors are responsible for contacting the Chief Investigator for the purpose of monitoring.  
The monitor is responsible for verifying the CRFs at regular intervals throughout the study to verify 
adherence to the protocol and GCP; completeness, accuracy, and consistency of the data and, on the 
conduct of clinical research. The monitor should have access to participant medical records and other 
study-related records needed to verify the entries on the CRFs. The monitor will ensure that all data is 
handles according to the Data Protection Act (1998) and that participant confidentiality is respected. 
The investigator agrees to cooperate with the monitor to ensure that any problems detected in the course 
of these monitoring visits, including delays in completing CRFs, are resolved. Any discrepancies found 
between source documents and completed CRFs will be addressed by the study site. Every effort should be 
made to account for any missing data from the CRF. 
OPTIMAL Coordinating Trial team will contact sites at least once annually for the purposes of monitoring, 
either remotely or in person. There may also be additional triggered monitored visits if there is cause for 
concern or a specific issue has been identified. In all cases sufficient notice will always be given and a time 
convenient for all parties agreed. OPTIMAL Trial Coordinating Team will monitor only anonymised trial 
documentation and will not access or verify identifiable information or medical notes.   
16. SERIOUS BREACHES 
   
The Medicines for Human Use (Clinical Trials) Regulations (Regulation 29A of the Medicines for Human Use 
(Clinical Trials) Regulations 2004 [Statutory Instrument 2004/1031], as amended by Statutory Instrument 
2006/1928) contains a requirement for the notification of "serious breaches" to the MHRA within 7 days of 
the Sponsor becoming aware of the breach. 
A serious breach is defined as “A breach of GCP or the trial protocol which is likely to effect to a significant 
degree –  
(a) the safety or physical or mental integrity of the subjects of the trial; or 
(b) the scientific value of the trial”. 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 58 of 84 
 
In the event that a serious breach is suspected the Sponsor must be contacted within 1 working day. In 
collaboration with the C.I., the serious breach will be reviewed by the Sponsor and, if appropriate, the 
Sponsor will report it to the REC committee, Regulatory authority and NHS host organisation within 7 
calendar days. 
17. ETHICAL AND REGULATORY CONSIDERATIONS 
17.1 Declaration of Helsinki 
The Investigator will ensure that this trial is conducted in accordance with the principles of the Declaration 
of Helsinki. 
17.2 ICH Guidelines for Good Clinical Practice 
The Investigator will ensure that this trial is conducted in full conformity with relevant regulations and with 
the ICH Guidelines for Good Clinical Practice (CPMP/ICH/135/95) July 1996. 
17.3 Approvals 
The Investigator, in association with the Sponsor, will ensure all relevant regulatory approvals are met and 
maintained throughout the study, including approvals from Research Ethics Committee (REC), Competent 
Authority (MHRA in UK) and local NHS permissions.  
 
17.4 Reporting 
The Chief Investigator shall submit once a year throughout the clinical trial, or on request, an Annual 
Progress Report to the REC, host organisation and Sponsor.  In addition, an End of Trial notification and 
final report will be submitted to the MHRA, the REC, host organisation and Sponsor. Copies of submitted 
reports will be disseminated to sites for local sites.  
OPTIMAL Trial Coordinating Centre will also submit reports to funders and any other individuals and groups 
as required or as outlines in any contractual agreements.  
 
 17.5 Access to Data and Confidentiality 
All participant data will be regarded as strictly confidential and will be handled and stored securely in 
accordance with ICH-GCP and relevant regulations and legislations, including Data Protection Act (1998). 
Local Investigators are responsible for ensuring trial documentation and participant data at each of their 
own sites is handled according to all relevant regulatory and legislative guidelines. Any individual or party 
related to the trial and accessing trial data will be bound by confidentiality agreements. Warwick Clinical 
Trials Unit will maintain confidentiality of all participant data and will not disclose information by which 
participants may be identified to any third party, other than those directly involved with the treatment of 
the participant.  Funders and pharmaceutical companies will not have access to any identifiable participant 
data. 
 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 59 of 84 
 
On all trial-specific documents, other than the signed consent form, the participant will be referred to using 
only Study ID No. and participant initials and date of birth; not by name. Any documentation detailing 
identifiable data such as signed Informed Consent Forms must be filed separately from any trial data such 
as CRF’s and transferred using only secure methods (see section 14.2) 
All clinical information will be securely stored and will only be accessible by authorized personnel for the 
purposes of this study. Direct access to personal data will be granted to authorised representatives from 
the Sponsor, host institution and the regulatory authorities to permit trial-related monitoring, audits and 
inspections. This will be detailed on the PIS and Informed Consent Form.  
Participants will be asked to consent fo their General Practitioner (G.P.) to be informed of their 
participation in the study and for information to be shared with medical staff if relevant to participant’s 
clinical care.  
Central Laboratory Samples sent to Birmingham will include participant identifiable data in order to 
produce a report for the PI which may influence participant treatment or care.  This report will only be 
available to the clinical care team and if filed in trial documentation will be anonymised using particpant 
Study ID as per protcool (see Section 8.3). Samples sent to Oxford will be link-anonymised so that only the 
individual research sites will be able to identify participants from a log they will maintain which will identify 
individuals.  
 
17.6 Expenses and Benefits 
Participants will not receive any remuneration for participating in this trial. 
18. FINANCE AND INSURANCE 
18.1 Funding 
OPTIMAL is an investigator-led study funded by Janssen- Cilag and Bloodwise ( (formerly  Leukaemia and 
lymphoma Research). The study has previously been supported by NAPP Pharmaceuticals. 
18.2 Indemnity and Insurance 
NHS bodies are legally liable for the negligent acts and omissions of their employees. If a participant is 
harmed whilst taking part in a clinical trial as a result of negligence on the part of a member of the trial 
team, this liability cover would apply. 
Non-negligent harm is not covered by the NHS indemnity scheme. The Oxford University NHS Foundation 
Trust, therefore, cannot agree in advance to pay compensation in these circumstances. In exceptional 
circumstances an ex-gratia payment may be offered. 
18.3 Publication Policy 
The results of the trial will be reported in a peer reviewed journal on behalf of all collaborators and 
investigators.  The trial collaborators will draft the main report, and the sponsor, before submission for 
publication, will agree the final version. 
 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 60 of 84 
 
Authorship and accountability:  
As per ICMJE guidelines an author is generally considered to be anyone who provides substantive 
intellectual contributions to a published study. Specifically, authorship credit should be based on:  
1. substantial contributions to study conception and design, or acquisition of data, or analysis and 
interpretation of data, and  
2. drafting the article or revising it critically for important intellectual content, and  
3. final approval of the version to be published.  
 
All three conditions should be met.  
 
Conversely, individuals who do not contribute in this manner do not warrant named authorship. Individuals 
who do not meet criteria for authorship but who contributed materially to the manuscript will be 
recognized in acknowledgments when the manuscript is published. In some cases, journals recognise 
contributors rather than authors. Subject to journal policy, we will list the names of all investigators at the 
end of a manuscript. The lead author is generally responsible for defending the content and the integrity of 
the manuscript when submitted to a journal.  
 
The success of the trial depends on the collaboration of all participants.  Equal credit will be given to those 
who have wholeheartedly collaborated in the trial.  The trial will be reported in accordance with the 
Consolidated Standards of Reporting Trials (CONSORT) guidelines (www.consort-statement.org). A copy of 
the final report will be sent to the sponsor.  
 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 61 of 84 
 
19. REFERENCES 
1.   [cited 2012 25/02]; Available from: 
http://info.cancerresearchuk.org/cancerstats/types/multiplemyeloma/incidence/index.htm. Cancer 
Research UK. 
2. Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, et al. Improved survival in 
multiple myeloma and the impact of novel therapies. Blood. 2008 Mar 1;111(5):2516-20. 
3. Brenner H, Gondos A, Pulte D. Expected long-term survival of patients diagnosed with multiple 
myeloma in 2006-2010. Haematologica. 2009 Feb;94(2):270-5. 
4. Landgren O, Kyle RA, Pfeiffer RM, Katzmann JA, Caporaso NE, Hayes RB, et al. Monoclonal 
gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a 
prospective study. Blood. 2009 May 28;113(22):5412-7. 
5. Knudsen LM, Hippe E, Hjorth M, Holmberg E, Westin J. Renal function in newly diagnosed multiple 
myeloma--a demographic study of 1353 patients. The Nordic Myeloma Study Group. Eur J Haematol. 
1994 Oct;53(4):207-12. 
6. Eleutherakis-Papaiakovou V, Bamias A, Gika D, Simeonidis A, Pouli A, Anagnostopoulos A, et al. 
Renal failure in multiple myeloma: incidence, correlations, and prognostic significance. Leuk Lymphoma. 
2007 Feb;48(2):337-41. 
7. Clark AD, Shetty A, Soutar R. Renal failure and multiple myeloma: pathogenesis and treatment of 
renal failure and management of underlying myeloma. Blood Rev. 1999 Jun;13(2):79-90. 
8. Drayson M, Begum G, Basu S, Makkuni S, Dunn J, Barth N, et al. Effects of paraprotein heavy and 
light chain types and free light chain load on survival in myeloma: an analysis of patients receiving 
conventional-dose chemotherapy in Medical Research Council UK multiple myeloma trials. Blood. 2006 
Sep 15;108(6):2013-9. 
9. Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Navarro Coy N, et al. Cyclophosphamide, 
thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients 
destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results. 
Haematologica. 2011 Nov 4. 
10.  Augustson BM, Begum G, Dunn JA, Barth NJ, Davies F, Morgan G, et al. Early mortality after 
diagnosis of multiple myeloma: analysis of patients entered onto the United kingdom Medical Research 
Council trials between 1980 and 2002--Medical Research Council Adult Leukaemia Working Party. J Clin 
Oncol. 2005 Dec 20;23(36):9219-26. 
11. Torra R, Blade J, Cases A, Lopez-Pedret J, Montserrat E, Rozman C, et al. Patients with multiple 
myeloma requiring long-term dialysis: presenting features, response to therapy, and outcome in a series 
of 20 cases. Br J Haematol. 1995 Dec;91(4):854-9. 
12. Kastritis E, Anagnostopoulos A, Roussou M, Gika D, Matsouka C, Barmparousi D, et al. Reversibility 
of renal failure in newly diagnosed multiple myeloma patients treated with high dose dexamethasone-
containing regimens and the impact of novel agents. Haematologica. 2007 Apr;92(4):546-9. 
13. Knudsen LM, Hjorth M, Hippe E. Renal failure in multiple myeloma: reversibility and impact on the 
prognosis. Nordic Myeloma Study Group. Eur J Haematol. 2000 Sep;65(3):175-81. 
14. Alexanian R, Barlogie B, Dixon D. Renal failure in multiple myeloma. Pathogenesis and prognostic 
implications. Arch Intern Med. 1990 Aug;150(8):1693-5. 
15. MT Drayson JB, DR Cohen, N Iggo4, WM Gregory SB, A Howie, D Samson,, GH Jackson GG. Serum 
FLC Levels Can Be Reduced Rapidly; Lower Levels Are Associated with Renal Recovery. IMW 2009: 
Clinical Lymphoma & Myeloma, Vol. 9, Suppl. 2, S3-S95, 2009; DOI: 10.3816/CLM.2009.s.009, 2009. 
16. Gandhi V. Metabolism and mechanisms of action of bendamustine: rationales for combination 
therapies. Semin Oncol. 2002 Aug;29(4 Suppl 13):4-11. 
17. Preiss RTJ, Po¨nisch, W., Niederwieser, D., Matthias, M. & Merkle, K.H. Bendamustine in patients 
with renal insufficiency. Onkologie. 2003;26(Suppl 5):S131: P717. 
18. Gaul L, Mandl-Weber S, Baumann P, Emmerich B, Schmidmaier R. Bendamustine induces G2 cell 
cycle arrest and apoptosis in myeloma cells: the role of ATM-Chk2-Cdc25A and ATM-p53-p21-pathways. 
J Cancer Res Clin Oncol. 2008 Feb;134(2):245-53. 
19. Ponisch W, Mitrou PS, Merkle K, Herold M, Assmann M, Wilhelm G, et al. Treatment of 
bendamustine and prednisone in patients with newly diagnosed multiple myeloma results in superior 
complete response rate, prolonged time to treatment failure and improved quality of life compared to 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 62 of 84 
 
treatment with melphalan and prednisone--a randomized phase III study of the East German Study 
Group of Hematology and Oncology (OSHO). J Cancer Res Clin Oncol. 2006 Apr;132(4):205-12. 
20. Knop S, Straka C, Haen M, Schwedes R, Hebart H, Einsele H. The efficacy and toxicity of 
bendamustine in recurrent multiple myeloma after high-dose chemotherapy. Haematologica. 2005 
Sep;90(9):1287-8. 
21. Haubitz M, Bohnenstengel F, Brunkhorst R, Schwab M, Hofmann U, Busse D. Cyclophosphamide 
pharmacokinetics and dose requirements in patients with renal insufficiency. Kidney Int. 2002 
Apr;61(4):1495-501. 
22. Eriksson T, Hoglund P, Turesson I, Waage A, Don BR, Vu J, et al. Pharmacokinetics of thalidomide in 
patients with impaired renal function and while on and off dialysis. J Pharm Pharmacol. 2003 
Dec;55(12):1701-6. 
23. Tosi P, Zamagni E, Cellini C, Cangini D, Tacchetti P, Tura S, et al. Thalidomide alone or in 
combination with dexamethasone in patients with advanced, relapsed or refractory multiple myeloma 
and renal failure. Eur J Haematol. 2004 Aug;73(2):98-103. 
24. Morgan GJ, Davies FE, Gregory WM, Russell NH, Bell SE, Szubert AJ, et al. Cyclophosphamide, 
thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable 
for autologous transplantation. Blood. 2011 Aug 4;118(5):1231-8. 
25. Ramasamy K, Hazel B, Mahmood S, Corderoy S, Schey S. Bendamustine in combination with 
thalidomide and dexamethasone is an effective therapy for myeloma patients with end stage renal 
disease. Br J Haematol. 2011 Dec;155(5):632-4. 
26. Jagannath S, Barlogie B, Berenson JR, Singhal S, Alexanian R, Srkalovic G, et al. Bortezomib in 
recurrent and/or refractory multiple myeloma. Initial clinical experience in patients with impared renal 
function. Cancer. 2005 Mar 15;103(6):1195-200. 
27. Chanan-Khan AA, Kaufman JL, Mehta J, Richardson PG, Miller KC, Lonial S, et al. Activity and safety 
of bortezomib in multiple myeloma patients with advanced renal failure: a multicenter retrospective 
study. Blood. 2007 Mar 15;109(6):2604-6. 
28. San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et al. Bortezomib 
plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008 Aug 
28;359(9):906-17. 
29. Wolfram Pönisch MA, Ina Wagner, Doreen Hammerschmidt, Ute Kreibich, Andreas Schwarzer,  
Thomas Zehrfeld, Maik Schwarz, Cornelia Winkelmann, Sirak Petros, Anette Bachmann, Tom Lindner 
and Dietger Niederwieser. Successful Treatment with Bortezomib in Combination with Bendamustine 
and Prednisone of Patients with Newly Diagnosed/Untreated Multiple Myeloma and Light Chain 
Induced Renal Failure. Blood (ASH Annual Meeting Abstracts) 2011 118: Abstract 2938. 2011. 
30. James R. Berenson OY, Alberto Bessudo, Ralph V. Boccia, Stephen J. Noga,  Donald S. Gravenor,  
Dipti Patel-Donnelly,  Robert S. Siegel, Tarun Kewalramani,  Edward J. Gorak,  Regina A. Swift and Debra 
Mayo. Bendamustine Combined with Bortezomib Has Efficacy in Patients with Relapsed or Refractory 
Multiple Myeloma: A Phase 1/2 Study. Blood (ASH Annual Meeting Abstracts) 2011 118: Abstract 1857. 
2011. 
31. Jesus G. Berdeja DRC, Patrick Murphy, Ralph V. Boccia, Victor Priego, John D. Hainsworth, Inés M. 
Macias-Pérez, and Ian W. Flinn. A Phase II Trial of Combined Bendamustine, Bortezomib and 
Dexamethasone in Newly Diagnosed Multiple Myeloma (MM) Patients Who Are Not Candidates for 
High-Dose Chemotherapy: Results of a Planned Interim Safety Analysis. Blood (ASH Annual Meeting 
Abstracts) 2011 118: Abstract 653. 2011. 
32. Heinz Ludwig HK, Werner Linkesch,  Josef Thaler Richard Greil,  Clemens Leitgeb Daniel Heintel, 
Elisabeth Rauch, Niklas Zojer, Ludek Pour, Adelheid Seebacher  and Zdenek Adam. Bortezomib-
Bendamustine-Dexamethasone in Patients with relapsed/refractory Multiple Myeloma (MM) Shows 
Marked Efficacy and Is Well Tolerated, but Assessment of PNP Symptoms Shows Significant 
Discrepancies between Patients and Physicians. Blood (ASH Annual Meeting Abstracts) 2011 118: 
Abstract 2928. 2011. 
33. Fenk R, Michael M, Zohren F, Graef T, Czibere A, Bruns I, et al. Escalation therapy with bortezomib, 
dexamethasone and bendamustine for patients with relapsed or refractory multiple myeloma. Leuk 
Lymphoma. 2007 Dec;48(12):2345-51. 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 63 of 84 
 
34. Meletios A Dimopoulos MR, Maria Gkotzamanidou, Erasmia Psimenou, Despoina Mparmparoussi, 
Charis Matsouka, Evangelos Terpos and Efstathios Kastritis. The Role of Novel Agents on Reversibility of 
Renal Impairment in Newly Diagnosed Patients with Multiple Myeloma; a Single Center Experience on 
112 Patients. Blood (ASH Annual Meeting Abstracts) 2011 118: Abstract 3961. 2011. 
35. Colin A Hutchison AB, Graham Mead and Mark Cook. An International Study of High Cut-off 
Haemodialysis for the Management of Myeloma Kidney. Blood (ASH Annual Meeting Abstracts) 2011 
118: Abstract 3974. 2011. 
36. Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, et al. International uniform 
response criteria for multiple myeloma. Leukemia. 2006 Sep;20(9):1467-73. 
37. Dimopoulos MA, Terpos E, Chanan-Khan A, Leung N, Ludwig H, Jagannath S, et al. Renal impairment 
in patients with multiple myeloma: a consensus statement on behalf of the International Myeloma 
Working Group. J Clin Oncol. 2010 Nov 20;28(33):4976-84. Epub 2010 Oct 18. 
38.  The EuroQol Group (1990). EuroQol-a new facility for the measurement of health-related quality of 
life. Health Policy 16(3):199-208 
39.  Fischbach F, Dunning M. Manual of Laboratory and Dianostic Tests, 2004. 
40.  Bladé J, Samson D, Reece D, Apperley J, Björkstrand B, et al. (1998) Criteria for evaluating disease 
response and progression in patients with multiple myeloma treated by high-dose therapy and 
haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for 
Blood and Marrow Transplant. British Journal of Haematology, 102, 1115-1123. 
41. BGM Durie1, J-L Harousseau2, JS Miguel, J Blade, B Barlogie, et al. International uniform response 
criteria for multiple myeloma Leukemia 2006, May: 20(10):1–7. 
42. Rajkumar SV. Multiple myeloma: 2011 update on diagnosis, risk-stratification and manaement 
American Journal of Hematology 2011 Jan 86:1, 57-65. 
 
 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 64 of 84 
 
20. APPENDICES 
Appendix A:  Schedule of Events for Participant Study Visits 
 
Screening 
 
Cycles 1 - 4 
Cycle 5 & 6 (if 
applicable) 
1 month  
Follow-
up 
12 
month 
follow-
up 
Procedures/ Assessments 
≤  21 days 
before 
randomisation  
≤ 14 days 
before 1st 
treatment 
Wk 1 
Wk 2 
Wk 3 
Wk 1 
Wk 2 
Wk 3 
Inclusion / Exclusion criteria 
X 
 
 
Informed Consent  
X 
 
 
Complete Medical History 
X 
 
 
Physical Examination 
X 
 
X 
 
 
X 
 
 
X 
X 
Concomitant Medication 1 
X 
 
X 
X 
X 
X 
X 
X 
 
Adverse Events  2 
X 
 
X 
X 
X  
X 
X 
X 
X 
X 
Height  
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
 
 
X 
 
 
X 
 
ECOG performance status score 
X 
 
X 
X 
X 
X 
Skeletal survey (including spine) 
X 
 
 
Chest X ray 
X 
 
 
 
 
 
 
 
 
 
MRI (if clinically indicated) 
X 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
Haematology (FBC) (local) 3 
X 
X 
X 
X 
Biochemistry (local) 4, 5 
X 
X 
X 
X 
X5 
Immunology (local) 6 
X 
X 
X 
X 
Pregnancy test (urine) 7  
 
X 
X 
 
 
X 
 
 
X 
 
Bone Marrow Assessment (local)  
X 
X 
Central Lab (Birmingham) samples  -
Blood serum and urine 8 
 
X 
X8 
X8 
X8 
 
 
 
X 
 
Central Lab (Birmingham) samples - 
Bone marrow aspirate 9 
 
X 
 
 
 
 
 
 
X 
 
Central Lab (Oxford) samples- Bone 
marrow aspirate and slides 10 
 
X 
 
 
 
 
 
 
X 
 
Drug dispensing & Participant 
Treatment Diary Card(s) 
Dexamethasone (Arm A and Arm B) 
Thalidomide (Arm B only)    
 
 
X 
 
 
X 
 
 
 
 
Accountability & Collection of 
Participant Treatment Diary Card(s) 
Dexamethasone (Arm A and Arm B) 
Thalidomide (Arm B only)  
 
 
 
 
X 
 
 
X 
X 
 
Administration of Bortezomib Days 1, 
4 ,8 &11 of each cycle–Arm A only 11  
 
 
X 
X 
 
X 
X 
 
 
 
Administration of Bendamustine Days 
1 & 8 of each cycle  
 
 
X 
X 
 
X 
X 
 
 
 
QoL questionnaire (EQ-5D-3L) 
 
X 
X 
X 
X 
Summary of Treatment(s) received 
 
 
 
 
X 
 
 
X 
X 
X 
Treatment efficacy information  12 
 
 
 
 
 
 
 
 
X 
 
Survival information  
 
X 
X 
X 
1. Concomitant Medications to be recorded at screening and at start and end of each treatment cycle (see sections 7.3, 7.5)     
2. Adverse Events to be recorded during treatment cycles and at 1 and 12 month follow up (see sections 7.3, 7.5)     
3. Haematology: Haemoglobin, Haematocrit, WBCs, Platelet Count, bilirubin, Neutrophils, Lymphocytes, Monocytes (see section 8.1)    
4. Biochemistry: Sodium, Potassium, Total Protein, Albumin, Adjusted Calcium, Bicarbonate, Magnesium, Phosphate, Urea, Creatinine, 
LFTs, CRP, LDH, Uric acid, Glucose, Creatinine Clearance: in ml/min measured based on the abbreviated MDRD equation : 186 x (Creat / 88.4)-1.154 
x (Age)-0.203 x (0.742 if female) x (1.210 if black) using creatinine micromol/L. The calculator for this can be found at http://www.renal.org/egfrcalc/ 
5. Biochemistry: Creatinine, eGFR only at 12 month follow up 
6. Immunology: Beta-2 microglobulin, sFLC, Paraprotein, Quantitative Immunoglobulins (see section 8.1) 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 65 of 84 
 
7. Pregnancy test: For women of child-bearing potential (WCP) Pregnancy test to be performed at screening (not more than 14 days 
before start of treatment) and again on the day of, or the day before, day 1 of each cycle. Final test should be done approximately 30 
days after the last dose of study drug (see section 8.1) 
8. Central Lab (Birmingham): Blood 5 ml (EDTA), Blood 10 ml (clotted), Urine sample 20 ml (universal container)(if participant 
undergoing 24 hour urine collection as an inpatient take 20 ml aliquot). Collect at end of weeks 1, 2, 3, 4, 5, 6, 9 & 12 NB. For cycles 3-4, 
week 3 sampling only (see protocol section 8.2 & Central Lab Sample Manual).  
9. Central Lab (Birmingham) Bone marrow aspirate 2 ml (EDTA) (See section 8.2) & Central Lab Sample Manual) 
10. Central Lab (Oxford):  Bone marrow aspirate: 5ml (EDTA) & 2 unstained slides. For consenting participants only (see section 8.2 & 
Central Lab Sample Manual) 
11. Bortezomib: For cycles 3-4 (and 5-6, where relevant), bortezomib may be given as 1.3 mg/m2 weekly for 3 weeks in a 21 day cycle 
in combination with Bendamustine and dexamethasone as per local practice.  The dosing regimen used must be documented in the 
CRF. 
12. Definition of response to treatment: serum paraprotein, serum & urine FLCs, immunofixation & imaging (if clinically required)  
 
 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 66 of 84 
 
 
Appendix B:  ECOG Performance Status 
 
Grade Description  
 
0 = Normal activity: asymptomatic  
 
1 = Symptomatic: fully ambulatory  
 
2 = Symptomatic: in bed < 50% of time  
 
3 = Symptomatic: in bed > 50% of time - not bedridden  
 
4 = 100% bedridden  
 
 
 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 67 of 84 
 
Appendix C: International Staging System (ISS) 
 
Stage 
 Criteria 
I 
Serum β2 microglobulin <3.5 mg/L Serum albumin ≥ 3.5 g/dL 
II 
Neither stage l or II 
III 
Serum β2 microglobulin >5.5 mg/L 
 
 
 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 68 of 84 
 
Appendix D: International Myeloma Working Group (IMWG) Uniform Response 
Criteria for Multiple Myeloma 1 (36, 27) 
Response sub-category 
Response Criteria 
sCR 
(Stringent Complete Response) 
 
 
CR as defined below plus normal FLC ratio and absence of clonal 
cells 
in 
bone 
marrow 
2 
by 
immunohistochemistry 
or 
immunofluorescence 3 
 
CR  
(Complete Response) 
Negative immunofixation on the serum and urine and 
disappearance of any soft tissue plasmacytomas and < 5% plasma 
cells in bone marrow 2 
 
VGPR 
(Very Good Partial Response) 
Serum and urine M-protein detectable by immunofixation but not 
on electrophoresis or  ≥ 90% reduction in serum M-protein plus 
urine M-protein level < 100 mg/24 h 
 
PR 
(Partial Response) 
≥ 50% reduction of serum M-protein and reduction in 24 hours 
urinary M-protein by ≥90% or to < 200 mg/24 h 
 
If the serum and urine M-protein are not measurable 4, a ≥ 50% 
decrease in the difference between involved and uninvolved FLC 
levels is required in place of the M-protein criteria 
 
If serum and urine M-protein are not measurable, and serum free 
light assay is also not measureable, ≥ 50% reduction in plasma cells 
is required in place of M-protein, provided baseline bone marrow 
plasma cell percentage was ≥ 30% 
 
In addition to above listed criteria, if present at baseline, a ≥ 50% 
reduction in the size of soft tissue plasmacytomas is also required 
 
SD  (Stable Disease)  
 
Not meeting criteria for CR, VGPR, PR, or progressive disease 5 
Progressive 
Disease 4 
Increase of ≥ 25% from lowest response value in any one or more 
of the following: 
- 
Serum M-component and/or (the absolute increase must be ≥ 
0.5 g/dL) 6 
- 
Urine M-component and/or (the absolute increase must be 
≥200 mg/24 h) 
- 
Only in participants without measurable serum and urine M-
protein levels; the difference between involved and uninvolved 
FLC levels. The absolute increase must be > 10 mg/dL 
- 
Bone marrow plasma cell percentage; the absolute percentage 
must be ≥ 10% 6 
- 
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 hypercalcaemia (corrected serum calcium > 
11.5 mg/dL or 2.65 mmol/L) that can be attributed solely to 
the plasma cell proliferative disorder 
 
Relapse 
Clinical relapse requires one or more of: 
 
Direct indicators of increasing disease and/or end organ 


OPTIMAL_Protocol_V12.0_01Aug2017  
 
 Page 69 of 84 
 
dysfunction (CRAB features 6. It is not used in calculation of time to 
progression or progression-free survival but is listed here as 
something that can be reported optionally or for use in clinical 
practice 
1. Development of new soft tissue plasmacytomas or bone 
lesions 
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) [2.65 mmol/L] 
4. Decrease in haemoglobin of ≥ 2 g/dL [1.25 mmol/L] 
5. Rise in serum creatinine by 2 mg/dL or more [177 mol/L or 
more] 
Relapse from 
CR 4  
 
(to be used only if the end 
point studied is DFS) 8 
Any one or more of the following: 
- 
Reappearance of serum or urine M-protein by immunofixation 
or electrophoresis 
- 
Development of ≥ 5% plasma cells in the bone marrow 7 
- 
Appearance of any other sign of progression (i.e., new 
plasmacytoma, lytic bone lesion, or hypercalcaemia) 
Note: A clarification to IMWG criteria for coding CR and VGPR in participants in whom the only measurable disease is 
by serum FLC levels: CR in such participants is defined as a normal FLC ratio of 0.26–1.65 in addition to CR criteria 
listed above. VGPR in such participants is defined as a >90% decrease in the difference between involved and 
uninvolved free light chain (FLC) levels. 
1 adapted from BGM Durie et al. International uniform response criteria for multiple myeloma. Leukemia (2006) 1‐7. 
2 Confirmation with repeat bone marrow biopsy not needed. 
3 Presence/absence of clonal cells is based upon the kappa/lambda ratio. An abnormal kappa/lambda ratio by 
immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal 
ratio reflecting presence of an abnormal clone is kappa/lambda of > 4:1 or < 1:2. 
4 All relapse categories require two consecutive assessments made at any time before classification as relapse or 
disease progression and/or the institution of any new therapy. In the IMWG criteria, CR participants must also meet 
the criteria for progressive disease shown here to be classified as progressive disease for the purposes of calculating 
time to progression and progression-free survival. The definitions of relapse, clinical relapse and relapse from CR are 
not to be used in calculation of time to progression or progression free survival. 
5 not recommended for use as an indicator of response; stability of disease is best described by providing the time to 
progression estimates 
6 For progressive disease, serum M-component increases of ≥1 gm/dL are sufficient to define relapse if starting M-
component is ≥5 g/dL. 
7 Relapse from CR has the 5% cut-off versus 10% for other categories of relapse. 
8 For purposes of calculating time to progression and progression-free survival, CR participants should also be 
evaluated using criteria listed above for progressive disease.  


OPTIMAL_Protocol_V12.0_01Aug2017 
 
 Page 70 of 84 
 
Appendix E: Health Questionnaire 
 
 
 
 
 
Health Questionnaire  
 
 
English version for the UK  
(validated for Ireland) 
 
 
 
 


OPTIMAL_Protocol_V12.0_01Aug2017 
 
 Page 71 of 84 
 
By placing a tick in one box in each group below, please indicate which statements best describe 
your own health state today. 
 
Mobility 
I have no problems in walking about 
 
I have some problems in walking about 
 
I am confined to bed 
 
 
Self-Care 
I have no problems with self-care 
 
I have some problems washing or dressing myself 
 
I am unable to wash or dress myself 
 
 
Usual Activities (e.g. work, study, housework, family or 
leisure activities) 
I have no problems with performing my usual activities 
 
I have some problems with performing my usual activities 
 
I am unable to perform my usual activities 
 
 
Pain/Discomfort 
I have no pain or discomfort 
 
I have moderate pain or discomfort 
 
I have extreme pain or discomfort 
 
 
Anxiety/Depression 
I am not anxious or depressed 
 
I am moderately anxious or depressed 
 
I am extremely anxious or depressed 
 
 
 


OPTIMAL_Protocol_V12.0_01Aug2017 
 
 Page 72 of 84 
 
 
To help people say how good or bad a health state is, 
we have drawn a scale (rather like a thermometer) on 
which the best state you can imagine is marked 100 
and the worst state you can imagine is marked 0. 
 
We would like you to indicate on this scale how good or 
bad your own health is today, in your opinion. Please 
do this by drawing a line from the box below to 
whichever point on the scale indicates how good or bad 
your health state is today. 
 
 
 
 
 
 
 
 
 
 
 
 
Your own 
health state 
9 0 
8 0 
7 0 
6 0 
5 0 
4 0 
3 0 
2 0 
1 0 
100 
   Worst 
    imaginable 
0 
Best  
imaginable 


 
OPTIMAL_Protocol_V12.0_01Aug2017 
 
 Page 73 of 84 
 
Appendix F: SAE Reporting Flow Chart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event 
Assign severity grade 
Investigate to assess causality 
Is the event related to trial treatment? 
Was the event or reaction serious based on following criteria? 
 
Results in death 
 
Is life-threatening 
 
Requires inpatient hospitalisation or prolongation of existing hospitalisation 
 
Results in persistent or significant disability/ incapacity 
 
Consists of a congenital anomaly or birth defect 
 
Other important medical events (e.g. pregnancy) 
No
Yes 
Is the SAE exempt from requiring an 
SAE Reporting Form as stated in 
protocol Section 10.7? 
Yes 
No 
Complete SAE Reporting Form and fax to 
OPTIMAL trial coordinator with SAE Fax 
cover sheet within 24 hours of becoming 
aware of event (see section 10.6) 
Complete Adverse Events CRF  
No
Yes 
Adverse Event (AE) 
Adverse Reaction (AR) 


 
OPTIMAL_Protocol_V12.0_01Aug2017 
 
 Page 74 of 84 
 
Appendix G: Definition of Women of Childbearing Potential 
 
Women not of childbearing potential include women who 
– Are age ≥ 50 years and naturally amenorrhoeic for ≥ 1 year not induced by chemotherapy 
– Or have 
• Premature ovarian failure confirmed by a specialist gynaecologist 
• Previous bilateral salpingo-oophorectomy, or hysterectomy 
• XY genotype, Turner’s syndrome, uterine agenesis 
• Women of childbearing potential are all other women who are menstruating or perimenopausal, even 
those who abstain from sexual intercourse.  
 
 


 
OPTIMAL_Protocol_V12.0_01Aug2017 
 
 Page 75 of 84 
 
Appendix H: Pregnancy Report Form A 
 
 


 
OPTIMAL_Protocol_V12.0_01Aug2017 
 
 Page 76 of 84 
 
 


 
OPTIMAL_Protocol_V12.0_01Aug2017 
 
 Page 77 of 84 
 
 


 
OPTIMAL_Protocol_V12.0_01Aug2017 
 
 Page 78 of 84 
 
 
 
 


 
OPTIMAL_Protocol_V12.0_01Aug2017 
 
 Page 79 of 84 
 
Appendix I: Pregnancy Report Form B 
 


 
OPTIMAL_Protocol_V12.0_01Aug2017 
 
 Page 80 of 84 
 
 
 


 
OPTIMAL_Protocol_V12.0_01Aug2017 
 
 Page 81 of 84 
 
 


 
OPTIMAL_Protocol_V12.0_01Aug2017 
 
 Page 82 of 84 
 
 
 
 


 
OPTIMAL_Protocol_V12.0_01Aug2017 
 
 Page 83 of 84 
 
Appendix J: Flowchart for Bortezomib SC to IV switch 
 
 
 
 


 
OPTIMAL_Protocol_V12.0_01Aug2017 
 
 Page 84 of 84 
 
Appendix K: OPTIMAL Trial Schema 
 


 
OPTIMAL_Protocol_V12.0_01Aug2017 
 
 Page 85 of 84