A Randomized Phase II Trial Comparing Bendamustine and Melphalan With Melphalan Alone as Conditioning Regimen for Autologous Stem Cell Transplantation (ASCT) in Myeloma Patients
Phase: PHASE2
Conditions: Multiple Myeloma
Sponsor: Insel Gruppe AG, University Hospital Bern

 
 
 
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A randomized phase II trial comparing Bendamustine and 
Melphalan with Melphalan alone as conditioning regimen 
for autologous stem cell transplantation (ASCT) in 
myeloma patients (BEB-2 trial). 
 
Clinical Study Protocol 
 
 
 
 
  Short title:  
 
 
        Bendamustine and melphalan in myeloma. 
Study Type: 
Clinical trial investigating the chemotherapeutic compound 
Bendamustine (Ribomustin) in myeloma patients.  
Study Categorisation: 
Risk category according to LHR: category B 
Study Registration: 
SNCTP 000002150 
Trials.gov #: NCT03187223 
Study Identifier: 
BEB-2 trial 
Sponsor-Investigator: 
This is an investigator initiated trial (IIT); Sponsor is the 
University Hospital/Inselspital; 3010 Bern. Sponsor/Principal 
Investigator is Prof. Dr. med. Thomas Pabst; Associate 
Professor; Department of Medical Oncology; University 
Hospital/Inselspital; 3010 Bern; Switzerland. Phone +41 31 632 
84 30; Fax +41 31 632 34 10; Email: thomas.pabst@insel.ch;   
 
Investigational Product: 
Bendamustine hydrochloride (Ribomustin) 
Protocol Version and Date: 
Version 2.2, 21.03.2018 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
The information contained in this document is confidential. The information may not - in full or in part - 
be transmitted, reproduced, published, or disclosed to others than the applicable Competent Ethics 
Committees and Regulatory Authorities without prior written authorisation from the sponsor except to 
the extent necessary to obtain informed consent from those who will participate in the study. 

 
 
 
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Signature Page 
 
 
Study number 
EudraCT 2016-000231-40 
Study Title 
A randomized phase II trial comparing Bendamustine and 
Melphalan with Melphalan alone as conditioning regimen for 
autologous stem cell transplantation (ASCT) in myeloma patients 
(BEB-2 trial). 
 
 
 
The Principle Investigator has approved the protocol version 2.1 (dated 21/03/2018), and confirms 
hereby to conduct the study according to the protocol, current version of the World Medical Association 
Declaration of Helsinki, ICH-GCP guidelines or ISO 14155 norm if applicable and the local legally 
applicable requirements. 
Sponsor-Investigator: Prof. Dr. Thomas Pabst; Department of Medical Oncology; University 
Hospital/Inselspital; Freiburgstrasse 10; 3010 Berne. 
 
 
 
 
 
Place/Date 
 
Signature 
 
 
 
 
 
 
The Local Principal Investigator at study site: 
I have read and understood this trial protocol and agree to conduct the trial as set out in this study 
protocol, the current version of the World Medical Association Declaration of Helsinki, ICH-GCP 
guidelines or ISO 14155 norm and the local legally applicable requirements. 
 
Site 
     ................................................................................................... 
 
Local Principal investigator 
................................................................................................... 
 
 
 
 
Place/Date 
 
Signature 
 
 

 
 
 
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Table of Contents 
STUDY SYNOPSIS ................................................................................................................................. 6 
STUDY SUMMARY IN LOCAL LANGUAGE ....................................................................................... 12 
ABBREVIATIONS ................................................................................................................................. 13 
STUDY SCHEDULE .............................................................................................................................. 15 
1. 
STUDY ADMINISTRATIVE STRUCTURE .................................................................................... 16 
1.1 
Sponsor ....................................................................................................................................... 16 
1.2 
Principal Investigator ................................................................................................................... 16 
1.3 
Statistician ("Biostatistician") ....................................................................................................... 16 
1.4 
Laboratory ................................................................................................................................... 16 
1.5 
Monitoring institution ................................................................................................................... 16 
1.6 
Data Safety Monitoring Committee (DSMC) ............................................................................... 16 
1.7 
Any other relevant Committee, Person, Organisation, Institution ............................................... 16 
2. 
ETHICAL AND REGULATORY ASPECTS .................................................................................. 17 
2.1 
Study registration ........................................................................................................................ 17 
2.2 
Categorisation of study................................................................................................................ 17 
2.3 
Competent Ethics Committee (CEC) .......................................................................................... 17 
2.4 
Competent Authorities (CA) ........................................................................................................ 17 
2.5 
Ethical Conduct of the Study ....................................................................................................... 17 
2.6 
Declaration of interest ................................................................................................................. 18 
2.7 
Patient Information and Informed Consent ................................................................................. 18 
2.8 
Participant privacy and confidentiality ......................................................................................... 18 
2.9 
Early termination of the study ...................................................................................................... 18 
2.10 Protocol amendments ................................................................................................................. 18 
3. 
BACKGROUND AND RATIONALE .............................................................................................. 19 
3.1 
Background and Rationale .......................................................................................................... 19 
3.2 
Investigational Product ................................................................................................................ 19 
3.3 
Evidence of clinical activity of Bendamustine from previous studies .......................................... 20 
3.4 
Evidence for selecting Bendamustine as a component of a high-dose chemotherapy regimen 20 
3.5 
Dose Rationale for Bendamustine in conditioning regimens ...................................................... 21 
3.6 
Explanation for choice of comparator .......................................................................................... 21 
3.7 
Risks / Benefits ............................................................................................................................ 21 
3.8 
Justification of choice of study population ................................................................................... 22 
4. 
STUDY OBJECTIVES ................................................................................................................... 22 
4.1 
Overall Objective ......................................................................................................................... 22 
4.2 
Primary Objective ........................................................................................................................ 22 
4.3 
Secondary Objectives ................................................................................................................. 22 
4.4 
Safety Objectives ........................................................................................................................ 23 
5. 
STUDY OUTCOMES ..................................................................................................................... 23 
5.1 
Primary Outcome ........................................................................................................................ 23 
5.2 
Secondary Outcomes .................................................................................................................. 23 
5.3 
Other Outcomes of Interest ......................................................................................................... 23 
5.4 
Safety Outcomes ......................................................................................................................... 23 
6. 
STUDY DESIGN ............................................................................................................................ 23 
6.1 
General study design .................................................................................................................. 23 

 
 
 
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7. 
STUDY POPULATION .................................................................................................................. 24 
7.1 
Eligibility criteria ........................................................................................................................... 24 
7.2 
Recruitment and screening ......................................................................................................... 25 
7.3 
Assignment to study groups ........................................................................................................ 25 
7.4 
Criteria for withdrawal / discontinuation of participants ............................................................... 25 
8. 
STUDY INTERVENTION ............................................................................................................... 26 
8.1 
Identity of Investigational Products (treatment) ........................................................................... 26 
8.2 
Packaging, Labelling and Supply (re-supply) .............................................................................. 26 
8.3 
Administration of experimental and control interventions ........................................................... 27 
8.3.1 Experimental Intervention – high-dose chemotherapy BenMel (Bendamustine  
 
and Melphalan) ................................................................................................................... 27 
8.3.2 Control Intervention – high-dose chemotherapy Mel (with Melphalan only) ....................... 27 
8.4 
Dose modifications ...................................................................................................................... 27 
8.5 
Compliance with study intervention ............................................................................................. 27 
8.6 
Data Collection and Follow-up for withdrawn participants .......................................................... 28 
8.7 
Trial specific preventive measures .............................................................................................. 28 
8.8 
Concomitant Interventions (treatments) ...................................................................................... 28 
8.9 
Supportive treatment during neutropenia after ASCT ................................................................. 28 
8.10 Study Drug Accountability ........................................................................................................... 28 
8.11 Return or Destruction of Study Drug ........................................................................................... 29 
9. 
STUDY ASSESSMENTS ............................................................................................................... 30 
9.1 
Study flow chart(s) / table of study procedures and assessments. Study schedule ................... 30 
STUDY SCHEDULE .............................................................................................................................. 30 
ASSESSMENTS OF OUTCOMES ....................................................................................................... 31 
9.1.1 Assessment of primary outcome ......................................................................................... 31 
9.1.2 Assessment of secondary outcomes .................................................................................. 31 
9.1.3 Assessment of safety outcomes ......................................................................................... 31 
9.1.4 Assessments in participants who prematurely stop the study ............................................ 31 
9.2 
Procedures at each visit .............................................................................................................. 32 
9.2.2 Assessments during ASCT (Day -4 until day of hospital discharge) .................................. 32 
9.2.3 Assessments after ASCT (Day +30 to +75 after ASCT) ..................................................... 32 
9.2.4 Response criteria ................................................................................................................ 32 
10. SAFETY ......................................................................................................................................... 33 
10.1 Study type ................................................................................................................................... 33 
10.1.1 Definition and assessment of (serious) adverse events and other safety related events .. 33 
10.1.2 Reporting of serious adverse events (SAE) and other safety related events ..................... 34 
10.1.3 Reporting to the manufacturer of bendamustine hydrochloride .......................................... 34 
10.1.4 Reporting of SAEs............................................................................................................... 35 
10.1.5 Reporting of Deaths ............................................................................................................ 35 
10.1.6 Reporting of SUSARs ......................................................................................................... 35 
10.1.7 Reporting of Safety Signals ................................................................................................ 35 
10.1.8 Reporting and Handling of Pregnancies ............................................................................. 35 
10.1.9 DSUR .................................................................................................................................. 35 
10.1.10 Follow up of (Serious) Adverse Events ............................................................................. 35 

 
 
 
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11. STATISTICAL METHODS ............................................................................................................. 36 
11.1 Hypothesis ................................................................................................................................... 36 
11.2 Determination of Sample Size ..................................................................................................... 36 
11.3 Randomization ............................................................................................................................ 36 
11.4 Populations for Analysis .............................................................................................................. 36 
11.5 Planned Analyses / Analytical Methods ...................................................................................... 37 
11.6 Analysis of demographics and baseline characteristics .............................................................. 37 
11.7 Analysis of primary efficacy parameter ....................................................................................... 37 
11.8 Analysis of secondary efficacy parameters ................................................................................. 37 
11.9 Analysis of safety ........................................................................................................................ 37 
11.10 Statistical criteria of termination of trial ....................................................................................... 37 
11.11 Deviation(s) from the original statistical plan ...................................................................... 37 
11.12 Handling of missing data and drop-outs...................................................................................... 37 
12 QUALITY ASSURANCE AND CONTROL .................................................................................... 37 
12.1 Data handling and record keeping / archiving ............................................................................. 38 
12.1.1 Case Report Forms ............................................................................................................. 38 
12.1.2 Specification of source documents ..................................................................................... 38 
12.1.3 Record keeping / archiving ................................................................................................. 38 
12.1.4 Data Management System ................................................................................................. 38 
12.1.5 Data security, access and back-up ..................................................................................... 38 
12.1.6 Analysis and archiving ........................................................................................................ 39 
12.1.7 Electronic and central data validation ................................................................................. 39 
12.2 Monitoring .................................................................................................................................... 39 
12.3 Audits and Inspections ................................................................................................................ 39 
12.4 Confidentiality, Data Protection ................................................................................................... 39 
12.5 Storage of biological material and related health data ................................................................ 39 
13 PUBLICATION AND DISSEMINATION POLICY.......................................................................... 39 
14 FUNDING AND SUPPORT ............................................................................................................ 40 
14.1 Funding ....................................................................................................................................... 40 
14.2 Other Support .............................................................................................................................. 40 
15 INSURANCE .................................................................................................................................. 40 
16 APPENDICES ................................................................................................................................ 41 
16.1 Appendix 1: Translated excerpt from CTC adverse events version v4.0 .................................... 41 
16.2 Appendix 2: Performance status scale (ECOG) ......................................................................... 43 
16.3 Appendix 3: Response criteria .................................................................................................... 44 
16.4 Appendix 4: HCTCI score ........................................................................................................... 46 
16.5 Appendix 5: Declaration of Helsinki ............................................................................................ 47 
16.6 Appendix 6: Fragebogen zur Lebensqualität EORTC QLQ-C30 ................................................ 51 
17 REFERENCES ............................................................................................................................... 56 
  
 

 
 
 
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Study synopsis 
 
Sponsor / Sponsor-
Investigator 
This is an investigator initiated trial (IIT); Sponsor is the University 
Hospital/Inselspital; 3010 Berne. Sponsor/Principal Investigator is Prof. 
Dr. med. Thomas Pabst; Associate Professor; Department of Medical 
Oncology; University Hospital/Inselspital; 3010 Berne; Switzerland. Phone 
+41 31 632 84 30; Fax +41 31 632 34 10; Email: thomas.pabst@insel.ch.  
Study Title: 
A randomized phase II trial comparing Bendamustine and Melphalan with 
Melphalan alone as conditioning regimen for autologous stem cell 
transplantation (ASCT) in myeloma patients (BEB-2 trial). 
Short Title / Study ID: 
Bendamustine and melphalan in myeloma. 
Protocol Version and 
Date: 
Version 2.2; 21.03.2018 
Trial registration: 
SNCTP 000002150 
Trials.gov #: NCT03187223 
Study category and 
Rationale 
Risk category according to LHR: category B. Bendamustine is licensed in 
Switzerland for the treatment of lymphoma patients; in this study, it is used 
as a part of a conditioning regimen together with melphalan before 
autologous transplantation in myeloma patients. 
Melphalan is licensed in Switzerland for the treatment of myeloma 
patients. Monotherapy with high-dose melphalan is standard of care as a 
conditioning treatment before ASCT. 
Clinical Phase: 
Randomized prospective non-blinded clinical phase II trial investigating 
the drugs bendamustine hydrochloride and melphalan. 

 
 
 
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Background and 
Rationale: 
Consolidation of the first-line treatment in myeloma patients with high-
dose chemotherapy (HDCT) and autologous stem cell transplantation 
(ASCT) is standard of care since more than 20 years, and Melphalan at a 
total dose of 200mg/m2is the standard HDCT conditioning regimen before 
ASCT in the last two decades. Despite remarkable progress using novel 
agents both for induction before ASCT as well for maintenance after 
ASCT, definite cure in myeloma patients remains exceptional due to 
residual disease escaping intensive treatment. Current treatment efforts 
aim at achieving high-quality complete remssions. Thus, improving 
effectiveness of myeloma treatment remains an unmet clinical need. 
Alternative conditioning regimens have been reported including 
combinations of melphalan with other compounds such as with bortezomib 
(MelVel), with etoposide, cytarabine and BCNU (BEAM), and with 
busulfan (BuMel). However, no randomized trial has ever prospectively 
compared high-dose melphalan alone with a melphalan combination (or 
with another regimen) before ASCT in myeloma patients. Consequently, 
high-dose melphalan alone has remained the standard conditioning 
regimen in HDCT in myeloma patients.  
Two phase 1 and 2 studies have reported combinations of melphalan with 
bendamustine as first-line conditioning regimen before ASCT in myeloma 
patients. A phase 1 trial added escalating doses of bendamustine to 
standard melphalan, with melphalan given at a dose of 100 mg/m2/day at 
days -2 and -1. 25 patients were enrolled into 6 cohorts; a maximum 
tolerated dose of bendamustine was not encountered; the highest dose 
level cohort of bendamustine comprising 125 mg/m2/day on day -2 and 
100 mg/m2/day on day -1   together with melphalan 100 mg/m2/day at 
days -2 and -1 was expanded to further evaluate safety. At day +100, 
overall response rate was 79%, with 38% of stringent CR, 4% of CR, 33% 
of VGPR and 4% of PR. Ten patients progressed after a median of 473 
days after ASCT, and six patients died. Median PFS was 791 days, and 
the median OS was not reached, but the 2-year OS rate was 70%. 
   Martino et al. recently reported data on the feasibility and efficacy of the 
combination of bendamustine and melphalan (BenMel) as a conditioning 
regimen to second ASCT in patients with myeloma. All 32 patients enrolled 
have received melphalan 100 mg/m2/day at days -2 and -1 as conditioning 
regimen before the first ASCT. The conditioning regimen before second 
ASCT was bendamustine (100 mg/m2/day at days -4 and -3) and 
melphalan (140 mg/m2/day at day -2). No added toxicity was observed 
between the first and second ASCT. The 2y-OS and 2y-PFS were 97% 
and 79%, respectively.  
In addition, extensive experience is available on the use of bendamustine 
(200mg/m2/day given on days -7 and -6) together with melphalan 
(140mg/m2/day day -1) and two additional drugs, cytarabine and etoposide 
(each on days -5 to -2) in the BeEAM conditioning regimen which is 
increasingly used as the standard conditioning regimen in lymphoma 
patients, also in our clinic, with an acceptable tolerability and safety profile.  
In summary, these data suggest that combinations of melphalan and 
bendamustine are usually well tolerated and that the maximum tolerated 
dose of bendamustine is not reached with the doses of 200mg/m2/day 
given on two days added to melphalan, etoposide and cytarabine (BeEAM 
regimen). We therefore suggest in this study to directly compare 
bendamustine 200 mg/m2/day (on days -4 and -3) plus melphalan 
100mg/m2/day (on days -2 and -1) with melphalan 100mg/m2/day (days -
2 and -1) in a randomized trial. 

 
 
 
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Objective(s): 
Primary objective: 
• 
To show a clinically meaningful improvement by 15% of the rate 
of complete remission (CR1) 60 days after ASCT in myeloma 
patients from 50% with melphalan alone to 65% with the 
combination of bendamustine and melphalan. 
 
• 
Secondary objectives:To assess acute and late toxicities/adverse 
events (CTCAE 4.0) during the study period in patients treated 
with the combination of bendamustine and melphalan as 
compared to melphalan alone. 
• 
To assess the hematologic engraftment in patients treated with 
the combination of bendamustine and melphalan as compared to 
melphalan alone. 
• 
To particularly assess early renal toxicity in patients treated with 
the combination of bendamustine and melphalan as compared to 
melphalan alone. 
• 
To assess differences in overall survival and progression free 
survival in patients treated with the combination of bendamustine 
and melphalan as compared to melphalan alone after one year. 
• 
To assess the quality of life prior to ASCT and at day 60 
assessment thereafter. 
Outcome(s): 
To assess the rate of complete remission (CR1) 60 days after ASCT in 
myeloma patients treated with the combination of bendamustine and 
melphalan as compared to melphalan alone by routine laboratory 
myeloma parameters (serum M-gradient and light chain ratio) and bone 
marrow assessments in patients with CR1. 
Study design: 
Randomized two-arm open-label prospective phase II trial. 

 
 
 
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Inclusion / Exclusion 
Criteria: 
 
 
 
 
 
 
Key inclusion criteria: 
Eligible are myeloma patients after standard first-line induction treatment. 
A second induction regimen in refractory myeloma patients is allowed. 
Patients must be considered being fit for subsequent consolidation with 
high-dose chemotherapy with melphalan with autologous stem cell 
support. 
Patients must be aged 18-75 years. 
Patients must have an ECOG < 3. 
Patients must have a creatinine clearance ≥ 40 ml/min. 
Patients must have a LVEF ≥ 40% within three months prior to start of 
study medication (Echo can be postponed to study treatment visit if 
clinically indicated). 
Female patients of child-bearing potential;. No known pregnancy (a 
pregnancy test in female patients of child-bearing potential is not 
mandatory since patients are already under induction chemotherapy or 
mobilization chemotherapy, and pregnancy was excluded before starting 
chemotherapy…) 
Patients must have given voluntary written informed consent. 
 
Key exclusion criteria: 
Patients with uncontrolled acute infection.  
Patients with a transplantation comorbidity index (HCTCI) > 6 points. 
Patients with concurrent malignant disease with the exception of 
basalioma/spinalioma of the skin or early-stage cervix carcinoma, or early-
stage prostate cancer. Previous treatment for other malignancies (not 
listed above) must have been terminated at least 24 months before 
registration and no evidence of active disease shall be documented since 
then. 
Patients with major coagulopathy or bleeding disorder.  
Patients with other serious medical condition that could potentially 
interfere with the completion of treatment according to this protocol or that 
would impair tolerance to therapy or prolong hematological recovery. 
Lack of patient cooperation to allow study treatment as outlined in this 
protocol.  
Pregnancy or lactating female patients. 
The use of any anti‐cancer investigational agents within 14 days prior to 
the expected start of trial treatment. 
Contraindications and hypersensitivity to any of the active chemotherapy 
compounds. 
Measurements  
The primary endpoint is improvement of the complete remission (CR1) 
rate 60 days after ASCT in myeloma patients treated with the combination 
of bendamustine and melphalan as compared to melphalan alone. This 
assessment will be performed by routine laboratory myeloma parameters 
(serum M-gradient and light chain ratio). A bone marrow assessment will 
be done in patients with CR1 according to serum myeloma parameters to 
assess the quality of CR1. 
Quality of life Forms (EORTC Q30) will be collected at screening and at 
the day 60 assessment; for details see Appendix 6. 

 
 
 
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Study Product  and 
Interventions:  
Two HDCT regimens (melphalan alone versus the combination of 
melphalan and bendamustine) used for conditioning treatment before 
ASCT will be compared in a 1:1 randomization. The experimental arm is 
the bendamustine and melphalan (BenMel) combined regimen. The 
melphalan alone (Mel) regimen is the control (standard) treatment. 
 
BenMel regimen (experimental arm):  
Patients will receive bendamustine at a total dose of 400mg/m2, divided in 
two doses of 200mg/m2/day on days -4 and -3. Melphalan is given at a 
total dose of 200mg/m2, divided in two doses of 100mg/m2/day, each on 
days -2 and -1, with the ASCT at day 0.  
In patients with a reduced renal function with a creatinine clearance of ≥ 
40 ml/min and <50 ml/min, the bendamustine dose will be reduced to a 
total dose of 200mg/m2, divided in two doses of 100mg/m2/day on days -4 
and -3; the melphalan dose will be reduced to a total dose of 140mg/m2, 
divided in two doses of 70mg/m2day on days -2 and -1, with the ASCT at 
day 0. 
Control Intervention: 
Mel regimen (standard arm):  
Patients will receive melphalan at a total dose of 200mg/m2, divided in two 
doses of 100mg/m2/day on days -2 and -1, with the ASCT at day 0.  
In patients with a reduced renal function with a creatinine clearance of ≥ 
40 ml/min and <50 ml/min, the melphalan dose will be reduced to a total 
dose of 140mg/m2, divided in two doses of 70mg/m2/day on days -2 and -
1, with the ASCT at day 0. 
Number of Participants 
with Rationale: 
Applying a statistical power of 80% and a one-sided significance level of 
20%, 60 evaluablepatients will be needed in each group to show a 
clinically meaningful improvement by 15% of the rate of complete 
remission (CR1) 60 days after ASCT in myeloma patients, from 50% with 
melphalan alone to 65% with the combination of bendamustine and 
melphalan. Thus, a total of 120 evaluable patients will be needed. 
Study Duration: 
The total study duration is 36 months. The University Hospital/Inselspital 
in Bern/Switzerland is currently treating 60-70 first-line myeloma patients 
per year. Thus, a total of 36 months is considered to be sufficient to recruit 
the 120 patients needed. 
Study Schedule: 
Submission to EC authorities/Swissmedic: March 2016 
Trial activation:  March 2017 
First-Participant-In: April 2017 
Last-Participant-In: April 2020 
Last-Patient-evaluable: October 2020 
First-Analysis-available: December 2020 
Final-Analysis-available: March 2021 
Investigator(s) / Study 
Center(s): 
Prof. Dr. Thomas Pabst; Department for Medical Oncology; University 
Hospital/Inselspital; 3010 Berne; Phone +41 31 632 84 30; Fax +41 31 
632 34 10; Email: thomas.pabst@insel.ch. 
Single center: Berne / Switzerland.   
Stratification 
Parameters: 
Two stratification parameters will be applied: 
(1) Remission status at registration: CR/VGPR versus PR/SD/PD 
(2) Renal function: creatinine-clearance ≥50 ml/min versus <50 ml/min 

 
 
 
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Statistical 
Considerations: 
This study involves two treatment arms and applies a 1:1 randomization, 
additionally considering the stratification for remission status and renal 
function. No interim analysis is planned, and all calculations will be 
performed on anintention-to-treat basis. The primary endpoint is to show 
animprovement by 15% of the rate of complete remission (CR1) 60 days 
after ASCT in myeloma patients from 50% with melphalan alone to 65% 
with the combination of bendamustine and melphalan. 
Arm A is the standard arm (Mel: melphalan alone chemotherapy), and arm 
B is the experimental arm (BenMel: bendamustine and melphalan 
chemotherapy). The null hypothesis is that the rate of complete remissions 
(CR1) determined 60 days after ASCT is equal in both arms (CR1A = 
CR1B). The aim of the study is to ultimately show an improvement by 15% 
of the rate of complete remission (CR1) 60 days after ASCT in myeloma 
patients from 50% with melphalan alone to 65% with the combination of 
bendamustine and melphalan, with CR1A < CR1B.  
Based on a previous cohort of 122 myeloma patients at our center (2010-
2013), we anticipate a CR1 rate in the standard (Mel) arm of 50% (CR1A). 
Our hypothesis is that the experimental (BenMel) arm will show a CR1 rate 
of ≥ 65% (CR1B), thus a difference of at least 15 percentage points. The 
superiority margin in the proposed prospective randomized study is 0.15, 
i.e. the improvement of the CR1 rate in the experimental arm (BenMel) is 
considered a success compared to the standard (Mel) arm if its CR1 rate 
at least 15 percentage points better. 
With CR1A and CR1B being the (true) success rates in the Mel arm and in 
the BenMel arm, respectively, the hypotheses are: 
     H0: CR1 BenMel chemotherapy is < 0.65 when CR1 Mel is 0.50. 
     H1: CR1 BenMel chemotherapy is ≥ 0.65 when CR1 Mel is 0.50. 
Applying a one-sided significance level of 20%, 60 evaluable patients will 
be needed in each group to have 80% power to reject the null hypothesis 
of no difference between the CR1 rates of the treatment arms using a t-
test. Thus, a total of 120 evaluable patients will be needed. The 
significance level actually achieved by this design is 0.2057. All statistical 
analysis for sample size calculations were performed using the software 
package PASS 11. 
For statistical analysis of this study, continuous endpoints will be 
summarized using descriptive statistics including mean, median, standard 
deviation, first and third quartiles, minimum and maximum values, and 
where appropriate by graphical techniques (e.g. histogram, box plot). For 
categorical endpoints, the number and percentage of patients in each 
category will be summarized. Where appropriate, a two-sided 95% 
confidence interval for the proportion will be reported. The primary 
endpoint in the two groups will be tested using a t-test. 
GCP Statement: 
This study will be conducted in compliance with the protocol, the current 
version of the Declaration of Helsinki, the ICH-GCP as well as all national 
legal and regulatory requirements.  
 
 
 

 
 
 
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Study summary in local language 
 
Die Hochdosis-Chemotherapie (HDCT) mit Melphalan gefolgt von einer autologen Stammzell-
Transplantation (ASCT) ist Teil der Standard Erstlinien-Therapie bei Patienten mit Therapie-bedürftigem 
Multiplem Myelom. Dabei ist die HDCT seit mehr als zwei Dekaden unverändert Melphalan in einer 
totalen Dosis von 200mg/m2. Verschiedene Modifikationen dieses Schema wurden in Phase 1 und 2 
Studien untersucht, so die Zugabe von Bortezomib (VelMel), von BCNU, Cytarabin und Etoposid 
(BEAM), oder von Busulfan (BuMel). Keines dieser Schemas wurde allerdings je randomisiert 
prospektiv geprüft gegen Melphalan allein, und so bleibt Melphalan Monotherapie bis heute die 
Standard Konditionierungs-Chemotherapie vor ASCT für Myelom Patienten.  
 
Bendamustin ist zugelassen in der Schweiz für die Behandlung von Lymphom Patienten. Es wird in der 
Schweiz neben der Lymphom-Therapie durchaus ab der dritten Linie auch bei Myelom-Patienten 
eingesetzt, ist hierzu aber in der Schweiz nicht zugelassen. In der EU ist Bendamustin beim multiplen 
Myelom zugelassen, falls eine Hochdosistherapie mit ASCT, oder falls eine Thalidomid oder Bortezomib 
enthaltende Behandlung nicht geeignet ist. Bisher haben zwei Studien die Kombination von Melphalan 
und Bendamustin als Konditionierung vor ASCT untersucht. Eine Phase 1 Studie fügte in 6 Kohorten 
eine Dosissteigerung von Bendamustin einer Standard Melphalan Therapie von total Dosis von 200 
mg/m2 zu (100mg/m2 pro Tag an den Tagen -2 and -1). Eine maximal tolerierte Dosis von Bendamustin 
wurde dabei nicht identifiziert, mit einer höchsten Bendamustin Totaldosis von 225 mg/m2 gegeben an 
den gleichen Tagen wie Melphalan (Bendamustin 125 mg/m2 pro Tag am Tag -2 und 100 mg/m2 pro 
Tag am Tag -1). 100 Tage nach ASCT war die Gesamtansprechrate 79%, mit 38% stringent CR1, 4% 
CR1, 33% VGPR und 4% PR. Das mediane progressions-freie Überleben (PFS) betrug 791 Tage, und 
das mediane Überleben (OS) wurde bisher nicht erreicht. Das 2y-OS betrug 70%.  
 
In einer Phase 2 Studie wurden Bendamustin und Melphalan kombiniert eingesetzt bei Myelom 
Patienten als Konditionierung vor einer zweiten ASCT. Die Patienten erhielten dabei Melphalan 100 
mg/m2 pro Tag an den Tagen -2 and -1 als Konditionierung vor der ersten ASCT. Das Konditionierungs-
Regime vor der zweiten ASCT war Bendamustine (100 mg/m2 pro Tag, Tage -4 and -3) und Melphalan 
(140 mg/m2 pro Tag, Tag -2). Dabei wurde keine zusätzliche Toxizität beobachtet zwischen der ersten 
und zweiten ASCT. Das 2y-OS war 97% und das 2y-PFS war 79%. 
 
In der vorliegenden prospektiven zwei-armigen monozentrischen Studie wird nun in einer 1:1 
Randomisierung die Standard-HDCT mit Melphalan (totale Dosis von 200 mg/m2) verglichen mit der 
experimentellen HDCT mit der Kombination von Bendamustin und Melphalan. Melphalan wird in beiden 
Armen gesplittet verabreicht, in einer Dosis von jeweils 100 mg/m2 pro Tag an den Tagen -2 und -1, vor 
der ASCT am Tag 0. Im experimentellen Arm wird Bendamustin verabreicht in einer Dosis von jeweils 
200 mg/m2 pro Tag an den Tagen -4 und -3. Mit dieser Studie möchten wir eine Verbesserung der CR1 
Rate 60 Tage nach ASCT um 15% erreichen. Wir gehen auf Grund einer früheren Kohorte von 122 
Myelom Patienten mit ASCT am Inselspital (2010-2013) von einer CR1 Rate von 50% aus mit Melphalan 
alleine, und wir erhoffen uns von der Bendamustin/Melphalan Kombination eine Verbesserung der CR1 
Rate auf über 65%. Dazu sind total 120 Patienten nötig, und wir planen dazu eine Studiendauer von 36 
Monaten. 
 
 

 
 
 
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Abbreviations 
Provide a list of abbreviations used on the protocol - to be completed 
 
AE 
ALC 
ANC 
Adverse Event  
Absolute lymphocyte count 
Absolute neutrophil count 
ASCT 
BCNU 
BEAM 
BeEAM 
BenMel 
BM 
CA 
Autologous stem cell transplantation 
1,3-Bis(2-chloroethyl)-1-nitrosourea, Carmustine 
BCNU-Etoposide-Cytarabin-Melphalan 
Bendamustine-Etoposide-Cytarabine-Melphalan 
Bendamustine-Melphalan 
Bone Marrow 
Competent Authority (e.g. Swissmedic) 
CEC 
CR 
Competent Ethics Committee 
Complete Remission 
CRF 
Case Report Form  
ClinO 
Ordinance on Clinical Trials in Human Research (in German: KlinV, in French: 
OClin) 
eCRF 
Electronic Case Report Form  
CTCAE 
DFS 
Common terminology criteria for adverse events 
Disease Free Survival 
DSUR 
Development safety update report 
DSMC 
Data safety monitoring committee 
ECHO 
ECOG 
GCP 
HC 
HCTCI 
HDCT 
Echocardiography 
Eastern Cooperative Oncology Group 
Good Clinical Practice  
Hematopoietic cell  
hematopoietic cell transplantation comorbidity index 
High-dose chemotherapy 
IB 
Investigator’s Brochure 
Ho 
Null hypothesis 
H1 
Alternative hypothesis 
HFG 
Humanforschungsgesetz (Law on human research) 
HMG 
Heilmittelgesetz  
HRA 
Federal Act on Research involving Human Beings 
IMP 
Investigational Medicinal Product 
IIT 
Investigator-initiated Trial 
ISO 
International Organisation for Standardisation 
ITT 
Intention to treat 
KlinV 
 
LC 
Verordnung über klinische Versuche in der Humanforschung (in English: ClinO, in 
French OClin) 
 

 
 
 
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Mel 
LVEF 
MGUS 
MM 
Light Chain 
Melphalan 
Left ventricular ejection fraction 
Monoclonal Gammopathy of Unknown Significance 
Multiple Myeloma 
OClin 
 
OS 
Ordonnance sur les essais cliniques dans le cadre de la recherche sur l'être humain 
(in German : KlinV, in English : ClinO) 
Overall Survival 
PI 
PLT 
PD 
PFS 
PR 
Principal Investigator  
Platelets 
Progressive Disease 
Progression Free Survival 
Partial Remission 
RBC 
SAE 
SD 
Red blood cell  
Serious Adverse Event 
Stable Disease 
SDV 
Source Data Verification  
SOP 
Standard Operating Procedure 
SPC 
Summary of product characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TMF 
TRM 
VGPR 
QoL 
Trial Master File  
Treatment related mortality 
Very Good Partial Remission 
Quality of life 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
Bendamustine and Melphalan in Myeloma                          Page 15 of 59                Version 2.2; 21.03.2018 
 
    Study schedule 
Study Periods 
 
Screening 
Treatment 
Day 
60 
assessment 
Follow-up 
Visits 
1 
2 
3 
4 10 
Time (days) 
-35 to -5 
-4 until end of 
hospitalization 
+30 to +75 
___ 
Patient informed consent 
x 
 
 
 
Height/weight/body surface 
x 
 
 
 
In- / exclusion criteria 
x 
 
 
 
HCTCI score 
x 
 
 
 
ECOG score,  
x 
 
x 
 
Echocardiogaphy (TTE)1 
x 
 
 
 
Hematology 
x 
x 2 
x 
 
Serum biochemistry 3 
x 
x 4 
x 
 
Pregnancy Test5 
x 
 
 
 
Randomization 
x 
 
 
 
Response (serum free light chain ratio 
and M-gradient; 6 
x 
 
x 
x 
QoL (EORTC Q30) 
x 
 
x 
 
Administer study medication 
 
x 
 
 
Number of CD34+ cells for ASCT 7 
 
x 
 
 
Engraftment, lymphocyte, neutrophil and 
platelet recovery 
 
x 
 
 
RBC & platelet transfusions 
 
x 
 
 
Days of T>38.0°; number of febrile 
episodes 
 
x 
x 
 
Bone marrow 
 
 
x 8 
 
CD4/CD8 determination (bone marrow) 
 
 
x 9 
 
CD4/CD8 determination (blood) 
 
 
x 9 
 
Adverse Events 
 
x 
x 
 
1 Echo results can be accepted within three months prior to HDCTX ,the echo can be omitted or postponed untill treatment visit if clinically indicated 
2 Hematology (hemoglobin, leukocytes, platelets) will be assessed on a a daily basis as soon as leukocytes drop < 0.5 G/L until and including the day 
of neutrophils raising again > 0.5 G/l, lymphocytes raising > 0.5 G/l and platelets raising > 20 G/l.  
3 Biochemistry includes creatinine, urea, and uric acid; creatinine clearance is assessed once during screening and at the day 60 assessment. 
4 Starting with the first day of HDCT treatment, creatinine, urea, and uric acid will be assessed on a daily basis until including day 3 after ASCT. In 
case of clinically significant renal toxicity, creatinine, urea, and uric acid will be assessed as long as clinically indicated. 
5 pregnancy test will be requested at screening visit or before study treatment, if indicated 
6Assessment includes free light chain kappa and lambda and the ratio, serum electrophoresis with immunofixation, and urine electrophoresis with 
immunofixation if indicated. 
7Apheresis of hematopoietic cell could be possible also before day -35, representing a part of the standard of care for myeloma patients. 
8optional: Bone marrow is performed only in patients fulfilling the criteria for CR1. The bone marrow can alternatively be performed at the end of the 
ASCT hospitalization, thus before the day 60 assessment. Bone marrow should include flowcytometric assessment of minimal residual disease 
(MRD) for clonal plasma cells. Bone marrow assessment can be done between recovery from neutropenia until day +75.  
 9CD4 and CD8 determination is performed at the day of bone marrow (+/- 14 days, in bone marrow and in blood) and could be repeated in blood 
between day (+30- +75) 
10 Follow-up is according to the treating physician. It should include assessment of myeloma serum parameters (without urine analysis and without 
bone marrow). If relapse is suspected, assessment of myeloma serum parameters (including urine analysis) should be performed. Patients withdrawn 
from the protocol are documented until the day 60 assessment. 
 

 
 
 
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1. STUDY ADMINISTRATIVE STRUCTURE  
1.1 
Sponsor 
 
University Hospital/Inselspital 
Freiburgstrasse 10; 3010 Bern  
 
 
1.2 
Principal Investigator 
 
Prof. Thomas Pabst; M.D. 
Department for Medical Oncology; University Hospital/Inselspital 
Freiburgstrasse 10; 3010 Bern  
Tel: +41 31 632 84 30; Fax: +41 31 632 34 10; E-Mail: thomas.pabst@insel.ch 
 
 
 
1.3 
Statistician ("Biostatistician")  
 
Dr. Martin Bigler 
SAKK Coordinating Center 
Effingerstrasse 40; 3008 Bern 
Tel: +41 31 389 93 54; Fax: +41 31 389 92 00; E-Mail: martin.bigler@sakk.ch 
 
 
1.4 
Laboratory 
 
Not applicable; no central specific laboratory analyses are planned in this trial. 
 
 
1.5 
Monitoring institution 
 
Monitoring will be performed by the Clinical Trial Unit (CTU) of the University of Berne, Switzerland. 
 
 
1.6 
Data Safety Monitoring Committee (DSMC) 
 
Not applicable; no DSMC is useful for this single-center trial. 
 
 
1.7 
Any other relevant Committee, Person, Organisation, Institution  
 
Not applicable. 
 

 
 
 
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2. ETHICAL AND REGULATORY ASPECTS  
Before the study will be conducted, the protocol, the patient information and the consent form as well 
as other study-specific documents will be submitted to the Competent Ethics Committee (CEC) in Berne 
and to the competent authorities (Swissmedic) for formal approval. Any amendment to the protocol will 
as well be approved (if legally required) by these institutions. 
The decision of the CEC and Swissmedic competent authority concerning the conduct of the study will 
be made in writing to the Principle Investigator before commencement of the study. The clinical study 
can only begin once written approval from the required authoritiy has been received. Any additional 
requirements imposed by the authorities shall be implemented. 
 
2.1 
Study registration  
This study is registered in the WHO International Clinical Trials Registry Platform (ICTRP, 
http://www.who.int/ictrp/en/): (http://clinicaltrials.gov). In addition, it is registered in the Swiss Federal 
Complementary 
Database 
(Portal) 
http://www.kofam.ch/gesuch-verfahren/klinischen-versuch-
registrieren-via-snctp.html.  
 
2.2 
Categorisation of study  
This clinical trial falls into Category B since the investigational compound bendamustine (Ribomustin®) 
is approved in Switzerland for the treatment of Non-Hodgkin lymphoma (NHL) patients. However, it is 
formally not registered for the treatment of myeloma patients representing a specific subtype of NHL. In 
this trial, Bendamustine is used for the treatment of myeloma patients as a part of a high-dose 
chemotherapy regimen, thus definitely outside of its approved indication. 
 
2.3 
Competent Ethics Committee (CEC)  
The principle investigator ensures that approval from an appropriately constituted Competent Ethics 
Committee (CEC) is sought for the clinical study. All changes in the research activity and all 
unanticipated problems involving risks to humans will be reported including in case of planned or 
premature study end and the final report. No changes will be made to the protocol without prior CEC 
approval, except where necessary to eliminate apparent immediate hazards to study participants. 
Premature study end or interruption of the study is reported within 15 days. The regular end of the study 
is reported to the CEC within 90 days, the final study report shall be submitted within one year after 
study end. Amendments are reported according to chapter 2.10. 
 
2.4 
Competent Authorities (CA)  
The Sponsor will obtain approval from the competent authority (Swissmedic) before the start of the 
clinical trial. All changes in the research activity and all unanticipated problems involving risks to humans 
will be reported including in case of planned or premature study end and the final report. No changes 
will be made to the protocol without prior approval, except where necessary to eliminate apparent 
immediate hazards to study participants. 
Premature study end or interruption of the study is reported within 15 days. The regular end of the study 
is reported to the CEC within 90 days, the final study report shall be submitted within one year after 
study end. Amendments are reported according to chapter 2.10. 
 
2.5 
Ethical Conduct of the Study  
This trial will be conducted in compliance with the protocol, ICH guidelines (International Conference on 
Harmonisation) and the applicable local regulatory requirement(s) and directives. The study will be 
carried out in accordance to the protocol and with principles enunciated in the current version of the 
Declaration of Helsinki as well as the guidelines of Good Clinical Practice (GCP) issued by ICH. The 
competent Ethics Committees (CECs) and local regulatory authorities will receive annual Development 
Safety Update Report (DSUR) and be informed about study stop/end in agreement with local 
requirements and institutional SOP. Any changes or amendments to the study protocol will be 
documented by the Principle Investigator in writing and sent to the local CEC, and regulatory authorities. 

 
 
 
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2.6 
Declaration of interest  
No conflicts of interest are reported. 
 
2.7 
Patient Information and Informed Consent 
Participants will be comprehensively informed about the study and consent is sought from each 
participant; no compensation for study participation is made in this trial. The investigators will explain to 
each participant the nature of the study, its purpose, the procedures involved, the expected duration, 
the potential risks and benefits and any discomfort it may entail. Each participant will be informed that 
the participation in the study is voluntary and that he/she may withdraw from the study at any time and 
that withdrawal of consent will not affect his/her subsequent medical assistance and treatment. The 
participant will be informed that his/her medical records may be examined by authorised individuals 
other than their treating physician. 
All participants for the study will be provided a participant information sheet and a consent form 
describing the study and providing sufficient information for participants to make an informed decision 
about their participation in the study. Enough time needs to be given to the participant to ask questions 
and decide whether to participate or not. The patient information sheet and the consent form will be 
submitted to the CEC to be approved. The consent of a participant, using the approved consent form, 
must be obtained before the participant is submitted to any study procedure.   
The participant will read and consider the statement before signing and dating the informed consent 
form, and will be given a copy of the signed document. The original consent form will also be signed 
and dated by the investigator (or his designee) and it will be retained as part of the study records. 
 
2.8 
Participant privacy and confidentiality  
The investigator affirms and upholds the principle of the participant's right to privacy and that they shall 
comply with applicable privacy laws. Especially, anonymity of the participants shall be guaranteed when 
presenting the data at scientific meetings or publishing them in scientific journals.  
Individual subject medical information obtained as a result of this study is considered confidential and 
disclosure to third parties is prohibited. Subject confidentiality will be further ensured by utilising subject 
identification code numbers to correspond to treatment data in the computer files. 
For data verification purposes, authorised representatives of the Sponsor (-Investigator), a competent 
authority (e.g. Swissmedic), or an ethics committee may require direct access to parts of the medical 
records relevant to the study, including participants’ medical history. 
 
2.9 
Early termination of the study  
The Sponsor-Investigator (and any competent authority) may terminate the study prematurely according 
to certain circumstances for example: 
• 
Ethical concerns; 
• 
Insufficient participant recruitment; 
• 
When the safety of the participants is doubtful or at risk, respectively; 
• 
Alterations in accepted clinical practice that make the continuation of a clinical trial unwise; 
• 
Early evidence of benefit or harm of the experimental intervention.  
 
2.10 Protocol amendments 
The Principle Investigator is allowed to amend the protocol or to provide suggestions for a protocol 
amendment. Substantial amendments are only implemented after approval of the CEC and CA, 
respectively. Under emergency circumstances, deviations from the protocol to protect the rights, safety 
and well-being of human subjects may proceed without prior approval of the sponsor and the CEC/CA. 
Such deviations shall be documented and reported to the sponsor and the CEC/CA as soon as possible. 
All Non-substantial amendments are communicated to the CA as soon as possible if applicable and to 
the CEC within the Annual Safety Report (ASR).  

 
 
 
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3. BACKGROUND AND RATIONALE  
3.1 
Background and Rationale  
High-dose chemotherapy with melphalan and autologous stem cell transplantation (ASCT) remains an 
integral component of the myeloma treatment algorithm for patients considered eligible for the 
procedure, nowadays performed in myeloma patients up to the age of 75 years. The traditional 
approach to patients with newly diagnosed myeloma, considered to be candidates for ASCT, has been 
to provide initial therapy with 4 to 6 cycles of a non–alkylator-containing regimen followed by collection 
of stem cells and high-dose therapy. The initial therapy for the disease allows time to obtain necessary 
insurance approvals as well as control disease-related symptoms, simultaneously controlling toxicity 
by limiting the number of cycles. In addition, adequate disease control provides an opportunity to 
reverse disease-related complications wherever feasible, and generally improve the functional status 
of the patient, allowing for a safer transplantation.  
The majority of the randomized clinical trials have demonstrated a superior progression-free survival 
among patients undergoing ASCT compared with those treated with only conventional therapies, and 
ASCT was associated with superior overall survival in the majority of those studies (1-7). Subsequent 
randomized trials have further defined the role of ASCT by demonstrating equivalent overall survival 
for delayed transplantation compared with upfront ASCT, albeit with some compromise in the quality-
of-life parameters (8). Introduction of novel agents such as thalidomide, lenalidomide, and bortezomib 
have resulted in a paradigm change in the therapy of myeloma (9-14). The high response rates with 
these agents, hitherto seen only in the context of high-dose therapy, have once again raised questions 
regarding the utility of ASCT in the setting of myeloma. Given the lack of long-term follow-up of patients 
treated with these new agents, the durability of these responses as well as their potential long-term 
adverse effects remain to be demonstrated. Noteworthy, recently published studies suggest that the 
novel induction regimens together with consolidating high-dose treatment act in an additive manner 
allowing increasing rates of complete remission ranging between 50 up to 70% after autologous 
transplantation. Thus, ASCT continues to be an important part of myeloma therapy, nowadays more 
than ever. At the University Hospital in Bern, the number of ASCT is increasing each year, with 
myeloma representing the most common entity, comprising roughly 50% of all ASCT. 
These facts add to the observation that there is a continuous increase in the number of ASCTs reported 
to the Center for International Blood and Marrow Transplant Research (CIBMTR). Currently, the novel 
agents appear best suited to be used as first-line therapy, enhancing the quality of responses prior to 
proceeding to ASCT or as adjuncts to transplant conditioning regimens or as maintenance therapy in 
patients undergoing ASCT (15-23). Furthermore, in a randomized trial evaluating single versus double 
ASCT a survival advantage with tandem ASCT was demonstrated in an unplanned subset analysis for 
those patients not obtaining at least a very good partial response after the first ASCT. This observation 
has increased the number of ASCTs being performed for patients not achieving very good partial 
response after the first ASCT (24). In addition, ASCT can also be used as part of second-line therapy 
after relapse, especially among patients who achieved a durable response after the first ASCT (6;23).  
 
3.2 
Investigational Product 
The bendamustine molecule is composed of three structural elements: a bis (2-chloroetylo) amine 
group (nitrogen mustard), a purine-like benzimidazolering and a butyric acid side chain (24). The bis 
(2-chloroetylo) amine group confers the alkylator properties and the benzimidazole ring that replaces 
the benzene ring present in chlorambucil, the antimetabolite properties. While, the butyric acid side 
chain makes this drug water soluble (25). The antineoplastic effect of bendamustine is due to 
production of both single- and doublestrand breaks (26–29). The DNA breaks, observed after 
bendamustine exposure, are more extensive and significantly more durable than those induced by 
other alkylators. This extensive DNA damage leads to inefficient DNA repair mechanisms, resulting in 
mitotic checkpoint inhibition (26). 
In addition, bendamustine can also lead to phosphorylation of Ser-15 and increases protein expression 
of Bax, inducing a traditional apoptosis via the activation of P53-dependent pathways (26, 27). 
Bendamustine is administered intravenously (i.v.) over 30–60 min; peak plasma concentration (Cmax) 
occurs at the end of the infusion. The majority of the drug (95%) is bound to serum plasma proteins, 
particularly to albumin; however, only unbound bendamustine is pharmacologically active (30–34). 
Some preclinical and clinical studies demonstrated that bendamustine undergoes extensive first-pass 
hepatic metabolism, primarily by hydrolysis, via the cytochrome P450 1A2 (CYP1A2) isoenzyme (31; 
32; 35). 

 
 
 
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The major metabolite is β-hydroxybendamustine, which does not significantly contribute to 
bendamustine’s activity (36). Phase II conjugation with glutathione also plays a role in the metabolism 
of bendamustine (35). The drug is eliminated mainly via the faeces (90%) and to a lesser extent in the 
urine (37). Following a single dose of bendamustine, concentrations declined in a triphasic manner, with 
rapid distribution, intermediate and slow terminal phases (34). Estimates of t1/2a, t1/2b and t1/2c for 
bendamustine were 0.29 h, 0.7 h and 110 h, respectively. The AUC for the terminal phase accounted 
for <1% of the total AUC; thus, the t1/2 of the b-phase (40 min) is considered to be reflective of half-life 
of bendamustine (25). Age, as well as mild or moderate renal impairment or hepatic dysfunction did not 
alter bendamustine pharmacokinetics. Nevertheless, it is recommended to use this drug with caution in 
patients with mild to moderate hepatic impairment, and it should be avoided in those with severe hepatic 
dysfunction (26). Furthermore, some drugs such as omeprazole or tobacco, strong inducers of CYP1A2, 
seem to decrease bendamustine concentration in plasma and reduce its efficacy (38). 
 
3.3 
Evidence of clinical activity of Bendamustine from previous studies 
Knop et al. (39) published 2005 the results of a phase I study of bendamustine in 31 patients up to age 
70 yr with myeloma progressing after high-dose therapy + autologous stem cell transplantation (HDT + 
ASCT). The initial dose was 30 mg/m2/day on days 1 and 2 of each 28-days cycle, and it was escalated 
up to 50 mg/m2/day. The total dose of 100 mg/m2 was found to be the maximum dose tolerated (MDT). 
The overall response rate (ORR) was 55%, with a median progression free survival (PFS) of 26 week. 
A retrospective analysis investigated the use of bendamustine in 39 relapsed myeloma patients (40). 
Patients have received a median of 3 (1–10) cycles of bendamustine at the dosage of 80–150 
mg/m2/day on days 1 and 2 every 28 days. In 39% of cases, bendamustine was administered alone, 
while in the remaining 61%, in combination with steroids. The ORR was 36% [no complete response 
(CR) was observed]; the median event-free survival (EFS) and overall survival (OS) were 7 and 17 
months, respectively. No difference in terms of response rate was observed between elderly and 
younger patients (40). Finally, Damaj et al. reported data of a French compassionate use programme 
that had enrolled 110 relapsed/refractory myeloma patients who received bendamustine at dosage of 
60–150 mg/m2/day on days -3 and -2 in combination with variable dose of steroids for a median of 4 
(range 1–13) cycles every 28 days. The ORR was 30%, including 2% of CR; the median PFS and OS 
were 9.3 and 12.4 months (41). These results highlight the role of bendamustine as an effective salvage 
therapy option for relapsed/refractory myeloma patients. Further, bendamustin is approved in the EU 
for the treatment of multiple myeloma patients not eligible to receive a HDT with ASCT or a thalidomide 
or bortezomib-containing regimen (Ref Fachinformation bendamustin). 
 
3.4 
Evidence for selecting Bendamustine as a component of a high-dose chemotherapy regimen 
High dose melphalan is the standard of care conditioning regimen before ASCT (42), given at a total 
dose of 200 mg/m2, for myeloma patients (43, 44). As bendamustine showed a good efficacy and safety 
profile, a phase I trial was conducted with the aim of evaluating whether the addition of bendamustine 
to melphalan in the ASCT conditioning could improve the response without adding toxicity (45). 
Escalating doses of bendamustine (from 30 mg/m2/day  at day -1 up to 125 mg/m2/day at day -2 plus 
100 mg/m2/day at day -1  added to melphalan 100 mg/m2/day at the same days (days -2 and -1) were 
administered to 25 patients with active myeloma as conditioning regimen. The MTD was not 
encountered at the highest dose level. At day +100, ORR was 79%, with 38% of stringent CR, 4% of 
CR, 33% of VGPR and 4% of PR. Ten patients progressed after a median of 473 d after ASCT and six 
patients died. Median PFS was 791 d, and the median OS was not reached, but the 2-yr OS rate was 
70% (45). 
Martino et al. recently reported phase II data regarding feasibility and efficacy of the association between 
bendamustine and melphalan (BM) as a conditioning regimen to second ASCT in patients with myeloma 
(46). All 32 patients enrolled have received a bortezomib-containing regimen as first-line induction 
therapy and received melphalan 100 mg/m2/day on days -2 and -1 as conditioning regimen before the 
first ASCT. The conditioning regimen before second ASCT was bendamustine (100 mg/m2/day on days 
-4 and -3) and melphalan (140 mg/m2/day on day -2). No added toxicity was observed between the first 
and second ASCT. The 2y-OS and 2y-PFS were, respectively 97% and 79% (46). Finally, Breitkreutz 
et al. recently reported data of 28 consecutive myeloma patients treated with a dose-intensified 
bendamustine (180 mg/m2/day, days -3 and -2) followed by autologous blood stem-cell support (ASCS) 
(47). All patients relapsed from the last treatment (median of 3 prior lines of therapy) with very limited 
bone marrow function and were therefore ineligible for conventional chemotherapy, novel agents or trial 
enrolment. This schedule allowed of improving hematopoiesis as reflected by a significant increase of 
platelet counts and white blood cell counts at day +100. Furthermore, 36% of patients achieved at least 

 
 
 
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a minimal response. Nevertheless, the median PFS was limited to 2.14 months. Most importantly, 
patients, by improving the hematopoiesis, were once again eligible for alternative treatments including 
enrolment into clinical trials (47). 
 
Justification and definition of primary endpoint: The achievement of stringent CR1 is generally 
considered a prerequisite for potential long-time cure in myeloma patients. This highlights the 
importance of not only achieving normalization of light chain ratio and absence of a paraprotein in the 
serum, but also of complete elimination of clonal plasma cells in the bone marrow assessed by sensitive 
flowcytoemtric analysis. These facts form the basis of our attempt of an intensified conditioning HDCT 
regimen aiming to increase the proportion of patients with CR1 after ASCT, thus representing the 
primary endpoint of this study. 
 
3.5 
Dose Rationale for Bendamustine in conditioning regimens 
As outlined above (section 3.4), two phase 1 and 2 studies have reported combinations of melphalan 
with bendamustine as first-line conditioning regimen before ASCT in myeloma patients. The phase 1 
trial added escalating doses of bendamustine (days -2 and -1) to standard melphalan. Bendamustine 
was administered at the same days of melphalan and maximum tolerated dose was not encountered; 
the highest dose level cohort of bendamustine total dose of 225 mg/m2 and melphalan total dose of 200 
mg/m2 was expanded to further evaluate safety (45). 
Recently, Martino et al. reported their data regarding feasibility and efficacy of the combination of 
bendamustine and melphalan (BM) as a conditioning regimen to second ASCT in patients with Myeloma 
(46). In this phase II study multiple myeloma patients underwent tandem autologous stem cell 
transplants as part of their treatment. All patients (n= 32) received melphalan 100 mg/m2/day on days -
2 and -1 as conditioning regimen before the first ASCT. Bendamustine 200 mg/m2/day on days -4 and 
-3 plus melphalan 140 mg/m2/day on day -2 was the conditioning regimen before the second ASCT. 2y-
OS was 79% and 2y-OS was 97%. No added toxicities were observed between the first and the second 
ASCT: differences in toxicities were not statistically significant, except for mucositis and nausea that 
were higher after the first conditioning regimen with only melphalan (!). The majority of the toxicities 
were grade 1 or 2. No treatment related mortality was reported (46). 
In addition, extensive experience is available on the use of bendamustine (200mg/m2/day given on days 
-7 and -6) together with melphalan (140mg/m2/day day -1) and cytarabine/etoposide (each on days -5 
to -2) in the BeEAM conditioning regimen which is increasingly used as the standard conditioning 
regimen in lymphoma patients, as is also the case in our clinic, in which we observe acceptable toxicity 
justifying the use of high dose bendamustine HDCT conditioning (48-50).                                           
In summary, these data suggest that combinations of melphalan and bendamustine are usually well 
tolerated and that the maximum tolerated dose of bendamustine is not reached with the dose of 
200mg/m2/daygiven on two days added to melphalan, etoposide cytarabine (BeEAM regimen). We 
therefore suggest in this study to directly compare bendamustine 200 mg/m2/day given on days -4 and 
-3 plus melphalan at standard dose of 100mg/m2/day on days -2 and -1 versus with standard melphalan 
alone (100mg/m2/day on days -2 and -1), in a randomized trial in order to compare effectiveness and 
tolerability of the combination treatment. To limit toxicity, the schedule for the administration of the study 
medication is planned as follows: bendamustine given on days -4 and -3 and melphalan on days -2 and 
-1, thereby avoiding to administer both drugs at the same days (-2 and -1). 
 
3.6 
Explanation for choice of comparator 
Improving the efficacy of HDCT with Melphalan together with ASCT is an unmet clinical need in myeloma 
patients. Currently, this approach is not curative and adds significant transient burden in terms of 
impaired quality of life. The combination of bendamustine and melphalan appears promising and 
reasonable, based upon the results summarized above. We therefore consider a direct randomized 
comparison justified between melphalan versus the combination of melphalan with bendamustine. 
 
3.7 
Risks / Benefits  
Routinely performed high-dose chemotherapy with ASCT is associated with significant side effects 
requiring detailed information of the patient. Usually, it is associated with a hospitalization of at least 3 
weeks. Bendamustine treatment is usually associated with a good safety profile. In fact, when this drug 
is administered alone or in combination with steroids, toxicity is usually moderate. The most frequently 
reported adverse events (AEs) are reversible myelosuppression, fever, allergic reactions, 

 
 
 
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gastrointestinal symptoms (nausea and vomiting) and infections (51). When administered alone or in 
combination with steroids in relapsed/ refractory myeloma patients, the majority of AEs were mild and 
consisted mainly of hematological AEs (39–41). As first-line therapy, myeloma patients who received 
bendamustine and prednisone showed a higher rate of severe nausea and vomiting compared with 
those who received melphalan plus prednisone (52). Although no significant differences in the incidence 
of various hematological adverse events were observed, the percentage of patients receiving 
bendamustine and prednisone who required dose reduction for leukopenia (8.6 vs. 4.1%) and 
thrombocytopenia (1.8 vs. 0.9%) was higher than that of patients receiving melphalan and prednisone 
(52). The combination of bendamustine with bortezomib and steroids was well tolerated in 
relapsed/refractory patients (53). Also in this setting, the most frequent severe AEs were hematological, 
while severe non-hematological AEs were uncommon and consisted in gastrointestinal disturbances, 
fatigue and infections (53). When administered as first-line treatment, safety profile of this combination 
was manageable and most AEs were of grade 1–2. The most common toxicities were as follows: 
peripheral neuropathy, neutropenia, asthenia and infection (54,55). The combinations of bendamustine 
with 
thalidomide 
plus 
dexamethasone/prednisone 
(56) 
and 
with 
lenalidomide 
plus 
dexamethasone/prednisone (57) showed acceptable tolerability profiles in relapsed/refractory patients. 
Again, the most frequent severe AEs were hematological. 
Although in the absence of anticoagulant prophylaxis, no thromboembolic events were observed. 
Finally, the addition of bendamustine to high-dose melphalan in ASCT conditioning does not seem to 
enhance toxicities. No transplant-related mortality events correlated to bendamustine administration 
were reported (45, 46). Patients should be observed for dehydration which is another common AE. 
 
3.8 
Justification of choice of study population  
This study does not involve vulnerable participants (e.g. minors, adolescents, participants incapable of 
judgement or participants under tutelage, emergency treatment of unconscious patients or others). The 
age limits are between 18 and 75 years. However, high-dose bendamustine and melphalan require 
adequate renal function. This requires that myeloma patients with significantly reduced renal function 
(defined as a creatinine clearance < 40 ml/min) are not eligible for this study. 
 
4. STUDY OBJECTIVES  
4.1 
Overall Objective 
This study aims to demonstrate that adding bendamustine to standard high-dose melphalan conditioning 
chemotherapy before ASCT is improving response rates in myeloma patients. 
 
4.2 
Primary Objective 
• 
This study aims to show a clinically meaningful improvement by 15% of the rate of complete 
remission (CR1) 60 days after ASCT in myeloma patients from 50% with melphalan alone to 
65% with the combination of bendamustine and melphalan. 
 
4.3 
Secondary Objectives 
This study intends  
• 
to assess acute and late toxicities/adverse events (CTCAE 4.0) during the study period in 
patients treated with the combination of bendamustine and melphalan as compared to 
melphalan alone; 
• 
to assess the hematologic engraftment in patients treated with the combination of bendamustine 
and melphalan as compared to melphalan alone; 
• 
to particularly assess early renal toxicity in patients treated with the combination of 
bendamustine and melphalan as compared to melphalan alone; 
• 
to assess differences in overall survival and progression free survival in patients treated with 
the combination of bendamustine and melphalan as compared to melphalan alone after one 
year; 

 
 
 
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• 
to assess the quality of life prior to ASCT and 60 days thereafter.  
 
4.4 
Safety Objectives 
As one of the secondary objectives outlined above, this study aims to assess toxicities of bendamustine 
combined with high-dose melphalan as compared to melphalan alone in myeloma patients undergoing 
high-dose chemotherapy with autologous stem cell transplantation. Particular attention will be given to 
detect and monitor eventual renal toxicity. Any other adverse event will be also recorded. 
5. STUDY OUTCOMES  
5.1 
Primary Outcome 
A clinically meaningful increase of the efficacy of a novel high-dose conditioning chemotherapy is 
defined in this study as an increase of the rate of complete remissions (CR1) 60 days after ASCT from 
50% with melphalan alone to ≥ 65% with the combination melphalan and bendamustine (see appendix 
3 for definition of CR). 
 
5.2 
Secondary Outcomes 
Toxicities/adverse events are assessed according to the CTCAE 4.0 during the study period. 
Hematologic engraftment after high-dose chemotherapy induced myelosuppression is defined as the 
first day of neutrophils rising again above 0.5 G/l, and of platelets rising again above 20 G/L in the 
absence of platelet transfusions in the previous 3 days. 
Overall survival is defined as the time from ASCT until death of any cause or date of last follow-up. 
Progression free survival is defined as the time from ASCT until first recurrence of myeloma or date of 
last follow-up whatever occurs first. 
 
5.3 
Other Outcomes of Interest 
Not applicable. 
 
5.4 
Safety Outcomes 
This study aims to assess toxicities of bendamustine combined with high-dose melphalan as compared 
to melphalan alone in myeloma patients undergoing high-dose chemotherapy with autologous stem cell 
transplantation. Particular attention will be given to detect and monitor eventual renal toxicity. Any other 
adverse event will also be recorded. 
 
6. STUDY DESIGN  
6.1 
General study design 
This is a 1.1 randomized parallel open-label prospective phase II trial investigating myeloma patients 
considered clinically fit to undergo high-dose chemotherapy with autologous stem cell transplantation.  
Two high-dose chemotherapy regimens (Mel versus BenMel) used for conditioning treatment before 
autologous stem cell transplantation will be compared in a 1:1 randomization (see trial diagram below). 
The experimental arm is the BenMel regimen; the Mel regimen is the control treatment. Both regimens 
use melphalan at identical doses and at identical days (100mg/m2/day each on days -2 and -1). 
However, myeloma patients in the experimental arm receive two additional doses of bendamustine 200 
mg/m2/day given on days -4 and -3. Response will be assessed by serum light chain ratio and M-gradient 
before study treatment and 60 days after ASCT.   
There will be 60 patients in each group to show a clinically meaningful improvement by 15% of the rate 
of complete remission (CR1) 60 days after ASCT in myeloma patients, from 50% with melphalan alone 
to 65% with the combination of bendamustine and melphalan. The anticipated total study duration will 
be 36 months  

 
 
 
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Methods of minimising bias: this is a 1:1 randomized parallel open-label prospective phase II trial. 
Patients will be stratified for remission status (CR/VGPR versus PR/SD/PD), and for presence/absence 
of reduced renal function defined as a creatinine clearance ≥ 50 ml/min versus <50 ml/min but ≥ 40 
ml/min. 
Randomization is performed by the coordinating study nurse, the specifically designed study nurse or 
his/her replacent of the Klinische Forschungseinheit Onkologie, University Hospital/Inselspital, 3010 
Bern. Randomisation will be performed using REDCap software. Two stratification parameters 
(response and renal function) will be applied. Patients can be registered 24 h / 7 days. 
Blinding procedures: not applicable; this is an open-label trial. 
Unblinding Procedures (Code break): not applicable; this is an open-label trial. 
 
 
 
 
7. STUDY POPULATION  
7.1 
Eligibility criteria  
 
Participants fulfilling all of the following inclusion criteria are eligible for the study: 
- 
Eligible are myeloma patients after standard first-line induction treatment. A second induction 
regimen in refractory myeloma patients is allowed. 
- 
Patients must be considered being fit for subsequent consolidation with high-dose 
chemotherapy with melphalan with autologous stem cell support. 
- 
Patients must be aged 18-75 years. 
- 
Patients must have an ECOG < 3. 
- 
Patients must have a creatinine clearance ≥ 40 ml/min. 
- 
Patients must have a LVEF ≥ 40% within three months prior to start of study medication (Echo 
can be postponed to study treatment visit in asymptomatic patients). 
- 
Female patients of child-bearing potential;. . No known pregnancy (a pregnancy test in female 
patients of child-bearing potential is not mandatory since patients are already under induction 
chemotherapy or mobilization chemotherapy, and pregnancy was excluded before starting 
chemotherapy. Patient must implement adequate measures (hormonal treatment p.o. or i.m., 
Study treatment: 
Phase II: High-dose melphalan chemotherapy with versus without 
bendamustin followed by autologous transplant at day 0: 
Arm A (Mel):       Melphalan 100mg/m2/day iv days -2 and -1    
Arm B (BenMel): Melphalan 100mg/m2/day iv days -2 and -1 
                                      and Bendamustine 200mg/m2/day iv days -4 and -3 
Registration 
Perform screening procedures and confirm subject eligibility 
Follow up 

 
 
 
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intra uterine surgical devices, or latex condoms) to avoid pregnancy during study treatment and 
for additional 12 months. No pregnant or lactating patients are allowed. Thus Pregnancy test 
could be omitted from the screening visit and could be postponed to the study treatment if 
indicated.  
- 
Patients must have given voluntary written informed consent. 
 
The presence of any one of the following exclusion criteria will lead to exclusion of the participant: 
- 
Patients with uncontrolled acute infection.  
- 
Patients with a transplantation comorbidity index (HCTCI) > 6 points.( HCTCI may be postponed 
to the treatment visit) 
- 
Patients with concurrent malignant disease with the exception of basalioma/spinalioma of the 
skin or early-stage cervix carcinoma, or early-stage prostate cancer. Previous treatment for 
other malignancies (not listed above) must have been terminated at least 24 months before 
registration and no evidence of active disease shall be documented since then. 
- 
Patients with major coagulopathy or bleeding disorder.  
- 
Patients with other serious medical condition that could potentially interfere with the completion 
of treatment according to this protocol or that would impair tolerance to therapy or prolong 
hematological recovery. 
- 
Patients with lack of cooperation to allow study treatment as outlined in this protocol.  
- 
Pregnancy or lactating female patients. 
- 
The use of any anti‐cancer investigational agents within 14 days prior to the expected start of 
trial treatment  
- 
Patients with contraindications and hypersensitivity to any of the active chemotherapy 
compounds. 
 
7.2 
Recruitment and screening 
Participants are recruited to this study by screening myeloma patients routinely referred to our centre 
for autologous stem cell transplantations. No specific advertisement for this study is performed. The 
screening procedure is outlined in section 9.3.1. No payment or compensation is given to study 
participants. 
 
7.3 
Assignment to study groups  
Randomization is performed by the coordinating study nurse, the specifically designed study nurse or 
his/her replacent of the Klinische Forschungseinheit Onkologie, University Hospital/Inselspital, 3010 
Bern. Randomisation will be performed using REDCap software. Two stratification parameters 
(response and renal function) will be applied. Patients can be registered 24 h / 7 days. 
Patients will be stratified for remission status (CR/VGPR versus PR/SD/PD), and for presence/absence 
of reduced renal function defined as a creatinine clearance ≥ 50 ml/min versus <50 ml/min but ≥ 40 
ml/min. If an already registered patient is later found not to completely fulfill the inclusion/exclusion 
criterias, he/she will be documented on the enrollment-log at the centre. The exclusion of this patient 
will be reported to the coordinating investigator. The patient will not be included in the final analysis, and 
his/her patient number will not be replaced by another patient. 
 
7.4 
Criteria for withdrawal / discontinuation of participants  
 
Withdrawal of informed consent by the participant; 
 
lack of compliance of the participant to follow the study procedures;  
 
relevant protocol violation; 
 
lost to follow up; 
 
Unacceptable toxicity or death. 

 
 
 
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Any participant has the right to withdraw the consent to participation in this trial at any time. Details of 
the date and the circumstances of the withdrawal have to be recorded in the patient charts and in the 
eCRFs. The treating physician can withdraw the patient from the study if considered necessary. Again, 
the date and the circumstances of the withdrawal have to be recorded in the patient charts and in the 
eCRFs. Patients withdrawn from this protocol are documented up to 60 days after ASCT. All patients 
terminating study treatment before 60 days after ASCT will be analyzed until the last documented follow-
up. Patients withdrawn from the protocol won’t be replaced. 
8. STUDY INTERVENTION  
8.1 
Identity of Investigational Products (treatment)  
This is a 1.1 randomized parallel open-label prospective phase II trial investigating myeloma patients in 
first remission considered clinically fit to undergo high-dose chemotherapy with autologous stem cell 
transplantation.  
Two high-dose chemotherapy regimens (Mel versus BenMel) used for conditioning treatment before 
autologous stem cell transplantation will be compared in a 1:1 randomization. The experimental arm is 
the BenMel regimen; the Mel regimen is the control treatment. Both regimens use melphalan at identical 
doses and at identical days (100mg/m2/day each on days -2 and -1). However, myeloma patients in the 
experimental arm receive two additional doses of bendamustine 200 mg/m2/day given on days -4 and -3. 
ASCT is performed in both arms on day 0. Response will be assessed by serum light chain ratio and M-
gradient before study treatment and 60 days after ASCT (day 60 assessment is possible from day +35 
to day +75).   
 
• 
Experimental Intervention (treatment)                BenMel regimen 
Bendamustine 120min iv 
 
200mg/m2/day  
days -4 and -3 
Melphalan 
  60min iv 
 
100mg/m2/day  
days -2 and -1  
 
 
 
 
 
 
 
• 
Control Intervention (standard treatment)          Mel regimen 
Melphalan 
  60min iv 
 
100mg/m2/day  
days -2 and -1  
 
 
 
 
 
 
 
 
8.2 
Packaging, Labelling and Supply (re-supply)  
Bendamustine (Ribomustin®) will be provided in single brown glass vials containing 100 mg of 
bendamustine hydrochloride (HCl) powder. Labeling of bendamustine is performed by the manufacturer 
in accordance to GMP and the local regulatory requirements. Each vial will be affixed with a label 
describing the protocol number, patient number, content of each vial, dosage form, and route of 
administration, lot number, expiration date, storage conditions, and the Sponsor’s name. The label will 
contain also the sentences “for clinical use only”. Packaging and shipping will be according to the 
manufacturer’s standards and local regulations. Upon receipt of bendamustine by the study site, 
pharmacy personnel should check for damage and verify proper quantity, identity, and integrity. Any 
complaints and deviations from the delivery notes have to be reported to Mundipharma Medical 
Company upon discovery. Starting from April 2018 the commercial product (Ribomustine®) will be used 
after adding the study label.  
Mundipharma Medical Company will receive orderings for bendamustine study medication via a specific 
fax ordering form. Distribution of bendamustine will be performed by Alloga Switzerland to the pharmacy 
of the study site in Berne/Switzerland. A stock of study medication will be provided in advance which 
has to be replenished by fax-order sent to Mundipharma Medical Company. Appropriate fax ordering 
forms and fax numbers are provided in the Investigator Study File. 
Drug supply has to be ordered by study staff by fax to the local hospital pharmacy for each patient prior 
to treatment start. Appropriate fax ordering forms and fax numbers are provided in the Investigator Study 
File. 
Storage of Investigational Product: the investigational product bendamustine will be stored at < 25°C 
and protected from light in a secure location accessible only by authorized personnel. All drug supplies 

 
 
 
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are to be used only for this protocol and not for any other purpose. 
Commercial products will be used for Melphalan (Alkeran ®).  
 
8.3 
  Administration of experimental and control interventions  
8.3.1 
Experimental Intervention – high-dose chemotherapy BenMel (Bendamustine and Melphalan) 
Bendamustine: before administration, bendamustine powder must be dissolved in sterile water for 
injection and then immediately diluted in 500 ml of 0.9% sodium chloride. Once reconstituted, 
bendamustine is chemically and physically stable in conventional polyethylene i.v. bags and infusion 
sets for 3.5 hours at room temperature (25°C/60% relative humidity) or for maximally two days under 
refrigerated conditions (2º-8ºC) and is photostable. From a microbiological point of view, the solution 
should be used immediately. If not used immediately, in-use storage times and conditions prior use are 
the responsibility of the user. Because compatibility studies have not been performed, bendamustine 
should not be combined with other agents or solutions (e.g. glucose). 
Bendamustine will be given at a dose of 200mg/m2/day at days -4 and -3, and the dose will be calculated 
according to the BSA (body surface area). No dose capping (e.g. for under-weight or over-weight 
patients) will be performed. The BSA has to be determined only once at screening. Bendamustine is 
administered by i.v. infusion over 120 minutes with sufficient hydration before and after administration 
of bendamustine (volume of at least 4000 ml of NaCL 0.9% solution administered i.v as in the following 
schedule: 2000ml before bendamustine, plus furosemide 20 mg i.v.,  and 2000 ml NaCl 0.9% thereafter). 
An in-line filter is not required for administration. For patients with decreased renal function defined as 
a creatinine clearance <50 ml/min and ≥ 40 ml/min, bendamustine will be reduced to 100 mg/m2/day at 
days -4 and -3. 
As bendamustine is a mildly to moderately emetogenic drug, premedication with antiemetic drugs is 
advised (e.g. a 5-HT3 receptor antagonist). Bendamustine is not considered to be a vesicant when 
diluted and administered as recommended. However, if bendamustine extravasates during infusion, it 
might cause some irritation to affected tissues (follow instructions of SmPC in case of extravasation). 
Vials are for single use only. Vials used for one subject may not be used for any other subject. Partly 
unused or expired medication can be destroyed by the pharmacy at the study site according to local 
guidelines, but only after monitor's approval. The destruction shall be either documented by completing 
the drug return or the drug destruction log. 
 
Melphalan at a dose of 100mg/m2/day will be administered as single  i.v. infusion over 60 minutes at 
days -2 and -1 before ASCT (day 0). No dose capping (e.g. for under-weight or over-weight patients) 
will be performed. Antiemetics, extensive hydration, control of renal function and supportive care are 
according to local hospital guidelines. For patients with decreased renal function defined as a creatinine 
clearance <50 ml/min and ≥ 40 ml/min, melphalan will be reduced to 70 mg/m2/day at days -2 and -1. 
 
8.3.2 
Control Intervention – high-dose chemotherapy Mel (with Melphalan only) 
Melphalan at a dose of 100mg/m2/day will be administered as single  i.v. infusion over 60 minutes at 
days -2 and -1 before ASCT (day 0). No dose capping (e.g. for under-weight or over-weight patients) 
will be performed. Antiemetics, extensive hydration, control of renal function and supportive care are 
according to local hospital guidelines. For patients with decreased renal function defined as a creatinine 
clearance <50 ml/min and ≥ 40 ml/min, melphalan will be reduced to 70 mg/m2/day at days -2 and -1. 
 
8.4 
Dose modifications  
No discontinuation of (one or several) study compounds or dose modification of the allocated 
interventions is allowed by this protocol for a given trial participant. However, for patients with decreased 
renal function defined as a creatinine clearance <50 ml/min and ≥ 40 ml/min, melphalan will be reduced 
to 70 mg/m2/day at days -2 and -1, and bendamustine will be reduced to 100 mg/m2/day at days -4 and 
-3. 
 
8.5 
Compliance with study intervention  
All study data come from procedures and treatments performed in the University Hospital of Bern, 
Switzerland, by staff authorized for this study. The adherence to the study protocol implies for subjects 
in the experimental arm two extra days caused by drug administration (and hospitalization): days -4 and 

 
 
 
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-3 for bendamustine 200 mg/m2/day. Other screening procedures, measument, assessment or 
treatments of the study protocol are identical in both arms. The control group will receive the standard 
procedure for screening, treatment and follow-up. The administration of the entire study treatment 
(including investigational products) and the assessment data will be recorded in the appropriate sections 
of the electronic case report forms. According to the intention-to-treat principle, non-compliant patients 
will not be excluded from the analysis. Non-compliant patients will be documented for a total of 60 days 
after ASCT. All patients terminating study treatment before 12 months will be analyzed until the last 
documented follow-up. 
 
8.6 
Data Collection and Follow-up for withdrawn participants  
Any participant has the right to withdraw the consent to participation in this trial at any time. Details of 
the date and the circumstances of the withdrawal have to be registered in the patient charts and in the 
CRFs. The treating physician can withdraw the patient from the study treatment if considered necessary. 
Again, the date and the circumstances of the withdrawal have to be registered in the patient charts and 
in the CRFs. Patients withdrawn from this protocol are documented for up to 60 days after ASCT. All 
patients terminating study treatment before 60 days after ASCT will be analyzed until the last 
documented follow-up. If patients withdraw their consent to this study, their study data will be 
anonymized after completion of the study analysis. 
 
8.7 
Trial specific preventive measures 
Not included in this trial will be female participants of childbearing potential, which are not using and not 
willing to continue using a medically reliable method of contraception for the entire study duration, such 
as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices, or who are not 
using any other method considered sufficiently reliable by the investigator in individual cases. Female 
participants who are surgically sterilized, hysterectomised or post-menopausal for longer than 2 years 
are not considered as being of child bearing potential. Men should not father a chilld during and up to 
12 months after the trial intervention. 
 
8.8 
Concomitant Interventions (treatments)  
No specific recommendations are made excluding specific medication not allowed during study 
treatment.  
 
8.9 
Supportive treatment during neutropenia after ASCT 
• 
All patients receive G-CSF (filgrastim) 5 µg/kg b.w. starting at day +6 for a total of seven days 
after ASCT (or longer if clinically indicated). 
• 
Platelet infusions are given if levels < 10.000/µl; or in case of fever or coagulopathy if platelets 
are <20.000 µl or if clinically indicated. 
• 
Red cell transfusions if Hb < 8 /dL. Packed RBCs and platelet transfusions should be given to 
maintain a hemoglobin level > 8 g/dL and a platelet count > 10x109/L, or if clinically indicated.  
• 
Fungal prophylaxis with 400mg of fluconazole p.o. ought to be given starting at day +1 once per 
week until recovery from myelosuppression. 
• 
Cotrimoxazole prophylaxis three times a week for 3 weeks after ASCT, and Acyclovir 
prophylaxis twice daily 500mg p.o. for three months will be administered to the patients or 
according to the hospital policy, until recovery from myelosuppression. 
• 
Daily clinical assessment and documentation of toxicities exceeding grade 2 during 
neutropenia. 
 
8.10 Study Drug Accountability  
The investigational product is Bendamustine (Ribomustin®). Accordingly, Bendamustine is provided 
free of charge for all patients in this study by the company Mundipharma, and all Bendamustine sent to 
the sites must be accounted for. All other components of the chemotherapy conditioning before ASCT 
are considered standard of care, and are reimbursed by the insurance company of the patients. The 
investigator is responsible for the control of application and handling of the drugs as requested per 

 
 
 
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protocol. 
Adequate records of receipt, administration, storage, destruction or return of the study drugs have to be 
maintained. All logs have to be completed by the study site staff in a timely manner, and thus should be 
kept current. All records, logs and study drugs (used and un-used) at the site have to be available for 
the inspection at any time. Upon termination of the study, all logs have to be completed and returned to 
the monitor to be passed to the Sponsor. Copies thereof, have to be maintained by the study site. 
 
8.11 Return or Destruction of Study Drug  
All Bendamustine sent to the site must be accounted for. In addition, the amount (in mg) of 
Bendamustine dispensed for each patient must be recorded on an Investigational Product Accountability 
Log and the amount (in mg) administered documented on the case report form (CRF). An accurate 
record of the date and amount of Bendamustine dispensed to each patient must be available for 
inspection at any time. Partially used vials may be destroyed per institutional guidelines and 
documented. All unopened and unused vials of Bendamustine will be destroyed upon completion of the 
study or if drug expires unless otherwise directed by the Principle Investigator. The study site will 
document all receipt, complete destruction, and return (if applicable) of Bendamustine. 
 

 
 
 
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9. 
STUDY ASSESSMENTS  
9.1 
Study flow chart(s) / table of study procedures and assessments. Study schedule  
. 
 
 
    Study schedule 
Study Periods 
 
Screening 
Treatment 
Day 
60 
assessment 
Follow-up 
Visits 
1 
2 
3 
4 10 
Time (days) 
-35 to -5 
-4 until end of 
hospitalization 
+30 to +75 
___ 
Patient informed consent 
x 
 
 
 
Height/weight/body surface 
x 
 
 
 
In- / exclusion criteria 
x 
 
 
 
HCTCI score 
x 
 
 
 
ECOG score,  
x 
 
x 
 
Echocardiogaphy (TTE)1 
x 
 
 
 
Hematology 
x 
x 2 
x 
 
Serum biochemistry 3 
x 
x 4 
x 
 
Pregnancy Test5 
x 
 
 
 
Randomization 
x 
 
 
 
Response (serum free light chain ratio 
and M-gradient; 6 
x 
 
x 
x 
QoL (EORTC Q30) 
x 
 
x 
 
Administer study medication 
 
x 
 
 
Number of CD34+ cells for ASCT 7 
 
x 
 
 
Engraftment, lymphocyte, neutrophil and 
platelet recovery 
 
x 
 
 
RBC & platelet transfusions 
 
x 
 
 
Days of T>38.0°; number of febrile 
episodes 
 
x 
x 
 
Bone marrow 
 
 
x 8 
 
CD4/CD8 determination (bone marrow) 
 
 
x 9 
 
CD4/CD8 determination (blood) 
 
 
x 9 
 
Adverse Events 
 
x 
x 
 
 
1 Echo results can be accepted within three months prior to HDCTX ,the echo can be omitted or postponed untill treatment visit if clinically indicated 
2 Hematology (hemoglobin, leukocytes, platelets) will be assessed on a a daily basis as soon as leukocytes drop < 0.5 G/L until and including the day 
of neutrophils raising again > 0.5 G/l, lymphocytes raising > 0.5 G/l and platelets raising > 20 G/l.  
3 Biochemistry includes creatinine, urea, and uric acid; creatinine clearance is assessed once during screening and at the day 60 assessment. 
4 Starting with the first day of HDCT treatment, creatinine, urea, and uric acid will be assessed on a daily basis until including day 3 after ASCT. In 
case of clinically significant renal toxicity, creatinine, urea, and uric acid will be assessed as long as clinically indicated. 
5 pregnancy test will be requested at screening visit or before study treatment if indicated 
46Assessment includes free light chain kappa and lambda and the ratio, serum electrophoresis with immunofixation, and urine electrophoresis with 
immunofixation if indicated. 
57Apheresis of hematopoietic cell could be possible also before day -35, representing a part of the standard of care for myeloma patients. 

 
 
 
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68optional: Bone marrow is performed only in patients fulfilling the criteria for CR1. The bone marrow can alternatively be performed at the end of the 
ASCT hospitalization, thus before the day 60 assessment. Bone marrow should include flowcytometric assessment of minimal residual disease 
(MRD) for clonal plasma cells. Bone marrow assessment can be done between recovery from neutropenia until day +75.  
 9CD4 and CD8 determination is performed at the day of bone marrow (+/- 14 days, in bone marrow and in blood) and could be repeated in blood 
between day (+30- +75) 
10 Follow-up is according to the treating physician. It should include assessment of myeloma serum parameters (without urine analysis and 
without bone marrow). If relapse is suspected, assessment of myeloma serum parameters (including urine analysis) should be 
performed. Patients withdrawn from the protocol are documented until the day 60 assessment.Assessments of 
outcomes     
9.1.1 
Assessment of primary outcome  
The primary outcome – thus, to show a clinically meaningful increase of the CR1 rate - will be assessed 
by determining the serum M-gradient and light chain ratio and the. A bone marrow at the day 60 
assessment, including the myeloma immunophenotype, is recommended in patients with complete 
remission according to the serum. Since this is an open-label trial, assessment of the primary endpoint 
cannot occur in a blinded manner. 
 
9.1.2 
Assessment of secondary outcomes 
• 
to assess acute and late toxicity/adverse events using the CTCAE 4.0 classification during the 
study period in patients treated with the combination of bendamustine and melphalan as 
compared to melphalan alone; 
• 
to assess the hematologic engraftment on a a daily basis starting on the day of ASCT until and 
including the day of neutrophils raising again > 0.5 G/l, lymphocytes raising > 0.5 G/l and 
platelets raising > 20 G/l;  
• 
to particularly assess early renal toxicity in patients treated with the combination of 
bendamustine and melphalan as compared to melphalan alone; Starting with the first day of 
HDCT treatment, creatinine, urea, and uric acid will be assessed on a daily basis until including 
day 3 after ASCT. In case of clinically significant renal toxicity, creatinine, urea, and uric acid 
will be assessed as long as clinically indicated; 
• 
to assess differences in overall survival and progression free survival in patients treated with 
the combination of bendamustine and melphalan as compared to melphalan alone. Follow-up 
is according to the treating physician. It should include assessment of myeloma serum 
parameters (without urine analysis and without bone marrow). If relapse is suspected, 
assessment of myeloma serum parameters should be performed; 
• 
to assess the quality of life prior to ASCT and 60 days thereafter. The EORTC Q30 
questionnaire will be given to patients at screening and at the day 60 assessment. 
 
9.1.3 
Assessment of safety outcomes 
Adverse events  
For AE definition and procedures, see section 10.  
 
9.1.4 
Assessments in participants who prematurely stop the study 
According to the intention-to-treat principle, non-compliant patients will not be excluded from the 
analysis. Non-compliant patients will be documented until to the day 60 assessment. All patients 
terminating study treatment before the day 60 assessment will be analyzed until the last documented 
follow-up.  
Any participant has the right to withdraw the consent to participation in this trial at any time. Details of 
the date and the circumstances of the withdrawal have to be registered in the patient charts and in the 
eCRFs. The treating physician can withdraw the patient from the study treatment if considered 
necessary. Again, the date and the circumstances of the withdrawal have to be registered in the patient 
charts and in the eCRFs. Patients withdrawn from this protocol are documented until to the day 60 
assessment. All patients terminating study treatment before the day 60 assessment will be analyzed 
until the last documented follow-up. If patients withdraw their consent to this study, their study data will 
be anonymized after completion of the study analysis. 
 

 
 
 
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9.2 
Procedures at each visit 
9.2.1 
Screening visit (Day -35 to -5) 
 
Written informed consent  
 
Height, weight and body surface 
 
Pregnancy test pregnancy test will be requested at screening visit or before study treatment, if 
indicated  
 
Hematopoietic stem cell transplantation comorbidity score (HCTCI) 39 (see Appendix 4) 
 
ECOG Score (see Appendix 2) 
 
Echocardiography (Echo results can be accepted within three months prior to HDCTX ,the echo 
can be omitted or postponed untill treatment visit if clinically indicated) 
 
Hematology  
 
Biochemistry  
 
Myeloma assessment  
 
QoL (EORTC Q30) : for details see Appendix 6 
 
9.2.2 
Assessments during ASCT (Day -4 until day of hospital discharge) 
• 
Date of ASCT and date of engraftment 
• 
Number of CD34+ cells transplanted and lymphocyte count in the autograft 
• 
Number of infused red blood cell (RBC) units and platelet transfusion units 
• 
Hematology to assess the time to platelet recovery > 20 x 109/L and  > 50 x 109/L, the time of 
lymphocyte recovery >1x109/L, and the time to recovery of ANC > 0,5x109/L 
• 
Biochemistry to assess renal function 
• 
Number of days of temperature > 38.0° and number of febrile episodes 
• 
Assessment of CTCAE 4.0 highest toxicity score observed during ASCT until dismission from 
hospital for toxicities with at least grade 3 
 
9.2.3 
Assessments after ASCT (Day +30 to +75 after ASCT) 
 
ECOG Score 
 
Hematology  
 
Biochemistry (according to the centres policy) 
 
Myeloma assessment  
 
Acute and late toxicity/adverse events (CTCAE 4.0) 
 
QoL (EORTC Q30): for details see Appendix 6 
 
Bone marrow in case of CR1. If a bone marrow assessment is performed, determination of CD4 
and CD8 at the day of bone marrow (in bone marrow and blood) and between day +30 and day 
+75 (in blood) will be collected. 
 
Any relapse or death will be reported as soon as known. The remission status will be assessed using 
serum myeloma parameters, and intervals of follow-ups are at the discretion of the treating physician. 
A three months control interval is recommended. If relapse is suspected, assessments of myeloma 
parameters are recommended.  
 
9.2.4 
Response criteria 
• 
See Appendix 3 attached 
 
 

 
 
 
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10. SAFETY  
10.1 Study type  
This is a Category B trial. During the study, all serious adverse events (SAEs) until day 60 after ASCT 
are collected, fully investigated and documented in source documents and electronic case report forms 
(eCRF). Study duration encompassed the time from when the participant signs the informed consent 
until the last protocol-specific procedure has been completed, including the day 60 assessments.  
Adverse Events have to be reported in the source documents and in the electronic case report forms 
from the time the participant is randomised until 30 days after ASCT. Serious Adverse Events have to 
be reported in case report forms from the time the participant signs the informed consent until 60 days 
after ASCT. 
 
Adverse Events have to be reported, with the exception of: 
 
• 
A pre-existing condition that does not increase in severity; the pre-existing condition should 
be reported on the baseline concomitant diseases eCRF. 
• 
AEs of CTCAE grade ≤2 (including AEs leading to a postponement of HDCT) 
• 
Abnormal laboratory values that have been recorded as being not clinically significant by the 
investigator in the source documents. 
• 
Progression of the disease under study; complications as a result of disease progression 
remain reportable Adverse Events. 
• 
 
• 
Nausea/vomiting/loss of appetite. 
• 
Hematological toxicities. 
• 
Diarrhoea. 
• 
Febrile neutropenia:  The number of episodes are captured in the eCRF; thus, episodes do not need 
to be additionally reported as AEs  
• 
Other expected AEs during HDCT. 
 
10.1.1 Definition and assessment of (serious) adverse events and other safety related events 
An Adverse Event (AE) is any untoward medical occurrence in a patient after administration of a 
pharmaceutical product which does not necessarily have a causal relationship with the study procedure. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not related to the medicinal (investigational) product. [ICH E6 1.2] 
Serious Adverse Event (SAE) is classified as any untoward medical occurrence that: 
• 
results in death 
• 
is life-threatening 
• 
requires in-patient hospitalization more than 24 hours or prolongation of existing 
hospitalization. 
• 
results in persistent or significant disability/incapacity, or 
• 
is a congenital anomaly/ birth defect. 
In addition, important medical events that may not be immediately life-threatening or result in death, or 
require hospitalization more than 24 hours, but may jeopardise the patient or may require intervention 
to prevent one of the other outcomes listed above should also usually be considered serious. [ICH E2A] 
SAEs should be followed until resolution or stabilisation. Participants with ongoing SAEs at study 
termination (including safety visit) will be further followed up until recovery or until stabilisation of the 
disease after termination. 
 
Assessment of Causality 
The involved Investigator makes a causality assessment of the event to the study drug, based on the 
criteria listed in the ICH E2A guidelines: 
Relationship 
Description 

 
 
 
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Definite 
Temporal relationship 
Improvement after dechallenge* 
Recurrence after rechallenge 
(or other proof of drug cause) 
Probable 
Temporal relationship 
Improvement after dechallenge 
No other cause evident 
Possible 
Temporal relationship 
Other cause possible 
Unlikely/remote 
Any assessable reaction that does not fulfil the above conditions 
Unrelated 
Causal relationship can be ruled out 
Cannot be classified 
Reaction that cannot be judged because information is 
insufficient 
or 
contradictory 
and 
data 
that 
cannot 
be 
supplemented or verified 
*Improvement after dechallenge only taken into consideration, if applicable to reaction 
 
Unexpected Adverse Drug Reaction 
An “unexpected” adverse drug reaction is an adverse reaction, the nature or severity of which is not 
consistent with the applicable product information (e.g. Investigator’s Brochure for drugs that are not yet 
approved and Product Information for approved drugs, respectively).  
 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
The Sponsor-Investigator evaluates any SAE that has been reported regarding seriousness, causality 
and expectedness. If the event is related to the investigational product and is both serious and 
unexpected, it is classified as a SUSAR.  
 
Assessment of Severity 
To document the severity grades, the “Common Terminology Criteria for Adverse Events CTCAE 
Version 4.0” terminology will be used.  
 
10.1.2 Reporting of serious adverse events (SAE) and other safety related events  
All SAEs and other relevant safety related events until day 60 after ASCT have to be reported by the 
local investigator immediately to the Prinicipal Investigator within 24h of knowledge. The appropriate 
fax-numbers and email addresses are provided on the SAE-reporting form. 
SAEs of all patients, who received study medication in this trial, have to be reported to the Prinicipal 
Investigator until day 60 assessment visit  
Excluded from the reporting are as follows:  
• 
All planned surgeries or hospitalizations known at the time of study initiation, 
• 
All routinely required hospitalizations for chemotherapy and/or ASCT,  
• 
Progression or death due to the underlying malignancy.  
• 
Hematological toxicities. 
• 
Expected SAEs during HDCT 
 
10.1.3 Reporting to the manufacturer of bendamustine hydrochloride 
The Sponsor-Investigator will supply Mundipharma (i.e.Mundipharma Research GmbH & Co.KG, 
Germany, and Mundipharma Medical Company, Switzerland) with  

 
 
 
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• A copy of all SAEs until 60 days after ASCT within 24 hours of being aware of the event regardless 
of whether or not the event is listed in the reference document (Product Information). 
• A copy of all pregnancy reports within 24 hours of being aware of the event. 
• A copy of all SUSARs within one business day at the time of the submission to the regulatory 
authorities, the ECs and investigators  
• A copy of the DSUR at the time of the submission to the regulatory authorities and the ECs. 
  
The appropriate and actual fax-numbers and email addresses are provided in the separate Safety Data 
Exchage Agreement (SDEA) agreement with Mundipharma. 
 
10.1.4 Reporting of SAEs 
All SAEs must be reported immediately and within a maximum of 24 hours to the Sponsor-Investigator 
and Principal Investigator of the study by using the SAE reporting form. The Sponsor-Investigator and 
Principal Investigator will re-evaluate the SAE and return the form to the site.  
 
10.1.5 Reporting of Deaths 
SAEs resulting in death are reported to the local Ethics Committee (via local Investigator) within 7 days. 
The other in the trial involved Ethics Committees receive SAEs resulting in death via the Principle 
Investigator within 7 days. 
 
10.1.6 Reporting of SUSARs 
A SUSAR needs to be reported to the local Ethics Committee (local event via local Investigator) and to 
Swissmedic for category B and C studies (via Principle Investigator for Swiss centers) within 7 days, if 
the event is fatal, or within 15 days (all other events). 
This is not a multi-centre trial: The Principle Investigator (Sponsor) must inform all investigators 
participating in the clinical study of the occurrence of a SUSAR. The involved Ethics Committee will be 
informed about SUSARs in Switzerland via the Principle Investigator according to the local reporting 
requirements, directives and timelines. 
 
10.1.7 Reporting of Safety Signals 
All suspected new risks and relevant new aspects of known adverse reactions that require safety-related 
measures, i.e. so called safety signals, must be reported to the Principal Investigator (Sponsor) within 
24 hours. The Principal Investigator must report the safety signals within 7 days to the local Ethics 
Committee (local event via local investigator) and to Swissmedic. 
This is not a multi-centre trial: the Principle Investigator must immediately inform all participating 
investigators about all safety signals. The involved Ethics Committee will be informed about safety 
signals in Switzerland via the Principle Investigator. 
 
10.1.8 Reporting and Handling of Pregnancies 
Pregnant participants must immediately be withdrawn from the clinical study. Any pregnancy during the 
treatment phase of the study and within 6 months after discontinuation of study medication will be 
reported to the Principle Investigator within 24 hours. The course and outcome of the pregnancy should 
be followed up carefully until birth of the child, and any abnormal outcome regarding the mother or the 
child should be documented and reported according to local reporting requirements, directives and 
timelines. 
 
10.1.9 DSUR 
The DSUR is submitted once a year to the local Ethics Committee and to Swissmedic via the Principle 
Investigator (Sponsor). The Principle Investigator is responsible for the data collection and preparation 
of the DSUR, and submits it to the local EC.   
 
10.1.10 Follow up of (Serious) Adverse Events 
The follow up of participants terminating the study (either regularly or prematurely) with reported ongoing 

 
 
 
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SAE, or any ongoing AEs of laboratory values or of vital signs being beyond the alert will be documented 
until resolution or death of the patient. All adverse events (AE) (until 30 days after ASCT) and all serious 
adverse events (SAE) (until day 60 assment visit ) are collected, fully investigated and documented in 
the source document and appropriate case report form (CRF). 
11. STATISTICAL METHODS  
11.1 Hypothesis 
This study involves two treatment arms and applies a 1:1 randomization, additionally considering the 
stratification for remission status and renal function. No interim analysis is planned, and all calculations 
will be performed on a strict intention-to-treat basis. The primary objective is to show a clinically 
meaningful improvement by 15% of the primary endpoint, the rate of complete remission (CR1) 60 days 
after ASCT in myeloma patients from 50% with melphalan alone to 65% with the combination of 
bendamustine and melphalan. 
 
11.2 Determination of Sample Size  
Arm A is the control arm (Mel: Melphalan alone chemotherapy), and arm B is the experimental arm 
(BenMel: bendamustine and melphalan chemotherapy). The null hypothesis is that the rate of complete 
remissions (CR1) determined 60 days after ASCT is equal in both arms (CR1A = CR1B). The aim of the 
study is to ultimately show an improvement by 15% of the rate of complete remission (CR1) 60 days 
after ASCT 
 in myeloma patients from 50% with melphalan alone to 65% with the combination of bendamustine and 
melphalan, with CR1A < CR1B.  
Based on a cohort of 122 myeloma patients at our cohort (2010-2013), we anticipate a CR1 rate in the 
standard (Mel) arm of 50% (CR1A). Our hypothesis is that the experimental (BenMel) arm will show a 
CR1 rate of ≥ 65% (CR1B), thus a difference of at least 15 percentage points.  
With CR1A and CR1B being the (true) success rates in the Mel arm and in the BenMel arm, respectively, 
the hypotheses are: 
     H0: CR1 BenMel chemotherapy = CR1 Mel. 
     H1: CR1 BenMel chemotherapy ≥ CR1 Mel is 0.50. 
Applying a one-sided significance level of 20%, 60 patients will be needed in each group to have 80% 
power to reject the null hypothesis of no difference between the CR1 rates of the treatment arms using 
a t-test. Thus, a total of 120 evaluable patients are needed. The significance level actually achieved by 
this design is 0.2057. All statistical analysis for sample size calculations were performed using the 
software package PASS 11.  
For statistical analysis of this study, continuous endpoints will be summarized using descriptive statistics 
including mean, median, standard deviation, first and third quartiles, minimum and maximum values, 
and where appropriate by graphical techniques (e.g. histogram, box plot). For categorical endpoints, the 
number and percentage of patients in each category will be summarized. Where appropriate, a two-
sided 95% confidence interval for the proportion will be reported. The primary endpoint in the two groups 
will be tested using a t-test. Progression free survival and overall survival will be assessed using Kaplan-
Meier plots and log-rank test. 
 
11.3 Randomization 
Randomization is performed by the coordinating study nurse, the specifically designed study nurse or 
his/her replacent of the Klinische Forschungseinheit Onkologie, University Hospital/Inselspital, 3010 
Bern. Randomisation will be performed using REDCap software. Two stratification parameters 
(response and renal function) will be applied. Patients can be registered 24h/7days. 
 
11.4 Populations for Analysis 
All patients randomised to treatment who have taken at least one dose of study medication will be 
considered evaluable and will be included in the evaluation of safety. The entire analysis will be on an 
intention-to-treat basis (ITT). The ITT set includes all randomized patients in the groups to which they 

 
 
 
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were randomly assigned, regardless of their adherence with the entry criteria, regardless of the 
treatment they actually received, and regardless of subsequent withdrawal from treatment or deviation 
from the protocol. The evaluation of efficacy will be based on the intention to treat (ITT) population.  
 
11.5 
Planned Analyses / Analytical Methods 
All analyses will be on an intention-to-treat basis (ITT). All other statistical testing will be two-tailed at 
the 5% level of significance. The final analysis of the study will be initiated 12 months after inclusion of 
the last study patient. No subgroup analysis is planned. No interim analysis is planned. Safety analysis 
will be performed at the end of the study. No data safety monitoring board is planned in this study. 
 
11.6 
Analysis of demographics and baseline characteristics 
Continuous measurements (e.g. age) will be summarized using n, mean, standard deviation (SD), 
median, minimum and maximum while discrete measurements (e.g. sex) will be summarised using 
frequency counts and percentages. No formal statistical testing will be performed on these data. 
 
11.7 
Analysis of primary efficacy parameter 
This is a superiority trial (see also section 11.2). The study aims to show an improvement by 15% of the 
rate of complete remission (CR1) 60 days after ASCT in myeloma patients. Day 60 CR1 for the control 
arm (Mel) is assumed as 50% and for experimental arm (BenMel) as 65%. The hypotesis for the primary 
endpoint will be tested using one-sided t-test. The trial will be considered statistically positive, if the p-
value for the comparison of the CR1 rates 60 days after ASCT between the arms is <0.20. 
 
11.8 
Analysis of secondary efficacy parameters 
For the description of quantitative variables, median and mean values will be used as well as standard 
deviations, minimum and maximum values. For qualitative variables such as hematologic recovery and 
engraftment after three months, percentages and absolute frequency will be indicated. Early and late 
toxicities, particularly renal toxicity, will be compared using Fishers Exact Test tests. Survival rates (OS; 
PFS) will be assessed after 12 months.  
 
11.9 
Analysis of safety 
Acute and late toxicities will be graded and described using the highest grade observed.   
 
11.10 
Statistical criteria of termination of trial  
Given the existing (own and by others) data on the promising tolerance and efficacy of the experimental 
treatment (BenMel chemotherapy), no stopping rules or discontinuation criteria are planned in this trial 
for individual participants, for parts of the trial and for the entire trial. 
 
11.11 
Deviation(s) from the original statistical plan  
No major deviation(s) from the original statistical plan are to be expected. 
 
11.12 
Handling of missing data and drop-outs  
The design of the trial does not consider a relevant drop-out rate, thus a toal of 60 patients are supposed 
to be included in each of the two treatment arms.   
 
12 QUALITY ASSURANCE AND CONTROL  
The following procedures guarantee quality of trial conduct: 
• 
Reviews of protocol and forms according to standard operating procedures. 
• 
No paper CRFs will be used. Data will be entered into a database using the REDCap system. 

 
 
 
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Computerized consistency checks will be performed.  
• 
Data review by the primary local investigator or a delegated person.  
• 
Safety monitoring. 
• 
Validation of database and statistical analysis. 
• 
Accountability of study drugs. 
• 
Requirements for potential sub-investigators for participation: signed and dated CV. 
 
12.1 
Data handling and record keeping / archiving  
Source data are kept available for auditing and monitoring by the competent authorities. 
The randomization list is concealed from any personnel involved in patient recruitment. 
 
12.1.1 Case Report Forms  
No paper CRFs will be used. Data will be entered into a database using the REDCap system. 
Computerized consistency checks will be performed. eCRFs will be kept current to reflect subject status 
at each phase during the course of study. Participants will not be identified in the eCRF by name or 
initials and birth date. Appropriate coded identification, e.g. participant number will be used (e.g. 
combination of initials and year of birth). A defined study nurse will be identified to be authorized to 
perform eCRF entries, and it will be assured that any authorized person can be identified.  
 
12.1.2 Specification of source documents  
Source data will be available at the site to document the existence of the study participants. Source data 
will include the original documents relating to the study, as well as the medical treatment and medical 
history of the participant. The path where to find all the source documents/data will be summarized in a 
form called “Source Data Location List”. Only authorized study staff can access to this document and 
manage it. 
 
12.1.3 Record keeping / archiving  
All study data will be archived in the center for a minimum of 10 years after study termination or 
premature termination of the clinical trial. The investigator will retain copies of the patient trial records 
(patient informed consent statement, laboratory printouts, drug transportation and destruction forms, 
and all other information collected during the trial) and documentation until at least 10 years after the 
termination of the trial. In the event that the investigator retires or changes employment, custody of the 
records may be transferred to another suitable person who will accept responsibility for those records. 
Notice of such transfer will be given in written to the EC. 
 
12.1.4 Data Management System  
No paper CRFs will be used. Data will be entered into a database using the REDCap system. 
Computerized consistency checks will be performed. eCRFs will be kept current to reflect subject status 
at each phase during the course of study. Participants will not be identified in the CRF by name or initials 
and birth date. Appropriate coded identification, e.g. participant number will be used (e.g. combination 
of initials and year of birth). A defined study nurse will be identified to be authorized to perform eCRF 
entries, and it will be assured that any authorized person can be identified.  
 
12.1.5 Data security, access and back-up  
The database used will be based on the REDCap software. Access to database information will be 
restricted to the Principle investigator, to the data management team and to the responsible statistician. 
Changes to database entries as well as user information will be documented using audit trial function. 
Data entries will only be made by authorized personnel of the data management team. Patient data are 
entered anonymously using unique patient identification number and not using full name or complete 
date of birth. Key (patient identification log) to get information about patient identity is only available at 
treatment site of patient. The key will not be available to sponsor (with exception of patient data from 
site of sponsor-investigator) and third parties. 
 

 
 
 
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12.1.6 Analysis and archiving 
All study data will be archived in the center for a minimum of 10 years after study termination or 
premature termination of the clinical trial. The investigator will retain copies of the patient trial records 
(eCRFs, patient informed consent statement, laboratory printouts, drug transportation and destruction 
forms, and all other information collected during the trial) and other relevant documentation (protocol, 
contracts etc.) until at least 10 years after the termination of the trial. In the event that the investigator 
retires or changes employment, custody of the records may be transferred to another suitable person 
who will accept responsibility for those records. Notice of such transfer will be given in written to the 
Sponsor and CEC. 
 
12.1.7 Electronic and central data validation  
Computerized and manual consistency checks will be performed. 
 
12.2 
Monitoring  
The clinical trial unit (CTU) in Berne will perform monitoring of this trial. The monitors will be allowed to 
inspect the various records of the trial in accordance with local requirements. The monitor will maintain 
patient confidentiality. Source data verification of the Informed Consent will be performed for every 
patient and of the following data in 20% of the patients 
 
· 
Inclusion/exclusion criteria. 
· 
Serious Adverse Events (SAE). 
· 
Primary endpoint. 
· 
Accountability of study drugs. 
 
12.3 
Audits and Inspections  
Regulatory authorities and delegates of the local Ethic Committees have the right to perform inspections 
and to verify original data. The investigators are obliged to actively participate during an audit or 
inspection. They have to ensure that all required source data and collected patient data are made 
available during an audit or inspection and that adequate facilities are provided for the audit or 
inspection. Access to source data verification has to be provided within a reasonable peiod of time, In 
case of an announcement of an inspection, the investigator has to inform the Sponsor promptly.   
 
12.4 
Confidentiality, Data Protection  
The investigator affirms and upholds the principle of the participant's right to privacy and that they shall 
comply with applicable privacy laws. All patients will be informed as to the strict confidentiality of their 
patient data, which will not be handed over to non-authorized third parties. However, they will also be 
informed and have given written informed consent that their medical records (anonymised data) may be 
reviewed for trial, scientific or monitoring purposes by authorized individuals other than their treating 
physicians. 
 
12.5 
Storage of biological material and related health data  
No samples are stored in this study, and no biobank will be involved in this study.  
13 PUBLICATION AND DISSEMINATION POLICY  
The Principal Investigator will be responsible to publish the data of the trial in a peer-reviewed journal 
within 12 months after study completion. All study data collected will be kept confidential by all 
investigators prior to publication. Release of any abstract, manuscript or presentation will be shared and 
discussed between the Principal Investigator and Co-investigators. The company supplying the study 
medication has the right to review manuscripts and abstracts prior to submission for publication. 
The Principle Investigator agrees to inform the company supplying the study medication about any 
impending publication and release of any abstract, relating to the outcome of the trial. Without prejudice 
to the Principle Investigator’s autonomy in respect to the publication of the results of the trial, the 
Principle Investigator agrees to provide to the companies the proposed manuscript in advance at least 

 
 
 
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thirty and abstracts at least fourteen days before. The Supplier may propose changes to the text up to 
twenty-eight days from receipt of the manuscript and up to twelve days from receipt of the abstract. The 
Principle Investigator shall respond in good faith to any reasonable and justified requested revisions of 
the manuscript, always provided that the Principle Investigator shall have the final say in deciding on 
the contents and wording of the text. The Principle Investigator shall give appropriate acknowledgement 
to the Supplier’s or its Associates employees, if applicable, in the publication. 
14 FUNDING AND SUPPORT  
14.1 
Funding  
This study is supported in Switzerland by a grant from the company Mundipharma Medical Company. 
Bendamustine hydrochloride is provided free of charge by the company Munidpharma Medical 
Company in Switzerland.  
 
14.2 
Other Support  
No other support is available for this study. 
15 INSURANCE  
The Inselspital Berne is sponsor of this study. The insurance for patients in Switzerland will be provided 
by the Sponsor. A copy of the certificate is filed in each investigator site file and the trial master file. 

 
 
 
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16 APPENDICES 
16.1 Appendix 1: Translated excerpt from CTC adverse events version v4.0  
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
Adverse event/ 
Toxizitäts-Grad 
1 gering –  
Leicht 
2 mäßig – deutlich 
3 stark – 
ausgeprägt 
4 lebensbedrohlich 
Neutropenie 
< LLN – 1500/mm³ 
< 1500 – 1000/mm³ 
< 1000 – 500/mm³ 
< 500/mm³ 
Thrombopenie 
< LLN – 75.000/mm³ 
< 75.000 – 50.000/mm³ 
< 
50.000 
– 
25.000/mm³ 
< 25.000/mm³ 
Anämie 
Hb < LLN –  
10.0 g/dl 
Hb 10.0 – 8.0 g/dl 
Hb 8.0 – 6.5 g/dl  
Hb < 6.5 g/dl 
Nausea 
Appetitsverlust 
ohne Veränderung 
der 
normalen 
Essgewohnheiten 
Nahrungsaufnahme 
etwas 
vermindert- 
, 
Kein Gewichtsverlust 
Unzureichende 
orale Kalorien bzw. 
Flüssigkeitszufuhr; 
i.v. Flüssigkeits- 
zufuhr, parenterale 
Ernährung > 24h 
Lebensbedrohliche 
Konsequenzen 
Erbrechen 
1 Episode in 24 h 
2 – 5 Episoden in 24 h; 
i.v. Flüssigkeitszufuhr < 
24 h 
6 
oder 
mehr 
Episoden in 24 h; i.v. 
Flüssigkeits- zufuhr 
bzw. 
parenterale 
Ernährung > 24 h  
Lebensbedrohliche 
Konsequenzen 
Diarrhoe  
Anstieg auf < 4 
Stühle pro Tag über 
baseline 
Anstieg auf 4-6 Stühle 
pro Tag über baseline; 
i.v. Flüssigkeitszufuhr < 
24 
h; 
beeinträchtigt 
Alltagsaktivitäten nicht 
Anstieg 
über 
7 
Stühle pro Tag über 
baseline; 
i.v. 
Flüssigkeitszufuhr > 
24 
h; 
stationäre 
Aufnahme; 
beeinträchtigt 
Alltagsaktivitäten 
Lebensbedrohliche 
Konsequenzen 
d. 
Diarrhoe 
Fatigue 
Leichte 
Fatigue; 
stärker 
als 
bei 
baseline 
Mäßige 
Fatigue; 
beeinflusst Ausübung 
einiger Aktivitäten 
Schwere 
Fatigue; 
Alltagsaktivitäten 
beeinträchtigt 
Inaktivierend  
Mukositis 
klin. 
Untersuchung 
Erythem 
der 
Schleimhaut 
Nicht 
konfluierende 
Ulzerationen 
od. 
Pseudomembranen 
Konfluierende 
Ulzerationen 
od. 
Pseudomembranen; 
Blutung 
bei 
Minimaltrauma  
Gewebsnekrose; 
signifikante spontane 
Blutung; 
lebensbedrohliche 
Konsequenzen 
Neuropathie 
Sensorisch 
Abgeschwächte 
Sehnenreflexe oder 
Parästhesien; keine  
Funktions- 
Einschränkung 
Veränderung 
der 
Sensorik 
od. 
Parästhesien; 
Funktions-
Einschränkung, jedoch 
Alltagsaktivität 
nicht 
beeinträchtigt 
Veränderung 
der 
Sensorik 
od. 
Parästhesie; 
Alltagsaktivität 
beeinträchtigt 
Inaktivität 
Infektion – 
Febrile 
Neutropenie  
 
--- 
--- 
Bestehende febrile 
Neutropenie  
Lebensbedrohliche 
Konsequenzen (z.B. 
septischer 
Schock, 
Hypotension, 
Acidose, Nekrose)  
Allergien 
Transienter Rush   
Fieber< 38° 
Rush, 
Urtikaria, 
Dyspnoe  
Fieber>38° 
Symptomatische 
Bronchospasmen 
die 
intravenöse 
Medikation 
erfordern, 
Hypotension 
 
Anaphylaxie 

 
 
 
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Schmerzen 
Leicht, 
keine 
Funktionseinschrän
kung 
Mittel 
mit 
Funktionseinschränkun
g 
Schwer 
mit 
massiver 
Funktionseinschrän
kung 
 
Dysphagia 
Symptomatisch, 
kann 
normale 
Ernährung zu sich 
nehmen 
Symptomatisch, 
mit 
veränderten Ess- und 
Schluckgewohnheiten; 
i.v. Flüssigkeitszufuhr < 
24 h 
Symptomatisch mit 
stark 
veränderten 
Ess- 
und 
Schluckgewohnheit
en; i.v. Flüssigkeits 
zufuhr, parenterale 
Ernährung >24 h 
Lebensbedrohliche 
Konsequenzen (z.B. 
Obstruktion, 
Perforation) 
Gewichtsverlu
st 
5 – < 10 % von 
Baseline 
 10 – < 20 % von 
Baseline; 
Zusatzernährung 
indiziert 
> 
20 
% 
von 
Baseline; 
PEG-
Sonde 
oder 
parenterale 
Ernährung indiziert 
___ 
Soor 
___ 
Lokalisiert; 
lokale 
Therapie nötig 
i.v. 
Intervention 
nötig;  
Radiologischer oder 
operativer 
Eingriff 
nötig  
Lebensbedrohliche 
Konsequenzen (z.B. 
septischer 
Schock, 
Hypotonus, Acidose, 
Nekrose)   
 

 
 
 
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16.2 Appendix 2: Performance status scale (ECOG) 
 
 
0   
 normale Aktivität möglich ohne Einschränkung 
1 
Einschränkung bei körperlich anstrengender Tätigkeit aber leichte Tätigkeiten möglich und  
keine Bettlägerigkeit 
2 
nicht arbeitsfähig, selbständig, tagsüber weniger als 50% Ruhe bzw. Hinlegen erforderlich 
3 
Selbstversorgung sehr eingeschränkt möglich, tagsüber mehr als 50% Ruhe bzw. Hinlegen 
erforderlich, Pflege bzw. Hilfe erforderlich 
4 
bettlägerig und völlig pflegebedürftig 
5 
tot 
 

 
 
 
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16.3 Appendix 3: Response criteria 
 
The response criteria used in this study are modified. As a basis, the Bladé Response Criteria for 
patients diagnosed with Multiple Myeloma 58 are used for definition of response, relapse and progression 
in patients with multiple myeloma treated by high dose therapy and stem cell transplantation. 
 
Complete Response (CR): 
Requires all of the following 
 
• 
Absence of the original monoclonal paraprotein (M-gradient) in the serum by immunofixation. 
The presence of oligoclonal bands consistent with oligoclonal immune reconstitution does not 
exclude CR. 
• 
Normalized light chain ratio in the serum. 
• 
< 5% plasma cells in a bone marrow aspirate and bone biopsy if biopsy / aspirate are performed. 
A bone marrow examination is not needed for assessing CR. 
• 
No increase in size or number of lytic bone lesions (development of a compression fracture 
does not exclude response). 
• 
Disappearance of soft tissue plasmocytomas. 
 
Stringent Complete Response (sCR): 
Requires all of the following 
 
• 
All criteria above defining complete response (CR) 
• 
Bone marrow: minimal residual disease (MRD) is assessed by flow cytometry from bone marrow 
samples, and MRD negativity is required for sCR. sCR is defined as less than 50 aberrant 
plasma cell events, and at least 200’000 cell events need to have been analysed. 
 
Very Good Partial response (VGPR): 
Requires all of the following 
 
• 
≥ 90% reduction in the level of the serum monoclonal paraprotein (M-gradient and light chain). 
• 
For patients with non secretory myeloma only, ≥ 50% reduction in plasma cells in a bone marrow 
aspirate and on trephine biopsy, if biopsy is performed, 
• 
No increase in the size or number of lytic bone lesions (development of a compression fracture 
does not exclude response). 
 
Partial response (PR): 
Requires all of the following 
 
• 
≥ 50% reduction in the level of the serum monoclonal paraprotein (M-gradient and light chain). 
• 
For patients with non secretory myeloma only, ≥ 50% in plasma cells in a bone marrow aspirate 
and on trephine biopsy, if biopsy is performed,  
• 
≥50% reduction in the size of soft tissue plasmacytomas (by radiography or clinical 
examination). 
• 
No increase in the size or number of lytic bone lesions (development of a compression fracture 
does not exclude response). 
 
 
Minimal response (MR): 
Requires all of the following 
 

 
 
 
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• 
25-49% reduction in the level of the serum monoclonal paraprotein (M-gradient and light chain). 
• 
For patients with non-secretory myeloma only, 25-49% reduction in plasma cells in a bone 
marrow aspirate and on trephine biopsy, if biopsy is performed. 
• 
No increase in the size or number of lytic bone lesions (development of a compression fracture 
does not exclude response). 
 
 
No change (NC): 
• 
Not meeting the criteria for either minimal response or progressive disease 
 
 
Relapse from CR: 
Requires at least one of the following 
 
• 
Reappearance of serum paraprotein (M-gradient or light chain) on immunofixation or routine 
electrophoresis confirmed by at least one further investigation and excluding oligoclonal 
immune reconstitution. 
• 
≥ 5% plasma cells in a bone marrow aspirate or on trephine bone biopsy. 
• 
Development of new lytic bone lesions or soft tissue plasmacytomas or definite increase in the 
size of residual bone lesions (development of a compression fracture does not exclude 
continued response and may not indicate progression). 
• 
Development of hypocalcaemia (corrected serum calcium > 2.8 mmol/l) not attributable to any 
other cause. 
 
 
Progressive disease (for patients not in CR): 
Requires one of more of the following 
 
• 
> 25% increase in the level of the serum monoclonal paraprotein (M-gradient or light chain) 
which must also be an absolute increase of at least 5g/l (M-gradient) and confirmed by at least 
one repeated investigation. 
• 
> 25% increase in plasma cells in a bone marrow aspirate or on trephine biopsy which must be 
also an absolute increase of at least 10%. 
• 
Definite increase in the size of existing bone lesions or soft tissue plasmacytomas. 
• 
Development of new bone lesions or soft tissue plasmacytomas (development of a compression 
fracture does not exclude continued response and may not indicate progression). 
• 
Development of hypocalcaemia (corrected serum calcium > 2.8 mmol/l) not attributable to any 
other cause. 
 

 
 
 
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16.4 Appendix 4: HCTCI score 
 
Comorbidity  
Explanation  
HCT-CI 
score 
Arrhythmia 
Atrial fibrillation or flutter, sick sinus syndrome, or ventricular arrhythmias 
1 
Cardiac 
Coronary artery disease, congestive heart failure, myocardial infarction or 
EF < 50% 
1 
IBD 
Crohn's disease or ulcerative colitis 
1 
Diabetes 
Requiring treatment with insulin or oral hypoglycemics 
1 
CVD 
Transient ischemic attack or cerebrovascular accident 
1 
Psychiatric disturbance 
Depression or anxiety requiring psychiatric consult or treatment 
1 
Hepatic, mild1 
Chronic hepatitis: bilirubin >ULN to 2.0 × ULN and AST/or ALT >ULN to 
3.0 × ULN lasting for at least 2 months 
1 
Obesity 
Patients with a body mass index >35 kg/m2  
1 
Infection 
Requiring treatment after day 0 
1 
Rheumatologic 
SLE, RA, polymyositis, mixed CTD, or polymyalgia rheumatica 
2 
Peptic ulcer 
Requiring treatment 
2 
Moderate/severe renal 
Serum creatinine > 180 µmol/lor dialysis, or prior renal transplantation 
2 
Moderate pulmonary 
DLCO and FEV1 66–80% or dyspnea on slight activity 
2 
Prior solid tumor 
Treated at any time point in the patient's history, excluding non-melanoma 
skin cancer 
3 
Heart valve disease 
Except mitral valve prolapse 
3 
Severe pulmonary 
DLCO and FEV1 
65% or dyspnea at rest or requiring oxygen 
3 
Moderate/severe hepatic 
Liver cirrhosis, bilirubin >ULN to 2.0 × ULN and AST or ALT >ULN to 3.0 
× ULN lasting for at least 2 months 
3 
Abbreviations: AST/ALT=aspartate aminotransferase/alanine aminotransferase; CTD=connective tissue disease; 
CVA=cerebrovascular disease; DLCO=diffusion capacity of carbon monoxide; EF=ejection fraction; FEV1, forced 
expiratory volume in 1 second; HCT-CI=hematopoietic cell transplantation-specific comorbidity index; 
IBD=inflammatory bowel disease; RA=rheumatoid arthritis; SLE=systemic lupus erythematosis; ULN=upper limit of 
normal. 1AST or ALT has to be measured. 
 
 
 
 

 
 
 
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16.5 Appendix 5: Declaration of Helsinki 
 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53th WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
Preamble 
1.         The World Medical Association (WMA) has developed the Declaration of Helsinki as a  
 
statement of ethical principles for medical research involving human subjects, including 
 
research on identifiable human material and data. 
 
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
 
should be applied with consideration of all other relevant paragraphs. 
2.       Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. 
 
The WMA encourages others who are involved in medical research involving human subjects 
 
to adopt these principles. 
General Principles 
3.       The Declaration of Geneva of the WMA binds the physician with the words, “The health of my 
 
patient will be my first consideration,” and the International Code of Medical Ethics declares 
 
that, “A physician shall act in the patient’s best interest when providing medical care.” 
4.         
It is the duty of the physician to promote and safeguard the health, well-being and rights 
of  
patients, including those who are involved in medical research. The physician’s knowledge 
 
and conscience are dedicated to the fulfilment of this duty. 
5.      Medical progress is based on research that ultimately must include studies involving human 
 
subjects. 
6.         The primary purpose of medical research involving human subjects is to understand the  
 
causes, development and effects of diseases and improve preventive, diagnostic and 
 
therapeutic interventions (methods, procedures and treatments). Even the best proven 
 
interventions must be evaluated continually through research for their safety, effectiveness, 
 
efficiency, accessibility and quality. 
7.        Medical research is subject to ethical standards that promote and ensure respect for all human 
 
subjects and protect their health and rights. 
8.       While the primary purpose of medical research is to generate new knowledge, this goal can 
 
never take precedence over the rights and interests of individual research subjects. 
9.      It is the duty of physicians who are involved in medical research to protect the life, health, 
 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal information 
 
of research subjects. The responsibility for the protection of research subjects must always 
 
rest with the physician or other health care professionals and never with the research 
 
subjects, even though they have given consent. 
10.    Physicians must consider the ethical, legal and regulatory norms and standards for research 
 
involving human subjects in their own countries as well as applicable international norms and 
 
standards. No national or international ethical, legal or regulatory requirement should reduce 

 
 
 
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or eliminate any of the protections for research subjects set forth in this Declaration. 
11.        
Medical research should be conducted in a manner that minimises possible harm to the 
 
 
environment. 
12.    Medical research involving human subjects must be conducted only by individuals with the 
 
appropriate ethics and scientific education, training and qualifications. Research on patients or 
 
healthy volunteers requires the supervision of a competent and appropriately qualified 
 
physician or other health care professional. 
13.     Groups that are underrepresented in medical research should be provided appropriate access 
 
to participation in research. 
14.   Physicians who combine medical research with medical care should involve their patients in 
 
research only to the extent that this is justified by its potential preventive, diagnostic or 
 
therapeutic value and if the physician has good reason to believe that participation in the 
 
research study will not adversely affect the health of the patients who serve as research 
 
subjects. 
15.   Appropriate compensation and treatment for subjects who are harmed as a result of 
 
participating in research must be ensured. 
Risks, Burdens and Benefits 
16.        
In medical practice and in medical research, most interventions involve risks and 
burdens. 
 
Medical research involving human subjects may only be conducted if the importance of the 
 
objective outweighs the risks and burdens to the research subjects. 
17.  
All medical research involving human subjects must be preceded by careful assessment of 
 
predictable risks and burdens to the individuals and groups involved in the research in 
 
comparison with foreseeable benefits to them and to other individuals or groups affected by 
 
the condition under investigation. 
 
Measures to minimise the risks must be implemented. The risks must be continuously 
 
monitored, assessed and documented by the researcher. 
18.      Physicians may not be involved in a research study involving human subjects unless they are 
 
confident that the risks have been adequately assessed and can be satisfactorily managed. 
 
When the risks are found to outweigh the potential benefits or when there is conclusive proof 
 
of definitive outcomes, physicians must assess whether to continue, modify or immediately 
 
stop the study. 
Vulnerable Groups and Individuals 
19.     Some groups and individuals are particularly vulnerable and may have an increased likelihood 
 
of being wronged or of incurring additional harm. 
 
All vulnerable groups and individuals should receive specifically considered protection. 
20.   Medical research with a vulnerable group is only justified if the research is responsive to the 
 
group. In addition, this group should stand to benefit from the knowledge, practices or 
 
interventions that result from the research. 
Scientific Requirements and Research Protocols 
21.   Medical research involving human subjects must conform to generally accepted scientific 
 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
 
sources of information, and adequate laboratory and, as appropriate, animal experimentation. 
 
The welfare of animals used for research must be respected. 
22.     The design and performance of each research study involving human subjects must be clearly 
 
described and justified in a research protocol. 
 
The protocol should contain a statement of the ethical considerations involved and should 
 
indicate how the principles in this Declaration have been addressed. The protocol should 
 
include information regarding funding, sponsors, institutional affiliations, potential conflicts of 
 
interest, incentives for subjects and information regarding provisions for treating and/or 
 
compensating subjects who are harmed as a consequence of participation in the research 
 
study. 
 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial 

 
 
 
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provisions. 
Research Ethics Committees 
23.   The research protocol must be submitted for consideration, comment, guidance and approval 
 
to the concerned research ethics committee before the study begins. This committee must be 
 
transparent in its functioning, must be independent of the researcher, the sponsor and any 
 
other undue influence and must be duly qualified. It must take into consideration the laws and 
 
regulations of the country or countries in which the research is to be performed as well as 
 
applicable international norms and standards but these must not be allowed to reduce or 
 
eliminate any of the protections for research subjects set forth in this Declaration. 
 
The committee must have the right to monitor ongoing studies. The researcher must provide 
 
monitoring information to the committee, especially information about any serious adverse 
 
events. No amendment to the protocol may be made without consideration and approval by 
 
the committee. After the end of the study, the researchers must submit a final report to the 
 
committee containing a summary of the study’s findings and conclusions. 
Privacy and Confidentiality 
24.    Every precaution must be taken to protect the privacy of research subjects and the 
 
confidentiality of their personal information. 
Informed Consent 
25.       Participation by individuals capable of giving informed consent as subjects in medical research 
 
must be voluntary. Although it may be appropriate to consult family members or community l
 
eaders, no individual capable of giving informed consent may be enrolled in a research study 
 
unless he or she freely agrees. 
26.   In medical research involving human subjects capable of giving informed consent, each 
 
potential subject must be adequately informed of the aims, methods, sources of funding, any 
 
possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits 
 
and potential risks of the study and the discomfort it may entail, post-study provisions and any 
 
other relevant aspects of the study. The potential subject must be informed of the right to  
 
refuse to participate in the study or to withdraw consent to participate at any time without 
 
reprisal. Special attention should be given to the specific information needs of individual 
 
potential subjects as well as to the methods used to deliver the information. 
 
After ensuring that the potential subject has understood the information, the physician or 
 
another appropriately qualified individual must then seek the potential subject’s freely-given 
 
informed consent, preferably in writing. If the consent cannot be expressed in writing, the non-
 
written consent must be formally documented and witnessed. 
 
All medical research subjects should be given the option of being informed about the general 
 
outcome and results of the study. 
27.   When seeking informed consent for participation in a research study the physician must be 
 
particularly cautious if the potential subject is in a dependent relationship with the physician or 
 
may consent under duress. In such situations the informed consent must be sought by an 
 
appropriately qualified individual who is completely independent of this relationship. 
28.    For a potential research subject who is incapable of giving informed consent, the physician 
 
must seek informed consent from the legally authorised representative. These individuals 
 
must not be included in a research study that has no likelihood of benefit for them unless it is 
 
intended to promote the health of the group represented by the potential subject, the research 
 
cannot instead be performed with persons capable of providing informed consent, and the 
 
research entails only minimal risk and minimal burden. 
29.      When a potential research subject who is deemed incapable of giving informed consent is 
 
able to give assent to decisions about participation in research, the physician must seek that 
 
assent in addition to the consent of the legally authorised representative. The potential 
 
subject’s dissent should be respected. 
30.    Research involving subjects who are physically or mentally incapable of giving consent, for 
 
example, unconscious patients, may be done only if the physical or mental condition that 
 
prevents giving informed consent is a necessary characteristic of the research  group. In such 
 
circumstances the physician must seek informed consent from the legally authorised 
 
representative. If no such representative is available and if the research cannot be delayed, 
 
the study may proceed without informed consent provided that the specific reasons for 

 
 
 
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involving subjects with a condition that renders them unable to give informed consent have 
 
been stated in the research protocol and the study has been approved by a research ethics 
 
committee. Consent to remain in the research must be obtained as soon as possible from the 
 
subject or a legally authorised representative. 
31.   The physician must fully inform the patient which aspects of their care are related to the 
 
research. The refusal of a patient to participate in a study or the patient’s decision to withdraw 
 
from the study must never adversely affect the patient-physician relationship. 
32.     For medical research using identifiable human material or data, such as research on material 
 
or data contained in biobanks or similar repositories, physicians must seek informed consent 
 
for its collection, storage and/or reuse. There may be exceptional situations where consent 
 
would be impossible or impracticable to obtain for such research. In such situations the 
 
research may be done only after consideration and approval of a research ethics committee. 
Use of Placebo 
33.  
The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
 
those of the best proven intervention(s), except in the following circumstances: 
 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
 
Where for compelling and scientifically sound methodological reasons the use of any 
 
intervention less effective than the best proven one, the use of placebo, or no intervention is 
 
necessary to determine the efficacy or safety of an intervention and the patients who receive 
 
any intervention less effective than the best proven one, placebo, or no intervention will not be 
 
subject to additional risks of serious or irreversible harm as a result of not receiving the best 
 
proven intervention. 
 
Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34. 
In advance of a clinical trial, sponsors, researchers and host country governments should 
 
make provisions for post-trial access for all participants who still need an intervention 
 
identified as beneficial in the trial. This information must also be disclosed to participants 
 
during the informed consent process. 
Research Registration and Publication and Dissemination of Results 
35. 
Every research study involving human subjects must be registered in a publicly accessible 
 
database before recruitment of the first subject. 
36. 
Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard 
 
to the publication and dissemination of the results of research. Researchers have a duty to 
 
make publicly available the results of their research on human subjects and are accountable 
 
for the completeness and accuracy of their reports. All parties should adhere to accepted 
 
guidelines for ethical reporting. Negative and inconclusive as well as positive results must be 
 
published or otherwise made publicly available. Sources of funding, institutional affiliations 
 
and conflicts of interest must be declared in the publication. Reports of research not in 
 
accordance with the principles of this Declaration should not be accepted for publication. 
Unproven Interventions in Clinical Practice 
37. 
In the treatment of an individual patient, where proven interventions do not exist or other 
 
known interventions have been ineffective, the physician, after seeking expert advice, with 
 
informed consent from the patient or a legally authorised representative, may use an 
 
unproven intervention if in the physician’s judgement it offers hope of saving life, re-
 
establishing health or alleviating suffering. This intervention should subsequently be made the 
 
object of research, designed to evaluate its safety and efficacy. In all cases, new information 
 
must be recorded and, where appropriate, made publicly available. 

 
 
 
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16.6 Appendix 6: Fragebogen zur Lebensqualität EORTC QLQ-C30 
 
 
UPN: …………………...                      
 vor ASCT                                              
 3 Monate nach ASCT    
 
Hier möchten wir Sie bitten, die Kästchen der Fragen so genau wie es Ihnen möglich ist, anzukreuzen. Herzlichen 
Dank! 
 
 
1) Bereitet es Ihnen Schwierigkeiten, sich körperlich anzustrengen (z. B. eine schwere Einkaufstasche 
oder einen Koffer zu tragen)? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
 
2) Bereitet es Ihnen Schwierigkeiten einen längeren Spaziergang zu machen? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
 
3) Bereitet es Ihnen Schwierigkeiten eine kurze Strecke außer Haus zu gehen? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
 
4) Müssen Sie tagsüber im Bett liegen oder in einem Sessel sitzen? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
 
5) Brauchen Sie Hilfe beim Essen, Anziehen, Waschen oder Benutzen der Toilette? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
 
6) Waren Sie bei Ihrer Arbeit oder bei anderen tagtäglichen Beschäftigungen eingeschränkt? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
 
7) Waren Sie bei Ihren Hobbys oder anderen Freizeitbeschäftigungen eingeschränkt? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
8) Waren Sie kurzatmig? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
9) Hatten Sie Schmerzen? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
10) Mussten Sie sich ausruhen? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
11) Hatten Sie Schlafstörungen? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
12) Fühlten Sie sich wach? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
13) Hatten Sie Appetitmangel? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
14) War Ihnen übel? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 

 
 
 
Bendamustine and Melphalan in Myeloma                          Page 52 of 59                Version 2.2; 21.03.2018 
 
 
15) Haben Sie erbrochen?  
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
16) Hatten Sie Verstopfung? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
17) Hatten Sie Durchfall? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
18) Waren Sie müde? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
19) Fühlten Sie sich durch Schmerzen in Ihrem alltäglichen Leben beeinträchtigt? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
20) Hatten Sie Schwierigkeiten sich auf etwas zu konzentrieren, z. B. auf das Lesen oder das Fernsehen? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
21) Fühlten Sie sich angespannt? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
22) Haben Sie sich Sorgen gemacht? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
23) Waren Sie reizbar? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
24) Fühlten Sie sich niedergeschlagen? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
25) Hatten Sie Schwierigkeiten, sich an Dinge zu erinnern? 
 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
26) Hat Ihr körperlicher Zustand oder Ihre medizinische Behandlung Ihr Familienleben beeinträchtigt? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
27) Hat Ihr körperlicher Zustand oder Ihre medizinische Behandlung Ihr Zusammensein oder Ihre 
gemeinsamen Unternehmungen mit anderen Menschen beeinträchtigt? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
28) Hat Ihr körperlicher Zustand oder Ihre medizinische Behandlung für Sie finanzielle Schwierigkeiten 
mit sich gebracht? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
29) Hatten Sie Knochenschmerzen? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
30) Hatten Sie Rückenschmerzen? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
31) Hatten Sie Schmerzen in der Hüfte? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 

 
 
 
Bendamustine and Melphalan in Myeloma                          Page 53 of 59                Version 2.2; 21.03.2018 
 
 
32) Hatten Sie Schmerzen in den Armen oder Schultern? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
33) Hatten Sie Brustschmerzen? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
34) Wenn Sie Schmerzen hatten, verstärkten sie sich bei körperlicher Tätigkeit? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
35) Fühlten Sie sich schläfrig? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
36) Waren Sie durstig? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
37) Fühlten Sie sich krank? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
38) Hatten Sie einen trockenen Mund? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
39) Hatten Sie Haarausfall? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
40) Nur bei Haarausfall ausfüllen: 
Hat Sie der Haarausfall belastet? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
41) Verspürten Sie ein Kribbeln in Händen oder Füssen? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
42) Fühlten Sie sich unruhig oder aufgeregt? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
43) Hatten Sie saures Aufstossen oder Sodbrennen? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
44) Hatten Sie brennende oder entzündete Augen? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
45) Fühlten Sie sich wegen Ihrer Erkrankung oder Behandlung körperlich weniger anziehend? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
46) Haben Sie sich Gedanken über Ihre Krankheit gemacht? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
47) Befürchteten Sie, sterben zu müssen? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
48) Haben Sie sich Sorgen über Ihre künftige Gesundheit gemacht? 
 
 
 überhaupt nicht      
 wenig 
    
 mässig  
     
 sehr 
 
 

 
 
 
Bendamustine and Melphalan in Myeloma                          Page 54 of 59                Version 2.2; 21.03.2018 
 
 
Bitte kreuzen Sie bei den folgenden Fragen die Zahl zwischen 1 (= miserabel) und 7 (= optimal) an, die am 
besten auf Sie zutrifft 
49) Wie würden Sie insgesamt Ihren Gesundheitszustand einschätzen? 
 
 
 
   1   
   2   
   3   
   4   
   5   
   6   
   7 
 
 
50) Wie würden Sie insgesamt Ihre Lebensqualität einschätzen? 
 
 
 
   1   
   2   
   3   
   4   
   5   
   6   
   7 

 
 
 
Bendamustine and Melphalan in Myeloma                          Page 55 of 59                Version 2.2; 21.03.2018 
 
Um Sie bei der Einschätzung, wie gut oder wie schlecht Ihr Gesundheitszustand ist, zu unterstützen, haben wir 
eine Skala gezeichnet, ähnlich einem Thermometer. Der best denkbare Gesundheitszustand ist mit einer 
„100“ gekennzeichnet, der schlechteste mit „0“. 
Wir möchten Sie nun bitten, auf dieser Skala zu kennzeichnen, wie gut oder schlecht Ihrer Ansicht nach Ihr 
persönlicher Gesundheitszustand ist, indem Sie einen horizontalen Strich auf der Skala setzen.  
                         Ihr aktueller Zustand  
                   
 
 
  
 

 
 
 
Bendamustine and Melphalan in Myeloma                          Page 56 of 59                Version 2.2; 21.03.2018 
 
17 REFERENCES   
 
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Bendamustine and Melphalan in Myeloma                          Page 59 of 59                Version 2.2; 21.03.2018 
 
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long-term results from a prospective randomized trial from the Spanish cooperative group 
PETHEMA. Blood. 2005;106:3755–3759.