Conditions: Multiple Myeloma
Keywords: Multiple myeloma hematopoietic stem cell transplant
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 65
Healthy volunteers: no

Brief summary:
High-dose chemotherapy and autologous stem cell transplantation (ASCT) as part of the up-front treatment of patients with multiple myeloma has been associated with improved disease-free and overall survival in multiple large randomized controlled trials. Following 3-6 cycles of standard induction therapy with biologic agents, consolidation with high dose Melphalan and ASCT has become the standard-of-care approach for fit myeloma patients up to 70 years of age. Single-agent high-dose Melphalan (200mg/m2) is currently the standard-of-care preparative regimen prior to autologous transplant in Myeloma. Historical studies utilizing Busulfan- or Total Body Irradiation-based preparative regimens have yielded similar results to single-agent Melphalan with higher toxicity.

Detailed description:
Myeloma patients, following up-front induction therapy, will receive an ASCT following a high-dose bendamustine-based preparative regimen (BeEAM). The primary endpoint of this trial will be the rate of CR at day 100 post-transplant. Experience from the literature, as well as results from our institution, suggests that following ASCT for the upfront treatment of myeloma, the rate of CR at day 100 post-transplant is approximately 45%. It is hoped that under this protocol, this rate will be at least 65%. Thus we statistically formalize this study by testing the null hypothesis that p, the CR rate is 0.65 or more versus the alternative hypothesis that p is less than 0.45. A sample size of 65 pts gives 90% power with an alpha=0.05, using the formula for a one sample binomial (two-sided) test of a proportion.

Arms:
arm 1: Bendaumustine, Etoposide, Cytrabine and Melphalan in autologous transplant for multiple myeloma

Interventions: intervention 1: BeEAM
Intervention descriptions: intervention 1: BeEAM

Protocol document:
Prot_SAP_000.pdf: 
Blood & Marrow Transplant Program 
Northside Hospital 
 
 
 
Confidential 
 
05May17 
1
CLINICAL STUDY PROTOCOL  
 
 
A Phase II Trial of High-dose Bendamustine, Etoposide, Cytarabine, and Melphalan 
(BeEAM) in the Up-front Treatment of Multiple Myeloma 
 
 
 
 
 
 
Indication: 
Multiple Myeloma, following induction therapy 
 
Phase: 
Phase II 
 
 
 
Protocol History 
Original 
 
29Sept2014 
Amendment #1 
 
05May2017 
 
 
Scott R. Solomon, MD 
Blood and Marrow Transplant Program at Northside Hospital 
5670 Peachtree Dunwoody Rd. NE 
Suite 1000 
Atlanta, GA  30342 
404-255-1930 
 
 
 
 
 
 
This is an investigator-initiated study.  The principal investigator Scott R. Solomon, MD, (who 
may also be referred to as the sponsor-investigator), is conducting the study and acting as the 
sponsor.  Therefore, the legal/ethical obligations of the principal investigator include both those 
of a sponsor and those of an investigator. 


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PROTOCOL SUMMARY  
Study Title:  A Phase II Trial of High-dose Bendamustine, Etoposide, Cytarabine, and Melphalan 
(BeEAM) in the Up-front Treatment of Multiple Myeloma 
Phase:  II 
Number of Patients:  65 
Study Objectives  
Primary 
 To estimate the response at day 100 following transplant. 
Secondary 
 To obtain estimates of overall survival (OS), event-free survival (EFS), and non-relapse 
mortality (NRM). 
 Characterize the hematologic and non-hematologic toxicities of high-dose bendamustine 
when given as part of the BeEAM preparative regimen prior to autologous stem cell 
transplantation. 
Overview of Study Design:   
High-dose chemotherapy and autologous stem cell transplantation (ASCT) as part of the up-front 
treatment of patients with multiple myeloma has been associated with improved disease-free and 
overall survival in multiple large randomized controlled trials.  Following 3-6 cycles of standard 
induction therapy with biologic agents, consolidation with high dose Melphalan and ASCT has 
become the standard-of-care approach for fit myeloma patients up to 70 years of age. Single-agent 
high-dose Melphalan (200mg/m2) is currently the standard-of-care preparative regimen prior to 
autologous transplant in Myeloma.  Historical studies utilizing Busulfan- or Total Body Irradiation-
based preparative regimens have yielded similar results to single-agent Melphalan with higher 
toxicity. 
Achievement of a complete response (CR) following autologous transplant for myeloma has been 
associated with improved disease-free and overall survival in multiple studies1-5.  Therefore, more 
efficacious high-dose chemotherapy regimens that improve post-transplant CR rates should translate 
into better survival for myeloma patients.  The regimen BeEAM, utilizing high-dose bendamustine, 
etoposide, cytarabine, and melphalan, has been utilized successfully in older lymphoma patients with 
excellent activity (80% CR rate), acceptable morbidity and no treatment-related mortality6.  
Bendamustine is an active agent in the treatment of multiple myeloma7.  We hypothesize that 
incorporation of bendamustine in the high-dose preparative regimen will translate into better quality 
and more durable responses in myeloma patients. 
Myeloma patients, following up-front induction therapy, will receive an ASCT following a high-
dose bendamustine-based preparative regimen (BeEAM). The primary endpoint of this trial will be 
the rate of CR at day 100 post-transplant. Experience from the literature, as well as results from our 
institution, suggests that following ASCT for the upfront treatment of myeloma, the rate of CR at 
day 100 post-transplant is approximately 45%.  It is hoped that under this protocol, this rate will be 
at least 65%. Thus we statistically formalize this study by testing the null hypothesis that p, the CR 
rate is 0.65 or more versus the alternative hypothesis that p is less than 0.45. A sample size of 65 pts 
gives 90% power with an alpha=0.05, using the formula for a one sample binomial (two-sided) test 


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of a proportion. 
Study Population:   
Eligible patients will be 18 – 70 years of age, with adequate performance status and organ function, 
and have a diagnosis of multiple myeloma, within 9 months of the start of induction therapy. 
Duration of Study:  # months from FPI to LPI: 24 months 
# months from LPI to LPO: 3 months. 
# months to complete study: 27 months  
Study Drug: Bendamustine will be provided by Teva Pharmaceuticals for purposes of this study.  
 
 
 
 
 
 
 


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SCHEDULE OF EVENTS 
Test 
Screen 
Daily 
through 
D21* 
Weekly 
D21-
42* 
Month 
3 
(Day 
100) 
Month 
6 
Month 
12 
H & P 
X 
X 
X 
X 
X 
X 
CBC with 
differential 
X 
X 
x 
X 
X 
X 
Chemistry  
X 
X 
X 
X 
X 
X 
Myeloma 
Assessments 
(SPEP, UPEP, 
SIFE, UIFE, Free 
Kappa Light 
Chains, 
Immunoglobulins)* 
X 
 
 
X 
X 
X 
Myeloma Residual 
Disease 
Assessment* 
X 
 
 
X 
 
 
PFT 
X 
 
 
 
 
 
ECHO 
X 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
IDMs including 
Hepatitis & HIV 
X 
 
 
 
 
 
Pregnancy test 
(FOCBP) 
X 
 
 
 
 
 
Toxicity 
Assessment 
 
X 
X 
X 
X 
 
Bone marrow 
biopsy & aspirate  
X 
 
 
X 
X 
X 
Bone Survey 
x 
 
 
X 
X 
X 
Survival 
 
 
 
 
 
 
New malignancy 
assessment 
 
 
 
 
 
 
*per standard of care  
 
 
 


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TABLE OF CONTENTS 
PROTOCOL SUMMARY ....................................................................................................... 2 
SCHEDULE OF EVENTS ...................................................................................................... 4 
1. BACKGROUND AND STUDY RATIONALE ................................................................. 6 
1.1 Introduction  ................................................................................................................... 6 
1.2 Anti-myeloma effect of Bendamustine .......................................................................... 7 
1.3 Rationale for use of Bendamustine in HDT/ASCT ....................................................... 8 
1.4 Potential Risks and Benefits .......................................................................................... 8 
2. STUDY OBJECTIVES ...................................................................................................... 11 
2.1 Primary Objectives ...................................................................................................... 11 
2.2 Secondary Objectives .................................................................................................. 11 
3. STUDY DESIGN............................................................................................................... 12 
3.1 Overview of Study Design ........................................................................................... 12 
3.2 Number of Patients ...................................................................................................... 14 
3.3 Duration of Study ......................................................................................................... 13 
4. STUDY POPULATION .................................................................................................... 14 
4.1 Inclusion Criteria ......................................................................................................... 13 
4.2 Exclusion Criteria ........................................................................................................ 14 
5. TREATMENT PLAN/STUDY DRUG ............................................................................. 15 
5.1 Transplant Regimen ..................................................................................................... 15  
6. STATISTICAL AND QUANTITATIVE ANALYSES .................................................... 17 
6.1 STATISTICAL METHODS ............................................................................................ 17 
6.1.1 Determination of Sample Size .............................................................................. 17 
7. ADVERSE EVENTS ......................................................................................................... 17 
7.1 Definitions ................................................................................................................... 17 
7.1.1 Pretreatment Event Definition .............................................................................. 17 
7.1.2 Adverse Event Definition...................................................................................... 18 
7.13 Serious Adverse Event Reporting ………………………………………………...18 
7.1.4 Serious Adverse Event Definition......................................................................... 19 
7.2 Procedures for Reporting Serious Adverse Events ...................................................... 20 
8. ADMINISTRATIVE REQUIREMENTS ......................................................................... 22 
8.1 Good Clinical Practice ................................................................................................. 22 
8.2 Ethical Considerations ................................................................................................. 22 
8.3 Patient Information and Informed Consent ................................................................. 23 
8.4 Patient Confidentiality ................................................................................................. 23 
8.5 Investigator Compliance .............................................................................................. 23 
8.6 On-site Audits .............................................................................................................. 24 
8.7 Investigator and Site Responsibility for Drug Accountability ..................................... 24 
8.8 Closure of the Study .................................................................................................... 24 
8.9 Record Retention ......................................................................................................... 25 
8.10 Study Drug ………………………………………………………………………….25 
9. USE OF INFORMATION ................................................................................................. 25 
10. REFERENCES ................................................................................................................ 26 
 
 


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1.0 BACKGROUND AND STUDY RATIONALE 
1.1 
Introduction 
Multiple myeloma (MM) is a clonal plasma cell disorder characterized by lytic bone disease, 
renal dysfunction, abnormal hematopoietic function, and the presence of a monoclonal 
paraprotein in the blood and/or urine. Historical induction regimens rarely achieved major 
responses [very good partial remission (VGPR) or complete remission (CR)], and before the use 
of high-dose therapy (HDT) and autologous stem cell transplantation (ASCT), few therapeutic 
options showed significant improvements in overall survival (OS) for newly diagnosed myeloma 
patients1,2. Over the last several decades, the treatment of MM has improved strikingly. Although 
not curative, autologous stem cell transplantation (ASCT) improves the likelihood of a complete 
response (CR), prolongs progression-free survival (PFS) and overall survival (OS), and 
represents a major advance in MM therapy. 
 
Led first by the Intergroupe Francophone du Myelome (IFM), several groups have now shown 
improvements in survival for patients randomized to receive HDT when compared with 
conventional dose chemotherapy3, rendering HDT a standard treatment approach for younger 
patients with newly diagnosed MM. In addition, the IFM has shown that achievement of a VGPR 
is a surrogate for improvement in PFS and OS4, adding it as a new category in the revised 
International Myeloma Working Group response criteria5. CR is a prerequisite for tumor control 
and eventual cure in most, if not all, hematologic malignancies. CR rates in myeloma have 
improved substantially with stem cell transplantation. Improving CR rates is felt to be an 
important surrogate for the long-term goal of improving survival in myeloma.  Achievement of 
CR following autologous transplant for myeloma has been associated with improved disease-free 
and overall survival in multiple studies6-10. 


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Despite these improvements, patients are rarely, if ever, cured of MM through the use of HDT. 
To improve the efficacy of the HDT maneuver itself, groups have explored the use of multiple 
cycles of HDT (tandem transplant11-13), the use of combination chemotherapy conditioning 
regimens using agents in addition to or replacing melphalan in HDT conditioning14-17, and the 
addition of radiation therapy using targeted antibodies18-19 or external beam radiation20. 
Unfortunately, none of these approaches has been shown to be superior to the use of 200 mg/m2 
of melphalan. Thus, if we are to improve on the efficacy of HDT, alternative combination 
approaches are needed.  
1.2 
 Anti-myeloma effect of Bendamustine 
Bendamustine is a novel bifunctional alkylating agent consisting of three structural elements: a 
2-chloroethylamine alkylating group; a butyric acid side chain; and a benzimidazole ring. 
Although its precise mechanism of action is as yet unknown, it appears to exert its antineoplastic 
effects via a different mechanism to those of other alkylating agents.  Bendamustine has 
demonstrated significant efficacy in patients with indolent lymphomas and chronic lymphocytic 
leukemia (CLL), including in patients with disease refractory to conventional alkylating agents 
and rituximab. The toxicity profile of bendamustine is also superior to that of conventional 
alkylating agents. Bendamustine has promising activity in multiple myeloma (MM)21-25. 
Bendamustine seems to be efficacious either in monotherapy or in combination with other drugs 
in previously treated or untreated patients. Moreover, it has an acceptable toxicity profile and is 
suitable for patients with renal impairment. It is currently licensed in Europe for use as frontline 
treatment with prednisolone for patients with MM who are unsuitable for transplantation and 
who are contraindicated for thalidomide and bortezomib therapy.   


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1.3 
Rationale for use of Bendamustine in HDT/ASCT    
 
Given the efficacy and favorable safety profile of bendamustine, it is natural to explore this drug 
in the HDT/ASCT setting.   In the setting of relapsed/refractory lymphoma, Visani and 
colleagues performed a phase 1-2 study to test the safety and the efficacy of increasing doses of 
bendamustine, coupled with fixed doses of etoposide, cytarabine, and melphalan (BeEAM), in 
the conditioning regimen prior to ASCT for resistant/relapsed lymphoma patients26.  Forty-three 
patients (median age, 47 years) with non-Hodgkin (n = 28) or Hodgkin (n = 15) lymphoma were 
consecutively treated. Nine patients entered the phase 1 study; no patients experienced a dose-
limiting toxicity. Thirty-four additional patients were then treated in the phase 2 study. All 
patients engrafted, with a median time to absolute neutrophil count > 0.5 x 10(9)/L of 10 days. 
The 100-day transplantation-related mortality was 0%. After a median follow-up of 18 months, 
35 of 43 patients (81%) were in complete remission, whereas 6 of 43 relapsed and 2 of 43 did not 
respond. 
1.4 
Potential Risks and Benefits 
Bendamustine 
Bendamustine is a bifunctional mechlorethamine derivative containing a purine-like 
benzimidazole ring. Mechlorethamine and its derivatives form electrophilic alkyl groups. These 
groups form covalent bonds with electron-rich nucleophilic moieties, resulting in interstrand 
DNA crosslinks. The bifunctional covalent linkage can lead to cell death via several pathways. 
Bendamustine is active against both quiescent and dividing cells. The exact mechanism of action 
of bendamustine remains unknown.  The drug is 94%–96% bound to plasma proteins, and is 
primarily metabolized via hydrolysis to non-cytotoxic metabolites. Two minor active metabolites 
are formed via CYP1A2. Bendamustine does not induce nor inhibit CYP metabolic pathways. 


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Approximately 90% of the administered drug is recovered from the excreta, primarily feces. 
Bendamustine is currently FDA approved for the treatment of patients with chronic lymphocytic 
leukemia and indolent non-Hodgkin’s lymphoma.  Bendamustine has promising activity in 
multiple myeloma and is currently licensed in Europe for use as frontline treatment with 
prednisolone for patients with MM who are unsuitable for transplantation and who are 
contraindicated for thalidomide and bortezomib therapy.  Most common adverse reactions are 
neutropenia, anemia, thrombocytopenia, lymphopenia, nausea, fatigue, vomiting, diarrhea, 
pyrexia, constipation, anorexia, cough, headache, weight loss, dyspnea, rash, and stomatitis. 
 
Etoposide  
Etoposide is a semisynthetic derivative of the podophyllotoxins, an epipodophyllotoxin. It 
inhibits DNA topoisomerase II, thereby inhibiting DNA synthesis. Etoposide is cell cycle 
dependent and phase specific, affecting mainly the S and G2 phases.  Etoposide is metabolized in 
the liver via the cytochrome p450 system (CYP3A4 involved).  Elimination is described by two 
compartment open model, with the primary route of elimination being renal. Biliary excretion 
accounts for up to 44% recovery in feces.  Etoposide is currently FDA approved in the treatment 
of testicular cancer and small cell lung cancer.  Most common adverse reactions are neutropenia, 
anemia, thrombocytopenia, nausea, vomiting, diarrhea, stomatitis, esophagitis, hypotension, 
alopecia, hepatic toxicity, and allergic reactions.   
 
Cytarabine 
Cytarabine is an antineoplastic agent. Cytarabine is a synthetic pyrimidine nucleoside, which is 
converted intracellularly to the nucleotide, cytarabine triphosphate. The exact mechanism of 
action of cytarabine is not fully understood, but cytarabine triphosphate appears to inhibit DNA 


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synthesis by the inhibition of DNA polymerase. Cytarabine’s actions are cell-cycle specific.  
Cytarabine is rapidly metabolised, mainly in the liver, to the inactive metabolite 1-β-D-
arabinofuranosyluracil. About 70 to 80% of a dose is excreted in the urine within 24 hours; 
approximately 90% as the metabolite and 10% as unchanged cytarabine.  Cytarabine in 
combination with other approved anticancer drugs is indicated for remission induction in acute 
non-lymphocytic leukemia of adults and children. It has also been found useful in the treatment 
of acute lymphocytic leukemia and the blast phase of chronic myelocytic leukemia.  Most 
common adverse reactions are neutropenia, anemia, thrombocytopenia, nausea, vomiting, 
diarrhea, stomatitis, alopecia, skin rash, and conjunctivitis. 
 
Melphalan 
Melphalan, a bifunctional nitrogen mustard-derivative alkylating agent, is the L-isomer of 
mechlorethamine.  Melphalan inhibits DNA and RNA synthesis via formation of interstrand 
cross-links with DNA, likely binding at the N7 position of guanine. Melphalan is cell cycle 
phase-nonspecific.  Melphalan does not undergo metabolic activation and is inactivated in the 
plasma, primarily by non-enzymatic hydrolysis to monohydroxymelphalan and 
dihydroxymelphalan.  At conventional intravenous dosage, melphalan is indicated in the 
treatment of multiple myeloma and ovarian cancer. At high intravenous dosage, it is indicated, 
with or without hematopoietic stem cell transplantation, for the treatment of multiple myeloma 
and childhood neuroblastoma.  Most common adverse reactions are neutropenia, anemia, 
thrombocytopenia, nausea, vomiting, diarrhea, stomatitis, esophagitis, and alopecia. 


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Regimen-related toxicities  
Toxicities directly related to the administration of high-dose chemotherapy include 
gastrointestinal toxicity (nausea, vomiting, mucositis), alopecia, infertility (which may be 
permanent), interstitial pneumonitis, idiopathic cardiomyopathy, hepatic sinusoidal obstruction 
syndrome, or multi-organ failure which may be fatal. 
 
Infection 
Infection is a major cause of morbidity in ASCT and is a major concern in these patients.  
Infections may be bacterial, viral, parasitic, or fungal.  Often, these infections are life-
threatening, particularly when caused by viral or fungal organisms, and are associated with high 
mortality in the transplant population. 
 
Reproductive Considerations 
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, 
she must inform the investigator immediately and must permanently discontinue study drug. This 
also applies to male patients whose partners become pregnant while the patient is on study or 
within the 12 week period after last dose of study drug. Patients of reproductive potential (males 
and females) must practice double-barrier methods of contraception during treatment and for 12 
weeks following the last dose of Bendamustine. Adequate contraception is defined as double-
barrier protection (i.e., condom plus spermicide in combination with a diaphragm, cervical/vault 
cap, or intrauterine device). Birth control pills, birth control patches and/or injections of 
hormones or (in males) surgical sterilization (i.e., status post-vasectomy) to prevent pregnancy 
are not considered an adequate method of preventing pregnancy, and double-barrier protection is 


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required while on study and for 12 weeks after last dose, or the patient must completely abstain 
from heterosexual intercourse. 
 
2.0  
 
STUDY OBJECTIVES    
 
2.1 
 
Primary Objective 
 To estimate the response at day 100 following transplant. 
2.2  
 
Secondary Objectives 
 To obtain estimates of overall survival (OS), event-free survival (EFS), and non-relapsed 
mortality (NRM). 
 Characterize the hematologic and non-hematologic toxicities of high-dose bendamustine 
when given as part of the BeEAM preparative regimen prior to autologous stem cell 
transplantation. 
3.0  
 
STUDY DESIGN  
3.1    
 
Overview of Study Design 
Patients will be required to meet institutional guidelines for transplantation and follow the 
institutional standard for post-transplant care.  At a minimum, patients will need to be seen for 
study related purposes according to the following schedule. Other tests and exams will be done 
according to physician preference.  


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Test 
Screen 
Daily 
through 
D21* 
Weekly 
D21-
42* 
Month 
3 (Day 
100) 
Month 
6 
Month 
12 
H & P 
X 
X 
X 
X 
X 
X 
CBC with 
differential 
X 
X 
x 
X 
X 
X 
Chemistry  
X 
X 
X 
X 
X 
X 
Myeloma 
Assessments 
(SPEP, UPEP, 
SIFE, UIFE, Free 
Kappa Light 
Chains, 
Immunoglobulins)* 
X 
 
 
X 
X 
X 
Myeloma Residual 
Disease 
Assessment* 
X 
 
 
X 
 
 
PFT 
X 
 
 
 
 
 
ECHO 
X 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
IDMs including 
Hepatitis & HIV 
X 
 
 
 
 
 
Pregnancy test 
(FOCBP) 
X 
 
 
 
 
 
Toxicity 
Assessment 
 
X 
X 
X 
X 
 
Bone marrow 
biopsy & aspirate  
X 
 
 
X 
X 
X 
Bone Survey 
x 
 
 
X 
X 
X 
Survival 
 
 
 
 
 
 
New malignancy 
assessment 
 
 
 
 
 
 
*per standard of care  
 
 
 
 


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3.2     
Number of Patients 
Sixty-five (65) patients will be enrolled on this study.  Should a patient sign consent and not be 
transplanted, they will be considered a screen failure and replaced.      
3.3     
Duration of Study 
Adverse events will be collected for 30 days post-transplant.  Patients will be followed for 
disease status and survival at 3, 6 and 12 months post-transplant.  All other follow-up will be 
done per institutional guidelines and data will be collected form the BMT database to analyze 
progression free and overall survival.   
 
4.0     
STUDY POPULATION 
4.1    
Inclusion Criteria 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
1. Age between 18 - 70 years 
2. Karnofsky status ≥ 70% 
3. Diagnosis of Multiple Myeloma 
4. Within 9 months of the start of induction chemotherapy and no evidence of relapse or 
progression. 
5. Availability of Cryopreserved peripheral blood stem cells with a CD34 dose of at least 
2x106/kg. 
4.2     
Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
1. 
Patients will not be excluded on the basis of sex, racial or ethnic background.  
2. 
Poor cardiac function: left ventricular ejection fraction <40% 
3. 
Poor pulmonary function: FEV1, FVC, or DLCO <40% predicted  


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4. 
Poor liver function: bilirubin >2.5 mg/dl (not due to hemolysis, Gilbert’s or primary 
malignancy), AST/ALT > 3X ULN 
5. 
Poor renal function: Creatinine >2.0 mg/dl or creatinine clearance < 40 mL/min (calculated 
creatinine clearance is permitted) 
6. 
Ongoing or active systemic infection, active hepatitis B or C virus infection, or known 
human immunodeficiency virus (HIV) positive. 
7. 
Women of childbearing potential who currently are pregnant or who are not practicing 
adequate contraception 
8. 
Patients who have any debilitating medical or psychiatric illness which would preclude 
their giving informed consent or their receiving optimal treatment and follow-up.  
 
5.0 
 TREATMENT PLAN / STUDY DRUG 
5.1    Transplant Regimen 
Preparative Regimen 
Days –7, -6 
Bendamustine 200 mg/m2/day for 2 days 
 
 
Days –5 -2 
cytarabine, 400 mg/m2/day for 4 days 
 etoposide, 200 mg/m2/day for 4 days 
 
 
Day –1 
Melphalan 140 mg/m2 


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Chemotherapy Dosing:   
All chemotherapy should be dosed based on ideal body weight (IBW) for patients who weigh 
100-130% of their IBW.  For patients who weigh less than 100% of their IBW, dosing should be 
based on actual body weight (ABW).  For patients who weigh more than 130% of their IBW, 
dosing should be based on the adjusted ideal body weight (AIBW).  .   
 Ideal Body Weight (IBW) Formulas: 
 
 
Males IBW = 50 kg + 2.3 kg/inch over 5 feet 
 
 
Females IBW = 45.5 + 2.3 kg/inch over 5 feet 
 
 
For patients less than 5 feet, subtract 2.3 kg/inch 
 Adjusted Ideal Body Weight (AIBW) Formula: 
 
 
AIBW = IBW + [(0.25) x (ABW – IBW)] 
Dosing Adjustments:   
 
CHEMOTHERAPEUTIC AGENT 
 
Adjustment for Renal Insufficiency (GFR in ml/min) 
*Percentage of normal dose 
 
60 - 51 
 
≤50 
 
Etoposide 
 
100% 
 
75% 
 
CHEMOTHERAPEUTIC 
AGENT 
Adjustment for Hepatic Dysfunction 
% of Standard Dose To Be Administered 
T.Bili 
< 1.5 
AST 
< 60 
T.Bili 
1.5-3.0 
AST 
60-180 
T.Bili 
3.1-5 
AST 
> 180 
T. Bili 
> 5.0 
Bendamustine 
100% 
Omit if AST/ALT ≥2.5xULN or T. Bili ≥1.5xULN 
Etoposide 
100% 
50% 
omit 
omit 
 
Growth factor support:  Patients will receive G-CSF (Filgrastim) 5 mcg/kg/d SQ starting day +6 
and continuing until the ANC >1000/mm3 x 3 days or 1500/mm3 x 1 day. 


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Supportive Care: Antibiotic prophylaxis and other supportive care measures will be implemented 
according to institutional guidelines.  
 
6.0 
  STATISTICAL AND QUANTITATIVE ANALYSES 
6.1 
Statistical Methods 
6.1.1   
Determination of Sample Size 
The primary endpoint of this trial will be the rate of CR at day 100 post-transplant. Experience 
from the literature, as well as results from our institution, suggests that following ASCT for the 
upfront treatment of myeloma, the rate of CR at day 100 post-transplant is approximately 45%.  
It is hoped that under this protocol, this rate will be at least 65%. Thus we statistically formalize 
this study by testing the null hypothesis that p, the CR rate is 0.65 or more versus the alternative 
hypothesis that p is less than 0.45. A sample size of 65 pts gives 90% power with an alpha=0.05, 
using the formula for a one sample binomial (two-sided) test of a proportion.  We expect that 
patients will be accrued over 2 years. 
 
7.0 
   ADVERSE EVENTS   
7.1 
Definitions 
7.1.1 
Pretreatment Event Definition 
A pretreatment event is any untoward medical occurrence in a patient or subject who has signed 
informed consent to participate in a study but before administration of any study medication; it 
does not necessarily have to have a causal relationship with study participation. 


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7.1.2 
Adverse Event Definition 
Adverse event (AE) means any untoward medical occurrence in a patient or subject administered 
a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product whether or not it is related to the medicinal product.  
This includes any newly occurring event, or a previous condition that has increased in severity or 
frequency since the administration of study drug. 
 
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline.   
 
Adverse events will be collected from the time the patient signs the informed consent and ends 
30 days after the discontinuation of dosing or completion of the patient’s participation in the 
study if the last scheduled visit occurs at a later time.  
7.1.3 
Serious Adverse Event Reporting 
The investigator will comply with all safety reporting regulations as set forth in the Code of 
Federal Regulations.  The investigator being the sponsor of the study has the sole responsibility 
for reporting all serious adverse events to the Northside Hospital Institutional Review Board (the 
IRB of record), TEVA pharmaceuticals and if serious and either likely, possibly, probably, or 
definitely related to study drug to the FDA.  For informational purposes any correspondence to 
the FDA regarding adverse events or other safety issues will be simultaneously copied to 
us.clinops.sae@tevapharm.com or reported to Teva via facsimile at 215-619-3825. The 


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investigator will communicate the occurrence of serious adverse events to Teva and the IRB of 
record within 24 hours of becoming aware of the event.  Reporting of Adverse Events to Teva 
does not preclude the responsibility of the investigator to report adverse events to the FDA.   
7.1.4 
Serious Adverse Event Definition 
Serious AE (SAE) means any untoward medical occurrence that at any dose: 
 Results in death. 
 Is life-threatening (refers to an AE in which the patient was at risk of death at the time of 
the event.  It does not refer to an event which hypothetically might have caused death if it 
were more severe). 
 Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph below on planned hospitalizations). 
 Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions). 
 Is a congenital anomaly/birth defect. 
 Is a medically important event.  This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious 
when, based on appropriate medical judgment, may jeopardize the patient, require 
medical or surgical intervention to prevent 1 of the outcomes listed above, or involves 
suspected transmission via a medicinal product of an infectious agent.   Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse; any 
organism, virus, or infectious particle (e.g., prion protein transmitting Transmissible 


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Spongiform Encephalopathy), pathogenic or nonpathogenic, is considered an infectious 
agent.   
 Results in a development of drug dependency or drug abuse 
 Is a serious adverse drug experience 
Clarification should be made between a serious AE (SAE) and an AE that is considered severe in 
intensity (Grade 3 or 4), because the terms serious and severe are NOT synonymous.  The 
general term severe is often used to describe the intensity (severity) of a specific event; the event 
itself, however, may be of relatively minor medical significance (such as a Grade 3 headache).  
This is NOT the same as serious, which is based on patient/event outcome or action criteria 
described above, and  is usually associated with events that pose a threat to a patient’s life or 
ability to function.  A severe AE (Grade 3 or 4) does not necessarily need to be considered 
serious.  For example, a white blood cell count of 1000/mm3 to less than 2000 is considered 
Grade 3 (severe) but may not be considered serious.  Seriousness (not intensity) serves as a guide 
for defining regulatory reporting obligations. 
7.2 
Procedures for Reporting Serious Adverse Events 
The following AEs will be reported to the Northside Hospital Institutional Review Board, from 
the date the participant receives the first dose of study drug through 30 days after administration 
of the last dost of Bendamustine: 
·         Grade 1 adverse events do not need recorded 
·         Grade 2 unexpected and probably/definitely related 
·          All non-hematologic grades 3, 4 & 5 possibly/probably/definitely related 
Any SAE that occurs at any time during treatment with Bendamustine or for 30 days after the 
completion of Bendamustine treatment that the sponsor-investigator and/or sub-investigator 


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considers to be possibly/probably/definitely related to the study drug must be reported to 
Northside Hospital Institutional Review Board. The investigator must notify Teva of any serious 
adverse events that may occur after this time period which the investigator believes to be 
definitely, likely or possibly related to the study product.   
 
Additionally, the following will also be deemed to be adverse events for purposes of this study; 
pregnancy exposure, infant exposure during breastfeeding, overdose, abuse, misuse, medication 
errors, lack of efficacy, infectious agents, as well as all reports of accidental pediatric exposure 
and other safety information as reasonably requested by the sponsor.  In the event the IRB 
requests additional safety information from the investigator, investigator will notify Teva of such 
request within one (1) business day. 
 
New primary malignancies that occur during the follow-up periods must be reported, regardless 
of causality to study regimen, for a minimum of three years after the last dose of the 
investigational product, starting from the first dose of study drug.  
 
Planned hospital admissions or surgical procedures for an illness or disease that existed before 
the patient was enrolled in the trial are not to be considered SAEs unless the condition 
deteriorated in an unexpected manner during the trial (e.g., surgery was performed earlier or later 
than planned).  A visit to the hospital emergency room or hospital clinic would not be considered 
inpatient hospitalization; however, it could be considered serious if medical intervention was 
necessary in order to prevent a serious outcome.  It should be noted that disease progression, and 
death due to disease progression will be considered clinical endpoints for the study, and will not 
be considered serious adverse events. 


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All SAEs should be monitored until they are resolved or are clearly determined to be due to a 
patient’s stable or chronic condition or intercurrent illness(es). 
 
8.0 
ADMINISTRATIVE REQUIREMENTS 
8.1 
Good Clinical Practice 
The study will be conducted in accordance with the International Conference on Harmonisation 
(ICH) for Good Clinical Practice (GCP) and the appropriate regulatory requirement(s).  The 
investigator will be thoroughly familiar with the appropriate use of the study drug as described in 
the protocol and Investigator’s Brochure.  Essential clinical documents will be maintained to 
demonstrate the validity of the study and the integrity of the data collected.  Master files should 
be established at the beginning of the study, maintained for the duration of the study and retained 
according to the appropriate regulations.   
8.2 
Ethical Considerations 
The study will be conducted in accordance with applicable regulatory requirement(s) and will 
adhere to GCP standards.  The IRB/IEC will review all appropriate study documentation in order 
to safeguard the rights, safety and well-being of the patients.  The study will be conducted only 
at sites where IRB/IEC approval has been obtained.  The protocol, Investigator’s Brochure, 
informed consent form, advertisements (if applicable), written information given to the patients 
(including diary cards), safety updates, annual progress reports, and any revisions to these 
documents will be provided to the IRB/IEC by the investigator.  Teva requests that informed 
consent documents be reviewed by Teva or designee prior to IRB/IEC submission.   


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8.3 
Patient Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from either 
the patient or his/her guardian or legal representative before study participation.  The method of 
obtaining and documenting the informed consent and the contents of the consent must comply 
with the ICH-GCP and all applicable regulatory requirements. 
8.4 
Patient Confidentiality 
In order to maintain patient privacy, all data capture records, drug accountability records, study 
reports and communications will identify the patient by initials and the assigned patient number.  
The patient’s confidentiality will be maintained and will not be made publicly available to the 
extent permitted by the applicable laws and regulations. 
8.5 
Investigator Compliance 
The investigator will conduct the study in compliance with the protocol given approval/favorable 
opinion by the IRB/IEC and the appropriate regulatory authority(ies).  Changes to the protocol 
will require approval from Teva and written IRB/IEC approval/favorable opinion prior to 
implementation, except when the modification is needed to eliminate an immediate hazard(s) to 
patients.  The IRB/IEC may provide, if applicable regulatory authority(ies) permit, expedited 
review and approval/favorable opinion for minor change(s) in ongoing studies that have the 
approval /favorable opinion of the IRB/IEC.  The investigator will submit all protocol 
modifications to Teva and the regulatory authority(ies) in accordance with the governing 
regulations.  
Any departures from the protocol must be fully documented in the source documents.   


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8.6 
On-site Audits 
Regulatory authorities, the IEC/IRB and/or Teva may request access to all source documents, 
data capture records, and other study documentation for on-site audit or inspection.  Direct 
access to these documents must be guaranteed by the investigator, who must provide support at 
all times for these activities. 
8.7 
Investigator and Site Responsibility for Drug Accountability 
Accountability for the study drug at all study sites is the responsibility of the principal 
investigator.  The investigator will ensure that the drug is used only in accordance with this 
protocol.  Accountability records will include dates, quantities, lot numbers, expiration dates (if 
applicable), and patient numbers.   
8.8 
Closure of the Study 
This study may be prematurely terminated, if in the opinion of the investigator or Teva, there is 
sufficient reasonable cause.  Written notification documenting the reason for study termination 
will be provided to the investigator or Teva by the terminating party.   
Circumstances that may warrant termination include, but are not limited to: 
 Determination of unexpected, significant, or unacceptable risk to patients 
 Failure to enter patients at an acceptable rate 
 Insufficient adherence to protocol requirements 
 Insufficient, incomplete and/or unevaluable data 
 Determination of efficacy based on interim analysis 
 Plans to modify, suspend or discontinue the development of the drug 


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8.9 
Record Retention 
The investigator will maintain all study records according to the ICH-GCP and applicable 
regulatory requirement(s). 
8.10 
Study Drug  
Bendamustine will be provided by Teva Pharmaceuticals for purposes of this clinical research study.  
 
9 
    
USE OF INFORMATION 
All information regarding Bendamustine supplied by Teva to the investigator is privileged and 
confidential information.  The investigator agrees to use this information to accomplish the study 
and will not use it for other purposes without consent from Teva.  It is understood that there is an 
obligation to provide Teva with complete data obtained during the study.  The information 
obtained from the clinical study will be used toward the development of Bendamustine and may 
be disclosed to regulatory authority(ies), other investigators, corporate partners, or consultants as 
required. 
Upon completion of the clinical study and evaluation of results by Teva, the hospital or 
institution and/or investigator may publish or disclose the clinical trial results pursuant to the 
terms contained in the applicable Clinical Trial Agreement.    
 


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10 
    
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