Conditions: Multiple Myeloma
Keywords: Multiple Myeloma Bortezomib Autologous Stem Cell Purging In-vivo purging Ex-vivo purging Leukapheresis Contaminated Stem Cell Harvest Stem Cell Transplant Transplantation
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 101
Healthy volunteers: no

Brief summary:
Explore stem cell collection with or without bortezomib with in-vivo purging in multiple myeloma.

Detailed description:
High dose chemotherapy with autologous stem cell transplant has resulted in improved overall survival and is currently considered an effective first line therapy applicable to the majority of patients with multiple myeloma. However disease relapse is inevitable and remains the primary cause of mortality in this cohort.

The purpose of this study is to estimate the proportion of subjects with plasma cell contamination of harvested stem cell product in standard and treatment arms. The study will explore whether or not in-vivo purging of malignant tumor plasma cells will improve progression free survival (PFS) for patients.

The study will consist of two groups:

Group A: Standard of Care (SOC) stem cell collection without in-vivo purging with bortezomib. Granulocyte colony-stimulating factor (G-CSF) and Mozobil used if needed.

Group B: Bortezomib 1.3mg/m\^2 will be given subcutaneously (SQ) on days -11 and -8 followed by Granulocyte colony-stimulating factor (G-CSF) on days -4 through -1 prior to stem cell harvest (day 0).

Arms:
arm 1: Standard of Care Stem cell collection without in-vivo purging with Bortezomib. Standard of Care drugs Granulocyte colony-stimulating factor (G-CSF) +/- Mozobil (the latter if needed).

NOTE: Multiparametric Flow Cytometry to be performed on samples for BOTH groups A and B arm 2: Bortezomib will be given subcutaneously (SQ) at 1.3 mg/m2 on day -11 and day -8 followed by Granulocyte colony-stimulating factor (G-CSF) given SQ on day -4 thru day -1 and continued until the collection is completed. Mozobil will be given if needed.

There must be at least 72 hours between each dose of bortezomib. NOTE: Multiparametric Flow Cytometry to be performed on samples for BOTH groups A and B

Interventions: intervention 1: Bortezomib intervention 2: Granulocyte colony-stimulating factor (G-CSF) intervention 3: Mozobil
Intervention descriptions: intervention 1: Bortezomib will be given to Group B participants by injection under the skin 11 days and 8 days before stem cell collection. intervention 2: Granulocyte colony-stimulating factor (G-CSF) will be given to all participants by injection under the skin 4 days and 1 day before stem cell collection, and then continued until the stem cell collection is completed. intervention 3: Mozobil will be given to all participants by injection under the skin only if needed per Investigator.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
Investigator - Initiated Trial 
 
 
2015-IIT-BMT-MM-AutoSCT 
 
An exploratory trial to estimate the proportion of  patients with tumor cell 
contaminated, flow positive leukapheresis products collected with and 
without bortezomib as in-vivo purging prior to autologous stem cell harvest 
for multiple myeloma   
 
 
 
PRINCIPAL INVESTIGATOR 
Siddhartha Ganguly, MD 
University of Kansas Medical Center 
Westwood Campus, MS 5003 
2330 Shawnee Mission Parkway, Suite 210 
Westwood, KS 66205 
Telephone:  913-588-6030 
 
 
Protocol ID:  
2015-IIT-BMT-MM-AutoSCT 
Study Drug:  
Bortezomib (Velcade) 
Initial Version:  
1.0 dated 07-29-2015 / 1.1 dated 11-18-2015 / 1.2 dated 12-14-15 
 
1.3 dated 01-21-2016 
Post-Initial Approval 
Modifications:  
Revised Protocol Version 2.0 dated 02-11-2016 
 
Revised Protocol Version 3.0 dated 03-14-2016 
 
Revised Protocol Version 4.0 dated 04-06-2016 
 
Revised Protocol Version 5.0 dated 11-21-2016 
 
 
CONFIDENTIAL 
This material is the property of The University of Kansas Cancer Center.  Do not disclose or use 
except as authorized in writing by the study sponsor. 
 


2015-IIT-BMT-MM-AutoSCT 
Principal Investigator:  Siddhartha Ganguly, MD 
HSC # STUDY00002857 
LIST OF KEY PERSONNEL 
 
 
PRINCIPAL INVESTIGATOR:  
Siddhartha Ganguly, MD 
 
SUB-INVESTIGATOR(S):  
Joseph McGuirk, DO 
Sunil Abhyankar, MD 
Anurag Singh, MD 
Leyla Shune, MD 
Tara Lin, MD 
 
BIOSTATISTICIAN: 
Milind Phadnis, PhD 
 
COLLABORATORS: 
Pathology: 
Mark Cunningham, MD 
Janet Woodroof, MD 
 
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2015-IIT-BMT-MM-AutoSCT 
Principal Investigator:  Siddhartha Ganguly, MD 
HSC # STUDY00002857 
PROTOCOL AGREEMENT 
 
I have read the protocol specified below. In my formal capacity as Investigator, my duties 
include ensuring the safety of the study participants enrolled under my supervision and 
providing complete and timely information, as outlined in the protocol.  It is understood that all 
information pertaining to the study will be held strictly confidential and that this confidentiality 
requirement applies to all study staff at this site. Furthermore, on behalf of the study staff and 
myself, I agree to maintain the procedures required to carry out the study in accordance with 
accepted GCP principles and to abide by the terms of this protocol. 
 
Protocol Number: 
2015-IIT-BMT-MM-AutoSCT 
 
Protocol Title:  
An exploratory trial to estimate the proportion of patients with tumor 
cell contaminated, flow positive leukapheresis products collected with 
and without bortezomib as in-vivo purging prior to autologous stem 
cell harvest for multiple myeloma 
 
Protocol Version and Date: 
Protocol Version 5.0 dated 11-21-2016  
 
 
 
Principal Investigator Signature: ______ ________________ 
_____         ____________ 
 
 
 
 
 
 
 
 
 
 
 
     Date 
 
Print Name and Title: __________________________________________________________ 
 
 
Site Number: N/A 
 
Site Name: 
The University of Kansas Cancer Center / University of Kansas Medical Center 
 
 
 
 
 
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2015-IIT-BMT-MM-AutoSCT 
Principal Investigator:  Siddhartha Ganguly, MD 
HSC # STUDY00002857 
TABLE OF CONTENTS 
ABBREVIATION LIST .................................................................................................................................. 6 
STUDY SCHEMA ......................................................................................................................................... 8 
STUDY SUMMARY ...................................................................................................................................... 8 
1.0 BACKGROUND AND RATIONALE .................................................................................................. 10 
1.1 
DISEASE BACKGROUND...................................................................................................... 10 
1.2 
STUDY AGENT(S) BACKGROUND AND ASSOCIATED KNOWN TOXICITIES ................................ 11 
1.3 
OTHER AGENTS ................................................................................................................. 16 
1.4 
RATIONALE ........................................................................................................................ 16 
1.5 
CORRELATIVE STUDIES ...................................................................................................... 17 
2.0 STUDY OBJECTIVES ....................................................................................................................... 17 
2.1 
PRIMARY OBJECTIVES ........................................................................................................ 17 
2.2 
SECONDARY OBJECTIVES .................................................................................................. 18 
3.0 SUBJECT ELIGIBILITY ..................................................................................................................... 18 
3.1 
INCLUSION CRITERIA .......................................................................................................... 18 
3.2 
EXCLUSION CRITERIA ......................................................................................................... 19 
4.0 TREATMENT PLAN........................................................................................................................... 19 
4.1 
TREATMENT DOSAGE AND ADMINISTRATION ........................................................................ 19 
4.2 
TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS ..................................................... 20 
4.3 
CONCOMITANT MEDICATIONS/TREATMENTS ........................................................................ 20 
4.4 
DURATION OF THERAPY ..................................................................................................... 21 
4.5 
REMOVAL OF PATIENTS FROM PROTOCOL THERAPY ............................................................ 21 
5.0 STUDY PROCEDURES ..................................................................................................................... 22 
5.1 
SCREENING/BASELINE PROCEDURES .................................................................................. 22 
5.2 
PROCEDURES DURING TREATMENT .................................................................................... 23 
5.3 
FOLLOW-UP PROCEDURES ................................................................................................. 23 
5.4 
SCHEDULE OF EVENTS ....................................................................................................... 24 
5.5 
REMOVAL OF SUBJECTS FROM STUDY TREATMENT AND STUDY ........................................... 25 
6.0 ADVERSE EVENTS ........................................................................................................................... 25 
6.1 
DEFINITIONS ...................................................................................................................... 25 
6.2 
REPORTING REQUIREMENTS FOR ADVERSE EVENTS ........................................................... 28 
7.0 DRUG INFORMATION....................................................................................................................... 29 
7.1 
AGENT BORTEZOMIB .......................................................................................................... 29 
8.0 MEASUREMENT OF EFFECT .......................................................................................................... 38 
8.1 
ANTITUMOR EFFECT- HEMATOLOGIC TUMORS ..................................................................... 38 
8.2 
SAFETY / TOLERABILITY ..................................................................................................... 38 
9.0 DATA AND SAFETY MONITORING ................................................................................................. 38 
9.1 
OVERSIGHT AND MONITORING PLAN ................................................................................... 38 
9.2 
SAFETY REVIEW AND OVERSIGHT REQUIREMENTS .............................................................. 38 
9.3 
DATA SAFETY MONITORING COMMITTEE (DSMC) REPORTING ............................................ 39 
10.0 
REGULATORY CONSIDERATIONS ............................................................................................ 40 
10.1 
PROTOCOL REVIEW AND AMENDMENTS .............................................................................. 40 
10.2 
INFORMED CONSENT.......................................................................................................... 40 
10.3 
ETHICS AND GOOD CLINICAL PRACTICE (GCP) ................................................................... 40 
 
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HSC # STUDY00002857 
11.0 
REGISTRATION PROCEDURES ................................................................................................. 41 
11.1 
GENERAL GUIDELINES FOR KUCC AND OTHER PARTICIPATING ORGANIZATIONS ................. 41 
11.2 
REGISTRATION PROCESS FOR KUCC AND OTHER PARTICIPATING CENTERS ....................... 41 
12.0 
STUDY MANAGEMENT ................................................................................................................ 42 
12.1 
INVESTIGATOR FILES AND RETENTION OF DOCUMENTS ........................................................ 42 
12.2 
CASE REPORT FORMS ....................................................................................................... 42 
12.3 
STUDY MONITORING .......................................................................................................... 42 
13.0 
STATISTICAL CONSIDERATIONS .............................................................................................. 43 
13.1 
STUDY DESIGN/STUDY ENDPOINTS .................................................................................... 43 
13.2 
SAMPLE SIZE AND ACCRUAL ............................................................................................... 43 
13.3 
DATA ANALYSES PLANS ..................................................................................................... 44 
13.4 
INTERIM ANALYSIS AND DATA SUPERVISION ........................................................................ 44 
14.0 
REFERENCES ............................................................................................................................... 46 
15.0 
APPENDICES ................................................................................................................................ 50 
APPENDIX A PERFORMANCE STATUS ..................................................................................................... 50 
APPENDIX B BODY SURFACE AREA ........................................................................................................ 51 
APPENDIX C STANDARD OPERATING PROCEDURES – STEM CELL HARVEST ............................................ 52 
APPENDIX D GUIDANCE FOR USE OF HEPARIN AND MOZOBIL IN PERFORMING LARGE VOLUME APHERESIS
 
82 
APPENDIX E STANDARD OPERATING PROCEDURES – CYTOPLASMIC STAINING ........................................ 84 
APPENDIX F MULTIPARAMETRIC FLOW CYTOMETRY (MFC) – VALIDATION MODEL MULTIPLE MYELOMA 
(MM)-MINIMAL RESIDUAL DISEASE (MRD)................................................................................................. 91 
APPENDIX G 8-COLOR LEUKEMIA / LYMPHOMA IMMUNOPHENOTYPING PROCESSING PROCEDURE ............. 92 
APPENDIX H SUMMARIES OF CHANGES ................................................................................................ 101 
 
 
 
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ABBREVIATION LIST 
AE 
 
Adverse Event 
ALT 
 
Alanine Aminotransferase 
ARDS  
Acute Respiratory Distress Syndrome 
ASBMT 
American Society for Blood and Marrow Transplantation 
AST 
 
Aspartate Aminotransferase 
BA (study) 
Bioavailability 
BE (study) 
Bioequivalence 
BSA 
 
Body Surface Area 
BUN 
 
Blood Urea Nitrogen 
CBC 
 
Complete Blood Count 
CMP  
Comprehensive Metabolic Panel 
CFR 
 
(United States) Code of Federal Regulations 
CR 
 
Complete Response 
CRF 
 
Case Report Form 
CRIS  
Comprehensive Research Information System 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP  
Cancer Therapy Evaluation Program 
CV 
 
Cardiovascular 
DFS 
 
Disease-Free Survival 
DLT 
 
Dose Limiting Toxicity 
DNA 
 
Deoxyribonucleic Acid 
DSMC  
Data and Safety Monitoring Committee 
EBMT  
European Blood and Marrow Transplantation 
ECG 
 
Electro-cardiogram 
ECOG  
Eastern Cooperative Oncology Group 
EMAX   
Maximum Effect 
EOT 
 
End of Treatment 
EU 
 
European Union 
FDA 
 
United States Food and Drug Administration 
G-CSF  
Granulocyte colony-stimulating factor 
GCP 
 
Good Clinical Practice(s) 
GI 
 
Gastro-Intestinal 
GGT 
 
Gamma-glutamyltransferase 
HCT 
 
Hematopoietic Cell Transplantation 
HSC 
 
Human Subjects Committee 
Hgb 
 
Hemoglobin 
ICF 
 
Informed Consent Form 
ICH 
 
International Conference on Harmonisation 
IMWG  
International Myeloma Working Group 
IND 
 
Investigational New Drug 
IRB 
 
Institutional Review Board 
IUD 
 
Intra-uterine Device 
IV 
 
Intravenous 
KPS 
 
Karnosky Performance Status 
KU 
 
University of Kansas 
KUCC  
The University of Kansas Cancer Center 
LDH 
 
Lactic Dehydrogenase 
MCL 
 
Mantle Cell Lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFC 
 
Multi-parametric Flow Cytometry  
 
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µL 
 
Microliter 
MM 
 
Multiple Myeloma 
MR 
 
Minor Response 
MRD  
Minimal Residual Disease 
MTD 
 
Maximum Tolerated Dose 
NCI 
 
National Cancer Institute 
NEC 
 
Not Elsewhere Classifiable 
NHL 
 
Non-Hodgkins Lymphoma 
ORR  
Overall Response Rate 
OS 
 
Overall Survival 
PBMC  
Peripheral Blood Mononuclear 
PCR 
 
Polymerase Chain Reaction 
PFS 
 
Progression Free Survival 
PI 
 
Principal Investigator 
PK 
 
Pharmacokinetics 
PR 
 
Partial Response 
QA 
 
Quality Assurance 
SAE 
 
Serious Adverse Event 
SQ 
 
Subcutaneous 
TTP 
 
Time to Progression 
ULN 
 
Upper Limit of Normal 
USP 
 
United States Pharmacopeia 
WBC  
White Blood Cell (count) 
 
  
 
 
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STUDY SCHEMA    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY SUMMARY 
Title 
An exploratory trial to estimate the proportion of  patients 
with tumor cell contaminated, flow positive leukapheresis 
products collected with and without bortezomib as in-vivo 
purging prior to autolgous stem cell harvest for multiple 
myeloma.   
Short Title 
2015-IIT-BMT-MM-AutoSCT 
Phase 
Phase 2  
Methodology 
open label; randomized 
Study Duration 
2 years 
Study Center(s) 
Single-center  
Objectives 
Estimate proportion of subjects with plasma cell 
contamination of harvested stem cell product in standard 
and treatment arms. 
Number of Subjects 
100 patients 
Diagnosis and Main 
Inclusion Criteria 
Multiple myeloma patients undergoing autologous stem 
cell transplantation 
Patient Identification 
Preparation of Stem Cell Harvest 
Transplant 
 
Eligible adult patient 
ready for stem  
cell harvest 
 
Bortezomib Injection Days -11 and -8 
G-CSF Days -4 through -1 
Mozobil used if needed.  
See Appendices C and D 
 
Stem Cell Mobilization by Pheresis Day 0 
Window for stem cell collection: 
(Day 0 + 4 days) 
Flow cytometric analysis of stem cell product 
for malignant plasma cells 
 
 
Standard of Care Stem cell collection without 
in-vivo purging with Bortezomib.  G-CSF and 
Mozobil used if needed. See Appendix C 
 
Stem Cell Transplant 
with Routine Post-
transplant follow-up 
 
R 
B 
A 
 
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Study Product(s), Dose, 
Route, Regimen 
Group A:   Standard of Care Stem cell collection without 
in-vivo purging with Bortezomib.  G-CSF and Mozobil used 
if needed. See Appendices C and D 
 
Group B:  Bortezomib ; SQ; Days -11 and -8; 1.3 mg/m2 
followed by G-CSF Days -4 through -1, prior to stem cell 
harvest (Day 0) G-CSF and Mozobil used if needed. See 
Appendices C and D 
 
o Stem cell collection can occur up to 12 days after the 
last injection of bortezomib, if needed, for participant 
safety and convenience. Window: Day 0 (+4 days) 
 
Duration of 
Administration 
2 doses 
Reference Therapy 
Standard of Care Stem cell collection without in-vivo 
purging with Bortezomib.  G-CSF and Mozobil used if 
needed.  
See Appendices C and D  
Interim Monitoring 
Internal DSMC for IITs at KU 
Statistical Methodology 
Descriptive, numerical, only; Estimate the proportion of 
products Positive for contamination under the standard of 
care stem cell collection and under in-vivo purging with 
Bortezomib stem cell collection. Confidence intervals will 
be provided. 
 
 
 
 
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HSC # STUDY00002857 
1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
High dose chemotherapy with autologous stem cell transplant has resulted in improved overall 
survival and is currently considered an effective first line therapy applicable to the majority of 
patients with multiple myeloma. However disease relapse is inevitable and remains the primary 
cause of mortality in this cohort.  
1.1.1 Myeloma Cell Contamination: 
Myeloma cells contamination of the leukapheresis product has been demonstrated in previous 
studies, but, the contamination rate or percentage of patients with contaminated graft 
undergoing autologous stem cell transplantation is not well known. 
Mariette et al, 1994, used the immunoglobulin heavy chain gene radioactive fingerprinting 
polymerase chain reaction (PCR) method to detect clonal cells in the graft from 10 patients. The 
sensitivity of the technique allowed the detection of one clonal cell among 10(4) normal blood 
mononuclear cells. A clonal band was detected in 4 of 11 leukapheresis samples (36%). 
In another paper by Miklos et al. Blood 2014, myeloma cell contamination was checked by PCR 
not by flow, and was present at a median level of 62.7 myeloma molecules/million PBMCs 
(range 0-11,951) after Cycle of chemo and 43.6 myeloma molecules/million PBMCs (range 0-
4,489) after Cycle 2 of chemotherapy. 2 out of 38 observations were free from tumor cell 
contamination (personal communication). 
The impact of contaminated leukapheresis product is disputed, however evidence from 
prospective study by Gertz et al (Gertz et al., 1997) suggest that myeloma graft contamination 
leads to poor disease free survival. This is further supported by a recent clinical study, which 
showed low graft contamination (< 4.5 x 105 plasma cell/kg of patient’s body weight) did result in 
improved PFS (Vogel, Kopp, Kanz, & Einsele, 2005). In that series the number of contaminating 
plasma cells in the harvested product was 0.08% (median) with a range of 0-2.26%. Authors did 
not state how many patients did not have tumor contamination (0% plasma cells in the 
harvested graft).  
1.1.2 Methods of Measurement of Minimal Residual Disease: 
In the International Myeloma Workshop held in Kyoto, Japan (2013), two methods to measure 
MRD were given emphasis, viz. flow cytometry and real time PCR for gene sequencing.  
 
Multiparametric flow cytometry (MFC) is a novel way of checking for minimal residual disease.  
 
As per the recently published ASBMT myeloma guidelines (Shah, Callander, Ganguly et al, 
2015), MRD testing after auto-HCT in MM can reveal patients at risk for poorer outcomes and 
should be considered for disease evaluation (Grade B). If MRD testing is attempted, 
multiparametric flow cytometry following European Myeloma Network consensus guidelines 
should be the method of choice.  
 
1.1.3 Level of Detection: 
Rawstron AC et al published the consensus guidelines on multiparametric flow cytometry in 
multiple myeloma and related disorders which established the presently accepted methods for 
measuring minimal residual disease in myeloma samples (Rawstron et al. 2008). In their 
 
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guidelines paper they recommended, that it is possible to detect neoplastic plasma cells by flow 
cytometry above the clinically relevant threshold of 0.01%. It is recommended that at least 100 
neoplastic plasma cell events should be acquired for accurate enumeration. Hence, according 
to the consensus 1) at least 0.01% clonal plasma cells and 2) at least 100 cells per product 
would be considered as positive for minimal residual disease. 
1.1.4 Purging: 
Unfortunately multicenter studies with ex-vivo purging using CD 34 positive cell selection of the 
harvest product did not improve progression free survival (Stewart et al., 2001). 
In vivo purging has been tried using various chemo-immunotherapeutic agents in diseases like 
lymphoma. PCR or minimal residual disease (MRD) negative products have been associated 
with improved progression free survival.  In vivo purging has not been done in patients with 
multiple myeloma. In patients with lymphoma, in vivo purging and PCR negative products have 
been shown to improve disease-free survival (DFS).  
 
For the purpose of the transplant, hematopoietic stem cells are mobilized from the bone marrow 
niche by using either chemotherapy with G-CSF or G-CSF alone. Bortezomib is approved for 
treatment in all stages of myeloma. In a single arm study at our institution we had shown 
successful collection and mobilization of stem cells using Bortezomib/G-CSF strategy.  
In a recent study (Oakervee et al, 2007), use of bortezomib as induction therapy prior to stem 
cell transplantation did not adversely impact the mobilization and actually resulted in robust 
stem cell collection in all the enrolled patients. Bortezomib thus does not have any stem cell 
toxic effects. This study aims to determine the effectiveness of a combination of bortezomib and 
G-CSF in a tumor free stem cell mobilization. 
Ex vivo purging of stem cell products by bortezomib with or without rituximab has successfully 
decreased the tumor contamination. 24-hour incubation with bortezomib at 80 nmol/L induced 
80% to 90% growth inhibition in the myeloma cell lines, however, it also markedly inhibited 
(80%) the growth of normal CD34+ cells. In contrast, a lower dose of bortezomib (20 nmol/L) for 
16 hours was sufficient to induce 70% to 90% growth inhibition in myeloma cell lines, with only 
20% growth inhibition in normal CD34+ cells (Yang H et al. 2011). 
In an attempt to decrease tumor contamination in the stem cell product by in vivo purging, 
bortezomib was chosen as the drug of choice, as we already have experience in using 
bortezomib in the similar setting for stem cell mobilization (Abhyankar et al. 2013)  
We have already presented our experience of in vivo purging in lymphoma (Singh et al. 2015), 
and planning to extend the similar concept in plasma cell disorders. 
 
1.2 
Study Agent(s) Background and Associated Known Toxicities 
 
VELCADE® (bortezomib) for Injection 
 
1.2.1 Scientific Background 
VELCADE® (bortezomib) for Injection is a small molecule proteasome inhibitor 
developed by Millennium Pharmaceuticals, Inc., (Millennium) as a novel agent to treat 
human malignancies.  Bortezomib is currently approved by the United States Food and 
Drug Administration (FDA) for the treatment of patients with multiple myeloma (MM).  It 
 
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is also indicated for the treatment of patients with mantle cell lymphoma (MCL) who have 
received at least 1 prior therapy.  In the European Union (EU), bortezomib in 
combination with melphalan and prednisone is indicated for the treatment of patients 
with previously untreated MM who are not eligible for high-dose chemotherapy with bone 
marrow transplant.  Bortezomib is indicated as monotherapy for the treatment of 
progressive MM in patients who have received at least 1 prior therapy and who have 
already undergone or are unsuitable for bone marrow transplantation. 
By inhibiting a single molecular target, the proteasome, bortezomib affects multiple 
signaling pathways.  The anti-neoplastic effect of bortezomib likely involves several 
distinct mechanisms, including inhibition of cell growth and survival pathways, induction 
of apoptosis, and inhibition of expression of genes that control cellular adhesion, 
migration and angiogenesis.  Thus, the mechanisms by which bortezomib elicits its 
antitumor activity may vary among tumor types, and the extent to which each affected 
pathway is critical to the inhibition of tumor growth could also differ.   Bortezomib has a 
novel pattern of cytotoxicity in National Cancer Institute (NCI) in vitro and in vivo assays 
(Adams et al., 1999).  In addition, bortezomib has cytotoxic activity in a variety of 
xenograft tumor models, both as a single agent and in combination with chemotherapy 
and radiation (Steiner et al., 2001; Teicher et al., 1999; Cusack et al., 2001; LeBlanc et 
al., 2002; Pink et al., 2002).  Notably, bortezomib induces apoptosis in cells that over 
express bcl-2, a genetic trait that confers unregulated growth and resistance to 
conventional chemotherapeutics (McConkey et al., 1999). 
The mechanisms of action leading up to apoptosis have been more clearly defined and 
include initiation of the unfolded protein response and direct/indirect effects on various 
molecular targets including cell cycle control proteins p27 and p21, cyclins, signal 
transduction molecules, transcription factors c-jun and HIF-1, tumor suppressor protein 
p53, angiogenesis factors, and many others.   Bortezomib is thought to be efficacious in 
multiple myeloma via its inhibition of nuclear factor κB (NF-κB) activation, its attenuation 
of interleukin-6 (IL-6)-mediated cell growth, a direct apoptotic effect, and possibly anti-
angiogenic and other effects (Hideshima et al., 2001).  
1.2.2 Nonclinical Pharmacology 
Pharmacokinetic (PK) and pharmacodynamic studies were conducted in the rat and 
cynomolgus monkey.  Upon intravenous (IV) bolus administration, bortezomib displays a 
rapid distribution phase (t½α <10 minutes) followed by a longer elimination phase (t½β 
5–15 hours).   Bortezomib has a large volume of distribution (range 5–50 L/kg).  The 
plasma PK profile is well described by a 2-compartment model. 
The pharmacodynamic action of bortezomib is well established and can be measured 
through an ex vivo assay (20S proteasome activity) (Lightcap et al., 2000).  This assay 
was used to determine the duration of drug effect in lieu of the PK data in the early 
preclinical toxicology studies as well as to set a guide for dose escalation in humans.  
Following dosing with bortezomib in the rat and cynomolgus monkey, proteasome 
inhibition in peripheral blood had a half-life less than 24 hours, with proteasome activity 
returning to pretreatment baseline within 24 hours in monkey and within 48 to 72 hours 
in rat after a single dose of bortezomib.  Further, intermittent but high inhibition (>70%) of 
proteasome activity was better tolerated than sustained inhibition.  Thus, a twice-weekly 
clinical dosing regimen was chosen in order to allow return of proteasome activity 
towards baseline between dose administrations. 
 
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1.2.3 Nonclinical Toxicity 
Single-dose IV toxicity studies were conducted with bortezomib in the mouse, rat, dog, 
and monkey to establish the single-dose maximum tolerated dose (MTD).  The MTDs 
were 0.25 mg/kg (1.5 mg/m2) and 0.067 mg/kg (0.8 mg/m2) in the 2 most sensitive 
species, rat and monkey, respectively. 
Repeat-dose multi-cycle toxicity studies of 3 and 6 months in the rat and 9 months in the 
monkey, each with 8-week recovery periods, were conducted to characterize the chronic 
toxicity of bortezomib when administered by the clinical route and regimen of 
administration.  The MTD in the 6-month rat study was 0.10 mg/kg (0.6 mg/m2) and the 
key target organs were the gastrointestinal (GI) tract, hematopoietic and lymphoid 
systems.  The MTD in the 9-month monkey study was 0.05 mg/kg (0.6 mg/m2) and the 
key target organs were the GI tract, hematopoietic and lymphoid systems, peripheral 
nervous system, and kidney.  Full or partial reversibility was observed for each of the 
toxicities described to date.   
In general, the nature of the toxicity of bortezomib is similar across species, and target 
organs of toxicity in animals have been largely predictive of human toxicity.  The toxicity 
of bortezomib in animals is characterized by a steep dose-response with mortality seen 
at dosages above the MTD.  The cause of death at acutely lethal dosages is considered 
to be related to indirect cardiovascular (CV) effects of hypotension and vascular changes 
with secondary bradycardia and the cause of death in long-term studies has been 
attributed to GI or hematologic toxicity.  The pharmacologic effects of bortezomib on the 
CV system have been extensively characterized and have demonstrated that indirect 
effects on CV function occur only at acutely lethal dosages and are abrogated by routine 
supportive care. 
Additional detailed information regarding the nonclinical pharmacology and toxicology of 
BORTEZOMIB may be found in the Investigator’s Brochure. 
1.2.4 Clinical Pharmacokinetics and Pharmacodynamics 
The clinical pharmacology characterization of bortezomib has been determined from 
phase 1 studies in subjects with solid tumors and hematological malignancies, and 
confirmed in phase 2 studies in subjects with multiple myeloma. 
Bortezomib demonstrates multi-compartmental pharmacokinetics. Following intravenous 
administration of 1.0 mg/m2 and 1.3 mg/m2 dose, the mean first-dose maximum 
observed plasma concentrations of bortezomib were 57 and 112 ng/mL, respectively in 
11 patients with multiple myeloma and creatinine clearance values > 50 mL/min 
participating in a pharmacokinetics study.  In subsequent doses, mean maximum 
observed plasma concentrations ranged from 67 to 106 ng/mL for the 1.0 mg/m2 dose 
and 89 to 120 ng/mL for the 1.3 mg/m2 dose.  The mean elimination half-life of 
bortezomib upon multiple dosing ranged from 40 to 193 hours. Bortezomib is eliminated 
more rapidly following the first dose.  Mean Total Body Clearances were 102 and 112 
L/h following the first dose for doses of 1.0 mg/m2 and 1.3 mg/m2, respectively, and 
ranged from 15 to 32 L/h following subsequent doses for doses of 1.0 and 1.3 mg/m2, 
respectively.  Clinical experience has shown that the change in clearance does not result 
in overt toxicity from accumulation in this multi-dose regimen in humans. 
In subjects with advanced malignancies, the maximum pharmacodynamic effect 
(inhibition of 20S activity) occurred within 1-hour post dose.  At the therapeutic dose of 
1.3 mg/m2 in subjects with multiple myeloma, the mean proteasome inhibition at 1-hour 
post dose was approximately 61%. 
 
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The time course of proteasome inhibition in subjects is characterized by maximum 
inhibition observed within the first hour after administration, followed by partial recovery 
of proteasome activity over the next 6 to 24 hours to within 50% of the pretreatment 
activity.  On the Day 1, 4, 8, and 11 schedule, variable (10%–30%) levels of proteasome 
inhibition have been observed at next scheduled dosing.  In theory, this advantage 
allows cells to recover proteasome activity for normal cellular housekeeping functions 
between doses. 
The relationship between bortezomib plasma concentrations and proteasome inhibition 
can be described by a maximum effect (Emax) model.  The Emax curve is initially very 
steep, with small changes in plasma bortezomib concentration over the range of 0.5 to 
2.0 ng/mL relating to large increases in the percent inhibition (0–60%).  After that, a 
plateau occurs where marginal increases of proteasome inhibition are observed in spite 
of large changes in plasma bortezomib concentrations. 
1.2.5 Clinical Experience  
It is estimated that as of June 2011, more than 300,000 patients have been treated with 
bortezomib, including patients treated through Millennium-sponsored clinical trials, 
Investigator-Initiated Studies, the US NCI Cancer Therapy Evaluation Program (CTEP), 
and with commercially available drug.  Bortezomib has been commercially available 
since 13 May 2003. 
 
The overall goal of the Millennium phase 1 program was to determine the MTD and 
dose-limiting toxicity (DLT) of bortezomib in a number of therapeutic settings involving 
subjects with various advanced malignancies.  In a Phase I trial in patients with 
refractory hematologic malignancies, the MTD for a twice weekly for 4 weeks of a 42 day 
cycle was 1.04 mg/m2/dose, with DLTs of thrombocytopenia, hyponatremia, 
hypokalemia, fatigue, and malaise (Orlowski et al., 2002).  The toxicity was greatest 
during the third and fourth weeks of therapy. In the 3-week schedule of bortezomib 
monotherapy (4 doses, given on Days 1, 4, 8, and 11 of a 21-day treatment cycle), the 
DLT occurred at 1.56 mg/m2/dose (3 subjects with Grade 3 diarrhea and 1 with 
peripheral sensory neuropathy).  Therefore, the MTD at this schedule was 1.3 
mg/m2/dose.  In a 35-day treatment cycle with 4 weekly doses of bortezomib 
monotherapy, the MTD was 1.6 mg/m2/dose and DLT included hypotension, tachycardia, 
diarrhea, and syncope. 
In phase 1 clinical studies, anti-tumor activity was reported in subjects with NHL, multiple 
myeloma, Waldenström’s Macroglobulinemia, squamous cell carcinoma of the 
nasopharynx, bronchoalveolar carcinoma of the lung, renal cell carcinoma, and prostate 
cancer. 
The safety and efficacy of bortezomib in subjects with multiple myeloma were 
investigated in two phase 2 clinical studies, studies M34100-024 (subjects with first 
relapse) (Jagannath et al, 2004) and M34100-025 (subjects with second or greater 
relapse and refractory to their last prior therapy) (Richardson et al, 2003).  In 
M34100-025, 202 heavily pre-treated subjects with refractory multiple myeloma after at 
least 2 previous treatments received bortezomib, 1.3 mg/m2 on Days 1, 4, 8, and 11 of a 
21-day treatment cycle. The European Group for Blood and Marrow Transplant (EBMT) 
response criteria, as described by Blade (Blade et al., 1998) were utilized to determine 
disease response.  CRs were observed in 4% of subjects, with an additional 6% of 
patients meeting all criteria for CR but having a positive immunofixation test.  PR or 
better was observed in 27% of subjects, and the overall response rate (CR, PR and 
 
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minor response [MR] combined) was 35%.  Seventy percent of subjects experienced 
stable disease or better.   
The phase 3 study (M34101-039) (Richardson et al, 2005), also referred to as the APEX 
study, was designed to determine whether bortezomib provided benefit (time to 
progression [TTP], response rate, and survival) to patients with relapsed or refractory 
MM relative to treatment with high-dose dexamethasone.  The study was also designed 
to determine the safety and tolerability of bortezomib relative to high-dose 
dexamethasone, and whether treatment with bortezomib was associated with superior 
clinical benefit and quality of life relative to high-dose dexamethasone. A total of 669 
patients were enrolled and 663 patients received study drug (bortezomib: 331; 
dexamethasone: 332).  Patients randomized to bortezomib received 1.3 mg/m2 I.V. push 
twice weekly on days 1, 4, 8, and 11 of a 3-week cycle for up to eight treatment cycles 
as induction therapy, followed by 1.3 mg/m2 bortezomib weekly on days 1, 8, 15, and 22 
of a 5-week cycle for three cycles as maintenance therapy. Patients randomized to 
dexamethasone received oral dexamethasone 40 mg once daily on days 1 to 4, 9 to 12, 
and 17 to 20 of a 5-week cycle for up to four treatment cycles as induction therapy, 
followed by dexamethasone 40 mg once daily on days 1 to 4 followed of a 4-week cycle 
for five cycles as maintenance therapy. The European Group for Blood and Marrow 
Transplant (EBMT) response criteria, as described by Blade (Blade et al., 1998) were 
utilized to determine disease response.  There was a 78% increase in TTP for the 
bortezomib arm. Median TTP was 6.2 months for the bortezomib arm and 3.5 months for 
the dexamethasone arm (P<.0001). CR (complete response) + PR (partial response) 
was 38% with bortezomib vs. 18% with dexamethasone (P<.0001). CR was 6% with 
bortezomib vs. <1% with dexamethasone (P<.0001). The CR + nCR rate was 13% with 
bortezomib vs. 2% with dexamethasone. In patients who had received only one prior line 
of treatment (bortezomib: 132; dexamethasone: 119), CR + PR was 45% with 
bortezomib vs. 26% with dexamethasone (P=.0035). With a median 8.3 months of 
follow-up, overall survival was significantly longer (P=.0013) for patients on the 
bortezomib arm vs. patients on the dexamethasone arm. The probability of survival at 
one year was 80% for the bortezomib arm vs. 66% for the dexamethasone arm, which 
represented a 41% decreased relative risk of death in the first year with bortezomib 
(P=.0005). In patients who had received only one prior line of treatment, the probability 
of survival at one year was 89% for the bortezomib arm vs. 72% for the dexamethasone 
arm, which represented a 61% decreased relative risk of death in the first year with 
bortezomib (P=.0098). Updated response rates and survival data were reported for 
M34101-039 (Richardson ASH, 2005). The updated CR (complete response) + PR 
(partial response) rate was 43% with bortezomib. The CR + nCR rate was 16% with 
bortezomib. With a median 22 months of follow-up, overall survival was significantly 
longer for patients on the BORTEZOMIB arm vs. patients on the dexamethasone arm. 
The median overall survival was 29.8 months (95% CI: 23.2, not estimable) for the 
bortezomib arm vs 23.7 months (95% CI: 18.7, 29.1) for the dexamethasone arm 
(hazard ratio = 0.77, P= 0.0272). The probability of survival at one year was 80% for the 
bortezomib arm vs. vs 67% for the dexamethasone arm (P=0.0002).    
1.2.6 Potential Risks of Bortezomib 
To date, more than 300,000 patients have been treated with bortezomib in both clinical 
trials investigating its use in hematological malignancies and solid tumors, and in 
patients who were treated with commercially available bortezomib. 
 
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Prescribing physicians and health care practitioners are referred to their locally approved 
product label for bortezomib regarding indications and usage, contraindications, 
warnings, and precautions. 
The known anticipated risks of bortezomib therapy are presented in Table 1 later in this 
protocol (see section with title DRUG INFORMATION).  These risks are grouped 
according to the combined frequency observed in an integrated analysis of AEs in 
sponsored clinical studies of single-agent bortezomib dosed at 1.3 mg/m2 twice weekly 
on a 21-day schedule, in patients with multiple myeloma and mantle cell lymphoma. 
1.3 
Other Agents 
G-CSF (Filgrastim) or Filgrastim G-CSF Biosimilar (ZarxioTM) 
 
Filgrastim is human granulocyte colony-stimulating factor (G-CSF) produced by recombinant 
DNA technology.  G-CSF stimulates the production, maturation, and activation of neutrophils 
and activates neutrophils to increase their migration and cytotoxicity.  Toxicities that are likely to 
occur include myalgias and medullary bone pain.  The bone pain can be generally controlled 
with non-narcotic analgesia.  Less likely side effects include fluid retention, pericardial effusion, 
local inflammation at the injection site and transient laboratory abnormalities including mild 
elevations in uric acid, lactic dehydrogenase (LDH), alkaline phosphatase, and leukocytosis.  
Rare but serious side effects include reported cases of spleen swelling resulting in splenic 
rupture, adult respiratory distress syndrome (ARDS), and allergic reactions. 
1.4 
Rationale 
The study plans to estimate the contamination rate of harvested stem cell products collected per 
standard of care approach and after using two doses of bortezomib as a part of in vivo purging 
method used in a prior published study (Abhyankar et al. 2013). 
 
Multiparametric flow cytometry will be used to measure minimal residual disease (MRD) in the 
harvested product of patients with multiple myeloma. 
 
Tumor contamination of the stem cell product is common in patients undergoing stem cell 
transplantation. Use of multi parametric flow cytometry in measuring low percentage of plasma 
cells contaminating harvested stem cell product has never been used. 
 
MFC is the standard of care in measuring MRD. Contamination rate of >0.01% with >100 
plasma cells per flow will be considered as positive for study purpose per guidelines (Rawstron 
AC et al, 2008). 
 
Bortezomib has been used as anti-myeloma drug during ex vivo purging. Role of bortezomib 
used prior to stem cell collection in lowering tumor contamination of the stem cell product is an 
intriguing concept that has not been tested.  
 
The rationale for bortezomib prior to the G-CSF is as follows: 
 
Bortezomib causes thrombocytopenia; similar to the manner in which cyclophosphamide is 
given followed by G-CSF for stem cell mobilization. Usually a cycle of bortezomib for myeloma 
therapy consists of 4 doses, but this may result in more significant drop in the platelet count. 
Low platelet counts may preclude adequate stem cell collection. The mobilization with 
bortezomib and G-CSF will be approximately 3 -4 weeks after completion of the initial therapy 
for the primary disease. 
 
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Patients meeting eligibility criteria and who give informed consent will be randomized to receive 
mobilization using bortezomib at 1.3 mg/m2 on day -11 and day -8 followed by G-CSF  at 10 
mcg/kg from day -4 to day -1  vs treatment with G-CSF 10 mcg/kg alone on days -4 through -1. 
For both groups stem cell collection will be done on day 0 (window: + 4 days) per standard of 
care regimen and protocol with processing of 4 - 6 blood volumes. Stem cell enumeration by 
flow cytometry will be done prior to the collection. The number of CD 34 positive cells (stem cell 
phenotype) / kg obtained each day of collection will be noted. G-CSF will be continued daily until 
adequate numbers of stem cells are obtained for the performance of a single autologous 
transplant (> 2.5 million CD 34 cells/kg of recipient weight). Subsequently the data for 
engraftment of neutrophils and platelets will be monitored as is routine for all patients 
undergoing autologous transplant. 
Multiparametric Flow Cytometry will be used to determine presence (>0.01%) or absence 
(<0.01%) of malignant plasma cells in the harvested products. A positive flow cytometry also will 
have to have >100 plasma cells per analysis. 
Recently the International Myeloma Working Group (IMWG) panel approved definitions of 
immunophenotypic CR and molecular CR to be incorporated into the IMWG criteria.  In addition, 
several studies have prospectively employed multiparameter flow cytometry (MFC) and shown 
improved outcome in MRD- negative patients after auto-HCT.   The European Myeloma 
Network (EMN) and ASBMT respectively developed a consensus for plasma cell enumeration, 
sample preparation, gating and immunophenotype for clonality assessment and guidelines for 
MRD assessment in patients with myeloma undergoing autologous stem cell transplantation 
(Rawstron AC et al, 2008 and Shah, Callander and Ganguly et al, 2015).   
1.5 
Correlative Studies 
 
None 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
2.1.1 To estimate the proportion of subjects with plasma cell contamination (defined as 
>0.01% and at least 100 cellular events) (Rawstron AC et al, 2008 and Shah, 
Callander and Ganguly et al, 2015) of harvested stem cell product by multi 
parametric flow cytometry from patients with myeloma undergoing autologous 
stem cell collection by standard of care mobilization using GCSF with or without 
Mozobil. 
2.1.2 To estimate the proportion of subjects with plasma cell contamination (defined as 
>0.01% and at least 100 cellular events) (Rawstron AC et al, 2008 and Shah, 
Callander and Ganguly et al, 2015) of harvested stem cell product by multi 
parametric flow cytometry from patients with myeloma undergoing autologous 
stem cell collection after two doses of bortezomib as in vivo purging plus 
standard of care using GCSF with or without Mozobil 
 
 
 
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2.2 
Secondary Objectives  
2.2.1 To estimate the proportion of subjects who have a successful collection of stem 
cells (> 2 million CD34 cells/Kg of body weight) for autologous transplant in both 
treatment groups. 
2.2.2 To estimate the percentage of CD 34 positive cells in peripheral blood on the 
days of collection 
3.0 
SUBJECT ELIGIBILITY 
3.1 
Inclusion Criteria 
Subjects must meet all of the inclusion criteria to participate in this study. 
3.1.1 Ability to understand, and the willingness to sign a written Informed Consent 
Form 
3.1.2 Diagnosis of multiple myeloma undergoing planned autologous stem cell 
transplantation 
3.1.3 Age ≥ 18 years 
3.1.4 KPS 70 or above, ECOG 0, 1 or 2 (APPENDIX A) 
3.1.5 Adequate organ and marrow function as defined below: 
- leukocytes 
 
 
≥ 3,000/mcL 
- absolute neutrophil count 
≥ 1,500/mcL 
- platelets  
 
 
≥ 100,000/mcL 
- total bilirubin 
 
 
within normal institutional limits  
NOTE: For this study, subjects with bilirubin 
levels > 1.5 ULN are excluded from this 
enrollment in this study. 
- AST (SGOT) 
 
 
≤ 2.5 X institutional upper limit of normal 
- ALT (SPGT) 
 
 
≤ 2.5 X institutional upper limit of normal 
3.1.6 Women of child-bearing potential and men with partners of child-bearing potential 
must agree to use adequate contraception (hormonal or barrier method of birth 
control; abstinence) prior to study entry, for the duration of study participation, 
and for 30 days following completion of therapy.  Should a woman or partner 
become pregnant or suspect she is pregnant while participating in this study, she 
should inform her treating physician and the investigator immediately. 
3.1.6.1 A woman of child-bearing potential is any female (regardless of sexual 
orientation, having undergone a tubal ligation, or remaining celibate by 
choice) who meets the following criteria: 
• 
Has not undergone a hysterectomy or bilateral oophorectomy; 
OR 
• 
Has not been naturally postmenopausal for at least 12 
consecutive months (i.e., has had menses at any time in the 
preceding 12 consecutive months) 
 
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3.2 
Exclusion Criteria 
Subjects meeting any of the exclusion criteria at baseline will be excluded from study 
participation. 
3.2.1 Current or anticipated use of other investigational agents. NOTE the following 
clarification for this study:   
Prohibited Concurrent Therapy: 
Participation in clinical trials with other investigational agents, not included in this 
trial, within 14 days of the start of this trial until 2 weeks after subject has 
received the last dose of bortezomib for mobilization. Hypersensitivity to 
bortezomib, boron or mannitol or G-CSF. 
3.2.2 Subject has received > 6 months of lenalidomide (Revlimid®) therapy prior to 
stem cell collection. 
3.2.3 Subject has known brain metastases. Presence of brain metastases should be 
excluded from this clinical trial because of poor prognosis and because patients 
often develop progressive neurologic dysfunction that would confound the 
evaluation of neurologic and other adverse events. 
3.2.4 Grade 3 or higher peripheral neuropathy  
3.2.5 Bilirubin levels > 1.5 ULNl 
3.2.6 Uncontrolled inter-current illness including, but not limited to 
• ongoing or active infection 
• symptomatic congestive heart failure 
• unstable angina pectoris 
• cardiac arrhythmia 
• psychiatric illness/social situations that would limit compliance with study 
requirements 
3.2.7 Pregnant or nursing: There is a potential for congenital abnormalities and for this 
regimen to harm nursing infants. 
4.0 
TREATMENT PLAN 
4.1 
Treatment Dosage and Administration 
Treatment will be administered only to eligible subjects under the supervision of the investigator 
or identified sub-investigator(s).  Subjects may be treated on an out-patient basis, if possible.   
 
Study treatment will be prepared under the supervision of a pharmacist, or appropriately 
qualified and trained personnel.  The amount (in mg) of drug to be administered will be 
determined based on body surface area.  Body surface area is to be calculated based on body 
weight using a standard nomogram (See APPENDIX B). 
 
Treatment Regimen Group A 
Standard of Care Stem cell collection without in-vivo purging with Bortezomib.  G-CSF and 
Mozobil used if needed. Physician discretion will be used to advise on the plan which may 
include the continuation of Mozobil.  The provider has the discretion of collection outside the 
algorithm included in Appendix C (See Appendices C and D). 
 
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Treatment Regimen Group B 
Bortezomib will be given SQ at 1.3 mg/m2 on day -11 and day -8 followed by GCSF 
given SQ on day -4 thru day -1 and continued until the collection is completed. 
Mozobil used if needed.  Physician discretion will be used to advise on the plan 
which may include the continuation of Mozobil.  The provider has the discretion of 
collection outside the algorithm included in Appendix C (See Appendices C and D). 
NOTES: 
1. There must be at least 72 hours between each dose of bortezomib. 
2. Multiparametric Flow Cytometry to be performed on samples for  
BOTH groups A AND B 
3. Stem cell collection can occur up to 12 days after the last injection of bortezomib, if 
needed, for participant safety and convenience. Window: Day 0 (+4 days). 
4.2 
Toxicities and Dosing Delays/Dose Modifications 
Before each drug dose, the subject will be evaluated for possible toxicities that may have 
occurred after the previous dose(s).  Toxicities are to be assessed according to the NCI 
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03.   
 
Subjects who experience bortezomib-related neuropathic pain and/or peripheral sensory 
neuropathy after the first injection are to be managed as standard of care. No dose reduction 
will be necessary for Grades 1 and 2 AEs. If patient complains of Grade 3 or 4 neuropathic pain 
that is treatment-emergent after first dose, patient will be withdrawn from the study. 
 
Time to engraftment will be monitored for all subjects.  If a subject has delayed or non-
engraftment of neutrophils and / or platelets the etiology of the delay will be determined and if 
believed to be possibly related, then the study will be halted. 
 
Subjects with mild hepatic impairment (bilirubin < 1.5 × ULN) do not require a starting dose 
adjustment.  Please note that subjects with bilirubin levels > 1.5 ULN are excluded from 
enrollment in this protocol. 
4.3 
Concomitant Medications/Treatments 
Investigators should consider using antiviral prophylaxis in subjects being treated with 
bortezomib. 
 
Prohibited Concurrent Therapy 
Participation in clinical trials with other investigational agents, not included in this trial, within 14 
days of the start of this trial until 2 weeks after subject has received the last dose of bortezomib 
for mobilization.   
 
Precautions and Restrictions 
It is not known what effects bortezomib has on human pregnancy or development of the embryo 
or fetus.  Therefore, female subjects participating in this study should avoid becoming pregnant, 
and male subjects should avoid impregnating a female partner.  Nonsterilized female subjects of 
reproductive age and male subjects should use effective methods of contraception through 
defined periods during and after study treatment as specified below. 
 
 
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Female subjects must meet 1 of the following: 
• 
Postmenopausal for at least 1 year before the screening visit, or 
• 
Surgically sterile, or 
• 
If they are of childbearing potential, agree to practice 2 effective methods of 
contraception from the time of signing the informed consent form through 30 days after 
the last dose of bortezomib, or agree to completely abstain from heterosexual 
intercourse. 
It is strongly recommended that at least 1 of these 2 methods be highly effective (see examples 
below). 
Highly effective methods 
Other effective methods (barrier methods) 
Intra-uterine devices (IUD) 
Latex condom 
Hormonal contraceptives (birth control 
pills/oral contraceptives, injectable 
contraceptives, contraceptive patches, or 
contraceptive implants) 
Diaphragm with spermicide 
Cervical cap 
Sponge 
If one of the highly effective methods cannot be used, using 2 effective methods at the 
same time is recommended.  
 
Male subjects, even if surgically sterilized (i.e., status post vasectomy) must agree to 1 of the 
following: 
• 
Practice effective barrier contraception during the entire study treatment period and 
through a minimum of 30 days after the last dose of study drug, or completely abstain 
from heterosexual intercourse. 
4.4 
 Duration of Therapy 
Subjects will be on study from the first study treatment and will complete the study when an 
adequate number of stem cells are harvested. Subjects will be followed as per standard 
transplant protocol until engraftment of neutrophils (first of 3 days when absolute neutrophil 
count is equal or greater than 500/uL) and platelets (day to platelet counts of more than 
20,000/uL). Usually this is accomplished by 30 days after transplantation.  Subjects will be 
followed for adverse events until 30 days post-collection. 
Participation in this clinical trial will not preclude enrollment in any other cooperative or 
consortium trial if subjects are in the standard of care arm. 
 
4.5 
Removal of Patients from Protocol Therapy 
Subjects will be informed that they have the right to withdraw from the study at any time for any 
reason, without prejudice to their medical care.  The investigator also has the right to withdraw, 
and in some cases is required to withdraw subjects from the study for any of the following 
reasons: 
• 
Intercurrent illness 
• 
Occurrence of an unacceptable adverse event 
• 
Subject request 
• 
Protocol violations 
 
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• 
Non-compliance 
• 
Administrative reasons 
• 
Failure to return for follow-up 
• 
General or specific changes in the subjects condition unacceptable for further treatment 
in the judgment of the investigator 
• 
Failure of mobilization following investigational treatment (see NOTE below for definition 
of failure of mobilization 
NOTE: Failure of mobilization is defined as a patient body failure to collect CD34+ cells at 
least 2 million/Kg after standard procedure of using G-CSF with or without Plerixafor. 
• 
At the time of withdrawal, the primary reason for a subject’s withdrawal from the study is 
to be recorded in the source documents.  The subject will be followed as per standard 
transplant protocol. 
5.0 
STUDY PROCEDURES 
5.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only after 
obtaining Informed Consent. Assessments performed for clinical indications (not exclusively to 
determine study eligibility) may be used for baseline values even if the studies were done before 
Informed Consent was obtained. 
 
All screening procedures must be performed within 30 days prior to registration unless 
otherwise stated. The screening procedures include: 
5.1.1 Informed Consent 
5.1.2 Medical history 
Complete medical, surgical and oncology history as well as history of infections 
are obtained at screening. Any changes from Screening (e.g. worsening severity 
or abnormal findings) are considered to be adverse events (AEs). 
5.1.3 Demographics 
Demographic profile will include date of birth, gender, race, ethnicity and zip 
code. 
5.1.4 Review subject eligibility criteria 
Review of eligibility criteria to ensure subject qualification for study entry. 
5.1.5 Review previous and concomitant medications 
All prior medication taken by the subject within 30 days before starting the study 
is to be recorded. At minimum, the start year of the medication should also be 
recorded. Concomitant medications taken by the subject during the study are to 
be recorded up until 30 days after the participant’s last protocol therapy 
(collection). If a reportable adverse event (see section with title Adverse Events) 
occurs within 30 days after the participant’s last protocol therapy (collection), 
recording of concomitant medications should continue until resolution of the 
adverse event. 
 
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5.1.6 Physical exam including vital signs, height and weight 
Vital signs (temperature, pulse, respirations, blood pressure), height, weight, and 
assessment of all major body systems 
5.1.7 Performance status 
Performance status evaluated prior to study entry. Specific criteria for assessing 
performance status can be found in APPENDIX A. 
5.1.8 Adverse event assessment 
Baseline assessment of subject status for determining adverse events. See 
section with title Adverse Events monitoring and reporting. 
5.1.9 Hematology 
Hematology to include hemoglobin (Hgb), platelets, total white blood cell count 
(WBC) and differential. 
5.1.10 Serum chemistries 
Comprehensive metabolic panel (CMP) to include: albumin, alkaline 
phosphatase, ALT, AST, BUN, creatinine, electrolytes (sodium, potassium, 
calcium, chloride, bicarbonate), glucose, and total bilirubin.  
5.1.11 Pregnancy test (for women of child bearing potential) 
5.2 
Procedures During Treatment 
• 
Day -1:  Hematology and CMP  
• 
Day 0:  Stem Cell Harvest / CD34 enumeration  
NOTES: 
1.  Multiparametric Flow Cytometry (MFC) analysis to be performed Day 0 only 
2. CD34 enumeration to be performed per standard of care (Every day of stem 
cell collection) 
3. Stem cell collection can occur up to 12 days after the last injection of 
bortezomib, if needed, for participant safety and convenience. Window: Day 0 
(+4 days).. 
5.3 
Follow-up Procedures 
Subjects will be followed after stem cell harvest usually within a week to start the high dose 
therapy and autologous stem cell transplantation. Thereafter subjects are followed per 
institutional transplant protocols. Study ends 30 days after the participant’s last protocol therapy 
(collection) for the purpose of AE reporting. 
 
 
 
 
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5.4 
Schedule of Events 
Bortezomib Along With G-CSF For Hematopoietic Stem Cell Mobilization In Subjects 
Undergoing Autologous Transplantation For Myeloma 
 
Study Calendar 
Screening/ 
Baseline 
Day -11 
Day -8 
Day -4 
Day -3 
Day -2 
Day -1 / 
EOT 
Day 0 
(+ 4 Days) 
Informed 
Consent 
X 
 
 
 
 
 
 
 
Medical History 
Demographics 
X 
 
 
 
 
 
 
 
Performance 
Status 
X 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
Concomitant 
Medication 
Review 
X 
 
 
 
 
 
 
 
CBC/Serum 
Chemistries 
X 
 
 
 
 
 
X 
 
Pregnancy Test 
X 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
Bortezomib 
 
X 
X 
 
 
 
 
 
GCSF 
 
 
 
X 
X 
X 
X 
X 
Stem Cell 
Collection / 
CD34 
Enumeration1 
 
 
 
 
 
 
 
X1 , 2 
 
Footnote: 
1. Multiparametric Flow Cytometry (MFC) analysis to be performed for both study groups 
on Day 0 only.  CD34 enumeration to be performed every day of stem cell collection. 
2. Stem cell collection can occur up to 12 days after the last injection of bortezomib, if 
needed, for participant safety and convenience. Window: Day 0 (+4 days). 
 
 
 
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5.5 
Removal of Subjects from Study Treatment and Study 
Subjects can be taken off the study treatment and/or study at any time at their own request, or 
they may be withdrawn at the discretion of the investigator for safety, behavioral or 
administrative reasons.  
 
The reason(s) for discontinuation will be documented and may include: 
5.5.1 Subject voluntarily withdraws from treatment (follow-up permitted);  
5.5.2 Subject withdraws consent (termination of treatment and follow-up); 
5.5.3 Subject is unable to comply with protocol requirements; 
5.5.4 Subject demonstrates disease progression (unless continued treatment with 
study drug is deemed appropriate at the discretion of the investigator); 
5.5.5 Subject experiences toxicity that makes continuation in the protocol unsafe; 
5.5.6 Treating physician judges continuation on the study would not be in the subject’s 
best interest; 
5.5.7 Subject becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event; see section with title Adverse Events); 
5.5.8 Development of second malignancy (except for basal cell carcinoma or 
squamous cell carcinoma of the skin) that requires treatment, which would 
interfere with this study; 
6.0 
ADVERSE EVENTS 
Text below in italics is verbatim from “Guidance for Industry and Investigators. Safety Reporting 
Requirements for INDs and BA/BE Studies”, issued December 2012 by U.S. Department of 
Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and 
Research, and Center for Biologics Evaluation and Research.  The guidance may be retrieved 
from:  
 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
CM227351.pdf?source=govdelivery 
6.1 
Definitions 
6.1.1 Adverse Event [21 CFR 312.32(a)]  
An adverse event means any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related. 
 
An adverse event (also referred to as an adverse experience) can be any unfavorable 
and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a drug, and does not imply any judgment about 
causality.  An adverse event can arise with any use of the drug (e.g., off-label use, use in 
combination with another drug) and with any route of administration, formulation, or 
dose, including an overdose. 
 
 
 
 
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HSC # STUDY00002857 
This study will use the descriptions and grading scales from Common Terminology 
Criteria for Adverse Events version 4.03 (CTCAE v4.03) for hematologic and non-
hematologic toxicities.  Detailed information may be found on the Cancer Therapy 
Evaluation Program (CTEP) website: 
 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
Information for adverse events, whether reported by the subject, directly observed, or 
detected by physical examination, laboratory test or other means, will be collected, 
recorded, followed and reported in the CRF as described in the following sections.  
 
Adverse events experienced by subjects will be collected and reported from time of 
signing of informed consent, throughout the study, and within 30 days of the last dose of 
protocol therapy (collection).  Subjects who experience an ongoing adverse event 
related to a study procedure and/or study medication beyond 30 days will continue to be 
contacted by a member of the study team until the event is resolved, stabilized, or 
determined to be irreversible by the principal investigator. Study subjects should also be 
instructed to report any new serious post-study event(s) that might reasonably be related 
to participation in this study. 
 
NOTE:  For this study, planned hospital admission will NOT be considered a Serious 
Adverse Event. 
 
Medical conditions/diseases, or cancer related symptoms present before starting study 
treatment are considered adverse events only if they worsen after initial screening. 
Adverse clinical events occurring before starting study drug but after signing the 
Informed Consent form are to be recorded in the subject’s medical record. All significant 
cancer-related symptoms that have occurred in the last 30 days prior to start of study 
drug must also be recorded in the medical record. 
 
Abnormal laboratory values or test results constitute adverse events only if they induce 
clinical signs or symptoms, or require therapy.  In this case they will be recorded in the 
medical record, along with the associated signs, symptoms or diagnosis. 
As far as possible, each adverse event will also be described by: 
• 
its duration (start and end dates), 
• 
grading of severity, 
• 
its relationship to the study drug, 
• 
the action(s) taken,  
• 
outcome. 
6.1.2 Suspected Adverse Reaction [21 CFR 312.32(a)] 
Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of safety reporting, 
‘reasonable possibility’ means there is evidence to suggest a causal relationship 
between the drug and the adverse event. A suspected adverse reaction implies a lesser 
degree of certainty about causality than adverse reaction, which means any adverse 
event caused by a drug.  
 
Suspected adverse reactions are the subset of all adverse events for which there is a 
reasonable possibility that the drug caused the event. Inherent in this definition, and in 
the requirement to report suspected adverse reactions, is the need for the sponsor to 
 
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HSC # STUDY00002857 
evaluate the available evidence and make a judgment about the likelihood that the drug 
actually caused the adverse event.  
 
Factors to be considered in assessing the relationship of the adverse event to study drug 
include: 
• 
The temporal sequence from study drug administration: The event should occur after 
the study drug is given.  The length of time from study drug exposure to event should 
be evaluated in the clinical context of the event. 
• 
Recovery on discontinuation (de-challenge), recurrence on reintroduction (re-
challenge): Subject’s response after drug discontinuation (de-challenge) or subject’s 
response after study drug re-introduction (re-challenge) should be considered in the 
view of the usual clinical course of the event in question. 
• 
Underlying, concomitant, intercurrent diseases: Each report should be evaluated in 
the context of the natural history and course of the disease being treated and any 
other disease the subject may have. 
• 
Concomitant medication or treatment: The other drugs the subject is taking or the 
treatment the subject receives should be examined to determine whether any of 
them may be suspected to cause the event in question. 
• 
The pharmacology and pharmacokinetics of the study drug: The pharmacokinetic 
properties (absorption, distribution, metabolism and excretion) of the test drug(s), 
coupled with the individual subject’s pharmacodynamics should be considered. 
 
Attribution is the relationship between an adverse event or serious adverse event and 
the study treatment. Attribution will be assigned as follows: 
• 
Unrelated - The AE is clearly NOT related to the study treatment. 
• 
Unlikely - The AE is doubtfully related to the study treatment. 
• 
Possible – The AE may be related to the study treatment.  
• 
Probable – The AE is likely related to the study treatment. 
• 
Definite – The AE is clearly related to the study treatment. 
6.1.3 Unexpected [21 CFR 312.32(a)] 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not 
listed in the investigator brochure or is not listed at the specificity or severity that has 
been observed; or, if an investigator brochure is not required or available, is not 
consistent with the risk information described in the general investigational plan or 
elsewhere in the current application… "Unexpected," as used in this definition, also 
refers to adverse events or suspected adverse reactions that are mentioned in the 
investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring 
with the Particular drug under investigation. 
 
This definition relies entirely on a listing of the adverse events or suspected adverse 
reactions in the investigator brochure…as the basis for determining whether newly 
acquired information generated from clinical trials or reported from other sources is 
unexpected. This means that events not listed for the Particular drug under investigation 
in the investigator brochure are considered “unexpected” and those listed are considered 
“expected.”  When new adverse event information is received, it is the sponsor’s 
responsibility to determine whether the event is “unexpected” for safety reporting 
purposes. 
 
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6.1.4 Serious [21 CFR 312.32(a)] 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or sponsor, it results in any of the following outcomes: Death, a 
life-threatening adverse event, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions, or a congenital anomaly/birth defect. Important medical 
events that may not result in death, be life-threatening, or require hospitalization may be 
considered serious when, based upon appropriate medical judgment, they may 
jeopardize the patient or patient and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 
6.1.5 Life-threatening 
An adverse event or suspected adverse reaction is considered “life-threatening” if, in the 
view of either the investigator or sponsor, its occurrence places the patient or patient at 
immediate risk of death. It does not include an adverse event or suspected adverse 
reaction that, had it occurred in a more severe form, might have caused death. 
6.2 
Reporting Requirements for Adverse Events 
6.2.1 Submitting Serious Adverse Events Reports to IRB 
For serious adverse events, the clinical research site will follow local IRB policies and 
procedures.  
 
NOTE:  For this study, planned hospital admission will NOT be considered a Serious 
Adverse Event. 
 
6.2.2 Study Investigator Notification of Adverse Events 
All expected and unexpected serious adverse events occurring after the subject has 
signed the Informed Consent and has started protocol treatment must be reported to the 
study principal investigator within 24 hours of becoming aware of the event: 
 
 
 
PI Name:  
Siddhartha Ganguly, MD 
 
 
Office Phone: 913-588-6030 
 
 
Fax:    
913-588-3996 
 
NOTE:  For this study, planned hospital admission will NOT be considered a Serious 
Adverse Event. 
 
6.2.3 DSMC Notification of SAEs 
All expected and unexpected serious adverse events occurring after the subject has 
signed the Informed Consent and has started protocol treatment must be reported by 
phone or email to the KUCC DSMC within 24 hours of becoming aware of the event to: 
 
 
 
 
Phone:   
913-588-4791 
 
 
Fax: 
 
913-945-4394 
 
 
Email: 
 
mpark@kumc.edu  
 
NOTE:  For this study, planned hospital admission will NOT be considered a Serious 
Adverse Event. 
 
 
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HSC # STUDY00002857 
 
A follow-up written report in the form of a MEDWATCH Form FDA 3500A is required 
within 5 days.  
6.2.4 Recording Adverse Events and Documentation in VELOS 
All expected and unexpected adverse events and serious adverse events occurring 
after the patient has signed the Informed Consent and has started protocol treatment 
must be fully recorded in the subject’s case record form. 
 
NOTE:  For this study, planned hospital admission will NOT be considered a Serious 
Adverse Event. 
 
All AEs and SAEs regardless of causality must be entered in the KU implementation of 
eVelos, also called the Comprehensive Research Information System (CRIS).  All SAEs 
regardless of causality must be entered into eVelos within 24 hours.  Unexpected and 
expected adverse events must be entered within 5 days and include:  new unexpected 
adverse events; worsening baseline conditions; clinically significant laboratory findings; 
disease-related signs and symptoms that were not present at baseline, and any event of 
findings that the Investigator feels is clinically significant. 
 
Documentation must be supported by an entry in the subject’s file.  A laboratory test 
abnormality considered clinically relevant, e.g., causing the subject to withdraw from the 
study, requiring treatment or causing apparent clinical manifestations, or judged relevant 
by the investigator, should be reported as an adverse event.  Each event should be 
described in detail along with start and stop dates, severity, relationship to 
investigational product, action taken and outcome. 
6.2.5 Reporting of Unexpected, Related SAEs for Concomitant Medications 
For concomitant medications, all unexpected, related serious adverse experiences will 
be forwarded to the product manufacturer by the investigator using the Voluntary 
MEDWATCH Form FDA 3500. 
6.2.6 Summary of Expedited Serious Adverse Event Reporting 
 
Relationship 
to Study Drug 
KUCC 
DSMC 
IRB 
PI 
Velos 
Unexpected SAE 
Related 
24 hrs 
Follow local 
IRB reporting 
requirements 
24 hrs 
24 hrs 
Unexpected SAE 
Not-related 
24 hrs 
24 hrs 
24 hrs 
Expected SAE 
Related 
24 hrs 
24 hrs 
24 hrs 
Expected SAE 
Not-related 
24 hrs 
24 hrs 
24 hrs 
7.0 
DRUG INFORMATION 
7.1 
Agent Bortezomib 
Please refer to Investigator’s Brochure for more comprehensive information. 
• 
Other names for the drug(s): Bortezomib 
• 
Classification - type of agent: Proteasome inhibitor 
• 
Mode of action: Anti Myeloma 
Velcade® (bortezomib) for injection is a sterile lyophilized powder for reconstitution and is 
supplied in vials containing bortezomib and mannitol at a 1:10 ratio.  For example, vials 
containing 3.5 mg of bortezomib contain 35 mg of mannitol.   
 
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HSC # STUDY00002857 
Storage and stability: Bortezomib will be supplied in vials as open-label stock.  Both the box 
label and vial label will fulfill all requirements specified by governing regulations Vials containing 
lyophilized bortezomib for injection should be stored according to the label requirements.  For 
the United States, store at USP Controlled Room Temperature which is 25ºC (77ºF); for Europe, 
do not store above 30ºC (86ºF); excursions permitted from 15 to 30ºC (59 to 86ºF).   To date, 
stability data indicate that the lyophilized drug product is stable for at least 18 months when 
stored under the recommended conditions. Stability studies are ongoing, and Millennium 
Pharmaceuticals, Inc. will notify the investigator should this information be revised during the 
conduct of the study. 
Preparation:  Bortezomib is cytotoxic.  As with all cytotoxic drugs, caution is required when 
preparing and handling bortezomib solutions.  Cytotoxic drugs should only be handled by staff 
specially trained in the safe handling of such preparations. The use of gloves and other 
appropriate protective clothing is recommended.  In case of skin contact, wash the affected area 
immediately and thoroughly with soap and water for at least 15 minutes.  If product contacts 
eye, immediately flush eye thoroughly with water for at least 15 minutes.  Always contact a 
physician after any form of body contact. All materials that have been used for preparation 
should be disposed of according to standard practices. A log must be kept of all disposed 
materials. 
Drug is available in sterile, single use vials containing 3.5 mg of bortezomib.  Each vial of 
bortezomib for injection should be reconstituted under a laminar flow biological cabinet (hood) 
within eight hours before dosing with 1.4 mL of normal (0.9%) saline, Sodium Chloride Injection 
USP, so that the reconstituted solution contains bortezomib at a concentration of 2.5 mg/mL.  
Prior to reconstitution the vials should remain in the cartons to protect them from light.  
Dissolution is completed in approximately 10 seconds.  The reconstituted solution is clear and 
colorless, with a final pH of 5 to 6.  Reconstituted bortezomib should be administered promptly 
and in no case more than 8 hours after reconstitution.   
• 
Route of administration for this study: Subcutaneous Injection (SQ) 
• 
Incompatibilities: NA 
• 
Availability: commercially available 
• 
Side effects:  
o To date, more than 300,000 patients have been treated with bortezomib in both 
clinical trials investigating its use in hematological malignancies and solid tumors, 
and in patients who were treated with commercially available bortezomib. 
o Prescribing physicians and health care practitioners are referred to their locally 
approved product label for bortezomib regarding Indications and Usage, 
Contraindications, Warnings, and Precautions. 
 
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2015-IIT-BMT-MM-AutoSCT 
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HSC # STUDY00002857 
The known anticipated risks of bortezomib therapy are presented in Table 1 below.  These 
risks are grouped according to the combined frequency observed in an integrated analysis 
of AEs in sponsored clinical studies of single-agent bortezomib dosed at 1.3 mg/m2 twice 
weekly on a 21-day schedule, in patients with multiple myeloma and mantle cell 
lymphoma. 
Table 1 
Known Anticipated Risks of Bortezomib by MedDRA System Organ 
Class, Observed Incidence, and Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
Blood and Lymphatic System Disorders 
Most common 
Thrombocytopenia*, anemia* 
Very common  
Neutropenia* 
Common  
Lymphopenia, pancytopenia*, leukopenia*, 
febrile neutropenia 
Cardiac Disorders 
Common  
Tachycardia, atrial fibrillation, palpitations, 
cardiac failure congestive* 
Uncommon 
Cardiogenic shock*, atrial flutter, cardiac 
tamponade*±, bradycardia, atrioventricular 
block complete, arrhythmia, cardiac arrest∗, 
cardiac failure, arrhythmia, pericardial effusion, 
pericarditis, pericardial disease±, 
cardiopulmonary failure± 
Ear and Labyrinth Disorders 
Uncommon 
Deafness, hearing impaired 
Eye Disorders 
Common  
Blurred vision, conjunctivitis, conjunctival 
hemorrhage  
Gastrointestinal Disorders 
Most common 
Constipation, diarrhea*, nausea, vomiting* 
Very common  
abdominal pain (excluding oral and throat) 
Common  
Dyspepsia, pharyngolaryngeal pain, 
gastroesophageal reflux, abdominal 
distension, gastritis, stomatitis, mouth 
ulceration, dysphagia, gastrointestinal 
hemorrhage*, lower gastrointestinal 
hemorrhage*± rectal hemorrhage 
 
 
 
 
 
 
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2015-IIT-BMT-MM-AutoSCT 
Principal Investigator:  Siddhartha Ganguly, MD 
HSC # STUDY00002857 
The known anticipated risks of bortezomib therapy are presented in Table 1 below.  These 
risks are grouped according to the combined frequency observed in an integrated analysis 
of AEs in sponsored clinical studies of single-agent bortezomib dosed at 1.3 mg/m2 twice 
weekly on a 21-day schedule, in patients with multiple myeloma and mantle cell 
lymphoma. 
Table 1 
Known Anticipated Risks of Bortezomib by MedDRA System Organ 
Class, Observed Incidence, and Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
 
Gastrointestinal Disorders (cont.) 
Uncommon 
 
 
Eructation, gastrointestinal pain, tongue 
ulceration, retching, upper gastrointestinal 
hemorrhage*, hematemesis*, oral mucosal 
petechiae, ileus paralytic*, ileus, odynophagia, 
enteritis, colitis, esophagitis, enterocolitis, 
diarrhea hemorrhagic, acute pancreatitis*, 
intestinal obstruction 
General Disorders and Administration Site Conditions 
Most common 
Fatigue, pyrexia 
Very common  
Chills, edema peripheral, asthenia 
Common  
Neuralgia, lethargy, malaise, chest pain, 
mucosal inflammation* 
Uncommon 
Injection site pain, injection site irritation, 
injection site phlebitis, general physical health 
deterioration*, catheter-related complication 
Hepatobiliary Disorders 
Uncommon 
Hyperbilirubinemia, hepatitis*± 
Immune System Disorders 
Uncommon 
Drug hypersensitivity, angioedema 
Infections and Infestations 
Very common  
Upper respiratory tract infection, 
nasopharyngitis, pneumonia*, Herpes zoster* 
Common  
Lower respiratory tract infection*, sinusitis, 
pharyngitis, oral candidiasis, urinary tract 
infection*, sepsis∗, bacteremia*, cellulitis∗, 
Herpes simplex, bronchitis, gastroenteritis*, 
infection 
 
 
 
 
 
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2015-IIT-BMT-MM-AutoSCT 
Principal Investigator:  Siddhartha Ganguly, MD 
HSC # STUDY00002857 
The known anticipated risks of bortezomib therapy are presented in Table 1 below.  These 
risks are grouped according to the combined frequency observed in an integrated analysis 
of AEs in sponsored clinical studies of single-agent bortezomib dosed at 1.3 mg/m2 twice 
weekly on a 21-day schedule, in patients with multiple myeloma and mantle cell 
lymphoma. 
Table 1 
Known Anticipated Risks of Bortezomib by MedDRA System Organ 
Class, Observed Incidence, and Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
Infections and Infestations (Cont.) 
Uncommon 
 
Septic shock*, catheter-related infection*, skin 
infection*, Herpes zoster disseminated*, lung 
infection∗, infusion site cellulitis, catheter site 
cellulitis, infusion site infection, urosepsis*, 
Aspergillosis*, tinea infection, Herpes zoster 
ophthalmic, Herpes simplex ophthalmic, 
meningoencephalitis herpetic±, varicella, 
empyema±, fungal esophagitis± 
Injury, Poisoning, and Procedural Complications  
Common 
Fall 
Uncommon 
Subdural hematoma 
Investigations 
Common  
Weight decreased, alanine aminotransferase 
(ALT) increased, aspartate aminotransferase 
(AST) increased, blood alkaline phosphatase 
increased, liver function test abnormal, blood 
creatinine increased* 
Uncommon 
Gamma-glutamyltransferase (GGT) increased, 
oxygen saturation decreased*, blood albumin 
decreased, ejection fraction decreased* 
Metabolism and Nutritional Disorders 
Very common  
Decreased appetite, anorexia, dehydration* 
Common  
Hyperglycemia, hypoglycemia, hyponatremia, 
hypokalemia, hypercalcemia* 
Musculoskeletal and Connective Tissue Disorders 
Very common  
Bone pain, myalgia, arthralgia, back pain 
Common 
Muscular weakness 
Uncommon 
Limb discomfort 
Neoplasms, Benign, Malignant, and Unspecified (including cysts and polyps) 
Uncommon 
Tumor lysis syndrome* 
 
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2 0 1 5 -II T-B M T -M M -A ut o S C T  
Pri n ci p al I n v e sti g at or:  Si d d h art h a G a n g ul y, M D  
H S C # S T U D Y 0 0 0 0 2 8 5 7  
T h e k n o w n a nti ci p at e d ri s k s of b ort e z o mi b t h er a p y ar e pr e s e nt e d i n T a bl e 1 b el o w.  T h e s e 
ri s k s ar e gr o u p e d a c c or di n g t o t h e c o m bi n e d fr e q u e n c y o b s er v e d i n a n i nt e gr at e d a n al y si s 
of A E s i n s p o n s or e d cli ni c al st u di e s of si n gl e -a g e nt b ort e z o mi b d o s e d at 1. 3 m g/ m 2  t wi c e 
w e e kl y o n a 2 1 -d a y s c h e d ul e, i n p ati e nt s wit h m ulti pl e m y el o m a a n d m a ntl e c ell 
l y m p h o m a. 
T a bl e 1 
K n o w n A nti ci p at e d Ri s k s of B ort e z o mi b b y M e d D R A S y st e m Or g a n 
Cl a s s, O b s er v e d I n ci d e n c e, a n d Pr ef err e d T er m  
S y st e m Or g a n Cl a s s  
O b s er v e d I n ci d e n c e  
Pr ef err e d T er m  
N er v o u s S y st e m Di s or d er s  
M o st c o m m o n  
P eri p h er al n e ur o p at h y (i n cl u di n g all pr ef err e d 
t er m s u n d er t h e M e d D R A Hi g h-l e v el t er m 
P eri p h er al n e ur o p at h y N E C)  
V er y c o m m o n  
P ar e st h e si a, di z zi n e s s e x cl u di n g v erti g o, 
h e a d a c h e  
C o m m o n  
P ol y n e ur o p at h y, s y n c o p e, d y s e st h e si a, 
d y s g e u si a, p o st h er a p e uti c n e ur al gi a  
U n c o m m o n  
C o n v ul si o n, l o s s of c o n s ci o u s n e s s, a g e u si a, 
e n c e p h al o p at h y, p ar al y si s*, a ut o n o mi c 
n e ur o p at h y, r e v er si bl e p o st eri or 
l e u k o e n c e p h al o p at h y s y n dr o m e±  p o st eri or 
r e v er si bl e e n c e p h al o p at h y s y n dr o m e 
 
P s y c hi atri c Di s or d er s  
V er y c o m m o n  
A n xi et y, i n s o m ni a  
C o m m o n  
C o nf u si o n al st at e  
U n c o m m o n  
D eliri u m  
 
R e n al a n d Uri n ar y Di s or d er s  
C o m m o n  
R e n al i m p air m e nt*, r e n al f ail ur e*, h e m at uri a  
U n c o m m o n  
Mi ct uriti o n di s or d er  
R e s pir at or y, T h or a ci c, a n d M e di a sti n al Di s or d er s  
V er y c o m m o n  
C o u g h, d y s p n e a  
C o m m o n  
E pi st a xi s, d y s p n e a e x erti o n al, pl e ur al 
eff u si o n*, r hi n orr h e a, h y p o xi a*, p ul m o n ar y 
e d e m a ∗ 
U n c o m m o n  
H e m o pt y si s*, a c ut e r e s pir at or y di str e s s 
s y n dr o m e*, r e s pir at or y f ail ur e*, p n e u m o niti s*, 
l u n g i nfiltr ati o n, p ul m o n ar y al v e ol ar 
h e m orr h a g e*, i nt er stiti al l u n g di s e a s e*, 
p ul m o n ar y h y p ert e n si o n*, pl e uri s y, pl e uriti c 
p ai n  
 
 
 P a g e 3 4  of 1 0 6  
2 0 1 5 -II T-B M T -M M -A ut o S C T  
Pr ot o c ol V er si o n 5 . 0 d at e d 1 1 -2 1 -2 0 1 6   
 


2015-IIT-BMT-MM-AutoSCT 
Principal Investigator:  Siddhartha Ganguly, MD 
HSC # STUDY00002857 
The known anticipated risks of bortezomib therapy are presented in Table 1 below.  These 
risks are grouped according to the combined frequency observed in an integrated analysis 
of AEs in sponsored clinical studies of single-agent bortezomib dosed at 1.3 mg/m2 twice 
weekly on a 21-day schedule, in patients with multiple myeloma and mantle cell 
lymphoma. 
Table 1 
Known Anticipated Risks of Bortezomib by MedDRA System Organ 
Class, Observed Incidence, and Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
 
Skin and Subcutaneous Tissue Disorders 
Very common 
Rash 
Common 
Rash pruritic, rash erythematous, urticaria, 
petechiae 
Uncommon 
Cutaneous vasculitis, leukocytoclastic 
vasculitis±  
Vascular Disorders 
Common 
Hypotension*, orthostatic hypotension 
Uncommon 
Cerebral hemorrhage* 
Source:  Velcade® (Bortezomib) Investigator’s Brochure Edition 15. 
Most common = ≥ 30%, Very common = 10% to 29%, Common = 1% to 9%, Uncommon = < 1%. 
* Fatal outcomes have been reported. 
± Indicates a Preferred term not listed in the source table, however the event is deemed medically important 
and so is included. 
Effective MedDRA update to version 14.0, the term ‘reversible posterior leukoencephalopathy syndrome’ 
updated to ‘posterior reversible encephalopathy syndrome (PRES)’. 
 
 
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Table 7-1    
Reports of Adverse Reactions From Post marketing Experience 
System Organ Class 
Preferred Term 
Observed 
Incidencea 
Blood and lymphatic system disorders 
 
 
Disseminated intravascular coagulation  
Rare 
Cardiac Disorders 
 
 
Atrioventricular block complete 
Rare 
 
Cardiac tamponade 
Rare 
Ear and labyrinth disorders 
 
 
Deafness bilateral 
Rare 
Eye Disorders 
 
 
Ophthalmic herpes 
            Optic neuropathy 
Blindness 
Rare 
Rare 
Rare 
Gastrointestinal Disorders 
 
 
Acute pancreatitis  
Rare 
 
Ischemic colitis 
Rare 
Hepatobiliary disorders 
 
 
Hepatitis 
Uncommon 
 
Liver failure 
Unknown 
Infections and infestations 
 
 
Herpes meningoencephalitis 
Rare 
 
Septic shock 
           Progressive multifocal leukoencephalopathy 
Rare 
Very Rare 
Immune System Disorders 
 
 
Angioedema 
Rare 
Nervous System Disorders 
 
 
Autonomic neuropathy 
Rare 
 
Dysautonomia 
Unknown 
 
Encephalopathy 
Rare 
Respiratory, thoracic and mediastinal disorders: 
 
 
Acute diffuse infiltrative pulmonary diseaseb  
Rare 
 
Acute respiratory distress syndrome (ARDS) 
Rare 
 
Interstitial pneumonia 
Rare 
 
 
 
 
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HSC # STUDY00002857 
Table 7-1    
Reports of Adverse Reactions From Post marketing Experience 
System Organ Class 
Preferred Term 
Observed 
Incidencea 
 
Respiratory, thoracic and mediastinal disorders (Cont.): 
Lung infiltration 
Rare 
 
Pneumonitis 
Rare 
 
Pulmonary hypertension 
Rare 
Skin and subcutaneous system disorders 
 
 
Acute febrile neutrophilic dermatosis 
Unknown 
 
Toxic epidermal necrolysis 
Unknown 
Source:  Velcade® (Bortezomib) Investigator’s Brochure Edition 15. Addendum 1. 
a Incidence is assigned using the following convention:  very common (≥ 1/10); common (≥ 1/100 and 
< 1/10); uncommon (≥ 1/1000 and < 1/100); rare (≥ 1/10,000 and < 1/1000 ); very rare (< 1/10,000, 
including isolated reports). 
b Acute diffuse infiltrative pulmonary disease is a MedDRA Lower Level Term which corresponds to a 
Preferred Term of Interstitial lung disease. 
Other medical events of interest that are considered not causally related to bortezomib include hepatic 
failure and QT prolongation.  Fatal outcomes have been reported. 
Women of childbearing potential should avoid becoming pregnant while being treated with bortezomib.  
Genotoxicity testing has shown that bortezomib is negative in the in vitro Ames assay and in the in vivo 
micronucleus assay, but it is a clastogen in the in vitro chromosomal aberration assay.   
Additional details on the potential risks of bortezomib may be found in the current Investigator’s 
Brochure. 
• 
Nursing implications: SQ injection on Days -11 and -8 at KUCC BMT treatment center 
 
7.1.1 
Return and Retention of Study Drug 
Bortezomib is commercially available and available through the University of Kansas Hospital 
Pharmacy 
7.1.2 
Drug Accountability/Subject Compliance 
All drugs will be administered to eligible subjects under the supervision of the investigator or 
identified sub-investigator(s).   
 
 
 
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HSC # STUDY00002857 
8.0 
MEASUREMENT OF EFFECT 
8.1 
Antitumor Effect- Hematologic Tumors 
Positive or negative by flow cytometry of the stem cell harvest product 
8.2 
Safety / Tolerability  
Analyses will be performed for all subjects having received study therapy. The study will use the 
CTCAE version 4.03: 
 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
9.0 
DATA AND SAFETY MONITORING 
9.1 
Oversight and Monitoring Plan 
The Data Safety Monitoring Committee (DSMC) of the KUCC is responsible for monitoring 
subject safety for this trial.  
The Data Safety Monitoring Committee will include at least two external members. These 
individuals will not have any appointment, volunteer or otherwise, or membership with either the 
KU Cancer Center or University of Kansas Medical Center. 
 
The external DSMC members have been identified as: 
 
Rony Aboujawde, MD 
Mosaic Life Care, St Joseph, MO 
Rony.abou-jawde@mymlc.com 
 
Dr. Leo Shunyakov 
Central Cancer Care, Bolivar, MO 
cancercare@gmail.com 
 
These members will serve as ad-hoc voting members for this protocol. This protocol will be 
reviewed at the beginning of each committee meeting and these external members will attend 
the meetings by phone. 
 
The DSMC is responsible for: 
• 
Review of all clinical trials conducted by the KUCC for progress and safety  
• 
Review of all adverse events requiring expedited reporting as defined in the protocol  
• 
Submission of recommendations for corrective action to the PI and the Deputy 
Director of the KUCC or designee 
• 
Notification of external sites participating in multi-institution clinical trials coordinated 
by the KUCC of adverse events requiring expedited reporting and subsequent 
committee recommendations for study modifications.  
• 
The University of Kansas Cancer Center Quality Assurance Unit will audit study 
activity and reported data on at least a quarterly basis for any collaborating sites 
9.2 
Safety Review and Oversight Requirements 
a) Serious Adverse Event  
Serious adverse events that require expedited reporting will be reviewed by the DSMC 
Chair or designee who will determine if immediate action is required. If determined to be 
 
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necessary by the DSMC, all participating sites will be notified of the event and of any 
resulting action within one working day of this determination.  
b) Review of Adverse Event Rates  
Once per month, adverse event rates will be monitored by the DSMC Coordinator. If any 
study has had 2 or more of the same SAE reported within one month, or more than 6 of 
the same SAE in 6 months, the DSMC will review summaries of SAEs, and discuss 
events in detail with the PI. The DSMC chair or designee determines whether further 
action is required.  The DSMC Coordinator ensures that collaborating investigators and 
IRBs for all participating sites are notified of any resulting action. 
 
c) Study Safety and Progress – Quarterly Review 
An overall assessment of toxicities as described in the protocol is reviewed at quarterly 
DSMC meetings.  This review enables DSMC members to assess whether significant 
risks are occurring that would warrant study suspension/closure or protocol amendment. 
9.3 
Data Safety Monitoring Committee (DSMC) Reporting 
 
All Data Safety Monitoring Committee (DSMC) reports, including those recommending 
continuation of the study, are forwarded to the KUMC Human Subjects Committee (HSC).  Any 
DSMC recommendations for modifications to the trial are forwarded to the Deputy Director of 
KUCC or their designee. The PI is notified of this recommendation in order that he/she may alert 
all investigators about the potential action. At this time the PI may submit to the Deputy Director 
of KUCC or their designee additional information that could affect the committee’s decision. The 
Deputy Director of the KUCC or their designee will notify the PI if he/she concurs with the 
DSMC’s recommendation, including suspension or closure. The PI will notify all investigators 
involved with the study, the IRB, the sponsor and the funding agency and provide written 
documentation of these notifications to the DSMC. 
 
NOTE:  The Data Safety Monitoring Committee will include at least two external members. 
These individuals will not have any appointment, volunteer or otherwise, or membership with 
either the KU Cancer Center or University of Kansas Medical Center. 
 
The external DSMC members have been identified as: 
 
Rony Aboujawde, MD 
Mosaic Life Care, St Joseph, MO 
Rony.abou-jawde@mymlc.com 
 
Dr. Leo Shunyakov 
Central Cancer Care, Bolivar, MO 
cancercare@gmail.com 
 
These members will serve as ad-hoc voting members for this protocol. This protocol will be 
reviewed at the beginning of each committee meeting and these external members will attend 
the meetings by phone. 
 
 
 
 
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Principal Investigator:  Siddhartha Ganguly, MD 
HSC # STUDY00002857 
10.0 
REGULATORY CONSIDERATIONS 
10.1 
Protocol Review and Amendments 
This protocol, the proposed Informed Consent and all forms of participant information related to 
the study (e.g., advertisements used to recruit participants) and any other necessary documents 
must be submitted, reviewed and approved by a properly constituted IRB governing each study 
location.  
 
Any changes made to the protocol must be submitted as amendments and must be approved 
by the IRB prior to implementation. Any changes in study conduct must be reported to the IRB. 
The Principal Investigator will disseminate protocol amendment information to all participating 
investigators.  
 
All decisions of the IRB concerning the conduct of the study must be made in writing. 
10.2 
Informed Consent 
All participants must be provided a consent form describing this study and providing sufficient 
information for participants to make an informed decision about their participation in this study. 
The formal consent of a participant, using the IRB approved consent form, must be obtained 
before the participant is involved in any study-related procedure. The consent form must be 
signed and dated by the participant or the participant’s legally authorized representative, and by 
the person obtaining the consent. The participant must be given a copy of the signed and dated 
consent document. The original signed copy of the consent document must be retained in the 
medical record or research file. 
10.3 
Ethics and Good Clinical Practice (GCP) 
This study is to be conducted according to the following considerations, which represent good 
and sound research practice: 
 
1. ICH Consolidated Good Clinical Practice: Guidelines (E6) 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida
nces/UCM073122.pdf 
2. US Code of Federal Regulations (CFR) governing clinical study conduct and 
ethical principles that have their origin in the Declaration of Helsinki 
http://www.ecfr.gov/cgi-bin/text-
idx?SID=3ee286332416f26a91d9e6d786a604ab&mc=true&tpl=/ecfrbrowse/Title21/21ta
b_02.tpl 
 
With attention to the following specific regulations: 
 
• Title 21 Part 50 – Protection of Human Patients  
• Title 21 Part 56 – Institutional Review Boards  
• Title 21 Part 312 – Investigational New Drug Application Responsibilities of 
Sponsors and Investigators  
3. State laws 
4. Institutional research policies and procedures  
http://policy.ku.edu/research/human-subjects 
 
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AND 
 
http://www.kumc.edu/human-research-protection-program/institutional-review-
board/policies-and-regulations.html 
 
It is understood that deviations from the protocol should be avoided, except when necessary to 
eliminate an immediate hazard to a research participant. In such case, the deviation must be 
reported to the IRB according to the local reporting policy.  
 
11.0 
REGISTRATION PROCEDURES 
11.1 
General Guidelines for KUCC and Other Participating Organizations 
Institutions will register eligible subjects through the KUCC Clinical Research Office central 
registration process.  Registration must occur prior to the initiation of therapy, with treatment 
assignment (for both randomized and non-randomized studies) provided by KUCC.  Any subject 
not registered to the protocol before treatment begins will be considered ineligible and 
registration will be denied.  
 
The completed source documentation provided for eligibility verification and registration must be 
kept in the subject binder for monitoring purposes and documentation of subject eligibility. 
 
Issues that would cause treatment delays should be discussed with the Principal 
Investigator. If a subject does not receive protocol therapy following registration, notify 
the KU Cancer Center Project Director or designee so that the subject’s status can be 
changed in the CRIS system. 
11.2 
Registration Process for KUCC and Other Participating Centers 
The Coordinating Center (KUCC), specifically the Project Director or designee is 
accessible for registration Monday through Friday from 8:00 AM to 5:00 PM Central 
Time.  
 
The registration procedures are as follows: 
1. Obtain written informed consent from the subject prior to the performance of any 
study related procedures or assessments.  NOTE – if tests required at screening 
were performed as part of standard of care prior to signing consent for this study, 
the results from those tests are allowed in this study IF those tests were 
performed within the timeframe listed in the section of this protocol with title 
Screening/Baseline Procedures. 
 
2. Complete the appropriate baseline demographic information in CRIS and any 
required registration forms using the eligibility assessment documented in the 
subject’s medical/research record.  To be eligible for registration to the study, the 
subject must meet each inclusion and none of the exclusion criteria listed in this 
protocol. 
 
 
 
 
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3. Fax or send via e-mail the eligibility checklist (checklist to be created from each 
version of this protocol and maintained by study project director and clinical 
team) and all pages of the consent form to the appropriate KUMC study project 
director (see below).  
 
Fax Number:  913-588-8279 
 
Project Director:  Kelly Daniels  -  kdaniels2@kumc.edu 
Associate Project Director:  Renee Sol  -  rsol@kumc.edu  
 
4. The KU Project Director or designee will a) validate eligibility and b) register the 
subject on the study, assigning the subject to a treatment group 
 
5. The KU Project Director or designee will send an email confirmation of the 
registration to the person initiating the registration immediately following the 
registration. 
12.0 
STUDY MANAGEMENT 
12.1 
Investigator Files and Retention of Documents 
The investigator must prepare and maintain adequate and accurate case histories designed to 
record all observations and other data pertinent to the study for each research participant. This 
information enables the study to be fully documented and the study data to be subsequently 
verified. Original source documents supporting entries in the case report forms include but are 
not limited to hospital records and clinic charts, laboratory and pharmacy records, ECG, signed 
ICFs, subject diaries and pathology reports. All study-related documents must be retained for 
the maximum period required by applicable federal regulations and guidelines or institutional 
policies.  
12.2 
Case Report Forms 
Electronic case report forms (eCRFs) will be completed for each subject enrolled and entered 
into eVelos.  All eCRFs will be customized by the KU Biostatistics Department for this study, 
and will be complete and accurate. The medical chart and any other clinical worksheets, 
procedural reports, etc. are the source of verification of the data captured into the study 
database.   
12.3 
Study Monitoring 
Data collection and analysis will be independently reviewed by a researcher with suitable 
expertise designated by the Associate Vice Chancellor for Research. The results of that review 
will be reported to the Associate Vice Chancellor for Research. 
 
The study will be monitored at appropriate intervals to assure compliance to GCP and to assess 
the data quality and study integrity. The frequency of monitoring may vary depending on 
enrollment rate and the quality of data collected. 
 
The investigator and staff are expected to cooperate and provide all relevant study 
documentation in detail at each site visit on request for review. The study monitor will have 
direct access to source data for data verification. Data verification will be conducted by 
comparing the data entered into the CRFs with source data. 
 
 
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HSC # STUDY00002857 
13.0 
STATISTICAL CONSIDERATIONS 
13.1 
Study Design/Study Endpoints 
This is an open label, randomized study intended to: 
 
• 
Estimate the proportion of subjects with positive plasma cell contamination 
(expressed as percentage as mentioned in the consensus guidelines; >0.01% 
and at least 100 cellular events) (Rawstron AC et al, 2008 and Shah, Callander 
and Ganguly et al, 2015) of harvested stem cell product by multi parametric flow 
cytometry from patients with myeloma undergoing autologous stem cell collection 
1) by standard of care mobilization using GCSF with or without Mozobil and 2) 
after two doses of bortezomib as in vivo purging plus standard of care using 
GCSF with or without Mozobil. 
• 
Estimate the proportion of subjects who have a successful collection of stem 
cells (> 2 million CD34 cells/Kg of body weight) for autologous transplant in both 
treatment groups. 
• 
Estimate the percentage of CD 34 positive cells in circulating peripheral blood as 
a measure of mobilization on the days of collection 
13.2 
Sample Size and Accrual 
• 
N=100 
• 
Patients will be randomized using sequential assignment of predetermined block 
randomized 1:1 treatment assignments provided by the study statistician prior to 
activation. 
• 
Dichotomous yes or no response on tumor contamination of products in two study 
arms 
 
Justification for Sample Size 
 
YEAR 
Number of Stem Cell 
Harvests 
Number of Autologous 
Transplantations 
2011 
60 
71 
2012 
78 
94 
2013 
100 
102 
2014 
87 
89 
 
NOTE:  An average of 5-7% patients failed to collect with or without Mozobil historically over 
the last four years at the KU BMT program. 
 
With 50 evaluable products in each treatment arm, 95% confidence interval width for the 
proportions of contaminated products will be no greater than 29% using the exact binomial 
method.   Contamination is defined as >0.01% cancer cells and at least 100 cellular events 
(Rawstron AC et al, 2008 and Shah, Callander and Ganguly et al, 2015).  
 
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13.3 
Data Analyses Plans 
13.3.1 Descriptive statistics, such as means, standard deviations, frequencies, and 
proportions, will be generated for subject demographics and clinical 
characteristics, including disease and transplant-related factors.   Estimates and 
95% exact binomial confidence intervals will be calculated for the primary 
endpoint, the proportion of subjects in which the leukapheresis product was 
contaminated with tumor cells, within each treatment group. These estimates will 
provide critical information for designing future studies formally testing the 
effectiveness of this therapy.  Attrition is not expected since the primary endpoint 
is an assessment of the leukapheresis product.  All leukapheresis products are 
expected to be evaluable for contamination.  Should a product NOT be 
evaluable, it would conservatively be considered contaminated in the primary 
analysis.  Similar methods will be used to estimate and provide 95% exact 
binomial confidence intervals for the proportion of subjects who experience 
successful extraction of product for transplantation.   Summary statistics will be 
provided for proportion of subjects who would have adequate number of CD 34 
cells collected and the percentage of CD34 positive cells in peripheral blood on 
the days of collection.  
13.3.2 Stopping Rules 
Data collection and analysis will be independently reviewed by a researcher with 
suitable expertise designated by the Associate Vice Chancellor for Research. 
The results of that review will be reported to the Associate Vice Chancellor for 
Research. 
 
In addition, as a routine and normal SOC for KU BMT Stem Cell lab, ongoing QA 
meetings are held and all patient collection data are reviewed in an ongoing 
basis per FACT guidelines (Foundation for the Accreditation of Cellular Therapy). 
KU BMT stem cell first week collection success over last 4 years had been 93%. 
Hence, if the collection rate falls below that i.e. if 7% or more patients fail to 
collect (as defined by failure to at least collect 2 million/Kg CD 34 + cells with 
GCSF and with or without Plerixafor mobilization procedure); root cause analysis 
is done by the team (SOC-per QA team). This trial stopping rule will be no 
exception to that policy as well.  
 
Based on a binomial probability calculation, after 25 patients (half way through) 
are enrolled in each arm, we will calculate the collection rate and if more than 4 
patients fail to mobilize in any arm, the trial will be stopped and further analysis 
and SOC root cause analysis would be done. Trial will only be resumed if it is 
determined that the failure to collect is due to the other factors and not due to 
bortezomib usage. The QA committee is entrusted with this analysis which is a 
requirement for FACT (Foundation for the Accreditation of Cellular Therapy). 
 
NOTE:  Failure of mobilization is defined as a patient’s body’s failure to collect 
CD34+ cells at least 2 million/Kg after standard procedure of using G-CSF 
with or without Plerixafor. 
13.4 
Interim Analysis and Data Supervision 
Data collection and analysis will be independently reviewed by a researcher with suitable 
expertise designated by the Associate Vice Chancellor for Research. The results of that 
review will be reported to the Associate Vice Chancellor for Research. 
 
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In addition, as a routine and normal Standard of Care (SOC) process for KU BMT Stem 
Cell Lab, ongoing QA meetings are held, data is collected and analyzed for reporting 
purposes independent of any clinical trial. The data collected as a part of this trial will be 
entered by the trial data coordinator, and during the interim analysis will be available for 
analysis by the KU Biostatistics Department.  Concurrently, data from the KU BMT Stem 
Cell Collection Lab will be made available to the KU Biostatistics Department, in order to 
match the results and document congruity. The AEs and SAEs are posted in the CRIS 
environment of KUCC website. AEs and SAEs are also noted by the KU BMT Stem Cell 
lab. Any discrepancy will be addressed during the interim analysis or at any time if 
deemed necessary by the DSMC, BMT QI committee or the KU Biostatistics 
Department. In essence, three independent groups will have access to the data, i.e. 
DSMC, KU BMT QI committee and the KU Biostatistics Department. Any discrepancy 
will be addressed immediately and will be brought to IRB attention. 
 
 
 
 
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14.0 
REFERENCES 
 
1. Abhyankar S, DeJarnette S, Merkel D, Bunch J, Daniels K, Aljitawi O, Ganguly S, McGuirk 
J. Biol Blood and marrow Transplantation. 2013; 19 (suppl 2): S178 
2. Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD et al. 
Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 
1999; 59 (11):2615-22. 
3. Attal, M., Harousseau, J. L., Stoppa, A. M., Sotto, J. J., Fuzibet, J. G., Rossi, J. F., Bataille, 
R. (1996). A prospective, randomized trial of autologous bone marrow transplantation and 
chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med, 
335(2), 91-97. doi: 10.1056/nejm199607113350204 
4. Barlogie, B., Jagannath, S., Vesole, D. H., Naucke, S., Cheson, B., Mattox, S., Tricot, G. 
(1997). Superiority of tandem autologous transplantation over standard therapy for 
previously untreated multiple myeloma. Blood, 89(3), 789-793.  
5. Blade J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G et al. Criteria for 
evaluating disease response and progression in patients with multiple myeloma treated by 
high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of 
the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol 1998; 102 
(5):1115-23. 
6. Child, J. A., Morgan, G. J., Davies, F. E., Owen, R. G., Bell, S. E., Hawkins, K., Selby, P. J. 
(2003). High-dose chemotherapy with hematopoietic stem-cell rescue for multiple 
myeloma. N Engl J Med, 348(19), 1875-1883. doi: 10.1056/NEJMoa022340 
7. Cusack JC, Jr., Liu R, Houston M, Abendroth K, Elliott PJ, Adams J et al. Enhanced 
chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic 
nuclear factor-kappaB inhibition. Cancer Res 2001; 61 (9):3535-40. 
8. Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F et al. Randomized 
phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-
small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. 
The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 2000; 18 (12):2354-
62. 
9. Fossella F. Docetaxel + Cisplatin (DC) and Docetaxel + Carboplatin (DCb) vs Vinorelbine + 
Cisplatin (VC) in chemotherapy-naïve patients with advanced and metastatic non-small cell 
lung cancer (NSCLC): Results of a multicenter, randomized phase III study. European 
Journal of Cancer, European Cancer Conference, ECCO 11, 2001; Lisbon, Portugal. 
37(suppl 6):S154. Abstract 562  
10. Gertz, M. A., Witzig, T. E., Pineda, A. A., Greipp, P. R., Kyle, R. A., & Litzow, M. R. (1997) 
Monoclonal plasma cells in the blood stem cell harvest from patients with multiple myeloma 
are associated with shortened relapse-free survival after transplantation. Bone Marrow 
Transplant, 19(4), 337-342. doi: 10.1038/sj.bmt.1700670 
11. Gibson, J., Ho, P. J., & Joshua, D. (2004). Evolving transplant options for multiple 
myeloma: autologous and nonmyeloablative allogenic. Transplant Proc, 36(8), 2501-2503. 
doi: 10.1016/j.transproceed.2004.06.033 
12. Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, Adams J et al. The 
proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug 
resistance in human multiple myeloma cells. Cancer Res 2001; 61 (7):3071-6. 
13. Jagannath S, Barlogie B, Berenson J et al. A Phase 2 study of two doses of bortezomib in 
relapsed or refractory myeloma. Br J Haematol 2004: 127:165-172 
 
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14. Lapidot T, Petit I. Current understanding of stem cell mobilization: the roles of chemokines, 
proteolytic enzymes, adhesion molecules, cytokines, and stromal cells. Exp Hematol. 
2002;30:973–981 
15.  LeBlanc R, Catley LP, Hideshima T, Lentzsch S, Mitsiades CS, Mitsiades N et al. 
Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs 
survival in a murine model. Cancer Res 2002; 62 (17):4996-5000.  
16. Levesque J-P, Liu F, Simmons PJ, et al. Characterization of hematopoietic progenitor 
mobilization in protease-deficient mice. Blood. 2004;104:65–72.[ 
17. Lightcap ES, McCormack TA, Pien CS, Chau V, Adams J, Elliott PJ. Proteasome inhibition 
measurements: clinical application. Clin Chem 2000; 46 (5):673-83. 
18. Mariette, X., Fermand, J. P., & Brouet, J. C. (1994). Myeloma cell contamination of 
peripheral blood stem cell grafts in patients with multiple myeloma treated by high-dose 
therapy. Bone Marrow Transplant, 14(1), 47-50.  
19. McConkey DJ, Pettaway C, Elliott P, Adam J, Papandreou C, Herrmann JL et al. The 
proteasome as a new drug target in metastatic prostate cancer. 7th Annual Genitourinary 
Oncology Conference, 1999; Houston, TX. Abstract 
20. Metzler I, Krebbel H, Hecht M et al. Bortezomib inhibits human osteoclastogeneis. 
Leukemia 2007; 21; 2025-2034 
21. Miklos DB, Logan AC, Ryan CE, Schoenrock K, Garcia M, Klinger M, Kong K, Faham M, 
Negrin R and Benjamin JE.  Assessment of Tumor Depletion Following Tandem 
Mobilization in Multiple Myeloma Patients Receiving Autologous Stem Cell Transplantation. 
December 06, 2014; 124 (21), Abstract 2010 
22. Oakervee H, Popat R, Cavenagh J. Use of bortezomib as induction therapy prior to stem 
cell transplantation in front line treatment of multiple myeloma: Impact on stem cell 
harvesting and engraftment.  Leuk & lymph Oct 2007; 48(10):1910-1921 
23. Orlowski RZ, Stinchcombe TE, Mitchell BS, Shea TC, Baldwin AS, Stahl S et al. Phase I 
Trial of the Proteasome Inhibitor PS-341 in Patients with Refractory Hematologic 
Malignancies. J Clin Oncol 2002; 20 (22):4420-7. 
24. Paiva B, Vidriales MB, Cervero J, Mateo G, Perez JJ, Montalban MA, et al. Multiparameter 
flow cytometric remission is the most relevant prognostic factor for multiple myeloma 
patients who undergo autologous stem cell transplantation. Blood. 2008;112:4017-23. 
25. Papandreou C, Daliani D, Millikan RE, Tu S, Pagliaro L, Adam J. Phase I Study of 
Intravenous (I.V.) Proteasome Inhibitor PS-341 in Patients (Pts) with Advanced 
Malignancies. Proc Am Soc Clin Oncol, 2001. Abstract 340  
26. Papayannopoulou T. Current mechanistic scenarios in hematopoietic stem/progenitor cell 
mobilization. Blood. 2004;103:1580–1585  
27. Papayannopoulou T, and David T. Scadden Stem-cell ecology and stem cells in motion 
Blood, 15 April 2008, Vol. 111, No. 8, pp. 3923-3930. 
28. Pink MM, Pien CS, Ona VO, Worland P, Adams J, Kauffman MG. PS-341 enhances 
chemotherapeutic effect in human xenograft models. Proc Am Assoc Cancer Res, 2002; 
San Francisco, CA. Abstract 787 
29. Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, et al. 
Consensus recommendations for the uniform reporting of clinical trials: report of the 
International Myeloma Workshop Consensus Panel 1. Blood. 2011;117:4691-5. 
30. Rawstron AC, Orfao A, Beksac M, Bezdickova L, Brooimans RA, Bumbea H, et al. Report 
of the European Myeloma Network on multiparametric flow cytometry in multiple myeloma 
and related disorders. Haematologica. 2008;93:431-8. 
 
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31. Rawstron AC, Child JA, de Tute RM, Davies FE, Gregory WM, Bell SE, et al. Minimal 
residual disease assessed by multiparameter flow cytometry in multiple myeloma: impact 
on outcome in the Medical Research Council Myeloma IX Study. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology. 2013;31:2540-7. 
32. Richardson PG, Barlogie B, Berenson J et al. A Phase II study of Bortezomib in Relapsed, 
Refractory Myeloma. N Engl J Med 2003; 348:2609-2617 
33. Richardson PG, et al., Bortezomib or High-Dose Dexamethasone for Relapsed Multiple 
Myeloma. N Engl J Med 2005; 352:2487-98.  
34. Richardson et al, Bortezomib Continues to Demonstrate Superior Efficacy Compared With 
High-Dose Dexamethasone in Relapsed Multiple Myeloma: Updated Results of the APEX 
Trial. Blood, 2005; 106: Abstract 2547. 
35. Shah N, Callander N, Ganguly S, Gul Z, Hamadani M, Costa L, Sengsayadeth S, Abidi M, 
Hari P, Mohty M, Chen YB, Koreth J, Landau H, Lazarus H, Leather H, Majhail N, Nath R, 
Osman K, Perales MA, Schriber J, Shaughnessy P, Vesole D, Vij R, Wingard J, Giralt S, 
Savani B., Hematopoietic Stem Cell Transplantation for Multiple Myeloma: Guidelines from 
the ASBMT, Biol Blood Marrow Transplantation 2015 Jul;21(7):1155-116 
36. Shimizu K. Overview of the International Myeloma Workshop 2013 Kyoto. Clinical 
Lymphoma Myeloma and Leukemia. 2014; 14: 2-4 
37. Singh A, Divine C,  Aljitawi O,  Abhyankar S, McGuirk JP, and Ganguly S. In Vivo Purging 
May Not Be Required In The ERA Of Universal Use Of Rituximab Containing Chemo-
Immunotherapy In Patients With Follicular And Mantle Cell Lymphoma: A Single Center 
Experience, ASBMT Tandem Meeting, San Diego, CA Feb 2015. Biol Blood Marrow 
Transplat 2015; 21; S135-136 
38. Steiner P, Neumeier H, Lightcap E, Sadis S, Pien C, Pink M et al. Adaptation of Human 
Tumor Cell Lines to PS-341. AACR-NCI-EORTC International Conference, 2001; Miami 
Beach, FL. Millennium Pharmaceuticals, Inc., 75 Sidney Street, Cambridge, MA 02139. 
Abstract  
39. Stewart, A. K., Vescio, R., Schiller, G., Ballester, O., Noga, S., Rugo, H., . . . Berenson, J. 
(2001). Purging of autologous peripheral-blood stem cells using CD34 selection does not 
improve overall or progression-free survival after high-dose chemotherapy for multiple 
myeloma: results of a multicenter randomized controlled trial. J Clin Oncol, 19(17), 3771-
3779.  
40. Teicher BA, Ara G, Herbst R, Palombella VJ, Adams J. The proteasome inhibitor PS-341 in 
cancer therapy. Clin Cancer Res 1999; 5 (9):2638-45.  
41. Thirukkumaran, C. M., Shi, Z. Q., Luider, J., Kopciuk, K., Bahlis, N., Neri, P., . . . Morris, D. 
G. (2014). Reovirus as a successful ex vivo purging modality for multiple myeloma. Bone  
Marrow Transplant, 49(1), 80-86. doi: 10.1038/bmt.2013.130 
42. Thomas J, Liu F, Link DC. Mechanisms of mobilization of hematopoietic progenitors with 
granulocyte colony-stimulating factor. Curr Opin Hematol. 2002;9:183–189. 
43. Uy GL, Trivedi R, Peles S, Fisher NM, Zhang QJ, Tomasson MH, DiPersio JF, Vij R. 
Bortezomib inhibits osteoclast activity in patients with multiple myeloma. Clin Lymphoma 
Myeloma. 2007 Nov;7(9):587-9 
 
 
 
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44. Vogel, W., Kopp, H. G., Kanz, L., & Einsele, H. (2005). Myeloma cell contamination 
ofperipheral blood stem-cell grafts can predict the outcome in multiple myeloma patients 
after high-dose chemotherapy and autologous stem-cell transplantation. J Cancer Res Clin 
Oncol, 131(4), 214-218. doi: 10.1007/s00432-004-0635-y 
45. Yang H, Robinson SN, Nieto Y, Jones RJ, Gocke CD, Lu J, Giralt SA, Jones RB, Decker 
WK, Xing D, Steiner D, Champlin RE, McMannis JD, Ng J, Thomas MW, Shah N, 
Andersson BS, Parmar S, Shpall EJ. Ex vivo graft purging and expansion of autologous 
blood progenitor cell products from patients with multiple myeloma. Cancer Res. 2011 Jul 
15;71(14):5040-9. doi: 10.1158/0008-5472.CAN-11-0842. Epub 2011 Jun 6 
46. Popat et al. Impairment of Filgrastim-Induced Stem Cell Mobilization after Prior 
Lenalidomide in Patients with Multiple Myeloma. Biol Blood and Marrow Transplant 2009: 
15: 718-723 
 
 
 
 
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15.0 
APPENDICES 
 
APPENDIX A Performance Status 
The following table presents the Karnofsky performance status scale: 
Points 
Description 
100 
Normal, no complaints, no evidence of disease 
90 
Able to carry on normal activity 
80 
Normal activity with effort; some signs or symptoms of disease 
70 
Cares for self; unable to carry on normal activity or to do active work 
60 
Requires occasional assistance but is able to care for most of his/her needs 
50 
Requires considerable assistance and frequent medical care 
40 
Disabled; requires special care and assistance 
30 
Severely disabled; hospitalization indicated.  Death not imminent 
20 
Very sick; hospitalization necessary; active support treatment necessary 
10 
Moribund; fatal processes progressing rapidly 
0 
Dead 
 
Zubrod (ECOG) Performance Status 
 
POINT 
DESCRIPTION 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light housework, office work. 
2 
Ambulatory and capable of self-care but unable to carry out any work activities; 
up and about more than 50% of waking hours 
3 
Capable of limited self-care, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or 
chair. 
 
 
 
 
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APPENDIX B Body Surface Area  
Body surface area (BSA) should be calculated using a standard nomogram that yields the 
following results in meters squared (m2): 
BSA = 
3131
)
(
)
(
lbs
Wt
inches
Ht
×
 
or 
BSA = 
3600
)
(
)
(
kg
Wt
cm
Ht
×
 
 
 
 
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APPENDIX C Standard Operating Procedures – Stem Cell Harvest 
 
 
 
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APPENDIX D Guidance For Use Of Heparin And Mozobil In Performing Large Volume 
Apheresis  
 
Indications And Usage Of Heparin Anticoagulant 
 
A) Heparin may be used as an anticoagulant additive to ACDA on patients having a stem 
cell collection procedure in certain instances. Guidelines for heparin usage are to be 
determined on each patient by CD34 assessment and a clinical assessment.  
1) For patients on anticoagulant therapy, i.e., Coumadin, Lovenox, etc, do not use 
heparin as an anticoagulant. 
2) For patients with heparin induced antibodies, do not use heparin as an 
anticoagulant. 
3) All large volume collections procedures are dependent upon patient’s tolerance for 
procedure and other clinical/medical conditions, i.e., platelet counts, hypervolemia, 
dialysis, etc. 
 
Circulating Peripheral Cd34 Count And Mozobil® Usage 
 
A) Patients needing cells for one or multiple peripheral stem cell transplants. 2.5 x x106 
CD34/Kg is the desired goal for each transplant. 
1) If the CD34 count is less than 5 cells/ul, do not perform collection   
a. Give 10 mcg/kg G-CSF now. 
b. Administer Mozobil® that evening.  
c. Perform another peripheral CD34 count on the following morning. 
d. If on second day the CD34 count is less than 5 cells/ul, do not perform 
collection.  
e. The physician is to advise on the plan which may include the continuation of 
Mozobil®. 
2) If the CD34 count is greater than 5 and less than 10 cells/ul, do not perform 
collection   
a. Give G-CSF now. 
b. Administer Mozobil® that evening.  
c. G-CSF will also be given 1 hour pre-collection the following morning, if the 
pre-collection WBC count is < 65K. 
d. Perform a larger volume collection (approximately 5 - 6 blood volumes) 
utilizing heparin/ACDA as the anticoagulant. Each blood volume processed 
can reduce the patient’s platelet count by 10%. 
3) If the CD34 count is greater than 10 cells/ul, Perform collection as in 2)d. above. 
4) The provider has the discretion to perform a collection outside of this algorithm.  
 
 
 
 
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Post-Collection Results And Mozobil Usage 
 
A) If on the first day of collection the collected product contains LESS THAN 65% of the 
desired dose, use Mozobil® that evening. G-CSF will also be given 1 hour pre-collection 
the following morning if the WBC count is <65,000. 
 
B) Goal  
 
65% of goal 
2.5 x 106 CD34/Kg  
(<1.63 x 106 CD34/Kg)  
5.0 x 106 CD34/Kg  
(<3.25 x 106 CD34/Kg)  
7.5 x 106 CD34/Kg  
(<4.88 x 106 CD34/Kg)  
 
Mozobil Dosage And Administration 
 
1) Notify BMT Pharmacist. To reach correct pharmacist call BMT Triage Nurse at 
913-588-9821. The triage nurse will direct the call to the pharmacist. 
2) BMT Pharmacist to consult and write order for use of Mozobil®. 
3) Repeat Mozobil® dose up to 4 consecutive days. 
4) Select dose based on 0.24 mg/kg actual body weight (0.012 X patient’s actual body 
weight in kg = volume to be administered in mL). 
5) Maximum dose is 24 mg or 1 vial. (1.2 mL of a 20 mg/mL solution). 
6) Administer by subcutaneous injection approximately 10 - 14 hours prior to initiation of 
apheresis. 
7) Renal impairment: If creatinine clearance is ≤ 50 mL/min, decrease dose by one-third 
to 0.16 mg/kg.  
 
Adverse Reactions 
A) Most common adverse reactions (≥ 10%): diarrhea, nausea, fatigue, injection site 
reactions, headache, arthralgia, dizziness, and vomiting. 
 
 
 
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APPENDIX E Standard Operating Procedures – Cytoplasmic Staining 
 
 
 
 
 
 
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APPENDIX F Multiparametric Flow Cytometry (MFC) – Validation Model 
Multiple Myeloma (MM)-Minimal Residual Disease (MRD)  
 
 
 
 
 
 
 
 
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APPENDIX G 8-Color Leukemia / Lymphoma Immunophenotyping Processing Procedure 
 
 
1. PRINCIPLE /CLINICAL SIGNIFICANCE 
 
A. Principle of the Procedure 
Immunophenotypic analysis involves the identification and classification of the cells by 
the presence of surface antigens or intracellular antigens, which are identified by 
fluorochrome-labeled monoclonal antibodies directed against those antigens.  Panels of 
antibodies are utilized to determine the origin and stage of differentiation of 
hematopoietic neoplasms including acute and chronic leukemias and lymphomas. 
 
B. Clinical Significance 
Immunophenotypic analysis by flow cytometry is routinely utilized for diagnostic and 
therapeutic decision making for types of acute and chronic leukemias and lymphomas. 
 
2. SPECIMEN 
 
A. Specimen Type 
1. Peripheral Blood1,2 
• 
EDTA specimens are viable up to 24 hours at room temperature. 
• 
Heparin specimens are viable up to 48 hours at room temperature. 
• 
ACD specimens are viable up to 72 hours at room temperature. 
• 
Transport specimen in biohazard transport bag and hold at room temperature 
(18-25oC). 
• 
Do not refrigerate. 
2. Bone Marrow Aspirate 
• 
1-2mL of bone marrow in a heparinized syringe or collection tube at room 
temperature 
• 
Transport specimen in biohazard transport bag and hold at room temperature 
(18-25oC). 
• 
Do not refrigerate. 
3. Bone Marrow Biopsies 
• 
If bone marrow procedure was a dry tap, the bone marrow biopsy can be 
processed for flow. 
• 
Place into RPMI or saline and transport in a biohazard transport bag and hold at 
room temperature (18-25oC). 
• 
If biopsy is in saline, replace the saline with RPMI immediately and hold until 
processing. 
• 
Do not refrigerate. 
4. Fluids – CSF, pleural, bronchial lavage, etc. 
• 
Natural cellular suspension or supplemented with heparin in a collection or test 
tube. 
• 
Transport specimen in a biohazard transport bag and hold at room temperature 
(18-25oC). 
• 
Do not refrigerate. 
 
 
 
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5. Tissue – lymph node, spleen, other soft tissue, etc. 
• 
Tissue or cellular suspension held in supplemented RPMI. 
• 
Note:  Mince tissue and express through wire mesh screen to dislodge cells. 
• 
Transport specimen in biohazard transport bag and hold at 2-8oC.1 
6.   Post Stem Cell Apheresis Collection Product (PSC). 
 
B. Specimen Rejection 
1. Incomplete data or patient identification on label.  Pathologist will be consulted.  
Test will be canceled, if appropriate, in LIS and clinician will be notified. 
2. Improperly collected specimen:  clotted, auto-lysed, cracked or leaking tube. 
Indicate if clot present.  Pathologist will be consulted.  Test will be canceled, if 
appropriate, in LIS and clinician will be notified. 
3. Quantity not sufficient to perform test.  Pathologist will be consulted.  Test will be 
canceled, if appropriate, in LIS and clinician will be notified. 
4. Peripheral blood 
• 
EDTA specimens greater than 24 hours old. 
• 
Heparin specimens greater than 48 hours old. 
• 
ACD specimens greater than 72 hours old. 
If peripheral blood is greater than the designated acceptable range, then a 
viability will be performed and reported.  A text box will be added to the FCS 
Express layout informing the pathologist of the viability and age of the specimen.  
The reporting is at the discretion of the pathologist. 
5. Tissue and Body Fluid specimens that have a suboptimal viability of < 50%.  A 
text box will be added to the FCS Express layout informing the pathologist of the 
viability and reporting is at the discretion of the pathologist. 
6. CSF specimens greater than 4 days will have a text box added to the FCS 
Express layout informing the pathologist of the age of the specimen and reporting 
is at the discretion of the pathologist. 
7. Inappropriate orders:  The ordering physician will be contacted to verify the 
correct order and documentation will be included when the test is canceled. 
 
3. REAGENTS/SUPPLIES/EQUIPMENT 
 
A. Reagent Handling and Storage 
1. Conjugated Monoclonal Antibodies 
• 
Store at 2-8oC. 
• 
Do not freeze. 
• 
Stable until the expiration listed on the bottle. 
• 
Use according to manufacturer’s instructions or validated procedure. 
• 
Contains sodium azide to inhibit bacteria growth. Chronic exposure has shown to 
have mutagenic effects. PPE should be worn at all times. Wash thoroughly after 
handling. 
• 
Sodium azide is harmful if swallowed. Wear protective clothing. If swallowed, 
seek medical advice immediately and show container or label. Contact with acid 
liberates very toxic gas. Azide compounds should be flushed with large volumes 
of water during disposal to avoid deposits in lead or copper plumbing where 
explosive conditions can develop. 
 
 
 
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2. Propidium Iodide 
• 
Sigma, Catalog No. P4170 
• 
Store at 2-8oC. 
• 
Dissolve 0.005g into 500mL PBS. Store at 2-8oC. 
• 
Prepared PI is stable for 2 years. 
• 
PI is known to show possible mutagenic effects. PPE should be worn at all times. 
Wash thoroughly after handling. 
3. RPMI 5% FBS with Heparin 
• 
Cardinal Health, Catalog No. M7201-56 
• 
Store at 2-8oC. 
• 
Fetal Bovine Serum (FBS) – Sigma Aldrich, Catalog No. F4135-500mL 
• 
When received, thaw and aliquot out 50mL conical tubes of FBS. Label and 
refreeze. Store in freezer until outdate. 
• 
Penicillin/Streptomycin – Sigma Aldrich, Catalog No. P0781-20mL 
• 
Store in Freezer until outdate. 
• 
Heparin – 1,000 USP units/mL, 2mL vial 
• 
Store at room temperature. 
• 
Obtain from Bone Marrow bench. 
• 
Prepare using sterile technique; remove 35mL of RPMI and add 25mL of thawed 
FBS, 10mL of thawed Pen/Strep solution, and one vial of heparin to the RPMI. 
Store media in refrigerator. Stable for 6 months or until pH has changed. pH 
change is indicated when the salmon colored media has changed to a yellow or 
pink solution. 
• 
Store at 4oC for 6 months. 
• 
May cause irritation to skin and eyes. Wash with large amounts of water (eye 
wash). Call a physician if necessary. 
• 
Use appropriate PPE:  gloves, lab coat, and protective eye wear. 
4. Dulbecco’s Phosphate Buffered Saline (PBS) (10X) 
• 
Thermo Scientific, Catalog No. SH30378.02 
• 
Store 15-30oC. 
• 
Stable until the expiration listed on the bottle. 
• 
Dilute to 1X prior to use with DI water. 
• 
pH the 1X solution with pH indicator strips. It should fall within the range of 7.2-
7.4. Adjust as necessary with 1N NaOH or 1N HCl. 
• 
Expiration is one month from date of preparation. 
• 
Irritant to eyes, respiratory system, and skin. In case of contact, rinse 
immediately with plenty of water. 
5. RBC Lysis Buffer (10X) 
• 
BioLegend, Catalog No. 420301. 
• 
Store at 2-8oC. 
• 
Stable until the expiration listed on the bottle. 
• 
Measure 100mL of RBC Lysis Buffer. QS to 1L with DI water. 
• 
pH the 1X solution with pH indicator strips. It should fall within the range of 7.1-
7.4. Adjust as necessary with 1N NaOH or 1N HCl. 
• 
Warm the 1X solution to room temperature prior to use. 
• 
Stable for one month. 
 
 
 
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6. 1N NaOH 
• 
Sigma, Catalog No. S2770 
• 
Store at room temperature. 
• 
Irritant to eyes, respiratory system, and skin. In case of contact, rinse 
immediately with plenty of water and contact physician. 
7. 1N HCl 
• 
Sigma, Catalog No. H9892 
• 
Store at room temperature. 
• 
Irritant to eyes, respiratory system and skin. In case of contact, rinse immediately 
with plenty of water and contact physician. 
8. BD FACS Flow 
• 
BD Biosciences, Catalog No. 342003 
• 
Store at room temperature. 
• 
Stable until the expiration date listed on box. 
9. BD FACS Clean 
• 
BD Bioscience, Catalog No. 340345 
• 
Store at room temperature. 
• 
Stable until the expiration date listed on box. 
10. DI Water – Reagent Grade Type 1 Water 
• 
Ricca Chemical Co., Catalog No. 9150-5 
• 
Store unopened until expiration date listed on box. 
• 
After opening, use within 30 days. 
• 
Store at room temperature. 
11. Bleach Concentrate (6% sodium hypochlorite) 
• 
Store at room temperature. 
• 
Corrosive: Irritant to respiratory tract, skin, and eyes (flush with plenty of water – 
use eye wash/safety shower). Ingestion causes nausea and vomiting. Call a 
physician. 
• 
Use appropriate PPE: glove, lab coat, and protective eye wear. 
12. Bleach-Rite 
• 
Fisher Scientific, Catalog No. 14-412-53. 
• 
Store at room temperature. Do not expose to excessive heat or sunlight or UV 
light or else bleach efficacy may deteriorate. 
• 
1:10 dilution of bleach and detergent. 
• 
Stable until expiration date. 
• 
Irritant to eyes. Rinse with copious amounts of water for 15-20 minutes. 
• 
Use appropriate PPE: glove, lab coat, and protective eye wear. 
 
B. Materials and Equipment 
1. 12x75mm polystyrene test tubes 
2. Pipettes (20uL, 200uL, 1000uL) 
3. Pipette tips 
4. Repeat pipettor 
5. Disposable transfer pipettes – large and small tipped 
6. Test tube rack 
7. 17x100mm test tubes 
8. Petri dish 
9. Tissue sieve 
10. 10mL syringe plunger 
11. Scalpel and/or surgical scissors 
 
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12. 100um cell strainer 
13. pH indicator strips 
14. Centrifuge 
15. Vortex mixer 
16. Timer 
17. Mechanical rocker 
18. BD FACS Lyse Wash Assistant – Serial No. K14610025 
19. BD FACSCanto II – Serial No. V96300795, Serial No. V33896201741 
• 
Laser safety:  The FACSCanto II flow cytometer is a Class I laser product. The 
laser is fully contained within the structure and calls for no special work area 
safety requirements. Nevertheless, regulations require that a warning be posted 
to avoid tampering with the instrument. The protective shields surrounding the 
laser source should never be removed or altered except by the technical service 
personnel. Removal of any of these safety shields would place the operator at 
risk of scattered or direct exposure to laser radiation. 
 
4. QUALITY CONTROL 
 
A.   BD Cytometer Setup and Tracking Beads - Catalog No. 641319 
• 
Store the bead vial at 2-80C  
• 
Protect from light.   
• 
Do not freeze.   
• 
Dilute one drop of CS&T Beads with 450ul of BD FACSFlow reagent.  
B. Leukemia/Lymphoma QC panel - CD-Chex Plus  
• 
Stored at 2-8oC. Do not freeze. 
• 
Once open, tubes are good for 30 days. 
• 
A positive control panel is run twice a month.  Control results should fall within control 
ranges.  If control(s) are out of range, the test system must be evaluated for source of 
error. Determine cause by evaluating and troubleshooting. Repeat, remake, and/or 
check them. Note in the “Comments” section of the CD-Chex Plus QC Log any 
corrective action that has occurred.  
• 
All control specimens must be tested in the same manner and by the same personnel 
as patient samples. 
• 
QAP monthly report compares KU data to QC data reported by peer lots. Results 
reviewed against group results for precision accuracy. Investigate when SDIs and 
CV are >2.0. 
C. BD CompBeads – Anti-Mouse Ig/k, Negative Control Compensation Particles Set.  This 
panel is run weekly or whenever there has been service on the instrument. 
D. Gating Controls:  Population of interest by light scatter and anti-leukocyte antibody 
(CD45). 
E. pH Control Log – pH checks of reagents should be recorded on the monthly pH control 
log. 
 
 
 
 
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5. PROCEDURE 
 
A.  Manual Method: 
1. Concentrate cellular elements of the specimen by transferring an aliquot (1-2mL) of 
well-mixed sample to a 17x100mm tube. 
• 
If BM specimen, break up spicules with a small tipped pipette. 
• 
If tissue specimen, use tissue sieve and rubber tipped syringe plunger to gently 
dissociate. 
2. Add 5% FBS RPMI and centrifuge at 400g or 1600rpms for 5 minutes to wash the 
cells. 
3. If tissue or fluid specimen, proceed to step 9. 
4. Aspirate the supernatant. 
5. Add 10mL of 1X RBC Lysis Buffer to specimen and place on mixer for 10 minutes. 
6. Centrifuge at 400g or 1600 rpms for 5 minutes. 
7. Decant supernatant.  Note:  If incomplete lysis has occurred – repeat steps 4-6. 
8. Add PBS to specimen to wash cells.  Centrifuge at 400g or 1600 rpms for 5 minutes. 
9. Decant supernatant and resuspend the cells in 1 mL of 5% FBS RPMI. 
10. Obtain a cell count using CountBright Beads (see appropriate procedure).  Adjust the 
concentration to 10.0 x 106 WBC/mL (working solution). 
11. Pipette the appropriate antibodies into labeled tubes. 
12. Add 100uL of working solution of cells to the antibody panel. 
• 
If setting up any MRD panel, use 200uL of working solution if the cell 
concentration is < 10.0 x 106 WBC/mL. 
13. Incubate the panel for 15 to 30 minutes in the dark at room temperature. 
14. If tissue or fluid specimen, add 2 mLs of RBC Lysis Buffer and incubate in the dark 
for 10 minutes.  Centrifuge at 400g or 1600 rpms for 3 minutes.  Decant tubes. 
15. Add 2 mL of PBS to each tube and vortex gently. 
16. Centrifuge at 400g or 1600 rpms for 3 minutes. 
17. Decant supernatant and add 0.5 mL of PBS to each tube and gently vortex. 
18. Remove the PI viability tube (if appropriate) and place 1 mL of Propidium Iodide into 
the PI tube.  Vortex and place back into carousel rack.  PI will incubate while the 
panel is running. 
19. Run the panel on the BD FACSCanto II using the Diva Software.  Gate on the CD45 
bright population and/or population of interest.  Analyze data using FCS Express 
software. 
20. After analysis, tubes can be disposed of in a biohazard container. 
21. Original specimen is kept at room temperature for 7 days. 
 
B. Lyse Wash Assistant Method (LWA): 
1. Concentrate cellular elements of the specimen by transferring an aliquot (1-2 mL) of 
well-mixed sample to a 17 x 100mm tube.  
• 
if BM specimen, break up spicules with a small tipped pipette . 
• 
if tissue specimen, use tissue sieve and rubber tipped syringe plunger to gently 
dissociate. 
 
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2. Add 5% FBS RPMI and centrifuge at 400g or 1600 rpm for 5 minutes to wash the 
cells. 
3. If tissue or fluid specimen, proceed to step 6. 
4. Aspirate the supernatant. 
5. Add PBS to specimen to wash cells.  Centrifuge at 400g or 1600 rpms for 5 minutes. 
6. Decant supernatant and resuspend the cells in 1 mL of 5% FBS RPMI. 
7. Obtain a cell count using CountBright Beads (see appropriate procedure).  Adjust the 
concentration to 10.0 x 106 WBC/mL (working solution). 
8. Pipette the appropriate antibodies into labeled tubes. 
9. Add 100uL of working solution of cells to the antibody panel. 
• 
If setting up an AML/ALL MRD panel, use 200uL of working solution if the cell 
concentration is < 10.0 x 106WBC/mL. 
10. Gently vortex tubes and load the panel into a carousel rack. 
11. Place carousel on the LWA and close the lid. 
12. Make sure all reagent volumes are full. 
13. Select the KU/incub/lyse/wash protocol and then Run. 
14. When the LWA cycle is completed, open lid and remove carousel and place on the 
BD FACSCanto II. 
15. Remove the PI viability tube (if appropriate) and place 1 mL of Propidium Iodide into 
the PI tube.  Vortex and place back into carousel rack.  PI will incubate while the 
panel is running.  
16. Run the panel on the BD FACSCanto II using the Diva Software.  Gate on the CD45 
bright population and/or population of interest.  Analyze data using FCS Express 
software. 
17. After analysis, tubes can be disposed of in a biohazard container. 
18. Original specimen is kept at room temperature for 7 days. 
 
6. CALCULATIONS/INTERPRETATION/RESULT REPORTING/NORMAL VALUES/CRITICAL 
VALUES 
 
A. The results are analyzed using FCS Express software, by the flow cytometry 
technologists and delivered to the pathologist for interpretation.  The pathologist will 
complete the final report and notify the physician if indicated. 
 
7. CALIBRATION/LINEARITY/AMR/CALIBRATION VERIFICATION 
 
A. Instrument calibration is performed by BD Technical Service on a semi-annual basis. 
B. Application Settings are performed after every major maintenance or service issue and 
performed after a new CS&T baseline is established. 
C. Compensation is performed on a weekly basis. 
 
 
 
 
 
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8. PROCEDURE NOTES/LIMITATIONS 
 
A. To ensure that immunoglobulin staining is intrinsic and not extrinsic, CD19 is stained in 
the same tube with Kappa and Lambda.  Also, the specimen is washed with PBS prior to 
staining to alleviate non-specific binding.2 
B. The laboratory uses antibodies appropriate for the clinical situation. Pathologists review 
as necessary. 
C. The use of Hyaluronidase has been validated in BAL’s and fluids.  If these specimens 
are thick and mucoid add a few crystals of Hyaluronidase (found in Hematology’s 
freezer).   Wait until the sample liquefies then proceed with above procedure. 
D. There are numerous variables that may affect the staining properties or the identification 
of specific cell populations and thus result in inaccurate results.  These include the 
following: 
1. Patient’s disease state or therapy, such as immune-suppressive drugs, may affect 
the normal antibody staining characteristics. 
2. Purity of the gated cell population. 
3. Resolution between the positive and negative populations. 
4. Non-specific staining and auto-fluorescence. 
5. Cell count of population of interest may be too low to collect significant results. 
E. If the CS&T beads do not pass, the instrument should not be operated.  Refer to the 
troubleshooting information in the BD Cytometer Setup and Tracking Application Guide. 
F. If instruments are inoperable: 
a. For analyzer problems, call BD Bioscience at 1-877-232-8995 and log the problem in 
the Action Log with a reference number.   
b. If one instrument is down, use the other instrument only and contact technical 
service. 
c. If both instruments are down the hematology supervisor or medical staff on call for 
hematology should be notified at this time. 
d. All testing should be sent to St. Luke’s by courier.   Call the Flow Lab at St. Luke’s at 
816-932-6265 to let them know we are sending specimens. 
e. Have St. Luke’s fax flow cytometry requisition with indication of necessary 
information to be filled in. 
f. Use St. Luke's courier until 7:00 pm (816-932-3850).  After hours use KU's courier, 
Quicksilver (321-5959). 
g. Follow reference lab's protocol for collection and handling of specimens. 
 
 
 
 
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9. REFERENCES For this Appendix 
 
1. Stewart, C. C., Nicholson, J.K.A.  “Immunophenotyping.”  Page 181-182.  New York:  A 
John Wiley & Sons, Inc., 2000. Print.  
2. Hawley, T. S., Hawley, R. G.  “Flow Cytometry Protocols.”  Third Edition. Pages 297 and 
301.  New York:  Humana Press.  Print. 
3. Keren, D F.., McCoy Jr., J. Phillip, Carey, J. L.  “Flow Cytometry in Clinical Diagnosis.”  
4th Edition, ASCP Press, 2007. 
4. BD Cytometer Setup and Tracking Application Guide for BD FACS Digital Flow 
Cytometers.  BD Biosciences. com.   23-12881-00,  Rev.01  10/2010. 
5. BD FACSCanto II Instructions For Use, #644450, April 2009. 
6. BD Bioscience – BD FACSCanto II Operators Course Workbook, 23-10926-00, August 
2009. 
7. BD Bioscience – BD FACS Lyse Wash Assistant User’s Guide, 23-11113-00 Rev. A, 
January 2010. 
 
 
 
 
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HSC # STUDY00002857 
APPENDIX H Summaries of Changes 
 
Summary of Changes for Revised Protocol Version 5.0 dated 11-21-2016 
 
• 
Previous Protocol Version 4.0 dated 04-06-2016 
• 
Revised Protocol Version 5.0 dated 11-21-2016 
 
General Comments 
This protocol version incorporates the protocol clarification letter dated 05-18-2016 
(allows use of filgrastim biosimilar), removes an inclusion criterion, and includes 
administrative updates & clarifications. 
 
Key Protocol Changes: 
Section 
Summary of Change 
Rationale 
3.1.5 
Removed Inclusion Criterion:  
“Creatinine - within normal institutional limits” 
Patients with increased 
creatinine/kidney disease 
would not be 
contraindicated for stem 
cell collection.  
Bortezomib is the 
preferred myeloma drug 
for patients with kidney 
disease and using 
Bortezomib for 
mobilization may be of 
benefit for patients with 
kidney disease.  Patients 
who meet all other 
enrollment criteria but 
have kidney disease 
and/or increased 
creatinine should not be 
excluded from the clinical 
trial. 
4.0 
Added clarification for Treatment Group A & B: 
“Physician discretion will be used to advise on the 
plan which may include the continuation of 
Mozobil.  The provider has the discretion of 
collection outside the algorithm included in 
Appendix C.” 
Clarification 
Throughout 
 
Added clarification for Adverse Event reporting: 
The study ends 30 days after the participant’s last 
protocol therapy (collection) for the purpose of AE 
reporting.  If a reportable AE occurs within 30 
days after a participant’s collection, recording of 
concomitant medications should continue until 
resolution of the AE. 
Clarification - 
The last day should be 
the collection date 
because not all patients 
make it to AutoSCT. 
Throughout 
 
Added that Filgrastim G-CSF biosimilar (Zarxio) 
may/will be substituted for filgrastim 
Clarification 
(institutional standard) 
 
 
 
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Administrative Protocol Changes: 
Section 
Summary of Change 
Rationale 
All 
Added new protocol version and date 
Protocol tracking 
Page 2 
Updated biostatistician 
Personnel change 
Appendix H  Added latest protocol changes to this section 
Clarity/Consistency/QA 
All 
Formatting 
Administrative 
 
Consent Form Changes:  
Section 
Summary of Change 
Rationale 
Header 
Removed protocol version/date 
Administrative / 
Prevents maintenance 
when consent is 
unaffected by protocol 
amendments 
 
***Re-consent/notification of participants is not required.*** 
 
 
 
 
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Summary of Changes for Revised Protocol Version 4.0 dated 04-06-2016 
 
• 
Previous Protocol Version 3.0 dated 03-14-2016 
 
• 
Revised Protocol Version 4.0 dated 04-06-2016 
 
General Comments 
This revised protocol version 4.0 dated 04-06-2016, incorporates the addition of one 
exclusion criterion, a note (repeated in several places in the section on adverse events) 
regarding planned hospital admission, and a study staff change as listed below: 
 
• 
Patients who have received more than 6 months of lenalidomide (Revlimid®) therapy 
prior to stem cell collection are excluded from this study. 
• 
NOTE:  For this study, planned hospital admission will NOT be considered a Serious 
Adverse Event. 
• 
Brea Lipe, MD was removed as a sub-investigator 
• 
Other minor version-related administrative protocol changes were also completed. 
• 
Changes to the consent form were completed for clarity of standard of care study 
processes related to stem cell collection and timing 
• 
It is our opinion, because the changes clarify study procedures undergone by the 
study participants; any currently enrolled participants must re-sign this version of 
the consent form after IRB approval. 
 
Key Protocol Changes: 
Section 
Summary of Change 
Rationale 
3.2 
Added Exclusion Criterion –Patients who have 
received more than 6 months of lenalidomide 
(Revlimid®) therapy prior to stem cell collection 
are  excluded from this study. 
Excessive exposure to 
Lenalidomide (Revlimid®) 
prior to stem cell harvest is 
known to adversely affect 
stem cell mobilization. Due 
to that fact, heavily pre-
treated patients (  > 6 
months of Lenalidomide 
exposure) will not be 
included in this trial. 
 
This added exclusion 
increases participant 
safety 
Sections: 
6.1.1 
6.2.1 
6.2.2 
6.2.3 
6.2.4 
 
Added the following note:  
NOTE:  For this study, planned hospital 
admission will NOT be considered a Serious 
Adverse Event. 
(Repeated in multiple positions for clarity for 
study team during clinical operations) 
Clarification of study 
reporting for this disease. 
 
 
 
 
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Administrative Protocol Changes: 
Section 
Summary of Change 
Rationale 
Title Page 
Added information regarding current 
protocol version 
Clarity and Protocol tracking 
Header 
Updated to include current protocol version 
and date 
Protocol Tracking/ 
Clarification/Version Control 
Footer 
Updated to include current protocol version 
and date 
Protocol Tracking 
/Clarification/Version Control 
Table of 
Contents 
Updated page numbers and section titles 
Protocol consistency per changes 
in current version 
Section 14.0 
References 
Added reference # 46, pertinent to added 
exclusion criterion 
Clarity/Consistency 
Appendix H – 
Summaries 
of Changes 
Added latest changes to this section 
Clarity/Consistency/QA 
 
ALL Consent Form Changes  
Section 
Summary of Change 
Rationale 
Header 
Updated notation regarding protocol version 
and date 
Clarity for Study Team/Per SOPs 
What is 
being tested 
in this study? 
Changed “twelve” to “12” 
Correction per grammar rules 
What will I be 
asked to do? 
/ Group B 
Added note that bortezomib doses are per 
institutional standard 
Clarification/ Standard of Care 
treatment for this disease 
Study 
Treatment 
Added the word “NOTE” to notation 
regarding 72 hours required between each 
dose or bortezomib. 
 
Added note that bortezomib doses are per 
institutional standard  
Clarity/Emphasis 
 
 
Clarification/ Standard of Care 
treatment for this disease 
Study 
Calendar 
Treatment 
Period/ Day 
0  
 
 
 
 
 
Study 
Procedures 
and Tests / 
Bortezomib 
Changed collection window days from “ 4 to 
8 days” to “8 to 12 days” 
 
 
 
 
 
 
Added note that bortezomib doses are per 
institutional standard 
Calculation of days in window 
was incorrect – now corrected. 
This window was previously 
approved in Protocol version 3.0 
added at that time per standard of 
care for stem cell collection and 
for Participant safety and 
convenience 
 
 
Clarification/ Standard of Care 
treatment for this disease 
 
 
 
 
 
 Page 104 of 106 
2015-IIT-BMT-MM-AutoSCT 
Protocol Version 5.0 dated 11-21-2016  
 


2015-IIT-BMT-MM-AutoSCT 
Principal Investigator:  Siddhartha Ganguly, MD 
HSC # STUDY00002857 
Summary of Changes for Revised Protocol Version 3.0 dated 03-14-2016 
 
• 
Previous Protocol Version 2.0 dated 02-11-2016 
 
• 
Revised Protocol Version 3.0 dated 03-14-2016 
 
General Comments 
• 
This revised protocol version 3.0 dated 03-14-2016, incorporates only the addition and 
clarification of the following: 
o Clarification of Window for stem cell collection (Day 0 + 4 days) 
o Clarification that mozobil will be used if needed for BOTH groups A and B (per 
Standard of Care (SOC) 
o Addition of Appendix G - 8-Color Leukemia / Lymphoma Immunophenotyping 
Processing Procedure 
o Addition of Appendix H – Summaries of Changes 
• 
 Other administrative protocol changes related to this change, including template 
language and quality assurance updates, were also completed. 
• 
Changes to the consent form were completed for clarity of standard of care study 
processes related to stem cell collection timing 
• 
It is our opinion, because the changes clarify study procedures undergone by the 
study participants; any currently enrolled participants must re-sign this version of 
the consent form after IRB approval. 
 
Key Protocol Changes for Revised Protocol Version 3.0 dated 03-14-2016: 
 
Section 
Summary of Change 
Rationale 
Schema 
Study Summary 
1.4 – Paragraph 8 
4.1 
5.2 
5.4 
Clarification of Window for stem cell collection 
(Day 0 + 4 days) 
Clarification that mozobil will be used if 
needed for BOTH groups A and B (per 
Standard of Care (SOC) 
Clarification / Participant 
safety and convenience 
15.0 
Added Appendix G - 8-Color Leukemia / 
Lymphoma Immunophenotyping Processing 
Procedure 
 
Added Appendix H – Summaries of Changes 
Clarity 
 
Per KUCC Quality 
Assurance, going 
forward, summaries of 
changes should be 
included in the protocol 
document. 
 
 
 
 
 Page 105 of 106 
2015-IIT-BMT-MM-AutoSCT 
Protocol Version 5.0 dated 11-21-2016  
 


2015-IIT-BMT-MM-AutoSCT 
Principal Investigator:  Siddhartha Ganguly, MD 
HSC # STUDY00002857 
 
Administrative Protocol Changes for Revised Protocol Version 3.0 dated 03-14-
2016: 
Section 
Summary of Change 
Rationale 
Title 
Page 
Added information and corrected section 
header regarding previous and current 
protocol modifications 
Clarity and Protocol tracking 
Header 
Updated to include current protocol version 
and date 
Protocol Tracking/ 
Clarification/Version Control 
Footer 
Updated to include current protocol version 
and date 
Protocol Tracking 
/Clarification/Version Control 
Table of 
Contents 
Updated page numbers and section titles 
Protocol consistency per changes in 
current version 
 
Consent Form Changes for Revised Protocol Version 3.0 dated 03-14-2016: 
Section 
Summary of Change 
Rationale 
Header 
Changed Amendment/Version 
Information 
Auditing reference/version control 
What is being 
tested in this 
study? 
Paragraph 
regarding Group B 
Added that stem cell collection may 
occur approximately eight to twelve 
days after the second dose of 
bortezomib. 
Clarification / 4 –day window 
clarification added per standard of 
care for stem cell collection and 
for Participant safety and 
convenience 
What is being 
tested in this 
study? 
Moved and bolded note that both 
Group A and B participants will receive 
G-CSF and may have Mozobil if 
needed 
Clarification 
What will I be 
asked to do? 
Group B 
Added that stem cell collection may 
occur up to 12 days after second dose 
of bortezomib. 
See rationale for “What is being 
tested in this study?”, above 
Study Treatment 
Group B – modified language in bullet 3 
per the clarification to the window for 
standard of care for stem cell collection. 
 
Added bullet 4 to indicate mozobil will 
be used for this group also, if needed 
See rationale for “What is being 
tested in this study?”, above 
 
 
Clarification 
Study Calendar 
Changed/expanded treatment-period 
column headings (only) per the 
clarification to the window for standard 
of care for stem cell collection. 
 
Clarification and see rationale for 
“What is being tested in this 
study?”, above. 
Blood tests 
Deleted “Day – 1” per the clarification to 
the window for standard of care for 
stem cell collection. 
 
Consistency 
 
 
 
 Page 106 of 106 
2015-IIT-BMT-MM-AutoSCT 
Protocol Version 5.0 dated 11-21-2016  
 

ICF_001.pdf: 
Page 1 of 18                                                                                             
Protocol #: 2015-IIT-BMT-MM-AutoSCT
RESEARCH CONSENT FORM
An exploratory trial to estimate the proportion of  patients with tumor cell 
contaminated, flow positive leukapheresis products collected with and without 
bortezomib as in-vivo purging prior to autolgous stem cell harvest for multiple 
myeloma
Protocol # 2015-IIT-BMT-MM-AutoSCT
Sponsor:  The University of Kansas Cancer Center
TO BE CONDUCTED BY:
Siddhartha Ganguly, MD
University of Kansas Medical Center
Westwood Campus, MS 5003
2330 Shawnee Mission Parkway, Suite 210
Westwood, KS 66205
Telephone:  913-588-6030
You are being asked to join a research study.  Participating in research is different from 
getting standard medical care. The main purpose of research is to create new 
knowledge for the benefit of future patients and society in general.  Research studies 
may or may not benefit the people who participate.  
Research is voluntary, and you may change your mind at any time.  There will be no 
penalty to you if you decide not to participate, or if you start the study and decide to 
stop early.  Either way, you can still get medical care and services at the University of 
Kansas Medical Center (KUMC) and its affiliates.    
This consent form explains what you have to do if you are in the study.  It also 
describes the possible risks and benefits.  Please read it carefully and ask as many 
questions as you need to, before deciding about this research.  
You can ask questions now or anytime during the study.  The researchers will tell you if 
they receive any new information that might cause you to change your mind about 
participating.  You may be asked to sign a new consent form if this occurs.  
This research study will take place at the University of Kansas Medical Center (KUMC) 
with Siddhartha Ganguly, MD as the researcher.  About 100 people will be in the study 
at KUMC.
KUMC IRB # STUDY00002857 | Approval Period 5/28/2019 – 11/27/2019 | FWA# 00003411


Page 2 of 18                                                                                             
Protocol #: 2015-IIT-BMT-MM-AutoSCT
Why am I being asked to take part in this study?
You are being asked to take part in this study because you have been diagnosed with 
multiple myeloma (MM) and are planning to have what is called an “autologous stem 
cell transplantation”.
Multiple myeloma is a blood cancer that affects the parts of your blood called “plasma 
cells”.  Plasma cells are a kind of white blood cell found in the soft insides of your 
bones, called marrow. Plasma cells are part of your body's immune system. They make
antibodies to help fight off infections.
There is no cure for multiple myeloma, but treatment can often help you feel better and 
live longer.
Patients with certain types of cancer require treatment with very high doses of 
chemotherapy.  A side effect of high chemotherapy doses is damage to the bone 
marrow where our blood and immune system cells are produced.
Stem cells (or progenitor cells) are the source of all blood cells.  They are formed in the 
bone marrow (the spongy cavity in the center of large bones).  The stem cells receive 
signals that direct them to become red cells, white cells or platelets.  This happens 
before they are released into the blood stream.  Stem cells circulating in the blood 
stream can be collected through a process called “apheresis” or “stem cell collection”.  
The cells are then processed and frozen to preserve them.  After chemotherapy has 
been given the stem cells are thawed and given back intravenously (IV:  into the vein), 
like a blood transfusion.  The stem cells in the collection will find their way back into the 
bone marrow space and, after a few days, will start to produce the blood and immune 
cells as they normally would.   Having your own stem cells collected and returned to you 
later is called an “autologous transplant”. The goal of doing this is to help your bone 
marrow start to work right again. 
In this study, half of the people in the study will have the routine, standard of care 
treatment for multiple myeloma, and according to that treatment, a sample of stem cells 
will be collected before the routine chemotherapy and radiation is done.
Other people in this study will have a certain dose of chemotherapy given before the 
stem cells are collected.
Why is this study being done?   
Following the routine, standard of care process for treatment of multiple myeloma, the 
blood that is removed from your body is collected before any transplant-related 
chemotherapy or radiation.  This means that some of the diseased cells in the blood 
stay in the sample that is processed and put back into your body during the stem cell 
transplantation.
KUMC IRB # STUDY00002857 | Approval Period 5/28/2019 – 11/27/2019 | FWA# 00003411


Page 3 of 18                                                                                             
Protocol #: 2015-IIT-BMT-MM-AutoSCT
There is a difference in opinion of whether the presence of diseased cells in the sample 
affects how well the overall multiple myeloma treatment works.  Some doctors say the 
presence of the diseased cells does make a difference; others say it doesn’t make a 
difference.
Doctors have tried killing the diseased cells in the sample while it is outside of the body, 
but this has not seemed to make a difference in whether or not the blood cancer comes 
back after the sample is put back in the person’s body.
Good results have been noted from giving patients medicines to kill the diseased cells 
in the blood before the stem cell sample is taken out, but this has not been tried yet in 
people who have the specific kind of blood cancer you have.
In this study, we want to find out if giving patients a chemotherapy drug called 
“bortezomib” before the stem cell collection will decrease or eliminate the number of 
cancer cells remaining in the sample of blood collected for stem cells.
What is being tested in this study?
The drug being tested in this study is called “bortezomib” (also called VELCADE®). It is 
a drug that is approved by the US Food and Drug Administration (FDA) for the 
treatment of people with multiple myeloma (MM).
Another drug that will be used in this study is called “G-CSF” (sometimes it is called
“Filgrastim”).  It is a drug that is approved by the FDA for people who need a medicine 
to help their bodies keep certain blood cells at a healthy level, such as people with 
blood cancer and people having stem cell transplants.  
“Mozobil” is another drug that may be used in this study, and it is also approved by the
FDA to use for people with multiple myeloma who are having autologous stem cell 
transplants.  It is used with G-CSF and helps your body release stem cells from your 
bone marrow so there will be plenty of them in the blood sample that will be given back 
to you.  It is used as needed.
The study will have two groups. 
Patients in Group A will have “regular, standard of care” collection of the blood needed 
for the stem cell sample – that means they will not receive the study drug bortezomib 
before collection of the stem cell sample.  
Patients in Group B will have two doses of the study drug bortezomib before collection 
of the stem cell blood sample.  
The stem cell blood sample will be collected 
approximately eight to 12 days after the second dose of bortezomib. 
Both groups will also have G-CSF and may have Mozobil as needed.
KUMC IRB # STUDY00002857 | Approval Period 5/28/2019 – 11/27/2019 | FWA# 00003411


Page 4 of 18                                                                                             
Protocol #: 2015-IIT-BMT-MM-AutoSCT
You should know, the goal of this study, is NOT to see if one study treatment works 
better than another for treatment of your cancer.  The goal is to see if adding the study 
drug bortezomib before the routine, standard of care treatment for the type of cancer 
you have will reduce the number of cancer cells in the stem cell sample that is collected 
and used for stem cell transplantation.
How long will I be in the study?
Your participation in this study is expected to last approximately 2 months.
Your participation in this study is voluntary and you can choose to withdraw from the 
study at any time. 
What will I be asked to do? 
If you decide to join the study, you will be asked to read and sign this consent form 
before any study procedures take place.  
You will be assigned to one of the following two treatment groups:
•
Group A will have “routine, standard of care” collection of the blood needed for 
the stem cell sample.  This group will not receive study drug bortezomib before 
stem cell collection.
•
Group B will receive two doses of bortezomib before collection of the stem cell
blood sample.  The stem cell blood sample will be collected eight to 12 days 
after the second dose of bortezomib.  Bortezomib doses are per institutional 
standard.
If you are eligible and you decide to join this study, you will be randomly assigned (like 
flipping a coin) to either Group A or Group B. You have an “equal” or 50% chance of
being in Group A or Group B.  A computer will decide which group you are in.  
If it is determined that you are eligible for participation in this study, you will then 
continue with stem cell collection, high dose chemotherapy and autologous stem cell 
transplantation, as described below.
The entire process of stem cell collection and transplantation will be discussed with you 
as a part of your standard of care consenting process.
Study Periods
This study will be divided into the following 3 periods: Screening, Treatment and 
Follow-Up. Each period is described below and includes procedures and tests that will 
be discussed later in this consent form.
KUMC IRB # STUDY00002857 | Approval Period 5/28/2019 – 11/27/2019 | FWA# 00003411


Page 5 of 18                                                                                             
Protocol #: 2015-IIT-BMT-MM-AutoSCT
Screening:  If you would like to be in this study, your study doctor will check that you 
are qualified.  This is called “screening”. The procedures and tests performed during 
this period will determine if you can safely take part in the study and may be performed
over the course of 1 or more days. 
If the results of the procedures and tests indicate that you can take part in the study,
then you may enter the Treatment Period.  
If not, then the study doctor will discuss with you the treatment options that are
available.
Study Treatment:  During this period, the computer will assign you to one of the 
following treatment groups:
•
GROUP A:  Routine, Standard of Care stem cell collection with NO study drug 
(bortezomib).  G-CSF will be used and Mozobil will be used if needed.
OR
•
GROUP B:  BEFORE stem cell collection, the study drug bortezomib will 
be given under the skin with a needle (like a shot) as follows:
o
11 days before stem cell collection (day -11), participants in this group 
will receive 1.3 mg/m2 of the study drug
o
8 days before stem cell collection (day -8), participants in this group will 
receive 1.3 mg/m2 of the study drug.
o
G-CSF will be given each day during the days before stem cell collection 
is started, and continued until the collection is completed.
o
Mozobil will be used if needed.
NOTE:  There must be at least 72 hours between each dose of bortezomib.  
Bortezomib doses are per institutional standard.
Follow-up:  Any illnesses or side effects that you have will be followed for this study
from the time you sign the consent form until 30 days after your stem cells are 
transplanted back into your body.
Your health status will also be followed after the stem cell transplant according to the 
routine, standard of care procedures for stem cell transplantation as required by
KUMC. That follow-up is NOT a part of this study.
Below, you will find a study calendar that lists the study tests and procedures, along 
with the estimated time for visits. Most of these tests and procedures are part of regular 
cancer care, while others are for research purposes only and may be done more often 
for the purposes of this study. Some tests and procedures may not need to be repeated 
if they have already been done recently (your study doctor will let you know if this 
applies). After the study calendar, you will find descriptions of the study tests and 
procedures.
KUMC IRB # STUDY00002857 | Approval Period 5/28/2019 – 11/27/2019 | FWA# 00003411


Page 6 of 18                                                                                             
Protocol #: 2015-IIT-BMT-MM-AutoSCT
Study Calendar
Screening 
Period
Treatment Period
Follow-Up
Study Procedures
And Tests for 
Screening, Treatment 
and Follow-up
Screening/
Baseline
Day –11
Day –8 
Day –4
Day –3
Day –2
Day -1 
The day 
before 
Stem Cell 
Collection 
Day 0
This is Stem Cell 
Collection Day
(Collection may 
happen from 8 to 12 
days after your last 
dose of Bortezomib, 
depending on your 
blood counts)
Day 1 to Day 
30
After stem cell 
transplant
Estimated visit time
(in hours)
2-7
1
1
1
1
1
Informed Consent,
discuss and sign
X
Medical history review 
and Demographics
X
Performance status
X
Physical Exam
X
Current medications
review
X
Routine Blood Tests
X
X
Pregnancy Test
X
Side effects/illnesses 
review
X
X
X
X
X
X
Bortezomib (Doses per 
institutional standard)
X
X
G-CSF (Mozobil as 
needed)
X
X
X
Stem Cell Collection
X
Ongoing
Side Effects/ 
Illnesses 
Review
KUMC IRB # STUDY00002857 | Approval Period 5/28/2019 – 11/27/2019 | FWA# 00003411


Page 7 of 18                                                                                             
Protocol #: 2015-IIT-BMT-MM-AutoSCT
STUDY PROCEDURES & TESTS
Below are descriptions of the procedures and tests that will be done during this study.
Medical history, demographics, illnesses, and side-effects review: You will be 
asked questions about your medical history, demographics (personal information such 
as date of birth, age, gender, race, and ethnicity), any illness you have, and prior 
treatments. Your study doctor will also ask about any side-effects you may have at 
every visit during the study. 
Performance status: You will be asked questions about your ability to do daily tasks 
(called your performance status). 
Physical exam: The complete physical exam will include an evaluation of your head, 
neck, abdominal area, hair, nails, and limbs. The study doctor will also listen to your 
heart and lungs.  Your vital signs (heart rate, blood pressure and body temperature), 
height and weight will also be measured and recorded.
Current medications review: There are some medications (both prescribed and over-
the-counter, i.e., OTC), natural or herbal medicines, alternative medicines, and vitamins 
that may interact with the drugs on this study. If you are now being treated with any 
medicines, some of them may need to be stopped. This is to avoid a mix-up of effects 
between the old medicine and the study treatment. Please follow your study doctor’s 
instructions carefully and tell your doctor about any medications, vitamins, and 
treatments you would like to take while on study.  
Blood tests: A needle will be used to draw blood from a vein in your arm.  Sometimes 
a blood test may need to be repeated for safety reasons or if there are any problems 
with the sample.  If this happens the total amount of blood drawn will be more than this. 
Your blood will be used for:
•
Routine laboratory tests to monitor your general health - Approximately 2-3 
tablespoons of blood will be collected at screening and the day before your stem 
cell collection.
•
Pregnancy tests (if applicable) – Approximately 1 teaspoon of blood will be 
collected each time this test is required for all women of child-bearing potential.
If the pregnancy test is positive, you will not be able to participate in this 
study.
What are the possible risks or discomforts?
The study drugs and procedures may cause side effects or other problems, including 
death. The researchers will be checking your medical information during the study to 
watch for side effects.  However, you should tell the research team about anything that 
is bothering you or any changes in your health since the last visit.  The researchers may 
be able to take steps to reduce side effects.  
KUMC IRB # STUDY00002857 | Approval Period 5/28/2019 – 11/27/2019 | FWA# 00003411


Page 8 of 18                                                                                             
Protocol #: 2015-IIT-BMT-MM-AutoSCT
You may experience none, some, or all of the side effects listed below.  There may be 
other side effects or risks that are not yet known.
Allergic Reaction Risks
You could have an allergic reaction to any of the drugs being used in this study.  
Sometimes, people have serious allergic reactions to drugs. A severe allergic reaction 
could be life-threatening and may result in death. Symptoms of allergic reactions 
include:
•
Swelling of the mouth, throat or eyes
•
Rash
•
Difficulty breathing
•
Coughing
•
Wheezing
•
Sudden drop of blood pressure
•
Seizures
•
Flushing
•
A fast pulse
•
Sweating 
You should call 911 if you think you are having a severe allergic reaction.  Please also 
contact the study team if you have any of these or other side effects during the study.
Possible Risks of Bortezomib (also called VELCADE®)
The study drug called bortezomib should not be taken if you have ever had a serious 
allergic reaction to bortezomib, boron, or mannitol.  You face some risks or discomforts 
when you are treated with the study drug, bortezomib.  You are at risk of having all, 
some, or none of these symptoms and they may vary in severity.  The severity may be 
mild, moderate or severe, up to and including death.  Any symptoms or conditions that 
you have before you start study drug may get worse.  Also, there is always a chance 
that a risk that is rare or not yet known may occur.  If any of these symptoms occur, you 
must tell your doctor who may give you other drugs to ease discomforts you have. Your
doctor may lower or withhold the dose of bortezomib.  Also, if you have a very bad 
reaction to the study drug, your doctor may permanently stop the study treatment.  
Other drugs and supplements may affect the way bortezomib works.  Tell your doctor 
about all drugs and supplements you are taking while you are in this study.
Most Common Bortezomib Risks (occurs in 20% or more patients):
•
Feeling weak, tired, and generally uncomfortable 
•
Gastrointestinal effects such as constipation, diarrhea, nausea, vomiting, and 
loss of appetite.  These may result in dehydration and/or weight loss
•
Fever commonly with shaking chills
•
Painful feelings or numbness and tingling in hands and feet which may not get 
better after stopping bortezomib. Uncommonly, the nerves that control things like
your heart rate, gut movement and urinary bladder may be affected.
•
Lowered platelets;  that may increase the chance of bleeding 
•
Lowered red cells or anemia which may make you feel tired
KUMC IRB # STUDY00002857 | Approval Period 5/28/2019 – 11/27/2019 | FWA# 00003411


Page 9 of 18                                                                                             
Protocol #: 2015-IIT-BMT-MM-AutoSCT
Very Common Bortezomib Risks (occurs in 10 to 19% of patients):
•
Lowered number of white blood cells which may increase your risk of infection 
and is uncommonly associated with fever; commonly you may have lowered 
white blood cells called lymphocytes or have lowered red blood cells, white blood 
cells and platelets at the same time 
•
Flu-like symptoms and other upper respiratory tract infections, such as chills, 
sore throat, and runny nose and sinus and throat infections
•
Abdominal (belly) pain 
•
Aches and pains in muscles and joints pain in bones and in arms and legs
•
Swelling or fluid buildup in the arms and legs, and feeling dizzy and weight gain.  
You should not drive or operate any dangerous tools or machines if you have 
these or any other symptoms. 
•
Cough, feeling short of breath, lung infections including pneumonia and 
commonly bronchitis  
•
Headache  
•
Skin rash with itching and redness.  An uncommon risk is a severe, life-
threatening or deadly rash with skin peeling and mouth sores.    
•
Herpes virus such as shingles (herpes zoster) that can sometimes cause local 
pain that does not go away for a while.  Shingles can sometimes spread over 
large parts of the body.  Both may also affect the eyes or brain, but this is 
uncommon
•
Feeling anxious 
•
Problems sleeping (insomnia)
•
Back pain  
Common Bortezomib Risks (occurs in 1 to 9% of patients):
• Lowered blood pressure that can commonly cause you to feel light headed or 
faint when you stand up. 
• Changes in heart rate and heart beat that can cause you to possibly feel light-
headed, dizzy, faint, short of breath, and/or have chest pain.  This may also 
cause you to feel confused.  An uncommon risk is a possible life threatening 
abnormal heart beat.
• New or worsening heart failure that can show up as feeling short of breath, 
swelling in the legs, and/or chest pain, or decreased heart function and can 
uncommonly be severe.  If you have heart failure or other diseases that put you 
at risk of getting heart failure, you should tell your doctor. 
• Fluid buildup around the lungs
• Infection and/or inflammation of the eye or eyelids
• Blurred vision 
• Painful sores of the mouth and/or throat, which may make swallowing difficult 
• Heartburn, acid reflux and stomach bloating
• Severe bleeding, including bleeding in the stomach and intestines (gut) that 
maybe linked with low platelet counts, and blood clotting changes.  Uncommonly, 
this bleeding may cause bloody diarrhea and/or bloody vomit.  
KUMC IRB # STUDY00002857 | Approval Period 5/28/2019 – 11/27/2019 | FWA# 00003411


Page 10 of 18                                                                                             
Protocol #: 2015-IIT-BMT-MM-AutoSCT
• Nosebleeds 
• Kidney function that gets worse 
• Infections of the bladder, sinuses, throat, stomach and intestines (gut), skin and       
at the area of skin where your catheter is placed 
• Fungal infections in the mucous membrane such as the mouth and throat and     
uncommonly in the skin and nails 
• Life-threatening infections in the blood (sepsis)
• Changes in blood sugar have been reported in a few diabetic patients who took 
oral antidiabetic medicine.  If you are taking oral antidiabetic medicines you may 
need your blood sugar levels watched more closely.  
• Blood in the urine 
• Feeling confused  
• Changes in the way things taste
• Abnormal liver tests and decreased protein in the blood  
• Lowered amount of potassium and sodium in your blood and increase in the  
amount of calcium in your blood
• Infection 
• Fall that may cause injury
• Muscular weakness
Uncommon Bortezomib Risks (occurs in less than 1% of patients):
•
Inflammation and fluid buildup in the lungs, or pus build up between the layers 
surrounding the lungs that may cause breathing problems, and can be life-
threatening or lead to death. Increased blood pressure in the lungs, called 
pulmonary hypertension, has also been reported.  This can cause breathing 
problems and can be life-threatening.  If you have new or worsening breathing 
problems you should tell your doctor.
•
Inflammation of the layers surrounding your heart or collection of fluid around the 
heart may cause chest pain or breathing problems and can be life-threatening or 
lead to death.  If you have new or worsening chest pain or breathing problems 
you should tell your doctor.
•
Hepatitis (inflammation of the liver) and liver failure (in patients who also got 
many drugs and had other serious medical problems).
•
Pain, redness, swelling and infection in the area of the skin where bortezomib is 
injected
•
Pain in the mouth and throat when swallowing 
•
Loss of hearing 
•
Intestinal obstruction (blockage in the gut) that may get better on its own and 
may need surgery and inflammation of the intestines, pancreas or stomach 
•
Coughing up blood 
•
Bleeding in the brain and subdural hematoma which is bleeding between the 
skull and your brain
•
Fast death of cancer cells that may let toxins into the blood and injure organs, 
such as the kidneys 
KUMC IRB # STUDY00002857 | Approval Period 5/28/2019 – 11/27/2019 | FWA# 00003411


Page 11 of 18                                                                                             
Protocol #: 2015-IIT-BMT-MM-AutoSCT
•
Allergic reactions that may include skin swelling and/or swelling of the face or 
throat and could be severe or life threatening 
•
Severe muscle weakness and paralysis (not being be able to move your arms 
and legs)
•
Changes to the brain that may cause convulsions and confusion
•
Inflammation of the back side of the brain, which is reversible (also called 
“posterior leukoencephalopathy syndrome”) and may cause headaches, changes 
in your vision, changes in your mental status, or seizures (sudden abnormal 
electrical activity in the brain that causes you to lose control of part or all of your 
body, such as jerking, shaking, drooling, staring, etc.)
•
Cardiac arrest (fatal outcome have been reported)
•
Loss of some to all vision affecting one or both eyes, which may be caused by 
damage to the nerve in the eye.  Loss of vision may or may not be reversible.
Possible Risks of G-CSF
Most Common (occurs in 5% or more of patients)
•
aching bone pain (usually relieved by Tylenol™)
•
headache
•
muscle ache
•
tiredness
•
nausea
•
vomiting
•
trouble sleeping
Rare but Serious (occurs in an estimated 1 out of 10,000 patients)
There is a small risk of pain and bleeding from the spleen reported among people 
receiving G-CSF.  Symptoms of this side effect are pain on the upper left side just 
below the rib cage.  If you feel pain in this area, you should contact your transplant 
physician immediately. 
Possible Risks of Mozobil
Most Common (occurs in 10% or more of patients)
•
diarrhea
•
nausea
•
fatigue
•
reaction where mozobil is injected
•
headache
•
dizziness
•
vomiting
•
joint pain
KUMC IRB # STUDY00002857 | Approval Period 5/28/2019 – 11/27/2019 | FWA# 00003411


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Risks of Stem Cell Collection and Transplantation: Because stem cell collection and 
transplantation procedures are a standard of care procedure for the type of cancer you 
have, the risks of stem cell collection and transplantation will be discussed with you as 
a part of your standard of care consenting process.
Blood Draw Risks 
You will need to have samples of blood taken during the study for laboratory testing.  
You may experience temporary discomfort from these periodic blood draws.  These 
needle sticks may cause local pain, bruising and swelling, lightheadedness, dizziness 
and rarely, fainting and/or a local infection. 
Pregnancy Risks 
The study drugs used in this study might hurt an unborn child or a child who is breast-
feeding.  You cannot be in this study if you are a woman who is pregnant, nursing a 
baby, or if you are trying to get pregnant.
Women (of child-bearing potential) will have a pregnancy test before the study starts. 
Men and women (of child-bearing potential) must agree to take appropriate precautions 
to avoid becoming pregnant, or fathering a child.  Even men that have been surgically 
sterilized (had a vasectomy) must agree to follow these precautions.
Women must either completely abstain from sexual intercourse (abstinence) or use two 
acceptable forms of birth control from the time you sign this informed consent form 
through at least 30 days after your last treatment.  Acceptable forms of birth control 
(besides abstinence) are:
•
Barrier method (cervical cap with spermicide plus male condom; diaphragm with 
spermicide plus male condom)
PLUS
•
Hormonal method (oral contraceptives, implants, or injections) or an intrauterine 
device (e.g., Copper T).
Men must agree to one of the following:
•
Use the barrier method as described above from the time of signing this consent 
form through at least 30 days after the last treatment, or
•
Completely abstain from sexual intercourse.
The study doctor must approve the form of birth control. You must talk to your study 
doctor before changing any birth control methods you have already agreed to use.
There may be pregnancy risks that are not known yet.  For this reason, you must tell 
the researcher right away if you get pregnant during the study. 
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Are there benefits to being in this study?  
You may or may not benefit from this study.  If the study drug is effective, and you are 
randomized to receive the study drug, you may lower your risk of the cancer coming 
back at a later time.  Researchers hope that the information from this research study 
may be useful in the treatment of other patients with multiple myeloma.
Will it cost anything to be in the study?  
Most of the procedures performed in this study are part of your regular cancer care 
(typically called “standard of care”) and will not be paid for by the study.  This includes 
the cost of any medications to treat side effects.  The study will collect data from the 
standard of care you receive.  The standard of care procedures (those that would be 
part of your cancer care whether or not you participate in the study) will be charged to 
your insurance or Medicare, if applicable. 
It is possible that your insurance or Medicare will not pay for these standard of care 
charges because they take place within a research study.  You may want to talk to your 
insurance company and review your specific benefits and coverage before deciding to 
participate. You will be responsible for normal co-pays, deductibles and non-covered 
services that are not the responsibility of the study. Some procedures require Pre-
Certification from your insurance company and representatives of the clinic or hospital 
will be helping you with that process. Pre-Certification is not a guarantee of payment. If 
you have further questions about tests covered by the study, please talk to a member of 
the study team.  
You can still be in the study even if your insurance denies coverage for your standard of 
care treatment or if you are uninsured. The University of Kansas Hospital may have a 
financial assistance program to patients who qualify. If you do not qualify for the 
financial assistance (or your hospital does not provide financial assistance), you will be 
charged for all bills that are not the responsibility of the study.  Please contact The 
University of Kansas Hospital’s Patient Financial Services for more information.
The study drug bortezomib and the other drugs (G-CSF and Mozobil) used in this study 
are commercially available.  You or your insurance company will be responsible for the 
cost of the drugs, as well as for the costs associated with preparing the drugs and 
giving the drugs to you.
For more information on clinical trials and insurance coverage, you can visit the 
National Cancer Institute’s Web site at:  
http://www.cancer.gov/clinicaltrials/learningabout/payingfor
You can print a copy of the “Clinical Trials and Insurance Coverage” information from 
this Web site.  Another way to get the information is to call 1-800-4-CANCER 
(1-800-422-6237) and ask them to send you a free copy.
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Will I get paid to participate in the study?
You will not receive any payment for participating in the study.
Will the researchers get paid for doing the study? 
The University of Kansas Medical Center (KUMC) is being paid to perform this study.
The University of Kansas (KU) is paid a royalty based on the sales of the drug, 
bortezomib (VELCADE). None of the investigators conducting this study will receive 
personal monetary benefit from the study’s success. 
Two committees at the University of Kansas Medical Center have independently 
reviewed this project. The University’s relationship will be reviewed by those two 
committees on an annual basis. Their goal is to minimize any influence of the financial 
interests on the conduct of the study. However, you should make your own decision 
about whether these financial interests affect your decision to participate. If you would 
like more information, please ask the person obtaining informed consent from you. You 
may also contact the Office of Compliance at (913) 588-1288 or toll-free 1-877-588-
5757 and TDD (913) 588-7963.
What happens if I get hurt or sick during the study?  
If you have a serious side effect or other problem during this study, you should 
immediately contact Dr. Siddhartha Ganguly at 913-588-6030, which is also listed on 
the front of this consent form.  
If it is after 5:00 p.m., a holiday or a weekend, you should call 913-588-5000 and ask for 
the hematologist on call.  A member of the research team will decide what type of 
treatment, if any, is best for you at that time. 
If you have a bodily injury as a result of participating in this study, treatment will be 
provided for you at the usual charge.  Treatment may include first aid, emergency care 
and follow-up care, as needed.  Claims will be submitted to your health insurance 
policy, your government program, or other third party, but you will be billed for the costs 
that are not covered by the insurance.  You do not give up any legal rights by signing 
this form.
If you think you have been harmed as a result of participating in research at the 
University of Kansas Medical Center (KUMC), you should contact the Director, Human 
Research Protection Program at Mail Stop #1032, University of Kansas Medical Center, 
3901 Rainbow Blvd., Kansas City, KS 66160.  You may also call (913) 588-1240.  
Under certain conditions, Kansas s state law or the Kansas Tort Claims Act may allow 
payment to persons who are injured in research at KUMC.
Do I have to be in the study?
Being in research is voluntary.  You can choose whether or not to participate.  Even if 
you decide not to join the study, you can still come to KUMC for services and treatment. 
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Protocol #: 2015-IIT-BMT-MM-AutoSCT
What other choices do I have?
You can choose not to be in the study.  Instead of being in this study, you can receive 
treatment that is already available, such as autologous stem cell transplantation without 
the study drug, bortezomib.
Your other choices may include:
•
Getting treatment or care for your cancer without being in a study.  The treatment 
on this study may be available at this center or at other locations.
•
Taking part in another study
•
Getting no treatment
•
Getting comfort care, also called palliative care.  This type of care helps reduce 
pain, tiredness, appetite problems and other problems caused by the cancer.  It 
does not treat the cancer directly, but instead tries to improve how you feel.   
Comfort care tries to keep you as active and comfortable as possible.  
Talk to your doctor about your choices before you decide if you will take part in this 
study.  
How will my privacy be protected? 
The researchers will protect your information, as required by law.  
Absolute 
confidentiality cannot be guaranteed because persons outside the study team may 
need to look at your study records.  Your health information is protected by a federal 
privacy law called HIPAA.  By signing this consent form, you are giving permission for 
KUMC to use and share your health information.  If you decide not to sign the form, you 
cannot be in the study.  
The researchers will only use and share information that is needed for the study.  To do 
the study, they will collect health information from the study activities and from your 
medical record.  Your medical records at KUMC may contain information such as name, 
address, phone, date of birth, social security number, or other identifiers.  Your health 
information will be used at KUMC by Dr. Ganguly, members of the research team, The 
University of Kansas Hospital Medical Record Department, the KUMC Research 
Institute, Data Safety Monitoring Committee and officials at KUMC who oversee 
research, including members of the KUMC Human Subjects Committee and other 
committees and offices that review and monitor research studies.  
By signing this form, you are giving Dr. Ganguly, and the research team permission to 
share information about you with persons or groups outside KUMC.  Your information 
will be shared with the laboratory that processes study lab samples, the study’s Data 
and Safety Monitoring Committee, the U.S. Food and Drug Administration (FDA) and 
U.S. agencies that oversee human research (if a study audit is performed), and similar 
agencies in foreign countries.  
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These groups or agencies may make copies of study records for audit purposes.  The 
purpose for using and sharing your information is to make sure the study is done 
properly and to evaluate the safety and effectiveness of the study drug, bortezomib.
The HIPAA privacy law may not apply to everyone who receives your health 
information.  Your information might not be protected by HIPAA if persons outside 
KUMC disclose it.  In some cases, there may be other laws that protect your information 
from improper use.  
Your permission to use and share your health information will not expire unless you 
cancel it.  Any research information that is placed in your medical record will be kept 
indefinitely.  
While you are participating in this study, you may see and copy any study information 
that is placed in your KUMC medical record.  However, some study information is kept 
only by the researcher.  The records kept only by the researcher may not be available 
to you until the end of the study.  
The researchers may publish the results of the study.  If they do, they will only discuss 
group results.  Your name will not be used in any publication or presentation about the 
study.  
Can I stop being in the study?
You may stop being in the study at any time.  Your decision to stop will not prevent you 
from getting treatment or services at KUMC.  If you would be harmed by stopping the 
study drug suddenly, the researchers may ask you to gradually reduce the dose.  You 
might be asked to come back for a final study visit.  
You have the right to cancel your permission for researchers to use your health 
information. If you want to cancel your permission, please contact Dr. Ganguly. The 
mailing address is:
Siddhartha Ganguly, MD
University of Kansas Medical Center
Westwood Campus, MS 5003
2330 Shawnee Mission Parkway, Suite 210
Westwood, KS 66205
If you cancel permission to use your health information, you will be withdrawn from the 
study. The researchers will stop collecting any additional information about you about 
you unless they need information about a side effect of the study drug, bortezomib.  
They are permitted to use and share information that was gathered before they 
received your cancellation.  
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Could my participation be stopped early? 
This study might be stopped, without your consent, by the FDA.  Your participation also 
might be stopped by the investigator or by the University of Kansas Medical Center if it 
is in your best interest or if you do not follow the study requirements.  
If necessary, the study doctor may decide to discontinue your treatment in this study if:  
•
Your disease worsens despite treatment
•
The side effect(s) of the drug(s) are too unsafe for you
•
New information about this combination of drugs becomes available that 
suggests the drugs may not be helpful or are unsafe for you
Neither the investigator nor the University of Kansas Medical Center will be obligated to 
provide you with any study drug (bortezomib) or treatment if the study is stopped early.  
Your physician will decide about future treatment, if it is needed.  
Who can I talk to about the study?  
Before you sign this form, Dr. Ganguly or other members of the study team should 
answer all your questions.  You can talk to the researchers if you have any more 
questions, suggestions, concerns or complaints after signing this form.  If you have any 
questions about your rights as a research subject, or if you want to talk with someone 
who is not involved in the study, you may call the Human Subjects Committee at 
(913) 588-1240.  You may also write the Human Subjects Committee at:
Human Subjects Committee
Mail Stop #1032
University of Kansas Medical Center
3901 Rainbow Blvd.
Kansas City, KS 66160
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site 
at any time.
KUMC IRB # STUDY00002857 | Approval Period 5/28/2019 – 11/27/2019 | FWA# 00003411


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CONSENT
Dr. Siddhartha Ganguly or the research team has given you information about this 
research study.  They have explained what will be done and how long it will take.  They 
explained any inconvenience, discomfort or risks that may be experienced during this 
study.  
By signing this form, you say that you freely and voluntarily consent to participate in this 
research study.  You have read the information and had your questions answered.  
You will be given a signed copy of the consent form to keep for your records.
____________________________________
Print Participant’s Name
_________________________
_______
__________________
Signature of Participant
Time
Date
____________________________________
Print Name of Person Obtaining Consent
____________________________________
__________________
Signature of Person Obtaining Consent
Date
KUMC IRB # STUDY00002857 | Approval Period 5/28/2019 – 11/27/2019 | FWA# 00003411