Conditions: Multiple Myeloma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 90
Healthy volunteers: no

Brief summary:
This randomized phase II trial compares how well adding XMO2 Filgrastim (Granix) to melphalan before a stem cell transplant works in treating patients with multiple myeloma. Chemotherapy drugs, such as melphalan, are given to prepare the bone marrow for the stem cell transplant. Giving colony-stimulating factors, such as XMO2 Filgrastim (Granix), may help multiple myeloma cells move from the patient's bone marrow to the blood where they may be more sensitive to treatment with melphalan. It is not yet known whether adding XMO2 Filgrastim (Granix) to melphalan before a stem cell transplant will work better than melphalan alone in treating multiple myeloma

Detailed description:

Arms:
arm 1: Granix on Day -7 through Day -2.

HDM intravenously (IV) on Day -2.

Autologous stem cell transplantation on Day 0 arm 2: HDM intravenously (IV) on Day -2.

Autologous stem cell transplantation on Day 0.

Interventions: intervention 1: Granix intervention 2: High dose melphalan (HDR) intervention 3: Autologous Stem Cell Transplant (ASCT)
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol document:
Prot_SAP_000.pdf: 
Protocol Version: 06/19/2017 
 
Page 1 of 
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A Study of Granix to Disrupt the Bone Marrow Microenvironment in Patients with Multiple 
Myeloma Undergoing Autologous Stem Cell Transplantation  
 
Washington University School of Medicine 
Division of Oncology 
660 South Euclid Avenue, Campus Box 8007 
St. Louis, MO  63110 
 
Protocol#: 201405057 
Teva Protocol#: TV44688-ONC-60114 
Version Date: 06/19/2017 
 
Principal Investigator: 
Meagan Jacoby, M.D., Ph.D. 
Phone:  (314) 454-8304 
E-mail:  mjacoby@wustl.edu 
 
Sub-Investigators 
Camille Abboud, M.D.  
 
 
Keith Stockerl-Goldstein, M.D. 
Amanda Cashen, M.D. 
 
             Matthew Christopher, M.D., Ph.D. 
 
Geoffrey Uy, M.D                                                John F. DiPersio, M.D., Ph.D.  
 
Ravi Vij, M.D.  
 
 
 
Todd Fehniger, M.D., Ph.D. 
 
 
Matthew Walter, M.D.  
 
 
Iskra Pusic, M.D. 
 
 
 
Lukas Wartman, M.D.  
 
 
Rizwan Romee, M.D.  
 
 
John Welch, M.D., Ph.D. 
 
 
Mark Schroeder, M.D. 
 
 
Peter Westervelt, M.D., Ph.D. 
 
Statistician: 
 
Kathryn (Kim) Trinkaus, Ph.D.  
 
Study Drug(s):  
tbo-filgrastim (Granix) 
Melphalan (Alkeran) 
 
IND#:  
 
122470 
 
clinicaltrials.gov #: 
NCT02112045  
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is confidential 
and may not be further disclosed by them. 
 


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A Study of Granix to Disrupt the Bone Marrow Microenvironment in Patients with Multiple 
Myeloma Undergoing Autologous Stem Cell Transplantation  
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
05/14/2014 
Amendment 1 
 
 
 
 
 
 
 
08/12/2014 
Amendment 2 (PRMC approved only) 
 
 
 
 
01/07/2015 
Amendment 2 
 
 
 
 
 
 
 
01/08/2015 
Amendment 3 
 
 
 
 
 
 
 
02/06/2015 
Amendment 4 
 
 
 
 
 
 
 
04/28/2015 
Amendment 5 
 
 
 
 
 
 
 
05/27/2015 
Amendment 6 
 
 
 
 
 
 
 
01/12/2016 
Amendment 7 
 
 
 
 
 
 
 
06/19/2017 
 
 
 


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STUDY SCHEMA 
Overview 
Patients will be randomized (1:1) to receive either Granix & HDM or HDM alone for ASCT 
conditioning. Granix will be administered Day -7 through Day -2 at a dose of 480 or 960 mcg/day 
(based on actual body weight). Melphalan will be administered on Day -2 at a dose of 140 or 200 
mg/m2 .  
 
Experimental Arm 
 
 
 
 
Day -7 
Granix (480 or 960 mcg) 
Day -6 
Granix (480 or 960 mcg) 
Day -5 
Granix (480 or 960 mcg) 
Day -4 
Granix (480 or 960 mcg) 
Day -3 
Granix (480 or 960 mcg) 
Day -2 
Granix (480 or 960 mcg) 
Melphalan (140 or 200 mg/m2) 
Day -1 
Rest Day 
Day 0 
Stem Cell Infusion 
 
Control Arm 
Day -2 
Melphalan (140 or 200 mg/m2) 
Day -1 
Rest Day 
Day 0 
Stem Cell Infusion 
 
 
 
 
 
 
 
 
 


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Table of Contents 
1.0 
BACKGROUND AND RATIONALE ....................................................................................................... 7 
1.1 
High Dose Melphalan Followed by Autologous Stem Cell Rescue in Multiple Myeloma ............. 7 
1.2 
The Multiple Myeloma Microenvironment .................................................................................. 8 
1.3 
G-CSF Treatment Leads to Remodeling of the Bone Marrow Microenvironment ....................... 9 
1.4 
Granix .......................................................................................................................................... 11 
1.5 
Rationale for Study ..................................................................................................................... 11 
2.0 
OBJECTIVES ..................................................................................................................................... 12 
2.1 
Primary Objective........................................................................................................................ 12 
2.2 
Secondary Objectives .................................................................................................................. 12 
2.3 
Exploratory Objective ................................................................................................................. 13 
3.0 
PATIENT SELECTION ........................................................................................................................ 13 
3.1 
Inclusion Criteria ......................................................................................................................... 13 
3.2 
Exclusion Criteria ......................................................................................................................... 14 
3.3 
Inclusion of Women and Minorities ........................................................................................... 14 
4.0 
REGISTRATION PROCEDURES .......................................................................................................... 14 
4.1 
Confirmation of Patient Eligibility ............................................................................................... 15 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ....................................... 15 
4.3 
Assignment of UPN ..................................................................................................................... 15 
4.4 
Randomization ............................................................................................................................ 15 
5.0 
TREATMENT PLAN ........................................................................................................................... 16 
5.1 
Overview ..................................................................................................................................... 16 
5.2 
Autologous Stem Cell Mobilization and Collection ..................................................................... 16 
5.3 
Agent Administration .................................................................................................................. 16 
5.4 
Stem Cell Transplantation ........................................................................................................... 18 
5.5 
General Concomitant Medication and Supportive Care Guidelines ........................................... 18 
5.6 
Women of Childbearing Potential............................................................................................... 19 
5.7 
Consolidation/Maintenance Therapy ......................................................................................... 19 
6.0 
SCHEDULE OF ASSESSMENTS .......................................................................................................... 20 
6.1 
Duration of Study and Follow Up ................................................................................................ 20 
7.0 
DATA SUBMISSION SCHEDULE ........................................................................................................ 21 
8.0 
CORRELATIVE STUDIES .................................................................................................................... 21 
8.1 
Sample Processing ...................................................................................................................... 22 


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9.0 
STATISTICAL CONSIDERATIONS ....................................................................................................... 23 
9.1 
Study Design................................................................................................................................ 23 
9.2 
Sample Size ................................................................................................................................. 23 
9.3 
Accrual Rate ................................................................................................................................ 23 
9.4 
Data Analysis ............................................................................................................................... 23 
9.5 
Toxicity and Plans for Data and Safety Monitoring .................................................................... 24 
9.6 
Correlative Studies ...................................................................................................................... 26 
10.0 
RESPONSE EVALUATION ................................................................................................................. 27 
10.1 
Complete Response .................................................................................................................... 27 
10.2 
Stringent Complete Response ..................................................................................................... 27 
10.3 
Very Good Partial Response........................................................................................................ 27 
10.4 
Partial Response .......................................................................................................................... 27 
10.5 
Stable Disease ............................................................................................................................. 28 
10.6 
Progressive Disease ..................................................................................................................... 28 
10.7 
Clinical Relapse ........................................................................................................................... 28 
10.8 
Progression-Free Survival ........................................................................................................... 29 
10.9 
Overall Survival ........................................................................................................................... 29 
10.10 
Treatment-Related Mortality .................................................................................................. 29 
10.11 
Engraftment ............................................................................................................................ 29 
11.0 
REGULATORY AND REPORTING REQUIREMENTS ........................................................................... 30 
11.1 
Definitions ................................................................................................................................... 30 
11.2 
Reporting to the Human Research Protection Office (HRPO) at Washington University ........... 32 
11.3 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at Washington 
University ................................................................................................................................................ 33 
11.4 
Reporting to the FDA .................................................................................................................. 33 
11.5 
Timeframe for Reporting Required Events ................................................................................. 34 
12.0 
DATA AND SAFETY MONITORING ................................................................................................... 34 
13.0 
REFERENCES .................................................................................................................................... 36 
APPENDIX A: ECOG Performance Status Scale ........................................................................................... 39 
APPENDIX B: Ideal Body Weight and Corrected Body Weight Formulas .................................................... 40 
 
 


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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
High Dose Melphalan Followed by Autologous Stem Cell Rescue in Multiple 
Myeloma   
 
Multiple myeloma (MM) is a plasma cell neoplasm arising from clonal expansion of 
plasma cells in the bone marrow.  The disease is characterized by the presence of a serum 
or urine monoclonal protein which can be used to follow disease progression, and 
patients with MM are at risk of complication from lytic skeletal lesions, renal failure, 
hypercalcemia, anemia, and recurrent infection due to aberrant immune function.   MM 
is the second most common hematologic malignancy in the United States with over 
19,000 new cases in 2010 and nearly 10,000 deaths.[1]  In recent years, several novel 
agents have been approved to treat MM, such as proteosome inhibitors and 
immunomodulatory agents, with dramatic improvements in response and overall 
survival.  Nevertheless, outside of allogeneic stem cell transplantation, the disease is still 
considered incurable in most cases and new treatment strategies are urgently needed.   
 
High dose melphalan (HDM) followed by autologous hematopoietic stem cell transplant 
(ASCT) has been a mainstay of MM treatment for many years and currently is considered 
standard of care for patients who are transplant candidates.  Transplantation may be 
performed either as salvage after relapse or as consolidation therapy after initial 
treatment.  In the latter setting, the initial therapy to reduce disease burden is chosen to 
minimize and effects on the ability to harvest stem cells.  Subsequently, stem cells are 
mobilized using G-CSF alone or in combination with other mobilizing agents, stored, and 
reinfused following treatment with HDM (200mg/m2). 
 
The efficacy of HDM has been demonstrated in a number of prospective clinical trials.  
The Myeloma VII trial randomized 401 patients to HDM plus ASCT versus standard dose 
chemotherapy and found improved complete response (CR) (44% vs 8%), with 
improvements in both progression-free survival (PFS) and overall survival (OS).[2]  
Similarly, the Intergroupe Francais du Myelome randomized 200 patients with 
intermediate to high stage myeloma to HDM plus ASCT versus standard chemotherapy 
and found improved CR (22% versus 5%) as well as improved OS.[3]  Treatment-related 
mortality was similar in each group.  While no prospective trials have compared HDM plus 
ASCT to standard therapy alone in the era of novel agents, HDM plus ASCT remains the 
standard of care with more than 5,300 transplants performed in 2012.[4]   
 
Given the effectiveness of HDM in this setting, several studies have examined whether 
adding other active drugs to the conditioning regimen would result in better outcomes.  
Unfortunately, to date these attempts have either not demonstrated improved efficacy 
or have added unacceptable toxicity.  Allegre et al reported a single-arm phase II study of 
busulfan plus melphalan, showing an improved CR rate compared to historical controls 


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but at the cost of increased mucositis and hematologic toxicity.[5]  Similarly, adding total 
body irradiation to melphalan does not improve CR rate but significantly increases 
mucositis.[6]  Finally, several retrospective studies have failed to show an advantage to 
adding agents such as cyclophosphamide, thiotepa, or idarubicin to HDM in the setting of 
ASCT.[7-9]  Of note,  these trials primarily enrolled younger, fitter patients, while “real 
world”  transplant centers face increasing numbers of patients aged 65 or older with 
significant co-morbidities.[10]  There is considerable interest, therefore, in improving 
transplant protocols to improve efficacy without increasing toxicity. 
 
1.2 
The Multiple Myeloma Microenvironment 
 
Besides hematopoietic cells, the bone marrow microenvironment—collectively termed 
“stroma”—is composed of non-hematopoietic elements such as osteoblasts and 
osteoblast lineage cells, osteoclasts, endothelial cells, CXCL12-abundant reticular cells 
(CAR cells), and the extracellular matrix (ECM).  A growing number of pre-clinical studies 
suggest that this microenvironment plays a key role in supporting the proliferation and 
survival of MM cells (reviewed in[11]).  For example, MM cells adhere to ECM and stromal 
cells via integrins such as VLA-4 and these interactions promote cell cycling and 
antiapoptotic pathways in MM cells.[12]  Similarly, interactions between Notch expressed 
on MM cells and Notch ligand presented by stromal cells leads to activation of pathways 
promoting MM cell survival and proliferation.[13]  Other pathways implicated in MM 
cell/stromal cell signaling include P-selectin/PSGL-1 interactions, the Hedgehog pathway, 
and the WNT pathway. [14-16]  These findings suggest that physical proximity of MM cells 
to the bone marrow stromal elements provides cues for the growth and survival of MM 
cells. 
 
Besides these cell-cell and cell-ECM interactions, the bone marrow microenvironment 
provides a rich supply of cytokines that support MM cell proliferation and survival.  IL-6 is 
a pro-inflammatory cytokine that acts as a potent mitogen for myeloma cells in vitro and 
in vivo.[17]  Elevated serum IL-6 levels are associated with poor prognosis in patients with 
MM, and treatment with anti-IL-6 neutralizing antibody leads to decreased tumor burden 
in animal models of MM.[18]  Besides IL-6, numerous other cytokines and growth factors 
have been implicated in MM survival and progression, including IGF-1 and VEGF.[19, 20] 
 
Of note, several factors that support normal B lymphopoiesis also appear to play a role in 
the growth of malignant MM cells in the bone marrow.  B-cell activating factor (BAFF) is 
a cytokine necessary for normal B cell development that is upregulated in patients with 
MM.  BAFF signaling induces NF-κB, PI-3/AKT and MAPK pathways in MM cells, promoting 
proliferation and survival.[21, 22]  Similarly, another key regulator of B lymphocyte 
development, IL-7, activates the oncogene MUC1 in MM cells, which in turn leads to 
activation of growth signals through activation of the beta catenin pathway. [23]  Finally, 
the chemokine stromal derived factor 1 (SDF-1, CXCL12) is a chemokine highly expressed 


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by CAR cells and osteoblasts in the bone marrow that plays a key role in B-cell survival 
primarily by promoting retention of B lineage precursors in the bone marrow.[24, 25]  
Blocking SDF-1 signaling leads to MM cell release from the bone marrow as well as 
disruption of MM cell homing to the marrow.[26]  
 
Taken together, these findings suggest a model wherein MM cells co-opt normal pro-
survival signaling mechanisms present in the bone marrow microenvironment for their 
own survival and growth.  This raises the possibility that pharmacologic targeting of MM 
cell-stromal interactions may deprive MM cells of pro-survival signals and sensitize MM 
cells to cytotoxic agents. 
 
1.3 
G-CSF Treatment Leads to Remodeling of the Bone Marrow Microenvironment 
 


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G-CSF is a glycoprotein member of the hematopoietic growth factor family that is the 
principal regulator of granulopoiesis.  Clinically, G-CSF is widely used to shorten the 
duration 
of 
neutropenia 
following 
chemotherapy 
and 
to 
mobilize 
hematopoietic 
stem 
cells 
prior 
to 
transplant.  The mechanisms of G-CSF-
induced stem cell mobilization have not 
been fully elucidated, but it appears to 
function at least in part by modifying the 
bone marrow microenvironment, disrupting 
key physical and signaling interactions 
between bone marrow stromal cells and 
both normal hematopoietic progenitors as 
well as malignant cells, promoting their 
egress to the peripheral blood (reviewed 
in[27]).  For instance, G-CSF treatment leads 
to downregulation of SDF-1 in the bone 
marrow, which results in loss of a key 
retention signal for hematopoietic cells and 
their subsequent egress.[28, 29] 
 
Preclinical 
studies 
have 
shown 
that 
mobilization of malignant cells from the 
bone 
marrow 
sensitizes 
them 
to 
chemotherapy, presumably through the loss 
of pro-survival signals provided by the bone 
marrow microenvironment.  For instance, 
Nervi et al. used AMD3100, a small molecule 
inhibitor of SDF-1 signaling,  to mobilize 
leukemic cells in a mouse model of APL and 
showed enhanced killing with cytotoxic 
chemotherapy in mobilized cells.[30]  Zeng 
et al. treated leukemic mice with G-CSF to mobilize blasts and similarly found increased 
sensitivity to chemotherapy.[31]  Currently, several clinical trials are underway to test this 
approach in MDS and acute leukemias.[30-32]  Of note, Azab et al. showed that disruption 
of MM cell-stromal cell interaction by treatment with AMD3100 led to increased 
sensitivity to chemotherapy in a small animal xenograft model of MM.[33]  Together, 
these findings raise the possibility that G-CSF-induced mobilization of myeloma cells could 
sensitize them to chemotherapy by physically disrupting pro-survival signals from stromal 
cells in the bone marrow microenvironment.  
  


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In addition to mobilizing myeloma cells from a protective bone marrow niche, preclinical 
data from our group suggests that G-CSF treatment could lead to overall reduction of pro-
survival signals for myeloma cells in the bone marrow.  G-CSF treatment causes a transient 
remodeling of the bone marrow microenvironment to suppress the lymphoid 
compartment, including plasma cells.  G-CSF treatment targets certain bone marrow 
stromal cells to suppress their production of factors that support lymphopoiesis and 
plasmablast maintenance.  Specifically, G-CSF targets CXCL12-abundant reticular (CAR) 
cells and osteoblasts (Figure 1A-B), both of which have been implicated in B 
lymphopoiesis [25, 34].  Expression of CXCL12, c-kit, IL-6, IL-7, and insulin-like growth 
factor-1 is markedly suppressed by G-CSF treatment in CAR cells and osteoblasts (Figure 
1C-E).   The loss of these supportive signals may lead to decreased myeloma cell survival 
and increased sensitivity to chemotherapy.  Indeed, in mice, G-CSF treatment results in 
an 
8-fold 
reduction 
of 
plasmablasts 
in 
the 
bone 
marrow 
(Figure 
2). 
 
1.4 
Granix 
 
The development of recombinant G-CSF has allowed for its widespread clinical use in the 
settings described above.  Until recently, the most commonly used recombinant G-CSF 
have been Filgrastim, manufactured using an Escherichia Coli expression system, and 
lenograstim, which is derived from Chinese hamster ovary cells.  Granix (also known as as 
Biograstim, Filgrastim ratiopharm, and Ratiograstim) has been FDA approved for use in 
febrile neutropenia prophylaxis after chemotherapy.  It has been shown to have 
equivalent efficacy and safety to the most commonly used recombinant G-CSF, filgrastim, 
in numerous in vitro, in vivo, and pharmacokinetic studies.[35-39]   
 
1.5 
Rationale for Study 
 
In the era of novel agents such as proteasome inhibitors and immunomodulatory agents, 
overall survival in MM has improved dramatically.  Nevertheless, cures are rare and 


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patients are typically managed with a succession of treatments designed to decrease 
disease burden and improve survival.  HDM followed by ASCT remains a potent tool in 
this regard; however, attempts to improve upon HDM by adding other active agents to 
transplant protocols have largely resulted in unacceptable increases in toxicity.  Current 
evidence suggests a major role for interactions between MM cells and the local bone 
marrow microenvironment in promoting expansion and survival of MM cells in the bone 
marrow.  G-CSF treatment causes the profound, transient changes in the bone marrow 
microenvironment that result in loss of many of the local signals that are postulated to 
support MM cell survival.  We hypothesize, therefore, that G-CSF will sensitize MM cells 
to HDM in the setting of ASCT, resulting in improved response rates while not increasing 
transplant-related toxicity.  We propose to test this hypothesis with a single center, phase 
II randomized study to test the safety and efficacy of the recombinant G-CSF Granix plus 
HDM versus HDM alone prior to ASCT.  
 
 
2.0 
OBJECTIVES 
 
2.1 
Primary Objective 
 
To compare the complete response rate (CR+sCR) at day 100 of patients treated with 
Granix + HDM followed by ASCT to patients treated with HDM alone followed by ASCT.  
 
2.2 
Secondary Objectives 
 
1. To compare the toxicity of Granix + HDM to HDM alone.  
 
2. To compare the overall response rate (CR+sCR+VGPR+PR) at day 100 of patients 
treated with Granix + HDM followed by ASCT to patients treated with HDM alone 
followed by ASCT. 
 
3. To compare the overall survival of patients treated with Granix + HDM followed by 
ASCT to patients treated with HDM alone followed by ASCT. 
 
4. To compare the progression-free survival of patients treated with Granix + HDM 
followed by ASCT to patients treated with HDM alone followed by ASCT. 
 
5. To compare the rate of neutrophil engraftment of patients treated with Granix + HDM 
followed by ASCT to patients treated with HDM alone followed by ASCT. 
 
6. To compare the rate of platelet engraftment of patients treated with Granix + HDM 
followed by ASCT to patients treated with HDM alone followed by ASCT. 
 


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2.3 
Exploratory Objective 
 
To describe the biological effects of Granix on the bone marrow and changes in the bone 
marrow cytokine and chemokine levels. This will include:  
a. Quantification of marrow osteoblasts and CAR cells  
b. Measurement of SDF-1 (CXCL12), IL-6 and BAFF  
c. Assessment of myeloma cell proliferation and survival in the bone marrow.   
d. Assessment of myeloma cell mobilization into the blood by G-CSF 
 
 
3.0 
PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
1. Symptomatic multiple myeloma requiring treatment 
 
2. Received at least two cycles of any regimen as initial systemic therapy for multiple 
myeloma and are within 2-12 months of the first dose of initial therapy 
 
3. At least 18 years of age  
 
4. Adequate autologous stem cell collection, defined as an unmanipulated, 
cryopreserved, peripheral blood stem cell collection containing at least 2 × 106 CD34+ 
cells/kg based on patient body weight. 
 
5. Adequate organ function as measured by: 
a. Cardiac function: Left ventricular ejection fraction at rest ≥40%  
b. Hepatic function: Bilirubin ≤2 × ULN and aspartate amino transferase/alanine 
amino transferase (AST/ALT) ≤3 × ULN 
c. Renal 
function: 
Creatinine 
clearance 
≥40 
mL/minute 
(measured 
or 
calculated/estimated) 
d. Pulmonary function: Carbon monoxide diffusing capacity (DLCO; corrected for 
hemoglobin [Hgb]), forced expiratory volume in 1 second (FEV1), forced expiratory 
vital capacity (FVC) ≥50% of predicted value  
e. Oxygen saturation ≥92% on room air  
 
6. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 (see 
Appendix A) 
 
7. Able to understand and willing to sign an IRB-approved written informed consent 
document 
 
 


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3.2 
Exclusion Criteria 
 
1. Evidence of multiple myeloma disease progression (as defined by IMWG) any time 
prior to ASCT 
 
2. Prior stem cell transplant (autologous or allogeneic) 
 
3. Smoldering MM not requiring therapy 
 
4. Plasma cell leukemia 
 
5. Systemic amyloid light chain amyloidosis 
 
6. Active bacterial, viral, or fungal infection 
 
7. Seropositive for human immunodeficiency virus (HIV) 
 
8. Known, active hepatitis A, B, or C Infection 
 
9. Pregnant or breastfeeding. 
 
10. Receiving other concurrent anticancer therapy (including chemotherapy, radiation, 
hormonal treatment, or immunotherapy, but excluding corticosteroids) within 7 days 
prior to the ASCT or planning to receive any of these treatments prior to the last study 
visit on Day +100. 
 
11. Hypersensitive or intolerant to any component of the study drug(s) formulation  
 
12. Receiving growth factors (filgrastim, XM02-filgrastim, peg-filgrastim, plerixafor, etc) 
or undergoing apheresis < 7 days prior to the start of treatment on protocol (Day -7).   
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this 
trial. 
 
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 


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The following steps must be taken before registering patients to this study: 
1. Confirmation of patient eligibility 
2. Registration of patient in the Siteman Cancer Center OnCore database 
3. Assignment of unique patient number (UPN) 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility collecting the information listed below: 
1. The registering MD’s name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form 
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
All patients must be registered through the Siteman Cancer Center OnCore database. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study. All data 
will be recorded with this identification number on the appropriate CRFs. 
 
4.4 
Randomization 
 
Eligible and consenting patients will be randomized on a 1:1 basis to receive either HDM 
+ Granix followed by ASCT or HDM alone followed by ASCT. Patients will be stratified 
based on response status at randomization (CR/VGPR v. PR/SD).   
 
Randomization will be in blocks of random size.  The randomization table will be uploaded 
in our REDCap system.  Randomization will occur via an online form with entry of the 
patient ID number and stratum information.  Once all information is entered, 
randomization is carried out via a submit button through REDCap.  The randomization 
scheme will be created using a formal probability model implemented in SAS (version 9.3 
or higher). 
 
 


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5.0 
TREATMENT PLAN 
 
5.1 
Overview 
 
Patients will be randomized (1:1) to receive either Granix plus HDM or HDM alone for 
ASCT conditioning. Patients randomized to receive Granix will be dosed daily on Days -7 
through -2 at a dose of 480 or 960mcg/day (dependent on weight). Melphalan will be 
given to all patients on Day -2 at a dose of 140 or 200mg/m2.  
 
5.2 
Autologous Stem Cell Mobilization and Collection 
 
Patients will undergo autologous stem cell mobilization following institutional guidelines 
prior to study entry. To prevent the potentially confounding effect of growth factors, stem 
cell mobilization and apheresis must be performed > 7 days prior to the start of treatment 
on protocol (Day -7).   
 
5.3 
Agent Administration 
 
5.3.1 Granix 
 
Granix will be administered subcutaneously (SQ) starting on Day -7 and continuing 
through Day -2 (6 total doses). Granix is supplied in single-use syringes with 480 
mcg of drug. Patients who weigh less than or equal to 100 kg will receive a dose 
of 480 mcg per day; patients who weigh more than 100 kg will receive a dose of 
960 mcg per day. Granix dose should be calculated on using actual weight from 
the screening visit; however, the dose should be recalculated if the patient’s 
weight changes by more than 10% at the Day -7 visit. On Day -2 Granix 
administration should occur at least approximately 1 hour prior to melphalan 
administration.  
 
5.3.2 Melphalan 
 
 
Melphalan will be administered intravenously (IV) via a central venous catheter 
over approximately 30 minutes on Day -2 at a dose of 140 or 200 mg/m2. Full dose 
melphalan (200mg/m2) should be administered to all patients unless contradicted 
due to advanced age, renal disease, etc.  
 
For the calculation of BSA, actual body weight should be used for patients who 
weigh less than 100% of their ideal body weight (IBW). Patients who weigh 100-
120% of their IBW, BSA should be calculated based on IBW. For patients who 
weigh more than 120% of their IBW, BSA should be calculated based on corrected 


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body weight (CBW). Formulas for calculating IBW and CBW are provided in 
Appendix B. 
 


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5.3.3 Dose Modifications and Delays 
 
5.3.3.1 Granix 
 
Blood counts will be monitored on Day -7 and Day -2 while on study. Granix 
should be held if WBC ≥ 100,000 /μl. Once WBC improves to < 100,000 /μl, 
Granix dosing may be resumed.  
 
For grade 3 or 4 non-hematologic toxicity related to Granix, hold Granix 
and monitor daily. Once toxicity resolves to ≤ grade 2, Granix dosing may 
be resumed.  
 
Granix dose schedule should not be altered for reasons other than toxicity. 
Missed doses for any reason, including toxicity, will not be made up.  
 
5.3.3.2 Melphalan 
 
Melphalan doses may be delayed for adverse events at the discretion of 
the treating physician with consultation of the Principal Investigator. 
Delayed doses can be made up.  
 
5.3.4 Pharmaceutical Information 
 
5.3.4.1 Granix  
 
Granix is a recombinant methionyl human granulocyte colony stimulating 
factor. It will be provided for study use by Teva Pharmaceuticals.  
 
5.3.4.2 Melphalan 
 
Melphalan, an alkylating agent, is a phenylalanine derivative of nitrogen 
mustard. It will be sourced from commercial supply. Prior to 
administration, melphalan will be diluted with 250mL of normal saline, to 
a final concentration of less than or equal to 2 mg/mL. 
 
5.4 
Stem Cell Transplantation 
 
Autologous peripheral blood stem cells (≥ 2x106 CD34+ cells/kg) will be given per 
institutional guidelines on Day 0.  
 
5.5 
General Concomitant Medication and Supportive Care Guidelines  
 


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Starting on Day +7, filgrastim (Neupogen) will be administered daily SC at a dose of 
5mcg/kg/day until neutrophil engraftment, per institutional guidelines. 
 
Supportive treatment, including anti-emetics, hydration, transfusions, and antibiotics will 
be per discretion of the treating physician. 
 
5.6 
Women of Childbearing Potential  
 
Women of childbearing potential (defined as women with regular menses, women with 
amenorrhea, women with irregular cycles, women using a contraceptive method that 
precludes withdrawal bleeding, and women who have had a tubal ligation) are required 
to have a negative serum pregnancy test within 14 days prior to Day -7.   
 
Female and male patients (along with their female partners) are required to use two 
forms of acceptable contraception, including one barrier method, during participation in 
the study and for 1 month following the administration of study treatment.  
 
5.7 
Consolidation/Maintenance Therapy 
 
To prevent confounding effects, consolidation or maintenance therapy after transplant is 
not permitted for the duration of the study, through the Day +100 visit. Any patient who 
begins consolidation or maintenance therapy prior to the Day +100 visit will be removed 
from the study. 
 
 
 
 


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6.0 
SCHEDULE OF ASSESSMENTS 
 
Table 1.  Overview of Study Activities 
Screening1 
Treatment 
D+30 
(+/-7)   
D+100 
(+/-21)   
F/U2 
D-7 
D-
6 
D-
5 
D-
4 
D-
3 
D-
2 
D-1 
D 0 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam including ECOG PS 
X 
 
 
 
 
 
 
 
 
X 
X 
X7 
CBC w/ diff 
X 
X9 
 
 
 
 
X 
X 
X3 
 
 
 
Chemistry4 
X 
 
 
 
 
 
 
 
 
X 
X 
 
SPEP and immunofixation 
X 
 
 
 
 
 
 
 
 
X 
X 
 
Serum free light chains 
X 
 
 
 
 
 
 
 
 
X 
X 
 
24 Hour Urine (Total Protein, UPEP and 
immunofixation) 
X 
 
 
 
 
 
 
 
 
X8 
X8 
 
Serum β-hCG5 
X 
 
 
 
 
 
 
 
 
 
 
 
ECHO or MUGA 
X 
 
 
 
 
 
 
 
 
 
 
 
PFT 
X 
 
 
 
 
 
 
 
 
 
 
 
BMBx morphology 
 
X10 
 
 
 
 
X10 
 
 
 
X 
 
Correlative Studies6 
 
X10 
 
 
 
 
X10 
 
 
 
 
 
Adverse event assessment11 
 
X ----------------------------------------------------------------------------- X 
 
 
1 Within 42 days prior to first study drug dose, with exception of ECHO/MUGA and PFT which are required within 180 days prior to first study drug dose. 
2 Every 6 months for 2 years after Day 0, for relapse and survival 
3 CBC to be performed daily until engraftment then at least weekly until platelet engraftment or Day +100 (whichever occurs first) 
4 Chemistry includes Na, K, CO2, glucose, BUN, creatinine, Ca, total protein, albumin, bilirubin, alkaline phosphatase, AST, ALT, LDH. Phosphorus to be 
included only on day 30.   
5 Required only in women of childbearing potential. 
6 See Section 8.0 for required samples 
7 A telephone visit to assess survival and disease status may be done in lieu of a physical exam.  
8 24 hour urine not required for patients without detectable urine protein on screening exam.  
9 Granix arm only 
10 Required only for the first 10 patients randomized to the Granix arm with measureable monoclonal paraprotein in the blood (by electrophoresis or serum 
free light chain)  
11 Adverse events will be followed until clinical resolution  
 
6.1 
Duration of Study and Follow Up 
 
If the constraints of this protocol are considered to be detrimental to the patient’s health 
and/or the patient no longer wishes to continue protocol therapy, the protocol therapy 
must be discontinued and the reason(s) for discontinuation documented in the case 
report forms. 
 
Patients will be removed from the study any of the following reasons: 
 Death 
 Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
 General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
 Suspected pregnancy 
 Serious noncompliance with the study protocol 
 Lost to follow-up 
 Patient withdraws consent 


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 Investigator removes the patient from study 
 The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue treatment for any reason other than withdrawal of 
consent or loss to follow-up will be followed as indicated in the schedule of assessments (Section 
6.0). 
 
In addition to follow-up visits on Days +30 and +100, patients will be followed every 6 months for 
2 years or until death, whichever occurs first.   
 
 
7.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
Registration Form 
Eligibility Form 
Myeloma Staging Form 
Treatment History Form 
Medical History Form 
Prior to starting treatment 
Study Drug Dosing Form 
Day 0 
Count Recovery Form 
Engraftment 
Follow Up Form 
Day 30 
Day 100 
Every 6 months for 2 years after Day 0 
Disease Assessment Form 
Baseline 
Day 100 
MedWatch Form 
See Section 11.0 for reporting requirements 
 
 
8.0 
CORRELATIVE STUDIES 
 
The specific objectives of the correlative studies are to measure the effect of G-CSF on: 1) 
mobilization of myeloma cells into the blood 2) osteoblast and CAR cell number in the bone 
marrow; 3) expression of CXCL12, IL-6, and BAFF in the bone marrow; and 4) myeloma cell 
apoptosis and cell cycle status in the bone marrow.  
 
To accomplish these objectives, up to ten patients randomized to the Granix arm with 
measureable monoclonal paraprotein in the blood (by electrophoresis or serum free light chain) 


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will have the following specimens collected prior to beginning treatment on Day -7 and 
subsequently before the first dose of melphalan on Day -2: 
 bone marrow aspirate: ~5mL in EDTA tube(s) 
 bone marrow core section: ~5-10mm in sterile PBS 
 peripheral blood: 20cc collected in EDTA tube(s)  
These samples are optional and only patients who indicate they wish to participate in the optional 
testing in the informed consent form will be included.  
 
8.1 
Sample Processing 
 
Samples should be maintained at room temperature and delivered to the laboratory of 
Daniel C. Link located at Room 613 Southwest Tower of the Washington University 
Medical Center.  
 
a) 
Myeloma cell mobilization. Mobilization of myeloma cells into the peripheral 
circulation following treatment with G-CSF is a surrogate for disruption of myeloma-
stromal cell interactions. The magnitude of mobilization will be determined by comparing 
Day -7 and Day -2 samples by flow cytometry. Cells will be stained with CD38 and CD138 
using protocols established in the clinical flow cytometry lab. Plasma cells will be 
identified as CD38high CD138+ cells. 
 
b) 
Osteoblast and CAR cell enumeration. Bone marrow core biopsies will be divided 
and the portion targeted for immunostaining will be fixed in zinc formalin overnight, 
decalcified, paraffin embedded and sectioned using the Anatomic and Molecular 
Pathology (AMP) Core lab at Washington University. Immunostaining protocols for 
human CXCL1231 (R&D systems, #MAB350) and osteocalcin32 (Biotrend Chemikalien 
GmBH) have been published. We have successfully used the CXCL12 antibody to stain 
human bone marrow sections (data not shown). Consistent with a previous report, we 
see CXCL12 expression in bone-lining osteoblasts and CAR cells. The sections will be 
analyzed independently in a blinded fashion by two individuals using standard 
histomorphometry tools to quantify the number of osteoblasts. 
 
c) 
Bone marrow cytokine / chemokine levels. To measure the effect of G-CSF on 
marrow cytokine/chemokine levels, we will analyze a portion of the core biopsy at 
baseline (Day -7) and on Day -2. The core biopsy will be mechanically disrupted and 
divided into cellular and cell-free fractions by centrifugation. Total RNA will be extracted 
from the cellular fraction and real time RT-PCR assays for CXCL12, IL-6, and BAFF will be 
performed in triplicate. The cell-free supernatant will be used to quantify CXCL12, IL-6, 
and BAFF protein expression (in triplicate) using commercially available ELISAs. 
Chemokine and cytokine protein levels from ELISAs will be normalized to total protein 
content. 
 


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d) 
Cell cycle analysis and apoptosis. The cell cycle status of plasma cells will be 
assessed based on Ki67 expression. Ki67 staining have been used assess cell cycle status 
in B and T cell lymphoproliferative disorders, and it has been shown to correlate well with 
cycle status in human tumors. Expression of activated caspase 3 is widely used to assess 
apoptosis. Blood mononuclear cells and bone marrow aspirate cells will be stained with 
CD38, CD138, and either Ki67 or activated caspase 3. Cycling plasma cells will be identified 
as CD38high CD138+ Ki67+ cells. Apoptotic cells will be identified as  
CD38high CD138+ activated-caspase 3+ cells. 
 
 
9.0 
STATISTICAL CONSIDERATIONS 
 
9.1 
Study Design 
 
This is an open label, single institution, two-arm, unstratified, randomized phase II study 
to test the safety and efficacy of Granix in combination with HDM compared with HDM 
alone in patients with MM undergoing ASCT for first-line treatment.  The primary 
endpoint of the study is CR at Day +100 after ASCT.   
 
9.2 
Sample Size 
 
The sample size was determined assuming a two-sided binomial test for difference of 
proportions with power=.80 and significance level=.05. The null hypothesis is H0: CR in 
Granix + HDM arm = CR in HDM-alone arm, against the alternative hypothesis H1: CR in 
Granix + HDM arm ≠ CR in HDM-alone arm. Historical data suggests an expected CR in the 
HDM-alone group of around 55%.  Eighty-eight patients in each arm will provide 80% 
power at a 5% significance level to detect a 20% difference in the proportion of patients 
with CR.   
 
9.3 
Accrual Rate 
 
The target enrollment is 176 patients. Expected accrual is approximately two years, given 
our institutional HDM+ASCT rate of 150-160 per year. 
 
9.4 
Data Analysis 
 
Demographic and clinical characteristics will be summarized using descriptive statistics 
(frequency or percentage with 95% confidence interval, mean, standard deviation, 
quartiles and interquartile range). Responses will be evaluated at Day +100 after 
transplant. The CR at Day +100 after ACST will be calculated, accompanied with 95% 
confidence interval (CI), and the CR in the Granix plus HDM arm will be compared with 
the CR in the HDM-alone arm using Fisher’s Exact test to evaluate the efficacy of Granix 


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plus HDM. Comparisons will be 2-sided, using P value less than 0.05 as significance level. 
PFS and OS will be analyzed by Kaplan-Meier (KM) method, illustrated by KM curves with 
95% CI.  
 
9.4.1 Interim Analysis 
 
One interim analysis to test for efficacy and futility will occur after 88 treated 
patients, 44 in each study arm, have completed the day +100 visit. Two one-sided 
tests for difference of proportions will be used. O’Brien-Fleming sequential 
stopping boundaries indicate that the study will be stopped for futility if the 
standardized Z value < .668 and for benefit if the value > 2.68. 
 
9.5 
Toxicity and Plans for Data and Safety Monitoring 
 
Toxicity will be reviewed on a continuous basis. Early stopping of this trial will be based 
on unacceptable toxicity, defined as excess mortality at Day +30, by assuming that Day 
+30 mortality rate of 10% or less is acceptable and that a toxicity rate of 20% or more 
would be unacceptable.  The plot and table below describe a continuous toxicity 
monitoring rule with 80% power and 0.05 significance level. If the TRM rate is as high as 
20% this rule has a high probability of correctly stopping the study early (probability = 
.95). If the TRM rate is a low as 10% it has a low probability of incorrect early stopping 
(probability = .051).   
 
Adverse events will be assessed using NCI CTCAE v4.0 and summarized by patient, type, 
grade and frequency.  
 
 


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Suspend for review if the 
number of transplant related 
deaths EXCEEDS: 
In the following number of 
patients: 
2 
5 
4 
10 
5 
15 
5 
20 
6 
25 
7 
30 
8 
35 
9 
40 
10 
45 
10 
50 
11 
55 
12 
60 
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95100105110115120125130135140145150155160165170175
Number of Transplant Related Deaths
Number of Patients Eavluable for Transplant Related Death
Suspend for review if the number of transplant related deaths 
falls ABOVE the circled points:


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13 
65 
13 
70 
14 
75 
15 
80 
15 
85 
16 
90 
17 
95 
17 
100 
18 
105 
19 
110 
19 
115 
20 
120 
21 
125 
21 
130 
22 
135 
23 
140 
23 
145 
24 
150 
25 
155 
25 
160 
26 
165 
26 
170 
27 
176 
 
 
 
 
9.6 
Correlative Studies 
 
For correlative studies, measurements collected on the patients enrolled in the Granix 
plus HDM arm will be compared pre-Granix and post-Granix to evaluate Granix effect.   All 
measurements will be summarized using descriptive statistics. Paired t-test or Wilcoxon 
signed rank test (when normality assumption is violated) will be used to test for pre- to 
post- treatment change. Nominal or binary categorical variables will be tabulated at 
baseline and a later time point while the association will be assessed by Fisher’s exact 
test. Ordinal and short scales with repeated observations of the same values will be 
compared using an ordinal test for trend such as Jonckheere’s test. 
 
In addition, since osteoblast and CAR cell enumeration are not established assays, we will 
assess intra-rater variability by computing intra class correlations (ICC), if reasonably 


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Gaussian, and utilize Bland-Altman plots to describe any observable disagreement 
between different raters. 
 
 
10.0 
RESPONSE EVALUATION 
 
Response will be assessed per the International Myeloma Working Group (IMWG) Response 
Criteria[41] as defined below.  
 
10.1 
Complete Response 
 
Complete response (CR) requires all of the following: 
 Disappearance of monoclonal protein by both protein electrophoresis and 
immunofixation studies from the blood and urine 
 <5% plasma cells in the bone marrow 
 Disappearance of soft tissue plasmacytomas 
 
10.2 
Stringent Complete Response 
 
Stringent complete response (sCR) requires all of the following: 
 CR as defined above 
 Normal free light chain ratio 
 Absence of clonal cells in the bone marrow by immunohistochemistry or 
immunofluorescence 
 
10.3 
Very Good Partial Response 
 
Very good partial response (VGPR) requires all of the following: 
 Serum and urine monoclonal protein detectable by immunofixation but not on 
electrophoresis 
OR 
> 90% reduction in serum monoclonal protein with urine monoclonal protein < 
100 mg per 24 hours 
 If present, > 50% reduction in the size of soft tissue plasmacytomas (by clinical or 
radiographic examinations)  
 
10.4 
Partial Response 
 
Partial response (PR) requires all of the following: 
 > 50% reduction in the level of the serum monoclonal protein. 
 Reduction in urine monoclonal protein by either > 90% or to < 200 mg 


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 If present, > 50% reduction in the size of soft tissue plasmacytomas (by clinical or 
radiographic examinations) 
 If serum and urine monoclonal protein are unmeasurable, a >50% decrease in 
difference between the involved and uninvolved free light chain levels is required 
in place of monoclonal protein criteria (The absolute decrease must be > 10 mg/dl) 
 If serum and urine monoclonal protein are unmeasurable and serum free light 
chain is unmeasurable, a > 50% reduction in plasma cells is required in place of 
monoclonal protein provided that baseline bone marrow plasma cell percentage 
was > 30% 
 
10.5 
Stable Disease 
 
Stable disease (SD) is defined as not meeting criteria for any other response as defined in 
this section. 
 
10.6 
Progressive Disease 
 
Progressive disease (PD) requires one or more of the following: 
 > 25% increase in the level of serum monoclonal protein, which must also be an 
absolute increase of at least 0.5 g/dL, and confirmed on a repeat investigation. 
 > 25% increase in 24-hour urine monoclonal protein, which must also be an 
absolute increase of at least 200 mg/24hr and confirmed on a repeat investigation. 
 > 25% increase in plasma cells in a bone marrow aspirate or on trephine biopsy, 
which must also be an absolute increase of at least 10%. 
 > 25% increase in the difference between involved and uninvolved free light chain 
levels (The absolute increase must be >10 mg/dl) (only in patients without 
measurable serum and urine monoclonal proteins) 
 Definite increase in the size of existing lytic bone lesions or soft tissue 
plasmacytomas. A definite increase is defined as at least 50% (and at least 1 cm) 
increase as measured serially as the sum of the products of the cross-diameters of 
the lesions. 
 Development of new bone lesions or soft tissue plasmacytomas (not including 
compression fracture). 
 Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL or 2.8 
mmol/L not attributable to any cause other than progressive multiple myeloma). 
 
Note: A response of progressive disease nullifies any other concurrent response. For 
example, at a given time point a participant meets criteria for VGPR but has development 
of new bone lesions the response is PD not VGPR. 
 
10.7 
Clinical Relapse 


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Clinical relapse (i.e. progressive disease requiring alternate myeloma treatment) requires 
one or more of the following: 
 Decrease in hemoglobin > 2 g/dl not attributable to any cause other than 
progressive multiple myeloma 
 Increase in creatinine by > 2 mg/dl not attributable to any cause other than 
progressive multiple myeloma 
 Other worsening laboratory result, or clinical condition that the treating physician 
determines is not attributable to any cause other than progressive multiple 
myeloma 
 
10.8 
Progression-Free Survival 
 
Progression-free survival (PFS) is defined as the duration from time of transplant Day 0 to 
time of first progression/clinical relapse, death, or the date the patient was last known to 
be in remission. 
 
10.9 
Overall Survival 
 
Overall survival (OS) is defined as the duration from the time of transplant Day 0 to death 
or last follow-up. 
 
10.10 Treatment-Related Mortality 
 
Treatment-related mortality (TRM), which is defined as death not due to disease 
progression before Day +100, will be calculated. This outcome measure will be 
summarized by the cumulative incidence estimated with 95% confidence intervals.  
 
10.11 Engraftment 
 
The rates of engraftment (neutrophil and platelets) and non-engraftment in the study 
population will be determined using the following definitions:  
 
Neutrophil engraftment is defined as ANC ≥ 0.5 × 109/L × 3 consecutive daily assessments. 
The first of 3 consecutive days for which ANC ≥ 0.5 × 109/L will be recorded as the date of 
neutrophil engraftment. Time to neutrophil engraftment will be calculated as the time 
from the date of the ASCT to the date of neutrophil engraftment.  
 
Non-engraftment is defined as failure to reach an ANC > 0.5 × 109/L × 3 consecutive daily 
assessments by Day +30.  
 


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Platelet engraftment is defined as an untransfused platelet measurement >20,000/mm3 
× 2 consecutive assessments separated by at least 3 days. The first day for which the 
untransfused platelet measurement is >20,000/mm3 will be recorded as the date of 
platelet engraftment. Time to platelet engraftment will be calculated as the time from 
receiving the date of ASCT to the date of platelet engraftment.  Untransfused is defined 
as no transfusions within 7 days.  
 
Non-engraftment is defined as failure to reach platelets > 20,000 × 109/L × 3 consecutive 
assessments by Day +100.  
 
Time to neutrophil and platelet engraftments will be calculated for each patient and 
summarized using Kaplan-Meier estimates.  
 
 
11.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outline below. 
 
The Washington University Human Research Protection Office (HRPO) requires that all events 
meeting the definition of unanticipated problem or serious noncompliance be reported as 
outlined in Section 11.2. 
 
The FDA requires that all serious and unexpected adverse events be reported as outlined in 
Section 11.4.  In addition, any fatal or life-threatening adverse experiences where there is a 
reasonable possibility of relationship to study intervention must be reported. 
 
11.1 
Definitions  
 
11.1.1 Adverse Events (AES) 
 
Definition: any unfavorable medical occurrence in a human subject including any 
abnormal sign, symptom, or disease. 
 
Grading: the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all 
toxicity reporting. A copy of the CTCAE version 4.0 can be downloaded from the 
CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the 
terms listed that should be used are those provided by the Department of Health 


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and Human Services’ Office for Human Research Protections (OHRP). A copy of 
this guidance can be found on OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
11.1.2 Serious Adverse Event (SAE) 
 
Definition:  any adverse drug experience occurring at any dose that results in any 
of the following outcomes: 
o Death 
o A life-threatening adverse drug experience 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant disability/incapacity (i.e., a substantial 
disruption of a person’s ability to conduct normal life functions) 
o A congenital anomaly/birth defect 
o Any other experience which, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above 
 
All unexpected SAEs must be reported to the FDA. 
11.1.3 Unexpected Adverse Experience  
 
Definition: any adverse drug experience, the specificity or severity of which is not 
consistent with the current investigator brochure (or risk information, if an IB is 
not required or available). 
Events that are both serious AND unexpected must be reported to the FDA.  
11.1.4 Life-Threatening Adverse Experience  
 
Definition: any adverse drug experience that places the subject (in the view of the 
investigator) at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that, had it occurred in a more severe form, might 
have caused death. 
 
Life-threatening adverse experiences must be reported to the FDA. 
11.1.5 Unanticipated Problems 
 
Definition: 


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 unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
 related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures 
involved in the research); and 
 suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
11.1.6 Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies that 
govern human subjects research or failure to follow the determinations of the IRB. 
Noncompliance may occur due to lack of knowledge or due to deliberate choice 
to ignore regulations, institutional policies, or determinations of the IRB. 
 
11.1.7 Serious Noncompliance 
 
Definition: noncompliance that materially increases risks, that results in 
substantial harm to subjects or others, or that materially compromises the rights 
or welfare of participants. 
 
11.1.8 Protocol Exceptions 
 
Definition: A planned deviation from the approved protocol that are under the 
research team’s control. Exceptions apply only to a single participant or a singular 
situation. 
 
Local IRB Pre-approval of all protocol exceptions must be obtained prior to the 
event. 
 
11.2 
Reporting to the Human Research Protection Office (HRPO) at Washington 
University 
 
The PI is required to promptly notify the IRB of the following events: 
 Any unanticipated problems involving risks to participants or others which occur 
at WU, any BJH or SLCH institution, or that impacts participants or the conduct of 
the study. 


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 Noncompliance with federal regulations or the requirements or determinations of 
the IRB. 
 Receipt of new information that may impact the willingness of participants to 
participate or continue participation in the research study. 
 
These events must be reported to the IRB within 10 working days of the occurrence of 
the event or notification to the PI of the event. The death of a research participant that 
qualifies as a reportable event should be reported within 1 working day of the occurrence 
of the event or notification to the PI of the event. 
 
11.3 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) 
at Washington University 
 
The PI is required to notify the QASMC of any unanticipated problem occurring at WU or 
any BJH or SLCH institution that has been reported to and acknowledged by HRPO as 
reportable.  (Unanticipated problems reported to HRPO and withdrawn during the 
review process need not be reported to QASMC.) 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via email to a 
QASMC auditor. 
11.4 
Reporting to the FDA 
 
The conduct of the study will comply with all FDA safety reporting requirements. PLEASE 
NOTE THAT REPORTING REQUIREMENTS FOR THE FDA DIFFER FROM REPORTING 
REQUIREMENTS FOR HRPO/QASMC. It is the responsibility of the investigator to report 
any unanticipated problem to the FDA as follows: 
 
 Report any unexpected fatal or life-threatening adverse experiences (Section 
11.1.4) associated with use of the drug  by telephone or fax no later than 7 
calendar days after initial receipt of the information. 
 Report any serious, unexpected adverse experiences (Section 11.1.2), as well as 
results from animal studies that suggest significant clinical risk within 15 calendar 
days after initial receipt of this information. All MedWatch forms will be sent by 
the investigator or investigator’s team to the FDA at the following address or by 
fax: 
 
 
 
 
Food and Drug Administration 


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Center for Drug Evaluation and Research 
Division of Hematology Products 
5901-B Ammendale Rd. 
Beltsville, MD 20705-1266 
FAX: 301-796-9845 
 
11.5 
Timeframe for Reporting Required Events 
 
Reportable adverse events will be collected from first dose of study treatment (Day -7) 
through the Day +30 visit.  For the purposes of this protocol, reportable adverse events 
are events grade 2 or greater events. Reportable adverse events will be followed until 
clinical resolution. Numerous grade 1 events are expected following high dose 
chemotherapy and stem cell transplantation and therefore will not be reported. 
Hematologic toxicities are expected and therefore the following adverse events will not 
be reported regardless of grade: anemia, white blood cell decreased, neutrophil count 
decreased, lymphocyte count decreased, and platelet count decreased.  In addition, the 
following grade 2 non-hematologic adverse events are expected and will not to be 
reported as adverse events: nausea, vomiting, diarrhea, anorexia, fatigue or alopecia.  
 
 
12.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the 
Principal Investigator will provide a Data and Safety Monitoring (DSM) report to the Washington 
University Quality Assurance and Safety Monitoring Committee (QASMC) semi-annually 
beginning six months after accrual has opened (if at least five patients have been enrolled) or 
one year after accrual has opened (if fewer than five patients have been enrolled at the six-month 
mark). 
 
The Principal Investigator will review all patient data at least every six months, and provide a 
semi-annual report to the QASMC. This report will include: 
 HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
 Date of initial HRPO approval, date of most recent consent HRPO approval/revision, date 
of HRPO expiration, date of most recent QA audit, study status, and phase of study 
 History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
 Study-wide target accrual and study-wide actual accrual 
 Protocol activation date 
 Average rate of accrual observed in year 1, year 2, and subsequent years 


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 Expected accrual end date 
 Objectives of protocol with supporting data and list the number of participants who have 
met each objective 
 Measures of efficacy 
 Early stopping rules with supporting data and list the number of participants who have 
met the early stopping rules 
 Summary of toxicities 
 Abstract submissions/publications 
 Summary of any recent literature that may affect the safety or ethics of the study 
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC according 
to institutional guidelines. 
 
 


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13.0 
REFERENCES 
 
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Peacock, C.D., et al., Hedgehog signaling maintains a tumor stem cell compartment in multiple 
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17. 
Klein B, Z.X., Jourdan M, Content J, Houssiau F, Aarden L, Piechaczyk M, and B. R, Paracrine rather 
than autocrine regulation of myeloma-cell growth anddifferentiation by interleukin-6. Blood. 
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18. 
Vink, A., et al., Mouse plasmacytoma growth in vivo: enhancement by interleukin 6 (IL-6) and 
inhibition by antibodies directed against IL-6 or its receptor. J Exp Med, 1990. 172(3): p. 997-1000. 
19. 
De Bruyne, E., et al., IGF-1 suppresses Bim expression in multiple myeloma via epigenetic and 
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Podar, K. and K.C. Anderson, The pathophysiologic role of VEGF in hematologic malignancies: 
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Mackay, F. and J.L. Browning, BAFF: a fundamental survival factor for B cells. Nat Rev Immunol, 
2002. 2(7): p. 465-75. 
22. 
Moreaux, J., BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 
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Greenbaum, A.M. and D.C. Link, Mechanisms of G-CSF-mediated hematopoietic stem and 
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Peled, A., et al., Dependence of human stem cell engraftment and repopulation of NOD/SCID mice 
on CXCR4. Science, 1999. 283(5403): p. 845-8. 
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Semerad, C.L., et al., G-CSF potently inhibits osteoblast activity and CXCL12 mRNA expression in 
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Nervi B, R.P., Rettig MP, Uy GL, Holt MS, Ritchey JK, Prior JL, and B.G. Piwnica-Worms D, Ley TJ, 
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Zeng, Z., et al., Targeting the leukemia microenvironment by CXCR4 inhibition overcomes 
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32. 
see clinicaltrials.gov trial identifier NCT01455025, N., NCT01101880, NCT01331590. 
33. 
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34. 
Belnoue, E., et al., Homing and Adhesion Patterns Determine the Cellular Composition of the Bone 
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del Giglio, A., et al., XM02 is superior to placebo and equivalent to Neupogen™ in reducing the 
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Engert, A., et al., XM02, the first granulocyte colony-stimulating factor biosimilar, is safe and 
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37. 
Gatzemeier, U., et al., XM02, the first biosimilar G-CSF, is safe and effective in reducing the 
duration of severe neutropenia and incidence of febrile neutropenia in patients with small cell or 
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Lubenau, H., et al., Pharmacokinetic and pharmacodynamic profile of new biosimilar filgrastim 
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20(9): p. 1467-73. 
 
 


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APPENDIX A: ECOG Performance Status Scale 
 
 
Grade 
 
 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease performance 
without restriction. 
1 
Symptoms, but ambulatory.  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 
In bed <50% of the time.  Ambulatory and capable of all self-care, but unable 
to carry out any work activities.  Up and about more than 50% of waking 
hours. 
3 
 
In bed >50% of the time.  Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours. 
 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair. 
5 
 
Dead. 
 
 
 
 


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APPENDIX B: Ideal Body Weight and Corrected Body Weight Formulas 
 
Ideal Body Weight Formula for Patients Over 5 Feet in Height 
Male IBW (kg) = 50 kg + 2.3 kg for each inch over 5 feet 
Female IBW (kg) = 45.5 kg + 2.3 kg for each inch over 5 feet 
 
Ideal Body Weight Formula for Patients Under 5 Feet in Height 
Male IBW (kg) = 50 kg – 2.3 kg for each inch under 5 feet 
Female IBW (kg) = 45.5 kg – 2.3 kg for each inch under 5 feet 
 
Corrected Body Weight 
CBW (kg) = IBW in kg + [0.2 x (actual body weight in kg – IBW in kg)]