Influenza Vaccination in Plasma Cell Dyscrasias
Phase: PHASE4
Conditions: Plasma Cell Neoplasm
Sponsor: Emory University

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TITLE:                                        INFLUENZA VACCINATION IN PLASMA CELL 
DYSCRASIAS 
 
Coordinating  Center: 
 
 
Winship Cancer Institute of Emory University  
 
Winship PI:  
 
 
 
 
Craig Hofmeister MD MPH 
 
Laboratory investigator: 
Madhav Dhodapkar MBBS 
 
Sanofi: 
Fluzone HD 
 
Commercial Agent: 
Prevnar 13 (PCV 13) 
 
Statistician:                           
Yuan Liu, Ph.D Winship BBISR 
 
Protocol / Date: 
Initial / 7-May-2019 
 
V 1.1 / 22-May-2019 
 
V 1.2 / 13-Jul-2019 
 
V 1.3 / 31-Oct-2019 
 
V 1.31 / 13-Nov-2019 
 
V 2.0 / 9-Mar-2020 
 
V 2.1 / 7-Apr-2020 
 
V 2.2 / 3-Jul-2020 
 
V 2.3 / 20-Jul-2020 
 
V 2.4 / 14-Sep-2020 
 
CTCAE version: 
5.0 
 
Total consented patients: 
175 total 
 
 
50 patients (2019-2020) of which 23 were evaluable 
 
 
125 patients (2020-2021) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Text color legend 
Blue text 
Instructions and detailed for correlative science for laboratory #1 
Blue text 
Instructions and detailed for correlative science for laboratory #2 

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SCHEMA 
 
 
 
This is a phase IV randomized trial of 148 evaluable patients with a plasma cell disorder to be 
enrolled as early as possible in the influenza season through 15-Dec.     
 
Fluzone HD refers to TIV formulation for 2019-2020 influenza season and QIV formulation 
for 2020-2021 season. 
 
After eligibility is confirmed, patients will be randomized 1:1 to either an experimental arm 
where each patient receives three injections of Fluzone HD and a control arm where each 
patient receives one injection of Fluzone HD.   
 
All patients receive Prevnar at week 5 if they have not received either PCV13 or PPSV23 in 
that calendar year. 
 
 
 

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STANDARD OF CARE AND RESEARCH INTERVENTIONS 
 
 
 

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Table of Contents 
 
1. 
PRIMARY HYPOTHESES, OBJECTIVES, AND ENDPOINTS ........................................................................... 6 
2. 
EXPLORATORY SCIENTIFIC HYPOTHESES, OBJECTIVES, AND ENDPOINTS ........................................ 6 
3. 
BACKGROUND ........................................................................................................................................................... 6 
3.1 
INFLUENZA OVERVIEW ........................................................................................................................................................... 6 
3.2 
INFLUENZA RISK IN ADULT CANCER PATIENTS ................................................................................................................... 6 
3.3 
INFLUENZA VACCINATION RESEARCH IN ALLOGENEIC TRANSPLANT PATIENTS ............................................................ 7 
3.4 
MULTIPLE MYELOMA .............................................................................................................................................................. 7 
3.5 
MYELOMA PATIENTS AND INFLUENZA ................................................................................................................................. 8 
3.6 
ASSESSMENT OF INFLUENZA VACCINATION RESPONSE ..................................................................................................... 9 
3.7 
STUDY RATIONALE ............................................................................................................................................................... 10 
3.8 
POTENTIAL RISKS AND BENEFITS ...................................................................................................................................... 10 
4. 
PATIENT SELECTION............................................................................................................................................. 11 
4.1 
INCLUSION CRITERIA ............................................................................................................................................................ 11 
4.2 
EXCLUSION CRITERIA .......................................................................................................................................................... 12 
5. 
REGISTRATION, ACCRUAL, AND EARLY TERMINATION .......................................................................... 12 
5.1 
ACCRUAL ................................................................................................................................................................................ 12 
5.2 
DURATION OF THERAPY ...................................................................................................................................................... 13 
5.3 
DURATION OF FOLLOW-UP ................................................................................................................................................. 14 
5.4 
CRITERIA FOR REMOVAL FROM STUDY .............................................................................................................................. 14 
5.5 
EARLY STOPPING RULES ...................................................................................................................................................... 14 
5.6 
PREMATURE TERMINATION OR SUSPENSION OF THE STUDY ......................................................................................... 14 
6. 
STUDY PROCEDURES & SCHEDULE.................................................................................................................. 14 
6.1 
AGENT ADMINISTRATION .................................................................................................................................................... 14 
6.2 
DEFINITION OF DOSE-LIMITING TOXICITY ........................................................................................................................ 15 
6.3 
STANDARD OF CARE STUDY PROCEDURES ........................................................................................................................ 15 
6.4 
RESEARCH SPECIFIC PROCEDURES ..................................................................................................................................... 15 
6.5 
SCHEDULE OF EVENTS ......................................................................................................................................................... 16 
6.6 
DOSE LEVELS FOR PROTOCOL-SPECIFIC DRUGS ............................................................................................................... 18 
6.7 
DOSE INTERRUPTIONS ......................................................................................................................................................... 18 
6.8 
DOSE REDUCTION FOR OVERLAPPING TOXICITIES ........................................................................................................... 18 
7. 
PHARMACEUTICAL INFORMATION ................................................................................................................. 18 
7.1 
FLUZONE HD ........................................................................................................................................................................ 18 
8. 
CORRELATIVE/SPECIAL STUDIES .................................................................................................................... 24 
8.1 
OBJECTIVE FOR LAB 1 - SANOFI ......................................................................................................................................... 24 
8.2 
OBJECTIVE FOR LAB 2 – DHODAPKAR LABORATORY ...................................................................................................... 24 
9. 
RESPONSE ................................................................................................................................................................. 26 
10. STATISTICAL CONSIDERATIONS ...................................................................................................................... 26 
10.1 
STATISTICAL HYPOTHESES.................................................................................................................................................. 26 
10.2 
ANALYSIS DATASETS ............................................................................................................................................................ 26 
10.3 
SAMPLE SIZE DETERMINATION .......................................................................................................................................... 26 
10.4 
STATISTICAL METHODS ....................................................................................................................................................... 27 
10.5 
MEASURE TO MINIMIZE BIAS .............................................................................................................................................. 29 
11. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ................................................................... 29 

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11.1 
IDENTIFICATION OF AES AND FOLLOW-UP ...................................................................................................................... 29 
11.2 
EXPECTEDNESS ..................................................................................................................................................................... 30 
11.3 
ADVERSE EVENT CHARACTERISTICS .................................................................................................................................. 30 
11.4 
DEFINITION OF SERIOUS ADVERSE EVENT (SAE) ........................................................................................................... 32 
11.5 
DEFINITION OF UNANTICIPATED PROBLEMS (UP) AND REPORTING REQUIREMENTS .............................................. 33 
11.6 
EXPEDITED ADVERSE EVENT REPORTING ......................................................................................................................... 34 
11.7 
MONITORING OF ADVERSE EVENTS AND PERIOD OF OBSERVATION ............................................................................. 35 
11.8 
SECOND AND SECONDARY MALIGNANCY ........................................................................................................................... 35 
12. DATA REPORTING / REGULATORY REQUIREMENTS ................................................................................ 35 
12.1 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA ..................................................................................................... 35 
12.2 
QUALITY ASSURANCE ........................................................................................................................................................... 35 
12.3 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES ........................................................................................... 36 
12.4 
STUDY RECORDS RETENTION .............................................................................................................................................. 36 
12.5 
WINSHIP DATA AND SAFETY MONITORING (DSMC) ................................................................................................... 36 
12.6 
PROTOCOL DEVIATIONS....................................................................................................................................................... 37 
12.7 
PUBLICATION AND DATA SHARING POLICY ....................................................................................................................... 38 
12.8 
AUDIT AND INSPECTION ...................................................................................................................................................... 38 
13. ETHICS AND PROTECTION OF HUMAN SUBJECTS ...................................................................................... 39 
13.1 
ETHICAL STANDARD ............................................................................................................................................................ 39 
13.2 
INSTITUTIONAL REVIEW BOARD ........................................................................................................................................ 39 
13.3 
INFORMED CONSENT ............................................................................................................................................................ 39 
13.4 
PARTICIPANT AND DATA CONFIDENTIALITY .................................................................................................................... 39 
13.5 
RESEARCH USE OF STORED SAMPLES, SPECIMENS, OR DATA ......................................................................................... 40 
REFERENCES ...................................................................................................................................................................... 41 
APPENDIX A – PERFORMANCE STATUS ................................................................................................................... 44 
 
 
 

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1. PRIMARY HYPOTHESES, OBJECTIVES, AND ENDPOINTS 
Clinical 
Hypothesis 
Objective 
Endpoint 
Continuous Fluzone 
HD throughout the flu 
season will improve 
hemagglutination 
inhibition (HAI > 40)  
as measured at the end 
of the season compared 
to those patients that 
receive Fluzone HD 
once. 
 
Demonstrate an absolute 
25% increase in 
seroprotection, defined as 
HAI>40 against all strains, 
at week 21 in the 
experimental arm compared 
to the control arm.   
 
HAI will be measured in all 
patients at baseline, week 5, and 
week 21 to calculate 
seroconversion at week 5 and 
seroprotection at week 21. 
 
Seroconversion: Pre-vaccination 
HAI<10 and a post-vaccination 
HAI>40 or a pre-vaccination 
HAI >10 and a ≥ 4-fold rise in 
post-vaccination HAI at week 5. 
 
 
 
 
The above measurables will appear in the results section of www.clinicaltrials.gov at trial completion 
2. EXPLORATORY SCIENTIFIC HYPOTHESES, OBJECTIVES, AND ENDPOINTS 
Measurement of B & T-cell subsets and flu-specific responses as a way of understanding 
immunosuppression in this patient population, correlating with influenza-like illness. 
3. BACKGROUND 
3.1 
Influenza overview  
Influenza is an acute viral respiratory illness from three main types (A, B, and C), 
where type A is subcategorized based on viral surface glycoproteins 
hemagglutinin (HA) and neuraminidase (NA).  Primary influenza pneumonia is a 
rare but severe, complicated by otitis media and exacerbations of chronic 
respiratory conditions. Other complications include otitis media, exacerbations of 
chronic respiratory disease, myocarditis – often the concern is for influenza 
infection to ‘set the stage’ for a subsequent lethal bacterial pneumonia.  Those at 
high-risk for complications include those with cardiopulmonary diseases, chronic 
care facility residents, and those over 65 years old. 
 
Influenza vaccines contain antigens of the circulating influenza viruses and are 
intended to trigger antibody-mediated protection. Influenza A viruses undergo 
continual changes in the hemagglutinin (HA) and neuraminidase (NA) proteins, 
which necessitate annual updates.   Current influenza vaccines are available as 
inactivated vaccine (IV), trivalent (TIV) or quadrivalent (QIV), usually A/H1N1, 
A/H3N2, and either one or two strains of B), and as a recombinant vaccine which 
may be TIV or QIV. 
3.2 
Influenza risk in adult cancer patients 
There is no perfect sign of acquired immunosuppression in humans.  Neutropenia 
is often the consequence of chemotherapy that is watched most closely as it is 
associated with lethal bacterial infections especially when the absolute neutrophil 
count is less than 500/uL, and not surprisingly is associated with more influenza-

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related complications than in the general population1. In two studies of different 
cancer patient populations, absolute lymphocyte count of less than 200/uL was an 
independent predictor of progression to influenza-related pneumonia2. 
 
A review of vaccine immunogenicity among patients with both liquid and solid 
tumors demonstrated decreased seroconversion rate among cancer patients 
receiving chemotherapy (17% to 52%) compared to cancer patients not receiving 
chemotherapy (50% to 83%) and compared to healthy controls (67% to 100%)3. 
 
People undergoing chemotherapy or those that have acquired profound 
immunosuppression seen after allogeneic stem cell transplantation are at increased 
risk of influenza-related complications4,5. People at highest risk include those with 
impaired cell-mediated and antibody-mediated immunity, as reflected by a 
decrease in the number or function of T and B cells6. Influenza-related 
hospitalization rates are four times higher and mortality 10 times higher among 
people with cancer compared with the general population7,8. 
3.3 
Influenza vaccination research in allogeneic transplant patients 
An open-label randomized trial included 78 patients at least a week before a 
planned allogeneic stem cell transplant9.  Odds ratio for all-cause mortality was 
1.05 (95% CI 0.4 to 2.77) among those vaccinated. Influenza-related mortality 
was similar as well between the groups (2/40 among vaccinated versus 2/38 
among non-vaccinated). Documented influenza infection rate was similar in 
vaccinated and unvaccinated patients (3/40 versus 4/38, respectively). GMTs at 30 
days post-vaccination among the vaccinated population were significantly higher 
for influenza A/H1N1 and influenza A/H3N2 strains (15 versus 10, p= 
0.03 and 30 versus 12.5, p< 0.001, respectively). 
 
Another open-label randomized trial enrolled 73 adults after allogeneic HSCT, of 
which 35 were randomized to receive an adjuvanted influenza vaccine (Fluad) and 
the rest (38) randomized to a non-adjuvanted influenza vaccine (Influvac)10. There 
were five cases (14%) of laboratory-confirmed influenza among patients receiving 
the adjuvanted vaccine compared to three cases (8%) in the non-adjuvanted 
vaccine group. Vaccine immunogenicity, reported as seroconversion rate, 
seroprotection rate, and GMTs, was not significantly higher in the adjuvanted 
vaccine group. This study was underpowered for conclusions regarding 
seroprotection or to identify differences in influenza-like illness between the 
groups. 
3.4 
Multiple myeloma 
Multiple myeloma (MM) affects approximately 83,000 US citizens and over 50% 
of patients die within 5 years of diagnosis; more than half of patients older than 70 
years with low albumin and high β2microglobulin die within a year of 
diagnosis11,12. Of the 30,330 new cases estimated in 2016 in the U.S.13, MM is 
twice as common in African Americans as Caucasians, and genetic changes 
accumulate as plasma cells degenerate from monoclonal gammopathy of 
undetermined significance, through smoldering myeloma, to MM14. MM is 
characterized by fractures, anemia, kidney failure, and hypercalcemia with a 

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predisposition for bacterial infections from the inherent immunoparesis and 
varicella reactivation often aided by proteasome inhibition15. 
 
Advances in high-dose chemotherapy and stem cell transplantation have improved 
overall survival and event-free disease periods in patients with MM, but relapses 
are inevitable16,17 New therapeutic agents, such as new generation proteasome 
inhibitors (carfilzomib and ixazomib), immunomodulatory agents (lenalidomide 
and pomalidomide, the histone deacetylase inhibitor (HDACi) panobinostat, and 
monoclonal antibodies (elutuzumab and daratumumab) have shown promising 
clinical benefit in patients with relapsed or refractory disease. Current treatments 
include regimens using proteasome inhibitors and/or immunomodulatory agents in 
combination with HDACi, alkylating agents, and monoclonal antibodies. 
3.5 
Myeloma patients and influenza 
In myeloma patients on treatment, there is a 20% likelihood of influenza-like 
illness18,19 with a 10-fold higher risk of viral URIs20 than the general population. 
Even patients with precancerous conditions such as monoclonal gammopathy of 
undetermined significance (MGUS) and Smoldering Myeloma are at increased risk 
of bacterial and viral infections21. While only 3-5% of these viral illnesses are 
influenza, the mortality is high in the immunosuppressed and post-influenza 
bacterial pneumonias have high morality. In addition myeloma and it’s precursor 
diseases provide a novel window to studying vaccination in a full spectrum of 
immunosuppression 
from 
non-cancerous 
low-risk 
MGUS 
to 
end-stage 
lymphopenic patients with relapsed multiple myeloma.  
Vaccine preventable illnesses have not been prevented in patients with myeloma 
due in part to lack of seroresponse with standard dosing algorithms. Based on 
available trial data restricted to myeloma patients, serologic protection (HAI titer 
≥40) to all three influenza strains following trivalent influenza vaccine is achieved 
in less than 20% of myeloma patients in each trial22-24.  There have been two trials 
investigating the benefit of booster vaccine in myeloma patients. In 2005 Ljungmen 
et al, studied 70 patients with hematologic malignancies (10 with myeloma and 4 
with WM) and administered a booster dose 30 days following standard influenza 
vaccine booster and found no increase in serologic protection25. More recently, in 
the past 2013-2014 flu season, Hahn et al gave a standard dose influenza booster 
vaccine after 30 days to 25 myeloma patients and noted a doubling of serologic 
protection (HAI titer ≥40) from 14% to 33%26. This suggests that there may be a 
role for booster vaccines in patients with hematologic malignancies, however there 
is obviously much room to improve. 
Prior studies by the Dhodapkar lab has evaluated serologic responses to repeat 
influenza vaccination in patients with plasma cell disorders. In the first 
SHIVERING trial, we analyzed a strategy of 2 vaccine Fluzone HD doses, which 
led to higher rates of seroprotection compared to historic controls27. This was 
followed by a placebo-assisted randomized controlled study (SHIVERING-2 trial) 
comparing single dose versus 2-dose vaccination strategy. This trial28 provided first 
evidence that 2-dose strategy leads to higher rates of seroprotection compared to 
current standard of annual influenza vaccination in these patients. At the end of the 
influenza season, the rates of sero-protection were 58% in the cohort with 2 
vaccines versus 33% for the cohort with standard vaccines (P<0.05). These results 

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however need to be replicated in an independent study, before considering a change 
in standard practice.  These considerations have led to the design of the current trial, 
wherein we will evaluate 3 doses of the vaccine (versus standard influenza 
vaccination) in order to further extend the rates of seroprotection at the end of study 
and test the hypothesis that repeat dosing of influenza vaccines leads to superior 
sero-protection in patients with plasma cell disorders, compared to that achieved 
with current standard vaccination strategy. If this trial replicates the findings with 
SHIVERING-2 trial, we believe it should lead to a change in current clinical 
practice for influenza vaccination in patients with plasma cell disorders. 
3.6 
Assessment of influenza vaccination response 
Influenza vaccines work by activating antigen-specific B-cells to proliferate and 
differentiate into plasmablasts that secrete protective antibodies and memory B 
cells that can rapidly proliferate and differentiate into plasmablasts upon re-
encountering the immunizing antigen. Studies in healthy individuals demonstrated 
a transient plasmablast response after vaccination peaking at around 7 days after 
vaccination at which point it makes up to 16% of all B-cell, and returning to 
baseline levels by day 14. Memory B-cell response, on the other hand, peaks at 
14-28 days after vaccination followed by a slower rate of decline29-31. A subset of 
the plasmablasts migrate to the bone marrow and become long-lived plasma cells 
secreting antigen-specific antibodies for protracted periods of time. Memory B-
cell and plasma cells provide a remarkably stable immunological memory that can 
persist over 50 years after vaccination in humans. Interestingly, plasma cells are 
not intrinsically long-lived and only a finite number of plasma cells survive after 
an immune response irrespective of the number of plasma cells generated, 
suggesting that plasma cells require a specialized niche for survival32. It remains 
unclear what factors direct the differentiation of activated, antigen-specific B-cells 
into either memory B-cells or plasmablasts and plasma cells. Studies in mice 
suggested that the B-cell repertoire in the memory B-cell and the plasma cells 
compartments differ in terms of antigen-binding affinity and breadth33.  
 
Generation of immunological memory is the hallmark of adaptive immune 
responses. Clinically, this can be measured by determining seroprotection, defined 
as the percentage of subjects with a post-vaccination hemagglutination antibody 
inhibtion (HAI) titer > 1:40; and seroconversion, the percentage of subjects with 
either a pre-vaccination HAI titer < 1:10 and a post-vaccination HAI titer > 1:40 
or a pre-vaccination HAI titer > 1:10 and a minimum four-fold rise in post-
vaccination HAI antibody titer by week 5.  
 
Clearance of viral infection and vaccine responses are dependent on cell 
mediated immunity. The most common serologic measurement of antibody 
protection following influenza vaccine administration is an HAI titer of 40 or 
higher. However, this cutoff corresponds to an estimated 50% clinical benefit of 
preventing influenza infections, based on studies in young healthy adults34,35. It is 
believed that cell-mediated immunity declines with age, which may help explain 
why the elderly are more vulnerable to influenza infections. HAI titers have also 
been shown to be lower in the elderly compared to young adults. Based on 
studies showing increased serologic protection, Fluzone HD (TIV) was FDA 
approved in 2009 for adults aged 65 and older, the QIV formulation in Nov-2019.  

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3.7 
Study rationale 
The challenge of decreasing influenza infection rate and severity in patients with 
hematologic malignancies are manifold: first, influenza virus undergoes antigenic 
drift and antigenic shift allowing it to overcome pre-existing immunity; second, 
the fact that most vaccine-elicited neutralizing antibodies are directed against 
hypervariable epitopes of the HA protein, facilitating the emergence of antibody-
escape viral variants; third, the apparent short half-life of vaccine-mediated 
antibody titers in immunocompetent individuals; forth, the underlying immune 
suppressive state caused by the hematologic malignancy and worsened by the 
treatments that these patients need to receive; and fifth, the lack of high quality 
data looking at the response to influenza vaccination in patients with hematologic 
malignancy at the different stages of their disease course. Therefore, more studies 
are needed to define the optimal timing of influenza vaccination in patients with 
hematologic malignancies and to design an influenza vaccination strategy that 
provides a long-lived antibody response targeting a conserved epitope in HA. 
 
The National Comprehensive Cancer Network still recommends yearly 
vaccination using an inactivated influenza vaccine with the hope of achieving 
some protection and decrease the severity in the event of an infection. It is 
presumed that the higher incidence of viral infections in patients with hematologic 
malignancies is due to immune suppression associated with treatment and poor 
rates of seroconversion after vaccination. However, the exact mechanism of how 
this occurs is not well understood, limiting our ability to design better preventive 
measures against influenza infection. This study will measure immune responses 
to influenza vaccination in patients with plasma cell dyscrasias. 
3.8 
Potential risks and benefits 
3.8.1 
Potential risks 
1. Additional blood draws - The physical risk of drawing blood is local 
pain and bruising at the site of venipuncture. Qualified phlebotomists 
or designee will draw blood samples. Care will be taken to obtain 
these specimens in a safe and hygienic manner. A small number of 
people experience lightheadedness or fainting. There is a slight risk of 
infection. To minimize these risks, attempts will be made to draw study 
blood samples at the same time as blood draws needed for routine 
clinical care are obtained. Repeated blood drawing may be associated 
with iron deficiency anemia. 
2. Extra influenza vaccination - The side effects from inactivated 
influenza vaccine are generally mild. They include soreness at 
injection site (10-64% of subjects) that lasts <2 days. When the 
vaccine is given, the subject may feel a slight pain and burning during 
the injection. Fever, malaise and myalgia can occur after vaccination 
with inactivated influenza vaccine. These reactions begin 6-12 hours 
after vaccination and can persist for 1-2 days. Patients with a history 
of severe allergic reaction are not eligible to participate in this study. 
Very rarely, occurring in about 1 in 4 million people given a 
vaccination, there can be a serious allergic reaction to a vaccine. 
These reactions can manifest as skin rash (hives), angioedema, 
bronchospasm, tachycardia, or hypotension. If these reactions occur, 
they can usually be stopped by the administration of emergency 

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medications by the study personnel.  It is not known whether 
additional influenza risk will increase the risk of Guillain-Barre 
syndrome (GBS), estimated at 2.84 per million doses. 
3. Data security- Subjects will be asked to provide personal health 
information (PHI). All attempts will be made to keep this PHI 
confidential within the limits of the law. However, there is a chance 
that unauthorized persons will see the subjects’ PHI. All records will 
be kept in a locked file cabinet or maintained in a locked room at the 
participating sites. Electronic files will be password protected behind 
an academic institutional firewall. Only people who are involved in the 
conduct, oversight, monitoring, or auditing of this study will be allowed 
access to the PHI that is collected. Any publications from this study 
will not use information that will identify subjects. Organizations that 
may inspect and/or copy research records maintained at the 
participating sites for quality assurance and data analysis include 
groups such as the National Cancer Institute (NCI) and Food and 
Drug Administration (FDA). 
3.8.2 
Potential benefits 
There is no guarantee of benefit to subjects who enroll in this protocol. 
However, seasonal influenza vaccine is considered beneficial to most 
subjects, as it generally provides protective immunity against the influenza 
strains within the vaccine. It is also considered standard of care for patients 
with hematologic malignancies. Data from this study may yield a better 
understanding of the current body of knowledge describing human 
infections with influenza viruses. 
4. PATIENT SELECTION 
4.1 
Inclusion criteria 
4.1.1 
Patient must have a plasma cell dyscrasia that fits in the IMWG diagnostic 
criteria15. 
4.1.2 
Both men and women of all races and ethnic groups are eligible for this 
study. 
4.1.3 
Age > 18 years.  Because plasma cell dyscrasias are extraordinarily rare 
in a pediatric population, children are excluded from this study. 
4.1.4 
ECOG performance status < 3 (Karnofsky >30%, see Appendix A) is 
required for eligibility.   
4.1.5 
Patient must be eligible to receive standard of care influenza vaccination.  
If the patient has a history of egg allergy with symptoms more severe than 
urticaria, e.g. angioedema, respiratory distress, lightheadedness, or 
recurrent emesis, they remain eligible to receive influenza vaccination but 
must receive the vaccine in a facility able to recognize and manage 
severe allergic reactions. Persons who are able to eat lightly cooked egg 

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(e.g., scrambled egg) without reaction are unlikely to be allergic, although 
egg-allergic persons might tolerate egg in baked products 
4.1.6 
Ability to understand and the willingness to sign a written informed 
consent document. 
4.2 
Exclusion Criteria 
4.2.1 
Patients who have already received the seasonal influenza vaccine in the 
current season. 
4.2.2 
History of Guillain-Barré Syndrome 
4.2.3 
Patients with a previous severe allergic reaction to influenza vaccination 
or PCV13. 
4.2.4 
Expected survival < 9 months 
4.2.5 
Prisoners 
5. REGISTRATION, ACCRUAL, AND EARLY TERMINATION 
5.1 
Accrual  
5.1.1 
Enrollment overall 
The research team member obtaining informed consent will tell the patient 
that (1) participation is voluntary, (2) participation or non-participation 
will not affect their usual care and management, and (3) patient 
confidentiality will be maintained if the results of the study are published. 
The potential toxicities of protocol therapy and the study calendar will be 
explained to the potential participant. Patients will be provided with a 
consent form to review, and an opportunity to discuss the study and have 
all questions answered.   
5.1.2 
Registration Process 
Patients will be registered after meeting all entry requirements and signing 
of the informed consent document. 
 
To register a patient, the following should be completed  
 
• 
Signed patient consent form 
• 
HIPAA authorization form (if separate from consent from) 
 
At Winship Cancer Institute [Emory], the research coordinator will verify 
eligibility per standard Clinical Trials Office procedures.  To complete the 
registration process, the research coordinator will 
 
• register the patient on the study 
• assign the patient a study sequence ID 

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5.1.3 
Strategies for recruitment and retention 
This protocol follows NIH policy on inclusion of women and minorities as 
participants in research involving human subjects.   
 
No incentives are provided to patients for trial participation.   
5.1.4 
Initial treatment arms 
The total sample size of 148 patients will be split equally between the 
single versus 3-shot arms. 
5.1.5 
Method of treatment allocation 
A patient number will be assigned upon registration. 
5.1.6 
Estimated accrual based on race, ethnicity and gender 
Ethnic Category 
Sex/Gender 
Females  
Males 
 Total 
Hispanic or Latino 
3 
+ 
4 
= 
15 
Not Hispanic or Latino 61 
+ 
80 
= 
165 
Ethnic Category: 
Total of all subjects 
64 
+ 
84 
= 
148 
Racial Category 
 
American Indian or 
Alaskan Native 
1 
+ 
0 
= 
1 
Asian 
1 
+ 
2 
= 
3 
Black or African 
American 
10 
+ 
18 
= 
28 
Native Hawaiian or 
other Pacific Islander 
1 
+ 
0 
= 
1 
White 
51 
+ 
64 
= 
115 
Racial Category: 
Total of all subjects 
64 
+ 
84 
= 
148 
 
5.2 
Duration of therapy 
Patient may remain on study until one of the following criteria applies: 
 
• 
Intercurrent illness that prevents administration of vaccine or follow-up, 
• 
Per physician discretion in the setting of unacceptable adverse event(s), or 
other medical condition or situation occurs such that continued participation in 
the study would not be in the best interest of the participant.  In patients who 
are randomized to the experimental arm only, specific adverse events include 
grade 3 adverse event that occurs without alternative etiology in the 7 days 
following the first study vaccination  

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• 
Patient decides to withdraw from the study, or 
• 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the PI. 
• 
Termination or suspension of the study for safety reasons 
5.3 
Duration of follow-up 
Patients will be followed for 4 weeks after removal from study and patient records 
will be reviewed until death or 2 years from enrollment (whichever comes first) to 
assess progression and survival.  Patients removed from study for unacceptable 
adverse event(s) will be followed until resolution or stabilization of the adverse 
event. 
5.4 
Criteria for removal from study 
Patients will be removed from study when any of the criteria listed in Duration of 
therapy applies.  The reason for study removal and the date the patient was 
removed must be documented in the appropriate case report form. 
5.5 
Early stopping rules 
If there are any deaths possible, probably, or definitely related to protocol therapy, 
the trial will be suspended and the DSMC will provide recommendations for 
proceeding with the study to the PI.  
5.6 
Premature termination or suspension of the study 
This study may be suspended or prematurely terminated if there is sufficient 
cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to the 
investigator, funding agency (as applicable) and regulatory authorities. If the study 
is prematurely terminated or suspended, the PI will promptly inform the IRB and 
will provide the reason(s) for the termination or suspension. 
 
Circumstances that may warrant termination or suspension include, but are not 
limited to: 
 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping Insufficient compliance 
to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination of futility 
6. STUDY PROCEDURES & SCHEDULE 
6.1 
Agent administration 
Treatment will be administered on an outpatient basis.  Reported adverse events 
and potential risks of protocol therapy are described in the pharmaceutical section.   
 

WINSHIP 4709-19 
SANOFI ISS FIM00017 
 
15 
 
No investigational or commercial agents or therapies other than those described in 
this protocol may be administered with the intent to vaccinate the patient for 
influenza or S. pneumoniae. 
6.1.1 
Experimental arm – Intense Fluzone HD 
Fluzone HD vaccine for a total of 3 doses beginning at the time of 
enrollment 
6.1.2 
Control arm – Single Fluzone HD 
Fluzone HD vaccine once at the time of enrollment for a total of 1 dose. 
6.2 
Definition of dose-limiting toxicity 
N/A 
6.3 
Standard of care study procedures 
See Standard of care and research interventions 
6.4 
Research specific procedures 
See Standard of care and research interventions 
 
 
 

 
 
16 
 
6.5 
Schedule of events  
Experimental arm 
Assessment 
Screening +  
First visit 
Week 
5a 
Week 
9a 
Week 
17a 
Week 
21a 
Signed informed consent 
X 
 
 
 
 
Vital signs 
X 
 
 
 
 
CBC/d/pd 
X 
 
 
 
 
CRP, Serum IG’s, LDH 
X 
 
 
 
 
Myeloma proteinse 
X 
 
 
 
X 
Blood for researchf 
40 mL 
40 mL 
 
 
40 mL 
Fluzone HD 
X 
 
X 
X 
 
Prevnar (PCV13) 
 
X 
 
 
 
Record grade ≥ 2 adverse eventsg 
X 
 
X 
X 
 
Influenza-like illness updateb 
 
X 
X 
X 
X 
PFS and OSh 
 
 
 
 
X 
 
Control arm 
Assessment 
Screening + First Visit 
Week 5a Week 9a 
Week 17a 
Week 21a 
Signed informed consent 
X 
 
 
 
 
Vital signs 
X 
 
 
 
 
CBC/d/pd 
X 
 
 
 
 
CRP, Serum IG’s, LDH 
X 
 
 
 
 
Myeloma proteinse 
X 
 
 
 
X 
Blood for researchf 
40 mL 
40 mL 
 
 
40 mL 
Fluzone HD 
X 
 
 
 
 
Prevnar (PCV13) 
 
X 
 
 
 
Record grade ≥ 2 adverse eventsg 
X 
 
 
 
 
Influenza-like illness updateb 
 
X 
X 
X 
X 
PFS and OSh 
 
 
 
 
X 

 
 
17 
 
a. Assessments on these days can be performed within a ± 5 day window.  Subsequent visits (weeks 5, 9, 17, 21) are based on the 
actual time of Fluzone HD vaccination, not the pneumonia vaccination.   
b. Involves contact between study personnel and the patient regarding influenza-like illness and SAEs.  An in-person visit is not 
required. 
c. All patients (N=148) will have research blood drawn for correlative science. In both arms, blood will be obtained at baseline, week 
5, and week 21.  The first 20 patients in each group (n=40 total), split evenly between intervention arm (20 experimental, 20 
control), had additional blood drawn 1 week after each Fluzone HD dose (week 2 for control arm and weeks 2, 10, and 18 in the 
experimental arm) – this was completed 17-Nov-2019.  
d. CBC, differential, and platelets will be performed pre-vaccination. 
e. If not done with results available within 30 days of initial vaccination, a modified myeloma disease assessment requested but not 
required to include SPEP and free light chains if either were measurable per IMWG criteria in the past.  Serum IgD or IgE are 
requested if a monoclonal IgD or IgE were present in the past.  For patients with an IgA monoclonal protein, Hevylite IgA can be 
used to replace serum immunoglobulins and SPEP. 
f. Peripheral blood samples will be obtained and analyzed as described in correlative science section.   
g. Adverse events related to vaccination will be assessed on day of vaccination, and 7 days after each Fluzone HD vaccination (in-
person visit for significant adverse events).  If patient is unable to be seen in-person, every effort will be made to obtain 
documentation of patient evaluation, treatment, and resolution of vaccine-related toxicities. 
h. Survival information will be collected through chart review only.  An in-person clinic visit is not required. 

 
 
18 
 
6.6 
Dose levels for protocol-specific drugs  
N/A 
6.7 
Dose interruptions 
N/A 
6.8 
Dose reduction for overlapping toxicities 
N/A 
 
7. PHARMACEUTICAL INFORMATION 
Complete production and toxicity information for commercial agents can be found in the 
appropriate FDA approved package insert.  Investigator brochure for study agent describes 
preclinical results and clinical experience to date. 
 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational products in accordance with the protocol and any applicable laws and 
regulations. 
7.1 
Fluzone HD 
Fluzone HD refers to QIV formulation for 2020-2021 season. 
 

 
 
19 
 
 
 
Fluzone HD refers to TIV formulation for 2019-2020 influenza season 

 
 
20 
 
 
7.1.1 
Formulation, appearance, packaging, and labeling 
Fluzone HD (TIV) [2019-2020]is supplied as a single-dose, prefilled syringe, 
without needle, 0.5 mL, in a package of 10.  
 
Fluzone HD Quadrivalent (QIV) [2020-2021] is supplied as a single-dose, 
prefilled syringe, without needle, 0.7 mL, in a package of 10. 
 
Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements. 
7.1.2 
Product storage and stability 
Fluzone HD will be stored at 2-8ºC 
 
The temperature of the storage unit must be recorded daily (excluding non-
business days and holidays as applicable), monitored during the duration of 
the trial per the sites’ standard operating procedures, and documentation will 
be maintained. If the temperature fluctuates outside of the required range, the 
affected study product(s) must be quarantined at the correct storage 
temperature and labeled as ‘Do Not Use’ (until further notice). The 
pharmacist must alert the site principal investigator and study coordinator, if 
the temperature fluctuates outside of the required range. In the event the 
temperature fluctuates outside of the required range, including accidental 
deep-freezing or disruption of the cold chain, the affected study product(s) 
must not be administered. Based on the information collected, the 
manufacturer will determine whether the affected study product(s) can be 
used. If it cannot be used, the site will receive specific instructions on how to 
return the affected study product(s) to the manufacturer or destroy it on site. 

 
 
21 
 
7.1.3 
Route of administration 
Each dose of study vaccine will be administered via a single IM injection 
given in the deltoid muscle of the subjects’ preferred arm. Aseptic technique 
will be used for the withdrawal and administration of each dose of study 
vaccine using a disposable sterile needle appropriate in length for each 
subject and a disposable sterile syringe. 
7.1.4 
Returns, reconciliation, and destruction 
The investigator is responsible for keeping accurate records of the clinical 
supplies received from pharmaceutical supply or designee, the amount 
dispensed to and returned by the subjects and the amount remaining at the 
conclusion of the trial.  
 
Sponsor/Investigator drug destruction is allowed provided the following 
minimal standards are met: 
 
• 
On-site disposal practices must not expose humans to risks from the 
drug. 
• 
On-site disposal practices and procedures are in agreement with 
applicable laws and regulations, including any special requirements for 
controlled or hazardous substances. 
• 
Written procedures for on-site disposal are available and followed. The 
procedures must be filed with the Sponsor SOPs and a copy provided to 
pharmaceutical supporter upon request. 
• 
Records are maintained that allow for traceability of each container, 
including the date disposed of, quantity disposed, and identification of the 
person disposing the containers. The method of disposal, ie, incinerator, 
licensed sanitary landfill, or licensed waste disposal vendor must be 
documented. 
• 
Accountability and disposal records are complete, up-to-date, and 
available for pharmaceutical supporter to review throughout the clinical 
trial period as per the study agreement.  
 
It is the Investigator’s responsibility to arrange for disposal of all empty 
containers, provided that procedures for proper disposal have been established 
according to applicable federal, state, local, and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept. 
 
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It 
is the Investigator’s responsibility to arrange for disposal of all empty 
containers, provided that procedures for proper disposal have been established 
according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept. 

 
 
22 
 
7.1.5 
Expected adverse events / toxicities  
Adult recipients of inactivated influenza virus vaccines may develop 
influenza-like reactions such as fever, feverishness (chills/shivering/ 
sweating), gastrointestinal side effects (emesis and diarrhea), fatigue 
(tiredness), malaise (general unwell feeling), myalgia (body aches/muscular 
pain), arthralgia (joint pain), headache, and/or nausea. Some subjects may 
develop reactions at the injection site, including pruritus (itching), ecchymosis 
(bruising), erythema (redness), induration (hardness)/swelling, pain, and/or 
tenderness. With unadjuvanted licensed, 
inactivated influenza virus vaccines most of these reactions peak in intensity 
in the first 24 hours after vaccination and usually disappear without treatment 
within 1 or 2 days. Analgesics (e.g., acetaminophen, or ibuprofen or similar 
non-steroidal anti-inflammatory drugs (NSAIDs)) and rest may generally 
relieve or lessen these reactions. Bruising can sometimes occur due to the 
vaccination procedure. 
 
In addition, post-marketing surveillance indicates the following adverse 
events of special interest (AESI) as potential risks for pandemic vaccines 
based on those identified for the seasonal influenza vaccines: neuritis, 
convulsions, severe allergic reactions, encephalitis, thrombocytopenia, 
vasculitis, and Guillain-Barré (GBS) syndrome. Reports of these reactions 
were rare; however, exact incidence rates cannot be precisely calculated.  
 
Acute and potentially life-threatening allergic reactions are also possible. Very 
rarely, occurring in about 1 in 4 million people given a vaccination, there can 
be a serious allergic reaction to a vaccine. These reactions can manifest as 
skin rash (hives), swelling around the mouth, throat or eyes, difficulty 
breathing, a fast pulse, or loss of blood pressure. If these reactions occur, 
they can usually be stopped by the administration of emergency medications 
by the study personnel. As with any vaccine or medication, there is a very 
small chance of a fatal reaction (death), although researchers do not expect 
this to occur. 
 
GBS: During the swine influenza (H1N1) vaccine campaign of 1976, some 
recipients developed a paralytic illness called Guillain-Barr. syndrome (GBS). 
GBS is an acute inflammatory neuropathy characterized by weakness, 
hyporeflexia or areflexia, and elevated protein concentrations in cerebrospinal 
fluid. The rate of GBS was significantly increased in individuals receiving the 
1976 swine influenza (H1N1) vaccine at about 1 per 100,000 vaccine 
recipients. This syndrome has not been seen consistently with other influenza 
vaccines. Most persons who develop GBS recover completely, although the 
recovery period may be as little as a few weeks or as long as a few years. 
About 30% of those with GBS still have residual weakness after 3 years and 
about 3% may suffer a relapse of muscle weakness and tingling sensations 
many years after the initial attack. Intensive surveillance of GBS after 
administration of inactivated influenza vaccines since 1976 has shown a slight 

 
 
23 
 
increase in risk over background cases (more than one additional case of GBS 
per million persons) following vaccination, typically with onset within 6 
weeks after vaccination36. Interestingly, although vaccination rates have 
increased in the last 10 years the numbers of reported cases of vaccine-
associated GBS have declined37. A recent study in Canada showed that the 
2009 H1N1 vaccine was associated with a small but significant risk of GBS in 
persons 50 years and older38. An active, population-based surveillance study 
conducted during the 2009-2010 influenza season found less than 1 excess 
GBS case per million doses of 2009 H1N1 vaccine administered – a rate 
similar to that associated with some previously administered annual influenza 
vaccines39,40. Another study using the Medicare system showed an elevated 
risk of GBS with 2009 monovalent H1N1 vaccination (incidence rate ratio = 
2.41, 95% confidence interval: 1.14, 5.11; attributable risk = 2.84 per million 
doses administered, 95% confidence interval: 0.21, 5.48)41. An international 
collaboration study also supported a conclusion of an association between 
2009 H1N1 vaccination and GBS42. 
 
 
 

 
 
24 
 
8. CORRELATIVE/SPECIAL STUDIES 
Assessment of biomarkers and changes relevant to influenza vaccination are paramount in this 
protocol.   
 
 
8.1 
Objective for lab 1 - Sanofi 
8.1.1 
Collection of specimens 
Peripheral blood will be drawn at baseline, week 5, and week 21. 
8.1.2 
Specimen handling 
Blood will be cryopreserved by the Dhodapkar laboratory and batch shipped 
to a central laboratory at Sanofi for processing. 
8.1.3 
Specimen analysis 
HAI titer will be assessed. 
8.1.4 
Site performing study 
Sanofi 
8.2 
Objective for lab 2 – Dhodapkar laboratory 
8.2.1 
Collection of specimens 
30-40 mL of peripheral blood will be drawn, labeled and logged under the 
supervision of the principal investigator and in accordance with site specific 
SOPs.  
 
Correlative Objective 
IHC/Assay/Test 
Tissue/Body Fluid Tested 
and Timing of Collection 
Determine seroconversion 
and seroprotection 
HAI titer 
Peripheral blood at baseline, week 5, 
and week 21 
B-cell and CD4 T-cell 
responses 
Mass cytometry & other 
immunologic assays 
Peripheral blood at baseline, week 5, 
and week 21.   

 
 
25 
 
8.2.2 
Specimen handling 
Specimens will be shipped to the Dhodapkar laboratory for processing – see 
protocol specific tissue collection worksheet. 
8.2.3 
Specimen analysis 
• 
Mass cytometry: Phenotypic analysis of T and B cells, including 
plasmablasts and TFH cells will be performed by mass cytometry utilized 
a panel as described.43  
• 
Pneumococcal antibody responses by Elisa 
• 
Antigen-specific T cells (CRM-197 and HA-specific T cells; T cells specific 
to control viral antigens (CMV, EBV). 
• 
B cell receptor sequencing (selected cases) 
• 
Single cell transcriptome analysis (selected cases). 
8.2.4 
Site performing study 
Dhodapkar laboratory 
 
 
 

 
 
26 
 
9. RESPONSE  
 
Time to progression (TTP): Time to progression is defined as the time from last treatment until 
progression. Patients who have died without evidence of progression are censored in the TTP 
analysis at the time of death and patients who are alive without progression are censored at the 
last disease assessment.  
 
Progression-Free Survival (PFS): Defined as the time from last treatment to the disease 
progression or death from any cause. Patients who have not progressed or died are censored at 
the date last known progression-free. Patients with no on-study assessment will be censored at 
the time of registration. 
 
Overall survival (OS): OS is defined as the time from randomization to death. Alive patients are 
censored at the date last known alive.  
 
10. STATISTICAL CONSIDERATIONS 
10.1 
Statistical hypotheses 
This is a randomized study to determine whether three doses of Fluzone HD, aka 
continuous dosing throughout the influenza season will maintain seroprotection 
throughout the entire study.  Specifically we hypothesize that 58% of patients in the 
experimental arm will achieve seroprotection at week 21, e.g. HAI>40;  the null 
hypothesis is that only 33% will demonstrate seroprotection at the end of the study.   
10.2 
Analysis datasets 
Safety Population: The safety analysis dataset will include all eligible patients who 
begin treatment and receive at least one dose of protocol therapy. Patients will be 
analyzed in the cohort to which they were enrolled. 
 
Efficacy Evaluable Population: All evaluable patients will be included in the 
analysis of efficacy endpoint. The term evaluable is defined as any eligible patient 
who receives at least one dose of protocol therapy and does not withdraw consent 
until the patient’s first response assessment.  Patients who fail to have a response 
assessment due to early progression or death will be categorized as non-responders.  
10.3 
Sample size determination 
In the initial design, the sample sizes of 81 in each group achieved 90% power to 
detect a difference between the group proportions of 0.2520. The proportion in group 
one (the intense Fluzone HD arm) is assumed to be 0.3330 under the null hypothesis 
and 0.5850 under the alternative hypothesis. The proportion in group two (the control 
group) is 0.3330. The test statistic used is the two-sided Z test with pooled variance.  
The significance level of the test (the alpha) was targeted at 0.0500, i.e. the 
probability of rejecting a true null hypothesis that was desired. The significance level 

 
 
27 
 
actually achieved by this design is 0.0513.  The planned power was 0.9, i.e. the 
probability of rejecting a false null hypothesis. We assume 10% drop off rate in the 
study so that we planned to enroll 90 patients in each group. 
 
During the first influenza season (2019-2020), we enrolled 50 patients of which only 
23 were evaluable as 27 patients missed the week 21 study assessment due to 
COVID19.   
 
We aim to complete the trial during the influenza season 2020-2021, and hence will 
need to control season as a confounder through a logistic regression model. A logistic 
regression of a binary response variable (e.g. HAI>40) on a binary independent 
variable (e.g. the treatment arms) with a sample size of 134 observations (of which 
the two treatment arms are evenly distributed) achieves 80% power at a 0.05 
significance level to detect a change in the rate of HAI>40 from the baseline value of 
0.333 to 0.585. This change corresponds to an odds ratio of 2.82. An adjustment was 
made since a multiple regression of the independent variable of interest on the other 
independent variables (e.g. the seasons) in the logistic regression obtained an R-
Squared of 0.1. Hence we will need 67 patients in each randomized arm. After taking 
into account the expected 10% dropout rate, we plan to enroll 74 patients in each arm, 
producing a total sample size of 148 patients.  Given we already accrued 11 evaluable 
patients per arm during the first season, we will plan to enroll an additional 125 
patients in the second season. 
10.4 
Statistical methods  
10.4.1 Design operating characteristics 
N/A 
10.4.2 Safety analyses 
Adverse event data will be described and graded per the NCI CTCAE 
guidelines. For each adverse event, information to be collected includes event 
description, time of onset, clinician assessment of severity, relationship to 
study product (assessed only by those with the training and authority to make 
a diagnosis), and time of resolution/stabilization of the event. All vaccine-
related AEs will be recorded with start dates occurring any time after patient 
receives any study drug until 7 (for non-serious AEs) or 100 days (for SAEs) 
after the last day of study participation. At each study visit, the investigator 
will inquire about the occurrence of AE/SAEs since the last visit. Events will 
be followed for outcome information until resolution or stabilization. 
 
Any medical condition that is present at the time that the participant is 
screened will be considered as baseline and not reported as an AE. However, 
if the study participant’s condition deteriorates at any time during the study, it 
will be recorded as an AE. Changes in the severity of an AE will be 
documented to allow an assessment of the duration of the event at each level 

 
 
28 
 
of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
 
The maximum grade for each type of toxicity will be recorded for each 
patient, and frequency tables will be reviewed to determine toxicity patterns. 
Adverse events will be summarized and described within each cohort. They 
will initially be reviewed regardless of attribution, but also whether they are 
possibly, probably, or definitely related to treatment. In addition, we will 
review all adverse event data that are graded as 3, 4, or 5 and classified as 
either “unrelated” or “unlikely to be related” to study treatment in the event of 
an actual relationship developing. The incidence of severe adverse events or 
toxicities will be described. We will assess the proportion of patients who 
experience grade 3 or higher non-hematologic toxicity. To assess tolerability, 
we will also capture the proportion of patients who go off treatment due to 
adverse events.  
 
Temporary suspension of enrollment due to toxicity (aka stopping rules) are 
described elsewhere.  
10.4.3 Baseline descriptive statistics 
Baseline characteristics will be summarized within each cohort using 
descriptive statistics. For categorical variables, frequencies and percentages 
will be presented. For continuous variables, the median and range will be 
presented.  Inferential tests will not be performed. 
10.4.4 Planned interim analyses (if applicable) 
N/A 
10.4.5 Analysis of influenza response and disease status endpoints 
HAI will first be measured and summarized with mean and standard deviation 
at different time-points, respectively. Paired t-test will be further used to test 
whether there is significant change in HAI at different time points from 
baseline, respectively. Two sample t-test will be used to compare the change 
in HAI from baseline between two groups, at different time-point, 
respectively. Chi-Square test will be used to compare the Seroconversion and 
Seroprotection between two groups, respectively. Logistic regression model 
will be used to compare adjusted difference in Seroconversion and 
Seroprotection between two groups after adjusting for other factors, 
respectively.  
 
Spearman/Pearson correlation coefficient will be used to measure the 
relationship between correlation between HAI, predefined risk of influenza-
like illness (low, moderate, high), respectively. Finally Mixed model will be 
employed to test their correlations over the whole period with and without 

 
 
29 
 
adjusting for other factors, respectively. Kaplan Meir method, Log-rank test, 
and Cox model will be used to test the relationship between peak HAI and 
PFS. 
   
10.4.6 Analysis of secondary endpoints  
Time to event outcomes including TTP, PFS and OS will be assessed with 
patients censored at time of last follow-up. TTP, PFS and OS rates of two 
patient groups will be estimated with the Kaplan-Meier method and compared 
between different groups using the log-rank test, respectively. The TTP, PFS 
and OS of each patient group at specific time points, such as 1 year, 3 years, 
and 5 years, etc. will be estimated alone with 95% CI. Cox proportional hazards 
models will be used in the multivariable analyses to assess adjusted effects of 
biomarkers on the patients’ TTP, PFS and OS after adjusting for other factors. 
The proportional hazards assumption will be evaluated graphically and 
analytically with regression diagnostics.  
 
Protocol therapy related toxicities rate will be summarized using descriptive 
statistics such as frequencies and proportions. Differences in the proportion of 
patients who experience protocol-related toxicities will not be compared 
between cohorts.  
 
10.5 
Measure to minimize bias 
10.5.1 Randomization 
The total sample size of 148 patients will be split equally between the arms. 
10.5.2 Evaluation of success of blinding (N/A) 
10.5.3 Breaking the study blind / participant code (N/A) 
 
11. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
11.1 
Identification of AEs and follow-up 
The occurrence of an AE or SAE may come to the attention of study personnel during 
study visits and interviews of a study participant presenting for medical care, or upon 
review by a study monitor.  
 
The only adverse events to be captured in this protocol must relate to 
vaccination or influenza-like illness, and these will be captured on the appropriate 
CRF. Changes in the severity of these AE’s only will be documented to allow an 
assessment of the duration of the event at each level of severity to be performed. 
These AEs will be followed to adequate resolution. 

 
 
30 
 
 
Information to be collected includes event description, time of onset, clinician 
assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the 
event.  
 
Any medical condition that is present at the time that the participant is screened will 
be considered as baseline and not reported as an AE. Unanticipated problems will be 
recorded in the data collection system throughout the study. 
 
The site PI will record all reportable events with start dates occurring any time after 
patient receives the any study drug until 7 (for non-serious AEs) or 14 days (for 
SAEs) after the last day of study participation. At each study visit, the investigator 
will inquire about the occurrence of AE/SAEs since the last visit. Events will be 
followed for outcome information until resolution or stabilization. 
11.2 
Expectedness 
Expected adverse reactions are AEs that are common and known to occur for the 
study agent being studied and should be collected in a standard, systematic format 
using a grading scale based on functional assessment or magnitude of reaction. 
Describe the method of determining the expectedness of an AE. Expectedness refers 
to the awareness of AEs previously observed, not based on what might be anticipated 
from the properties of the study agent. 
 
An AE or suspected adverse reaction is considered "unexpected" if it is not listed in 
the current Investigator’s Brochure (IB), consent, or is not listed at the specificity or 
severity that has been observed. "Unexpected," as used in this definition, also refers 
to AEs that are mentioned in the IB 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 drug under investigation. 
 
The PI, working together with treating physician, will be responsible for determining 
whether an AE is expected or unexpected. An AE will be considered unexpected if 
the nature, severity, or frequency of the event is not consistent with the risk 
information previously described in the IB for the study agent. 
11.3 
Adverse event characteristics 
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) will 
be utilized for AE reporting.  A copy of the CTCAE version can be downloaded from 
the Cancer Therapy Evaluation Program (CTEP) web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
For all collected AEs, the clinician who examines and evaluates the participant will 
determine the AE’s causality based on temporal relationship and his/her clinical 

 
 
31 
 
judgment.  The degree of certainty about causality will be graded using the categories 
below: 
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, 
and other possible contributing factors can be ruled out. The clinical event, 
including an abnormal laboratory test result, occurs in a plausible time 
relationship to drug administration and cannot be explained by concurrent 
disease or other drugs or chemicals. The response to withdrawal of the drug 
should be clinically plausible. The event must be pharmacologically or 
phenomenologically definitive, with use of a satisfactory re-challenge procedure if 
necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the 
influence of other factors is unlikely. The clinical event, including an abnormal 
laboratory test result, occurs within a reasonable time after administration of the 
drug, is unlikely to be attributed to concurrent disease or other drugs or 
chemicals, and follows a clinically reasonable response on withdrawal. Re-
challenge information is not required to fulfill this definition. 
• 
Possibly Related – There is some evidence to suggest a causal relationship 
(e.g., the event occurred within a reasonable time after administration of the trial 
medication). However, other factors may have contributed to the event (e.g., the 
participant’s clinical condition, other concomitant events). Although an AE may 
rate only as “possibly related” soon after discovery, it can be flagged as requiring 
more information and later be upgraded to “probably related” or “definitely 
related,” as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test 
result, whose temporal relationship to drug administration makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time 
after administration of the trial medication) and in which other drugs or chemicals 
or underlying disease provides plausible explanations (e.g., the participant’s 
clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study drug administration, 
and/or evidence exists that the event is definitely related to another etiology. 
There must be an alternative, definitive etiology documented by the clinician. 
 
The determination of causality will include some of the following characteristics: 
 
Exposure 
Is there evidence that the subject was exposed to the product 
such as: reliable history, acceptable compliance assessment 
(pill count, diary, etc), expected pharmacologic effect, or 
measurement of drug/metabolite in bodily specimen? 
Time course 
Did the AE follow in a reasonable temporal sequence from 
administration of the product?  Is the time of onset of the AE 
compatible with a drug-induced effect? 
Likely cause 
Is the AE not reasonably explained by another etiology such 
as underlying disease, other drug/vaccine, or other host or 
environmental factors 
Dechallenge 
Was the product discontinued or exposure reduced?  If yes, 
did the AE resolve or improve?   

 
 
32 
 
Rechallenge 
Was the subject re-exposed to the product in this study?  If 
yes, did the AE recur or worsen? 
Consistency with 
trial treatment 
profile 
Is the clinical presentation of the AE consistent with previous 
knowledge regarding the product or drug class? 
 
11.4 
Definition of serious adverse event (SAE) 
The only adverse events to be captured in this protocol must relate to 
vaccination or influenza-like illness.  Within this definition, an AE is considered 
"serious" if, in the view of either the investigator or sponsor, it results in any of the 
following outcomes:  
 
• 
Death,  
• 
Is life-threatening 
• 
Inpatient hospitalization (>24hrs) 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 subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.  
 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home thought to be related to an influenza-like 
illness or influenza vaccination. 
 
Events not considered to be serious adverse events (SAEs) are hospitalizations for 
 
• 
Routine treatment or monitoring of the studied indication, not associated with 
any deterioration in condition, or for elective procedures of a condition 
unrelated to the studied condition or its treatment 
• 
Elective or pre-planned treatment for a pre-existing condition that did not 
worsen 
• 
Emergency outpatient treatment for an event not fulfilling the serious criteria 
outlined above and not resulting in inpatient admission  
• 
Respite care 
 
Distinction between seriousness and severity of an AE. Severity is a measure of 
intensity of an event (mild, moderate, severe). However, the event itself may be of 
relatively minor medical significance; thus, a severe reaction may not necessarily be 
classified as a serious reaction. This differs from seriousness, which is based on 
patient/event outcome or action criteria described above and are usually associated 
with events that pose a threat to a patient’s life or functioning. A severe adverse event 

 
 
33 
 
does not necessarily need to be considered serious. Seriousness (not severity) serves 
as a guide for defining regulatory reporting obligations.  
 
Any vaccine- or influenza-like illness related-AE considered serious must be 
submitted on an SAE form to the Data and Safety Monitoring Committee (DSMC) if 
one exists for the study.  The DSMC may request to receive real-time notification of 
all SAEs or only SAEs thought to be related to study agent. 
 
All SAEs will be followed until satisfactory resolution or until the site investigator 
deems the event to be chronic or the adherence to be stable. Other supporting 
documentation of the event may be requested by the study sponsor and should be 
provided as soon as possible. The study sponsor will be responsible for notifying 
FDA of any unexpected fatal or life-threatening suspected adverse reaction as soon as 
possible but in no case later than 7 calendar days after the sponsor's initial receipt of 
the information. 
11.5 
Definition of unanticipated problems (UP) and reporting requirements 
The Office for Human Research Protections (OHRP) considers unanticipated 
problems involving risks to participants or others to include, in general, any incident, 
experience, or an outcome that meets all the following criteria: 
 
• 
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 participant population being studied; 
• 
Related or possibly related to participation in the research (“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 participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
 
This study will use the OHRP definition of unanticipated problems. Incidents or 
events that meet the OHRP criteria for UPs require the creation and completion of a 
UP report form. It is the site investigator’s responsibility to report UPs to their IRB 
and to the DCC/study sponsor. The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the 
IRB project number; 
• 
A detailed description of the event, incident, experience, or outcome; 
• 
An explanation of the basis for determining that the event, incident, experience, 
or outcome represents an UP; 
• 
A description of any changes to the protocol or other corrective actions that have 
been taken or are proposed in response to the UP. 
 
The PI will make an assessment of whether the event constitutes an unanticipated 
problem posing risks to subjects or others (UP). This assessment will be provided to 

 
 
34 
 
the Emory University IRB.  If the Emory IRB determines an event is a UP it will 
notify the appropriate regulatory agencies and institutional officials. 
11.6 
Expedited adverse event reporting 
All serious adverse events that occur after the date of informed consent signature, 
during treatment, or within 14 days of the last dose of study drug must be reported on 
a MEDWATCH FDA Form 3500A to the principal investigator. If a patient is 
permanently withdrawn from the study because of a SAE, this information must be 
included in the initial or follow-up SAE report form. 
 
11.6.1 Reporting to Sanofi 
SAE reports and reports of adverse events of special interest will be submitted 
to Sanofi Pharmacovigilance within 1 business day.   
11.6.2 Non-serious adverse event reporting 
Non-serious adverse events will be reported on the adverse event case report 
form(s). 
11.6.3 Reporting to the institutional review board (IRB) 
Clinical trials office (CTO) staff will report all serious adverse events directly 
to the IRB according to IRB reporting requirements.   
11.6.4 Coordinating center reporting to the food and drug administration (FDA) 
The Principal Investigator will be responsible for all applicable 
communication with the FDA.  
 
Unexpected fatal or life-threatening experiences associated with the use of the 
study treatment will be reported to FDA as soon as possible but no later than 7 
calendar days after initial receipt of the information.  
 
All other serious unexpected experiences associated with the use of the study 
treatment will be reported to FDA as soon as possible but in no event later 
than 15 calendar days after initial receipt of the information. Events will be 
reported to the FDA by telephone (1-800-FDA-1088) or by fax (1-800- FDA-
0178) using MEDWATCH Form FDA 3500A (Mandatory Reporting Form 
for investigational agents). Forms are available at 
http://www.fda.gov/medwatch/getforms.htm.  
 
An annual safety report containing all SAEs, expected and unexpected, will be 
sent to applicable regulatory authorities.  

 
 
35 
 
11.7 
Monitoring of adverse events and period of observation 
The only adverse events to be captured in this protocol must relate to 
vaccination or influenza-like illness.  These adverse events, both serious and non-
serious, and deaths that are encountered from the date of informed consent signature, 
throughout the study, and within 14 days of the last study drug treatment 
administration should be followed to their resolution, or until the participating 
investigator assesses them as stable, or the participating investigator determines the 
event to be irreversible, or the participant is lost to follow-up.  
 
The presence and resolution of AEs and SAEs (with dates) should be documented on 
the appropriate case report form and recorded in the participant’s medical record to 
facilitate source data verification.  
 
After this period, only SAEs considered reasonably study-related by the investigator 
must be reported to the sponsor (for example, a delayed SAE) without limitation.  
 
Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study.  
11.8 
Second and secondary malignancy 
n/a   
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
12.1 
Source documents and access to source data 
Each participating site will maintain appropriate medical and research records for this 
trial, in compliance with relevant federal and institutional requirements pertaining to 
ICH E6 for the protection of confidentiality of participants.   
 
If applicable, as part of participating in a NIH IC-sponsored or NIH IC -affiliated 
study, each site will permit authorized representatives of the NIH IC and regulatory 
agencies to examine (and when permitted by applicable law, to copy) clinical records 
for the purposes of quality assurance reviews, audits, and evaluation of the study 
safety, progress, and data validity.  
 
Source data are all information, original records of clinical findings, observations, or 
other activities in a clinical trial necessary for the reconstruction and evaluation of the 
trial. CRFs can be source documents as well as the medical record.   
12.2 
Quality assurance 
QC procedures will be implemented beginning with the data entry system and data 
QC checks that will be run on the database will be generated. Any missing data or 
data anomalies will be communicated to the site(s) for clarification/resolution. 

 
 
36 
 
 
Following written SOPs, the monitors will verify that the clinical trial is conducted 
and data are generated, documented (recorded), and reported in compliance with the 
protocol. 
 
The investigational site will provide direct access to all trial related sites, source 
data/documents, and reports for monitoring and auditing by the sponsor, and 
inspection by local and regulatory authorities. 
12.3 
Data collection and management responsibilities 
Data collection is the responsibility of the clinical trial staff at the site under the 
supervision of the site PI. The investigator is responsible for ensuring the accuracy, 
completeness, legibility, and timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure 
accurate interpretation of data. Black ink is required to ensure clarity of reproduced 
copies. When making changes or corrections, cross out the original entry with a single 
line, and initial and date the change.   
 
Copies of the electronic CRF (eCRF) will be provided for use as source documents 
and maintained for recording data for each participant enrolled in the study. Data 
reported in the eCRF derived from source documents should be consistent with the 
source documents or the discrepancies should be explained and captured in a 
progress note and maintained in the participant official electronic study record. 
 
At the coordinating center, clinical data (including AEs, concomitant medications, 
and expected adverse reactions data) and clinical laboratory data will be entered into 
OnCore, a data capture system available at each center. The data system includes 
password protection and internal quality checks, such as automatic range checks, to 
identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be 
entered directly from the source documents. 
12.4 
Study records retention 
Study documents should be retained for a minimum of 2 years after the last approval 
of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have 
elapsed since the formal discontinuation of clinical development of the investigational 
product. These documents should be retained for a longer period, however, if required 
by local regulations. No records will be destroyed without the written consent of the 
sponsor, if applicable. It is the responsibility of the sponsor to inform the investigator 
when these documents no longer need to be retained. 
12.5 
Winship Data and Safety Monitoring (DSMC) 
The Data and Safety Monitoring Committee (DSMC) of the Winship Cancer Institute 
will provide oversight for the conduct of this study.  The DSMC functions 

 
 
37 
 
independently within Winship Cancer Institute to conduct internal monitoring 
functions to ensure that research being conducted by Winship Cancer Institute 
Investigators produces high-quality scientific data in a manner consistent with good 
clinical practice (GCP) and appropriate regulations that govern clinical research.    
Depending on the risk level of the protocol, the DSMC review may occur every 6 
months or annually.  For studies deemed High Risk, initial study monitoring will 
occur within 6 months from the date of the first subject accrued, with 2 of the first 5 
subjects being reviewed.  For studies deemed Moderate Risk, initial study monitoring 
will occur within 1 year from the date of the first subject accrued, with 2 of the first 5 
subjects being reviewed.  Subsequent monitoring will occur in routine intervals per 
the Winship Data and Safety Monitoring Plan (DSMP).  
 
The DSMC will review pertinent aspects of the study to assess subject safety, 
compliance with the protocol, data collection, and risk-benefit ratio. Specifically, the 
Winship Cancer Institute Internal Monitors assigned to the DSMC may verify 
informed consent, eligibility, data entry, accuracy and availability of source 
documents, AEs/SAEs, and essential regulatory documents.  Following the 
monitoring review, monitors will provide a preliminary report of monitoring findings 
to the PI and other pertinent individuals involved in the conduct of the study.  The PI 
is required to address and respond to all the deficiencies noted in the preliminary 
report.  Prior to the completion of the final summary report, monitors will discuss the 
preliminary report responses with the PI and other team members (when appropriate).  
A final monitoring summary report will then be prepared by the monitor.  Final 
DSMC review will include the final monitoring summary report with corresponding 
PI response, submitted CAPA (when applicable), PI Summary statement, and 
available aggregate toxicity and safety data.   
 
The DSMC will render a recommendation and rating based on the overall trial 
conduct.  The PI is responsible for ensuring that instances of egregious data 
insufficiencies are reported to the IRB.  Continuing Review submissions will include 
the DSMC recommendation letter.  Should any revisions be made to the protocol-
specific monitoring plan after initial DSMC approval, the PI will be responsible for 
notifying the DSMC of such changes.  The Committee reserves the right to conduct 
additional audits if necessary. 
12.6 
Protocol deviations 
A protocol deviation in this protocol relates only to the administration of vaccine – 
specifically incorrect dose, incorrect timing, incorrect administration procedure 
(including injection).  Within this definition, a deviation is any noncompliance with 
the clinical trial protocol, GCP, or MOP requirements. The noncompliance may be 
either on the part of the participant, the investigator, or the study site staff. Because of 
deviations, corrective actions are to be developed by the site and implemented 
promptly. 
 
These practices are consistent with ICH E6: 
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 

 
 
38 
 
• 
5.1 Quality Assurance and Quality Control, section 5.1.1 
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
 
It is the responsibility of the site to use continuous vigilance to identify and report 
deviations within 60 working days of identification of the protocol deviation, or 
within 180 working days of the scheduled protocol-required activity. All deviations 
must be addressed in study source documents. Protocol deviations must be sent to the 
local IRB per their guidelines. The site PI/study staff is responsible for knowing and 
adhering to their IRB requirements.  
12.7 
Publication and data sharing policy 
This study will comply with the NIH Public Access Policy, which ensures that the 
public has access to the published results of NIH funded research. It requires 
scientists to submit final peer-reviewed journal manuscripts that arise from NIH 
funds to the digital archive PubMed Central upon acceptance for publication. 
 
The International Committee of Medical Journal Editors (ICMJE) member journals 
have adopted a clinical trials registration policy as a condition for publication. The 
ICMJE defines a clinical trial as any research project that prospectively assigns 
human subjects to intervention or concurrent comparison or control groups to study 
the cause-and-effect relationship between a medical intervention and a health 
outcome. Medical interventions include drugs, surgical procedures, devices, 
behavioral treatments, process-of-care changes, and the like. Health outcomes 
include any biomedical or health-related measures obtained in patients or 
participants, including pharmacokinetic measures and adverse events. The ICMJE 
policy, and the Section 801 of the Food and Drug Administration Amendments Act of 
2007, requires that all clinical trials be registered in a public trials registry such as 
ClinicalTrials.gov, which is sponsored by the National Library of Medicine.  
12.8 
Audit and inspection 
In accordance with GCP, the investigators agree to comply with the requirements of 
the sponsor and the Regulatory Authorities about an audit or inspection of the trial.  
 
The audit may be performed at any of the stages of the study, from development of 
the protocol to publication of the results.  
 
Regulatory authorities or the sponsor may request access to all source documents, 
data capture records, and other study documentation for on-site audit or inspection. 
Direct access to these documents must be granted by the investigator, who must 
provide support always for these activities.  
 

 
 
39 
 
13. ETHICS AND PROTECTION OF HUMAN SUBJECTS 
13.1 
Ethical standard 
The investigator will ensure that this study is conducted in full conformity with 
Regulations for the Protection of Human Subjects of Research codified in 45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, as well as the federal regulations pertaining 
to ICH E6. 
13.2 
Institutional review board 
The protocol, informed consent form, recruitment materials, and all participant 
materials will be submitted to the IRB for review and approval. Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled. 
Any amendment to the protocol will require review and approval by the IRB before 
the changes are implemented to the study. All changes to the consent form will be 
IRB approved; a determination will be made regarding whether previously consented 
participants need to be re-consented. 
13.3 
Informed consent 
Consent forms describing in detail the study agent, study procedures, and risks are 
given to the participant and written documentation of informed consent is required 
prior to starting intervention/administering study product.  
 
Informed consent is a process that is initiated prior to the individual consent to 
participate in the study and continues throughout the individual’s participation. 
Extensive discussion of risks and possible benefits of participation will be provided 
to the participants and their families. Consent forms will be IRB approved and the 
participant will be asked to read and review the document. The investigator will 
explain the research study to the participant and answer any questions that may arise. 
All participants will receive a verbal explanation in terms suited to their 
comprehension of the purposes, procedures, and potential risks of the study and of 
their rights as research participants.  Participants will have the opportunity to 
carefully review the written consent form and ask questions prior to signing. 
The participants should have the opportunity to discuss the study with their surrogates 
or think about it prior to agreeing to participate. The participant will sign the informed 
consent document prior to any procedures being done specifically for the study. The 
participants may withdraw consent at any time throughout the course of the trial. A 
copy of the informed consent document will be given to the participants for their 
records. The rights and welfare of the participants will be protected by emphasizing to 
them that the quality of their medical care will not be adversely affected if they 
decline to participate in this study. 
13.4 
Participant and data confidentiality 
Participant confidentiality is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s) and their agents. This confidentiality is extended to 

 
 
40 
 
cover testing of biological samples and genetic tests in addition to the clinical 
information relating to participants. Therefore, the study protocol, documentation, 
data, and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor. 
 
The study monitor, other authorized representatives of the sponsor, representatives of 
the IRB or pharmaceutical company supplying study product may inspect all 
documents and records required to be maintained by the investigator, including but 
not limited to, medical records (office, clinic, or hospital) and pharmacy records for 
the participants in this study. The clinical study site will permit access to such 
records. 
 
The study participant’s contact information will be securely stored at each clinical site 
for internal use during the study. At the end of the study, all records will continue to 
be kept in a secure location for as long a period as dictated by local IRB and 
Institutional regulations. 
 
Study participant research data, which is for purposes of statistical analysis and 
scientific reporting, will be transmitted to and stored. This will not include the 
participant’s contact or identifying information. Rather, individual participants and 
their research data will be identified by a unique study identification number. The 
study data entry and study management systems used by clinical sites and research 
staff will be secured and password protected. At the end of the study, all study 
databases will be de-identified and archived. 
13.5 
Research use of stored samples, specimens, or data 
13.5.1 Current use 
Samples and data collected under this protocol may be used to study multiple 
myeloma. Access to stored samples will be limited to IRB-approved 
investigators. Samples and data will be stored using codes assigned by the 
investigators or their designees. Data will be kept in password-protected 
computers. Only investigators will have access to the samples and data. 
 
All stored samples will be maintained in the laboratory to which it was sent 
initially for analysis. Study participants who request destruction of samples 
will be notified of compliance with such request and all supporting details will 
be maintained for tracking. 
13.5.2 Future use 
N/A 
 
 

 
 
41 
 
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44 
 
APPENDIX A – PERFORMANCE STATUS 
 
Performance Status Criteria 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
% 
Description 
0 
Normal activity.  Fully active, 
able to carry on all pre-disease 
performance without 
restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal 
activity; minor signs or 
symptoms of disease. 
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). 
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. 
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. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable 
assistance and frequent medical 
care. 
3 
In bed >50% of the time.  
Capable of only limited self-
care, confined to bed or chair 
more than 50% of waking 
hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated.  
Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to 
bed or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead.