Study of High-dose Influenza Vaccine Efficacy by Repeated Dosing IN Gammopathy Patients (SHIVERING 2)
Phase: PHASE2
Conditions: Influenza, Multiple Myeloma, Waldenstrom's Macroglobulinemia, Plasma Cell Disorders, MGUS
Sponsor: Yale University

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Phase: II
YCC Version 4.0 Date: 31-May-2017
Title:
Study of High-dose Influenza Vaccine Efficacy by 
Repeated dosing IN Gammopathy patients: A 2 Arm 
randomized study (SHIVERING 2 Trial)
HIC Protocol Number:  
1507016111
IND #: 
N/A
 
Version Date:
31-May-2017
Sponsor:
YCC
Principal Investigator: 
Madhav Dhodapkar, MD 
Yale University School of Medicine
333 Cedar Street,  
PO Box 208032
New Haven, CT, 06520
Ph:  203-785-4144
Pager: 203-974-2867
Fax: 203- 785-7531
Email: madhav.dhodapkar@yale.edu
Sub-Investigators
Andrew Branagan, MD
Yale University School of Medicine
333 Cedar Street,  
PO Box 208032
New Haven, CT, 06520
Ph:  475-202-9782
Pager: 203-370-3956
Fax: 203- 785-7531
Email: andrew.branagan@yale.edu

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pg. 2
Stuart Seropian, MD
Yale University School of Medicine
333 Cedar Street,  
PO Box 208032
New Haven, CT, 06520
Ph:  (203) 737-2730
Fax: 203- 785-7531
Email: stuart.seropian@yale.edu
Alfred Lee, MD
Yale University School of Medicine
333 Cedar Street,  
PO Box 208032
New Haven, CT, 06520
Ph:  (203) 737-6121
Fax: 203- 785-7531
Email: alfred.lee@yale.edu
Terri Parker, MD
Yale University School of Medicine
333 Cedar Street,  
PO Box 208032
New Haven, CT, 06520
Ph:  (203) 737-5312
Fax: 203- 785-7531
Email: terri.parker@yale.edu
Nikolai Podoltsev, MD
Yale University School of Medicine
333 Cedar Street,  
PO Box 208032
New Haven, CT, 06520
Ph:  (203) 737-4553
Fax: 203- 785-7531
Email: nikolai.podoltsev@yale.edu

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pg. 3
Iris Isufi, MD
Yale University School of Medicine
333 Cedar Street,  
PO Box 208032
New Haven, CT, 06520
Ph:  (203) 737-6307
Fax: 203- 785-7531
Email: iris.isufi@yale.edu
Natalia Neparidze, MD
Yale University School of Medicine
333 Cedar Street,  
PO Box 208032
New Haven, CT, 06520
Ph:  203-785-4144
Fax: 203- 785-7531
Email: natalia.neparidze@yale.edu
Eamon Duffy
Yale University School of Medicine
333 Cedar Street,  
PO Box 208032
New Haven, CT, 06520
Ph:  203-671-5094
Fax: 203- 785-7531
Email: eamon.duffy@yale.edu

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pg. 4
Statisticians:
Xiaopan Yao, PhD
Yale University School of Medicine
300 George Street, Suite 555
New Haven, CT, 06519
Email: xiaopan.yao@yale.edu
Daniel Zelterman, PhD
Yale University School of Medicine
300 George Street, Suite 555
New Haven, CT, 06519
Email: daniel.zelterman@yale.edu
Study Medication: 
Fluzone® High-Dose trivalent inactivated vaccine
Financial Support: 
 YCC. Vaccine to be purchased via philanthropic funds.
 
SUB-INVESTIGATORS:
YCC:
HEMATOLOGY:  *Madhav Dhodapkar, Madhav Andrew Branagan, Stuart 
Seropian, Alfred Lee, Terri Parker, Nikolai Podoltsev, Iris Isufi, Natalia Neparidze, 
Eamon Duffy
*Eligible to obtain informed consent

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pg. 5
Table of Contents
1. Protocol Synopsis………………………………………………………………....6
2. Schedule of Study 
Assessments……………………………………….....………………………......10
3. Background and Rationale ………………………………………………….…...11
4. Study Objectives and End Points ……………………………………………..…14
5. Investigational Plan…………………………………………………………...….14
6. Serious Adverse Events……………………………………………………….....18
7. Protocol Amendments and Deviations……………………………………….….19
8. Data Management…………………………………………………………….….19
9. Biostatistical Considerations………………………..……………………………20
10. References……………………………………………………………………..…23
11. Appendices……………………………………………………………….………25
A.  Correlative Studies and collection of research samples

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pg. 6
Protocol Synopsis
PROTOCOL SUMMARY:  A Randomized, Placebo-Controlled Study utilizing high dose 
trivalent influenza vaccine dose with a booster compared to standard of care in patients 
with monoclonal gammopathies
STUDY INTERVENTION:
Fluzone® High-Dose vaccine with a 30 day 
booster dose
INDICATION:
All patients with a diagnosis of a monoclonal 
gammopathy
STUDY Type:
Randomized, 
double 
blind, 
placebo-
controlled, Phase II Study
Background and Rationale:
Influenza is a major cause of morbidity in the US. Patients with monoclonal gammopathies are 
known to have increased risk of developing influenza. Furthermore, several of the medications 
(such as proteasome inhibitors), commonly used to treat these tumors, are known to further 
increase the risk of these tumors. Seasonal influenza vaccination has been shown to reduce 
influenza related morbidity and is approved for routine prophylaxis in US. In 2009, Fluzone® high-
dose vaccine was FDA approved in 2009 for adults aged 65 and older based on the data 
regarding higher rates of seroprotection (defined as hemoglutination antibody inhibition (HAI) titer 
of 40 or higher). 
Sensing of pathogens by the immune system is mediated by family of distinct pattern recognition 
receptors (such as toll like receptors, TLRs) that then activate immune response. In the setting of 
tumors involving the immune cells themselves, such as multiple myeloma, tumor cells commonly 
express TLRs and signaling via TLRs has been shown to regulate the growth and survival of 
tumor cells. This has led to the hypothesis that exposure to common pathogens may itself 
contribute to promoting the growth of tumor cells. Unfortunately, these patients also have immune 
paresis and are at increased risk for infections. Prevention of major seasonal infections may 
therefore have major impact not only on infection-related morbidity, but also tumor growth. In 
addition to potentially direct effect on tumor cells, pathogen-related morbidity also leads to 
interruption of therapy, which may further compromise disease control. Thus, influenza infections 
may cause mortality directly or indirectly by interfering with disease control. By measuring all-
cause mortality at the end of an influenza season it is possible to account for all possible effects 
of influenza which may be related to mortality. 
Although seasonal influenza vaccination is routinely employed in patients with monoclonal 
gammopathies, the data about its efficacy in this setting are limited and very few studies have 
specifically focused on this population. This is particularly true in the setting of newer agents that 
further reduce B cell function. Existing data suggest that routine seasonal influenza vaccination is 
not very effective in this population, with seroconversion rates of <20%. One approach to 
enhancing the efficacy of vaccination is the use of boosters. 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%. This suggests that 

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pg. 7
there may be a role for booster vaccines in these patients, however there is much room to 
improve. Although routinely used in adults 65 and older, there are no prospective data on high 
dose flu vaccine (and specifically booster) in patients with monoclonal gammopathies. Fluzone® 
High-Dose has been widely used since 2009 and proven to be safe. Knowing that high dose 
influenza vaccine increases serologic protection in adults over 65, there is a chance that our 
study population may benefit as well with a booster strategy including the high dose vaccine. 
We recently concluded a pilot study at Yale-New Haven Hospital over the 2014-2015 influenza 
season, (the SHIVERING Trial), using the same proposed high dose influenza vaccine with 
booster strategy. While much of the data analysis (including correlative studies of immune 
response) is currently ongoing, preliminary findings reveal that this strategy was safe and well 
tolerated in this population. All 51 patients who were enrolled received both high dose vaccine 
and booster doses and there were no grade 2 or above adverse events attributed to the study 
vaccine. In addition flu infection rate was only 4% of patients compared to an expected rate of 
20% in this population. The findings from the pilot study, if confirmed in the context of a 
randomized controlled trial as proposed here, therefore have practice changing implications for 
the care of patients with monoclonal gammopathies / myeloma. 
Our hypothesis is that the administration of Fluzone® High-Dose with booster to all patients with 
monoclonal gammopathies (irrespective of age) will lead to seroconversion rates exceeding 50% 
and more importantly, will reduce influenza-related morbidity, reduce interruptions in cancer 
therapy and reduce all-cause mortality at the end of the flu season.
In this study, we will administer Fluzone® High-Dose vaccine with a planned booster to patients 
with monoclonal gammopathies irrespective of age versus a standard of care control group. 
Primary endpoint is composite of documented infuenza infection rate and disease progression (as 
defined by International Myeloma Working Group criteria) at the end of the flu season. Based on 
the background data, we expect a higher rate of success in the experimental arm. As such, we 
power for success rates of 90% and 70% in the experimental and control arms, respectively.
We will also analyze several secondary endpoints including rates of influenza related morbidity, 
the analysis of humoral and cellular immune response to these vaccines and the rate of disease 
control (defined as lack of disease progression by standard international myeloma working group 
criteria).
By comparing this experimental approach directly to standard of care, data from estimates of 
effectiveness will inform the design of larger future controlled studies. As such, the data from this 
study can lead to practice-changing results. The data on immune correlates will also yield 
important information about in vivo “immune-competence” of these individuals, which in turn is 
important to design trials with emerging immune therapies.
STUDY Endpoints:
 
Primary:
1)
The primary clinical endpoint of this study is: to measure a composite of documented 
influenza infection rate and disease progression (as defined by International 
Myeloma Working Group criteria) at the end of the flu season following a high dose 
influenza vaccine booster strategy versus standard of care.

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pg. 8
Secondary:
1.
evaluate rates of serologic protection (defined as HAI titer >40) following 
Fluzone® High-Dose influenza vaccine with booster dosing versus standard of 
care.
2.
measure T cell subsets and flu-specific T cell responses following high dose 
influenza vaccine booster dosing strategy versus standard of care.
STUDY DESIGN:
This is a phase II randomized placebo-controlled interventional study.  
Patients will be 
randomized in a 2:1 allocation of experimental group A to standard of care group B. Experimental 
group will receive high dose influenza vaccine with a booster high dose flu vaccine one month 
later. Standard of care arm will receive a single influenza vaccine (standard dose if age <65 and 
high dose if age ≥ 65) and a placebo booster vaccine after one month. Both group A and B will be 
stratified by disease type to allow for a balanced study population. Patients can be viewed as two 
distinct populations, those with disease requiring therapy (defined as any plasma cell disorder 
having at any time required therapy) and those with early disease (defined as asymptomatic 
multiple myeloma, asymptomatic Waldenstrom macroglobulinemia, or monoclonal gammopathy 
of undetermined significance). As such, we will stratify patients by disease requiring therapy 
versus early disease by separately randomizing patients into the two protocol groups but with the 
same allocation ratio of 2:1. Patients treatment is summarized as follows:
Group
(Each group stratified by 
disease requiring therapy 
and early disease)
Randomization
Initial Influenza Vaccine 
at day 0
Second High Dose 
Influenza Vaccine at day 30 
(+14 days/-7days)
Experimental (A)
2
Standard of Care (B)
1
Fluzone® High-Dose 
Fluzone® High-Dose if age ≥ 
65,
Standard dose influenza 
vaccine if age < 65.
Fluzone® High-Dose
Placebo

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pg. 9
STUDY DURATION:   
2015-2016 influenza 
season 
TOTAL SAMPLE SIZE: 150 Subjects (100 in 
experimental group A and 50 in standard of 
care group B)
DOSING REGIMEN: 
Fluzone® 
High-Dose 
trivalent 
inactivated 
influenze vaccine given on day 0 and again on 
month +1 (+14 days/-7 days) in the experimental 
group.

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pg. 10
Schedule of Study Assessments 
2015 – 2016 Flu Season (August to May)
Procedure
Day of Initial Vaccine (Fluzone 
High Dose in experimental 
group A vs. standard of care in 
group B)
Day of Initial vaccine, study 
enrollment and randomization 
into experimental versus 
standard of care arm 
Day 7 (+/- 2 days)
Research blood draw 
only*
Day of Second Vaccine 
(Fluzone High Dose in 
experimental group A 
vs. placebo booster in 
group B)
Roughly 30 Days 
following Initial vaccine 
(+21 days/- 7 days)
Month 2
Roughly 30 Days following 
Second Vaccine  (+14 days/- 7 
days)
End of Study Visit4
(may be conducted in person, 
by telephone, or by email)
(End of flu season-May 1 to 
May 15, 2016)
SPEP OR IFE OR serum free light 
chains OR quantitative 
immunoglobulins 1
X
X
Research blood draw2
X
*X (patients may 
refuse this blood draw 
if it creates an 
inacceptable burden)
X
*X (if patients are unable to 
receive this blood draw 
within the above timeframe, 
blood draw may be delayed 
up to 90 days)
*X (patients may refuse this 
blood draw if it creates an 
inacceptable burden)
Inquire and document any influenza 
infection3, influenza-related 
hospitalization, or death during the 
study period
X
X
X
X
Assessment of all grade II and above 
adverse events 5
X
X
Pregnancy test for women of 
childbearing potential6
X
X
1 Assessment of disease status within 30 days prior to first vaccine and within 90 days of the End of Study Visit. Both patients with measurable or evaluable disease are 
eligible. The preferred method to monitor disease should be established at baseline and repeated at the end of study visit. For patients with measurable disease, SPEP or 
FLC are preferred. 
2 See Appendix A for details regarding collection of research samples and correlative studies.  
3 All subjects should be informed and reminded to present to a health care facility at the first symptoms of possible influenza infection to have DFA checked.
4 End of treatment and 30 days following second vaccine may be merged into a single visit if they fall within 15 days of each other. 
5 See Adverse Events section of the protocol for details. 
6 Childbearing potential is defined as a sexually mature woman who 1) has not undergone a hysterectomy or bilateral oophorectomy and 2) has not been post menopause for at least 24 
months. Pregnancy test to be performed within 2 weeks prior to each vaccine.

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 pg. 11
Background and Rationale
Introduction
Plasma cell dyscrasias or monoclonal gammopathies are a group of benign and malignant 
disorders consisting of monoclonal plasma cells which secrete monoclonal immunoglobulins1. 
These disorders include the pre-malignant entity Monoclonal Gammopathy of Undetermined 
Significance (MGUS), asymptomatic / active multiple myeloma, asymptomatic / active 
Waldenstrӧm Macroglobulinemia (WM), solitary plasmacytoma, and primary amyloidosis. 
Patients with monoclonal gammopathies are routinely offered influenza vaccines however there 
is no evidence that they are effective in preventing infections. 
Influenza Vaccination
Influenza is a major cause of morbidity in the US. The most vulnerable populations include 
adults over the age of 65 years, those with serious co-morbidities2. A particularly vulnerable 
population are thought to be patients with hematologic malignancies, particularly multiple 
myeloma. A population based study in Sweden of over 9,000 myeloma patients, demonstrated 
that myeloma was associated with a 5.4 fold increased risk of contracting influenza infections 
relative to healthy controls3.
Clearance of viral infection and vaccine responses are dependent on cell mediated 
immunity(CMI). The most accepted serologic measurement of antibody protection following 
influenza vaccine administration is hemoglutination antibody inhibition (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 adults4,5. It is believed that CMI 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 adults6. Based on 
studies showing increased serologic protection, Fluzone® high-dose vaccine was FDA approved 
in 2009 for adults aged 65 and older. 
Patients with plasma cell dyscrasias are known to have depressed immune function. Studies in 
myeloma have shown B cell dysfunction (hypogammaglobulinemia), functional abnormalities of 
dendritic and T cells, inversion of T cell CD4:CD8 ratio, abnormal T cell Th1/Th2 CD4+ ratio, 
and  dysfunction of natural killer cells7,8,9. Anti-cancer medications can further adversely affect 
the immune system. It is known that patients who received chemotherapy within 7 days of 
trivalent inactivated influenza vaccine have poorer responses10. There is no published data 
regarding the effects of more commonly used novel agents such as IMIDs and proteasome 
inhibitors on vaccine responses.
Several studies have demonstrated a poor serologic antibody response in those patients included 
with myeloma and WM. However, there is a paucity of prospective trials focusing exclusively on 
patients with monoclonal gammopathies.  No studies have specifically investigated influenza 

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 pg. 12
immunity in precursor states such as MGUS, although these patients may have similar risks of 
unresponsiveness to influenza vaccine and are known to have hypogammoglubulinemia.  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 trial11, 12, 13.  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 
protection14. 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%15. This suggests that there may be a role for booster 
vaccines in patients with hematologic malignancies, however there is obviously much room to 
improve.
Although routinely used in adults 65 and older, no one had studied high dose flu vaccine 
specifically in patients with monoclonal gammopathies. Fluzone® High-Dose has been widely 
used since 2009 and demonstrated to be safe. Knowing that high dose influenza vaccine 
increases serologic protection in adults over 65, our study population may benefit as well, given 
the similar but more significantly depressed cellular immunity in patients with monoclonal 
gammopathies. With this in mind, we have already designed the recent SHIVERING Pilot study 
at Yale New Haven Hospital over the 2014-2015 flu season. In this pilot study, all patients 
received Fluzone® High-Dose with a second booster dose after 30 days. Enrollment has closed 
and data analysis is ongoing. However, preliminary data revealed that all 51 patients enrolled 
tolerated the two vaccine doses well and no grade 2 or above adverse events related to vaccine 
were reported. In addition, with very close follow-up 2/51 patients (4%) patients developed 
documented flu infections despite an expected rate of 20% in this population (manuscript in 
preparation).
Rationale for Treatment in this Setting
Sensing of pathogens by the immune system is mediated by family of distinct pattern recognition 
receptors (such as toll like receptors, TLRs) that then activate immune response. In the setting of 
tumors involving the immune cells themselves, such as multiple myeloma, tumor cells 
commonly express TLRs and signaling via TLRs has been shown to regulate the growth and 
survival of tumor cells. For example, infectious particles can activate TLRs and cause 
proliferation of myeloma cell lines and secretion of IL-6 (a potent myeloma growth cycokine)16. 
This has led to the hypothesis that exposure to common pathogens may itself contribute to 
promoting the growth of tumor cells. Unfortunately, these patients also have immune paresis and 
are at increased risk for infections. Prevention of major seasonal infections may therefore have 
major impact not only on infection-related morbidity, but also tumor growth. In addition to 
potentially direct effect on tumor cells, pathogen-related morbidity also leads to interruption of 
therapy, which may further compromise disease control.

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 pg. 13
Ultimately if this novel vaccine strategy proves to be more effective, an important question will 
be if mortality will also be improved. As discussed above influenza infections are associated 
both with their own morbidity and mortality, and may have a negative impact on disease control, 
thereby indirectly increasing mortality. All-cause mortality as a clinical endpoint will take into 
account all possible relation of influenza infections to mortality. One year estimates are known 
for patients with plasma cell disorders. The most recent SEER data of one year survival for 
newly diagnosed myeloma, based on patients diagnosed in 2009 is 79.2%.17 Relapsed refractory 
patients have lower survival depending on many risk factors and is estimated as low as 60-
66%.18,19  MGUS patients are not believed to have much of a decrease in survival compared to 
age-matched controls and one-year survival is estimated to be 98%.20 Most of the patients seen at 
Smilow cancer Hospital are relapsed/refractory multiple myeloma patients. We anticipated that 
more than 2/3 of patients enrolled will be relapsed / refractory and less than 1/3 will be MGUS or 
newly diagnosed plasma cell disorder patients. As would be expected, relapsed patients have 
reduced time to progression with each successive line of therapy. Kumar, et al21 followed 355 
myeloma patients who have had at least two lines of therapy and showed that time to progression 
shortened with each line of therapy from 9.9 months after first therapy to 7.3 months after second 
therapy to less than 4 months after sixth line of therapy (see Figure 1 below). In our population 
of patients of relapsed patients mixed with newly diagnosed and early disease patients a 
conservative estimate of the proportion who would relapse from the time of initial vaccine to the 
end of the influenza season (which may range from roughly 4-8 months depending on when the 
patient receives their initial vaccine) is 10%. Considered together with an expected influenza 
infection rate of 20%, we would expect our control arm to have a combined disease progression 
and influenza infection rate of 30% (10%+20%). 
To the authors’ knowledge, there have not been any prior influenza vaccine studies in patients 
with monoclonal gammopathies, which have looked at clinical endpoints other than our pilot 
SHIVERING trial. Clinical endpoints which we plan to assess include number of influenza 
infections, influenza-related hospitalizations / deaths, and efficacy related to prior therapy.  
While prior studies have measured serologic response to influenza vaccines in patients with 
monoclonal gammopathies, there have not been any trials correlating T cell responses. We plan 
to try to better understand cell mediated immunologic response by looking at T cell functional 
assays. 
Our hypothesis is that the administration of Fluzone® High-Dose with booster to all patients 
with monoclonal gammopathies (irrespective of age) will lead to seroconversion rates exceeding 
50% and more importantly, will reduce influenza-related morbidity, prevent interruptions in 
cancer therapy and reduce disease progression at the end of the influenza season. 
In this study, we will administer Fluzone® High-Dose vaccine with a planned booster to patients 
with monoclonal gammopathies (randomized into the experimental group versus standard of 
care).  The experimental group will receive Fluzone® High-Dose vaccine with a second booster 
dose after 30 days, regardless of age. In the standard of care group, patients will receive 
influenza vaccine based on current standard of care clinical practice. Standard of care depends on 
age; patients 65 receive a single high dose influenza vaccine, patients <65 receive a single 

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 pg. 14
standard dose vaccine. In addition, patients in the standard of care group will receive a placebo 
vaccine after 30 days, which will aid in the blinding between groups and allow for stricter 
comparison between groups.
Primary endpoint is a composite of documented influenza infection rate and disease progression 
(as defined by International Myeloma Working Group criteria) at the end of the flu season. We 
will also analyze several secondary endpoints including rates of influenza related morbidity, 
analysis of humoral and cellular immune response to these vaccines, and rate of disease control 
(defined as lack of disease progression by standard international myeloma working group 
criteria). 
By comparing this experimental approach directly to standard of care, data from estimates of 
effectiveness will inform the design of larger future controlled studies. As such, the data from 
this study can lead to practice-changing results. The data on immune correlates will also yield 
important information about in vivo “immune-competence” of these individuals, which in turn is 
important to design trials with emerging immune therapies.
Study Objectives
Endpoints
Primary endpoints
The primary clinical endpoint of this study is to measure a composite of documented infuenza 
infection rate and disease progression (as defined by International Myeloma Working Group 
criteria) at the end of the flu season following a high dose influenza vaccine booster strategy 
versus standard of care. Please see sections under biostatistical considerations for details. 
Secondary study endpoints
The secondary endpoints are 1) rates of serologic protection (defined as HAI titer >40) 
following Fluzone® High-Dose influenza vaccine after booster dosing and 2) measurement of T 
cell subsets and flu-specific T cell responses.
Investigational Plan
Study vaccine description
Fluzone® High-Dose

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 pg. 15
Proper Name: Influenza Virus Vaccine
Trade Name: Fluzone® High-Dose Vaccine
Manufactuer: Sanofi Pasteur, Inc, License #1725
Indication:  Fluzone High-Dose is indicated for active immunization of persons 65 years of age 
and older against influenza disease caused by influenza virus subtypes A and type B contained in 
the vaccine.
Fluzone (Influenza Virus Vaccine) for intramuscular injection is an inactivated influenza virus 
vaccine, prepared from influenza virusespropagated in embryonated chicken eggs. The virus-
containing allantoic fluid is harvested and inactivated with formaldehyde. Influenza virus is 
concentrated and purified in a linear sucrose density gradient solution using a continuous flow 
centrifuge. The virus is then chemically disrupted using a nonionic surfactant, Octylphenol 
Ethoxylate (Triton®X-100), producing a “split virus”.
The split virus is further purified and then suspended in sodium phosphate buffered isotonic 
sodium chloride solution. 
Fluzone is standardized according to United States Public Health Service requirements and 
is formulated to contain HA of each of the following three influenza strains recommended for the 
current influenza season, including two A subtypes (H3N2 / HINI) and one influenza B subtype. 
Dosage form
Fluzone® High Dose is supplied in 0.5 mL for intramuscular injection
Adverse events:
In adults 18 through 64 years of age, the most common injection-site reaction was pain (>50%); 
the most common solicited systemic adverse events were headache and myalgia (>30%).
In adults>65 years of age, the most common injection-site reaction was pain(>20%); the most 
common solicited systemic adverse events were headachemyalgia, and malaise (>10%)
Post Marketing Experience
The following events have been spontaneously reported during the post-approval use of Fluzone.

Blood and Lymphatic System Disorders: Thrombocytopenia, lymphadenopathy.

Immune System Disorders: Anaphylaxis, other allergic/hypersensitivity reactions 
(including urticaria, angioedema)

Eye Disorders: Ocular hyperemia

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
Nervous System Disorders: Guillain-Barré syndrome (GBS), convulsions, febrile 
convulsions, myelitis (including encephalomyelitis and transverse myelitis), facial palsy 
(Bell’s palsy), optic neuritis/neuropathy, brachial neuritis, syncope (shortly after 
vaccination),dizziness, paresthesia

Vascular Disorders: Vasculitis, vasodilatation/flushing•

Respiratory, Thoracic and Mediastinal Disorders: Dyspnea, pharyngitis, rhinitis, cough, 
wheezing, throat tightness

Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome

General Disorders and Administration Site Conditions: Pruritus, asthenia/fatigue, pain in 
extremities, chest pain

Gastrointestinal Disorders: Vomiting
Screening and Eligibility
The Investigator is responsible for keeping a record of all subjects who sign an Informed 
Consent Form for entry into the study.  All subjects will be screened for eligibility.  Screening 
procedures are outlined in Section 2, Schedule of Study Assessments and may take place on or < 
30 days before the day of first vaccine administration. 
Approximately 150 of subjects with monoclonal gammopathies will be screened for enrollment 
and must meet the eligibility criteria below. 100 patients will be randomized into the 
experimental group and 50 subjects will be randomized into the standard of care group. During 
screening, patients will be identified by disease type as having either disease requiring therapy or 
early disease. In order to maintain balanced stratification, patients of each disease type will be 
separately allocated in the same ratio of 2:1 experimental to control group. If a patient dies or 
discontinues their participation for any reason, we will not add another patient in their place.
Inclusion Criteria
Subjects must meet the following inclusion/exclusion criteria to be eligible for the study.
Inclusion criteria 
1. Understand and voluntarily sign an informed consent form.
2. Age 18 years at the time of signing the informed consent form.
3. Diagnosis of any monoclonal gammopathy:  Monoclonal Gammopathy of Undetermined 
Significance (MGUS), asymptomatic / active multiple myeloma, asymptomatic / active 
Waldenstrӧm Macroglobulinemia (WM).
Exclusion criteria  
1. Any serious egg allergy or prior serious adverse reaction to an influenza vaccine.

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2. Use of any other influenza vaccine for the 2015 to 2016 flu season.
3. Women who are pregnant or plan to become pregnant in the study period.
Visit schedule and assessments
Screening Assessments and all on study scheduled visits and assessments are outlined in Section 
2 Table of Study Assessments. 
At the end of the 2015-2016 flu season between May 1 to May15, subjects will undergo off study 
evaluations per the Schedule of Assessments.   
Vaccine Administration
5.4.1 Treatment assignments
Individuals will be randomized at an allocation of 2:1 experimental to standard of care arm. The 
experimental group will receive high dose influenza vaccine with a booster high dose flu vaccine 
one month later. The standard of care group will receive a single influenza vaccine (standard 
dose if age <65 and high dose if age ≥ 65) and a placebo booster vaccine after one month. All 
study injections, whether vaccine or placebo will be redrawn into a fresh syringe to assist in 
blinding. Only the research pharmacist will have a record of the contents of each study injection. 
5.4.2
Dosing regimen
The planned vaccine administration for investigation for experimental group is: 
1) Fluzone® high-dose vaccine after flu vaccines are available (starting August 2015); 
2) Fluzone® high-dose vaccine as a second booster dose to all subjects in each cohort.
The planned vaccine administration for investigation for standard of care group is: 
1) Fluzone® high-dose vaccine if age ≥65 or standard dose trivalent inactivated influenza 
vaccine if age <65. Vaccines will be administered based on standard of care practice after flu 
vaccines are available (starting August 2015); 
2) Placebo normal saline injection as a second booster dose to all patients in this group.

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5.4.4 Record of administration
Accurate records will be kept of all vaccine administration. 
Discontinuation of Study Treatment 
Follow up will continue until the last study visit or the occurrence of any of the following events.  

Adverse event(s) that, in the judgment of the Investigator, may cause severe or permanent 
harm or which rule out continuation of the treatment regimen.

Withdrawal of consent

Lost to follow up

Death
Adverse events
Toxicity will be scored using CTCAE Version 4.0 for toxicity and adverse event reporting.  A 
copy of the CTCAE Version 4.0 can be downloaded from the CTEP homepage 
(http://ctep.info.nih.gov).  All appropriate treatment areas should have access to a copy of the 
CTCAE Version 4.0.  
Because any attribution of an adverse event from a vaccine would be expected to occur 
immediately or within several days, adverse events will only be recorded for a period of 30 days 
from each study vaccine. Within this time frame, all adverse clinical experiences grade 2 or 
higher, whether observed by the investigator or reported by the patient, must be recorded, with 
details about the duration and intensity of each episode, the action taken with respect to the study 
vaccine, and the patient’s outcome.
Following the 30-day window after the booster vaccine, survival data will be collected for the 
remainder of the influenza season in addition to any influenza-like illnesses and documented 
influenza infections. 
Serious Adverse Event (SAE) Definition 

Results in death

Is life-threatening1

Requires inpatient hospitalization or prolongation of existing hospitalization

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
Results in persistent or significant disability or incapacity2

Is an important medical event3
 1“Life-threatening” means that the subject was at immediate risk of death at the time of the serious 
adverse event; it does not refer to a serious adverse event that hypothetically might have caused death if it 
were more severe.
2“Persistent or significant disability or incapacity” means that there is a substantial disruption of a person’s 
ability to carry out normal life functions.
3Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in situations where none of the outcomes listed above occurred.  Important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may jeopardize the patient 
or may require intervention to prevent one of the other outcomes listed in the definition above should also 
usually be considered serious.  Examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse.  A new diagnosis of cancer during 
the course of a treatment should be considered as medically important. 
Protocol Amendments/Deviations
Protocol amendments
Any amendment to this protocol must be agreed to by the Principal Investigator and IRB. 
Protocol deviations
When an emergency occurs that requires a deviation from the protocol for a subject, a deviation 
will be made only for that subject.  A decision will be made as soon as possible to determine 
whether or not the subject (for whom the deviation from protocol was effected) is to continue in 
the study.  The subject’s medical records will completely describe the deviation from the 
protocol and state the reasons for such deviation.  In addition, the Investigator will notify the 
IRB/EC in writing of such deviation from protocol per IRB Policy 710.
Non-emergency minor deviations from the protocol will be permitted with approval of the 
Principal Investigator. 
Data Management
Analyses and Reporting
Clinical data will be coded and blinded from the study investigators after randomization. Data 
will be analyzed and reported after all accrual is completed. All subsequent data collected will be 
analyzed and reported in a follow-up clinical report. 

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Data Monitoring Committee
The study team will monitor the data on a regular basis. There is no formal DMC for this 
minimal risk study.  
The principal investigator is responsible for monitoring the data, assuring protocol compliance, 
and conducting the safety reviews at the specified frequency [monthly].  During the review 
process the principal investigator will evaluate whether the study should continue unchanged, 
require modification/amendment, or close to enrollment.
The principal investigator, the Institutional Review Board (IRB), Yale Cancer Center Data and 
Safety Monitoring Committee (DSMC) have the authority to stop or suspend the study or require 
modifications.
This protocol presents minimal risks to the subjects and adverse events or other problems are not 
anticipated. In the unlikely event that such events occur, Reportable Adverse Events (which are 
events that are serious or life-threatening and unanticipated (or anticipated but occurring with a 
greater frequency than expected) and possibly, probably, or definitely related) or unanticipated 
problems involving risks to subjects or others will be reported in writing to the IRB (using the 
appropriate forms from the website) and any appropriate funding and regulatory agencies per 
IRB policy 710. The investigator will apprise fellow investigators and study personnel of all 
adverse events that occur during the conduct of this research project [via email as they are 
reviewed by the principal investigator.]
Biostatistical Considerations
The primary endpoint of this randomized Phase II study is a composite measure of two clinical 
endpoints. A patient is considered a treatment failure if either of the following events occur 
during the 2015-6 flu season:

Progression of the underlying plasma cell disorder

Any documented flu infection
We plan to enroll 50 patients in the standard care group and 100 in the vaccine group for a total 
of 150. Patients will be separately allocated in this 1:2 ratio based on their disease type of early 
disease versus active disease in order to maintain balanced stratification between the groups. For 
each disease type, this 1:2 ratio will be performed in blocks of three in order to maintain balance 
in the study at all times. A randomization schedule will be prepared by the study biostatistician, 
Dr Yao, in advance of the trial beginning. If the standard care group has 0.70 probability of 
success (defined above) and the vaccinated group has probability of success equal to 0.90 then 
the power of this design is 0.93.  As another example, if the standard care group has 0.75 
probability of success and the vaccinated group has 0.90 probability of success then the power of 

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our design is 0.78 at significance level 0.1.  Patient deaths which are not related to influenza or 
disease progression will be censored for efficacy analysis.
Yale University’s online OnCore system will be used to randomize the patients. Randomization 
will be performed by the clinical trials office of Yale University and the information released 
only to the research pharmacist.
We will monitor the study for the toxicity of the vaccine. The unacceptable toxicities include any 
serious adverse event grade 3 or higher which is believed to be related to the study vaccine. The 
tolerability will initially be tested in the first 20 patients in the vaccine arm. We will consider the 
vaccine tolerable if the rate of vaccine related toxicity is 10% or less and intolerable if 30% or 
more. If, in the first 20 patients, we observe 5 or more patients with vaccine related toxicity, then 
the cohort will be terminated early. With this design, the probability of terminating the cohort 
early is 0.04 if the true but unknown toxicity rate is 10% and 0.76 if the true rate is 30%.
  
Regulatory Considerations
Institutional Review Board/Ethics Committee approval
The protocol for this study has been designed in accordance with the general ethical principles 
outlined in the Declaration of Helsinki.  The review of this protocol by the IRB/EC and the 
performance of all aspects of the study, including the methods used for obtaining informed 
consent, must also be in accordance with principles enunciated in the declaration, as well as ICH 
Guidelines, Title 21 of the Code of Federal Regulations (CFR), Part 50 Protection of Human 
Subjects and Part 56 Institutional Review Boards.
Any amendments to the protocol after receipt of IRB/EC approval must be submitted by the 
Investigator to the IRB/EC for approval.  The Investigator is also responsible for notifying the 
IRB/EC of any serious deviations from the protocol, or anything else that may involve added risk 
to subjects.
Any advertisements used to recruit subjects for the study must be reviewed and approved by the 
IRB/EC prior to use.
Informed consent
The Investigator must obtain informed consent of a subject or his/her designee prior to any study 
related procedures as per GCP as set forth in the CFR and ICH guidelines.
Documentation that informed consent occurred prior to the subject’s entry into the study and the 
informed consent process should be recorded in the subject’s source documents.  The original 

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consent form signed and dated by the subject and by the person consenting the subject prior to 
the subject’s entry into the study, must be maintained in the Investigator’s study files.
Subject confidentiality
The principle investigator affirms the subject’s right to protection against invasion of privacy.  
Study records requirements
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the study drug, that is copies of CRFs and source documents 
(original documents, data, and records [e.g., hospital records; clinical and office charts; 
laboratory notes; memoranda; or evaluation checklists; SAE reports, pharmacy dispensing 
records; recorded data from automated instruments; copies or transcriptions certified after 
verification as being accurate copies; microfiches; photographic negatives, microfilm, or 
magnetic media; x-rays; subject files; and records kept at the pharmacy, at the laboratories, and 
at medico-technical departments involved in the clinical study; original signed informed 
consents, etc) be retained by the Investigator for as long as needed to comply with national and 
international regulations (generally 2 years after study closes). 

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References
1.
Boccadoro M, Pileri A. Plasma cell dyscrasias: classification, clinical and laboratory 
characteristics, and differential diagnosis. Baillieres Clin Haematol. 1995;8:705-719.
2.
Fiore AE, Shay DK,  Broder K, et al. Prevention and control of influenza: 
recommendations of the Advisory Committee on Immunization Practices (ACIP), 2008. MMWR 
Recomm Rep. 2008; 57:1-60.
3.
Blimark C, Mellqvist U, Landgren O, et al. Multiple Myeloma and Infections:  A 
Population-Based Study Based On 9,610 Multiple Myeloma Patients. 54th ASH Annual Meeting 
and Exposition, December 8 -11, 2012. Poster #945.
4.
Hannoun C, Megas F, Piercy J. Immunogenicity and protective efficacy of influenza 
vaccination. Virus Res 2004;103:133-138.
5.
Hobson D, Curry RL, Beare AS, Ward-Gardner A. The role of serum haemagglutination-
inhibiting antibody in protection against challenge infection with influenza A2 and B viruses. J 
Hyg Camb 1972;70:767-777.
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Goodwin K, Viboud C, Simonsen L. Antibody response to influenza vaccination in the 
elderly: a quantitative review.Vaccine 2006;20;24:1159-1169.
7.
Mills KH, Cawley JC. Abnormal monoclonal antibody-defined helper/suppressor T-cell 
subpopulations in multiple myeloma: relationship to treatment and clinical stage. Br J Haematol 
1983;53:271-275.
8.
Brown RD,Pope B,Murray A,et al. Dendritic cells from patients with myeloma are 
numerically normal but functionally defective as they fail to up-regulate CD80 (B7-1) expression 
after huCD40LT stimulation because of inhibition by transforming growth factor-beta1 and 
interleukin-10. Blood 2001;98:2992-2998
9.
Ogawara H,Handa H,Yamazaki T,et al.High Th1/Th2 ratio in patients with multiple 
myeloma. Leuk Res 2005;29:135-40.
10.
Xu Y, Methuku N, Coimbatore B, et al. Immunogenicity of an inactivated monovalent 
2009 influenza A (H1N1) vaccine in patients who have cancer. Oncologist 2012;17:125–134.
11.
Musto P, Carotenuto M. Vaccination against influenza in multiple myeloma. Br J 
Haematol. 1997 May;97(2):505-6..
12.
Robertson JD, Nagesh K, Jowitt SN, et al. Immunogenicity of vaccination against 
influenza, Streptococcus pneumoniae and Haemophilus influenzae type B in patients with 
multiple myeloma. Br J Cancer 2000;82:1261-5.
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Rapezzi D, Sticchi L, Racchi O, et al. Influenza vaccine in chronic lymphoproliferative 
disorders and multiple myeloma. Eur J Haematol. 2003;70:225-230.
14.
Ljungman P, Nahi H, Linde A.Vaccination of patients with haematological
malignancies with one or two doses of influenza vaccine: a randomised study. Br J Haematol 
2005;130:96-98
15.
Hahn M, Schnitzler P, Brunhilde S, et al. Boost vaccination improves humoral immune 
response against influenza virus in patients with multiple myeloma . 55th ASH Annual Meeting 
and Exposition, December 7 -10, 2013. Poster #3116.
16.
Chiron D, Bekeredjian-Ding I, Pellat-Deceunynck C, et al. Toll-like receptors: lessons to 
learn from normal and malignant human B cells. Blood 2008. 112:2205-2213.

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 pg. 24
17.
Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) 
Research Data (1973-2012), National Cancer Institute, DCCPS, Surveillance Research Program, 
Surveillance Systems Branch, released April 2015, based on the November 2014 submission.
18.
Glasmacher A, Hahn C, Hoffmann F, et al. A systematic review of phase-II trials of 
thalidomide monotherapy in patients with relapsed or refractory multiple myeloma. Br J 
Haematol 2006;132:584–93.
19.
Richardson PG, Sonneveld P, Schuster M et al. Bortezomib or high-dose dexamethasone 
for relapsed multiple myeloma. New Engl J Med. 2005. 352:2487-98.
20.
Kristinsson SY, Björkholm M, Andersson TM-L, et al. Patterns of survival and causes of 
death following a diagnosis of monoclonal gammopathy of undetermined significance: a 
population-based study. Haematologica. 2009;94(12):1714-1720.
21.
Kumar SK, Therneau TM, Gertz MA, et al. Clinical course of patients with relapsed
multiple myeloma. Mayo Clin Proc 2004; 79: 867–874.

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Appendices
 
Appendix A – Correlative Studies and Collection of Research Samples
Timing:
Blood: 
30 ml in heparin anticoagulant (4 green tops)

Day of first vaccine + 1 week

7 Days after first vaccine + 2 days (optional)

Day of second vaccine + 1 week

30 Days after second vaccine (-1 week, + 90 days)

End of study blood draw between May 1 to May 15, 2016 (optional)
Correlative studies:
The Dhodapkar lab will process the research samples for performance of the following assays:

Measurement of T cell subsets, including CD4+/CD8+, NK cells (Flow cytometry)

Influenza-specific T cell response (intracellular cytokine analysis)

HAI titers for influenza A and B

Temporarily freeze PBMCs for cell mediated immune studies. Samples will be destroyed 
of after all testing is completed and the study is closed.

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Appendix B – Figures and Tables
*Figure 1: Gradual decrease in the response duration of myeloma patients with increasing order 
of treatment regimen
*Figure from Kumar, et al. Mayo Clin Proc 2004. Response duration is defined as time to death 
or start of a new therapy.