Pilot Study of Pembrolizumab and Single-Fraction, Low-Dose, Radiation Therapy in Patients With Relapsed or Refractory Multiple Myeloma
Phase: PHASE1
Conditions: ISS Stage I Plasma Cell Myeloma, ISS Stage II Plasma Cell Myeloma, ISS Stage III Plasma Cell Myeloma, Recurrent Plasma Cell Myeloma, Refractory Plasma Cell Myeloma
Sponsor: Emory University

Product:  Pembrolizumab (MK-3475, IND 130757)
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Protocol/Amendment No.:  Rad4106-17(MK-3475-749), v6/30/2022
TITLE: Pilot Study of Pembrolizumab and Single-fraction, Low-dose, Radiation Therapy in 
Patients with Relapsed or Refractory Multiple Myeloma
INVESTIGATORS: 
Principal Investigator
Radiation Oncology: Mohammad K. Khan, MD PhD, DABR
Principal Co-Investigator
Medical Oncology: Jonathan Kaufman, MD
Sub-Investigators
Radiation Oncology: Natia Esiashvili, MD
Medical Oncology: Sagar Lonial, MD    
 
       Ajay Nooka, MD 
                       
Translational Medicine: Rafi Ahmed, PhD.
Biostatistics: Jeffery Switchenko, PhD.
SPONSOR: Mohammad K. Khan, MD PhD
SUPPORTER: Merck Sharp & Dohme Corp.
IND NUMBER: 130757
EudraCT NUMBER (Studies in Europe only): N/A

Product:  Pembrolizumab (MK-3475, IND 130757)
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TABLE OF CONTENTS
         PAGES
1.0 
PROTOCOL SUMMARY
3
2.0 
TRIAL DESIGN/SCHEMA
4
3.0
STUDY OBJECTIVES, ENDPOINTS, & HYPOTHESES
10
4.0
BACKGROUND & RATIONALE
12
5.0
ADMINSTRATION OF STUDY PHARMACEUTICAL
17 
6.0 
DOSE MODIFICATION, DOSE LIMITING TOXICITIES, AND 
20
SUPPORTIVE CARE
7.0      DIET/ACTIVITY/CONTRACEPTION/OTHER CONSIDERATIONS
25
8.0      DELIVERY OF RADIATION THERAPY TREAMENT
 
29
9.0
TRIAL FLOW CHART
31
10.0
TRIAL PROCEDURES
33
11.0
STATISTICAL ANALYSIS PLAN
48
12.0
LABELING, PACKAGING, STORAGE, AND RETURN OF 
                        50
CLINICAL SUPPLIES
13.0     DATA SAFETY MONITORING BOARD 
52
14.0
APPENDICES:
             54
APPENDIX I:    CTCAE COMMON TOXICITY CRITERIA STUDY 
             54            
APPENDIX II:   RECIST CRITERIA
             55
APPENDIX III:  IMMUNE RELATED RECIST CRITERIA
             56
APPENDIX IV: IMWG RESPONSE CRITERIA
59
  
APPENDIX IV:  KARNOFSKY PERFORMANCE STATUS & ECOG              60            
APPENDIX VII:  ELIGIBILTY CHECKLIST
             61
15.0 
BIBLIOGRAPHY
63

Product:  Pembrolizumab (MK-3475, IND 130757)
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Protocol/Amendment No.:  Rad4106-17(MK-3475-749), v6/30/2022
1.
PROTOCOL SUMMARY
Abbreviated Title
Pilot Study of Pembrolizumab and Single-fraction, Low-dose, 
Radiation Therapy in Patients with Relapsed or Refractory 
Multiple Myeloma
Trial Phase
Pilot Study
Clinical Indication
Relapsed or Refractory Multiple Myeloma 
Trial Type
Pilot study 
Type of control
None
Route of administration
Patients will receive on day 1, cycle 1, radiotherapy (8 Gy/1fx) to 
an extra-osseous or osseous myeloma site followed by 
pembrolizumab (200 mg/kg i.v. on day 2 or 3, then every 3 weeks 
+/- 7 days).
Trial Blinding
N/A
Number of trial subjects
24 patients (20 patients minimum, with 4 extra patients to account 
for loss to follow-up/attrition and/or failure to comply with 
recommended treatments); 12 patients will be allowed to not have 
measurable myeloma disease.
Estimated enrollment period
2 years
Description of enrollment
Following evaluation by medical oncology and radiation oncology, 
patients will be enrolled.  Baseline assessment prior to enrollment 
may include bone marrow biopsy, peripheral blood collection, and 
staging of the patient per standard of care.  Baseline serum and urine 
paraprotein analysis, bone marrow biopsy, PET/CT imaging, 
routine blood work, and baseline physical exam prior to enrollment.  
Patient with measurable myeloma disease will be screened for 
tolerability to Pembrolizumab and radiotherapy.  Patients will be 
assessed at 1st month and every 3 month for response using the 
standard International Myeloma Working Group (IMWG) 
Response Criteria, and will undergo routine myeloma labs every 
6 weeks until progression or as clinically indicated; Patients 
with stable disease or better per IMWG response criteria will 
continue with maintenance pembrolizumab (200 mg/kg every 3 
weeks for 2 yrs).  Patients that have progressive disease, or relapse 
after a complete response will be removed from the trial and treated 
per standard of care at the discretion of the treating physician.
Duration of Intervention
At least 24 months of Pembrolizumab, or until progression.
Duration of Evaluation
3 year (2 yrs for accrual, and at least 1 year follow-up for the last 
patient accrued on the study)
Estimated duration of trial
3 years (2 years to accrue + 1 years to follow all patients)
Duration of Participation
3 years
Study Center
Emory University. Atlanta, Georgia.

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2.
TRIAL DESIGN/SCHEMA
1.
Trial Overview
Following evaluation by medical oncology and radiation oncology, patients with measurable 
myeloma disease will be enrolled.  Baseline assessment prior to enrollment may include bone marrow 
biopsy, peripheral blood collection, and staging of the patient per standard of care.  Baseline serum and 
urine paraprotein analysis, bone marrow biopsy, PET/CT imaging, skeletal survey, routine blood work, 
and baseline physical exam prior to enrollment.  Patient will be screened for tolerability to 
Pembrolizumab, and those that are also eligible for radiotherapy will be identified.  
Patients will receive on day 1, cycle 1, radiotherapy (8 Gy/1fx) to an extra-osseous site and/or any 
osseous bony site, followed by pembrolizumab (200 mg/kg i.v. on day 2 or 3).  Baseline peripheral 
blood will be collected for myeloma response as well as for correlative biomarker analysis (timing of 
blood draws are defined in the flow chart in section 10.0).  
Patients will be assessed for safety during routine visits, as well as treatment response using the standard 
International Myeloma Working Group (IMWG) Response Criteria (see Appendix II for IMWG 
Criteria) at 1 month (shortly after completion of cycle 2 of pembrolizumab, anytime between Day 23-
30 +/- 7 days), and at least every 3 months +/-14 days (or as clinically indicated).  Patients with 
stable disease or better per IMWG response criteria will continue with maintenance pembrolizumab 
(200 mg/kg every 3 weeks for 2 yrs).  Patients that have progressive disease, or relapse after a complete 
response will be removed from the trial and will be treated per standard of care at the discretion of the 
treating physician.  
Patients will continue to be monitored per standard of care on the trial.  Patients will be monitored for 
known radiation related toxicity, known pembrolizumab toxicity, as well as any unexpected toxicity, 
per standard of care. PET/CT scans will be done at baseline and every 3 months, per standard of 
care.  
The primary endpoint is to evaluate the safety and tolerability of concurrent single/low dose 
radiotherapy (8 Gy/1fx) in combination with pembrolizumab in relapsed and/or refractory myeloma 
patients at 3 months (acute toxicity, primary endpoint) and at 6 and 12 months (late toxicity). The 
secondary objective is to characterize the effect of radiation in combination with pembrolizumab on 
systemic response rates using international myeloma working group (IMWG) uniform response criteria 
for myeloma, to assess baseline changes in PET/CT as a result of combining pembrolizumab and 
radiotherapy, and to evaluate treatment response at irradiated and un-irradiated sites (i.e. the abscopal 
effect) using baseline PET/CT. Exploratory analysis would include analyzing Circulating Myeloma 
Tumor cells and phenotype of T cells as a prognostic and predictive biomarker. Compare blood 
Myeloma tumor cells with BM tumor cells. We are interested in comparing T cell phenotype after each 
treatment and using that as a prognostic biomarker.  We will also evaluate serum LDH, CRP, ESR, 
ALC, cytokines and chemokines (such as IL-6, s IL-6R) and other immune related biomarkers, and 
correlate their expression pre and post treatment and evaluate changes in bone marrow biopsy and 
peripheral blood for mutational load, mutational signature (whole exome sequencing), transcriptome of 
the T cells, mutation specific T cells, PD1 and PDL1 expression on MM cells and T cells by flow/IHC, 
RNA-seq. Other biomarker correlative exploratory analysis (role of exosomes, etc) may also be pursued 
as ancillary research to this trial; 

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2.
Acute Toxicity and Late Toxicity Assessment:
Acute toxicity (i.e, > Grade 2 CTCAE toxicity at 3 months) associated with radiation therapy 
at the radiated site will be analyzed as the primary safety endpoint in this pilot study; Goal 
would be to see less than 20% > grade 2 toxicity at 3 months within the radiated area. 
CTCAE criteria (see Appendix I) will be applied to assess acute toxicity. 
Other endpoints that may be analyzed include late toxicity (> Grade 2 CTCAE toxicity at the 
radiated site at 6 months and 12 months), systemic response against myeloma burden to 
localized radiation and pembrolizumab using IMWG uniform criteria, as well as other 
endpoints (defined in more detail in section 3.0). 
3.
Trial Schema
Figure 1: Trial Overview
Baseline work-up (per NCCN guideline) within 28 days +/- 14 days prior to enrollment: 
CBC with Diff, CMP, Calcium, Albumin, Serum Protein analysis, Quantitative 
Immunoglobulin, Serum Immunofixation (SIFE), 24 hr urine total protein, Urine Immune-
Fixation, Serum Free Light Chain, Bone Marrow Biopsy (with IHC, flow, cytogenetics, FISH), 

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Whole Body PET/CT, Biopsy of Osseous or extra-osseous site (only if clinically indicated); 
Pregnancy test;
Inclusion Criteria: 
1) ≥ 18 years old; ISS stage I-III multiple myeloma that has progressive, relapsed, or 
refractory disease;
2) Able to give informed consent;
3) ECOG 0-1;
4) Relapsed and/or refractory myeloma; There is no minimum or maximum number of 
previous therapies that a patient may have received previously before being put on the 
current trial. 
5)  ≥ 1 osseous and/or extra-osseous lesion that can be radiated; 
6) Candidate for pembrolizumab (as determined by physician, and adequate organ 
function as noted in Table 1);
7) Candidate for radiotherapy (as determined by treatment physician); These patients can 
have symptomatic disease and/or asymptomatic disease. A minimum of one site of 
radiation is required to any osseous and/or any extra-osseous disease. Radiation to any 
bony parts of the Head and Neck, Skull, Spine, ribs, and/or extremities are allowed. 
Radiation to any bony part for documented lytic disease is allowed. Radiation to any 
soft tissue plasmacytoma (including osseous and extra-osseous plasmacytoma) is 
allowed. The only exclusion criteria for radiation, is CNS metastases (see exclusion 
criteria # 16);  
8) Measurable myeloma disease (urine protein > 200 mg in 24 hr urine collection, 
serum free light chain ratio> 100 with an abnormal k/l ratio, serum M protein > 
0.5 g/dl) ; 12 of the 24 patients do not have to have measurable disease; 
9) Negative urine pregnancy test within 2 weeks for female subjects;
Female subjects of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  
If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required.  
a.
Female subjects of childbearing potential should be willing to use 2 methods of 
birth control or be surgically sterile, or abstain from heterosexual activity for the 
course of the study through 120 days after the last dose of study medication.  
Subjects of childbearing potential are those who have not been surgically sterilized 
or have not been free from menses for > 1 year. 
b. Male subjects should agree to use an adequate method of contraception starting 
with the first dose of study therapy through 120 days after the last dose of study 
therapy.

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c.
Abstinence is acceptable, if this is the usual life style and preferred contraception 
for the patient.
Exclusion Criteria: 
1) Previous anti-PD1 or anti-PD-L1; 
2) Solitary plasmacytoma;
3) Smoldering (asymptomatic) multiple myeloma; 
4) Currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device 
within 4 weeks of the first dose of treatment;
5) Has a diagnosis of immunodeficiency;
6) Known history of active TB   (Bacillus Tuberculosis);
7) Hypersensitivity to Pembrolizumab or any of its recipients;
8)  Known additional malignancy that is progressing or requires active treatment 
(exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the 
skin);
9)  Has active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs);
10)  Known history of, or any evidence of active, non-infectious pneumonitis;
11)  Active infection requiring systemic therapy;
12)  Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 
120 days after the last dose of trial treatment.
13) Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
14) Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected).
15) Has received a live vaccine within 30 days of planned start of study therapy.
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed.

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Protocol/Amendment No.:  Rad4106-17(MK-3475-749), v6/30/2022
16) Patients requiring radiation for CNS diseases are excluded (CNS defined as brain soft 
tissue/intra parenchymal metastases within the gray and white matter of the brain 
and/or for CSF disseminated disease, including leptomeningeal carcinomatous 
disease). 
17) Has a history of Allogeneic Stem Cell Transplantation.
Follow-up: 
Radiation Oncology: at 4 week post radiation and every 3 months (per standard of 
care, and as clinically indicated);  
 Medical Oncology: every 3 weeks, or as clinically indicated per standard of care for 
administration of pembrolizumab, and to monitor for any potential side effects from 
pembrolizumab;
Labs to be done during these visits: 
Prior to cycle 2 of Pembrolizumab: Myeloma labs (CBC with diff, CMP, 
Calcium, Quantitative Immunoglobulin, M-Protein (Serum and Urine), Serum 
Free Light Chain); 
Prior to Cycle 4 and every 6 weeks after that (until progression or 
as/clinically indicated): Myeloma labs (CBC with diff, CMP, Calcium, 
Quantitative Immunoglobulin, M-Protein (serum and Urine), Serum Free Light 
Chain); 
 
Imaging: PET/CT will be done every 3 months;
Bone Marrow Biopsy: one biopsy at 6 months (if clinically indicated); 

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Table 1 - Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute 
neutrophil 
count 
(ANC)
≥1,500 /mcL
Platelets
≥75,000 / mcL (rare exception for > 50K per PI*)
Hemoglobin
≥7.5 g/dL or ≥5.6 mmol/L and allow transfusion 
or EPO dependency (within 7 days of 
assessment)
Renal
Serum creatinine OR
Measured or calculateda 
creatinine clearance
(GFR can also be used in place 
of creatinine or CrCl)
≤1.5 X upper limit of normal (ULN) OR
≥60 mL/min for subject with creatinine levels > 
1.5 X institutional ULN
Hepatic
Serum total bilirubin
≤ 1.5 X ULN OR
Direct bilirubin ≤ ULN for subjects with total 
bilirubin levels > 1.5 ULN
AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN  OR
≤ 5 X ULN for subjects with liver metastases
Albumin
>2.5 mg/dL
Coagulation
International Normalized Ratio 
(INR) or Prothrombin Time 
(PT)
Activated Partial 
Thromboplastin Time (aPTT)
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy
as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy
as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants
aCreatinine clearance should be calculated per institutional standard.
*In rare exceptions, where medical interest of patient to get on the trial supercedes 
the platelet cutoff, the PI can make an exception to allow a lab value lower than 
75K. PI can allow for lab value up to 50K. * 50K cutoff is a lab value that used by 
several other myeloma protocols at Emory, especially for relapsed/refractory 
myeloma patients.  The maximum number of patients that can be allowed this 
exception on the protocol is no more than 3. Transfusion is allowed to help 
increase platelets. 

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3.
OBJECTIVES, ENDPOINTS & HYPOTHESES
1.
Primary Objective, Endpoint, & Hypothesis
Primary Objective  
To evaluate the safety of concurrent single/low dose radiotherapy (8 
Gy/1fx) in combination with Pembrolizumab in relapsed or refractory 
myeloma patients; Once 10 patients are enrolled, we will stop trial 
for 3 months to assess for acute toxicity, and then resume the trial. 
Primary Endpoint
CTCAE > grade 2 toxicity at the specific irradiated organ site at 3 
months (the Dose Limiting Toxicity); 
 
       Primary Hypothesis  
The primary hypothesis of this pilot study is that the use of concomitant 
Pembrolizumab and radiation therapy in multiple myeloma patients will 
be well tolerated and safe.
Alternative Hypothesis
It is possible that concurrent use of radiotherapy and Pembrolizumab in 
relapsed/refractory myeloma may increase CTCAE > grade 2 toxicity 
within the radiated site at 3 months.
2.
Secondary Objective(s), Endpoint(s) & Hypothesis (es)
                                    Secondary Objectives 
To characterize late toxicity (CTCAE > grade 2 toxicity at 6 and 12 
months) and the effect of radiation in combination with Pembrolizumab 
on systemic response rates using international myeloma working group 
(IMWG) uniform response criteria for multiple myeloma at 6 months 
and 12 months; 
To assess changes in PET/CT as a result of combining Pembrolizumab 
and radiotherapy at 6 months and 12 months; 

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Secondary Endpoints
a.
1. Number of patients achieving any response (from 
baseline) per IMWG response criteria at 6 months and 12 
months;
b. 2. Overall survival time at 6 months and 12 months;
c.
3. Overall response based on baseline changes on PET/CT 
at 6 months and 12 months; 
d. 4. Difference in pre and post treatment serum immune 
biomarkers;
Secondary Endpoint Definitions
a.
Response is defined per IMWG criteria, and will be calculated at 6 
months and 12 months; 
b. Overall survival will be defined as time from first treatment on 
cycle 1, day 1 to the earlier of date of death and/or last follow up at 
6 months and 12 months.
c.
Overall response will be defined using IMWG uniform response 
criteria. 
d. Several serum biomarkers will be analyzed.
Secondary Hypotheses
The secondary hypothesis is that low dose/single fraction (8Gy/1fx) will 
synergize with Pembrolizumab for a more effective anti-myeloma 
response per IMWG, via the radiation induced abscopal response. 

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4.
BACKGROUND & RATIONALE
          26,850 new myeloma cases with 11,240 deaths were expected in 2015.  While outcomes have 
improved with the introduction of new agents, patients continue to relapse after effective therapy, and 
ultimately develop refractory disease.   Treatment of relapsed myeloma include bortezomib, 
lenalidomide, dexamethasone, carfilzomib, pomalidomide, panobinostat, monoclonal antibodies and/or 
some combination of these. The role of pembrolizumab within myeloma, an anti PD-1 immune 
checkpoint inhibitor, is currently under investigation. The role of radiotherapy for relapsed myeloma is 
typically limited to palliation of bony pain and/or for prevention of significant neurological effects or 
end organ damage due to progression of extra-osseous manifestation of relapsed myeloma.  However, 
whether radiation therapy may enhance PD-1 inhibitor responses within myeloma is unknown. 
We believe that PD1 inhibitor in combination with radiotherapy may improve systemic 
responses. 
We have demonstrated that radiation therapy can augment the immune response via the 
radiation induced “abscopal effect”. We utilized a human equivalent syngeneic mouse model 
implanted with B16 melanoma cells on both flanks of a mouse; using a 10 Gy single dose of radiation, 
we observed significant delay of the radiated site, as well as the remote non-radiated tumor site (Fig. 
1A). This action at a distance implies that immune mechanisms are responsible. To validate this, we 
quantified the different immune cells that are responsible for the “abscopal effect” (Fig. 1B,1C & 1D). 
For many years, mouse xenograft models have dominated in cancer drug development fields. Due to 
its immunedeficiency, these models are not suitable to address immune response in cancer treatment. 
Our novel syngeneic mouse models provide us reliable platform for immunotherapy studies.   Our 
results are provocative given that post-irradiation increases PD-1 expression on T cells, and combining 
radiation with anti-PD1 antibody therapy demonstrates synergy1.   
Day 0
B16F10GP
0.5 Million
Day 10
Radia on
5,10,20 GY
Day 17
Sacrifice
A
10
12
14
17
0
200
400
600
Days After Tumor Innoculation
Tumor Volume (mm3)
No XRT
5 Gy XRT
10 Gy XRT
20 Gy XRT
10
12
14
17
0
200
400
600
Days After Tumor Innoculation
Tumor Volume (mm3)
No XRT
5 Gy XRT
10 Gy XRT
20 Gy XRT
Irradiated Tumor (Right)
Primary Tumor
Non-Irradiated Tumor (Le )
Secondary Tumor
B
Primary Tm
Right
Secondary Tm
Le
104
105
106
107
108
Dose
CD8+ T cells/g tumor
0 Gy
5 Gy
10 Gy
20 Gy
Right
Left
C
CD8
CD4
CD45 gated
D
<APC-Cy7-A>: CD11b
<FITC-A>: LY6G
0.0166
16.6
64.1
19.2
<APC-Cy7-A>: CD11b
<FITC-A>: LY6G
3.25e-3
1.99
67.4
30.6
CD11b
Ly6G
Primary Tm
Monocyte Gated
Figure 1. Mouse model of abscopal effect. A. 0.5x106 B16F10gp melanoma cells were injected subcutaneously 

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in the left and right flanks. Ten days post implantation, mice were irradiated with different radiation doses (right) 
flank, and tumors measured every other day. The mice were sacrificed at day 17. B. Tumor growth kinetics in mice 
with Irradiated tumor (blue) or un-Irradiated tumor (Red), demonstrating a decreased tumor volume with Irradiation 
in primary as well as secondary tumor C. Expansion of CD8 and CD4 T cells was found in irradiated side of tumor 
(left column) after radiation therapy, suggesting that radiation influences immune cell phenotypes within tumor 
microenvironment. D. Radiated decreased myeloid suppressor cells. All the Ly6G+ cells were Ly6C+ characteristic 
MDSCs.
Several reports have suggested that radiotherapy in combination with emerging immunotherapy agents 
such as PD-1, PD-L11, CTLA-4 inhibitors2 as well as other immunotherapy agents (FLT-3 ligand3, 4-
1 BB 4,5etc) may increase the efficacy of these agents. Sharabi et al.6 and Dovedi et al.7 together 
demonstrate that radiation therapy increases the T cell repertoire and antigen presentation to T cells; 
furthermore, adding radiation to PD-1 blockade in mice models demonstrate significant improvement 
in systemic response and local control.8 Trials using some of these agents (PD-1 and others, in 
combination with radiotherapy) are ongoing, while others are in the planning stages for a wide variety 
of malignancies. 
Clinically, the combination of the PD-1 inhibitor, pembrolizumab in combination with revlamid (Rd) 
produced responses in 76% of the 17 heavily pretreated patients with relapsed or refractory multiple 
myeloma in the KEYNOTE-023 study (San Miguel J, Mateos MV, Shah JJ, et al. 57th American 
Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract 505). Similar 
impressive results were seen with pembrolizumab in combination with pomalidomide and 
dexamethasone. Overall response rates of 60% among double refractory patients were seen with this 
safe combination. 
While future therapies for multiple myeloma may combine PD-1 inhibitors as part of their medical 
oncology designs, it is also possible that some of these patients may also receive local radiotherapy (for 
palliation and/or prophylaxis) as part of their standard of care treatments. Thus, we propose to evaluate 
the safety and efficacy of pembrolizumab in combination with radiotherapy.  Our pilot study will 
provide insights for future clinical trial designs and help guide future clinical management decisions 
regarding early safety and efficacy of this combination. Thus, we propose to evaluate the safety and 
outcomes of this combination in a small cohort of patients.
4.1 
The Immune System in Cancer
In 2000, Hanahan and Weinberg published their seminal review describing the 6 
biological hallmarks acquired during the development from benign to malignant to metastatic 
tumors9. Eleven years later, they illustrated 2 further important processes that were since 
realized, including “evading the immune system”10.
The immune system consists of two main components, innate and adaptive system. In 
brief, the innate system is a non-specific response to differences between innate and foreign 
pathogens, while the adaptive system is a more tailored response that induces memory. As part 
of this adaptive response, macrophages and dendritic cells present foreign antigens to the T 
cell’s receptors. Further T cell activation is regulated by multiple factors, including both 
positive (co-stimulatory) and negative (co-inhibitory) surface receptors. Tumors can subvert 
the related immune recognition in part through increase of co-inhibitory molecule expression; 
two of these regulatory molecules are cytotoxic T lymphocyte antigen-4 (CTLA-4) and 

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programmed death 1 (PD-1) receptor.
4.2
Anti-PD-1 in Pre-Clinical Models
Programmed death 1 (PD-1) (or CD279) is part of the CD28 family of proteins, which 
includes CTLA-4 and ICOS, that regulate T cell activity21. PD-1 is a glycoprotein receptor that 
can be expressed on the surface of T cells, B cells and myeloid cells (monocytes and dendritic 
cells)21.  In T cells, PD-1 expression is primarily induced by T cell receptor (TCR) engagement 
and ligation with PD-L1 and PD-L2, expressed on antigen presenting cells, and induces an 
inhibitory signal that antagonizes TCR signaling and other important pathways necessary for 
optimal T cell activation 
Interestingly, melanoma, and to a lesser effect NSCLC, expresses abundant PD-1 
ligand (PD-L1), whereas T cells of advanced cancer patients notoriously express increased 
levels of PD-1. The combined effect is that these cancer cells are spared from T-cell-mediated 
cytotoxicity, and tumor infiltrating lymphocytes are maintained in a dysfunctional state, 
described as T cell exhaustion. Indeed, PD-1 expression on T cells of patients has been 
associated with progression to metastatic disease. 
Targeting the PD-1 pathway in pre-clinical models has demonstrated promising 
activity. Utilizing murine cancer cells, anti-PD1 antibody decreased tumor growth and 
decreased metastatic potential. Uisng B16 cells ( a PD-L1 positive cell line) and 4T1 cell line 
( a PD-L1 negative cell line),  the author demonstrated similar efficacy of PD-1 pathway 
blockade. Prior studies demonstrate that PD-L1 expression varies in response to the 
microenvironment, including increased expression in response to cell death. Consistent with 
this model of variable PD-L1 expression over time, several authors have since demonstrated 
the efficacy of anti-PD-1 antibodies in both PD-L1 positive and negative tumors. We 
hypothesize that combining radiotherapy (Fig. 1) in combination with PD-1 blockade may 
enhance PD-1 responses in patients. 
4.3 Rationale for Pembrolizumab Dose Selection/Regimen/Modification 
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety 
and clinical activity of single agent MK-3475 (pembrolizumab).  The dose escalation portion 
of this trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 
2 weeks (Q2W) in subjects with advanced solid tumors.  All three dose levels were well 
tolerated and no dose-limiting toxicities were observed.  This first in human study of MK-
3475 showed evidence of target engagement and objective evidence of tumor size reduction 
at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has been identified to 
date.  10.0 mg/kg Q2W, the highest dose tested in PN001, will be the dose and schedule 
utilized in Cohorts A, B, C and D of this protocol to test for initial tumor activity.  Recent 
data from other clinical studies within the MK-3475 program has shown that a lower dose of 
MK-3475 and a less frequent schedule may be sufficient for target engagement and clinical 
activity.
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB). Pharmacodynamic 
data (IL-2 release assay) suggested that peripheral target engagement is durable (>21 days).  

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This early PK and pharmacodynamic data provides scientific rationale for testing a Q2W and 
Q3W dosing schedule.  
A population pharmacokinetic analysis has been performed using serum 
concentration time data from 476 patients. Within the resulting population PK model, 
clearance and volume parameters of MK-3475 were found to be dependent on body weight. 
The relationship between clearance and body weight, with an allometric exponent of 0.59, is 
within the range observed for other antibodies and would support both body weight 
normalized dosing or a fixed dose across all body weights.  MK-3475 has been found to have 
a wide therapeutic range based on the melanoma indication.  The differences in exposure for 
a 200 mg fixed dose regimen relative to a 200 mg Q3W body weight based regimen are 
anticipated to remain well within the established exposure margins of 0.5 – 5.0 for MK-3475 
in the melanoma indication. The exposure margins are based on the notion of similar efficacy 
and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 200 mg200 mg 
Q3W (i.e. 5-fold higher dose and exposure). The population PK evaluation revealed that 
there was no significant impact of tumor burden on exposure. In addition, exposure was 
similar between the NSCLC and melanoma indications. Therefore, there are no anticipated 
changes in exposure between different indication settings.
The rationale for further exploration of 200 mg and comparable doses of 
pembrolizumab in solid tumors is based on: 1) similar efficacy and safety of pembrolizumab 
when dosed at either 200 mg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-
response relationships of pembrolizumab for both efficacy and safety in the dose ranges of 200 
mg Q3W to 10 mg/kg Q3W, 3) the lack of effect of tumor burden or indication on distribution 
behavior of pembrolizumab (as assessed by the population PK model) and 4) the assumption 
that the dynamics of pembrolizumab target engagement will not vary meaningfully with tumor 
type.
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is 
based on simulations performed using the population PK model of pembrolizumab showing 
that the fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally 
consistent with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual 
patient exposures in the exposure range established in melanoma as associated with maximal 
efficacy response and 3) will maintain individual patients exposure in the exposure range 
established in melanoma that are well tolerated and safe. 
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage.
4.4 
Safety and toxicity of Pembrolizumab
Pembrolizumab has been administered to a total of 308 melanoma patients, from 2 
prospective clinical trials11. The first trial administered pembrolizumab at 3 different doses 
(2mg/kg q3weeks, 10mg/kg q3weeks, and 10mg/kg q2weeks) for 4 total cycles, followed by 
continued maintenance therapy until progression. Overall, 79% of patients develop any grade 
of toxicity. The most common toxicities were fatigue (30%), rash (21%), pruritus (21%), and 
diarrhea (20%). However, most of these symptoms were low grade, as only 13% developed 
grade 3- 4 toxicities. Furthermore, grade 3-4 adverse events were dose related: the 10mg/kg, 

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q2week cohort was 23%, while the q3week cohorts was 4-9%. The grade 3 clinical toxicities 
documented included rash (2%), pruritus (1%), hypothyroidism (1%), diarrhea (1%), 
abdominal pain (1%), decreased appetite (1%), elevated AST (1%), and renal failure (1%). In 
the 2 cases of renal failure, both cases improved with discontinuation of pembrolizumab and 
initiation of glucocorticoid therapy
In the trial of pembrolizumab in advanced melanoma patients, the toxicity profile was 
similar to that reported by Hamid et al: 82% developed any grade of toxicity, while 12% 
developed grade 3-4 toxicities. Most common toxicities were fatigue, pruritus, and rash. 
Reported grade 3-4 toxicities included fatigue (3%), elevated amylase (<1%), anemia (<1%), 
autoimmune hepatitis (<1%), confusion (<1%), diarrhea (<1%), dyspnea (<1%), 
encephalopathy (<1%), hypophysitis (<1%), hypoxia (<1%), muscular weakness (<1%), 
musculoskeletal pain (<1%), pancreatitis (<1%), peripheral motor neuropathy (<1%), 
pneumonitis (<1%), rash (<1%), rash maculopapular (<1%). Overall 6 patients (7%) developed 
adverse events leading to discontinuation of the drug. 3 of these cases (3%) were immune 
mediated. No drug related grade 5 toxicities were reported.  Other side effects that have been 
discovered include vasculitis and hypothyroiditis (refer to latest investigator brochure 
accompanying the trial). 
In the phase 1 study with 495 NSCLC patients12, no grade 3 or higher CNS toxicities 
were noted. Furthermore, the toxicity profile was similar to that identified in the two melanoma 
studies. Most common grade > 3 adverse events were fatigue (0.8%), decreased appetite 
(1.0%), nausea (0.8%), asthenia (1.0%), dyspnea (3.8%) and pneumonitis (1.8%). 1 patient 
who developed pneumonitis did die; overall, these findings demonstrate pembrolizumab is 
well tolerated and has similar toxicity profiles among the two histologies. 
Keynote 023 (San Miguel et al. Blood 2015, 126:505), conducted an open phase 1, 
multi-center, non-randomized, dose escalation trial to evaluate the safety, toxicity, and 
tolerability of pembrolizumab in combination with lenalidomide and low-dose dexamethasone 
in patients with relapsed/refractory myeloma. A 2 mg/kg q 2 weeks as well as a fixed 200 mg 
dose of pembrolizumab doses were used in combination with lenalidomide and dexamethasone 
in myeloma patients.  By July of 2015, 34 patients had been enrolled. No deaths of treatment 
discontinuation was noted.  Most frequent AEs were: thrombocytopenia (47%), neutropenia 
(41%), fatigue (29%), anemia, hyperglycemia, and muscle spasms (23%). No dose limiting 
toxicity were noted in the 10 mg-lenalidomide cohort; The MTD/MAD was defined as 200 mg 
fixed dose;  The objective response was 13/17 patients (76%) with 4 patients achieving a very 
good partial response and 9 patients achieving a partial response;  The authors concluded that 
PD-1 blockade showed promising anti-myeloma activity in heavily pre-treated 
relapsed/refractory myeloma patients.  

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5.
ADMINSTRATION OF STUDY PHARMACEUTICAL 
In 2015, FDA approved Pembrolizumab (Keytruda) for the treatment of advanced melanoma 
and NSCLC patients; Pembrolizumab is a monoclonal antibody that targets the PD-1 receptor. 
Programmed death 1 (PD-1) (or CD279) is part of the CD28 family of proteins, which includes 
CTLA-4 and ICOS, that regulate T cell activity. PD-1 is a glycoprotein receptor that can be 
expressed on the surface of T cells, B cells and myeloid cells (monocytes and dendritic cells).  
In T cells, PD-1 expression is primarily induced by T cell receptor (TCR) engagement and 
ligation with PD-L1 and PD-L2, expressed on antigen presenting cells, and induces an 
inhibitory signal that antagonizes TCR signaling and other important pathways necessary for 
optimal T cell activation.  Clinical trials with Pembrolizumab in advanced melanoma and 
NSCLC patients lead to approval by the FDA. Some efficacy in combination with lenalidomide 
for multiple myeloma has also been recently demonstrated. The recommended dose of 
Keytruda is 2mg/kg administered as IV infusion over 30 minutes every 3 weeks until disease 
progression, or unacceptable toxicity. Alternative dosing regimens are also available.  The dose 
used on the Keynote -023 trial was 200 mg.
Dose Selection
Patients will receive pembrolizumab 200 mg IV delivered over a 30-minute period every 3 
weeks until 2 years, or until disease progression, and/or unacceptable toxicity at the discretion 
of the treating physician. Infusions should be given over 30 minutes (not bolus or IV push).
Timing of Pembrolizumab Administration
Trial treatment should be administered on Day 2 or 3 and then every 3 weeks +/- 7 days after 
that as outlined in the Trial Flow Chart; 
All trial treatments will be administered on an outpatient basis.
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min).
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution.
Trial Blinding/Masking
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Randomization Allocation
Not applicable
Stratification

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Not applicable
Concomitant Medications/Vaccinations (allowed & prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required. The sponsor-investigator should discuss any questions regarding 
this with the Merck Clinical team. The final decision on any supportive therapy or vaccination 
rests with the sponsor-investigator and/or the subject's primary physician. 
1. Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date may also be included on the CRF.
All concomitant medications received within 28 days before the first dose of trial treatment 
and within 30 days after the last dose of trial treatment should be recorded.  Concomitant 
medications administered 30 days after the last dose of trial treatment should be recorded for 
SAEs and ECIs as defined in Section 11.
2. Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial:
1.
Antineoplastic systemic chemotherapy or biological therapy 
2.
Immunotherapy not specified in this protocol
3.
Chemotherapy not specified in this protocol
4.
Investigational agents other than pembrolizumab
Live vaccines within 30 days prior to the first dose of trial treatment and while participating in 
the trial.  Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid 
vaccine. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  Subjects 
may receive other medications that the investigator deems to be medically necessary.
The Exclusion Criteria describes other medications which are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
3. Administration of Pembrolizumab Beyond Progression 

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If the initial week 6-week 8 myeloma labs show disease progression per IMWG response 
criteria, patients are allowed to continue treatment until progression is confirmed again at a 
subsequent 4-8 week later, to account for atypical response patterns (especially, if the 
clinician suspects, that there may still be a benefit to continue for a little bit longer). A 
physician would be allowed the choice to continue the patients on the current trial or removed 
from the trial; 
If the repeat myeloma labs beyond the 12 weeks shows evidence of disease stabilization or 
objective response (relative to the previous scan that showed PD) as per IMWG response 
criteria, pembrolizumab may be continued per treatment calendar.  However, if the repeat 
assessment at 12 weeks per IMWG criteria shows disease progression relative to the previous 
labs that showed PD, then pembrolizumab should be discontinued;

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6.
DOSE MODIFICATION, DOSE LIMITING TOXICITIES, AND 
SUPPORTIVE CARE
Dose modification and toxicity management for immune-related AEs associated with 
pembrolizumab
AEs associated with pembrolizumab exposure may represent an immunologic etiology. 
These immune-related AEs (irAEs) may occur shortly after the first dose or several months 
after the last dose of pembrolizumab treatment and may affect more than on body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications.  Based on existing clinical trial data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab, administration of corticosteroids and/or other 
supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or 
exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin 
biopsy may be included as part of the evaluation. Based on the severity of irAEs, withhold or 
permanently discontinue pembrolizumab and administer corticosteroids. Dose modification 
and toxicity management guidelines for irAEs associated with pembrolizumab are provided 
in Table 2.
Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 3.
Other allowed dose interruption for pembrolizumab 
Pembrolizumab maybe interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Subjects should be 
placed back on study therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the Sponsor. The reason for interruption should be documented in the patient's 
study record.

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TABLE 2: Dose Modifications and Toxicity Management of irAEs associated with Pembrolizumab
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤ 10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
Grade 2
Withhold 
Pneumonitis 
Grade 3 or 4, or 
recurrent grade 2
Permanently 
discontinue

Administer corticosteroids (initial 
dose of 1-2mg/kg prednisone or 
equivalent) followed by taper

Monitor subjects for signs and symptoms of 
pneumonitis

Evaluate subjects with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment

Add prophylactic antibiotics for 
opportunistic infections
Grade 2 or 3
Withhold
Diarrhea / colitis 
Grade 4
Permanently 
discontinue

Administer corticosteroids (initial 
dose of 1-2mg/kg prednisone or 
equivalent) followed by taper

Monitor subjects for signs and symptoms of 
enterocolitis (i.e. diarrhea, abdominal pain, 
blood or mucus in stool with or without 
fever) and of bowel perforation (i.e. 
peritoneal signs and ileus).

Subjects with ≥ Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis. 

Subjects with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion.
AST / ALT 
elevation or 
Increased 
Grade 2
Withhold

Administer corticosteroids (initial 
dose of 0.5- 1mg/kg prednisone or 
equivalent) followed by taper

Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 

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Bilirubin
Grade 3 or 4 
Permanently 
discontinue

Administer corticosteroids (initial 
dose of 1-2mg/kg prednisone or 
equivalent) followed by taper
stable
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold

Initiate insulin replacement 
therapy for subjects with T1DM 

Administer anti-hyperglycemic in 
subjects with hyperglycemia 

Monitor subjects for hyperglycemia or other 
signs and symptoms of diabetes.
Grade 2
Withhold
Hypophysitis
Grade 3 or 4 
Withhold or 
permanently 
discontinue1 

Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.  

Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency) 
Grade 2
Continue 
Hyperthyroidism 
Grade 3 or 4 
Withhold or 
Permanently 
discontinue1

Treat with non-selective beta-
blockers (e.g. propranolol) or 
thionamides as appropriate 

Monitor for signs and symptoms of thyroid 
disorders. 
Hypothyroidism
Grade 2-4
Continue 

Initiate thyroid replacement 
hormones (e.g. levothyroxine or 
liothyroinine) per standard of care

Monitor for signs and symptoms of thyroid 
disorders. 
Grade 2
Withhold 
Nephritis and 
renal dysfunction
Grade 3 or 4 
Permanently 
discontinue

Administer corticosteroids 
(prednisone 1-2mg/kg or 
equivalent) followed by taper.

Monitor changes of renal function
Grade 3, or 
intolerable/ 
persistent Grade 2
Withhold
All Other 
immune-related 
AEs (i.e 
vasculitis, 
hypothyroidits,et
c)
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue

Based on severity of AE 
administer corticosteroids 

Ensure adequate evaluation to confirm 
etiology or exclude other causes

Refer to investigator brochure for additional 
side effects

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NOTES: 
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
2.
For subjects with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when 
AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM)

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Table 3: Dose Modification and Toxicity Management Related to Infusion Related 
Reactions to Pembrolizumab
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires therapy or 
infusion interruption 
but responds promptly 
to symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g. from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose.
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further study 
drug treatment
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of _____ with:
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic).

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Grades 3 or 4
Grade 3:
Prolonged (i.e., not 
rapidly responsive to 
symptomatic 
medication and/or brief 
interruption of 
infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization 
indicated for other 
clinical sequelae (e.g., 
renal impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; 
pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be 
used immediately.
Subject is permanently discontinued from 
further study drug treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period 
of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov

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7.
DIET/ACTIVITY/OTHER CONSIDERATIONS
Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting.
Contraception
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  For this trial, male 
subjects will be considered to be of non-reproductive potential if they have azoospermia 
(whether due to having had a vasectomy or due to an underlying medical condition).  
Female subjects will be considered of non-reproductive potential if they are either: 
(1) Postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) level 
in the postmenopausal range may be used to confirm a post-menopausal state in women 
not using hormonal contraception or hormonal replacement therapy. In the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient.); 
OR 
(2) Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; 
OR 
(3) Has a congenital or acquired condition that prevents childbearing.
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study drug and for 120 days after the last 
dose of study drug by complying with one of the following:  
(1) Practice abstinence† from heterosexual activity; 
OR 
(2) Use (or have their partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception are‡: 
Single method (one of the following is acceptable):
•
Intrauterine device (IUD)

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•
Vasectomy of a female subject’s male partner 
•
Contraceptive rod implanted into the skin
Combination method (requires use of two of the following):
•
Diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)
•
Cervical cap with spermicide (nulliparous women only)  
•
Contraceptive sponge (nulliparous women only) 
•
Male condom or female condom (cannot be used together)
•
Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection
 
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs.  
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception.  
‡If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region.
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in 
the study subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the initiation 
of study medication for oral contraception) throughout the study period up to 120 days after 
the last dose of trial therapy.  If there is any question that a subject of childbearing potential 
will not reliably comply with the requirements for contraception, that subject should not 
be entered into the study.
Use in Pregnancy
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study treatment.  The site will contact the subject 
at least monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the Sponsor and to Merck 
without delay and within 24 hours to the Sponsor and within 2 working days to Merck if the 

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outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn).  
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to the Sponsor.   If a male 
subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to the Sponsor and to Merck.
Use in Nursing Women
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment.
Subject Withdrawal/Discontinuation Criteria
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the sponsor-investigator if enrollment into the trial is inappropriate, the trial plan 
is violated, or for administrative and/or other safety reasons.
A subject must be discontinued from the trial for any of the following reasons:
8.
The subject or legal or legal representative (such as a parent or legal guardian) 
withdraws consent.
9.
Confirmed extra- extra-cranial radiographic disease progression.
10.
Unacceptable adverse experiences as described in section 6 and 7.
11.
Intercurrent illness that prevents further administration of treatment.
12.
Investigator’s decision to withdraw the subject.
13.
The subject has a confirmed positive serum pregnancy test.
14.
Noncompliance with trial treatment or procedure requirements.
15.
The subject is lost to follow-up.
16.
Completed at least 24 months of uninterrupted treatment with pembrolizumab 
or 35 administrations of study medication, or whichever occurs last;
Note: 24 months of study medication is calculated from the date of first dose. Subjects 
who stop pembrolizumab after 24 months may be eligible for up to one year of 
additional study treatment at the discretion of their treating physician, especially if 
their disease is clinically stable;
17.
Administrative reasons
18.
Confirmed radiographic disease progression per RECIST criteria
1.
Note: A subject may be granted an exception to continue on treatment 
with confirmed radiographic progression if clinically stable or clinically 
improved, please see Section 6 and 7.
The End of Treatment and Follow-up visit procedures are listed in Section 10 (Protocol Flow 
Chart) and Section 11. After the end of treatment, each subject will be followed for 30 days 
for adverse event monitoring (serious adverse events will be collected for 90 days after the end 
of treatment).  Subjects who discontinue for reasons other than progressive disease will have 

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post-treatment follow-up for disease status until disease progression, initiating a non-study 
cancer treatment, withdrawing consent or becoming lost to follow-up.  After documented 
disease progression each subject will be followed by telephone for overall survival until death, 
withdrawal of consent, or the end of the study, whichever occurs first.
Discontinuation of Study Therapy after CR 
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR that have been treated for at least 24 months with pembrolizumab and had at least two 
treatments with pembrolizumab beyond the date when the initial CR was declared.  Subjects 
who then experience radiographic disease progression may be eligible for up to one year of 
additional treatment with pembrolizumab via the Second Course Phase at the discretion of the 
investigator if no cancer treatment was administered since the last dose of pembrolizumab, the 
subject meets the safety parameters listed in the Inclusion/Exclusion criteria, and the trial is 
open.  Subjects will resume therapy at the same dose and schedule at the time of initial 
discontinuation.  
Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1) Quality or quantity of data recording is inaccurate or incomplete
2) Poor adherence to protocol and regulatory requirements
3) Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects
4) Plans to modify or discontinue the development of the study drug
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made.

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8.
DELIVERY OF RADIATION THERAPY TREATMENT
Patients will receive on day 1, radiotherapy (8 Gy/1fx) to an extra-osseous site and/or any bony site 
containing myeloma deposit, followed by pembrolizumab (200 mg/kg i.v. on day 3).
Radiation Simulation and Diagnostic Procedures
All simulation and treatment procedures represent current institutional practice, and will be 
the same for all study participants.  
A radiation patient should have some evidence of disease on imaging prior to CT simulation.  
This can include a lytic lesion in a bony site or an extra-osseous disease.  Lytic lesions and/or 
extra-osseous noted on X-Ray, CT scan, PET/CT, and/or MRI are allowed. 
CT Simulation: A CT simulation using appropriate immobilization will be performed for 
radiation therapy treatment planning purposes several days to the initiation of radiation 
therapy. This procedure consists of a CT scan performed in the treatment position. It is not for 
diagnostic purposes and is not itself therapeutic, but the CT image is required for radiation 
planning and delivery. 
Radiation Dose and Tumor Volume Definition
Patients will be treated per institutional standard of care protocol.
The prescribed radiation dose will be 8 Gy in 1 fraction prescribed to the planning target 
volume (PTV).   
Treatment shall be delivered with megavoltage machines of a minimum energy of 4 MV 
photons or electron machine containing a minimum energy of 4 MeV. Selection of the 
appropriate photon energy should be based on optimizing the radiation dose distribution within 
the target volume and minimizing dose to non-target normal tissue.
The Gross Tumor Volume (GTV) will contain the lytic lesion and/or the extra-osseous lesion 
noted on the simulation CT.  Image fusion to adjust the CT simulation based GTV is allowed.  
The Clinical Target Volume (CTV) will be a 0.5- 2.0 cm margin around the GTV.
The Planning Target Volume (PTV) will be an additional 0.3-1.0 cm margin around the 
CTV.  
Radiation Treatment Planning
Any radiation treatment planning approach is allowed. For superficial lesions amenable to 
electron treatments, use of En-Face electron technique is encouraged using appropriate energy 

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selection ranging from 4 MeV – 20 MeV.  For deeper seated tumors, photon therapy should be 
used with energy range of 4MV – 18 MV, based on appropriate coverage of the PTV.  The 
goals should be to provide adequate coverage, while minimizing hot spots as well as scattered 
radiation dose to the surrounding structures.
A range of radiation fields are allowed.  A single beam, an AP/PA, or multiple beams are 
allowed.   A range of radiation techniques (2D, 3DCRT, IMRT, IMRS) are allowed;
Institutional standard of care protocol will be followed when assessing adequate PTV coverage 
and dose volume histogram normal tissue limits.  
Radiation Toxicity Evaluation
Patients should undergo evaluation for development of acute and chronic radiotherapy toxicity 
at the time of protocol visits. This should be at done at 1 month+/- 2 weeks after completing 
radiotherapy and every 3 months for at least 1 year.  Toxicity will be graded per CTCAE 4.0 
adverse events grading system. If there is a suspicion of a novel or unexpected toxicity of grade 
3 or higher severity that is suspected to be related to the combination of pembrolizumab and 
radiotherapy, the study coordinator should be immediately notified. If possible, a 
determination should be made whether the toxicity is likely to be the result of immune therapy, 
radiotherapy, or was exacerbated by the combination. The AE or SAE should be attributed as 
definite, probable, possible, or unlikely for each.

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9.
TRIAL FLOW CHART
9.1 Study Flow Chart (Table 4: Trial Flow Chart)
 Procedure
Pre- Treatment  
(w ithin 28 
days  of 
s tarting)
Cycle 1, 
Day 1 
w eek 1
Cycle 1, 
Day 2-3
Cycle 2, 
Day 22
q 3 WK 
cycles
q6 WK 
cycles  x 2 
yr or until 
progres s ion
q 3 months  
(Rad Onc)
q 6 months
Initial S creening
X
Informed Cons ent
X
Inclus ion/Exclus ion
X
Prior and Concomitant Medication
X
Full Phys ical Examination
X
X
Review  of S ys tems
X
X
X
X
X
V ital S igns
X
X
X
X
X
X
Weight
X
X
X
X
X
X
ECOG Performance S tatus
X
X
X
X
X
X
HBcA b, HepC A b
X
*Bone Marrow  Biops y
X
 X (clinical indication)
PET/CT
X
X
A dvers e effects  A s s es s ment
X
X
X (Pembro )
X
X
X
Labs
Bas eline Labs  *
X
Myeloma Labs  *, LDH, ES R
X
X
     T3, FT4, TS H
X
X
     Pregnancy Tes t - urine or s eru
X
X
     Urinanalys is
X
X
uric acid, mg, phos , Coags  (PTT,a
X
Correlative Biomarkers
                S erum markers  (collect
X
X (pre-RT) X (Pre-PD1) x (pre-PD1)
X (3,6 mo) (Pre-PD1)
ExtraOs s eous /Os s eous  Biops y*(clinical indication)
T reatment
*Pem broliz um ab 200 m g  IV
X
X
X
RT ( 8 Gy/1fx)
X
S urvival A nalys is
X
IMWG Assessment*
         x
       x
C TC AE  Toxicity*
x
x
* EOS = end of study (at progression, or when patient stops being treated on the trial)
* Pembrolizumab 200 mg IV q3wk should be given for at least 2 yr and/or until progression.
* Baseline labs = CBC with Diff, CMP, calcium, Albumin, Serum Protein analysis, 
Quantitative Immunoglobulin, Serum Immunofixation (SIFE), 24 hr urine total protein, 
Urine Immune-Fixation, Serum Free Light Chain; 
*Bone Marrow Biopsy (with IHC, flow, cytogenetics, FISH);
*Whole Body PET/CT every 3 months (as long as insurance approves);
*Biopsy of Osseous or extra-osseous site (if clinically indicated at baseline); 

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*Myeloma labs: (CBC with diff, CMP, Calcium, Quantitative Immunoglobulin, M-Protein 
(serum and Urine), Serum Free Light Chain;
* IMWG Assessment = Done at least during 1st month and every 3 months, or as clinically 
indicated;
*CTCAE Toxicity at the radiated site once at 3 months, 6 months, and 12 months;
9.2 Serum Biomarker Correlates 
We plan to monitor the immune responses of the patients enrolled in this clinical trial, by 
collecting peripheral blood before treatment and during treatment, as outlined above under 
“serum biomarkers”. 
When possible, blood collection will be synchronized to pembrolizumab infusion cycles (C). 
Blood will be collected as outlined in the flow chart; 
Samples will be drawn into three 4-8 ml CPT tubes for PBMC and plasma isolation, and one 
4.5 ml K3EDTA tube, for whole blood analysis. Tubes will be labeled and logged at Emory's 
Winship Cancer Institute by a skilled clinical research nurse or phlebotomist.  They will be 
maintained at room temperature until transport to Dr. Ahmed's laboratory. Samples distributed 
to the Ahmed laboratory will only be identifiable by an assigned donor number, study identifier 
and a draw date. Samples will be transported in sealed biohazard containers between sites per 
standard protocol. Whole blood and/or PBMC will be used fresh or will be frozen and banked 
for future batch analyses. Plasma will be frozen at -80C. Frozen PBMC samples will be stored 
in liquid nitrogen at the Emory Vaccine center.  All assays will be performed as per Ahmed 
lab standard of practice.   Briefly, frequency and absolute cell counts will be determined for 
the major lymphocyte populations (CD3, CD4, CD8, CD19) and monocytes (CD14) through 
the use of BD TruCount tubes.  Detailed phenotypic analysis will be performed through whole 
blood staining with the following markers; CD3, CD4, CD8, Foxp3, CD45RA, CCR7, CD28, 
CD27, CD127, PD-1, Ki-67, Bcl-2, HLA-DR, CD38, ICOS, CD137, Tbet, eomes, Granzyme 
B, Perforin, CTLA-4, Tim-3, CD14, CD16, CD11c, CD123, PD-L1, CD86. Besides flow 
cytometry phenotypic analysis, sample collected at early time points after irradiation, will be 
used for transcriptional profiling. Frozen plasma will be used for monitoring cytokine 
expression.  Stored blood may also be used to analyze exosomes and/or search for other serum 
biomarker analysis. 
When possible, fresh tumor tissue will be collected from biopsy or surgical procedure (biopsy 
only done, if clinically indicated). Depending on material availability samples will be analyzed 
by flow cytometry or florescence microscopy with some of the markers listed above.

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10. TRIAL PROCEDURES
Trial Procedures
The Trial Flow Chart – Section 9.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to perform 
these procedures at unscheduled time points, if deemed clinically necessary by the investigator, 
and within standard of care.
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or 
Merck for reasons related to subject safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations.
Informed Consent
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial.
General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial.
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.

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Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial. 
Medical History
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as medical 
history.  
Prior and Concomitant Medications Review
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial.  Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication. 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded.
Disease Details and Treatments
The investigator or qualified designee will obtain prior and current details regarding disease 
status. 
Prior Treatment Details
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries.
Subsequent Anti-Cancer Therapy Status
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30-day Safety Follow-up visit must occur before the 
first dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject will 
move into survival follow-up. 
Adverse Event (AE) Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-
up period according to NCI CTCAE Version 4.0 (see APPENDIX I).  Toxicities will be 

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characterized in terms regarding seriousness, causality, toxicity grading, and action taken with 
regard to trial treatment. 
For subjects receiving treatment with pembrolizumab, all AEs of unknown etiology associated 
with pembrolizumab exposure should be evaluated to determine if it is possibly an event of 
clinical interest (ECI) of a potentially immunologic etiology (termed immune-related adverse 
events, or irAEs). 
Full Physical Exam
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening, 
Directed Physical Exam
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration.  
1.
 Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 9.0).  Vital signs may include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height may be measured at screening only.
2.
 Karnofsky Performance Status Scale and ECOG Performance Scale
The investigator or qualified designee may assess ECOG and/or KPS status at screening. 
ECOG status may be assessed prior to the administration of each dose of trial treatment and 
discontinuation of trial treatment as specified in the Trial Flow Chart.  After the initial 
assessment, ECOG alone during subsequent follow-up may be the minimum that is required 
on the trial.
3.
 Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. Laboratory tests for hematology, chemistry, urinalysis, and others are 
specified in Table 5.  Peripheral blood for serum biomarker analysis will also be obtained, as 
defined in section 9.0 at the appropriate time intervals.  

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Table 5:  Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum β-human chorionic gonadotropin†
Hemoglobin
Alkaline phosphatase
Glucose
  (β-hCG)†
Platelet count
Alanine aminotransferase (ALT)
Protein
PT (INR)
WBC (total and differential)
Aspartate aminotransferase (AST)
Specific gravity 
aPTT
Red Blood Cell Count
Lactate dehydrogenase (LDH)
Microscopic exam (If abnormal) 
Total thriiodothyronine (T3)
Absolute Neutrophil Count
Carbon Dioxide ‡
results are noted
Free thyroxine (T4)
Absolute Lymphocyte Count
  (CO2 or bicarbonate)
Urine pregnancy test †
Thyroid stimulating hormone (TSH)
Uric Acid
PK
Calcium
Chloride
Blood for correlative studies
Glucose

see biomarkers section 10.1

The additional blood that is 
collected will be sent to Dr Rafi 
Ahmed’s lab for this analysis
Phosphorus
 
Potassium  
 
Sodium
 
Magnesium
 
Total Bilirubin
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of normal)
Total protein
Blood Urea Nitrogen
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.  
‡ If considered standard of care in your region.

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Laboratory tests for screening or entry into the Second Course Phase should be performed 
within 14 days +/- 7 days prior to the first dose of treatment.  After Cycle 1, pre-dose laboratory 
procedures can be conducted up to 7 days prior to dosing.  Results must be reviewed by the 
investigator or qualified designee and found to be acceptable prior to each dose of trial 
treatment. 
Withdrawal/Discontinuation
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed 
in accordance with the safety requirements.  Subjects who a) attain a CR or b) complete at least 
24 months of treatment with pembrolizumab may stop taking the drug and discontinue the trial, 
at the discretion of the treating physician. After discontinuing treatment following assessment 
of CR, these subjects should return to the site for a Safety Follow-up Visit and then proceed to 
the Follow-Up Period of the study.
Blinding/Unblinding
Not Applicable, as this is an open pilot study.
Visit Requirements
Visit requirements are outlined in Section 8.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 9.0 - Trial Procedures.
Screening
The screening period will be 28 days from enrollment. 
Enrollment and Treatment Period
Enrollment period to accrue all 24 patients will be over two years. 12 patients will be allowed 
to not have measurable myeloma disease.
Treatment period will last from cycle 1, day 1 until disease progression and/or at least 24 
months of pembrolizumab being delivered q3wks. Pembrolizumab 200 mg IV q3 weeks will 
be given for at least 2 years as described above or until disease progression. Safety evaluations 
should be conducted during the first day of every other cycle (minimum criteria), as detailed 
in the flow sheet in section 9.0. All AEs that occurred leading up to these treatment visits 
should be recorded. Post-Treatment Visits and all subsequent imaging and myeloma 
assessments will be per standard of care. All required blood and imaging will be per standard 
of care, except for the biomarker analysis, as outlined in section 9.0.
Safety Follow-Up Visit

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The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 
or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  SAEs that occur 
within 90 days of the end of treatment or before initiation of a new anti-cancer treatment should 
also be followed and recorded.  Subjects who are eligible for retreatment with pembrolizumab  
may have up to two safety follow-up visits, one after the Treatment Period and one after the 
Second Course Phase.
Follow-up Visits
Subjects who complete treatment after 2 years or discontinue trial treatment for a reason other 
than disease progression should be assessed every 12 weeks (84 ± 14 days) or at physician’s 
discretions by radiologic imaging to monitor disease. Subjects who show disease progression 
after the initial week 12 scan must have another assessment 4-6 weeks later by radiologic 
imaging to confirm evidence of disease progression. If disease progression is evident, 
treatment should be discontinued and subject should be assessed every 12 weeks (84 ± 14 days) 
by radiologic imaging to monitor disease status.  Every effort should be made to collect 
information regarding disease status until the start of new anti-neoplastic therapy, disease 
progression, death, end of the study or if the subject begins retreatment with pembrolizumab 
as part of second phase enrollment.  Information regarding post-study anti-neoplastic treatment 
will be collected if new treatment is initiated.
Follow-up Visits for Patients Who Undergo Allogeneic Transplant:
Patients who undergo allogeneic transplant will be monitored for adverse events. For subjects 
who have an allogeneic SCT within 24 months of last study treatment, transplant parameters 
will be collected and specific events will be collected for 18 months from the date of the 
allogeneic transplant to include graft-versus-host-disease (acute and/or chronic), veno-
occlusive disease, febrile syndrome (a steroid-requiring febrile illness without an infectious 
cause), and encephalitis, for all grades, and regardless of relationship to study drug.   Additional 
medically important adverse events post-allogeneic SCT may be submitted at the Investigator’s 
discretion.  If available and relevant to an event post-allogeneic SCT, concomitant medications 
and/or laboratory results may also be reported.
Second Course Phase (Retreatment Period)
Subjects who stop pembrolizumab with SD or better may be eligible for up to one year of 
additional pembrolizumab therapy if they progress after stopping study treatment.  This 
retreatment is termed the Second Course Phase of this study and is only available if the study 
remains open and the subject meets the following conditions:

Either 
o
Stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR according to IMWG, and

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
Was treated for at least 24 weeks with pembrolizumab before discontinuing 
therapy

Received at least two treatments with pembrolizumab beyond the date when 
the initial CR was declared
OR
o
Had SD, PR or CR and stopped pembrolizumab treatment after 24 months of study 
therapy for reasons other than disease progression or intolerability
AND

Experienced an investigator-determined confirmed disease progression after stopping 
their initial treatment with pembrolizumab

Did not receive any anti-cancer treatment since the last dose of pembrolizumab

Has a performance status of 0 or 1 on the ECOG Performance Scale

Demonstrates adequate organ function

Female subject of childbearing potential should have a negative serum or urine 
pregnancy test within 72 hours prior to receiving retreatment with study medication.  

Female subject of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication.  Subjects of child 
bearing potential are those who have not been surgically sterilized or have been free 
from menses for > 1 year. 

Male subject should agree to use an adequate method of contraception starting with the 
first dose of study therapy through 120 days after the last dose of study therapy.  

Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation for the full duration of 
the trial or is not in the best interest of the subject to participate, in the opinion of the 
treating investigator.
Subjects who restart treatment will be retreated at the same dose and dose interval as when 
they last received pembrolizumab.  Treatment will be administered for up to one additional 
year.
Visit requirements are outlined in Section 9.0 – Trial Flow Chart.
 Survival Follow-up

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Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, 
the subject moves into the survival follow-up phase and should be contacted by telephone 
every 12 weeks to assess for survival status until death, withdrawal of consent, or the end of 
the study, whichever occurs first. 
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject associated with the use of a test article and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the use 
of the Merck’s product or radiotherapy, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples 
of this may include, but are not limited to, teething, typical crying in infants and children and 
onset of menses or menopause occurring at a physiologically appropriate time.
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or distributed 
by Merck for human use.
Adverse events may occur during the course of the use of Merck product or SRS in clinical 
trials or within the follow-up period specified by the protocol, or prescribed in clinical practice, 
from overdose (whether accidental or intentional), from abuse and from withdrawal.
Adverse events may also occur in screened subjects during any pre-allocation baseline period 
as a result of a protocol-specified intervention, including washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure.
Progression of the cancer under study is not considered an adverse event unless it is considered 
to be drug related by the investigator.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported to Merck and the PI by the investigator if they 
cause the subject to be excluded from the trial, or are the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure.
From the time of treatment allocation/randomization through 30 days following cessation of 
treatment, all adverse events must be documented by the investigator. Such events will be 

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Protocol/Amendment No.:  Rad4106-17(MK-3475-749), v6/30/2022
recorded at each examination on the Adverse Event case report forms/worksheets.  The 
reporting timeframe for adverse events meeting any serious criteria is described in section 9 
and 10. The investigator will make every attempt to follow all subjects with non-serious 
adverse events for outcome.
Definition of an Overdose for This Protocol and Reporting of Overdose to the Sponsor 
and to Merck
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose, for a 100 kg patient).  No specific information is 
available on the treatment of overdose of pembrolizumab. Appropriate supportive treatment 
should be provided if clinically indicated. In the event of overdose, the subject should be 
observed closely for signs of toxicity.  
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met.
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220)
Reporting of Pregnancy and Lactation to the Sponsor and to Merck
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.  
Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through 120 days following cessation of Merck product, or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier, must be reported 
by the investigator.  All reported pregnancies must be followed to the completion/termination 
of the pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220)

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Immediate Reporting of Adverse Events to the Sponsor and to Merck
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of a drug 
product that:

Results in death;

Is life threatening;

Results in persistent or significant disability/incapacity;

Results in or prolongs an existing inpatient hospitalization;

Is a congenital anomaly/birth defect;

Is an other important medical event 

Note: In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per ICH definition, are reportable to the Merck in the same 
timeframe as SAEs to meet certain local requirements. Therefore, these events are 
considered serious by Merck for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
Refer to Table 6 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study  that occurs 
to any subject must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause other than progression of the cancer under 
study, whether or not related to the Merck product, must be reported within 24 hours to the 
Sponsor and within 2 working days to Merck Global Safety.
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at 
any time following consent through the end of the specified safety follow-up period specified 
in the paragraph above, or at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to the Sponsor and to Merck Global Safety.
All subjects with serious adverse events must be followed up for outcome.

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SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA.
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 24 hours to the Sponsor and within 2 working days to Merck 
Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220).
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety if 
it causes the subject to be excluded from the trial, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not related 
to Merck product, must be reported within 24 hours to the Sponsor and within 24 hours to 
Merck Global Safety.
Events of clinical interest for this trial include:
1.  an overdose of Merck product, as defined in Section 11 - Definition of an Overdose for This 
Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results. 
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the 
upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. 
4.
Protocol-Specific Exceptions to Serious Adverse Event Reporting 
Efficacy endpoints as outlined in this section will not be reported to Merck as described section 
related to “Immediate Reporting of Adverse Events to the Sponsor and to Merck”, unless there 

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is evidence suggesting a causal relationship between the drug and the event. Any such event 
will be submitted to the Sponsor within 24 hours and to Merck Global Safety within 2 working 
days either by electronic or paper media.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is not 
progression of the cancer under study will be forwarded to Merck Global Safety as a SAE 
within 2 working days of determination that the event is not progression of the cancer under 
study
Hospitalization related to convenience (e.g.transportation issues etc.) will not be considered a 
SAE.
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.

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Table 6 Evaluating Adverse Events
Known  acute side effects for SRS include: Alopecia within the portal sites, fatigue, headache, nausea, vomiting, worsening baseline 
neurological deficits due to increased edema or radionecrosis, seizure, skin irritation or redness; Late side effects include radiation 
necrosis, secondary cancer, seizure, worsening neurological deficit due to edema, death, hair loss within the portal fields.  
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; disabling; 
limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of investigational product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours and to Merck within 2 
working days to meet certain local requirements); or

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Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours to the Sponsor and to 
Merck within 2 working days..
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause Merck product to be discontinued?
Relationship to 
Merck Product 
Did Merck product cause the adverse event? The determination of the likelihood that Merck  product caused the adverse event will be provided by an investigator who 
is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, ensures that a 
medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below are intended 
as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event based upon the available 
information.
The following components are to be used to assess the relationship between Merck product and the AE; the greater the correlation with the components and their 
respective elements (in number and/or intensity), the more likely Merck product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to Merck 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 
Merck 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors

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Sponsor Responsibility for Reporting Adverse Events
Written IND safety reports will be submitted to the FDA by the IND sponsor, for serious, 
unexpected suspected adverse reactions within 15 calendar days of learning of its occurrence. 
If the event is fatal or is deemed to be life threatening, the report will be made within 7 calendar 
days.  The IND sponsor will also make an assessment of whether the event constitutes an 
unanticipated problem posing risks to subjects or others (UP). This assessment will be provided 
to the Emory University IRB, which, in turn will make a final determination.  If the Emory 
IRB determines an event is a UP it will notify the appropriate regulatory agencies and 
institutional officials.

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11. STATISTICAL ANALYSIS PLAN
1.Statistical Analysis Plan Summary
Study Design 
The study is a pilot study to look at the safety of concurrent PD-1 inhibitor and SRS for 
relapsed/refractory myeloma.  A total of 24 patients will be enrolled on the trial (20 is 
the minimum, with an additional 4 patients, to make for any attrition and/or loss to 
follow-up). 12 patients will be allowed to not have measurable myeloma disease in this 
trial. Once 10 patients are enrolled, we will stop trial for 3 months to assess for acute 
toxicity, and then resume the trial.   The estimated exact Clopper-Pearson 95% 
confidence interval for a 20% rate based on 5 responses in 20 patients is (0.087, 0.491), 
with a precision of 0.185.  If we see lower than 20% difference in rate of toxicity at 3 
months, the combination will be deemed safe. 
A minimum of 20 patients are required to complete full treatments. An additional 20% 
is allowed for drop out/failure to adhere to required follow-up and treatment 
recommendations. Thus, 24 patients will be allowed to be enrolled on the trial to make 
for any attrition and/or loss to follow-up. 12 patients will be allowed to not have 
measurable myeloma disease.
# of Responses / # of Patients
95% confidence interval
5 / 20
(0.087, 0.491)
6 / 24
(0.098, 0.467)
Populations for analysis

Enrolled set: All subjects who signed an informed consent.

Safety set: All subjects who received at least one dose of any study drug.

Full analysis set: All subjects from the safety set who have the required follow-
up and treatment adherence to evaluate response and safety over time.
2.Statistical Analyses 
1.
Response
IMWG criteria will be used to assess response. Proportion of patients achieving stable 

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disease or better will be reported at 6 months and 12 months; Response rates will be 
reported along with 95% confidence intervals will be estimated using the Clopper-
Pearson method.
2.
Safety
Proportion of acute (at 3 months) and late toxicity (6 and 12 months) will be reported, 
and 95% confidence intervals will be estimated using the Clopper-Pearson method.  
3.
Overall Survival
For overall survival, death from any cause will be defined as the event. Patients will be 
censored at time of last follow-up. OS will be estimated using the Kaplan-Meier product-limit 
method.  Overall survival will be analyzed at 6 months, and 12 months.
4.
Biological variables
Descriptive statistics for the frequency and absolute cell counts for the major 
lymphocyte populations (CD3, CD4, CD8, CD19) T cells and monocytes (CD14) along 
with other markers listed above will be estimated.  

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12.  LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES
1.Investigational Product 
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 product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by Merck as summarized in Table 7.
Table 7  Product Descriptions
Product Name & Potency
Dosage Form
Pembrolizumab 50 mg
Lyophilized Powder for Injection
Pembrolizumab 100 mg/ 4mL
Solution for Injection
2.Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
3.Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided.
4.Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
5.Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial. 
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 

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institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.

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13.0 DATA AND SAFETY MONITORING PLAN 
The Data and Safety Monitoring Committee (DSMC) of the Winship Cancer Institute will 
provide oversight for the conduct of this study.  The DSMC functions 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. 
14.1. Data Collection: 
        Data that will be captured in OnCore for the following procedures
-       Inclusion/Exclusion Criteria
-       Vital Signs
-       Weight
-       Karnofsky Performance Status (KPS) & ECOG
-       HBcAb, HepC Ab
-       PET/CT Diagnostic Imaging [RECIST]
-       Adverse Events Assessment
-       CBC with differential

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-       CMP
-       T3, FT4, TSH
-       Pregnancy Test – urine or serum b-HCG
-       Urinalysis
-       Uric Acid, MG, Phos, Coags (PTT, PT, INR) - [seconds]
-       Serum Biomarkers
-       Osseous, extra-osseous, bone marrow biopsy (if done, and what date it was done)
 

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14.0 APPENDICES
APPENDIX I
CTCAE (Common Terminology Criteria for Adverse Events), version 4.03
The exact full criteria for toxicity assessment can be obtained at the NCI CTEP website at the 
following link: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 

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APPENDIX II
Tumor assessment via RECIST Criteria, Guideline Version 1.1
Eisenhauer, E.A., Therasse, P., Bogaerts, J., et al. New Response Evaluation Criteria in Solid 
Tumours: Revised RECIST Guideline (version 1.1). Europ J Cancer. 2009. 45; 228-247.
http://imaging.cancer.gov/clinicaltrials/imaging

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APPENDIX III
Tumor Assessment per Immune-Related Response Criteria
Immune-related Response Criteria (irRC) are derived from modified World Health
Organization (mWHO) conventions. Assessments of lymph nodes are derived from
current RECIST guidelines.
a.) Definitions of Measurable/non-Measurable Lesions
All measurable and non-measurable lesions should be assessed at the initial 
Screening/enrollment, at the defined tumor assessment time points (see Time and Events 
Schedule), and during regular maintenance.  Additional assessments may be performed, as 
clinically indicated for suspicion of progression. The Investigator will base response to 
treatment using the irRC.
i.) Measurable Disease
Measurable non-lymph node disease is defined as lesions that can be accurately 
measured in 2 perpendicular Diameters. Size criteria is defined based on the properties 
of the CT scan
-Spiral CT, 0.5cm thickness slice: both diameters must be at least > 1.0cm
-For > 0.5cm thickness slices: larger diameter >2.0cm; the other > 1.0cm
Lymph nodes are measurable only if CT slice thickness is <0.5cm. Size criteria are that 
the lymph node be at least 15 mm in short axis.
ii.) Non-Measurable Lesions
Non-measurable (evaluable) lesions are all other lesions, including one-dimensional
measurable disease and small lesions (not meeting the above criteria), and any of the 
following: 
-lesions occurring in a previously irradiated, extracranial area (unless they are 
documented as new lesions since the completion of radiation therapy), 

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bone lesions, 
-leptomeningeal disease, 
-ascites,
-effusion (pleural or pericardial)
-cystic lesions
-abdominal masses not histological confirmed
Lymph nodes with a short axis < 10 mm are considered not pathological, and are not 
measurable.
b.) Definitions of Index/non-Index Lesions
i.) Index Lesions
Measurable lesions, up to a maximum of 5 lesions per organ and ten lesions in total, 
must be identified as index lesions to be measured at Screening. The index lesions 
should be representative of all involved organs. In addition, index lesions must be 
selected based on their size (e.g., lesions with the longest diameters), their suitability 
for accurate repeat assessment by imaging techniques, and how representative they are 
of the subject’s tumor burden. At Screening, a Sum of the Product Diameters (SPD) for 
all index lesions will be calculated and considered the baseline SPD. The baseline sum 
will be used as the reference point to determine the objective tumor response of the 
index lesions at tumor
assessment.
ii.) Non Index Lesions
Measurable lesions, other than index lesions, and all sites of non-measurable disease, 
will be identified as non-index lesions. Non-index lesions will be evaluated at the same 
assessment time points as the index lesions. After the initial assessment, changes in 
non-index lesions will contribute only in the assessment of complete response.

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c.) Calculation of Sum of Product of Diameters (SPD)
Sum of Product of Diameters is an estimate of tumor burden. The 2 greatest
perpendicular diameters are used to estimate the size of each tumor lesion. The SPD is
calculated as the sum of the product of the diameters for index tumor lesions. Several
variations of the SPD are identified for the purpose of classification of tumor responses.
i.) SPD at Baseline 
The sum of the product of the diameters for all index lesions identified at baseline prior 
to treatment on Day 1.
ii.) SPD at tumor assessment
 For every on-study tumor assessment collected per protocol or as clinically indicated, 
the SPD at tumor assessment will be calculated using tumor imaging scans. All index 
lesions and all new measurable lesions that have emerged after baseline will contribute 
to the SPD at tumor assessment (irSPD).
iii.) SPD at NADIR
For tumors that are assessed more than 1 time after baseline, the lowest value of the 
SPD (SPD Baseline or SPD at tumor assessment) is used to classify subsequent tumor 
assessments for each subject. The SPD at tumor assessment using the irRC for 
progressive disease incorporates the contribution of new measurable lesions. Each net 
percentage change in tumor burden per assessment using irRC accounts for the size and 
growth kinetics of both old and new lesions as they appear. In this study the irRC as 
defined by the Investigator will serve as the basis of key endpoints for efficacy analyses 
and guide clinical care.

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APPENDIX IV
International Myeloma Working Group (IMWG) Uniform Response Criteria for 
Multiple Myeloma
http://myeloma.org/pdfs/IMWG_Response_criteria.pdf

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APPENDIX V
KARNOFSKY PERFORMANCE SCALE
100 Normal; no complaints; no evidence of disease
90 Able to carry on normal activity; minor signs or symptoms of disease
80 Normal activity with effort; some sign or symptoms of disease
70 Cares for self; unable to carry on normal activity or do active work
60 Requires occasional assistance, but is able to care for most personal needs
50 Requires considerable assistance and frequent medical care
40 Disabled; requires special care and assistance
30 Severely disabled; hospitalization is indicated, although death not imminent
20 Very sick; hospitalization necessary; active support treatment is necessary
10 Moribund; fatal processes progressing rapidly
       0 Dead
6.
ECOG Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair.
5
Dead.
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair.

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APPENDIX VI
Inclusion Criteria: 
1) ≥ 18 years old; ISS stage I-III multiple myeloma;
2) Able to give informed consent;
3) ECOG Performance Status between 0 and 1;
4) Relapsed and/or refractory myeloma;
5)  ≥ 1 osseous and/or extra-osseous lesion that can be radiated;
6) Candidate for pembrolizumab (as determined by physician, and adequate organ 
function as noted in Table 1);
7) Candidate for radiotherapy (as determined by physician);
8) Measurable myeloma disease ( urine protein > 200 mg in 24 hr urine collection, 
serum free light chain ratio> 100 with an abnormal k/l ratio, serum M protein > 
0.5 g/dl) ; 12 patients of the 24 patients do not have to have to measurable myeloma 
disease; 
9) Negative urine pregnancy test within 2 weeks for female subjects;
Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 2 weeks prior to receiving the first dose of study medication.  
If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required.  
1.
Female subjects of childbearing potential should be willing to use 2 
methods of birth control or be surgically sterile, or abstain from 
heterosexual activity for the course of the study through 120 days after 
the last dose of study medication.  Subjects of childbearing potential are 
those who have not been surgically sterilized or have not been free from 
menses for > 1 year. 
2.
Male subjects should agree to use an adequate method of contraception 
starting with the first dose of study therapy through 120 days after the 
last dose of study therapy.
3.
Abstinence is acceptable, if this is the usual life style and preferred 
contraception for the patient.

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Exclusion Criteria: 
1) Previous anti-PD1 or anti-PD-L1; 
2) Solitary plasmacytoma;
3) Smoldering (asymptomatic) multiple myeloma; 
4) Currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device 
within 4 weeks of the first dose of treatment;
5) Has a diagnosis of immunodeficiency;
6) Known history of active TB   (Bacillus Tuberculosis);
7) Hypersensitivity to pembrolizumab or any of its recipients;
8)  Known additional malignancy that is progressing or requires active treatment 
(exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the 
skin);
9)  Has active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs);
10)  Known history of, or any evidence of active, non-infectious pneumonitis;
11)  Active infection requiring systemic therapy;
12)  Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 
120 days after the last dose of trial treatment.
13) Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
14) Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected).
15) Has received a live vaccine within 30 days of planned start of study therapy.
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed.

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