Conditions: Multiple Myeloma
Keywords: Multiple Myeloma Anti-PD-1 Pembrolizumab Post-transplant Maintenance
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 32
Healthy volunteers: no

Brief summary:
Multiple myeloma (MM) is a common incurable blood cancer causing debilitating symptoms-bone pain, kidney failure, low blood counts and infection. Chemotherapy outcomes are disappointing due to short-term response and long-term toxicities.

1. Studies showed these patients have weak immune against MM due to the immune checkpoint mediated by the PD1/PD-L1 interaction between immune cells and MM. Anti-PD-1 antibody (anti-PD1) disrupts this interaction, thus unleashing immune cell function and leading to killing of MM cells.
2. Studies further showed enhancement of this "unleash" after autologous transplant and better MM control by anti-PD1 when used after transplant.
3. Anti-PD1 has been extensively studied in patients with other cancers. It is very safe and effective and has been FDA-approved. Complications are of mild degree and easy to manage successfully in out-patient setting. Severe complications are rare.

Thus, investigators proposed an efficacy study of anti-PD1 treatment after transplant to improve MM treatment outcomes. This was a collaborative study with Medical College of Wisconsin (headquarter of Center for International blood and Marrow Transplant Research). Investigators hypothesized that anti-PD1 treatment would increase the MM response and the MM control duration when added to the standard MM treatment after transplant. Anti-PD1 was given at the dose and interval, which had been studied previously (200 mg intravenous injection every 3 weeks) between 2 weeks until 6 months after transplant. Subjects were monitored closely during and after anti-PD1 therapy until at least 1 year post transplant. Late complications were followed for 3 years.

Detailed description:

Arms:
arm 1: Standard Treatment:

High-dose Melphalan and autologous stem cell transplantation with post-transplant maintenance of Lenalidomide.

Study Treatment:

200 mg/day of MK-3475 administered every 3 weeks, starting day +14 post-transplant for a total of 9 doses.

Interventions: intervention 1: Autologous Stem Cell Transplant intervention 2: Melphalan intervention 3: Lenalidomide intervention 4: MK-3475
Intervention descriptions: intervention 1: None intervention 2: 140-200 mg/m\^2 intervention 3: 5-15 mg/day starting 45-90 days post-transplant intervention 4: 200 mg/day every 3 weeks starting day +14 post-transplant for a total of 9 doses.

Protocol document:
Prot_SAP_000.pdf: 
Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
1 
 
 
 
 
TITLE: Phase 2 Multi-center Study of Anti-Programmed-Death-1 [anti-PD-1] during Lympho-
penic State After High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell 
Transplant [HDT/ASCT] for Multiple myeloma 
 
IND NUMBER: 125767 
 
EudraCT NUMBER: 
 
Institution Name:      University of Michigan (Primary Site) 
                                   Medical College of Wisconsin 
 
Principal Investigator Information: 
 
Name:                  Attaphol Pawarode, M.D. 
                             Assistant Professor of Internal Medicine 
                             Blood and Marrow Transplantation Program 
                             Division of Hematology/Oncology, Department of Internal Medicine 
                             University of Michigan Medical School 
 
  Address:                  University Hospital South, BMT Program, Room F4811 
                                  1500 E. Medical Center Drive 
                                   Ann Arbor, MI 48109, SPC 5271 
                             Phone: 734-936-8785; Fax: 734-232-4484 
                             Email Address: pawarode@med.umich.edu 
 
University of Michigan Co-Investigators:     
 
                                  Pavan Reddy, M.D., Professor of Translational Oncology 
                                  John Magenau, M.D. Assistant Professor of Internal Medicine 
                                  Mary Riwes, D.O. Assistant Professor of Internal Medicine 
                                  Brian Parkin, M.D. Clinical Lecturer 
                                  Vedran Radojcic, MD, Clinical Lecturer 
                                        Blood and Marrow Transplantation Program 
                                  Erica Campagnaro, M.D., Associate Professor of Hematology/Oncology 
                                  Craig Cole, M.D., Assistant Professor of Hematology/Oncology                          
                                       Division of Hematology/Oncology 
 
                                  Steven K. Lundy, Ph.D., Research Assistant Professor 
                                       Division of Rheumatology 
 
                                                                  
 
Medical College of Wisconsin Investigators: 
 
                                  Anita D'Souza, M.D., M.S. Assistant Professor of Medicine (Institutional PI) 
                                  Marcelo C. Pasquini, M.D., M.S., Professor of Medicine  
                                  Parameswaran Hari, M.D., M.S., Professor of Medicine 
                                  Timothy Fenske, MD Associate Professor of Medicine 
 
 Wael Saber,MD, MS, Associate Professor of Medicine 
William Drobyski, MD, Professor of Medicine 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
2 
 
 
 
 
Douglas Rizzo, MD, MS, Professor of Medicine 
Mehdi Hamadani, MD, Associate Professor of Medicine 
Mary Horowitz, MD, MS, Professor of Medicine 
Bronwen Shaw, MD, PhD, Professor of Medicine 
 
                                  Bryon Johnson, PhD, Professor of Pediatrics  
                                       Blood and Marrow Transplant Program 
                                       Hematology/Oncology  
                                  Medical College of Wisconsin 
 
Statistician:             Thomas Braun, Ph.D., Professor of Biostatistics 
                                  Department of Statistics, University of Michigan 
 
Study Coordinators: Jennifer Lay-Luskin, CCRP 
                                   Nancy McCullough, CCRP  
 
Address 
NCRC, Oncology-Clinical Trials Support Unit, 2800 Plymouth Rd., Bldg. 300, Ann Arbor, MI  
48109-2800  
Phone: 734-615-6872, 734-232-0758, 734-936-8538; Fax: 734-232-0744  
E-mail: jalay@med.umich.edu, smimiche@med.umich.edu, ntsai@med.umich.edu 
 
Data Managers:       Kathleen Granlund, CCRP, Karen Dziubek, BS, CCRP 
                                  Multi-Site Clinical Research Project Managers 
 
Address:  
NCRC, Oncolocy-Clinical Trials Support Unit, 2800 Plymouth Rd., Bldg. 300, Ann Arbor, MI  
48109-2800  
Phone: 734-936-0563, 734-763-2968; Fax: 734-232-0744  
E-mail: kemarsh@med.umich.edu, kdziubek@med.umich.edu 
 
Contracting Person: 
Name: Tricia Haynes, Assistant Project Representative 
Address: ORSP, Wolverine Tower, Room 1024, 3003 South State Street,  
Ann Arbor, MI 48109-1274 
Phone no 734-615-8383 
Fax no 734-763-4053; 764-8510 
Email Address: phaynes@umich.edu 
 
Protocol version date:  03/09/2017 
 
 
 
 
 
 
 
 
 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
3 
 
 
 
 
TABLE OF CONTENTS 
TITLE PAGE  
 
 
 
 
 
 
 
 
 
1 
TABLE OF CONTENTS 
 
 
 
 
 
 
 
 
3 
1 
STUDY SUMMARY  
 
 
 
 
 
 
 
4 
2 
STUDY SYNOPSIS  
 
 
 
 
 
 
 
4 
3 
OBJECTIVE(S) & HYPOTHESIS(ES) 
 
 
 
 
 
5 
 
 
4 
BACKGROUND & RATIONALE 
 
 
 
 
 
 
6 
 
 
5 
METHODOLOGY 
 
 
 
 
 
 
 
 
 
 
5.1 
ENTRY CRITERIA 
 
 
 
 
 
 
 
18 
5.1.1 DIAGNOSIS/CONDITION FOR ENTRY INTO THE TRIAL  
18 
5.1.2 SUBJECT INCLUSION CRITERIA 
 
 
 
 
19 
5.1.3 SUBJECT EXCLUSION CRITERIA  
 
 
 
20 
 
5.2 
INCLUSION CRITERIA TO INITIATE ON MK-3475  
 
 
21 
 
 5.3 
TREATMENTS 
 
 
 
 
 
 
 
23 
 
 
5.3.1 STANDARD MULTIPLE MYELOMA TREATMENT  
 
23 
 
     
5.3.2 MK-3475 TREATMENT 
 
 
 
 
 
24 
 
  
 
TREATMENT SCHEMA 
 
 
 
 
 
24 
 
     
5.3.3 STANDARD TRANSPLANTATION DRUGS  
 
 
24 
 
     
5.3.4  STUDY DRUG: MK-3475 
 
 
 
 
 
28 
 
5.4 
CONCOMITANT MEDICATIONS/VACCINATIONS  
 
 
31 
 
 5.5 
RESCUE MEDICATIONS & SUPPORTIVE CARE  
 
 
33 
 
5.6 
SUBJECT WITHDRAWAL/DISCONTINUATION CRITERIA 
 
37 
 
5.7 
SUBJECT REPLACEMENT STRATEGY 
 
 
 
 
38 
 
5.8 
CLINICAL CRITERIA FOR EARLY STUDY TERMINATION 
 
39 
 
5.9 
PLANS TO DISCONTINUE THE DEVELOPMENT OF THE MK-3475 
39 
 
5.10 
DEFINITION OF ENDPOINTS 
 
 
 
 
 
 
 
      
5.10.1  SAFTY END POINTS  
 
     
 
 
 
39 
 
       
5.10.2  EFFICACY END POINTS 
 
 
 
 
 
40 
 
 
      
5.10.3  CORRELATIVE STUDIES 
 
 
 
 
 
40 
6 
STUDY FLOW CHART  
 
 
 
 
 
 
 
43 
7 
STUDY PROCEDURES 
 7.1 
STUDY PROCEDURES 
 
 
 
 
 
 
47 
 
7.1.1 ADMINISTRATIVE PROCEDURES  
 
 
 
47 
 
7.1.2 CLINICAL PROCEDURES/ASSESSMENTS 
 
 
48 
 
7.1.3 LABORATORY PROCEDURES/ASSESSMENTS  
 
50 
 
 
7.1.4 OTHER PROCEDURES 
 
 
 
 
 
50 
 
 
 
7.1.5 STUDY VISIT REQUIREMENTS 
 
 
 
 
50 
7.1.6 STUDY DEFINITIONS 
 
 
 
 
 
51 
 
 7.2 
ASSESSING AND RECORDING ADVERSE EVENTS 
 
 
52 
8 
STATISTICAL ANALYSIS PLAN 
 8.1 
STATISTICAL ANALYSIS PLAN SUMMARY 
 
 
 
61 
 8.2 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
61 
8.3  
STOPPING RULES  
 
 
 
 
 
 
62 
9 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
63 
10   ADMINISTRATIVE AND REGULATORY DETAILS 
 
 
 
 
64 
11   ADMINISTRATIVE AND LEGAL OBLIGATIONS 
 
 
 
 
65 
12   LIST OF REFERENCES  
 
 
 
 
 
 
 
68 
13   APPENDICES 
 
 
 
 
 
 
 
 
 
77 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
4 
 
 
 
 
1.0 STUDY SUMMARY 
Abbreviated Title 
Phase 2 Study of Anti-PD-1 After Autologous Transplant 
for Multiple Myeloma 
Trial Phase 
2 
Clinical Indication 
Multiple myeloma patients with inadequate response 
from prior therapy 
Trial Type 
Multi-Center Phase 2 
Type of control 
None  
Route of administration 
Intravenous 
Trial Blinding 
None 
Treatment Groups  
Single Treatment Group 
Number of trial subjects 
A total of 50 subjects 
Estimated duration of Study 
2 years 
Duration of Participation 
7 months (Enrollment to End-of-Study Safety Evaluation) 
 
2.0 STUDY SYNOPSIS 
 
2.1 
Study Design 
Phase 2 Multi-center Single-arm Study 
 
2.2 
Treatments 
1. 
Standard Multiple Myeloma Treatments 
1.1 
High-dose Melphalan and Autologous Stem Cell Transplantation 
High-dose melphalan 140-200 mg/m2  (<200 mg/m2 for age >70 years) 
1.2 
Post-transplant Maintenance 
 
Lenalidomide 5-15 mg/day, starting day 45-90 post-transplant 
 
2. 
Study Treatment: 200 mg/day of MK-3475 will be administered every 3 weeks,  
 
 
starting day 14 post-transplant (or after engraftment) for a total of 9 doses or  
 
 
~180 days after transplant. Treatment days are +/- 4 days flexible.  
 
2.3 
Treatment Diagram 
 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
5 
 
 
 
 
3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 
Primary Objectives & Hypothesis 
Objectives:  
(1) 
To investigate the feasibility (safety and tolerability) of the addition of anti-PD1 after high 
dose therapy and autologous hematopoietic stem cell transplant in patients with multiple 
myeloma. 
(2) 
 To investigate the efficacy of the addition of anti-PD1 after high dose therapy and 
autologous hematopoietic stem cell transplant in improving complete response (CR) conversion 
rate for patients with multiple myeloma 
Hypothesis:  The administration of anti-PD-1 during the lymphopenic state after high dose 
therapy and autologous hematopoietic stem cell transplant is safe and tolerable and will enhance 
recognition and eradication of multiple myeloma by the recovering immune system and will result 
in a higher CR conversion rate. 
 
See Appendix 13.3 for the definition of complete response (CR). 
 
3.2 
Secondary Objective & Hypothesis 
 
Objective:   
To investigate the efficacy of this strategy in improving other transplant outcomes especially 2-
year progression-free and overall survival (PFS and OS). 
 
Hypothesis:  The intervention increases other transplant outcomes especially 2-year PFS among 
patients achieving CR by day 180. 
 
See Section 5.10 for the definition of PFS and OS. 
 
3.3 
Exploratory Objectives 
(1) 
To perform correlative studies of the effects of anti-PD-1 on T-cell and NK-cell function.  
Hypothesis:  Enhanced Th1-type and cytotoxic immune responses following anti-PD-1 
treatment will correlate with prolonged remission, while relapse will correlate with reduced Th1 
response or increased regulatory immune response. 
(2) 
To measure immune cell phenotypes in the autologous graft tissue being transplanted. 
Hypothesis:  Remission and relapse rates will correlate with differences in cell types present in 
the graft  
 
 
 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
6 
 
 
 
 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
1       Multiple Myeloma [MM] 
Multiple myeloma (MM) is a common hematologic malignancy with high disease morbidity burden 
in the western hemisphere. It was estimated that 70,000 new patients were diagnosed and 21,700 
patients died of MM in the US in 2012.[1] MM is a clonal neoplastic proliferation of plasma cells 
and is considered chronic and incurable, with current novel chemo-biologic targeted agents. In 
the previous conventional chemotherapy era, the median overall survival was ~4-5 years for 
average-risk patients while this has been estimated to be much improved to >7 years in the 
current targeted era.[102-108]  However, outcomes of high-risk or advanced MM therapy remain 
poor, with a median survival only ~8-14 months after therapy.[2-6] 
The current standard therapy for MM is partly based on the pre-biologic targeted era when high 
dose therapy and autologous stem cell transplant (HDT/ASCT) was proven to improve myeloma 
progression-free and overall survival. This consists of 3 phases: 1) primary induction therapy 2) 
consolidative HDT/ASCT and 3) maintenance therapy. The immune modulating agents, 
thalidomide and lenalidomide, and proteasome inhibitor bortezomib, are used in the induction and 
maintenance, while conditioning with high-dose melphalan, a conventional chemotherapeutic 
agent with high anti-MM activity, remains the standard agent.[7] Despite these measures, relapse 
or progression during maintenance is inevitable. Retreatment with or without second HDT/ASCT 
is often used but of less efficacy. Few effective treatment options are available for advanced 
relapsed MM. 
In addition, MM with certain cytogenetic abnormalities [17p-, t(4;14), t(14;16), (14:20), 13-, 
hypodiploidy and plasma cell leukemia] are of extremely poor prognosis, with a median survival 
of 8-14 months and 1-year and 2-year overall survival rates of 50% and 25% only, respectively, 
after HDT/ASCT [2-6]. These high risk MMs constitute ~30% of MM. Certain novel biologic agents 
e.g. bortezomib have been shown to overcome the resistance of these high risk MMs [8,9] but 
response is temporary and none is proven to be curative or to provide meaningful long-term MM 
control. 
In the initial pioneer stage ~30 years ago, full-intensity allo-HCT was extensively explored in 
advanced or relapsed/refractory MM but these resulted in high early TRM, regimen related 
toxicities and GVHD, up to 50% in the first 6 months post transplant.[10] However, those patients 
who had survived subsequently enjoyed a sustained long-term MM control and likely a cure of 
MM. These led to the use of reduced-intensity allo-HCT in an attempt to decrease TRM in the 
past 15-20 years. However, the success in decreasing TRM was at the expense of increasing 
MM relapse, thus resulting in no improvement of overall outcomes.[11-14] 
Failure of the use of allo-HCT in the advanced MM setting led to studying of its role in an upfront 
setting. And to improve MM control, high-dose therapy and autologous HCT was incorporated 
prior to reduced-intensity allo-HCT (tandem auto-allo HCTs). Several genetically randomized 
controlled trials (RCT) comparing tandem auto-allo HCTs versus tandem double auto-HCTs, 
according to the availability of matched siblings. As expected, auto-allo arms experienced 
increased TRM but a trend towards a better MM control after 3 years. However, there was still no 
definite improvement in the overall survival.[15-18] 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
7 
 
 
 
 
University of Michigan experience on allo-HCT for high-risk multiple myeloma showed a marginal 
improvement in outcomes, with 1-year and 2-year survival rates of 65% and 35%, respectively. 
Relapse rates were very high, with 1-year and 2-year progression-free survival rates of 40% and 
15% only, respectively. In addition, most surviving patients suffered debilitating chronic graft-
versus-host disease.[19,20] 
The use of novel targeted biologic agents in primary MM therapy has improved the outcome 
significantly. In addition, bortezomib has been reported to overcome the poor risk karyotype 
t(4;14).[21] Nonetheless, recent studies of primary novel targeted biologic agents, followed by 
HDT/ASCT reported 1-year progression-free survival of ~50% only.[21-23] 
2. 
Immunotherapy for Cancer 
The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation 
has been known for decades [24]. Accumulating evidence shows a correlation between tumor-
infiltrating lymphocytes (TILs) in malignant tissue and favorable prognosis in various malignancies 
[25-29].  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / FoxP3+ 
regulatory T-cells seems to correlate with improved prognosis and long-term survival in many 
solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related 
to CD28 and CTLA-4 which has been shown to negatively regulate antigen receptor signaling 
upon engagement of its ligands (PD-L1 and/or PD-L2) [30; 31].  The structure of murine PD-1 has 
been resolved 32].  PD-1 and family members are type I transmembrane glycoproteins containing 
an Ig Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail which is 
responsible for the binding of signaling molecules.  The cytoplasmic tail of PD-1 contains 2 
tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an 
immunoreceptor tyrosine-based switch motif (ITSM).  Following T-cell stimulation, PD-1 recruits 
the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading 
to the dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are 
involved in the CD3 T-cell signaling cascade [30; 33;-35].  The mechanism by which PD-1 down 
modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules 
regulate an overlapping set of signaling proteins [36; 37].  PD-1 was shown to be expressed on 
activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural 
Killer cells [38; 39].  Expression has also been shown during thymic development on CD4-CD8- 
(double negative) T-cells as well as subsets of macrophages and dendritic cells [40].  The ligands 
for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell 
types, including non-hematopoietic tissues as well as in various tumors [36; 41-43].  Both ligands 
are type I transmembrane receptors containing both IgV- and IgC-like domains in the extracellular 
region and contain short cytoplasmic regions with no known signaling motifs.  Binding of either 
PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor.  PD-L1 is 
expressed at low levels on various non-hematopoietic tissues, most notably on vascular 
endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting cells 
found in lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought to control 
immune T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-
cell function in peripheral tissues [36].  Although healthy organs express little (if any) PD-L1, a 
variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
8 
 
 
 
 
has been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma 
(MEL)[44].  This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune 
evasion and should be considered as an attractive target for therapeutic intervention. 
Similarly, dysfunction of immune surveillance of transformed cells leads to hematologic 
malignancies.[45,46] Chemotherapy is curative in a small proportion of patients. HDT/ASCT and 
allo-HCT have a curative potential in only some of these advanced refractory malignancies. In 
addition, allo-HCT may result in multiple debilitating or fatal complications. Thus, a safer approach 
of immune therapy is needed. 
Passive immunotherapy includes administration of target specific monoclonal antibody e.g. anti-
CD20 [rituximab] or tumor-specific effector T cells, while active immunotherapy involves the 
administration of tumor specific cell-based vaccines. These therapies are effective but of very 
short duration. The main mechanism of intolerance involves the regulatory elements e.g. immune 
check points [cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1) 
receptor/PD-1-Ligand (PD-1-L) axes) and myeloid derived suppressor cells (MDSC). Other 
contributing factors in the case of cell-based therapies are poor access of effector cells to 
activating cytokines due to presence of competitors of cytokines [cytokine sinks] and the lack of 
essential “space niche”.[45-48] 
3. 
The PD-1/PD-L1 axis 
PD-1 belongs to the B7 family and is a key immune check-point receptor in peripheral tissues.[28] 
Its ligands are the more common PD-1-L1 (B7-H1) and PD-L2 (B7-DC). It is expressed on 
antigen-activated T and B cells, which then become immunologically exhausted, resulting in 
termination of immune response after antigen activation. The PD-1 receptor-ligand interaction is 
a major pathway hijacked by tumors to suppress immune control. The normal function of PD-1 
receptors, which are expressed on the cell surface of activated T-cells under healthy conditions, 
are to down-regulate unwanted or excessive immune responses, including autoimmune 
reactions. 
PD-1, which is encoded by the gene PDCD1), is an Ig superfamily member related to CD28 and 
CTLA-4 and has been shown to negatively regulate antigen receptor signaling upon engagement 
of its ligands (PD-L1 and/or PD-L2) [49; 50]. The structure of murine PD-1 has been resolved [51]. 
PD-1 and family members are type I transmembrane glycoproteins containing an Ig Variable-type 
(V-type) domain responsible for ligand binding and a cytoplasmic tail which is responsible for the 
binding of signaling molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling 
motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-
based switch motif (ITSM). Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases 
SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation 
of effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell 
signaling cascade [49; 52-54]. The mechanism by which PD-1 down-regulates T-cell responses 
is similar to, but distinct from that of CTLA-4 as both molecules regulate an overlapping set of 
signaling proteins [55,56].  PD-1 is expressed on activated lymphocytes including peripheral 
CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells [57,58].  Expression has also been 
shown during thymic development on CD4-CD8- (double negative) T-cells as well as subsets of 
macrophages and dendritic cells [59]. The ligands for PD-1 (PD-L1 and PD-L2) are constitutively 
expressed or can be induced in a variety of cell types, including non-hematopoietic tissues as 
well as in various tumors [55,60-62]. Both ligands are type I transmembrane receptors containing 
both IgV- and IgC-like domains in the extracellular region and contain short cytoplasmic regions 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
9 
 
 
 
 
with no known signaling motifs. Binding of either PD-1 ligand to PD-1 inhibits T-cell activation 
triggered through the T-cell receptor. PD-L1 is expressed at low levels on various non-
hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 protein is only 
detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic 
inflammatory environments. PD-L2 is thought to control immune T-cell activation in lymphoid 
organs, whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral tissues [63]. 
Although healthy organs express no or little PD-L1, a variety of cancers express abundant levels 
of this T-cell inhibitor. PD-1 has been suggested to regulate tumor-specific T-cell expansion in 
subjects with melanoma (MEL) [64]. This suggests that the PD-1/PD-L1 axis plays a critical role 
in tumor immune evasion and is an attractive target for therapeutic intervention. 
For T cells, PD1 is a surface inhibitory molecule and is a receptor for its ligands, PD1-L1 and 
PD1-L2, which are expressed by tumor or virally infected cells.[46-48, 65] Like CTLA-4/ligand 
interaction, binding of PD-1 and its ligand results in inhibition of T-cell receptor (TCR) signaling 
and thus down-regulates T cell function (IFN-γ and IL-2 secretion) and survival/proliferation (BLC-
XL). In contrast, inhibition of PD-1/PD-1-L axis by either anti-PD-1 or anti-PD1-L1 leads to 
enhancement of T-cell response in vitro and preclinical anti-tumor activity.[66,67] 
4. 
Clinical Trials Targeting Cancer Immune Check Points 
The largest randomized controlled trial of anti-CTLA4 to leverage anti-tumor activity in patients 
with advanced melanoma revealed objective response but high incidence of 46% severe grade 
3/4 adverse reactions in the anti-CTLA4 alone arm.[68]  
In contrast, a pilot study of a fully humanized IgG4 anti-PD-1, later known as nivolumab, as a 
single administration on 39 patients with advanced solid tumor, including non-small cell lung 
cancers, showed safety and feasibility.[69] There were no serious adverse reactions and most 
immune reactions were of mild severity. The plasma half-life was 12-20 days after one single 
infusion, with >70% sustained PD-1 receptor occupancy for >2 months. Lastly, the clinical 
response was sustained. 
The success led to a larger phase 1 study of nivolumab on 296 patients with advanced solid tumor 
receiving one infusion (0.1 to 10 mg/kg) every 2 weeks for up to 2 years.[70] Nivolumab was well 
tolerated and MTD was not reached. The median Tmax was 1-4 hours after the start of infusion. 
The PK was linear, with a dose proportional increase in the Cmax and AUC calculated from day 1 
to day 14 in the dose range 0.1-10 mg/kg. The median PD-1-receptor occupancy was 64-70% for 
the dose of 0.1-10 mg/kg every 2 weeks. The incidence of grade 3/4 adverse events was 14%, 
with 3 deaths from pulmonary toxicity. The cumulative response rate (CR/PR) was 20-25% and 
20 of 31 responders had durable response for >1 year. Some had response for >2 years. Common 
adverse reactions were grade 1 or 2 and mainly immunologic skin events (rash, pruritus, urticaria, 
vitiligo) and diarrhea. 
A more recent second phase 1 study of another anti-PD-1 (lambrolizumab; a humanized IgG4 
kappa anti-PD-1 antibody) at a dose of 10 mg/kg IV every 2 or 3 weeks or 2 mg/kg IV every 3 
weeks in patients with advanced melanoma for patients who had received prior treatment with 
the anti-CTLA-4, ipilimumab, and those who had not.[71] Steady-state serum trough 
concentration was 20% higher in the patients receiving 10 mg/kg every 2 weeks, compared to the 
same dose every 3 weeks. The serum half-life time of lambrolizumab was 2-3 weeks. Common 
adverse events were low-grade fatigue rash, pruritus and diarrhea. The overall response rate was 
38%, with the highest response rate of 52% in the cohort receiving 10 mg/kg every 2 weeks. The 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
10 
 
 
 
 
response was sustained, with a median follow-up time of 11 months. There was no difference in 
the response rates of those having or not having had received anti-CTLA-4, ipilimumab. 
The most recent phase 1 study of combination of anti-PD-1 nivolumab and anti-CTLA-4 
ipilimumab has recently been reported.[72] The concurrent regimen for those not having had 
received ipilimumab consisted of IV doses of both agents in patients with advanced melanoma 
every 3 weeks for 4 doses followed by anti-PD-1 nivolumab alone every 3 weeks for 4 doses, 
followed by maintenance combined treatment every 12 weeks for up to 8 doses. The optimal 
doses being nivolumab at a dose of 1 mg/kg and ipilimumab at a dose of 3 mg/kg resulted in a 
53% objective response rate, with all tumor reduction of 80% or more. This study revealed a more 
rapid and deeper degree of response with the combination of both agents targeting two different 
immune checkpoints. 
A phase 1 study of anti-PD-L1 against the ligand PD-L1 on tumor cells was also performed on 
207 patients with advanced solid tumors. [73] The dose ranged from 0.3 to 10 mg/kg every 2 
weeks on a 6-week cycle basis up to 16 cycles. This agent was also very well tolerated and MTD 
was not reached. The grade 3/4 toxicities were only 9%. With a mean follow-up period of 12 
weeks (range, 20-111 weeks), the objective response rate was 6-17% and 8 of 16 responders 
had a durable response (>1 year). 
5. 
Multiple Myeloma Immune Evasion 
MM is an incurable malignancy due to its intrinsic chemotherapy- and immunotherapy-
refractoriness. In contrast to myeloid malignancies, allogeneic hematopoietic cell transplant and 
donor lymphocyte infusion have limited role in controlling or cure of MM, implicating the underlying 
MM-specific immune evasion. The two major possible mechanisms include[74,75]  
1) Immunologically hostile microenvironment: MM cells produce multiple cytokines that 
promote their own survival advantage, angiogenesis and osteoclast activity leading to 
osteolytic lesions and resultant impaired immune response.  These cytokines include 
TFG-β, IL-10, MUC-1, VEGF, IL-6, Fas/FasL, COX-2 and MMP.  
2) Cellular immune defect: Dysfunction of T-cells, NK-cells, NKT-cells, B-cells, dendritic cells. 
 
6. 
PD-1/PD-L1 axis and T cell Function in MM 
A MM mouse model study showed that PD-1 expression on T cells from MM-bearing mice was 
up-regulated in the tumor site, compared with non-tumor sites [peripheral blood and spleen].[76] 
PD-1 was expressed on CD8+ and CD4+ T cells and NK cells at the tumor sites. The CD8+ T 
cells expressing PD-1 showed immunologically exhausting phenotype as evidenced by the 
impairment of IL-2, TNF-α and IFN-γ secretion and increased Tim3 expression, compared with 
PD-1 negative CD8+ T cells from tumor site and non-tumor sites. In addition, PD-1 was up-
regulated in primary CD4+ and CD8+ T cells collected before HDT/ASCT from bone marrow and 
peripheral blood of MM patients. The peak of PD-1 expression occurred ~day 30 post transplant 
in these MM patients.[77] 
Blockade of PD-1/PD-L1 axis by anti-PD-L1 against PD-L1 ligands on tumor cells enhanced 
efficacy of post-transplant cell based vaccine.[49] In another mouse model, it was demonstrated 
that anti-PD-L1 facilitated sub-ablative radiation in MM killing, which was CD8+ and CD4+ T cell 
dependent. With a more intensive therapy, anti-PD-L1 synergized with ablative radiation and 
adoptive T cell transfer.[77] 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
11 
 
 
 
 
In a similar way, blockade of this axis by anti-PD1 against PD-1 on T cells was shown to enhance 
T cell migration in vitro.[78]  In a mouse model, anti-PD1 increased the efficacy of dendritic 
cell/myeloma fusion cell vaccine following HDT/ASCT.[79] The T cell response was enhanced ex 
vivo.[80] In another mouse model, anti-PD1 synergized with low-dose cyclophosphamide on 
enhancing the effect of vaccine therapy.[81] 
7. 
PD-1/PD-L1 axis and NK cell Function in MM 
Clinical observation revealed increasing NK cell dysfunction with the advancing stages of plasma 
cell neoplasm from MGUS to advanced stage multiple myeloma.[82] Moreover, absolute number 
of NK cell recovery after HDT/ASCT for patients with MM correlated with PFS and OS.[83-85] 
In addition to the general immunologically hostile microenvironment – increased levels of TGF-β, 
IL-10, IL-6 and PGE2, which inhibits MM killing abilities by NK cells, specific mechanisms against 
NK function include 1) direct interference by excessive MM monoclonal immunoglobulin 2) 
depletion of essential cytokines by secretion of decoy soluble IL-2 receptor and expression of 
surface IL-15 receptors 3) modulation of NK receptor ligations including loss or down-regulation 
of membrane MICA, NKG2D and DNAM-1 in advanced MM, increased membrane MHC class I 
expression and secretion of soluble MHC class I and beta-2-microglobulin 4) down-regulation and 
loss-of-function mutation of membrane Fas receptors on MM cells and 5) increased expression 
of PD-1-ligand on MM cells.[82,86] 
Pre-clinical data showed that NK cell lines were able to kill clonogenic MM cell lines in vitro and 
in vivo.[87] In addition, PD-1 was demonstrated to be up-regulated on primary NK cells from MM 
patients and MM bearing mice as a the function of MM burden.[88] In vitro data revealed that anti-
PD-1 enhanced NK cell cytotoxicity against and trafficking towards PD-L1+ MM cell lines. In 
addition, anti-PD-1 enhanced immune complex formation between NK and MM cells. 
Interestingly, lenalidomide was also shown to down-regulate PD-L1 expression on MM cells and 
this effect was synergistic with NK cytotoxicity against PD-L1+ MM cell lines.[88] 
8. 
Clinical Data on Leveraging NK cell versus MM effect 
Two activating lymphokines, IFN-α and IL-2, were investigated in clinical trials. IFN-α was shown 
to have activity against MM in vitro, ex vivo and in patients. It was found to mobilize peripheral 
NK cells into bone marrow, the MM site.[89,90] Two large meta-analyses of these randomized 
controlled trials revealed a 20% response rate and prolonged PFS and OS.[91,92] Thus, IFN-α 
has remained a standard option for MM treatment. However, significant adverse events precluded 
its long-term use. Similar outcomes were seen in studies using IL-2, which increased the number 
of lymphokine-activated killer [LAK] cells, with modest response rate.[93-96]  Unfortunately, IL-2 
was associated with more unacceptable toxicities, preventing long-term use.[95-97] 
Observation studies of HDT/ASCT for MM reported consistent correlation between early 
lymphocyte recovery and progression-free survival.[83-85,98,99] The dose of lymphocytes 
infused, especially the NK cell dose, predicted overall lymphocyte and NK cell recovery, which, in 
turn, correlated with survival.[85] Day-15 absolute lymphocyte count [ALC] >500/μL and day-30 
ALC >1000/μL correlated with PFS and OS.[81,82,96,97] More specifically, day-15 absolute NK-
cell count >80/μL correlated with PFS.[100] Mayo Clinic group demonstrated an augmentation of 
ex vivo day-14 primary NK cell cytotoxicity by IL-2 and IFN-α early post HDT/ASCT in patients 
with MM.[95] Lastly, Meehan et al conducted a phase 1/2 study of post-HDT/ASCT 
immunomodulation of NK cell function in MM patients with IL-2 therapy during lymphopenic state 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
12 
 
 
 
 
from day 0 for 4 weeks, in conjunction with GM-CSF. There was a significant increase in the 
number of CD3+T cells, CD4+Tcells, CD8+T cells and CD25+ and CD8+CD56+Treg cells, compared 
with control.[101]  Ex vivo cytotoxicity of peripheral blood mononuclear cell against MM cell lines 
increased significantly, compared with control.[101] 
9. 
Homeostatic Proliferation of Lymphocytes 
Active immunotherapy e.g. adoptive T cell transfer and cell based vaccines have been limited in 
sustained efficacy due to immune check point and other regulatory components and competition 
with native immune cells for space niche and essential homeostasis lymphokines.[45-48, 65]  
Lympho-depletion state occurring after irradiation or chemotherapy creates a suitable condition 
for transferred or newly activated lymphocytes to proliferate and be activated due to depletion of 
competitors for space niche, cytokines (cytokine sinks) and suppressors or regulators.[102-107] 
This effect is potentiated by higher intensity ablation and infusion of hematopoietic stem cells. 
With a higher degree of depletion of competitors or suppressor components, transferred 
lymphocytes proliferate and become activated more efficiently, with less intensity of antigen and 
co-stimulatory signals. In addition, infused hematopoietic stem cells provide more effector and 
precursor cells, which produce or induce other cells to secrete essential cytokines, growth factors 
and anti-apoptotic factors, nourishing transferred lymphocytes.[108,109] Condomines et al 
demonstrated a nadir of absolute lymphocyte count occurring ~day 3-8 post high-dose 
melphalan/HSCT in patients with MM and coinciding with the peak of serum IL-6, IL-7 and IL-15 
levels.[110] 
10.         Previous Related Clinical Studies on Lymphoid Malignancies 
A phase 2 study of a humanized anti-PD-1 monoclonal antibody, MK-3475 (Pembrolizumab), in 
66 patients with diffuse large B-cell lymphoma post-HDT/ASCT.[89] MK-3475 was administered 
at 1.5 mg/kg every 6 weeks for 3 cycles, starting between 30-90 days post transplant. This 
intervention was safe and feasible. The 18-month progression free survival was 72% (95%CI; 60-
82%) overall and 70% (95% CI; 51-82%) in 24 high-risk patients with PET+ disease prior to 
transplant. The results were very promising, when compared with historical data. Treatment was 
associated with increases in circulating lymphocyte subsets including PD-L1+ lymphocytes, 
suggesting an on-target in vivo effect of MK-3475. [111] 
A more recent phase 2 study of a combination of MK-3475 and the anti-CD20 rituximab in 32 
patients with advanced rituximab-sensitive follicular lymphoma at 3 mg/kg intravenously every 4 
weeks for 4 infusions, plus additional 8 optional infusions every 4 weeks for patients with stable 
disease or better. Rituximab was added on day 17 at 375 mg/m2 intravenously weekly for 4 weeks. 
The combination of MK-3475 and rituximab was well tolerated, with no autoimmune or treatment-
related adverse events of grade 3 or 4. The most common adverse events of grade 1 were 
anaemia (14 patients) and fatigue (13 patients), and the most common adverse event of grade 2 
was respiratory infection (5 patients). Of the 29 patients evaluable for activity, 19 (66%) achieved 
an objective response: complete responses were noted in 15 (52%) patients and partial 
responses in four (14%).[112] 
11. 
Anti-PD-1: MK-3475 (Pembrolizumab)[113] 
MK-3475 (previously known as SCH 900475) is a potent and highly selective humanized 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
13 
 
 
 
 
monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction 
between PD-1 and its ligands, PD-L1 and PD-L2 without ADCC or CDC activity.  
 
MK-3475 strongly enhances T-lymphocyte immune responses in cultured blood cells from healthy 
human donors, cancer patients, and primates. In T-cell activation assays using human donor 
blood cells, the EC50 (concentration where 50% of the maximum effect is achieved) has been ~0.1 
to 0.3 nM. In addition to interleukin-2 (IL-2), tumor necrosis factor alpha (TNFα), interferon gamma 
(IFNg), and levels of other cytokines were modulated by MK-3475. The antibody potentiates 
existing immune responses only in the presence of antigen and does not nonspecifically activate 
T-cells. Using an anti-murine PD-1 analog antibody, PD-1 blockade has been shown to 
significantly inhibit tumor growth in a variety of syngeneic murine tumor models. In these 
experiments in mice, anti-PD-1 therapy is synergistic with chemotherapeutic agents such as 
gemcitabine and 5-fluorouracil (5-FU) and combination therapy results in increased complete 
tumor regression rates in vivo. 
 
Therapeutic studies in mouse models have shown that administration of antibodies blocking PD-
1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T-cells and leads ultimately to 
tumor rejection, either as a mono-therapy or in combination with other treatment modalities.  Anti-
mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated anti-tumor responses as a 
mono-therapy in models of squamous cell carcinoma, pancreatic carcinoma, MEL and colorectal 
carcinoma.  Blockade of the PD-1 pathway effectively promoted CD8+ T-cell infiltration into the 
tumor and the presence of IFN-γ, granzyme B, and perforin, indicating that the mechanism of 
action involved local infiltration and activation of effector T-cell function in vivo 114-119].  
Experiments have confirmed the in vivo efficacy of PD-1 blockade as a mono-therapy as well as 
in combination with chemotherapy in syngeneic mouse tumor models (see the Investigator’s 
Brochure [IB]). 
Based on preclinical in vitro data, MK-3475 has high affinity and potent receptor blocking activity 
for PD-1. MK-3475 has an acceptable preclinical safety profile and is being advanced for clinical 
development as an immunotherapy for advanced malignancies. 
 
Clinical data from PN001 is presented in the report with a visit cut-off date of 26-Jul- 2013. As of 
26-Jul-2013, there have been 789 patients treated in PN001 with MK-3475 as a 30-minute IV 
infusion. Of these 789 patients, preliminary data are presented in this report from 479 patients. 
Data from 200 patients in Part B3 and 110 patients in Part F that were treated as of the cut-off 
data were not included in the analyses yet. Based upon this safety database consisting of patients 
treated up to 10 mg/kg once every two to three weeks, MK-3475 has been generally well-tolerated 
at doses up to 10 mg/kg every other week without DLTs. One (0.002%) patient assayed to date 
had samples confirmed positive for ADA, but no impact on safety has been observed. Five other 
clinical studies (PN002, PN006, PN010, PN011, and PN012) are ongoing however preliminary 
data analyses are not yet available. For these 5 studies, the number of treated patients indicated 
in this report is based on a visit cut-off date of 18-Oct-2013 to allow for more mature enrollment 
data and align with the Development Safety Update Report data cutoff 
date. MK-3475 PK results have been obtained from PN001 following the first dose at 1, 3 and 
10 mg/kg IV of MK-3475 administered to 17 patients with solid tumors. The observed 
pharmacokinetic profile of MK-3475 was typical of other IgG mAbs with a half-life (t½) of 
approximately 2 to 3 weeks. There was no indication of dose dependency of half-life in the 3 dose 
groups and a dose related increase in exposure was observed from 1 to 10 mg/kg. The long half-
life supports a dosing interval of every 2 or 3 weeks. Exposure obtained with sparse sampling 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
14 
 
 
 
 
after dosing melanoma and non-small cell lung cancer (NSCLC) patients at 2 and 10 mg/kg, every 
2 or 3 weeks, is consistent with this profile. As of 18-Oct-2013, PN002 has randomized 497 
patients with metastatic melanoma (495 patients were treated) across 3 treatment groups as 
follows, MK-3475 2 mg/kg Q3W, MK-3475 10 mg/kg Q3W, and chemotherapy (investigator choice 
of treatment) in a 1:1:1 ratio. PN006 has randomized 68 IPI-naïve patients with unresectable or 
metastatic melanoma across the 3 treatment groups: 10 mg/kg Q2W, 10 mg/kg Q3W, and 
ipilimumab in a 1:1:1 ratio. PN010 has randomized three patients with NSCLC across the 3 
treatment groups: 10 mg/kg Q3W, 2 mg/kg Q3W, and docetaxel 75 mg/m2 Q3W in a 1:1:1 ratio. 
In PN011 10 patients have been treated. In PN012, 109 patients have been treated across the 
three cohorts as of 18-Oct-2013. Durable objective responses have been reported in patients with 
melanoma and NSCLC. Adverse events have generally been manageable and infrequently 
require discontinuation of MK-3475 treatment.  
 
12. 
Significance 
This phase 2 study is embarking on leveraging T and NK cell function after standard high-dose 
therapy and autologous transplant for multiple myeloma by use of anti-PD-1 to disrupt the PD-
1/PD-L-1 immune checkpoint axis. This translational concept is based on the extensive pre-
clinical data of this axis specifically in myeloma and the positive clinical outcomes and safety 
profiles from recent phase I studies of this agent in patients with advanced solid tumors. Timing 
of treatment during post transplant lympho-penic state is expected to further enhance the effect 
of anti-PD-1. 
Multiple myeloma is a very common hematologic malignancy in the US but remains incurable, 
even with novel targeted agents and high-dose therapy/autologous transplant. Immunotherapy 
e.g. allogeneic hematopoietic cell transplant has a curative potential but at the expense of high 
treatment-related mortality (graft-versus-host disease, infection and other transplant specific 
events). Thus, the positive outcomes of this safer strategy will definitely be a break through and 
has great impact on the outcomes of therapy for this common cancer. 
 
4.2 
Rationale 
 
4.2.1 Rationale for the Study and Selected Subject Population 
 
1. 
Immunotherapy is highly potent but very short-lived in clinical setting; thus meaningful 
clinical benefits are lacking. Reasons include: a) presence of immune checkpoints [CTLA4 and 
PD-1 receptor/PD-1 ligand axes]; b) presence of other suppressor elements [regulatory T cells 
(Treg), myeloid derived suppressor cells (MDSC)]; c) presence of competitors for essential 
activating cytokines for T/NK cells [Cytokine Sinks]; and d) the lack of “space niche”.  
 
2.  
Patients with MM who do not respond adequately with primary therapy and those with 
high-risk cytogenetic features have worse treatment outcomes, compared with those who achieve 
a complete response status, which predicts favorable long-term outcomes. Complete response 
rate after primary therapy with highly effective targeted agents, followed by HDT/ASCT is 
disappointingly low (30% only). 
3. 
Early lymphocyte, especially NK cells, and antigen-presenting dendritic cell recovery post-
transplant is associated with decreased multiple myeloma relapse. 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
15 
 
 
 
 
4.  
Clinical trials using anti-Cytotoxic T-lymphocyte Antigen-4 [Anti-CTLA4] to leverage T cell 
function resulted in very promising anti-tumor outcomes but high rate of serious autoimmunity. 
5.  
Preclinical studies showed increased PD-1 expression on CD8+ and CD4+ T cells and NK 
cells at the multiple myeloma sites and their function was impaired. Disruption of the PD-1/PD-L1 
axis restored their cytotoxicity against and trafficking towards multiple myeloma. Lastly, in a 
mouse model, anti-PD1 increased the efficacy of dendritic cell/myeloma fusion cell vaccine 
following HDT/ASCT and synergized with low-dose cyclophosphamide on enhancing the effect of 
vaccine therapy. 
6. 
PD-1 was expressed on primary T and NK cells from multiple myeloma patients. In 
addition, PD-1 was expressed on primary CD4+ and CD8+ T cells collected before and after 
HDT/ASCT from bone marrow and peripheral blood of MM patients. The time peak of PD-1 
expression occurred ~day 30 post-transplant in these MM patients. 
7.   
Phase 1 studies of fully humanized IgG4 anti-PD-1 in advanced cancers showed its 
feasibility and safety for use in human, with a sustained anti-tumor activity and a more favorable 
adverse reaction profile, and pharmacokinetics and -dynamics profiles.  
8.    
Post high-dose chemotherapy lympho-depletion state is devoid of suppressor Treg or 
MDSC and competitors for enriching cytokines, with more available space niches.  
9.    
In addition, transfer of hematopoietic stem cells and T cells with autologous transplant 
augments the above effects of lympho-depletion to T cell/immune recovery.  
10.    Based on the above evidence, administration of anti-PD-1 to unleash and augment T and 
NK cell function during lymphopenic state early post HDT/ASCT when PD-1 expression on 
effector cells peaks and myeloma tumor burden nadirs may result in a maximal synergy on the 
cytotoxicity to multiple myeloma. This may then result in the improvement of multiple myeloma 
relapse post transplant and overall transplant outcomes. 
4.2.2 Rationale for Dose Selection/Regimen/Modification 
An open-label Phase I trial (Protocol 001) was conducted to evaluate the safety and clinical activity 
of single agent MK-3475.  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. 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 (98).  Pharmacodynamic data (IL-2 release 
assay) suggested that peripheral target engagement is durable (>21 days).  This early PK and 
pharmacodynamic data provides scientific rationale for testing a Q2W and Q3W dosing schedule.   
 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
16 
 
 
 
 
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 2 mg/kg 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 2 
mg/kg 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 dose regimen of 200 mg Q3W of MK-3475 is planned for all urothelial cancer trials. Available 
PK results in subjects with melanoma, non-small cell lung cancer (NSCLC), and other solid tumor 
types support a lack of meaningful difference in PK exposures obtained at a given dose among 
tumor types. An open-label Phase 1 trial (PN001) in melanoma subjects is being conducted to 
evaluate the safety and clinical activity of single agent MK-3475.  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 maximum tolerated dose (MTD) has been identified. 
In KEYNOTE-001, two randomized cohort evaluations of melanoma subjects receiving MK-3475 
at a dose of 2 mg/kg versus 10 mg/kg Q3W have been completed.  The clinical efficacy and safety 
data demonstrate a lack of clinically important differences in efficacy response or safety profile at 
these doses.  For example, in Cohort B2, advanced melanoma subjects who had received prior 
ipilimumab therapy were randomized to receive MK-3475 at 2 mg/kg versus 10 mg/kg Q3W.  The 
overall response rate (ORR) was 26% (21/81) in the 2mg/kg group and 26% (25/79) in the 10 
mg/kg group (full analysis set (FAS)).  The proportion of subjects with drug-related adverse events 
(AEs), grade 3-5 drug-related AEs, serious drug-related AEs, death or discontinuation due to an 
AE was comparable between groups or lower in the 10 mg/kg group.   
Available pharmacokinetic results in subjects with melanoma, NSCLC, and other solid tumor 
types support a lack of meaningful difference in pharmacokinetic exposures obtained at a given 
dose among tumor types.  Population PK analysis has been performed and has confirmed the 
expectation that intrinsic factors do not affect exposure to MK-3475 to a clinically meaningful 
extent.  Taken together, these data support the use of lower doses (with similar exposure to 2 
mg/kg Q3W) in all solid tumor indications.  2 mg/kg Q3W is being evaluated in NSCLC in PN001, 
Cohort F30 and PN010, and 200 mg Q3W is being evaluated in head and neck cancer in PN012, 
which are expected to provide additional data supporting the dose selection. 
Selection of 200 mg as the appropriate dose for a switch to fixed dosing is based on simulation 
results indicating that 200 mg will provide exposures that are reasonably consistent with those 
obtained with 2 mg/kg dose and importantly will maintain individual patient exposures within the 
exposure range established in melanoma as associated with maximal clinical response.  A 
population PK model, which characterized the influence of body weight and other patient 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
17 
 
 
 
 
covariates on exposure, has been developed using available data from 476 subjects from 
PN001.   The distribution of exposures from the 200 mg fixed dose are predicted to considerably 
overlap those obtained with the 2 mg/kg dose, with some tendency for individual values to range 
slightly higher with the 200 mg fixed dose.   The slight increase in PK variability predicted for the 
fixed dose relative to weight-based dosing is not expected to be clinically important given that the 
range of individual exposures is well contained within the range of exposures shown in the 
melanoma studies of 2 and 10 mg/kg to provide similar efficacy and safety.  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 tumor types and indication settings.  
Based on the PK/PD data, and the time peak of PD-1 expression on primary T-cells at day 30 
post-transplant in MM patients,[40] we will study anti-PD-1 at a fixed dose of 200 mg MK-3475 
intravenously every 3 weeks (+/-4 days), starting on day +14 or later after an engraftment until 
~day 182 post-transplant for a total of 9 doses. [See Schema] 
 
4.2.3 Rationale for Endpoints 
See Section 5.10 and Appendix 13.3 for the definition of Endpoints. 
 
4.2.3.1 Efficacy Endpoints 
We expect that the addition of anti-PD1 during lymphopenic state after high dose therapy and 
autologous transplant will augment immune reaction against multiple myeloma and increase 
complete response (CR) conversion rate at day 180. 
Primary Efficacy Endpoint:  CR rate at day 180 
Secondary Efficacy Endpoints 
- 
CR rate at day 100 
- 
Flow based minimal residual disease (MRD) rate at day 100 and day 180 
- 
Progression-free survival at 2 years 
- 
Overall survival at 2 years 
- 
Compliance with treatment:  
o Median Number of doses administered 
o Dose de-escalation requirements 
 
4.2.3.2 Safety Endpoints 
- 
Regimen-related toxicities (RRT) according to CTCAE v4 
- 
Engraftment 
- 
Treatment-related mortality (TRM) 
- 
Late adverse reactions especially autoimmune disorders 
 
4.2.3.3 Biomarker Research 
              
1) Measurement of immune cell phenotypes in autologous graft tissue pre-
transplant 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
18 
 
 
 
 
2) Quantification of immune recovery: Quantification of activated and effector CD4+ 
and CD8+ cells, NK cells, and regulatory T and B cells.  
3) Functional T cell subtypes and cytokine profiles: Intracellular IFN-α, IFN-γ, cytokine 
release spectrum, TH subset transcription factor profiling 
4) NK cell cytotoxicity: Intracellular granzyme B, tumor cell death 
5) PD-1-ligand expression on MM cells pre-transplant 
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
1. Subjects with multiple myeloma (MM) of any stage and of any cytogenetic risk per 
International Multiple Myeloma Working Group Criteria   (Appendix 13.2). 
 
Pathology review by Pathology Department of each institution is mandatory. 
 
2. Has no progressive disease (PD; Appendix 13.3) after initial primary therapy 
  
AND    
      
Has either of the following suboptimal response with primary therapy 
 
2.1 
Very good partial response (VGPR) or less (Appendix 13.3) after at least 2 
cycles of a triple regimen: 
 
An *IMiDs, a proteasome inhibitor and a systemic steroid OR 
A conventional chemotherapy, a proteasome inhibitor and a systemic steroid OR  
An equivalent triple regimen at the investigator discretion 
*IMiDs consists of thalidomide, lenalidomide, pomalidomide and other related –lidomides. 
2.2 
VGPR or less after at least 4 cycles of a double regimen:  
An IMiDs and a systemic steroid OR 
A proteasome inhibitor and a systemic steroid OR  
An equivalent double regimen at the investigator discretion 
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this study, the subject must: 
3. Be ≥ 18 years and ≤75 of age on day of signing informed consent. 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
19 
 
 
 
 
 
4. Had measurable disease of MM at diagnosis, defined as: 
 
o 
A monoclonal immunoglobulin spike on serum electrophoresis of at least 0.5 g/dL 
and/or  
o 
Urine monoclonal protein levels of at least 200 mg/24 hours 
  
o 
For subjects without measurable serum or urine M-protein levels, an abnormal free 
light chain ratio (normal value: 0.26-1.65) with involved FLC level ≥10 mg/dL (≥100 
mg/L). 
 
“Measurable disease” is NOT required at the time of enrollment. See “required MM 
status at enrollment” in 5.1.1 #2.  Final determination of measurable disease 
requirement is at PI’s discretion. 
 
5. Has no other hematopoietic stem cell transplant of any type prior to the current planned 
autologous hematopoietic cell transplant. 
 
6. Has a performance status of 0 or 1 on the ECOG Performance Scale. (≥70% Karnofsky 
Performance Score) (Appendix 13.1). 
 
7. Demonstrate adequate organ function per institutional guidelines for high-dose melphalan 
and autologous transplant at the time of enrollment. See separate laboratory criteria to 
initiate MK-3475 at day +14 post transplant (Table 1) which are not required at enrollment.  
8. Has had a successful peripheral blood stem cell collection with G-CSF (Filgrastim) +/- 
Plerixafor (Mozobil) only. The target cell dose is ≥2.0 x106 CD34+ cells/kg. 
9. Be willing and able to provide written informed consent/assent for the study. 
  
 
10. Female subject of childbearing potential should have a negative urine or serum pregnancy 
per institutional guidelines for high-dose melphalan and autologous transplant. If the urine 
test is positive or cannot be confirmed as negative, a serum pregnancy test will be 
required. 
 
11. Female subjects of childbearing potential must be willing to use 2 methods of birth control 
or be surgically sterile, or abstain from heterosexual activity for the course of the study 
starting with the first dose of MK-3475 through 120 days after the last dose of MK-3475 
(Section 5.5.4). Subjects of childbearing potential are those who have not been surgically 
sterilized or have not been free from menses for >2 year (Section 5.5.4). 
12. Male subjects must agree to use an adequate method of contraception starting with the 
first dose of MK-3475 through 120 days after the last dose of MK-3475 (Section 5.5.4). 
13. Subject is able to swallow capsules and is able to take or tolerate oral medications on a 
continuous basis. 
5.1.3 Subject Exclusion Criteria 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
20 
 
 
 
 
The subject must be excluded from participating in the trial if the subject: 
1. Has any type of amyloidosis, hyperviscosity, plasma cell leukemia, POEMS syndrome, 
Waldenström's macroglobulinemia, non-secretory multiple myeloma or IgM myeloma. 
2. Has known clinically active CNS involvement OR history of resolved CNS involvement 
by multiple myeloma. 
3. Has an active autoimmune disease or a documented history of autoimmune disease, or 
an autoimmune syndrome that requires systemic steroids or immunosuppressive agents.   
Note: Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to 
this rule.  Subjects that require intermittent use of bronchodilators or local steroid 
injections would NOT be excluded from the study. Subjects with hypothyroidism stable 
on hormone replacement or Sjorgen’s syndrome will NOT be excluded from the trial. 
4. Has a history of non-infectious pneumonitis that required steroids or current pneumonitis. 
5. Has evidence of interstitial lung disease. 
6. Has a diagnosis of immunosuppressive disorder OR is on any other form of 
immunosuppressive therapy within 7 days prior to transplant admission. 
7. Is currently participating in or has participated in any study of an investigational agent or 
using an investigational device within 4 weeks of transplant admission. 
8. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or 
anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including 
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or 
checkpoint pathways). 
9. Has had prior monoclonal antibody, chemotherapy (including dexamethasone for MM 
treatment), targeted small molecule therapy, or radiation therapy within 2 weeks prior to 
transplant admission (or ~4 weeks prior to the first dose of MK-3475). 
 
OR  
Has not recovered (i.e. ≤ Grade 1 or at baseline) from adverse events due to a previously 
administered agent more than 2 weeks prior to transplant admission or more than 4 
weeks prior to the first dose of MK-3475. 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may 
qualify for the study. 
Note:  If subject received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to transplant admission.   
Note: Toxicity that has not recovered to ≤ Grade 1 is allowed if it meets the requirements 
per institutional guidelines for high-dose melphalan and autologous transplant. 
10. Has been free of additional malignancy for at least 5 years.  Exceptions include basal cell 
carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that 
has undergone potentially curative therapy. 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
21 
 
 
 
 
11. Has an active infection requiring systemic therapy or history of repeated infections. 
12. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the study. 
13. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the study, starting with the pre-screening or screening visit through 
120 days after the last dose of MK-3475 (Section 5.5.4). 
14. Has a known Human Immunodeficiency Virus (HIV), Hepatitis B (HBV), or Hepatitis C 
(HCV) infection. 
15. Has a clinically significant coagulopathy per investigator’s assessment. 
16. Has known symptomatic congestive heart failure, unstable angina pectoris, or cardiac 
arrhythmia. 
17. Has received any type of hematopoietic cell transplant except for the current planned 
high dose melphalan and autologous stem cell transplant. 
18. Has received a live vaccine within 30 days prior to transplant admission. 
19. Is or has an immediate family member (spouse or children) who is investigational site or 
sponsor staff directly involved with this study, unless prospective IRB approval (by chair 
or designee) is given allowing exception to this criterion for a specific subject. 
5.2 
Inclusion Criteria to initiate on the first dose of MK-3475 on day 14 
The subject must demonstrate adequate organ function as defined in Table 1 prior to receiving 
the first dose of MK-3475 on day+14 (+/-4) post transplant. All labs should be performed within 3 
days of MK-3475 treatment initiation. 
 
Table 1:  Required Organ Function Laboratory Values Prior to the first MK-3475 Initiation only 
 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,000 /µL 
Platelets 
≥20,000 / µL  
Hemoglobin 
≥8 g/dL 
Renal 
 
Serum creatinine    
OR 
 
Measured or calculated1 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 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
22 
 
 
 
 
 
Note:  These criteria in Table 1 are not required or applicable to 8 subsequent doses of 
MK-3475.  Refer to 5.3.4.7 (Event of Clinical Interest (ECI) and immune-related Adverse 
Event (irAE)) and 5.3.4.8 (Dose Modification) for management of 8 subsequent doses. 
 
Subject Screening and Registration Procedure 
 
Subject registration for this study will be centrally managed by the Oncology Clinical Trials 
Support Unit (O-CTSU) of The University of Michigan Comprehensive Cancer Center as 
described below: 
 
A potential study subject who has been screened for the study and who has signed the Informed 
Consent document will be initially documented by the participating site on the Screening and 
Enrollment Log provided by the O-CTSU. 
 
It is the responsibility of the local site investigator to determine subject eligibility prior to submitting 
subject registration request to the O-CTSU. After subject eligibility has been determined, a copy 
of the completed Eligibility Worksheet together with all the pertinent de-identified source 
documents will be submitted by the requesting site to the O-CTSU, by email to CTSU-Oncology-
Multisite@med.umich.edu.   
 
A Multi-Site Coordinator (MSC) of the CTSU, who acts as the registrar, will review the submitted 
documents and process the registration. Sites should inform the Multi-Site Coordinator of a 
potential registration by 5 p.m. on the day prior to registration.  Same day registrations cannot be 
guaranteed.  
 
An email will be sent by the registrar to the requesting site registrar to confirm patient registration 
and to provide the study identification number that has been assigned to the patient. In addition, 
bilirubin levels > 1.5 X 
ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN   
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 
1 Creatinine clearance should be calculated per institutional standard. 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
23 
 
 
 
 
a copy of the completed Section of the Eligibility Worksheet signed and dated by the registrar, will 
be returned to the requesting site registrar. 
 
Subjects found to be ineligible for participation after being consented will be considered screen 
failures, and documented as such in the Screening and Enrollment Log. These subjects will not 
have study identification number assigned to them, and will not receive study treatment. 
 
Pre-study Documentation Requirements 
 
Informed consent, eligibility checklist and registration forms shall be obtained before subjects can 
receive the first study treatment of MK-3475 (pembrolizumab). 
 
Informed consent, eligibility checklist and registration forms should be obtained before 
“transplantation”. Failure to complete the registration before transplantation may be allowed at 
the discretion of the PI and will not be considered a protocol deviation or violation.  
 
Of note, conditioning chemotherapy (melphalan), autologous hematopoietic cell transplantation 
and lenalidomide maintenance therapy are standard treatments (see 5.3). 
 
5.3 
TREATMENTS 
 
5.3.1 Standard Multiple Myeloma Treatment 
  
 
5.3.1.1  High-dose Melphalan and Autologous Stem Cell Transplantation 
 
1.  High-dose melphalan 140-200 mg/m2  (<200 mg/m2 for subjects aged >70 years) 
 
2.  The procedure protocol of high-dose melphalan and autologous stem cell transplant  
     follows Institutional Guidelines. The target cell dose is ≥2.0 x106 CD34+ cells/kg. 
 
3. Use of filgrastim (Neupogen®) to facilitate engraftment is allowed per Institutional              
Guidelines 
 
5.3.1.2  Maintenance Treatment 
 
Lenalidomide 5-15 mg/day to start on day 45-90 post-transplant per standard multiple myeloma 
management as tolerated until multiple myeloma progression.  
 
Venous thromboembolism prevention and contraception required during lenalidomide 
maintenance treatment will follow standard of care or Institution Guidelines. Of note, warfarin is 
not allowed (see Section 5.4.2). 
 
**Failure to follow the standard multiple myeloma treatment procedures due to appropriate 
medical indications may not be considered a protocol deviation or violation at the PI’s discretion.** 
 
 
5.3.2 Study Treatment with MK-3475 (Pembrolizumab)  
 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
24 
 
 
 
 
A fixed MK-3475 dose of 200 mg/day will be administered as a 30-minute intravenous (IV) infusion 
every 3 weeks, starting ~day +14 post-transplant (Schema).  Dose days are 4 days flexible (+/- 4 
days). 
 
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). 
 
Treatment Schema 
 
 
Table 2: Study Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
MK-3475 
(Pembrolizumab) 
200 mg 
Every 3 
weeks  
(+/- 4 days) 
 
IV infusion 
Starting day +14 for 
a total of 9 doses 
Experimental 
The MK-3475 dosing interval may be increased due to toxicity as described in Section 5.3.4.8 (Table 4 
and 5) 
 
Premedication per institutional guidelines for monoclonal antibodies (e.g. acetaminophen and 
antihistamine) is allowed. Steroid premedication is not indicated and should be avoided. 
 
5.3.3 Standard Transplantation Drugs 
 
1. 
Melphalan [Evomela, Alkeran] 
Formulation:  Melphalan (L-phenylanine mustard) is a bifunctional alkylating agent.  It forms 
covalent linkages with susceptible cellular proteins. It induces formation of DNA interstrand and 
DNA protein cross-links. Alkeran: IV administration of melphalan revealed rapid elimination from 
plasma with terminal half-life of 1.8 hours.  13% is excreted in the urine.  It is rapidly distributed in 
total body water and eliminated in a biphasic manner. IP administration of 20-30 mg/M2 revealed 
a peak concentration in the peritoneal cavity of 6.4 ± 2.4  µg/ml and half-life of 85 ± 30 minutes.  
The peak plasma concentration was 1.22 µg/ml, and half-life was 86 ± 31 minutes. Evomela: IV 
administration has a comparable PK profile to conventional IV melphalan (Alkeran).   
Availability: Alkeran: The drug is available as an injectable kit.  This kit contains an ampule of 
100 mg (equivalent) melphalan, a 1 ml ampule of acid- alcohol diluent (containing 0.047 ml 37% 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
25 
 
 
 
 
HCl, q.s. to 1 ml with alcohol) and a 9 ml ampule of final diluent containing dipotassium phosphate, 
108 mg propylene glycol 5.4 ml sterile water for injection q.s. 9.0 ml.  Evomela: The drug is 
available as a lyophilized powder in a single-dose vial for intravenous use. Each vial contains 50 
mg melphalan free base equivalent to 56 mg melphalan hydrochloride and 2700 mg Betatex 
Sulfobutyl Ether Sodium. The Alkeran kits and Evomela vials should be stored at room 
temperature and projected from light.  
Administration: Alkeran: The 100 mg injectable formulation is put into solution initially with the 
addition of 1 m acid-alcohol diluent.  When dissolution is complete, the 9 ml final diluent is added.  
This final solution has a pH of > 7 and should be used promptly.  According to the manufacturer 
(8.5% hydrolysis 24 hours after mixing) a further dilution in D5W is also reportedly stable for 24 
hours. Evomela: Each 50 mg vial is reconstituted with 8.6 mL of normal saline solution (0.9% 
Sodium Chloride Injection, USP) to make a 50 mg/10 mL (5 mg/mL) nominal concentration of 
melphalan. The reconstituted Evomela drug product is stable for: 24 hours at refrigerated 
temperature (5oC) without any precipitation due to the high solubility, and for 1 hour at room 
temperature. Add the required volume of Evomela to the appropriate volume of 0.9% Sodium 
Chloride Injection, USP to a final concentration of 0.45 mg/mL. The Evomela admixture solution 
is stable for 4 hours at room temperature in addition to the 1 hour following reconstitution. 
Potential and Expected Toxicities: Human Toxicology: Melphalan's major systemic toxicity is 
bone marrow depression with secondary anemia, leukopenia and thrombocytopenia, usually 
occurring within three to five weeks of the onset of therapy and lasting four to eight weeks. These 
effects are exacerbated by prior chemotherapy or radiotherapy.  Other adverse reactions include 
nausea, vomiting, diarrhea, stomatitis, esophagitis, colitis, increases in liver function and kidney 
function tests, renal/bladder necrosis, pulmonary fibrosis, respiratory distress, peripheral 
neuropathy, paresthesia, alopecia, fever and hypersensitivity including edema, rash and 
anaphylaxis. At high doses, supraventricular arrhythmias, including atrial fibrillation, may occur.  
The occurrence of acute leukemia has been reported rarely in patients treated with 
anthracycline/alkylator combination chemotherapy.  
 
2. 
FILGRASTIM (r-metHuG-CSF, NEUPOGEN®) 
Formulation: Filgrastim, (recombinant human granulocyte-colony stimulating factor, r-metHuG-  
CSF), is a protein produced by E. coli into which has been inserted the human granulocyte colony-
stimulating factor gene.  Filgrastim differs from the natural protein in that the N-terminal amino 
acid is a methionine and it is not o- glycosylated.  G-CSF functions as a hematopoietic growth 
hormone; it increases the proliferation, differentiation, maturation and release of precursor cells 
into mature blood cells of the neutrophil lineage.  G-CSF has demonstrated in vitro effects on 
mature neutrophils, including an increased expression of chemotactic receptors, enhanced 
phagocytosis and intracellular killing of certain organisms, as well as enhanced killing of target 
cells that are bound by antibodies.  
Approximately 6,400 patients in U.S. and international based trials have participated in clinical 
trials of filgrastim to date, and the worldwide commercial populations receiving filgrastim totaled 
approximately 190,000.  The drug has been found to be well tolerated at dosages up to 69 
µg/kg/day given IV or SC, with no toxic effects attributable to filgrastim.  A maximum tolerated 
dose has not yet been determined.  
Availability:  Recombinant G-CSF, filgrastim, NEUPOGEN®, is supplied as a clear, colorless 
preservative-free liquid for parenteral administration.  Single use vials contain filgrastim 300 µg/ml 
in a preservative-free solution with 0.59 mg/ml acetate, 50 mg/ml sorbitol, 0.004% Tween® 80, 
0.035 mg/ml sodium, and water for injection, USP, pH 4.0 to make 1 ml filgrastim Neupogen® is 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
26 
 
 
 
 
commercially available in 2 vial sizes:  300 µcg/1 ml and 480 µg/1.6 ml. Dilution:  If required, 
filgrastim may be diluted in 5% dextrose.  Filgrastim diluted to concentrations between 5 and 15 
µg/ml should be protected from adsorption to plastic materials by addition of albumin (Human) to 
a final concentration of 2 mg/ml.  When diluted in 5% dextrose or 5% dextrose plus albumin 
(Human), filgrastim is compatible with glass bottles, PVC and polyolefin IV bags, and 
polypropylene syringes.  Dilution of filgrastim to a final concentration of less than 5 µg/ml is not 
recommended at any time.  Do not dilute with saline at any time; product may precipitate. Storage 
and Stability:  Filgrastim should be stored in the refrigerator at 2 - 8°C  (36 - 46°F).  Avoid shaking.  
Prior to injection, filgrastim may be allowed to reach room temperature for a maximum of 24 hours  
Any vial left at room temperature for greater than 24 hours should be discarded.  Parenteral drug 
products should be inspected visually for particulate matter and discoloration prior to 
administration, whenever solution and container permit; if particulates or discoloration are 
observed, the container should not be used.  
Administration:  Filgrastim is administered as a single daily injection by SC bolus injection, by 
short IV infusion (15 - 30 minutes), or by continuous SC or continuous IV infusion.    
Potential and Expected Toxicities: The most frequently reported adverse effect was medullary 
bone pain, occurring in 20 - 25% of patients in Phase II and III trials.  When bone pain was reported 
it often preceded a rise in the circulating neutrophil count; it occurred more  frequently in patients 
treated with 20 - 100 µg/kg/day of intravenously administered filgrastim and less often in lower 
subcutaneous doses.  The pain was generally mild to moderate in severity, and usually controlled 
with non-narcotic analgesics such as acetaminophen.  Other side effects include transient but 
reversible increases of alkaline phosphatase, lactate dehydrogenase and uric acid levels.  These 
occurred in 27-58% of patients, without clinical sequelae observed.  Elevations of leukocyte 
alkaline phosphatase levels have also been noted but the significance is not yet known.  Less 
frequently reported adverse events related to filgrastim administration include subclinical 
splenomegaly, exacerbation of pre-existing skin rashes, alopecia, and thrombocytopenia, and 
cutaneous vasculitis. Rarely, allergic-type reactions have occurred.  Since the commercial 
introduction of filgrastim there have been reports (< 1 in 4,000 patients) of symptoms suggestive 
of an allergic-type reaction, but in which an immune component has not been demonstrated.  
These have generally been characterized by systemic symptoms involving at least two body 
systems, most often skin (rash, urticaria, edema), respiratory (wheezing, dypsnea), and 
cardiovascular (hypotension, tachycardia).  Some reactions occurred on initial exposure.  
Reactions tended to occur within the first thirty minutes after administration and appeared to occur 
more frequently in those patients who received filgrastim intravenously.  Rapid resolution of 
symptoms occurred in most cases after administration of standard supportive care, and symptoms 
recurred in more than half the patients when rechallenged. 
 
3. 
LENALIDOMIDE (REVLIMID®) 
Formulation: A thalidomide analogue, is an immunomodulatory agent with anti-angiogenic 
properties. The chemical name is 3-(4-amino-1-oxo 1,3-dihydro -2H-isoindol-2-yl) piperidine-2,6-
dione and the gram molecular weight is 259.3. The mechanism of action of lenalidomide remains 
to be fully characterized. Lenalidomide possesses immunomodulatory and antiangiogenic 
properties. Lenalidomide inhibited the secretion of proinflammatory cytokines and increased the 
secretion of anti-inflammatory cytokines from peripheral blood mononuclear cells. Lenalidomide 
inhibited the expression of cyclooxygenase-2 (COX-2) but not COX-1 in vitro. Lenalidomide, in 
healthy volunteers, is rapidly absorbed following oral administration with maximum plasma 
concentrations occurring between 0.625 and 1.5 hours post-dose. Co administration with food 
does not alter the extent of absorption (AUC) but does reduce the maximal plasma concentration 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
27 
 
 
 
 
(Cmax) by 36%. The pharmacokinetic disposition of lenalidomide is linear. Cmax and AUC 
increase proportionately with increases in dose. Multiple dosing at the recommended dose-
regimen does not result in drug accumulation. In multiple myeloma patients maximum plasma 
concentrations occurred between 0.5 and 4.0 hours post-dose both on Days 1 and 28. AUC and 
Cmax values increase proportionally with dose following single and multiple doses. Exposure 
(AUC) in multiple myeloma patients is 57% higher than in healthy male volunteers. 
 
Availability: Lenalidomide (REVLIMID®) is available in 5, 10, 15 and 25 mg capsules for oral 
administration. Each capsule contains lenalidomide as the active ingredient and the following 
inactive ingredients: lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, and 
magnesium stearate. The 5 mg capsule shell contains gelatin, titanium dioxide and black ink. The 
10 mg capsule shell contains gelatin, FD&C blue #2, yellow iron oxide, titanium dioxide and black 
ink. Lenalidomide is an off-white to pale-yellow solid powder. It is soluble in organic solvent/water 
mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in organic solvents and 
low pH solutions. Solubility was significantly lower in less acidic buffers, ranging from about 0.4 
to 0.5 mg/ml. Lenalidomide has an asymmetric carbon atom and can exist as the optically active 
forms S(-) and R(+), and is produced as a racemic mixture with a net optical rotation of zero.  
 
Administration: Lenalidomide (REVLIMID®) is administered as an oral route, preferably at the 
same time. 
 
Potential and Expected Toxicities: Hematologic: anemia, neutropenia, leucopenia, 
lymphopenia and thrombocytopenia; thromboembolic events (deep vein thrombosis and 
pulmonary embolism). Neurologic: Somnolence, dizziness, headache, confusion, tremor, loss of 
co-ordination, asthenia, paresthesia, numbness, and leukoencephalopathy (radiographic 
findings). Gastrointestinal: Constipation, dehydration, dry mouth, diarrhea, dyspepsia, nausea, 
vomiting and stomatitis. Constitutional: Weakness, insomnia, rigors, chills, sweating, weight loss 
and fever. Reproductive: teratogenicity and miscarriage. Musculoskeletal: arthralgia, back/neck 
pain, joint pain, muscle cramp and weakness. Cardiac: hypotension. Dermatologic: rash, dry skin, 
itching. Endocrine: hypothyroidism. Infection. Pulmonary: cough, dyspnea. Metabolic: 
hypokalemia, liver damage. Renal: increased creatinine, renal failure.  
 
Note: Pregnancy reporting: Due to its structural similarities to thalidomide, a known human 
teratogen, lenalidomide is contraindicated in pregnant women and women capable of 
becoming pregnant. When there is no alternative, females of childbearing potential may be 
treated with lenalidomide provided adequate precautions are taken to avoid pregnancy. Females 
must commit either to abstain continuously from heterosexual sexual intercourse or to use two 
methods of reliable birth control, including at least one highly effective method (e.g., IUD, 
hormonal contraception, tubal ligation, or partner’s vasectomy) and one additional effective 
method (e.g., latex condom, diaphragm, or cervical cap), beginning 4 weeks prior to initiating 
treatment with REVLIMID® (lenalidomide), during therapy with REVLIMID® (lenalidomide), 
during therapy delay, and continuing for 4 weeks following discontinuation of REVLIMID® 
(lenalidomide) therapy. If hormonal or IUD contraception is medically contraindicated, two other 
effective or highly effective methods may be used. 
 
Note: Deep Venous Thrombosis and Pulmonary Embolism: lenalidomide has demonstrated a 
significantly increased risk of DVT and PE in patients with multiple myeloma who were treated 
with REVLIMID® (lenalidomide) combination therapy. Patients and physicians are advised to 
be observant for the signs and symptoms of thromboembolism. Patients should be instructed to 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
28 
 
 
 
 
seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or 
leg swelling.  
  
5.3.4 Study Drug: MK-3475 (Pembrolizumab) 
5.3.4.1 Description  
MK-3475 is a potent humanized IgG4 monoclonal antibody with high specificity of binding to the 
PD-1receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based on preclinical in vitro 
data, MK-3475 has high affinity and potent receptor blocking activity for PD-1. 
MK-3475 has an acceptable preclinical safety profile. 
 
MK-3475 is a humanized anti-PD-1 mAb of the IgG4/kappa isotype with a stabilizing S228P 
sequence alteration in the fragment crystallizable (Fc) region. MK-3475 binds to human PD-1 and 
blocks the interaction between PD-1 and its ligands. The theoretical molecular weight of the 
polypeptide is 146,288 Da and its theoretical pI is 7.5. The parental murine anti-human PD-1 
antibody (hPD-1.09A) was produced by immunizing mice with hPD-1 DNA. The MK-3475 
antibody was generated by humanization of the parental antibody by the Medical Research 
Council (Cambridge, UK) using complementarily-determining region (CDR) grafting technology 
(U.S. Patent No. 5,225,539). The gene segments encoding the variable heavy and light chains of 
MK- 3475, as well as human IgG4, were codon-optimized, synthesized, and ligated into a vector. 
 
A single expression plasmid, pAPD11V1-GA was constructed for the expression of both the heavy 
and light antibody chains of MK-3475. The nucleotide sequences encoding the heavy and light 
chains, along with their respective promoters and poly A signal sequences have been confirmed 
by DNA sequence analysis. The pAPD11V1-GAexpression vector was subsequently used to 
transfect CHO-DXB-11 cells for the development of the MK-3475-producing cell line. 
 
5.3.4.2 Formulation  
 
MK-3475 Solution will be used. Refer to the Investigator Brochure (IB). 
 
5.3.4.3 Storage  
MK-3475 Solution is stored under refrigerated conditions (2°C - 8°C).  Refer to the IB. 
 
5.3.4.4 Administration   
MK-3475 is administered as a 30-minute IV infusion. Refer to the IB.  
 
5.3.4.5 Dose Selection 
 
Dose Selection Rationale 
The dose regimen of 200 mg Q3W of MK-3475 is planned for all urothelial cancer trials. Available 
PK results in subjects with melanoma, NSCLC, and other solid tumor types support a lack of 
meaningful difference in PK exposures obtained at a given dose among tumor types. An open-
label Phase 1 trial (PN001) in melanoma subjects is being conducted to evaluate the safety and 
clinical activity of single agent MK-3475.  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 maximum tolerated dose (MTD) has been identified. 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
29 
 
 
 
 
 
In KEYNOTE-001, two randomized cohort evaluations of melanoma subjects receiving 
pembrolizumab at a dose of 2 mg/kg versus 10 mg/kg Q3W have been completed.  The clinical 
efficacy and safety data demonstrate a lack of clinically important differences in efficacy response 
or safety profile at these doses.  For example, in Cohort B2, advanced melanoma subjects who 
had received prior ipilimumab therapy were randomized to receive pembrolizumab at 2 mg/kg 
versus 10 mg/kg Q3W.  The overall response rate (ORR) was 26% (21/81) in the 2mg/kg group 
and 26% (25/79) in the 10 mg/kg group (full analysis set (FAS)).  The proportion of subjects with 
drug-related adverse events (AEs), grade 3-5 drug-related AEs, serious drug-related 
SAEs, death or discontinuation due to an AE was comparable between groups or lower in the 10 
mg/kg group.   
Available pharmacokinetic results in subjects with melanoma, NSCLC, and other solid tumor 
types support a lack of meaningful difference in pharmacokinetic exposures obtained at a given 
dose among tumor types.  Population PK analysis has been performed and has confirmed the 
expectation that intrinsic factors do not affect exposure to MK-3475 to a clinically meaningful 
extent.  Taken together, these data support the use of lower doses (with similar exposure to 2 
mg/kg Q3W) in all solid tumor indications.  2 mg/kg Q3W is being evaluated in NSCLC in PN001, 
Cohort F30 and PN010, and 200 mg Q3W is being evaluated in head and neck cancer in PN012, 
which are expected to provide additional data supporting the dose selection. 
Selection of 200 mg as the appropriate dose for a switch to fixed dosing is based on simulation 
results indicating that 200 mg will provide exposures that are reasonably consistent with those 
obtained with 2 mg/kg dose and importantly will maintain individual patient exposures within the 
exposure range established in melanoma as associated with maximal clinical response.  A 
population PK model, which characterized the influence of body weight and other patient 
covariates on exposure, has been developed using available data from 476 subjects from 
PN001.   The distribution of exposures from the 200 mg fixed dose are predicted to considerably 
overlap those obtained with the 2 mg/kg dose, with some tendency for individual values to range 
slightly higher with the 200 mg fixed dose.   The slight increase in PK variability predicted for the 
fixed dose relative to weight-based dosing is not expected to be clinically important given that the 
range of individual exposures is well contained within the range of exposures shown in the 
melanoma studies of 2 and 10 mg/kg to provide similar efficacy and safety.  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 tumor types and indication settings.  
The treatment to be used in this study is outlined below in Table 2. 
Table 2:  Study Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
MK-3475 
(Pembrolizumab) 
200 mg 
Every 3 
weeks (+/- 
4 days) 
IV infusion 
Starting day +14 for 
a total of 9 doses 
Experimental 
The MK-3475 dosing interval may be increased due to toxicity as described in Section 5.3.4.8 (Table 4 
and 5) 
 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
30 
 
 
 
 
A fixed dose of 200 mg/day 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). 
 
Premedication per institutional guidelines for monoclonal antibodies (e.g. acetaminophen and 
antihistamine) is allowed. Steroid premedication is not indicated and should be avoided. 
 
 
5.3.4.6 Timing of Dose Administration 
MK-3475 will be started on “day +14 post-transplant” AND “after all assessments prior to the first 
dose of MK-3475” have been completed as detailed in Table 1 and the Study Flow Chart (Section 
6.0).   
 
The criteria to initiate the first dose of MK-3475 on day 14 in Table 1 are NOT required or 
applicable to 8 subsequent doses of MK-3475. Refer to the Study Flow Chart (Section 6.0), 
Section 5.3.4.7 (Event of Clinical Interest (ECI) and immune-related Adverse Event (irAE)) and 
Section 5.3.4.8 (Dose Modification) for required assessments prior to and managements of 8 
subsequent doses of MK-3475, respectively. 
 
 
MK-3475 may be administered up to +/- 4 days of each dose of MK-3475 due to clinical and 
administrative reasons. 
 
MK-3475 will be administered on an outpatient basis, but may be administered during transplant 
admission as appropriate. 
 
5.3.4.7 Event of Clinical Interest (ECI) and immune-related Adverse Event (irAE) 
An ECI is defined as an immune-related adverse event (irAE) that is considered MK-3475 
related, after other causes are excluded. 
 
An irAE is defined as a clinically significant AE of any organ system that is associated with MK-
3475 exposure and is consistent with an immune-related mechanism. irAEs were reported in 
21.4% of melanoma patients; most of these events (15.8%) were considered drug-related by the 
investigator. The most commonly reported irAEs across the dose schedules are rash (3.2%), 
pruritus (2.9%), vitiligo (2.9%), hypothyroidism (2.7%), arthralgia (2.2%), diarrhea (2.2%), and 
pneumonitis (1.9%). The organ most frequently affected by irAEs with MK-3475 is the skin. Less 
frequently affected tissues include thyroid gland, colon, lung, kidney, and liver. Severe but rare 
irAEs include Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) and 
immune-mediated myocarditis. 
 
 
ECI/irAEs can be categorized according to organ systems or syndromes (see the Manual 
“Pembrolizumab Program (MK-3475): Event of Clinical Interest Guidance Document”). 
 
ECI/irAEs must be reported to Merck according to the Manual “Pembrolizumab Program (MK-
3475): Event of Clinical Interest Guidance Document” within a specified time period (e.g. within 
24 hours according to the Document Version most updated. See Section 7.2.3.2 for reporting 
procedure.


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
31 
 
 
 
 
5.3.4.8 Dose Modification 
 
For immune-related AEs, including immune-related hematologic AEs (e.g. autoimmune 
hemolytic anemia, immune thrombocytopenic purpura etc.), dose modification and management 
will follow the Manual “Pembrolizumab Program (MK-3475): Event of Clinical Interest Guidance 
Document”. 
 
For non-immune-related hematological AEs (e.g. neutropenia, thrombocytopenia etc.) dose 
modification and management will follow Table 4 below. Determination of immune related  versus 
non-immune-related etiology is at the investigator’s discretion. 
 
For SJS, TEN and immune-mediated myocarditis, see the Investigator Brochure for 
management. 
 
Recommendations to managing irAEs and any AEs not detailed in the Manual are provided in 
Table 5. (5.5.2) 
For subjects who are receiving maintenance treatment, lenalidomide will be withheld before or at 
the same time of MK-3475 withhold at the investigator’s discretion.  Determination of cause-effect 
relationship of AEs (lenalidomide versus MK-3475) is at investigator’s discretion. 
Table 4: Dose Modification Guidelines for Non-Immune-Related Hematological Drug-
Related Adverse Events 
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
restarting 
treatment 
Dose/Schedule 
for restarting 
treatment 
Discontinue 
Subject (after 
consultation 
with PI) 
Non-immune-related 
Hematological Toxicity 
(e.g. neutropenia, 
thrombocytopenia, 
etc.) 
 
1, 2, 3 
No 
N/A 
N/A 
N/A 
4  
Yes 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
May increase 
the dosing 
interval by 1 
week. 
Toxicity does 
not resolve 
within 4 weeks 
of last infusion 
Permanent 
discontinuation 
should be 
considered for 
any severe or 
life-threatening 
event 
 
5.4 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during 
the ongoing study. If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the study, discontinuation from study therapy or 
vaccination may be required. The investigator/Institution should discuss any questions regarding 
this with the Merck. The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician. However, the decision to continue the subject 
on study therapy or vaccination schedule requires the mutual agreement of the Investigator, 
Merck, and the subject. 
 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
32 
 
 
 
 
5.4.1 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 BMT community standards 
of medical care. All concomitant medication will be captured in patient medical record including 
all prescription, over-the-counter (OTC), herbal supplements, and IV medications and fluids. If 
changes occur during the study period, documentation of drug dosage, frequency, route, and date 
may also be included on the CRF. Only the concomitant medications taken during any SAEs or 
ECI/ irAEs will be recorded on the Case Report Form (CRF).  
 
All concomitant medications received within 28 days before the first dose of MK-3475 (or ~14 
days prior to transplant) and 30 days after the last dose of MK-3475 should be captured in patient 
medical record. 
 
Glucocorticoid up to an equivalent dose of prednisolone 30 mg/day for 5 days is allowed for the 
treatment of engraftment syndrome. See glucocorticoid dosing for suspected acute infusion 
reactions (see 5.5.1 and the Manual “Pembrolizumab Program (MK-3475): Event of Clinical 
Interest Guidance Document)) and immune-related adverse reactions (see 5.5.2, 5.5.3 and the 
Manual “Pembrolizumab Program (MK-3475): Event of Clinical Interest Guidance Document). 
 
As stated above, any treatments, including systemic glucocorticoid, which the investigator 
considers necessary for a subject’s welfare may be administered at the discretion of the 
investigator in keeping with the BMT community standards of medical care. 
 
Thus, inevitable systemic corticosteroid treatment for a subject’s welfare is NOT considered a 
protocol violation or deviation. 
 
5.4.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies not specified in the study protocol 
during the Study Treatment Period: 
 
• 
 Anti-multiple myeloma systemic chemotherapy or biological agents not specified in this 
protocol: 
 
IMiDs (lenalidomide other than maintenance therapy specified in this protocol, 
thalidomide, pomalidomide), proteasome inhibitors (bortezomib, carfilzomib) and other 
new related targeted biologic agents. 
 
• 
Glucocorticoids for any purpose should be avoided. 
 
EXCEPT for the following conditions: 
o Engraftment syndrome as specified in this protocol 
o Acute infusion reactions as specified in Section 5.5.1 
o Event of clinical interest / immune-related adverse events (ECI / irAEs) as specified 
in Section 5.5.2 and Section 5.5.3 
o Adrenal insufficiency supplement with physiologic glucocorticoid dose at an 
investigator’s discretion 
 
However, as stated above, any treatments, including systemic glucocorticoid, which the 
investigator considers necessary for a subject’s welfare may be administered at the discretion 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
33 
 
 
 
 
of the investigator in keeping with the BMT community standards of medical care. Thus, 
inevitable systemic corticosteroid treatment for a subject’s welfare is NOT considered a 
protocol violation or deviation. 
 
• 
Sargramostin (Granulocyte/Macrophage-Colony Stimulating Factor: GM-CSF) 
 
• 
Warfarin 
• 
Immunotherapy not specified in this protocol 
 
• 
Any chemotherapy not specified in this protocol 
 
• 
Investigational agents other than MK-3475 
 
• 
Radiation therapy 
 
Radiation therapy to a symptomatic solitary lesion may be allowed after consultation with 
Investigator/Institution. Disease progression must be investigated accordingly. 
 
• 
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, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. 
Seasonal influenza vaccines for injection are generally killed virus vaccines and are 
allowed; however intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated 
vaccines, and are not allowed. 
  
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 study.  Subjects may receive 
other medications that the investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications that are prohibited in this study. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.5 
Rescue Medications & Supportive Care 
5.5.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator, including but not limited to, the common items outlined below: 
 
 
 
1. 
Diarrhea: 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, blood or mucus in stool, with or without fever) and of bowel perforation (such as 
peritoneal signs and ileus).  
 
In symptomatic subjects, standard post-transplant workup e.g. infectious etiologies must be 
performed, and if symptoms are persistent and/or severe, endoscopic evaluation should be 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
34 
 
 
 
 
considered before the diagnosis of MK-3475-related immunologic reaction is made. Information 
on how to identify and evaluate irAEs has been developed and is included in “the Manual 
“Pembrolizumab Program (MK-3475): Event of Clinical Interest Guidance Document” located in 
the Administrative Binder. 
 
All subjects who experience diarrhea should be advised to drink liberal quantities of clear fluids.  
If sufficient oral fluid intake is not feasible, fluid and electrolytes should be replaced via IV infusion. 
 
2. 
Nausea/vomiting:  
Nausea and vomiting should be treated aggressively, and consideration should be given in 
subsequent cycles to the administration of prophylactic antiemetic therapy according to standard 
institutional practice.  Subjects should be strongly encouraged to maintain liberal oral fluid intake. 
 
3. 
Infections:  
Subjects with a documented or suspicious infectious complication should receive oral or IV 
antibiotics or other anti-infective agents as considered appropriate by the treating investigator for 
a given infectious condition, according to standard institutional practice. 
 
4. 
Immune-related adverse events:  
See Section 5.5.2 and the Manual “Pembrolizumab Program (MK-3475): Event of Clinical Interest 
Guidance Document in the administrative binder regarding diagnosis, report and management of 
adverse experiences of a potential immunologic etiology. 
 
5. 
Acute Infusion Reactions: 
Acute infusion reactions, which may include cytokine release syndrome, angioedema and 
anaphylaxis, are different from allergic/hypersensitive reactions, although some of the 
manifestations are common to both AEs. 
Signs and symptoms usually develop during or shortly after MK-3475 infusion and generally 
resolve completely within 24 hours of completion of infusion. 
Signs/symptoms of acute infusion reactions may include:  
- 
Allergic reaction/hypersensitivity (including drug fever), rigors/chills, pruritus/itching, 
myalgia, urticaria (hives, welts, wheals) 
- 
Arthralgia (joint pain), fatigue (asthenia, lethargy, malaise) 
- 
Rash/desquamation 
- 
Bronchospasm; Cough; Dyspnea (shortness of breath) 
- 
Dizziness 
- 
Headache 
- 
Hypertension, hypotension, tachycardia 
- 
Nausea/ vomiting 
- 
Sweating (diaphoresis) 
- 
Tumor pain (onset or exacerbation of tumor pain due to treatment) 
 
See the Manual “Pembrolizumab Program (MK-3475): Event of Clinical Interest Guidance 
Document for diagnosis, report and management of acute infusion reactions. 
 
5.5.2  Supportive Care Guidelines for Events of Clinical Interest (ECI) and Immune-related 
Adverse Events (irAEs) 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
35 
 
 
 
 
 
An Event of clinical interest (ECI) of a potential immunologic etiology (irECIs) may be defined as 
an adverse event of unknown etiology, associated with MK-3475 exposure and is consistent with 
an immune phenomenon.  
irAEs may be predicted based on the nature of the MK-3475 compound, its mechanism of action, 
and reported experience with other immunotherapies that have a similar mechanism of action. 
Special attention should be paid to AEs that may be suggestive of potential irAEs.   
An irAE can occur shortly after the first dose or several months after the last dose of treatment. 
If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, toxin 
or other etiologic causes prior to labeling an adverse event as an irAE. Information on how to 
identify and evaluate irAEs has been developed and is included in the Manual “Pembrolizumab 
Program (MK-3475): Event of Clinical Interest Guidance Document located in the Administrative 
Binder. 
Subjects who develop a Grade 2 or higher irAE should be discussed immediately with 
Investigator/Institution and Merck.  
**For subjects who are receiving maintenance treatment, lenalidomide will be withheld before or 
at the same time of MK-3475 withhold at the investigator’s discretion.  Determination of cause-
effect relationship of AEs (lenalidomide versus MK-3475) is at investigator’s discretion. 
Recommendations to managing irAEs not detailed elsewhere in the protocol or the Manual 
“Pembrolizumab Program (MK-3475): Event of Clinical Interest Guidance Document are detailed 
in Table 5. 
Table 5: General Approach to Handling irAEs and any AEs NOT specified in the Manual 
“Pembrolizumab Program (MK-3475): Event of Clinical Interest Guidance Document” 
irAE 
Withhold/Discontinue 
Managements 
Grade 1 
No action 
Provide symptomatic treatment. 
Grade 2 
Withhold until resolving to 
Grade 1. 
Consider systemic corticosteroids as per Grade 
3, irAEs in addition to appropriate symptomatic 
treatment. 
May increase dosing interval by 1 week  (every 
4 weeks) after resolving to Grade 1 or less. 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
36 
 
 
 
 
Grade 3 
 
 
 
Withhold until resolving to 
Grade 1. 
Discontinue if unable to 
reduce corticosteroid 
dose to < 10 mg per day 
prednisone equivalent 
within 12 weeks of 
toxicity. 
Systemic corticosteroids are indicated in 
addition to appropriate symptomatic treatment. 
Prednisone 1-2 mg/kg/day or equivalent 
Add anti-inflammatory e.g. infliximab, if not 
improving in 48-72 hours. 
Steroid taper should be considered once 
symptoms improve to Grade 1 or less and 
tapered over at least 4 weeks. 
May increase dosing interval by 1 week  (every 
4 weeks) after resolving to Grade 1 or less. 
Grade 4 
Discontinue permanently 
Systemic corticosteroids are indicated 
Methylprednisolone 125 mg IV or prednisone 1-
2 mg/kg/day or equivalent, then follow the ECI 
Guidance Document. 
Add anti-inflammatory e.g. infliximab, if not 
improving in 48-72 hours. 
 
5.5.3 Management Guidelines for Pneumonitis 
Subjects with symptomatic pneumonitis should immediately stop receiving MK-3475 and have an 
evaluation. The evaluation may include bronchoscopy with bronchoalveolar lavage to rule out 
other causes such as infection. Management, report and dose modification will follow the Manual 
“Pembrolizumab Program (MK-3475): Event of Clinical Interest Guidance Document”.. 
 
**For subjects who are receiving maintenance treatment, lenalidomide will be withheld before or 
at the same time of MK-3475 withhold at the investigator’s discretion.  Determination of cause-
effect relationship of AEs (lenalidomide versus MK-3475) is at investigator’s discretion 
 
5.5.4   Diet/Activity/Other Considerations 
 
 
1. 
Diet 
Subjects should maintain a diet according to institutional guidelines for autologous transplant, 
unless modifications are required to manage an AE such as diarrhea, nausea or vomiting. 
 
 
2. 
Contraception 
In general, pregnancy is a contraindication for receiving high-dose melphalan and autologous 
transplant; however, becoming pregnant after transplant is not impossible in the first 6-12 months 
post-transplant. 
 
MK-3475 may have adverse effects on a fetus in utero. Furthermore, it is not known if MK-3475 
has transient adverse effects on the composition of sperm.  
 
Non-pregnant, non-breast-feeding women of child-bearing potential may be enrolled 1) if they are 
willing to use 2 methods of birth control until 120 days after the planned last dose of MK-3475 or 
2) if they are considered highly unlikely to conceive. 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
37 
 
 
 
 
Highly unlikely to conceive is defined as 1) surgically sterilized, or 2) postmenopausal (a woman 
who is ≥45 years of age and has not had menses for greater than 2 years will be considered 
postmenopausal), or 3) not heterosexually active for the duration of the study. 
 
Subjects should start using birth control from study visit 1 (first dose of MK-3475 treatment) 
throughout the study period up to 120 days after the last dose of MK-3475 therapy. 
 
The two birth control methods can be either  
1) two barrier methods or  
2) a barrier method plus a hormonal method to prevent pregnancy 
 
The following are considered adequate barrier methods of contraception: diaphragm, condom (by 
the partner), copper intrauterine device, sponge, or spermicide.   
 
Appropriate hormonal contraceptives will include any registered and marketed contraceptive 
agent that contains an estrogen and/or a progestational agent (including oral, subcutaneous, 
intrauterine, or intramuscular agents). 
 
Subjects should be informed that taking MK-3475 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 must adhere to the contraception requirement as 
described above for the duration of the study and during the follow-up period defined in the section 
7.2.2 – “Reporting of Pregnancy and Lactation to the Investigator/Institution and to Merck”. If there 
is any question that a subject will not reliably comply with the requirements for contraception, that 
subject should not be entered into the study. 
 
Subjects receiving standard lenalidomide maintenance therapy must strictly follow contraception 
requirement per lenalidomide program as a standard of care. 
 
 
3. 
Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with MK-3475, the subject will 
immediately be removed from the study. 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 Investigator/Institution and to Merck without 
delay and within 24 hours if the 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 Investigator/Institution and to 
Merck. 
 
If a male subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to the Investigator/Institution and to Merck and followed 
as described above and in Section 7.2.2. 
 
 
4. 
Use in Nursing Women 
It is unknown whether MK-3475 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. 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
38 
 
 
 
 
 
5.6 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be removed from the study at the 
discretion of the investigator should any untoward effect occur. In addition, a subject may be 
withdrawn by the investigator if enrollment into the study is inappropriate, the study plan is 
violated, or for administrative and/or other safety reasons. Specific details regarding 
discontinuation or withdrawal are provided in Section 7.1.4. 
 
Subjects who complete 9 doses of MK-3475 will be considered having completed the study 
treatment. 
 
A subject must be discontinued from the study for any of the following reasons: 
• 
Current planned autologous hematopoieitic cell transplant does not occur. 
• 
The subject or legal representative (such as a legal guardian) withdraws consent. 
• 
Confirmed disease progression 
• 
Unacceptable adverse experiences as described. 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Noncompliance with study treatment or procedure requirements 
• 
Investigator’s decision to withdraw the subject 
• 
The subject is lost to follow-up 
• 
The subject has a confirmed positive serum pregnancy test 
• 
Administrative reasons 
 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow Chart) 
and Section 7.1.5 (Study Visit Requirements). 
 
Evaluable subjects who received at least 2 doses of MK-3475 will have End of Treatment 
Evaluation (Table 8). They will have Follow-up visit and Survival Follow-up procedures per Table 
8, starting 8 weeks after End of Treatment Evaluation. 
 
Non-evaluable subjects who received less than 2 doses of MK-3475 will not have the “Efficacy 
Assessments” or the “Tumor Biopsies/Archival Tissue Collection/Correlative Studies” as parts of 
End of Treatment Evaluation (Table 8). They will have Follow-up visit and Survival Follow-up 
procedures per Table 8, starting 8 weeks after End of Treatment Evaluation. 
 
Non-evaluable subjects who have never received MK-3475 will NOT have End of Treatment 
Evaluation or Follow-up visit or Survival Follow-up procedures per Table 8. 
 
 
All subjects will be followed for disease status for at least 3 years after transplant (See Table 6: 
Study Flow Chart) or until disease progression, initiating a non-study multiple myeloma treatment 
(except maintenance therapy as specified in this protocol), 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. 
 
5.7 
Subject Replacement Strategy 
 
The following subjects will be replaced: 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
39 
 
 
 
 
 
1. 
Subjects who were screened and signed consent but received less than 2 doses of 
MK-3475 (non-evaluable subjects). 
2. 
Subjects who are poor adherence to protocol and regulatory requirements or who are 
lost to follow-up prior to the end-of-study evaluation after the completion of MK-3475 
treatment  
3. 
Quality or quantity of data recording is inaccurate or incomplete 
 
5.8 
Clinical Criteria for Early Study 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 reaction indicates a potential health hazard to 
subjects. 
 
5.9 
Plans to Modify or Discontinue the Development of the MK-3475 
 
In the event of Merck decision to no longer supply MK-3475, ample notification will be provided 
so that appropriate adjustments to subject treatment can be made. 
 
5.10 Definition of Endpoints 
 
5.10.1 
SAFTY ENDPOINTS 
 
 
1. 
ENGRAFTMENT and GRAFT FAILURE 
 
 
Neutrophil engraftment day will be defined as the first day of the 3 consecutive days (or 
of the 3 consecutive tests for >3 day-duration) of achieving an absolute neutrophil count (ANC) 
>500/uL. 
 
 
Platelet engraftment day will be defined as the first day of the 2 consecutive days (or of 
the 2 consecutive tests for >2 day duration) of achieving platelet count >20,000/uL, without 
transfusion support. 
 
 
Primary graft failure will be defined as the inability to maintain an ANC >500/uL AND a 
platelet count >20,000/uL, without transfusion support and without other causes, e.g. viral 
infection, other known myelosuppressive medication or multiple myeloma progression, in a 
subject who survives 35 days after transplant. 
 
 
Secondary graft failure will be defined as a decline of ANC to <500/uL after having 
engrafted that is unresponsive to growth factors, without other causes, e.g. viral infection, other 
known myelosuppressive medication or multiple myeloma progression. 
 
 
2. 
REGIMEN-RELATED TOXICITY [RRT] 
An RTT is defined as an adverse event (AE) that occurs during the period right after the first dose 
of MK-3457 (day 14 +/- 4) until 14 days thereafter (day 28 +/-4), and is considered to be a direct 
consequence and a related event as a result of the combination of conditioning chemotherapy, 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
40 
 
 
 
 
and MK-3475. 
 
3. 
TREATMENT-RELATED MORTALITY [TRM] 
TRM is defined as any death due to the transplant procedure, including death attributable directly 
to MK-3475 therapy. Death due to, but not limited to, the following events are considered a TRM: 
general transplant complications (e.g. infection, graft failure), RRT and Event of Clinical Interest 
(ECI) and immune-related AEs (irAEs).. 
 
5.10.2 
 EFFICACY ENDPOINTS 
 
 
1. 
RELAPSE / PROGRESSION 
 
See Appendix 13.3 for the definitions of Multiple Myeloma Response Criteria, including 
relapse/progression. 
 
2. 
PROGRESSION-FREE SURVIVAL [PFS] 
PFS is defined as the period from transplant day 0 to the day of the first Progression /Relapse. 
 
 
3. 
OVERALL SURVIVAL [OS] 
OS is defined as the period from transplant day 0 to the day of death from any cause. 
 
5.10.3        CORRELATIVE STUDIES 
 
The following correlative studies are planned; however, failure to obtain peripheral blood 
hematopoietic stem cell graft tissue and post transplant blood samples at specified time points is 
not a study violation as these studies are not primary endpoints. 
 
5.10.3.1  Pre-transplant phenotypic analysis of autologous graft tissue 
 
5.10.3.2  Quantitative ex vivo Immune Function Recovery Assays 
1) Lymphocyte subset recovery in anti-PD-1 enhanced HDT/ASCT 
2) Functional measurements of T cell subtypes and cytokine profiles 
3) NK cell cytotoxicity 
 
 
Table 6: Correlative Study: Medical College of Wisconsin Laboratory of Bryon D. Johnson, 
Ph.D. 
 
Biomarker name 
Assay 
Tissue/Body Fluid Tested 
and Timing of Assay 
Lymphocyte content of autologous 
graft pre-transplant  
 
Flow cytometry: Quantify activated and 
effector CD4+ and CD8+ cells, NK cells, 
and regulatory T and B cells.  
Graft tissue: pre-transplant day 0 or 
previously frozen samples 
 
 
 
 
 
 
 
 
 
 
 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
41 
 
 
 
 
Table 7: Correlative Studies: University of Michigan Laboratory of Steven K. Lundy, Ph.D. 
 
Biomarker name 
Assay 
Tissue/Body Fluid Tested 
and Timing of Assay 
Lymphocyte recovery in anti-PD-1 
enhanced HDT-ASCT  
 
Flow cytometry: Quantify activated and 
effector CD4+ and CD8+ cells, NK cells, 
and regulatory T and B cells.  
PBMC: pre-chemotherapy, day 14 post-
transplant [before first dose of anti-PD-1] 
and day 100±7 and day 182±7 post-
transplant 
Functional T cell subtypes and cytokine 
profiles  
 
 
Cytokine profiling: Intracellular IFN-α, 
IFN-γ (flow cytometry), cytokine release 
spectrum 
(Luminex), 
TH 
subset 
transcription factor profiling (Q-PCR)  
PBMC: pre-chemotherapy, day 14 post-
transplant [before first dose of anti-PD-1], 
day 100±7 post-transplant, and day 182±7 
post-transplant 
NK cell cytotoxicity   
 
 
Intracellular granzyme B (flow cytom), 
flow cytometric analysis of tumor cell 
death  
PBMC: day 100±7 post-transplant, and day 
182±7 post-transplant 
5.10.3.3 Sample collection  
We will obtain heparinized (green top; approximately 15 mL total/sample) peripheral blood 
hematopoietic stem cell graft tissue sample on day 0 or previously frozen graft sample and 
peripheral blood samples approximately on day +14 [or before the first dose of MK-3475], day 
100±7 post-transplant and at early termination, if any, or day 182±7 post-transplant from each 
patient for the flow cytometric study of immune recovery and ex vivo T cell function. NK cytotoxicity 
measurements will be performed on the day +100+7 and day 182±7 time points using an 
additional 15 mL/patient blood draw. [Schema]  
Samples [a 15-30 mL extra blood draw each; limit to maximal volume allowed per Institutional 
Policy)] will be collected coincidently with routine daily blood draws on the patients during 
transplant admission and clinic visits. All University of Michigan samples will be processed on the 
day of collection. Additional samples received from the Medical College of Wisconsin will be 
shipped overnight on wet ice and processed within 24 hours of being drawn. Plasma will be 
banked and frozen for analysis of anti-PD-1 antibody titers and other parameters if indicated. 
Leukocytes will be isolated by Ficoll gradient centrifugation and used for phenotypic and functional 
analyses described below.  Previously frozen graft samples will be shipped frozen. 
5.10.3.4  Flow cytometry 
Lymphocyte repopulation in peripheral blood and analysis of the peripheral blood graft tissue 
specimens will be assessed by multi-color flow cytometry using the cell surface and intracellular 
markers. For surface marker only staining, 2×105 PBMC will be stained with each panel and 
2×104 cells will be analyzed. Antibody panels are designed to include markers of activated T 
cells, as well as regulatory and cytotoxic T and B cell subsets. CXCR4 expression will be 
determined as a marker for bone marrow homing potential. For intracellular cytokine staining, 
5×106 PBMC will be stimulated for 3 days with anti-CD3 and anti-CD28 with the addition of 
brefeldin A for the last 5 hours to stop cytokine release. Cytotoxic cells will be stimulated for 3 
days with recombinant human IL-2 prior to staining for intracellular granzyme B and Fas ligand 
expression. Isotype control antibody staining will be used as control for non-specific binding of 
the intracellular markers. 
 
5.10.3.5 Cytokine release  
Cytokine production by PBMC will be analyzed at all time points. Culture supernatants will be 
collected from anti-CD3 and anti-CD28 stimulated PBMC (1×106 cells/mL) after 5 days of culture. 


Phase 2 Study of Anti-PD-1 After Autologous Transplant for Multiple Myeloma 
42 
 
 
 
 
Released cytokines will be measured by Luminex Cytokine Human 10-Plex Panel (Life 
Technologies). This panel simultaneously quantifies GM-CSF, IFNg, IL-1b, IL-2, IL-4, IL-5, IL-6, 
IL-8, IL-10, and TNFa in a single sample. 
 
5.10.3.6 Quantitative PCR  
The relative presence of CD4+ TH cell subsets (TH1, TH2, TH17, and Treg) in fresh 1 million freshly 
isolated PBMC will be determined at all time points using the Human T Helper Cell RT2 Profiler 
PCR Array (Qiagen-SABiosciences).[82] This array sensitively measures the mRNA levels of 84 
genes involved in TH cell differentiation without need of ex-vivo stimulation. 
 
5.10.3.7 Cytotoxicity assays  
Killer function of NK cells will be determined in patient samples collected on day 100+7 and day 
182+7 post-transplantation by flow cytometry.[83] Human multiple myeloma target cell lines 
(U266 and RPMI-8226) will be cocultured with CalceinAM-FITC-labeled patient PBMC for 4 hours. 
At the end of the coculture, NK cytotoxicity will be measured by labeling apoptotic cells with 7AAD 
and AnnexinV-APC and analysis by flow cytometry. 
 
5.10.3.8 Partnering PI experience and credentials:  
 
The laboratory correlative studies will be performed in the laboratories of Steven K. Lundy, 
Ph.D. and Bryon D. Johnson, Ph.D.  
Dr. Lundy is a Research Assistant Professor in the Department of Internal Medicine of the 
University of Michigan Medical School. Dr. Lundy has over 27 years of experience as a technician, 
trainee and faculty member working in the field of immunology research. He has a particularly 
high level of expertise in the cellular immunological assays outlined in this proposal. Dr. Lundy 
spent the earliest parts of his career performing chromium release assays to measure NK cell 
cytotoxicity of tumor target cells and mixed lymphocyte reactions. He has extensive experience 
in the cloning and functional characterization of human CD4+ and CD8+ T cells, as well as assays 
related to human prostate and lung cancer cell metastasis.[120,121] His doctoral work focused 
on TH cell death mediated by B cells in the S. mansoni worm egg granuloma model, with an 
emphasis on the role of Fas ligand-positive B cell subsets.[122,123] Dr. Lundy’s work continues 
to be focused on the interactions between killer lymphocytes and their targets.[124,125] His 
laboratory is well-equipped to compare the effects of treatment with anti-PD-1 antibodies on the 
phenotypes and functions of human T cells,[126] and the cytotoxic potential of NK cells in these 
patients. His laboratory is well-equipped to compare the effects of treatment with anti-PD-1 
antibodies on the phenotypes and functions of human T cells,[127] and the cytotoxic potential of 
NK cells in these patients[128].  
The Lundy laboratory does not have CLIA certification, and therefore, results will not be used for 
clinical diagnostics or for any purposes other than the research endpoints outlined in the 
protocol. 
Dr. Johnson is a Professor in the Department of Pediatrics at the Medical College of Wisconsin 
in Milwaukee. His laboratory recently generated new data using an animal model that shows 
blocking PD-1-Ligand on myeloma cells can promote elimination of the myeloma cells during 
lymhodepleted state in animals that had just been treated with a low dose of whole body 
irradiation. He was a recipient of 2012 Senior Research Grant Award from the Multiple Myeloma 
Research Foundation.


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