Phase II Study of Pembrolizumab in Multiple Myeloma Patients Relapsing After or Refractory to Anti-BCMA CAR-T Therapies
Phase: PHASE2
Conditions: Multiple Myeloma, Multiple Myeloma in Relapse, Multiple Myeloma, Refractory, Recurrent Plasma Cell Myeloma, Refractory Plasma Cell Myeloma
Sponsor: Alfred Chung, MD

Proprietary and Confidential
The information in this document is considered privileged and confidential and may not be disclosed to others except 
to the extent necessary to obtain Institutional Review Board approval and informed consent, or as required by federal 
and state laws.  Persons to whom this information is disclosed should be informed that this information is privileged 
and confidential and that it should not be further disclosed.
Phase II study of Pembrolizumab in Multiple Myeloma 
Patients Relapsing After or Refractory to Anti-BCMA CAR-T 
Therapies
Protocol Number:  CC #212530
Investigational Product(s):  pembrolizumab
Version Number:  1.8
Version Date:  04/24/2023
IND Number:  156292
NCT Number: NCT05191472
Principal Investigator (Sponsor-Investigator)
Alfred Chung, MD
University of California San Francisco
 
San Francisco, CA 94143
Statistician
Chiung-Yu Huang, PhD
Revision History
Version 1.0 
11/20/2020
Version 1.1
02/08/2021
Version 1.2
05/02/2021
Version 1.3
06/16/2021
Version 1.4
07/08/2021
Version 1.5
08/11/2021
Version 1.6
08/16/2021
Version 1.7
04/21/2022
Version 1.8
04/24/2023

UCSF Helen Diller Family Comprehensive Cancer Center
Version date: 04/24/2023
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Phase II – pembrolizumab
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Protocol Signature Page
1.
I agree to follow this protocol version as approved by the UCSF Protocol Review Committee 
(PRC), Institutional Review Board (IRB), and Data and Safety Monitoring Committee 
(DSMC). 
2.
I will conduct the study in accordance with Good Clinical Practices (ICH-GCP) and the 
applicable IRB, ethical, federal, state, and local regulatory requirements. 
3.
I certify that I, and the study staff, have received the required training to conduct this 
research protocol. 
4.
I agree to maintain adequate and accurate records in accordance with IRB policies, federal, 
state, and local laws, and regulations.
UCSF Principal Investigator 
Printed Name
Signature
Date

UCSF Helen Diller Family Comprehensive Cancer Center
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Phase II – pembrolizumab
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Abstract
Title
Phase II study of Pembrolizumab in Multiple Myeloma Patients 
Relapsing After or Refractory to Anti-BCMA CAR-T Therapies 
(abbreviated title: Pembrolizumab for relapsed myeloma after anti-
BCMA CAR-T)
Study Description
This is a single-arm, single-institution phase II study of the safety and 
efficacy of pembrolizumab in the treatment of relapsed/refractory 
multiple myeloma (RRMM) in patients who have relapsed or were 
refractory to anti-BCMA CAR-T therapies. A Simon’s minimax two-
stage design will be employed with Bayesian toxicity monitoring for 
assessment of adverse event data. We hypothesize that 
pembrolizumab will be able to elicit an overall response rate of 30% or 
better.
Phase of Study
Phase II
Investigational 
Products
Pembrolizumab
Study population
Patients ≥ 18 years of age with relapsed or refractory multiple 
myeloma after anti-BCMA CAR-T therapy
Primary Objective
To evaluate the efficacy of pembrolizumab therapy in patients who 
have relapsed MM after anti-BCMA CAR-T therapies. Specifically, we 
will examine the overall response rate (ORR), defined as the 
proportion of patients achieving a partial response (PR) or better 
based on IMWG criteria, after 4 cycles of pembrolizumab therapy.
Secondary 
Objectives

To evaluate the safety and tolerability of pembrolizumab in 
participants who relapsed or were refractory to anti-BCMA CAR-T 
therapies

To evaluate the depth of response for patients treated with 
pembrolizumab who had previously relapsed after or were 
refractory to anti-BCMA CAR-T therapies

To evaluate time-to-event outcomes, including time-to-next 
treatment (TNT), progression-free survival (PFS), and overall 
survival (OS) after initiation of pembrolizumab therapy
Sample Size
Stage 1: 15 participants
Stage 2: 10 participants
25-27 total participants expected
Duration of Study 
Treatment
Participants may continue study treatment for up to 2-years from the 
time of initiating treatment.

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Duration of Follow 
up
Participants will be followed for at least 30 days after last treatment or 
removal from study, or until death. Participants who have completed 
35 cycles of therapy or discontinued treatment for reasons other than 
disease progression will be followed for up to 1-year, until removal 
from study, start of new anti-cancer therapy, or death.

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List of Abbreviations
AE
adverse event
ALC
absolute lymphocyte count
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BCG
Bacillus Calmette–Guerin
BCMA
B-cell receptor maturation antigen
BMP
basic metabolic panel
BUN
blood urea nitrogen
CAR-T
chimeric antigen receptor T-cell
CBC
complete blood cell (count)
CD28
cluster of differentiation 28
CD3ζ
cluster of differentiation 3 zeta
CNS
central nervous system
CR
complete response
CRF
case report form
CRS
cytokine release syndrome
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
CTMS
Clinical Trial Management System
DILI
drug-induced liver injury (DILI)
DSMC
Data and Safety Monitoring Committee
DSMP
Data and Safety Monitoring Plan
ECIs
events of clinical interest
ECOG
Eastern Cooperative Oncology Group
FDA
Food and Drug Administration
FLC
free light chain
fT4
free thyroxine
GCP
Good Clinical Practice
GFR
glomerular filtration rate
HBcAb
Hepatitis B core antibody
HBsAb
Hepatitis B surface antibody
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HDFCCC
Helen Diller Family Comprehensive Cancer Center

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List of Abbreviations
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
ICANS
immune-effector cell-associated neurotoxicity syndrome
ICF
informed consent form
ICH
International Conference on Harmonization
IDS
Investigational Drug Services (UCSF)
Ig
immunoglobulin 
IgG4
immunoglobulin G4
IgV-type
immunoglobulin-variable–type
IMWG
International Myeloma Working Group
IND
investigational new drug application
IP
investigational product
irAE
immune-related adverse event
IRB
Institutional Review Board
IV
intravenous
LDH
lactate dehydrogenase
LFT
liver function tests
mAb
monoclonal antibody
MM
multiple myeloma
MRI
magnetic resonance imaging
NCI
National Cancer Institute
NSCLC
non-small cell lung cancer
ORR
overall response rate
OS
overall survival
OTC
over the counter
PD
disease progression
PD-L1
programmed cell death ligand 1
PET/CT
Positron emission tomography/computed tomography
PFS
progression-free survival
PI
Principal Investigator
PK
pharmacokinetics
PKCθ
protein kinase C theta
PO
Per os (by mouth, orally)
PR
partial response
PRC
Protocol Review Committee (UCSF)
Q3W
every 3 weeks

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List of Abbreviations
RRMM
Relapsed/refractory multiple myeloma
SAE
severe adverse events
sCR
stringent complete response
SD
stable disease
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SPEP
serum protein electrophoresis
SPIE
serum protein immunofixation electrophoresis
T3
triiodothyronine
TMDD
target-mediated drug disposition
TNT
time-to-next treatment
TSH
Thyroid-stimulating hormone
UMVUE
uniformly minimum variance unbiased estimator
UP
unanticipated problem
UPEP
urine protein electrophoresis
UPIE
urine protein immunofixation electrophoresis
WOCB
woman of childbearing potential
Zap70
zeta-chain associated protein kinase

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Table of Contents
Protocol Signature Page ............................................................................................................2
Abstract
3
List of Abbreviations...................................................................................................................5
Table of Contents.......................................................................................................................8
1
Introduction...................................................................................................................11
1.1
Background on Indication........................................................................11
1.2
Background on the Investigational Product and Associated Known 
Toxicities .................................................................................................12
1.2.1
Pharmaceutical and Therapeutic Background ..............................................13
1.2.2
Preclinical and Clinical Trial Data................................................................13
1.3
Rationale for the Proposed Study ............................................................13
1.4
Rationale for Endpoints ...........................................................................13
1.5
Rationale for the Dose Selection/Regimen..............................................15
2
Study Objectives ..........................................................................................................16
2.1
Hypothesis ...............................................................................................16
2.2
Primary Objective and Endpoint(s) .........................................................17
2.3
Secondary Objective(s) and Endpoint(s).................................................17
2.4
Exploratory Objective and Endpoint .......................................................18
3
Study Design................................................................................................................18
3.1
Characteristics..........................................................................................18
3.2
Sample Size..............................................................................................18
3.3
Eligibility Criteria....................................................................................19
3.3.1
Inclusion Criteria ..........................................................................................19
3.3.2
Exclusion Criteria .........................................................................................22
3.4
Inclusion of Women and Minorities........................................................24
3.4.1
Eligibility of Women and Minorities............................................................24
3.4.2
Recruitment of Minority Groups ..................................................................24
3.5
Inclusion Across the Lifespan..................................................................24
3.5.1
Age Range of Participants ............................................................................24
3.5.2
Study Design/Recruitment Considerations Related to Age Groups .............25
3.6
Duration of Treatment .............................................................................25
3.7
Duration of Follow Up.............................................................................25
3.8
Primary Completion.................................................................................25
3.9
Study Completion ....................................................................................25
4
Investigational Products ...............................................................................................26
4.1
Description, Supply, and Storage of Investigational Products ................26
4.1.1
Pembrolizumab .............................................................................................26
4.2
Accountability Records for Investigational Product................................27
4.3
Ordering Investigational Product.............................................................27
4.4
Returns and Reconciliation......................................................................27
5
Treatment Plan.............................................................................................................27

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Table of Contents
5.1
Dosage and Administration .....................................................................27
5.2
Dose Modifications and Dosing Delays ..................................................28
5.2.1
Dose modification for cytokine release syndrome (CRS) ............................34
5.2.2
Dose modification for immune-effector cell-associated neurotoxicity 
(ICANS) ....................................................................................................................34
5.2.3
Other allowed dose interruption for pembrolizumab....................................34
5.3
Stopping Rules.........................................................................................34
6
Study Procedures and Schedule of Events..................................................................34
6.1
Study Calendar.........................................................................................35
6.2
Participant Registration............................................................................38
6.3
Schedule of Procedures and Assessments ...............................................38
6.3.1
Pretreatment Period.......................................................................................38
6.3.2
Treatment Period...........................................................................................40
6.3.3
End-of-Treatment Study Procedures.............................................................43
6.3.4
Safety Follow-Up..........................................................................................44
6.3.5
Long Term/Survival Follow-up ....................................................................44
6.4
Use of Concomitant Medications ............................................................45
6.4.1
Concomitant Medications / Vaccinations (Allowed & Prohibited)..............45
6.4.2
Acceptable Concomitant Medications ..........................................................45
6.4.3
Prohibited Concomitant Medications ...........................................................45
6.4.4
Rescue Medications & Supportive Care.......................................................46
6.5
Dietary Restrictions .................................................................................48
6.6
Participant Discontinuation Criteria ........................................................48
6.7
Participant Withdrawal from Study.........................................................49
6.8
Participant Replacement Strategy............................................................49
6.9
Clinical Criteria for Early Trial Termination...........................................50
7
Reporting and Documentation of Results ....................................................................50
7.1
Evaluation of Efficacy: Antitumor Effect – Hematologic Tumors..........50
7.1.1
Methods for Evaluation of Measurable Disease ...........................................50
7.1.2
Response Criteria..........................................................................................51
7.1.3
Time to Event Definitions.............................................................................52
7.2
Evaluation of Safety.................................................................................52
8
Safety Parameters........................................................................................................53
8.1
Definitions ...............................................................................................53
8.1.1
Adverse Event (AE)......................................................................................53
8.1.2
Serious Adverse Event (SAE).......................................................................53
8.1.3
Unanticipated Problem (UP).........................................................................53
8.2
Classification of Adverse Events.............................................................54
8.2.1
Severity .........................................................................................................54
8.2.2
Attribution.....................................................................................................54
8.2.3
Expectedness.................................................................................................54
8.3
Recording of Adverse Events ..................................................................54
8.4
Expedited Reporting ................................................................................54

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Table of Contents
8.4.1
Reporting to the HDFCCC Data and Safety Monitoring Committee...........54
8.4.2
Reporting to Institutional Review Board ......................................................54
8.4.3
Expedited Reporting to the FDA ..................................................................55
8.4.4
Reporting to Industry Partners/External Collaborators.................................55
8.5
Follow-up of Adverse Events ..................................................................56
8.6
Adverse Events Monitoring.....................................................................57
8.7
Pregnancy and Exposure during Breastfeeding.......................................57
9
Statistical Considerations and Evaluation of Results ...................................................57
9.1
Sample Size Considerations.....................................................................57
9.1.1
Sample Size and Power Estimate..................................................................57
9.1.2
Accrual Estimates .........................................................................................58
9.2
Interim Analyses and Stopping Rules......................................................58
9.3
Analysis Plans..........................................................................................59
9.3.1
Primary Analysis (or Analysis of Primary Endpoints) .................................59
9.3.2
Secondary Analysis (or Analysis of Secondary Endpoints) .........................59
9.3.3
Exploratory Analysis ....................................................................................60
10
Study Management ......................................................................................................60
10.1
Pre-study Documentation ........................................................................60
10.2
Institutional Review Board Approval......................................................61
10.3
Informed Consent ....................................................................................61
10.4
Changes in the Protocol...........................................................................61
10.5
Handling and Documentation of Clinical Supplies .................................61
10.6
Case Report Forms (CRFs)......................................................................61
10.7
Oversight and Monitoring Plan................................................................62
10.8
Record Keeping and Record Retention ...................................................62
10.9
Publications..............................................................................................63
11
References...................................................................................................................64
Appendix 1
Performance Status Criteria............................................................................68
Appendix 2
Data and Safety Monitoring Plan for a Phase II or III Institutional Trial ..........69
Appendix 3
Contraceptive Guidance and Pregnancy Testing............................................72
Appendix 4
ASTCT Consensus Grading System for CRS.................................................75
Appendix 5
ASTCT Consensus Grading System for ICANS .............................................76
Appendix 6
IMWG Uniform Response Criteria...................................................................77
Appendix 7
Laboratory Procedures/Assessments .............................................................78

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1
Introduction
1.1
Background on Indication
Multiple myeloma (MM) is a hematologic malignancy caused by a monoclonal plasma cell 
neoplasm that leads to development of end-organ damage, including renal dysfunction, bone 
disease, and anemia. The treatment for multiple myeloma has evolved considerably over the 
last several years, with standard-of-care therapies now consisting of immune-modulatory 
agents, proteasome inhibitors, and monoclonal antibodies. Despite the advances in the 
treatment of multiple myeloma, the disease remains largely incurable, and most patients 
ultimately relapse and become refractory to available multiple myeloma therapies.
Chimeric antigen receptor t-cell (CAR-T) technologies have added a new tool in the 
armamentarium for treatment of hematologic malignancies. Given the success of CAR-T 
therapies in the treatment of relapsed acute lymphoblastic leukemia and diffuse large B-cell 
lymphoma, CAR-T therapies have been explored in the treatment of multiple myeloma, with 
most studies thus far being directed at the BCMA antigen, which is highly expressed in 
malignant plasma cells. Several BCMA-targeted CAR-T therapies have shown efficacy in early 
phase studies, with studies demonstrating overall response rates above 80%1,2. In the phase 1 
study of the anti-BCMA CAR-T bb2121 in relapsed/refractory multiple myeloma (RRMM), the 
overall response rate was 85% (28/33 patients), including 45% of patients achieving a CR or 
stringent CR. Median progression-free survival was 11.8 months1. Although these results are 
promising in this heavily pretreated population, long-term durable responses have not yet been 
achieved with the majority of patients eventually progressing. The efficacy of salvage therapies 
after CAR-T is limited, highlighting the need for developing new treatment strategies for patients 
who relapse or are refractory CAR-T treatments.
Most recently, there has been increasing evidence that the immunosuppressive effects of the 
tumor microenvironment may play an important role in the development of resistance to CAR-T 
therapy. Programmed death-1 (PD-1) is one of the co-inhibitory receptors that can be 
upregulated following antigen exposure and underlying tumor cells may increase expression of 
PD-1 ligand (PD-L1) to promote immune evasion, leading to reduction in the activity of cytotoxic 
T-cells3,4. Antibody therapy targeting the PD-1/PD-L1 axis is thus a potentially attractive target in 
abrogating the immunosuppressive effects of the tumor microenvironment to restore potency 
and/or augment the activity of CAR-T therapies.
In-vitro and in-vivo studies have demonstrated blockade of PD-1/PD-L1 axis is able to rescue 
CAR-T cell function in various tumor models4–7. Furthermore, studies have shown increased 
expression of PD-L1 in various hematologic malignancies, including MM8–10. In several studies, 
increased levels of PD-L1 on multiple myeloma cells along with increased PD-1 expression in T-
cells were found to be consistent with an “exhausted” phenotype, that was able to be 
ameliorated with PD-L1 blockade11–13. In addition, in the setting of active and relapsed MM, 
other cells in the tumor microenvironment including myeloid-derived suppressor cells and 
plasmacytoid dendritic cells were found to have higher levels of PD-L1, providing support that 
immunosuppressive effects of the tumor microenvironment may play an important role in 
relapsed disease11,14,15. An in-vivo murine myeloma model demonstrated that the combination of 
low-dose irradiation with anti-PD-1 treatment led to prolonged survival, with an increase in 
tumor-specific CD8+ T-cells16. One in-human study for patients with non-Hodgkin lymphoma 
who were refractory to or relapsing after CART19 therapy treated with pembrolizumab 200 mg 
IV every 3 weeks was able to show re-expansion of CART19 cells in 9 of 12 patients, eliciting 
an overall tumor response rate of 27% in evaluable patents17. Altogether, these studies suggest 
that combining blockade of PD-1/PD-L1 axis and induction of tumor-specific cytotoxic T-cells, 
such as those introduced by CAR-T therapies, may have a synergistic effect on tumor-killing18. 

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With regards to in-human multiple myeloma studies of PD-1 inhibitors, several studies have 
been performed with varying results. An initial phase 1b study of 27 patients with 
relapsed/refractory MM treated with single agent nivolumab demonstrated a response rate of 
4%, with one patient responding and achieving a CR19. Subsequently, combination therapy with 
immunomodulatory agents was conducted and demonstrated higher overall response rates. In 
the phase I KEYNOTE-023 study, pembrolizumab in combination with lenalidomide and low-
dose dexamethasone in patients with relapsed/refractory MM previously treated with at least 
two lines of therapy, demonstrated an overall response rate of 44%, with 16% of patients 
achieving VGPR or better. Grade 3-5 treatment-related adverse events were observed in 
approximately 60% of patients treated on combination therapy20. In a phase II study of 
pembrolizumab with pomalidomide and low-dose dexamethasone for patients with 
relapsed/refractory myeloma, an overall response rate of 60% was seen with 24% achieving 
VGPR or better; adverse events grade 3-4 occurred in 40% of patients, with the majority 
consisting of hematologic toxicities21.
Subsequently, two large Phase III trials were conducted with pembrolizumab and low-dose 
dexamethasone in combination with lenalidomide (KEYNOTE-185) in one study22 and in 
combination with pomalidomide (KEYNOTE-183) in another study23, both studies assessing for 
progression-free survival benefit over immunomodulatory and low-dose dexamethasone alone. 
On July 3, 2017, the FDA halted both trials due to inferior outcomes and increased risk of death 
in patients receiving pembrolizumab combination therapies. At database cut-off, the median 
progression-free survival was not reached in the KEYNOTE-185 trial in either arm (with 6-
months PFS 82% for pembrolizumab-arm versus 85% for non-pembrolizumab arm) with serious 
adverse events and deaths occurring more frequently in the pembrolizumab arm (serious 
adverse events: 54% vs. 39%; deaths 4% vs 1%). Overall response rates were similar between 
the two arms (64% for pembrolizumab arm vs 62% for non-pembrolizumab arm)22. In the 
KEYNOTE-183 trial, the median progression-free survival was 5.6 months in the pembrolizumab 
plus pomalidomide and dexamethasone group versus 8.4 months in the pomalidomide and 
dexamethasone group alone. More serious adverse events occurred in the pembrolizumab plus 
pomalidomide and dexamethasone arm (63% with 3% treatment-related deaths) compared in 
the pomalidomide and dexamethasone alone arm (46% with no treatment-related deaths)23.
Impairment of the immune system in these heavily pre-treated patient populations may have 
prevented tumor-specific T-cell responses after PD-1 blockade, hindering responses to 
pembrolizumab. Furthermore, combining pembrolizumab with immunomodulatory agents and 
dexamethasone may not be optimal, especially as concurrent steroid administration may 
attenuate the benefits of PD-1 blockade. Utilizing PD-1 blockade after tumor-targeted CAR-T 
cells are introduced could theoretically provide a more active and tumor-specific T-cell 
population that could better respond to PD-1 inhibition. In one small study, pembrolizumab 
therapy after BCMA CAR-T therapy was able to re-expand the CAR-T population in one out of 5 
patients, eliciting a minor response, highlighting the potential of PD-1 blockage after CAR-T 
therapy relapse in multiple myeloma24. 
1.2
Background on the Investigational Product and Associated Known Toxicities
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting its 
interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 
(PD-L2).  Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor 
blocking activity for PD-1.  Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an intravenous (IV) immunotherapy for advanced malignancies.  
Keytruda® (pembrolizumab) is indicated for the treatment of patients across a number of 

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indications because of its mechanism of action to bind the PD-1 receptor on the T cell.  For 
more details on specific indications refer to the Investigator brochure.
1.2.1 Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades25.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in various 
malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular 
carcinoma; malignant melanoma; and renal cell carcinoma.  Tumor-infiltrating lymphocytes can 
be expanded ex vivo and reinfused, inducing durable objective tumor responses in cancers 
such as melanoma26,27.
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 immunoglobulin (Ig) 
superfamily member related to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-
associated protein 4 (CTLA-4) that has been shown to negatively regulate antigen receptor 
signaling upon engagement of its ligands (PD-L1 and/or PD-L2)28,29.
The structure of murine PD-1 has been resolved30.  PD-1 and its family members are type I 
transmembrane glycoproteins containing an Ig-variable–type (IgV-type) domain responsible for 
ligand binding and a cytoplasmic tail 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, and an immunoreceptor tyrosine-based switch motif.  Following 
T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the 
immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein kinase C-theta 
(PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are involved in the CD3 T-cell 
signaling cascade26,29,31,32.  The mechanism by which PD-1 down-modulates T-cell responses is 
similar to, but distinct from, that of CTLA-4, because both molecules regulate an overlapping set 
of signaling proteins33,34.  As a consequence, the PD-1/PD-L1 pathway is an attractive target for 
therapeutic intervention in multiple myeloma after CAR-T therapy, as blocking this pathway may 
potentiate CAR T-cell response.
1.2.2 Preclinical and Clinical Trial Data
Refer to the Investigator’s Brochure for Preclinical and Clinical data.
1.3
Rationale for the Proposed Study
Currently, patients with multiple myeloma who relapse after BCMA CAR-T trials have limited 
treatment options and poor outcomes. Given the synergetic potential of PD-1 blockade and 
CAR-T therapy, we propose a phase II study for use of pembrolizumab in patients who have 
been treated with anti-BCMA CAR-T therapies and have evidence of relapsed or refractory 
disease. 
1.4
Rationale for Endpoints
Primary Objective: To evaluate the efficacy of pembrolizumab therapy in patients who have 
relapsed or refractory MM (RRMM) after anti-BCMA CAR-T therapies. Specifically, we will 

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examine the rate of achieving a partial response (PR) or better after 4 cycles of pembrolizumab 
therapy. 
Primary Efficacy Endpoint: Overall response rate, defined as proportion of patients achieving 
partial response (PR) or better by IMWG criteria after 4 cycles of pembrolizumab therapy. 
Treatment options for RRMM after anti-BCMA CAR-T cell therapies are limited and identifying 
therapies that are able to elicit tumor responses are important. Studies have demonstrated that 
depth of response is associated with increased progression-free survival and that patients who 
do not achieve disease response to therapy have poor outcomes35. In the triple-class refractory 
setting for which the majority of anti-BCMA CAR-T patients belong, response rates of 30% or 
greater would be clinically meaningful and justify further evaluation. As an example, Selinexor 
with dexamethasone was recently FDA-approved for treatment of triple-class refractory multiple 
myeloma after the STORM trial found an overall response rate of 26%, with the lower limit of its 
confidence interval meeting statistical significance36. We hypothesize that pembrolizumab given 
after anti-BCMA CAR-T therapies would be associated with a 30% or greater disease response 
rate (PR or greater), and we anticipate that these responses should be observed within 4 cycles 
of starting therapy. 
Secondary Objective (1):  To evaluate the safety of pembrolizumab in patients who relapsed or 
were refractory to anti-BCMA CAR-T therapies.
Secondary Endpoint (1): Frequency of adverse events, defined by CTCAE V5.0 and ASTCT 
(for cytokine release syndrome [CRS] and immune-effector cell-associated neurotoxicity 
syndrome [ICANS]); frequency of Grade 3 or higher non-hematologic adverse events; frequency 
of treatment discontinuations due to toxicity.
Given that PD-1 therapies after CAR-T represent a relatively novel treatment paradigm, we will 
report rates of adverse events as defined by NCI CTCAE V5.0 and ASTCT (for CRS and 
ICANS). Previous data with pembrolizumab across various cancers have suggested a severe 
AE rate (Grade 3 or higher) of 15 – 20%17,37–40, and thus we anticipate a similar frequency in our 
study irrespective of cause. Given that we hypothesize that pembrolizumab may be able to re-
activate quiescent CAR-T cells, there is potential for additional toxicity including CRS and 
ICANS, and thus a reasonable definition of safety would be having less than 30% of all treated 
participants incurring a Grade 3 or higher non-hematologic adverse event.  
Secondary Objective (2):  To evaluate the depth of response for patients treated with 
pembrolizumab who had previously relapsed after or were refractory to anti-BCMA CAR-T 
therapies.
Secondary Endpoint (2): Rates of stringent complete response (sCR), complete response 
(CR), very good partial response (VGPR), partial response (PR), stable disease (SD), and 
progressive disease (PD) at any time during pembrolizumab therapy  
Depth of myeloma response has been correlated with progression-free survival35. Thus, we will 
plan to evaluate depth of response based on the percentage of patients that achieve a complete 
response (CR), very good partial response (VGPR), partial response (PR), stable disease (SD), 
or progressive disease (PD) at any time during pembrolizumab therapy. 
Secondary Objective (3):  To determine time-to-event outcomes, including time-to-next 
treatment (TNT), progression-free survival (PFS), and overall survival (OS) after initiation of 
pembrolizumab therapy
Secondary Endpoint (3): TNT, PFS, OS 

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We will explore time-to-event outcomes with Kaplan-Meier method after initiation of 
pembrolizumab. These results can potentially be compared to historical controls.
Exploratory Objective: To explore the immune profile after pembrolizumab treatment, 
including changes in absolute lymphocyte count (ALC) and lymphocyte subsets by flow-
cytometry
Exploratory Endpoint: ALC, absolute CD3 T-cell count, absolute CD4 T-cell count, absolute 
CD8 T-cell count
We will assess whether participants have changes in their immune profile, specifically in their T-
cell numbers and composition, after administration of pembrolizumab and will assess whether 
these changes correlate to clinical response. These analyses will be predominately descriptive 
and exploratory. 
1.5
Rationale for the Dose Selection/Regimen 
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W).  Based on 
the totality of data generated in the Keytruda development program, 200 mg Q3W is the 
appropriate dose of pembrolizumab for adults across all indications and regardless of tumor 
type.  As outlined below, this dose is justified by:

Clinical data from 8 randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W), 

Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg Q3W across multiple indications, and

Pharmacology data showing full target saturation in both systemic circulation 
(inferred from pharmacokinetic [PK] data) and tumor (inferred from physiologically-
based PK [PBPK] analysis) at 200 mg Q3W
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and non-small cell lung cancer (NSCLC), covering different disease settings 
(treatment naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment 
settings (monotherapy and in combination with chemotherapy).  Five studies compared 2 mg/kg 
Q3W versus 10 mg/kg Q2W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), 
and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 
Cohort F2, and KN006).  All of these studies demonstrated flat dose- and exposure-response 
relationships across the doses studied representing an approximate 5- to 7.5-fold difference in 
exposure.  The 2 mg/kg (or 200 mg fixed dose) Q3W provided similar responses to the highest 
doses studied.  Subsequently, flat dose-exposure-response relationships were also observed in 
other tumor types including head and neck cancer, bladder cancer, gastric cancer, and classical 
Hodgkin Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of the tumor 
type.  These findings are consistent with the mechanism of action of pembrolizumab, which acts 
by interaction with immune cells, and not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W.  First, PK data 
in KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W.  Second, a 
PBPK analysis was conducted to predict tumor PD-1 saturation over a wide range of tumor 
penetration and PD-1 expression.  This evaluation concluded that pembrolizumab at 200 mg 
Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed-dosing provides 

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similar control of PK variability as weight-based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed-dose and 2 mg/kg Q3W dose.  Supported 
by these PK characteristics and given that fixed-dose has advantages of reduced dosing 
complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected for 
evaluation across all pembrolizumab protocols. 
PD-1 blockade given post-CAR T therapy has been shown to be safe and without increased risk 
of significant CRS, ICANS, or other immune-related adverse events. In a phase 1/2a study 
conducted by Chong et al. utilizing pembrolizumab for relapsed or refractory B-cell lymphomas 
after anti-CD19 CAR T cells, the only grade ≥3 adverse event observed was neutropenia in 3 of 
12 patients; 1 of 12 patients had reported Grade 2 CRS and was managed with supportive care 
alone and there were no cases of ICANS. The median time from CAR-T infusion to first 
pembrolizumab dose was 3.3 months (range: 0.4 – 42.8 months) and no CRS/ICANS was 
observed for patients who received pembrolizumab within the first 3 months after CAR-T 
infusion41. In the ZUMA-6 study, patients with refractory DLBCL received atezolizumab 1200 mg 
every 21 days starting at either Day 21, 14, and 1 post-axicabtagene ciloleucel in 3 different 
cohorts respectively. Only one grade ≥3 adverse events was attributed to atezolizumab. There 
was no clinically significant evidence of increased incidence of adverse events with the addition 
of atezolizumab; Grade ≥3 CRS and neurologic events were observed in 3 of 12 patients and 6 
of 12 patients respectively, comparable to those previously seen with axicabtagene-ciloleucel 
alone42.  
Furthermore, several studies have demonstrated that CAR-T persistence wanes over time and 
thus in may be advantageous to administer pembrolizumab earlier post-CAR-T. In the KarMMa 
study of idecabtagene-vicleucel, 99% of patients had detectable CAR-T cells at 1 month post-
infusion, 75% at 3 months, 59% at 6 months, and 36% at 12 months1. For ciltacabtagene-
autoleucel, in CARTITUDE-1, after cell expansion, the persistence phase of CAR-T was 
observed or all patients, and the reported median time for detectable CAR transgene levels was 
approximately 100 days (range: 28 – 365 days) post infusion 43. In the preliminary assessment 
of CARTITUDE-2 which treated RRMM with ciltacabtagene-autoleucel, the median persistence 
was 153 days (range, 57.1 – 336.8 days)44,45
Given that there have been no safety concerns identified with administering PD-1 inhibitors less 
than 1 month after CAR-T infusion, we propose that pembrolizumab can be given as early as 30 
days post-CAR-T in our study to increase likelihood of treatment response. 
2
Study Objectives 
2.1
Hypothesis
We hypothesize that, for multiple myeloma (MM) patients with relapsed or refractory disease 
after anti-BCMA CAR-T therapies, pembrolizumab will be associated with a 30% or greater 
disease response rate (PR or greater).

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2.2
Primary Objective and Endpoint(s)
Primary Objective
Endpoint(s)
Time Frame
To evaluate the overall response rate 
(ORR) of pembrolizumab in patients 
with relapsed or refractory MM 
(RRMM) after anti-BCMA CAR-T 
therapies

ORR (defined as the proportion 
of patients achieving a partial 
response (PR) or better based 
on IMWG criteria after 4 cycles 
of pembrolizumab therapy)
From initiation 
of study 
treatment until 
after 4 cycles of 
therapy
2.3
Secondary Objective(s) and Endpoint(s)
Secondary Objective
Endpoint(s)
Time Frame
1.
To evaluate the safety and 
tolerability of pembrolizumab in 
participants who relapsed or 
were refractory to anti-BCMA 
CAR-T therapies.

Frequency of adverse events, 
as graded by NCI CTCAE 
version 5.0, including 
frequency of non-hematologic 
grade 3 or higher adverse 
events

Frequency of CRS graded by 
ASTCT

Frequency of ICANS graded 
by ASTCT

Frequency of treatment 
discontinuations due to toxicity
From initiation of 
study treatment 
until safety follow-
up following 
treatment 
discontinuation
2.
To evaluate the depth of 
response for patients treated 
with pembrolizumab who had 
previously relapsed after or were 
refractory to anti-BCMA CAR-T 
therapies 

Rates of sCR, CR, VGPR, PR, 
SD, and PD at any time during 
pembrolizumab therapy
From initiation of 
study treatment 
until 
discontinuation of 
treatment
3.
To evaluate time-to-event 
outcomes, including time-to-next 
treatment (TNT), progression-
free survival (PFS), and overall 
survival (OS) after initiation of 
pembrolizumab therapy

TNT, PFS, OS assessed using 
Kaplan-Meier survival analysis
From initiation of 
study treatment 
until end of 
follow-up

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2.4
Exploratory Objective and Endpoint
Exploratory Objective
Endpoint(s)
Time Frame
To explore the immune profile after 
pembrolizumab treatment, including 
changes in absolute lymphocyte count 
(ALC) and lymphocyte subsets by 
flow-cytometry

ALC, absolute CD3 T-cell 
count, absolute CD4 T-cell 
count, and absolute CD8 T-
cell count
From initiation of 
study treatment 
until after 4 
cycles of therapy
3
Study Design
3.1
Characteristics
This is a Phase II, single-center study of pembrolizumab for the treatment of relapsed or 
refractory multiple myeloma (RRMM) after anti-BCMA chimeric antigen receptor T-cell (CAR-T) 
therapy. Eligible patients will receive pembrolizumab 200 mg over 30 minutes, intravenously, 
every 3 weeks for up to 2 years (35 cycles) or until disease progression/dose-limiting 
toxicities/discontinuation. The study will utilize a Simon’s two-stage design with 15 participants 
enrolled in stage I and 10 additional participants enrolled in stage II assuming that at least 2 or 
more participants achieve a treatment response after 4 cycles of therapy during stage I of the 
study. The primary endpoint will be overall response rate (partial response [PR] or better by 
International Myeloma Working Group [IMWG] criteria) after 4 cycles of therapy. A Bayesian 
toxicity monitoring design will be incorporated for ongoing safety analysis during the trial to 
pause enrollment if at any time the rate of grade 3 or higher non-hematologic adverse events 
exceeds 30%.
3.2
Sample Size
Participants with relapsed or refractory MM after anti-BCMA CAR-T therapies will be included in 
this study. We anticipate enrolling 25 - 27 participants to allow for the possibility of 10% 
Figure 1 Trial Schema

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participant dropout before receiving pembrolizumab therapy or during the response evaluation 
period. 

Stage 1: 15 participants will be accrued. The trial will be terminated at Stage 1 if 0 or 
1 response is observed; otherwise, it will continue to Stage 2. 

Stage 2: 10 more patients will be accrued (for a total of 25 patients). We will reject 
the null hypothesis if 6 or more responses are observed in 25 patients.
If a participant is enrolled but does not receive any doses of pembrolizumab, the participant may 
be replaced.
If a participant is enrolled and receives less than 4 cycles of therapy and discontinues therapy or 
withdraws from the study for reasons other than disease progression, the participant will not be 
evaluated for the primary efficacy endpoint and will be replaced. However, all participants who 
receive at least one dose of pembrolizumab will be included in the safety analysis for adverse 
events (including those that received < 4 cycles of therapy).
3.3
Eligibility Criteria
3.3.1 Inclusion Criteria
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria:
1.
Male/female participants who are 18 years of age or older on the day of signing informed 
consent with histologically confirmed diagnosis of multiple myeloma will be enrolled in 
this study.
2.
Ability to understand a written informed consent document, and the willingness to sign it 
or a legally acceptable representative (if applicable).
3.
Have an Eastern Cooperative Oncology Group (ECOG) performance status <2 
(Karnofsky >60%, see Appendix 1). Evaluation of ECOG is to be performed within 
7 days prior to the start of study treatment.  
4.
The effects of pembrolizumab on the developing human fetus are unknown. For this 
reason, women of child-bearing potential and men must agree to use adequate 
contraception detailed in Appendix 3 for the duration of study participation and 120 days 
after last administration of study treatment.  
(See Appendix 3 for more details) Female participants are eligible if not pregnant, not 
breastfeeding, and one of the following:
a) Not a WOCBP as defined in Appendix 3
OR
b) WOCBP who agrees to follow contraceptive guidance in Appendix 3 during treatment 
period and at least 120 days following last dose of study treatment
Should a woman become pregnant or suspect she is pregnant while she or her partner 
is participating in this study, she should inform her treating physician immediately.  
Men treated or enrolled on this protocol must also agree to use adequate contraception 
prior to the study, for the duration of study participation, and 120 days after last 

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administration of study treatment. Men should also refrain from donating sperm during 
this period.
5.
Participants must have either
a.
progressive disease after prior anti-BCMA CAR-T therapy and have not started 
another systemic anti-cancer therapy following progression after anti-BCMA 
CAR-T therapy. Patients who received localized radiotherapy alone for 
symptomatic relief of progressive disease following anti-BCMA CAR-T will be 
allowed. 
OR
b.
stable disease as best hematologic response after at least 30 days post anti-
BCMA CAR-T infusion.
Progression after anti-BCMA CAR-T is defined by International Myeloma Working 
Group (IMWG) criteria:
a) Increase of > 25% from lowest response value in any one or more of the 
following:
i.
Serum M-component and/or (the absolute increase must be > 0.5 g/dL) 
ii.
Urine M-component and/or (the absolute increase must be > 200 mg/24 
h)
iii.
Only in patients without measurable serum and urine M-protein levels; the 
difference between involved and uninvolved FLC levels. The absolute 
increase must be > 10 mg/dL
iv.
Bone marrow plasma cell percentage: the absolute percentage must be > 
10%
and/or:
b) Definite development of new bone lesions or soft tissue plasmacytomas or 
definite increase in the size of existing bone lesions or soft tissue 
plasmacytomas
and/or:
c)
Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL or 
2.65 mmol/L) that can be attributed solely to the plasma cell proliferative 
disorder
Stable disease is defined by IMWG criteria: Not meeting criteria for sCR, CR, VGPR, 
PR, or PD (see Appendix 6)
6.
Time from date of anti-BCMA CAR-T infusion to date of first administration of 
pembrolizumab (study drug) must be ≥ 30 days. In order to be eligible for this study, 
participants must not be candidates for treatment regimens known to provide clinical 
benefit in MM as assessed by the treating physician and must have previously received 

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or are intolerant to a proteasome inhibitor, an immunomodulatory agent, and an anti-
CD38 antibody. 
7.
Diagnosis of symptomatic multiple myeloma defined as: clonal bone marrow plasma 
cells >10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more 
of the following CRAB features and myeloma-defining events:
a) Hypercalcemia: serum calcium >0.25 mmol/L (>1mg/dL) higher than the upper limit 
of normal or >2.75 mmol/L (>11mg/dL)
b) Renal insufficiency: creatinine clearance <40 mL per minute or serum creatinine 
>177 micromol/L (>2mg/dL)
c)
Anemia: hemoglobin value of >20g/L below the lowest limit of normal, or a 
hemoglobin value <100g/L
d) Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET/CT.  
If bone marrow has <10% clonal plasma cells, more than one bone lesion is required 
to distinguish from solitary plasmacytoma with minimal marrow involvement
e) Any one or more of the following biomarkers of malignancy:
i.
60% or greater clonal plasma cells on bone marrow examination
ii.
Serum involved / uninvolved free light chain ratio of 100 or greater, provided 
the absolute level of the involved light chain is at least 100 mg/L 
iii.
More than one focal lesion on MRI that is at least 5mm or greater in size
8.
Active and measurable disease, defined by serum paraprotein (M-protein) > 0.5 g/dL, 
24-hour urine Bence Jones protein of >200 mg, or abnormal serum free light chain ratio 
with involved light chain of >10 mg/dL (100 mg/L).
9.
Have adequate organ function as defined in the following table (Table 3.3.1). Specimens 
must be collected within 10 days prior to the start of study treatment.
Table 3.3.1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥500/µL  a, b
Platelets
≥25 000/µL  a, b
Hemoglobin
≥8.0 g/dL  a, b 
Renal
Creatinine OR
Measured or calculatedc creatinine clearance
(GFR can also be used in place of creatinine or CrCl)
≤1.5 × ULN OR
≥30 mL/min for participant with creatinine 
levels >1.5 × institutional ULN
Hepatic
Total bilirubin
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin levels 
>1.5 × ULN

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3.3.2
Exclusion Criteria
An individual who meets any of the following criteria will be excluded from participation in this 
study:
1.
A WOCBP who has a positive urine pregnancy test within 72 hours prior to study 
treatment initiation (see Appendix 3).  If the urine test is positive or cannot be confirmed 
as negative, a serum pregnancy test will be required.
Note: in the event that 72 hours have elapsed between the screening pregnancy test 
and the first dose of study treatment, another pregnancy test (urine or serum) must be 
performed and must be negative in order for subject to start receiving study medication.
2.
Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an 
agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 
40, CD137). 
3.
Has received prior systemic anti-cancer therapy including investigational agents within 4 
weeks prior to study treatment initiation.
Note: Participants must have recovered from all AEs due to previous therapies to 
≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible.
Note: If participant received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting study treatment.
4.
Has received anti-BCMA CAR-T infusion < 30 days prior to study treatment initiation. 
5.
Has received subsequent systemic anti-cancer therapy following anti-BCMA CAR-T 
therapy. Participants who received localized radiotherapy alone for symptom control 
following anti-BCMA CAR-T therapy will be allowed to participate.
6.
Has received a live vaccine within 30 days prior to the first dose of study drug.  
Examples of live vaccines include, but are not limited to, the following:  measles, 
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-
Guerin (BCG), and typhoid vaccine.  Seasonal influenza vaccines for injection are 
generally killed virus vaccines and are allowed; however, intranasal influenza vaccines 
(e.g., FluMist®) are live attenuated vaccines and are not allowed. SARS-COV-2 
vaccines are generally mRNA-based or viral vector vaccines (replication-incompetent) 
and are allowed.
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for participants with 
liver metastases)
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate aminotransferase 
(serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of normal.
a  Growth factor and/or transfusion support is permissible to stabilize participant prior to study treatment if needed.
b  No lower limit if cytopenia is related to bone marrow involvement.
c Creatinine clearance (CrCl) should be calculated per institutional standard.
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be 
adapted according to local regulations and guidelines for the administration of specific chemotherapies.

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7.
Is currently participating in or has participated in a study of an investigational agent or 
has used an investigational device within 4 weeks prior to the first dose of study 
intervention.
Note: Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.
8.
Has a diagnosis of primary immunodeficiency or is receiving chronic systemic steroid 
therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study drug.
9.
Has an active second malignancy requiring treatment, unless potentially curative 
treatment has been completed with no evidence of malignancy for 2 years. Participants 
with the following low-risk or non-invasive malignancies will be allowed:
a.
Basal cell carcinoma of the skin
b.
Squamous cell carcinoma of the skin
c.
Carcinoma in-situ of the cervix
d.
Carcinoma in-situ of the breast
e.
Superficial bladder cancer
f.
Incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor, 
nodes, metastasis] clinical staging system) or prostate cancer that is curative or 
considered very-low or low risk in which observation is reasonable. 
g.
Other in-situ cancers
Note: The time requirement does not apply to participants who underwent successful 
definitive resection of basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, superficial bladder cancer, in situ cervical cancer, or other in-situ cancers
10. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Participants with previously treated brain metastases may participate 
provided they are radiologically stable, i.e., without evidence of progression for at least 4 
weeks by repeat imaging (note that the repeat imaging should be performed during 
study screening), clinically stable, and without requirement of steroid treatment for at 
least 14 days prior to first dose of study intervention.
11. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
12. Has active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive 
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment and is allowed.
13. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis.

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14. Has an active infection requiring systemic therapy. Prophylactic antibiotics/antivirals are 
allowed.
15. Has a known history of Human Immunodeficiency Virus (HIV) infection.
16. Has known active Hepatitis B virus infection (defined as Hepatitis B [HBV] DNA detected 
or Hepatitis B surface antigen [HbsAg] positive) or known active Hepatitis C virus 
infection (defined as Hepatitis C [HCV] RNA qualitative detected). Subjects who have 
been vaccinated against hepatitis B (positive for hepatitis B surface antibody [HBsAB]) 
who are negative for other markers of prior hepatitis B infection (e.g., Hepatitis B core 
antibody [HBcAb] negative) are eligible. Subjects with past exposure or known history of 
hepatitis B infection (e.g., HBcAb positive) are eligible for the study provided that they 
are negative by assessment for HBV DNA and HbsAg. Subjects with a history of 
hepatitis C infection (defined as detectable HCV antibody) are eligible as long as they 
have a negative HCV viral load. 
17. Has a known history of active TB (Bacillus Tuberculosis).  
18. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the subject’s participation for 
the full duration of the study, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator.  
19. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
20. Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through 120 days after 
the last dose of trial treatment.
21. Has had a history of allogenic bone marrow/tissue/solid organ transplant.
22. Has unmeasurable disease by serum/urine testing (oligo-secretory or non-secretory 
multiple myeloma).
23. Has diagnosis of Waldenstrom’s disease, light chain amyloidosis, or POEMS disease.
24. ECOG performance status ≥ 2.
3.4
Inclusion of Women and Minorities
3.4.1 Eligibility of Women and Minorities
Individuals of any sex/gender, race, or ethnicity are eligible for this study.
3.4.2 Recruitment of Minority Groups
The study recruitment strategy aims to achieve representation of minority groups that reflects 
the demographics of the affected population in the catchment area. 
3.5
Inclusion Across the Lifespan
3.5.1 Age Range of Participants
Individuals ages 18 and over are eligible for this study. Children are excluded from the study 
because the disease/condition does not occur regularly in children.

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3.5.2 Study Design/Recruitment Considerations Related to Age Groups
The study design and recruitment strategy aim to achieve representation of age groups that 
reflect the demographics of the affected population.
3.6
Duration of Treatment
In the absence of treatment delays due to adverse events (AEs), treatment may continue for up 
to 2 years or until:

Disease progression resulting in discontinuation of the study treatment;

Inter-current illness that prevents further administration of treatment;

Unacceptable adverse event(s);

Participant decides to withdraw from the study;

Significant participant non-compliance with protocol;

If the participant meets an exclusion criterion (either newly developed or not 
previously; or, recognized) that precludes further study participation

General or specific changes in the participant’s condition render the participant 
unacceptable for further treatment in the judgment of the investigator.
3.7
Duration of Follow Up
Participants will be followed for a minimum of 30 days after last treatment or removal from 
study, or until death, whichever occurs first.  Participants removed from study for unacceptable 
treatment or study-related adverse event(s) will be followed until resolution or stabilization (as 
determined by the investigator) or until initiation of new anti-cancer therapy, whichever occurs 
first.
After completing the follow-up period, participants will be followed every 12 weeks (+/- 14 days) 
to assess for survival/anti-cancer therapy status for up to 1 year after treatment completion or 
discontinuation. If possible, these visits will be done via video appointment or telephone follow-
up. 
Long term/Survival Follow-up visits are only required for patients who have either completed 35 
cycles of therapy or have discontinued treatment for reasons other than disease progression 
and have not yet started treatment with another anti-cancer therapy.
Participants who experienced confirmed disease progression or start a new anticancer therapy 
will be taken off study. Efforts will be made to contact these participants for survival follow-up by 
telephone every 12 weeks (± 14 days) to assess for survival status until death, withdrawal of 
consent, or the end of the trial, whichever occurs first for up to one year after treatment 
discontinuation.
3.8
Primary Completion 
The expected primary completion date is 30 months after the study opens to accrual.
3.9
Study Completion
The expected study completion date is 42 months after the study opens to accrual.

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4
Investigational Products
4.1
Description, Supply, and Storage of Investigational Products
4.1.1 Pembrolizumab
Classification
Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 
and its ligands, PD-L1 and PD-L2. Pembrolizumab is an IgG4 kappa immunoglobulin with an 
approximate molecular weight of 149 kDa. 
Mechanism of Action
Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T 
cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors 
and signaling through this pathway can contribute to inhibition of active T-cell immune 
surveillance of tumors. Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor 
and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of 
the immune response, including the anti-tumor immune response. 
Metabolism
Pembrolizumab is catalyzed into small peptides and single amino acids via general protein 
degradation, but it does not rely on metabolism for clearance.
Contraindications
None.
Formulation, Appearance, Packaging, and Labeling
Pembrolizumab, manufactured by Merck, is supplied as a sterile, preservative-free, clear to 
slightly opalescent, colorless to slightly yellow solution that requires dilution for intravenous 
infusion. Each vial contains 100 mg of pembrolizumab in 4 mL of solution. Each 1 mL of solution 
contains 25 mg of pembrolizumab and is formulated in: L-histidine (1.55 mg), polysorbate 80 
(0.2 mg), sucrose (70 mg), and Water for Injection, USP.
Supplies will be labeled in accordance with regulatory requirements.
Availability
Pembrolizumab is being obtained as commercial supply provided by Merck.
Storage and handling
Pembrolizumab is stored at the UCSF investigational pharmacy.
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label. Receipt and dispensing of trial medication must be recorded 
by an authorized person at the trial site. Clinical supplies may not be used for any purpose other 
than that stated in the protocol.
Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) in original carton to protect from 
light. Do not freeze. Do not shake.
Side Effects
Complete and updated adverse event information is available in the Investigational Drug 
Brochure (IB) and/or product package insert. 

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4.2
Accountability Records for Investigational Product
UCSF Investigational Drug Services (IDS) will manage drug accountability records for UCSF 
study supply of investigational product(s).
4.3
Ordering Investigational Product
UCSF will obtain pembrolizumab directly from Merck.
4.4
Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the participants, and the 
amount remaining at the conclusion of the trial. 
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s responsibility 
to arrange for disposal of all empty containers, provided that procedures for proper disposal 
have been established according to applicable federal, state, local and institutional guidelines 
and procedures, and provided that appropriate records of disposal are kept.
5
Treatment Plan
5.1
Dosage and Administration
Treatment will be administered on an outpatient basis. 
Trial interventions should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed in the Trial Flow Chart (Fig. 1, 
Section 3.1).  Trial interventions may be administered up to 3 days before or after the scheduled 
Day 1 of each cycle after Cycle 1 if needed for administrative reasons.
Pembrolizumab 200 mg will be administered as 30-minute IV infusion every 3 weeks.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min).
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution.
Table 5.1
Regimen Description
Investigational 
Product
Premedication; 
precautions
Dose
Route
Schedule
Cycle 
Length
Pembrolizumab
N/A
200 mg
Intravenous
Day 1 of each 
3-week cycle
3 weeks 
(21 days)
Trial intervention should begin as close as possible to the date on which intervention is 
allocated/assigned. The treatment is planned for a maximum of 35 cycles or until progression of 
disease/dose-limiting toxicities.
At least two doses of tocilizumab per patient must be available on site prior to dosing of 
pembrolizumab.

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5.2
Dose Modifications and Dosing Delays
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
immune-related AEs (irAEs) may occur shortly after the first dose or several months after the 
last dose of pembrolizumab treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment are critical to reducing 
complications.  Based on existing clinical study data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab, administration of corticosteroids, and/or other 
supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or 
exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin 
biopsy may be included as part of the evaluation. Dose modification and toxicity management 
guidelines for irAEs associated with pembrolizumab are provided in Table 5.2-1. Additional 
guidelines for toxicity management for cytokine release syndrome and neurotoxicity are outlined 
in Sections 5.2.1 and 5.2.2 respectively.

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Table 5.2-1
Dose modification and toxicity management guidelines for immune-related AEs associated with 
pembrolizumab
General instructions:
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids. 
Pembrolizumab must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of the 
last pembrolizumab treatment. 
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
If pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper.
irAEs
Toxicity grade 
(CTCAE V5.0)
Action with 
pembrolizumab
Corticosteroid and/or 
other therapies
Monitoring and follow-up
Grade 2
Withhold 
Pneumonitis 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue
Administer corticosteroids 
(initial dose of 1 – 2 mg/kg 
prednisone or equivalent) 
followed by taper
Add prophylactic 
antibiotics for opportunistic 
infections
Monitor participants for signs and symptoms 
of pneumonitis
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment
Grade 2 or 3
Withhold
Diarrhea / Colitis 
Grade 4 or 
recurrent Grade 3
Permanently 
discontinue
Administer corticosteroids 
(initial dose of 1 – 2 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor participants for signs and symptoms 
of enterocolitis (i.e., diarrhea, abdominal pain, 
blood, or mucus in stool with or without fever) 
and bowel perforation (i.e., peritoneal signs 
and ileus)
Participants with ≥Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion
AST or ALT 
elevation or 
Increased Bilirubin
Grade 2 a
Withhold
Administer corticosteroids 
(initial dose of 0.5 – 1 
mg/kg prednisone or 
equivalent) followed by 
taper
Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable)

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irAEs
Toxicity grade 
(CTCAE V5.0)
Action with 
pembrolizumab
Corticosteroid and/or 
other therapies
Monitoring and follow-up
Grade 3 b or 4 c
Permanently 
discontinue
Administer corticosteroids 
(initial dose of 1 – 2 mg/kg 
prednisone or equivalent) 
followed by taper
Type 1 diabetes 
mellitus (T1DM) or 
Hyperglycemia
New-onset T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold d
Initiate insulin replacement 
therapy for participants 
with T1DM
Administer anti-
hyperglycemic in 
participants with 
hyperglycemia
Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes
Grade 2
Withhold
Hypophysitis
Grade 3 or 4
Withhold or 
permanently 
discontinue d
Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)
Grade 2
Continue
Hyperthyroidism 
Grade 3 or 4
Withhold or 
permanently 
discontinue d
Treat with non-selective 
beta-blockers (e.g., 
propranolol) or thioamides 
as appropriate
Monitor for signs and symptoms of thyroid 
disorders
Hypothyroidism
Grade 2, 3, or 4
Continue
Initiate thyroid replacement 
hormones (e.g., 
levothyroxine or 
liothyronine) per standard 
of care
Monitor for signs and symptoms of thyroid 
disorders
Grade 2
Withhold
Nephritis and renal 
dysfunction:
grading according 
to increased 
Grade 3 or 4
Permanently 
Administer corticosteroids 
(prednisone 1 – 2 mg/kg or 
equivalent) followed by 
taper
Monitor changes in renal function

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irAEs
Toxicity grade 
(CTCAE V5.0)
Action with 
pembrolizumab
Corticosteroid and/or 
other therapies
Monitoring and follow-up
creatinine or acute 
kidney injury
discontinue
Grade 1 or 2
Withhold
Myocarditis
Grade 3 or 4
Permanently 
discontinue
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Intolerable/ 
persistent Grade 2
Withhold
Grade 3
Withhold or 
discontinue based 
on the event e. 
All Other immune-
related AEs
Grade 4 or 
recurrent Grade 3
Permanently 
discontinue
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm 
etiology or exclude other causes
a AST/ALT: >3.0 – 5.0 x ULN if baseline normal; >3.0 – 5.0 x baseline, if baseline abnormal; 
bilirubin:>1.5 – 3.0 x ULN if baseline normal; >1.5 – 3.0 x baseline if baseline abnormal
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 – 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 – 10.0 x ULN if baseline normal; >3.0 – 10.0 x baseline if baseline 
abnormal
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; 
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. For participants with Grade 3 or 4 immune-related 
endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement 
therapy or achieved metabolic control (in case of T1DM)
e Events that require discontinuation include but are not limited to: Guillain-Barre Syndrome, encephalitis, Stevens-Johnson Syndrome, and toxic epidermal necrolysis.

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Dose modification and toxicity management of infusion reactions related to pembrolizumab
Table 5.2-2
Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as medically indicated until the participant 
is deemed medically stable in the opinion of the investigator.
None
Grade 2
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs.
Stop Infusion.
Additional appropriate medical therapy may include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically indicated until the participant 
is deemed medically stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping drug infusion, the infusion may 
be restarted at 50% of the original infusion rate (e.g., from 100 mL/hr to 50 
mL/hr).  Otherwise, dosing will be held until symptoms resolve and the 
participant should be premedicated for the next scheduled dose.
Participants who develop Grade 2 toxicity despite adequate premedication 
should be permanently discontinued from further study drug intervention
Participant may be 
premedicated 1.5h (± 30 
minutes) prior to infusion of 
pembrolizumab with:
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 
mg po (or equivalent dose 
of analgesic).
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates)
Grade 4:
Stop Infusion.
Additional appropriate medical therapy may include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically indicated until the participant 
No subsequent dosing

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Life-threatening; pressor or 
ventilatory support indicated
is deemed medically stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be used immediately.
Participant is permanently discontinued from further study drug intervention.
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at http://ctep.cancer.gov

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5.2.1 Dose modification for cytokine release syndrome (CRS)
For participants who develop cytokine release syndrome grades 1-3 after pembrolizumab, 
further doses of pembrolizumab will be held until CRS completely resolves. Once CRS has fully 
resolved, the clinical investigator may resume pembrolizumab 200 mg every 3 weeks. 
Pembrolizumab will be discontinued for participants who develop grade 4 CRS or any grade 3 
CRS that does not resolve to Grade ≤ 1 or baseline within 48 hours with tocilizumab therapy 
and/or best medical care.
Guidelines for the management of patients who develop CRS, including the use of tocilizumab, 
are outlined in Section 6.4.4.1.
5.2.2 Dose modification for immune-effector cell-associated neurotoxicity 
(ICANS)
For participants who develop immune-effector cell-associated neurotoxicity grades 1-3 after 
pembrolizumab, further doses of pembrolizumab will be held until symptoms resolve. Once 
ICANS has fully resolved, the clinical investigator may resume pembrolizumab 200 mg every 3 
weeks. Pembrolizumab will be discontinued for participants who develop grade 4 ICANS or any 
grade 3 ICANS that does not resolve to Grade ≤ 1 or baseline within 48 hours with steroids, 
tocilizumab therapy, and/or best medical care.
Guidelines for the management of patients who develop ICANS, including the use of 
tocilizumab and steroids, are outlined in Section 6.4.4.2.
5.2.3 Other allowed dose interruption for pembrolizumab
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical/surgical events or logistical reasons not related to study therapy. Participants should be 
placed back on study therapy within 3 weeks of the scheduled interruption unless otherwise 
discussed with the Sponsor. The reason for interruption should be documented in the patient’s 
study record.
5.3
Stopping Rules
Fifteen evaluable participants will be enrolled in the first stage of the Simon two-stage trial. If 0 
or 1 responses according to IMWG criteria are noted in these initial 15 participants, then the trial 
will be stopped for futility. 
6
Study Procedures and Schedule of Events
The study-specific procedures and assessments are detailed in this section and outlined in the 
Study Calendar – Section 6.1.
Screening assessments must be performed within 28 days prior to the first dose of 
investigational product unless otherwise noted.  Any results falling outside of the reference 
ranges may be repeated at the discretion of the investigator. 
All on-study visit procedures are allowed a window of ± 3 days unless otherwise noted.  
Treatment or visit delays for public holidays, public health emergencies, or weather conditions 
do not constitute a protocol violation.

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6.1
Study Calendar
Period/
Procedure
Screening
Treatment Cycles (every 3 weeks)
End of 
Treatment 
Safety 
Follow-up 
Long-term 
Follow-up1
Study Day/Visit Day
-28 to -1
C1 
D1
C1 
D8
(+/- 3)
C2 
D1
(+/- 3)
C3 
D1
(+/- 3)
C4 
D1
(+/- 3)
C5+ 
D1
(+/- 3)2
(+/- 21)
30 days
(+/- 5)
post-EOT
Every 12 weeks
(+/- 14)
post safety follow-up
Study Treatment/Drug Administration
Pembrolizumab
X
X
X
X
X
Administrative Procedures
Informed consent
X
Clinical Assessments
Physical exam 3, 4
X
X
X
X
X
X
X
X
Medical history
X
Vital signs 4
X
X
X
X
X
X
X
X
Concomitant medications 4
X
X
X
X
X
X
X
X
X
X
AE assessment
X
X
X
X
X
X
X
X
X
X
Performance status 4
X
X
X
X
X
X
X
X
Post-treatment anticancer 
therapy status
X
X
Survival/Long-term Follow-up
X
X

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Period/
Procedure
Screening
Treatment Cycles (every 3 weeks)
End of 
Treatment 
Safety 
Follow-up 
Long-term 
Follow-up1
Study Day/Visit Day
-28 to -1
C1 
D1
C1 
D8
(+/- 3)
C2 
D1
(+/- 3)
C3 
D1
(+/- 3)
C4 
D1
(+/- 3)
C5+ 
D1
(+/- 3)2
(+/- 21)
30 days
(+/- 5)
post-EOT
Every 12 weeks
(+/- 14)
post safety follow-up
Laboratory Assessments
Hematology 4, 5
X
X
X
X
X
X
X
X
Chemistry 4, 6
X
X
X
X
X
X
X
X
Thyroid Function 4, 7
X
X
X
X
X
X
X
Tumor marker assessment: 
Urinalysis 8
X
X11
X11
X11
Pregnancy test 4. 9
X
X
X
X
X
X
Tumor marker assessment: 
Serum protein and 
immunofixation electrophoresis 
(SPEP/SPIE) and serum-free 
light chains (FLC) 4, 10
X
X
X
X
X
Lymphocyte subsets 4
X
X12
Tissue Collection/ Biopsy
Bone marrow biopsy 11
X
1 Follow-up visits will occur every 12 weeks, up to 1 year after treatment completion or discontinuation. Follow-up visits are only required for patients who have either 
completed 35 cycles of therapy or have discontinued treatment for reasons other than disease progression and have not yet started treatment with another anti-cancer 
therapy.
2 Up to total of 35 cycles.
3 Full physical exam at screening visit; directed physical exam at all other time points at which a physical exam is indicated
4 Assessments to be performed before study treatment administration. Labs can be drawn up to 3 days prior to study treatment administration.
5 Including CBC with differential and platelet count
6 Including alkaline phosphatase (ALP), ALT/AST, total bilirubin, calcium, phosphorus, (BUN), creatinine, total protein, albumin, fasting glucose, potassium, sodium, 
chloride, bicarbonate, uric acid, LDH, fasting lipid panel (LDL, total cholesterol, triglycerides), 
7 Including T3, FT4, and TSH
8 24-hour UPEP/UPIE will be obtained on all participants at screening. For participants that do not have measurable serum M-protein (M-protein < 1 g/dL) but measurable 
urine M-protein (M-protein ≥ 200 mg/24 hours) at screening, subsequent 24-hour UPEP/UPIE will be collected on C5D1 and then every 4 cycles thereafter to assess 
response. For participants with measurable serum M-protein (M-protein ≥ 1g/dL) and urine M-protein (M-protein ≥ 200 mg/24 hours), additional 24-hour UPEP/UPIE after 
screening will only be obtained at suspected achievement of sCR, CR, VGPR, PR, and PD to confirm IMWG response criteria. For participants with measurable serum M-

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protein and unmeasurable urine M-protein (M-protein ≤ 200 mg/24 hours), additional 24-hour UPEP and UPIE after screening will only be obtained at suspected 
achievement of sCR, CR, VGPR, and PD to confirm IMWG response criteria.
9 For women of child-bearing potential.  Urine or serum HCG must be negative within 72 hours of treatment administration.
10 Serum protein and immunofixation electrophoresis and serum-free light chains for disease assessment will be checked on C5D1 and then subsequently every 4 cycles 
thereafter for response assessment
11 To confirm CR, bone marrow biopsy is only required for participants who have serologic markers consistent with complete response (disappearance of serum and urine 
M-protein on electrophoresis for patients with measurable M-protein at treatment initiation or normalization of the free light chain ratio for those with elevated free light 
chain markers but unmeasurable M-protein at treatment initiation).
12 Lymphocyte subsets  will be checked on C5D1 only

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6.2
Participant Registration
A written, signed, informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated.  A copy of the signed ICF will be given to the subject and a copy will 
be filed in the medical record.  The original will be kept on file with the study records.  
All participants consented to the study will be registered in OnCore®, the UCSF Helen Diller 
Family Comprehensive Cancer Center Clinical Trial Management System (CTMS).  The system 
is password protected and meets HIPAA requirements.
6.3
Schedule of Procedures and Assessments
6.3.1 Pretreatment Period
6.3.1.1
Screening Assessments 
The Screening procedures and assessments must be completed within 28 days of initiating 
study treatment. 

Clinical Assessments
o
Documentation of disease assessment: 

Disease assessment: Disease assessment and responses will be 
assessed by serum and urine biomarkers including serum protein and 
immunofixation electrophoresis (SPEP/SPIE), 24-hour urine protein, 
and immunofixation electrophoresis (UPEP/UPIE), and serum-free 
light chain (FLC). The IMWG (International Myeloma Working Group) 
uniform response criteria will be used to assess disease response and 
progression46. See Appendix 6.
o
Full physical examination

The investigator or qualified designee will perform a complete physical 
exam during the screening period.  Clinically significant abnormal 
findings should be recorded as medical history.  A full physical exam 
should be performed during screening.
o
Complete medical history
o
Vital signs

The investigator or qualified designee will take vital signs at 
screening, prior to the administration of each dose of trial treatment, 
and at treatment discontinuation as specified in the Trial Flow Chart 
(Fig. 1, Section 3.1).  Vital signs should include temperature, pulse, 
respiratory rate, weight, and blood pressure.  Height will be measured 
at screening only.
o
Prior and Concomitant medication review

Prior medication review: The investigator or qualified designee will 
review prior medication use, including any protocol-specified washout 
requirement, and record prior medication taken by the participant 
within 28 days before starting the trial. Treatment for the disease for 
which the participant has enrolled in this study will be recorded 
separately and not listed as a prior medication.

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
Concomitant medication review: The investigator or qualified designee 
will record medication, if any, taken by the participant during the trial.  
o
AE assessment

The investigator or qualified designee will assess each participant to 
evaluate for potential new or worsening AEs as specified in the Trial 
Flow Chart and more frequently if clinically indicated.  Adverse 
experiences will be graded and recorded throughout the study and 
during the follow-up period according to NCI CTCAE Version 5.0. For 
CRS and ICANS, AEs will be graded and recorded according to the 
ASTCT consensus criteria (see Appendix 4 and 5).
Toxicities will be characterized in terms regarding seriousness, 
causality, toxicity grading, and action taken with regard to trial 
treatment. 
Please refer to Section 8.3 for detailed information regarding the 
assessment and recording of AEs.
o
Performance status

The investigator or qualified designee will assess ECOG status (see 
Appendix 1) at screening, prior to the administration of each dose of 
trial treatment and discontinuation of trial treatment as specified in the 
Trial Flow Chart.

Laboratory Assessments
o
Hematology labs - CBC with differential and platelet count 
o
Blood chemistry assessment, including: Alkaline phosphatase (ALP), 
aspartate aminotransferase/alanine aminotransferase (ALT/AST), total 
bilirubin, calcium, phosphorus, blood urea nitrogen (BUN), creatinine, total 
protein, albumin, fasting glucose, potassium, sodium, chloride, bicarbonate, 
uric acid, lactate dehydrogenase (LDH), fasting lipid panel (low-density 
lipoprotein [LDL], total cholesterol, triglycerides)
o
Thyroid function tests - thyroid-stimulating hormone (TSH), free thyroxine 
(FT4)
o
Pregnancy Test - For women of child-bearing potential. Urine or serum HCG 
must be negative within 72 hours of treatment administration.
o
Disease assessment: Disease assessment and responses will be assessed 
by serum and urine biomarkers including serum protein and immunofixation 
electrophoresis (SPEP/SPIE), 24-hour urine protein, and immunofixation 
electrophoresis (UPEP/UPIE), and serum-free light chain (FLC). The IMWG 
(International Myeloma Working Group) uniform response criteria will be used 
to assess disease response and progression46. See Appendix 6.

SPEP/SPIE, 24-hour UPEP/UPIE, and FLC will be performed at 
screening to ensure measurable disease. These studies are to be 
performed within 28 days prior to the date of receiving treatment.

Tumor marker assessments: Urinalysis

Tumor marker assessments - Serum protein and immunofixation 
electrophoresis (SPEP/SPIE) and serum-free light chains (FLC).

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6.3.2 Treatment Period
6.3.2.1
Study Procedures, Cycle 1, Day 1

Study Treatment/Drug Administration
o
Administration of 200 mg of pembrolizumab given intravenously

Clinical Assessments 
o
Directed physical exam

The investigator or qualified designee will perform a directed physical 
exam as clinically indicated prior to trial treatment administration.
o
Vital signs
o
Concomitant medications
o
AE assessment
o
Performance status

Laboratory Assessments (to be done prior to study drug administration)
o
Hematology
o
Chemistry
o
Thyroid function
o
Pregnancy test (for women of childbearing potential)
o
Lymphocyte subsets by flow cytometry
o
Disease assessment:

24-hour UPEP/UPIE measurements will be obtained depending on 
the participant’s disease status at screening:
Participants who have measurable disease by SPEP/SPIE (M-protein 
≥ 1 g/dL) and by 24-hour UPEP/UPIE (≥ 200 mg/24 hours) at 
screening will undergo a 24-hour UPEP/UPIE at time of suspected 
sCR, CR, VGPR, PR, and progressive disease. 
Participants with measurable disease by SPEP/SPIE (M-protein ≥ 1 
g/dL) but no measurable 24-hour UPEP/UPIE (< 200 mg/24 hours) at 
screening will undergo a 24-hour UPEP/UPIE at time of suspected 
sCR, CR, VGPR, and progressive disease to confirm IMWG response 
criteria. 
Participants with measurable disease by 24-hour UPEP/UPIE (≥ 200 
mg/24 hours) but not by SPEP/SPIE (M-protein < 1 g/dL) at screening 
will undergo a 24-hour UPEP/UPIE at C5D1, every 4 cycles thereafter 
while on study treatment, at treatment discontinuation and/or 
progression, and every 12 weeks during follow-up for patients who 
remain on study.
Participants with only measurable disease by FLC and without 
measurable disease by SPEP/SPIE and UPEP/UPIE at screening will 
undergo 24-hour UPEP/UPIE at time of suspected sCR, CR, VGPR, 
and progressive disease. 
For participants who develop serologic markers consistent with a 
complete response (disappearance of serum and urine M-protein on 

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electrophoresis for patients with measurable M-protein at treatment 
initiation or normalization of the free light chain ratio for those with 
elevated free light chain markers but unmeasurable M-protein at 
treatment initiation), a bone marrow biopsy is required to confirm 
IMWG complete response.  
For patients with extramedullary disease on study enrollment, imaging 
(PET/CT, CT, or MRI) is recommended to confirm IMWG response for 
patients who achieve at least a hematologic partial response. Imaging 
is also recommended if there is clinical concern for progressive 
disease.

Tumor marker assessment: Serum protein and immunofixation 
electrophoresis (SPEP/SPIE) and serum-free light chains (FLC)
6.3.2.2
Study Procedures Cycle 1, Day 8 (+/- 3 days) (Safety follow-up visit)

Clinical Assessments
o
Directed physical exam
o
Vital signs
o
Concomitant medications
o
AE assessment
o
Performance status

Laboratory Assessments
o
Hematology
o
Chemistry
6.3.2.3
Study Procedures Cycle 2, Day 1

Study Treatment/Drug Administration
o
Administration of 200 mg of pembrolizumab given intravenously

Clinical Assessments
o
Directed physical exam
o
Vital signs
o
Concomitant medications
o
AE assessment
o
Performance status

Laboratory Assessments (to be done prior to study drug administration)
o
Hematology
o
Chemistry
o
Thyroid function
o
Pregnancy test (for women of childbearing potential)
6.3.2.4
Study Procedures Cycle 3, Day 1

Study Treatment/Drug Administration

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o
Administration of 200 mg of pembrolizumab given intravenously

Clinical Assessments
o
Directed physical exam
o
Vital signs
o
Concomitant medications
o
AE assessment
o
Performance status

Laboratory Assessments (to be done prior to study drug administration)
o
Hematology
o
Chemistry
o
Thyroid function
o
Pregnancy test (for women of childbearing potential)
6.3.2.5
Study Procedures Cycle 4, Day 1

Study Treatment/Drug Administration
o
Administration of 200 mg of pembrolizumab given intravenously

Clinical Assessments
o
Directed physical exam
o
Vital signs
o
Concomitant medications
o
AE assessment
o
Performance status

Laboratory Assessments (to be done prior to study drug administration)
o
Hematology
o
Chemistry
o
Thyroid function
o
Pregnancy test (for women of childbearing potential)
6.3.2.6
Study Procedures Cycle 5 and every following cycle (every 3 weeks) 
for up to 35 cycles, Day 1

Study Treatment/Drug Administration
o
Administration of 200 mg of pembrolizumab given intravenously

Clinical Assessments
o
Directed physical exam
o
Vital signs
o
Concomitant medications
o
AE assessment
o
Performance status

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
Laboratory Assessments (to be done prior to study drug administration)
o
Hematology
o
Chemistry
o
Thyroid function
o
Pregnancy test (for women of childbearing potential)
o
Lymphocyte subsets by flow cytometry (for Cycle 5, Day 1 only)
o
Disease assessment:

Tumor marker assessment: urinalysis – 24-hour UPEP/UPIE (Cycle 5, 
Day 1, if clinically indicated, repeat every 4 cycles thereafter)

Tumor marker assessment: Serum protein and immunofixation 
electrophoresis (SPEP/SPIE) and serum-free light chains (FLC) 
(Cycle 5, Day 1, if clinically indicated, repeat every 4 cycles thereafter)
For participants who achieve serologic markers consistent with complete 
response (disappearance of serum and urine M-protein on electrophoresis for 
patients with measurable M-protein at treatment initiation or normalization of 
the free light chain ratio for those with elevated free light chain markers but 
unmeasurable M-protein at treatment initiation) after 4 cycles of therapy, a 
bone marrow biopsy will be obtained to evaluate for complete response (CR) 
according to IMWG criteria.

Tissue Collection/Biopsy
o
Bone marrow biopsy (only needed if serologic markers consistent with CR)
6.3.3 End-of-Treatment Study Procedures
To be completed within 21 days of the last administration of pembrolizumab.

Clinical Assessments
o
Concomitant medications
o
AE assessment

Laboratory Assessments
o
Disease assessment:

Tumor marker assessment: urinalysis 24-hour UPEP/UPIE (if clinically 
indicated)

Tumor marker assessment: Serum protein and immunofixation 
electrophoresis (SPEP/SPIE)
In participants who discontinue study treatment, SPEP/SPIE, FLC, and 24-hour UPEP/UPIE (for 
participants being monitored by 24-hour UPEP/UPIE due to unmeasurable SPEP/SPIE or if 
disease progression is suspected) should be performed at the time of treatment discontinuation 
(±3-week window).
For participants who discontinue study treatment without documented disease progression and 
who do not withdraw from the study, every effort should be made to continue monitoring their 
disease status by lab markers at least once every 3 months until the start of a new anticancer 
treatment, disease progression, pregnancy, death, withdrawal of consent, or the end of the 
study, whichever occurs first for up to one year.

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Participants who develop progression of disease and/or start subsequent anti-cancer treatment 
may be taken off study and will not require further disease assessments.
6.3.4 Safety Follow-Up 
Participants will be followed at 30 days (+/- 5 days) after discontinuing study treatment.  The 
following procedures will be performed at Follow Up visit:

Clinical Assessments
o
Directed physical exam
o
Vital signs
o
Concomitant medications
o
AE assessment
o
Performance status
o
Post-treatment anticancer therapy status

The investigator or qualified designee will review all new anti-
neoplastic therapy initiated after the last dose of trial treatment.  If a 
participant initiates a new anti-cancer therapy within 30 days after the 
last dose of trial treatment, the 30-day Safety Follow-up visit must 
occur before the first dose of the new therapy.  Once new anti-cancer 
therapy has been initiated the participant may be taken off study.
o
Survival/long-term follow-up

Laboratory Assessments
o
Hematology
o
Chemistry
o
Thyroid function
6.3.5 Long Term/Survival Follow-up 
After completing the follow-up period, participants will be followed every 12 weeks (+/- 14 days) 
to assess for survival/anti-cancer therapy status for up to 1 year after treatment completion or 
discontinuation. If possible, these visits will be done via video appointment. 
Long term/Survival Follow-up visits are only required for patients who have either completed 35 
cycles of therapy or have discontinued treatment for reasons other than disease progression 
and have not yet started treatment with another anti-cancer therapy.
The following procedures will be performed at each Long-Term/Survival Follow-Up visit:

Clinical Assessments
o
Concomitant medications
o
AE assessment
o
Post-treatment anticancer therapy status
o
Survival/long-term follow-up

Laboratory Assessments (review of markers if indicated)
o
Tumor marker assessment: urinalysis – 24-hour UPEP/UPIE (if clinically 
indicated)

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o
Tumor marker assessment: Serum protein and immunofixation 
electrophoresis (SPEP/SPIE) and serum FLC (free light chains)
Participants who experienced confirmed disease progression or start a new anticancer therapy 
will be taken off study. Efforts will be made to contact these participants for survival follow-up by 
telephone every 12 weeks (± 14 days) to assess for survival status until death, withdrawal of 
consent, or the end of the trial, whichever occurs first for up to one year after treatment 
discontinuation.
6.4
Use of Concomitant Medications
6.4.1 Concomitant Medications / Vaccinations (Allowed & Prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The final decision on any supportive therapy or vaccination rests 
with the investigator and/or the participant’s primary physician. However, the decision to 
continue the participant on study intervention requires the mutual agreement of the investigator, 
the Sponsor, and the participant.
6.4.2 Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. This includes supportive care measures such as antimicrobial/antiviral prophylaxis 
and intravenous immunoglobulin therapy for hypogammaglobulinemia.   All concomitant 
medication will be recorded on the case report form (CRF) including all prescriptions, over the 
counter (OTC), herbal supplements, and IV medications and fluids.  If changes occur during the 
trial period, documentation of drug dosage, frequency, route, and date may also be included on 
the CRF.
All concomitant medications received within 28 days prior to the first dose of trial intervention 
and up to 30 days after the last dose of trial intervention should be recorded.  Concomitant 
medications administered after 30 days after the last dose of trial intervention should be 
recorded for SAEs and events of clinical interest (ECIs) as defined in Section 8.3.
6.4.3 Prohibited Concomitant Medications
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial:

Antineoplastic systemic chemotherapy or biological therapy 
o For participants with a history of breast cancer, the use of endocrine therapy for 
breast cancer prevention (e.g. selective estrogen receptor modulators and 
aromatase inhibitors) is allowed. 

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Radiation therapy EXCEPT: localized radiation for symptomatic relief may be 
allowed at the investigator’s discretion during the screening phase of the trial and for 
isolated sites (field of radiation covers ≤ 5% of the total bone marrow) of symptomatic 
disease during the treatment phase assuming no evidence of systemic progression 

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and participants are deemed to be deriving clinical benefit from study treatment as 
assessed by study investigator. 

Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the study.  Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, 
and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., 
FluMist®) are live attenuated vaccines and are not allowed. SARS-COV-2 vaccines 
are generally mRNA-based or viral vector vaccines (replication-incompetent) and are 
allowed.

Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor.
Participants 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. All 
treatments that the Investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care.  
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the study, discontinuation from study therapy or vaccination may 
be required.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant’s primary physician.  However, the decision to continue the 
participant on study treatment requires the mutual agreement of the investigator, the Sponsor, 
and the participant. There are no prohibited therapies during the Post-Treatment Follow-up 
Phase.
6.4.4 Rescue Medications & Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 5.2 [Table 5.2-1].  Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do not 
improve with administration of corticosteroids.  Note that several courses of steroid tapering 
may be necessary as symptoms may worsen when the steroid dose is decreased.  For each 
disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care.  The treatment 
guidelines are intended to be applied when the investigator determines the events to be related 
to pembrolizumab. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
Given that pembrolizumab may reactivate anti-BCMA CAR-Ts, there is a theoretical risk for 
development of cytokine release syndrome (CRS). CRS is a well-known side-effect of CAR-T 
therapies and is characterized by systemic inflammation, fever, and organ dysfunction due to 
immune activation. Clinical manifestation of CRS includes high fevers, hypotension, tachypnea, 
hypoxia, confusion, fatigue, nausea, vomiting, headache, evidence of disseminated 
intravascular coagulation, and macrophage activation syndrome. The etiology of CRS is thought 
to be secondary to increased inflammatory cytokines and activation of T-lymphocytes, 

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macrophages, and endothelial cells. These factors are important for activation and clonal 
expansion of CAR-T therapies and thus some degree of CRS is to be expected with CAR-T 
therapy. However, in some cases, the over-activation of immune responses may be associated 
with significant organ dysfunction, and thus therapies, including anti-inflammatory and anti-
cytokine therapies, may be needed to modulate the degree of immune activation.
At least two doses of tocilizumab per patient must be available on site prior to dosing of 
pembrolizumab.
6.4.4.1
Cytokine Release Syndrome Management
For patients treated with CAR-T therapies, significant CRS can occur in more than one-half of 
patients, with the frequency of significant CRS depending on the underlying disease process 
and specific CAR-T product. In the treatment of MM, a CRS rate of 76% was observed in a 
phase I study of bb2121, an anti-BCMA CAR-T product, with the majority of events being grade 
1 or 2 (70%); 6% were grade 3 events with no grade 4 or higher events observed1. Similar 
findings were observed in other early phase anti-BCMA CAR-T studies47,48
Management of cytokine release syndrome has involved the selective use of anti-cytokine 
therapies and anti-inflammatories for those patients with moderate to severe CRS. For patients 
with mild CRS (grade 1-2), supportive care alone with antihistamines, antipyretics, intravenous 
fluids, and close monitoring may be sufficient. For patients with moderate to severe CRS (grade 
3 or higher; certain grade 2 cases), additional measures may be needed including: tocilizumab 
(anti-IL-6 receptor antibody), anakinra (IL-1 receptor antagonist), and/or dexamethasone. Given 
the success of tocilizumab in modulating severity of CRS, patients with moderate to severe CRS 
should be treated with tocilizumab first if supportive measures alone are unable to control the 
CRS. Tocilizumab is given as weight-based dose of 8 mg/kg intravenously at time of clinical 
instability, with the decision to administer and the timing individualized on a case-by-case basis 
with close consultation between the principal investigator (PI) and/or clinical investigators on the 
study. In severe cases or for those cases refractory to tocilizumab, additional therapies may be 
needed including: additional doses of tocilizumab, dexamethasone, or other anti-
inflammatory/cytokine therapies. 
Common indications for tocilizumab include any of the following:

Hemodynamic instability despite intravenous fluids, especially if requiring 
vasopressor support

Worsening respiratory status, including increasing oxygen requirements and/or need 
for high-flow oxygen, face mask, or mechanical ventilation. 

Any other significant deterioration thought to be secondary to CRS despite medical 
management.

Patients with CRS should also undergo evaluation for infection and other causes for 
fevers and organ dysfunction. Patients should be closely monitored and may need 
admission to an intensive care unit depending on the clinical situation. 

Grading of CRS utilizes the ASTCT consensus criteria49. Refer to Appendix 4 for 
details.
6.4.4.2
Immune-effector Cell-associated Neurotoxicity Syndrome
Given that pembrolizumab may re-activate anti-BCMA CAR-T cells, there is a theoretical risk for 
development of immune-effector cell-associated neurotoxicity syndrome (ICANS).

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Similar to CRS, ICANS is a well-described toxicity of CAR-T therapy and is also considered to 
be a result of excessive immune activation. Clinical symptoms include: altered levels of 
consciousness, impairment of cognitive function, aphasia, seizures, and cerebral edema. The 
typical onset of neurologic toxicity is usually within several days after onset of CRS but may 
occur independently of CRS. In the phase I study of the anti-BCMA CAR-T bb2121, 14 patients 
(42%) reported neurologic toxic effects, with 13 patients (39%) incurring grade 1 or 2 toxicities 
and 1 patient (3%) having grade 4 toxicity1. Similar rates were observed in early phase studies 
of other anti-BCMA CAR-T therapies47,48.
Treatment for ICANS depends on severity of presentation. The ASTCT criteria are useful for 
risk-stratifying patients (refer to Appendix 5)49. In general, patients with Grade 1 toxicity can be 
treated with supportive care and close monitoring (including frequent neurologic exams and 
assessment). Patients with Grade 2 or higher toxicity may require IV steroids, with 
dexamethasone 10 mg IV q6-12 hours as a standard front-line therapy. The use of other anti-
inflammatories, including tocilizumab may be considered, especially if there is concurrent CRS. 
Additional workup including neuroimaging, electroencephalogram, and pupillometry may be 
indicated.  Other supportive measures may include the addition of antiepileptics and in severe 
cases, transfer to the intensive care unit. Ultimately, each case of ICANS will be assessed and 
treated on a case-by-case basis, and any interventions to address ICANS, including the use of 
steroids, is acceptable when deemed medically appropriate by the treating physician in close 
consultation between the principal investigator (PI) and/or clinical investigators on the study.
6.5
Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea, or vomiting.
6.6
Participant Discontinuation Criteria
When a participant discontinues prior to trial completion, all applicable activities scheduled for 
the final trial visit should be performed at the time of discontinuation.  Any adverse events which 
are present at the time of discontinuation should be followed in accordance with the safety 
requirements outlined in Section 8.3.
Discontinuation of study intervention does not represent withdrawal from the study.
Participants may discontinue study treatment at any time for any reason or be dropped from the 
study treatment at the discretion of the investigator should any untoward effect occur.  In 
addition, a participant may be discontinued from study treatment by the investigator or the 
Sponsor if study treatment is inappropriate, the trial plan is violated, or for administrative and/or 
other safety reasons.  Specific details regarding procedures to be performed at study treatment 
discontinuation are provided in the subsequent sections.
A participant may be discontinued from study treatment but continue to be monitored in the 
study for any of the following reasons:

The participant or participant’s legally acceptable representative requests to 
discontinue study treatment.

Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment.

Unacceptable adverse experiences/dose-limiting toxicities including:
o
Grade 3 or higher immune-related AE that warrant discontinuation as outlined 
in Table 5.2-1

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o
Grade 3 or higher infusion reaction as outlined in Table 5.2-2
o
Grade ≥ 3 CRS not responsive to tocilizumab therapy and/or best medical 
care after 72 hours or grade 4 CRS 
o
Grade ≥ 3 ICANS not responsive to best medical care after 72 hours or grade 
4 ICANS
o
Recurrent grade 2 pneumonitis

The participant has a medical condition or personal circumstance which, in the 
opinion of the investigator and/or sponsor, placed the participant at unnecessary risk 
from continued administration of study treatment.

The participant has a confirmed positive serum pregnancy test

Noncompliance with study treatment or procedure requirements

The participant is lost to follow-up

Completion of 35 treatments (approximately 2 years) with pembrolizumab

Administrative reasons
6.7
Participant Withdrawal from Study
Participants who withdraw prior to completion of the trial should be encouraged to complete all 
applicable activities scheduled for the final study visit at the time of withdrawal. Any AEs that are 
present at the time of withdrawal should be followed in accordance with the safety requirements 
outlined in Section 8.3.
A participant must be withdrawn from the study if the participant or the participant’s legally 
acceptable representative withdraws consent from the study.
A participant may also be withdrawn from the study for the following reasons:

Progressive disease

Start of new anti-cancer therapy

Noncompliance with study treatment or procedure requirements

The participant is lost to follow-up

Investigator decision
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specified details regarding procedures to be performed at the time of withdrawal from the study 
are outlined in Section 6.3.3.
6.8
Participant Replacement Strategy
If a participant is enrolled but does not receive any doses of pembrolizumab, the participant may 
be replaced.
If a participant is enrolled and receives less than 4 cycles of therapy and discontinues therapy or 
withdraws from the study for reasons other than disease progression, the participant will not be 
evaluated for the primary efficacy endpoint and will be replaced. However, all participants who 
receive at least one dose of pembrolizumab will be included in the safety analysis for adverse 
events (including those that received < 4 cycles of therapy).

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6.9
Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1.
Quality or quantity of data recording is inaccurate or incomplete
2.
Poor adherence to protocol and regulatory requirements
3.
Incidence or severity of adverse drug reaction in this or other studies indicates a 
potential health hazard to participants
4.
Plans to modify or discontinue the development of the study drug
In the event of Merck's decision to no longer supply study drug, adequate notification will be 
provided so that appropriate adjustments to participant treatment can be made.
7
Reporting and Documentation of Results
7.1
Evaluation of Efficacy: Antitumor Effect – Hematologic Tumors
Measurement of antitumor effect will be primarily through tumor markers (SPEP/SPIE, FLC, 
UPEP/UPIE, and bone marrow biopsy [where applicable]) as per International Myeloma 
Working Group (IMWG) Uniform Response Criteria. Only participants that complete at least 4 
cycles of therapy or have progressive disease after at least one cycle of therapy will be included 
in the analysis for the primary endpoint. See Appendix 6 for additional details.
7.1.1 Methods for Evaluation of Measurable Disease
For participants with measurable disease by M-protein (serum M-protein ≥ 1 g/dL), response 
criteria will be determined primarily by SPEP/SPIE. For participants with measurable disease by 
24-hour UPEP/UPIE (≥ 200 mg/24 hours) but not by SPEP/SPIE (M-protein < 1 g/dL), response 
criteria will be determined primarily by UPEP/UPIE. For participants with only measurable 
disease by FLC and without measurable disease by SPEP/SPIE and UPEP/UPIE, response 
criteria will be determined primarily by FLC levels. 
Participants will also undergo 24-UPEP/UPIE at certain time points depending on 24-hour 
UPEP/UPIE at screening.

Participants who have measurable disease by SPEP/SPIE (M-protein ≥ 1 g/dL) 
and by 24-hour UPEP/UPIE (≥ 200 mg/24 hours) at screening will undergo a 24-
hour UPEP/UPIE at time of suspected sCR, CR, VGPR, PR, and progressive 
disease. 

Participants with measurable disease by SPEP/SPIE (M-protein ≥ 1 g/dL) but no 
measurable 24-hour UPEP/UPIE (< 200 mg/24 hours) at screening will undergo 
a 24-hour UPEP/UPIE at time of suspected sCR, CR, VGPR, and progressive 
disease to confirm IMWG response criteria. 

Participants with only measurable disease by FLC and without measurable 
disease by SPEP/SPIE and UPEP/UPIE at screening will undergo 24-hour 
UPEP/UPIE at time of suspected sCR, CR, VGPR, and progressive disease. 
For participants who develop serologic markers consistent with a complete response 
(disappearance of serum and urine M-protein on electrophoresis for patients with measurable 
M-protein at treatment initiation or normalization of the free light chain ratio for those with 

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elevated free light chain markers but unmeasurable M-protein at treatment initiation), a bone 
marrow biopsy is required to confirm IMWG complete response.  
For participants with known soft tissue plasmacytomas or extramedullary disease on enrollment, 
imaging (PET/CT, CT, or MRI) is recommended to confirm IMWG response for patients who 
achieve at least a hematologic partial response. Imaging is also recommended if there is clinical 
concern for progressive disease.
7.1.2 Response Criteria
The primary endpoint is the overall response rate (ORR), defined as the proportion of patients 
achieving a partial response (PR) or better (including sCR, CR, and VGPR) after 4 cycles of 
pembrolizumab therapy. The response criteria are described below (see Appendix 6 for 
additional details) :

Stringent complete response (sCR)
o
Requires achieving complete response (CR) defined below plus normal FLC ratio 
and absence of clonal plasma cells by immunohistochemistry or flow cytometry

Complete response (CR)
o
For patients with measurable serum or urine M-protein on enrollment: negative 
immunofixation of serum and urine and < 5% plasma cells in the bone marrow is 
required
o
For patients without measurable serum and urine M-protein levels on enrollment: 
a normal FLC ratio (0.6 – 1.65) is necessary in addition to the above criteria
o
For patients with known soft tissue plasmacytomas or extramedullary disease on 
enrollment, disappearance of all soft tissue plasmacytomas is required to meet 
CR

Very good partial response (VGPR)
o
For patients with measurable serum or urine M-protein on enrollment: detectable 
M-protein on immunofixation but not on electrophoresis or ≥ 90% reduction in 
serum M-protein plus urine M-component < 100 mg/24 hours is required.
o
For patients without measurable serum and urine M-protein levels on enrollment 
(only measurable disease is by serum FLC): ≥ 90% decrease in the difference 
between involved and uninvolved free light chains is required.

Partial response (PR)
o
For patients with measurable serum and urine M-protein on enrollment: ≥ 50% 
reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥ 
90% to < 200 mg/24 hours are required.
o
For patients with measurable serum but without measurable urine M-protein on 
enrollment: ≥ 50% reduction of serum M-protein is required.
o
For patients without measurable serum and urine M-protein levels on enrollment 
(only measurable disease is by serum FLC): ≥ 50% decrease in the difference 
between involved and uninvolved free light chains is required (provided the 

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serum-free light chain assay shows involved level > 10 mg/dL and the serum-free 
light chain is abnormal).
o
For patients with known soft tissue plasmacytomas or extramedullary disease on 
enrollment, ≥ 50% reduction in size of soft tissue plasmacytomas is required in 
addition to the above criteria. 

Stable Disease (SD)
o
Not meeting criteria for sCR, CR, VGPR, PR, or PD

Progressive Disease (PD)
Meeting one of the following criteria:
o
Increase of ≥ 25% from the lowest response value achieved in one or more of 
the following:

serum M-protein: absolute increase must be ≥ 0.5 g/dL) 

Urine M-component (absolute increase must be ≥ 200 mg/24h)

Only in patients without measurable serum and urine M-protein levels at 
enrollment: the difference between involved and uninvolved FLC levels 
(absolute increase must be > 10 mg/dL) 
o
Definite development of new bone lesions or soft tissue plasmacytomas or 
definite increase in the size of existing bone lesions or soft tissue 
plasmacytomas
o
Development of hypercalcemia (corrected serum calcium 11.5 mg/dL) that 
can be attributed solely to the plasma cell proliferative disorder.
7.1.3 Time to Event Definitions
Progression-free survival (PFS) is defined as the duration of time from start of treatment to time 
of progression or death, whichever occurs first.
Overall survival (PFS) is defined as the duration of time from start of treatment to time of death.
Time-to-next treatment (TNT) is defined as the duration of time from start of treatment to start of 
next line therapy. 
7.2
Evaluation of Safety
The safety parameters for this study include all laboratory tests and hematological 
abnormalities, physical findings, and spontaneous reports of adverse events reported to the 
investigator by participants.
Toxicity will be assessed according to the ASTCT criteria for CRS and ICANS and NCI CTCAE 
version 5.0 for all other toxicities. 
Safety analyses will be performed for all participants who receive at least one dose of 
pembrolizumab. 

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8
Safety Parameters
8.1
Definitions
8.1.1 Adverse Event (AE)
Adverse event means any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention-related (21 CFR 312.32 (a)).
8.1.2 Serious Adverse Event (SAE)
An adverse event is considered serious if, in the view of either the investigator or sponsor, it 
results in any of the following outcomes: 

Death

Life-threatening adverse event
o
An adverse event is considered life-threatening if, in the view of either 
the investigator or sponsor, its occurrence places the participant at 
immediate risk of death. It does not include an adverse event that, 
had it occurred in a more severe form, might have caused death.

Inpatient hospitalization or prolongation of existing hospitalization

A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life function

Congenital anomaly/birth defect
Important medical events that may not result in death, are life-threatening or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse.
8.1.3 Unanticipated Problem (UP)
An unanticipated problem (UP) is any incident, experience, or outcome that meets all of the 
following criteria:
1) unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being study;
2) related or possibly related to participation in the research; and 
3) suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) related to the 
research than was previously known or recognized.
Only a small subset of adverse events occurring in human subjects participating in research will 
meet these three criteria for an unanticipated problem. Furthermore, there are other types of 
incidents, experiences, and outcomes that occur during the conduct of human subjects research 
that represent unanticipated problems but are not considered adverse events. For example, 

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some unanticipated problems involve social or economic harm instead of the physical or 
psychological harm associated with adverse events. In other cases, unanticipated problems 
place subjects or others at increased risk of harm, but no harm occurs.
8.2
Classification of Adverse Events
8.2.1 Severity
Adverse events are graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0.
8.2.2 Attribution 
Adverse events are given an assignment of attribution or relationship to the investigational 
agent(s) or study procedure.  Attribution categories are:

Definite – The adverse event is clearly related to the investigational agent(s) or study 
procedure. 

Probable – The adverse event is likely related to the investigational agent(s) or study 
procedure. 

Possible – The adverse event may be related to the investigational agent(s) or study 
procedure. 

Unrelated – the adverse event is clearly not related to the investigational agent(s) or 
study procedure.
8.2.3 Expectedness
An adverse event is considered unexpected if the nature, severity, or frequency of the event is 
not listed in the study protocol, product inserts, investigator brochure, or informed consent 
document.
8.3
Recording of Adverse Events
Refer to the Data Safety Monitoring Plan, located in Appendix 2.
8.4
Expedited Reporting 
8.4.1 Reporting to the HDFCCC Data and Safety Monitoring Committee
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and it is determined to be related either to the study drug(s) 
or to a study procedure, the UCSF PI or his/her designee must notify the DSMC Chair (or 
qualified alternate) within 1 business day of knowledge of the event.  The contact may be by 
phone or e-mail.
8.4.2 Reporting to Institutional Review Board
The UCSF PI must report events to the IRB according to institutional guidelines.

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8.4.3 Expedited Reporting to the FDA
If the study is being conducted under an IND, the Sponsor (or the Sponsor-Investigator) is 
responsible for determining whether or not the suspected adverse reaction meets the criteria for 
expedited reporting in accordance with federal regulations (21 CFR §312.32). 
The Sponsor (or Sponsor-Investigator) must report in an IND safety report any suspected 
adverse reaction that is both serious and unexpected. The Sponsor needs to ensure that the 
event meets all three definitions: 

Suspected adverse reaction 

Unexpected 

Serious 
If the adverse event does not meet all three of the definitions, it should not be submitted as an 
expedited IND safety report.
The timeline for submitting an IND safety report to FDA is no later than 15 calendar days after 
the Investigator determines that the suspected adverse reaction qualifies for reporting (21 CFR 
312.32(c)(1)). 
Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA no 
later than 7 calendar days after the Investigator’s initial receipt of the information (21 CFR 
312.32(c)(2)). 
Any relevant additional information that pertains to a previously submitted IND safety report will 
be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the 
information is available (21 CFR 312.32(d)(2)). 
8.4.4 Reporting to Industry Partners/External Collaborators
Selected nonserious and SAEs are also known as events of clinical interest (ECIs) and must be 
reported to Merck. 
Events of clinical interest for this study include: 
1.
An overdose of pembrolizumab that is not associated with clinical symptoms or 
abnormal laboratory results. For purposes of this study, an overdose of pembrolizumab 
will be defined as any dose of 1,000 mg or greater (≥5 times the indicated dose).  No 
specific information is available on the treatment of overdose of pembrolizumab. In the 
event of overdose, the participant should be observed closely for signs of toxicity.  
Appropriate supportive treatment should be provided if clinically indicated.  If an adverse 
event(s) is associated with (“results from”) the overdose of a Merck product, the adverse 
event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met.
2.
An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is 
less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The purpose of 
the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology. 

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Additionally, any SAE brought to the attention of an investigator at any time outside of the time 
period specified above must be reported immediately to Merck if the event is considered drug 
related.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to Merck within the time frames as indicated in Table 8.4.4. 
Table 8.4.4
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time 
Period:
After the 
Protocol-
specified Follow-
up Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Merck:
Serious 
Adverse Event 
(SAE) 
including 
Cancer and 
Overdose
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Report if:
- drug/vaccine-
related.
(Follow ongoing to 
outcome)
Within 2 
business days 
but no longer 
than 3 calendar 
days of 
learning of 
event
Pregnancy/
Lactation 
Exposure
Report if:
- due to 
intervention
- causes exclusion
Report all
Previously 
reported – Follow 
to 
completion/termina
tion; report 
outcome
Within 2 
business days 
but no longer 
than 3 calendar 
days of 
learning of 
event
Event of 
Clinical 
Interest 
(require 
regulatory 
reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- potential drug-
induced liver injury 
(DILI)
- require regulatory 
reporting
Not required
Within 2 
business days 
but no longer 
than 3 calendar 
days of 
learning of 
event
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices Agency (PMDA), or other local 
regulators. Investigators will cross-reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally, investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety;
) at the time of submission to FDA.
8.5
Follow-up of Adverse Events
All participants who experience adverse events will be followed with appropriate medical 
management until resolved or stabilized, as determined by the investigator or until the initiation 

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of new anti-cancer therapy, whichever occurs first. For selected adverse events for which 
administration of the study drug/intervention was stopped, a re-challenge of the subject with the 
study drug/intervention may be conducted if considered both safe and ethical by the 
investigator.
8.6
Adverse Events Monitoring
Refer to the Data Safety Monitoring Plan, located in Appendix 2.
8.7
Pregnancy and Exposure during Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to Merck.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
9
Statistical Considerations and Evaluation of Results
This study will utilize a Simon’s two-stage design with 15 participants enrolled in stage I and 10 
additional participants enrolled in stage II assuming that at least 2 or more participants achieve 
a treatment response after 4 cycles of therapy during stage I of the study. The primary endpoint 
will be overall response rate (partial response [PR] or better) after 4 cycles of therapy. A 
Bayesian toxicity monitoring design will be incorporated for ongoing safety analysis during the 
trial to pause enrollment if at any time the rate of grade 3 or higher non-hematologic adverse 
events exceeds 30%. 
9.1
Sample Size Considerations
9.1.1 Sample Size and Power Estimate
The primary endpoint is the overall response rate (ORR), defined as the proportion of patients 
achieving a partial response (PR) or better after 4 cycles of pembrolizumab therapy. Simon’s 
minimax two-stage design will be used to test the null hypothesis that the true ORR is 10% 
against a one-sided alternative that the true ORR is higher than 30%. The two-stage minimax 
design described below will have an 80% power to reject the null hypothesis that ORR is 10% at 
one-sided Type I error rate of 5%, assuming that the ORR is 30%.
Stage 1: 15 participants will be accrued. The trial will be terminated at Stage 1 if 0 or 1 response 
is observed; otherwise, it will continue to Stage 2. Response rate for Stage I will be determined 
based on patients who have completed at least 4 cycles of therapy or have progressive disease 
after at least one cycle of therapy; participants who withdraw or drop out due to toxicities before 
meeting these endpoints will not be used in the analysis of response and will be replaced.
Stage 2: 10 more patients will be accrued (for a total of 25 patients). We will reject the null 
hypothesis if 6 or more responses are observed in 25 patients. 
Early stopping probability: Under this design, if the true response rate is 10%, the probability of 
stopping the trial early will be 55%.

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We plan to enroll 25-27 participants to allow for the possibility of 10% participant dropout before 
receiving pembrolizumab therapy or during the response evaluation period. 
9.1.2 Accrual Estimates
We anticipate enrolling approximately 12 – 15 patients a year. As an active clinical trial site and 
a center that offers commercial anti-BCMA CAR-T, we anticipate 30 to 50 patients to receive 
anti-BCMA CAR-T on a yearly basis; the majority of these patients will ultimately have disease 
progression, allowing for enrollment in this clinical trial. 
9.2
Interim Analyses and Stopping Rules
The clinical trial will be stopped for futility if after the first stage of Simon two-stage trial (after 
fifteen evaluable participants enrolled), there are only zero or one participant who responds with 
PR or better according to IMWG. 
There will also be monitoring for adverse events, specifically for non-hematologic grade 3 or 
higher adverse events. If at any point it is expected that the rate of grade 3 or higher non-
hematologic AE exceeds 30%, enrollment will be paused for safety review by the HDFCCC data 
and safety monitoring committee, study sponsor, and study PI. If after this safety review is 
conducted and the study is deemed unsafe to continue, the study will be stopped. 
Previous data suggested a severe grade 3-4 AE rate of around 15-20% in pembrolizumab 
monotherapy trials across various cancers17,37–40. These events would be expected to be 15-
20% in this study irrespective of cause. Hence, we will render the study treatment tolerable in 
this population if the observed severe adverse event rate is <30%. We will report the toxicity 
and advise the providers regarding excessive toxicity and pause enrollment for a safety review if 
at any point it is expected that the rate of grade 3 or higher non-hematologic AE exceeds 30%. 
Moreover, the study will be stopped and the FDA will be informed if at any point it is expected 
that the rate of Grade 4 or higher adverse events (including Grade 4 CRS and treatment-related 
immunologic AEs) or any treatment-related death exceeds 30%. In this case, the FDA must 
approve the study’s resumption prior to re-initiation of enrollment and study treatment. 
Specifically, we will apply a Bayesian toxicity monitoring rule with Beta (0.6, 3.4) as the prior 
distribution. This means that our prior guess of the proportion of toxicity is 15%, and there is 
90% chance that the rate of toxicity is 0.2%-48.9%. We will suspend enrollment if the posterior 
probability that the toxicity rate exceeds the threshold (30%) is 70% or higher and stop the study 
if the rate of Grade 4 or higher adverse events (including Grade 4 CRS and treatment-related 
immunologic AEs) or any treatment-related death meets these parameters. The monitoring will 
start from the first patient, and the decision rule for a safety pause/stop is as follows:

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Pause if at any time:
# toxicity and death
Out of # patients
2
2
3
3-5
4
6-8
5
9-11
6
12-14
7
15-17
8
18-20
9
21-23
10
24-25
Study enrollment will also be paused for safety review if any participants encounter:

Treatment-related death

Grade 4 toxicity (excluding clinically insignificant/temporary laboratory 
abnormalities)

Grade 4 CRS or Grade 3 CRS that does not resolve to Grade ≤ 1 or baseline within 48 
hours

Grade 4 ICANS or Grade 3 ICANS that does not resolve to Grade ≤ 1 or baseline within 
48 hours
9.3
Analysis Plans
9.3.1 Primary Analysis (or Analysis of Primary Endpoints)
Participants that complete at least 4 cycles of therapy or have progressive disease after at least 
one cycle of therapy will be included in the analysis.  
To account for the adaptive nature of Simon’s two-stage design, final analyses for the primary 
endpoint will calculate the uniformly minimum variance unbiased estimator (UMVUE), p-value, 
and 95% CI for the proportion of patients achieving partial response (PR) or better after 4 cycles 
of pembrolizumab therapy. The calculation will be performed using R clinfun package (www.r-
project.org). 
9.3.2 Secondary Analysis (or Analysis of Secondary Endpoints)
Continuous data will be summarized using descriptive statistics such as means, medians, 
standard deviations, and ranges. Categorical data will be summarized using frequency counts 
and percentages. Graphical summaries of selected endpoints may also be presented. 
Secondary Objective and Endpoints #1 - Safety and Tolerability Analysis: The safety population 
will consist of all participants who receive any amount of study treatment. Safety will be 
assessed by evaluation of AEs. The safety analyses will be performed using the safety 
population. Specific AEs will be counted once for each participant for calculating rates but will 
be presented in total in participant listings. 
Secondary Objective and Endpoints #2 -Depth of Response

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Point estimate and exact binomial confidence interval will be reported for the proportion of 
patients achieving PD (progressive disease), SD (stable disease), PR (partial response), VGPR 
(very good partial response), CR (complete response), and sCR (stringent complete response) 
for best-achieved response at any time during pembrolizumab therapy.
Secondary Objective and Endpoints #3 -Time to Event Outcomes
For overall survival (OS), participants who remain alive at the end of study follow-up will be 
censored at the time when they are known to be alive. For progression-free survival (PFS), 
participants without progression or death will be censored at the time of the last evaluable 
disease assessment, while participants without a disease assessment will be censored at the 
date of first study treatment received. OS and PFS will be summarized using the Kaplan-Meier 
(KM) method. The 12-months event-free probabilities, 25th percentile, median, and 75th 
percentile, along with their corresponding 95% confidence intervals, will be reported. Median 
duration of response among the responders will be reported along with 95% confidence 
intervals. Competing risks analysis will be performed for analyzing time to next treatment (TNT), 
with death as a competing event. For patients who are alive and do not receive the next line of 
therapy, TNT will be censored at the last study contact. Cumulative incidence function, along 
with 95% confidence intervals, will be reported for TNT.
9.3.3 Exploratory Analysis
For immunologic correlatives, analysis will be predominately descriptive. Lymphocyte counts 
(ALC, CD3, CD4, ad CD8 counts) may depicted graphically and changes for these endpoints 
pre- and post-pembrolizumab will be assessed and compared via paired t-test. Further 
exploratory analyses may include assessing whether changes in lymphocyte count and 
composition correlate with overall response rate. 
10 Study Management
10.1 Pre-study Documentation
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all 
applicable regulatory requirements.
Before initiating this trial, the PI will have written and dated approval from the Institutional 
Review Board for the protocol, written informed consent form, subject recruitment materials, and 
any other written information to be provided to participants before any protocol-related 
procedures are performed on any participants.  
The PI must comply with the applicable regulations in Title 21 of the Code of Federal 
Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory 
requirements.  The IRB must comply with the regulations in 21 CFR §56 and applicable 
regulatory requirements.
The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed, or the FDA has determined that the 
study is exempt from IND requirements. 

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10.2 Institutional Review Board Approval
The protocol, the proposed informed consent form, and all forms of participant-facing materials 
related to the study (e.g. advertisements used to recruit participants) will be reviewed and 
approved by the IRB of record.  Prior to obtaining IRB approval, the protocol must be approved 
by the Helen Diller Family Comprehensive Cancer Center Site Committee and by the Protocol 
Review Committee (PRC).  The initial protocol and all protocol amendments must be approved 
by the IRB prior to implementation.  
10.3 Informed Consent
All participants must be provided a consent form describing the study with sufficient information 
for each participant to make an informed decision regarding their participation.  Participants 
must sign the IRB -approved informed consent form prior to participation in any study-specific 
procedure.  The participant must receive a copy of the signed and dated consent document.  
The original signed copy of the consent document must be retained in the medical record or 
research file. 
10.4 Changes in the Protocol
Once the protocol has been approved by the IRB, any changes to the protocol must be 
documented in the form of an amendment.  The amendment must be signed by the PI and 
approved by PRC and the IRB prior to implementation.  
If it becomes necessary to alter the protocol to eliminate an immediate hazard to participants, an 
amendment may be implemented prior to IRB approval.  In this circumstance, however, the PI 
must then notify the IRB according to institutional requirements.  
10.5 Handling and Documentation of Clinical Supplies
The PI will maintain complete records showing the receipt, dispensation, return, or other 
disposition of all investigational drugs at the site.  The date, quantity, and batch or code number 
of the drug, and the identification of participants to whom the investigational product has been 
dispensed by participant number and initials will be included.  
The PI shall not make the investigational product available to any individuals other than to 
qualified study participants.  Furthermore, the PI will not allow the investigational product to be 
used in any manner other than that specified in this protocol.
10.6 Case Report Forms (CRFs)
The PI and/or designee will prepare and maintain adequate and accurate participant case 
histories with observations and data pertinent to the study.  Study-specific Case Report Forms 
(CRFs) will document safety and treatment outcomes for safety monitoring and data analysis.  
All study data will be entered into OnCore® via standardized CRFs in accordance with the 
CTMS study calendar, using single data entry with a secure access account.  Study personnel 
will complete the CRFs; the PI will review and approve the completed CRFs. 
The information collected on CRFs shall be identical to that appearing in original source 
documents.  Source documents will be found in the participant’s medical records maintained by 
study personnel.  All source documentation should be kept in separate research files for each 
participant. 

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In accordance with federal regulations, the PI is responsible for the accuracy and authenticity of 
all clinical and laboratory data entered onto CRFs.  The PI will approve all completed CRFs to 
attest that the information contained on the CRFs is true and accurate. 
The PI will be responsible for ensuring the accurate capture of study data.  At study completion, 
when the CRFs have been declared to be complete and accurate, the database will be locked.  
Any changes to the data entered into the CRFs after that time can only be made by joint written 
agreement among the PI and the trial statistician.
All source documentation and CTMS data will be available for review/monitoring by the UCSF 
DSMC and regulatory agencies. 
10.7 Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will be the 
monitoring/auditing entity for this study.  The UCSF DSMC will monitor or audit the study in 
accordance with the NCI-approved Data and Safety Monitoring Plan (DSMP).  The DSMC will 
routinely review all adverse events and serious adverse events.  The DSMC will review study-
related activities to ensure that the study is conducted in accordance with the protocol, local 
standard operating procedures, FDA regulations, and Good Clinical Practice (GCP).  Significant 
results of the DSMC monitoring/auditing review will be communicated to the IRB and the 
appropriate regulatory authorities at the time of continuing review, or in an expedited fashion, as 
applicable.  See Appendix 2 - Data and Safety Monitoring Plan.
10.8 Record Keeping and Record Retention
The PI is required to maintain adequate records of the disposition of the drug, including dates, 
quantity, and use by subjects, as well as written records of the disposition of the drug when the 
study ends.  
The PI is required to prepare and maintain adequate and accurate case histories that record all 
observations and other data pertinent to the investigation on each individual administered the 
investigational drug or employed as a control in the investigation. Case histories include the 
case report forms and supporting data including, for example, signed and dated consent forms 
and medical records including, for example, progress notes of the physician, the individual's 
hospital chart(s), and the nurses' notes. The case history for each individual shall document that 
informed consent was obtained prior to participation in the study.
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed participant consent 
forms).
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research 
study.
In accordance with FDA regulations, the PI shall retain records for a period of 2 years following 
the date a marketing application is approved for the drug for the indication for which it is being 
investigated; or, if no application is to be filed or if the application is not approved for such 
indication until 2 years after the investigation is discontinued and FDA is notified.

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10.9 Publications
The preparation and submittal for publication of manuscripts containing the study results shall 
be in accordance with a process determined by mutual written agreement among the Sponsor-
Investigator and collaborators.  

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11 References
1.
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Multiple Myeloma. N. Engl. J. Med. 380, 1726–1737 (2019).
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Rodríguez-Lobato, L. G. et al. CAR T-Cells in Multiple Myeloma: State of the Art and 
Future Directions. Front. Oncol. 10, (2020).
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McGray, A. J. R. et al. Immunotherapy-induced CD8+ T Cells Instigate Immune 
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Cherkassky, L. et al. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade 
resist tumor-mediated inhibition. J. Clin. Invest. 126, 3130–3144 (2016).
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Rupp, L. J. et al. CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy 
of human chimeric antigen receptor T cells. Sci. Rep. 7, (2017).
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John, L. B. et al. Anti-PD-1 Antibody Therapy Potently Enhances the Eradication of 
Established Tumors By Gene-Modified T Cells. Clin. Cancer Res. 19, 5636–5646 (2013).
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Li, P. et al. The Third Generation Anti-HER2 Chimeric Antigen Receptor Mouse T Cells 
Alone or Together With Anti-PD1 Antibody Inhibits the Growth of Mouse Breast Tumor Cells 
Expressing HER2 in vitro and in Immune Competent Mice. Front. Oncol. 10, (2020).
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Kearl, T. J., Jing, W., Gershan, J. A. & Johnson, B. D. PD-1/PD-L1 Blockade after 
Transient Lymphodepletion to Treat Myeloma. J. Immunol. Baltim. Md 1950 190, 5620–5628 
(2013).
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Paiva, B. et al. PD-L1/PD-1 presence in the tumor microenvironment and activity of PD-1 
blockade in multiple myeloma. Leukemia 29, 2110–2113 (2015).
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Tamura, H., Ishibashi, M., Sunakawa-Kii, M. & Inokuchi, K. PD-L1–PD-1 Pathway in the 
Pathophysiology of Multiple Myeloma. Cancers 12, (2020).
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Hallett, W. H. D., Jing, W., Drobyski, W. R. & Johnson, B. D. Immunosuppressive Effects 
of Multiple Myeloma Are Overcome by PD-L1 Blockade. Biol. Blood Marrow Transplant. 17, 
1133–1145 (2011).
12.
Ishibashi, M. et al. Myeloma Drug Resistance Induced by Binding of Myeloma B7-H1 
(PD-L1) to PD-1. Cancer Immunol. Res. 4, 779–788 (2016).
13.
Benson, D. M. et al. The PD-1/PD-L1 axis modulates the natural killer cell versus 
multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti–PD-1 
antibody. Blood 116, 2286–2294 (2010).
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Sponaas, A.-M. et al. PDL1 Expression on Plasma and Dendritic Cells in Myeloma Bone 
Marrow Suggests Benefit of Targeted anti PD1-PDL1 Therapy. PLOS ONE 10, e0139867 
(2015).

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15.
Ledergor, G. et al. Single cell Dissection of Resistance to anti-BCMA CAR-T cell 
Therapy. Clin. Lymphoma Myeloma Leuk. 19, e25–e26 (2019).
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Jing, W. et al. Combined immune checkpoint protein blockade and low dose whole body 
irradiation as immunotherapy for myeloma. J. Immunother. Cancer 3, 2 (2015).
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Chong, E. A. et al. Sequential Anti-CD19 Directed Chimeric Antigen Receptor Modified 
T-Cell Therapy (CART19) and PD-1 Blockade with Pembrolizumab in Patients with Relapsed or 
Refractory B-Cell Non-Hodgkin Lymphomas. Blood 132, 4198–4198 (2018).
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Atanackovic, D., Luetkens, T. & Kröger, N. Coinhibitory molecule PD-1 as a potential 
target for the immunotherapy of multiple myeloma. Leukemia 28, 993–1000 (2014).
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Lesokhin, A. M. et al. Nivolumab in Patients With Relapsed or Refractory Hematologic 
Malignancy: Preliminary Results of a Phase Ib Study. J. Clin. Oncol. 34, 2698–2704 (2016).
20.
Mateos, M.-V. et al. Pembrolizumab combined with lenalidomide and low-dose 
dexamethasone for relapsed or refractory multiple myeloma: phase I KEYNOTE-023 study. Br. 
J. Haematol. 186, e117–e121 (2019).
21.
Badros, A. et al. Pembrolizumab, pomalidomide, and low-dose dexamethasone for 
relapsed/refractory multiple myeloma. Blood 130, 1189–1197 (2017).
22.
Usmani, S. Z. et al. Pembrolizumab plus lenalidomide and dexamethasone for patients 
with treatment-naive multiple myeloma (KEYNOTE-185): a randomised, open-label, phase 3 
trial. Lancet Haematol. 6, e448–e458 (2019).
23.
Mateos, M.-V. et al. Pembrolizumab plus pomalidomide and dexamethasone for patients 
with relapsed or refractory multiple myeloma (KEYNOTE-183): a randomised, open-label, phase 
3 trial. Lancet Haematol. 6, e459–e469 (2019).
24.
Bernabei, L. et al. PD-1 Inhibitor Combinations As Salvage Therapy for 
Relapsed/Refractory Multiple Myeloma (MM) Patients Progressing after Bcma-Directed CAR T 
Cells. Blood 132, 1973–1973 (2018).
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Disis, M. L. Immune Regulation of Cancer. J. Clin. Oncol. 28, 4531–4538 (2010).
26.
Dudley, M. E. et al. Adoptive Cell Transfer Therapy Following Non-Myeloablative but 
Lymphodepleting Chemotherapy for the Treatment of Patients With Refractory Metastatic 
Melanoma. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 23, 2346–2357 (2005).
27.
Hunder, N. N. et al. Treatment of Metastatic Melanoma with Autologous CD4+ T Cells 
against NY-ESO-1. N. Engl. J. Med. 358, 2698–2703 (2008).
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Greenwald, R. J., Freeman, G. J. & Sharpe, A. H. The b7 family revisited. Annu. Rev. 
Immunol. 23, 515–548 (2004).
29.
Okazaki, T., Maeda, A., Nishimura, H., Kurosaki, T. & Honjo, T. PD-1 immunoreceptor 
inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing 
tyrosine phosphatase 2 to phosphotyrosine. Proc. Natl. Acad. Sci. U. S. A. 98, 13866–13871 
(2001).

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30.
Zhang, X. et al. Structural and Functional Analysis of the Costimulatory Receptor 
Programmed Death-1. Immunity 20, 337–347 (2004).
31.
Sheppard, K.-A. et al. PD-1 inhibits T-cell receptor induced phosphorylation of the 
ZAP70/CD3ζ signalosome and downstream signaling to PKCθ. FEBS Lett. 574, 37–41 (2004).
32.
Riley, J. L. PD-1 signaling in primary T cells. Immunol. Rev. 229, 114–125 (2009).
33.
Parry, R. V. et al. CTLA-4 and PD-1 Receptors Inhibit T-Cell Activation by Distinct 
Mechanisms. Mol. Cell. Biol. 25, 9543–9553 (2005).
34.
Francisco, L. M., Sage, P. T. & Sharpe, A. H. The PD-1 Pathway in Tolerance and 
Autoimmunity. Immunol. Rev. 236, 219–242 (2010).
35.
Mangal, N., Salem, A. H., Menon, R. M. & Freise, K. J. Use of depth of response to 
predict progression-free survival in relapsed or refractory multiple myeloma: Evaluation of 
results from 102 clinical trials. Hematol. Oncol. 36, 547–553 (2018).
36.
Chari, A. et al. Oral Selinexor–Dexamethasone for Triple-Class Refractory Multiple 
Myeloma. N. Engl. J. Med. 381, 727–738 (2019).
37.
Robert, C. et al. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-
006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 
study. Lancet Oncol. 20, 1239–1251 (2019).
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Nishijima, T. F., Shachar, S. S., Nyrop, K. A. & Muss, H. B. Safety and Tolerability of 
PD-1/PD-L1 Inhibitors Compared with Chemotherapy in Patients with Advanced Cancer: A 
Meta-Analysis. The Oncologist 22, 470–479 (2017).
39.
Garon, E. B. et al. Pembrolizumab for the Treatment of Non–Small-Cell Lung Cancer. N. 
Engl. J. Med. 372, 2018–2028 (2015).
40.
Reck, M. et al. Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-
Based Chemotherapy for Advanced Non–Small-Cell Lung Cancer With PD-L1 Tumor Proportion 
Score of 50% or Greater. J. Clin. Oncol. (2019) doi:10.1200/JCO.18.00149.
41.
Chong, E. A. et al. Pembrolizumab for B-cell lymphomas relapsing after or refractory to 
CD19-directed CAR T-cell therapy. Blood 139, 1026–1038 (2022).
42.
Jacobson, C. A. et al. End of Phase 1 Results from Zuma-6: Axicabtagene Ciloleucel 
(Axi-Cel) in Combination with Atezolizumab for the Treatment of Patients with Refractory Diffuse 
Large B Cell Lymphoma. Blood 132, 4192 (2018).
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CARVYKTI (ciltacabtagene autoleucel) [Prescribing Information].
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Einsele, H. et al. Biological correlative analyses and updated clinical data of 
ciltacabtagene autoleucel (cilta-cel), a BCMA-directed CAR-T cell therapy, in lenalidomide (len)-
refractory patients (pts) with progressive multiple myeloma (MM) after 1–3 prior lines of therapy 
(LOT): CARTITUDE-2, cohort A. J. Clin. Oncol. 40, 8020–8020 (2022).

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45.
Martin, T. et al. Ciltacabtagene Autoleucel, an Anti–B-cell Maturation Antigen Chimeric 
Antigen Receptor T-Cell Therapy, for Relapsed/Refractory Multiple Myeloma: CARTITUDE-1 2-
Year Follow-Up. J. Clin. Oncol. 41, 1265–1274 (2023).
46.
Rajkumar, S. V. et al. Consensus recommendations for the uniform reporting of clinical 
trials: report of the International Myeloma Workshop Consensus Panel 1. Blood 117, 4691–4695 
(2011).
47.
Wang, B.-Y. et al. Long-Term Follow-up of a Phase 1, First-in-Human Open-Label Study 
of LCAR-B38M, a Structurally Differentiated Chimeric Antigen Receptor T (CAR-T) Cell Therapy 
Targeting B-Cell Maturation Antigen (BCMA), in Patients (pts) with Relapsed/Refractory Multiple 
Myeloma (RRMM). Blood 134, 579–579 (2019).
48.
Madduri, D. et al. Results from CARTITUDE-1: A Phase 1b/2 Study of JNJ-4528, a 
CAR-T Cell Therapy Directed Against B-Cell Maturation Antigen (BCMA), in Patients with 
Relapsed and/or Refractory Multiple Myeloma (R/R MM). Blood 134, 577–577 (2019).
49.
Lee, D. W. et al. ASTCT Consensus Grading for Cytokine Release Syndrome and 
Neurologic Toxicity Associated with Immune Effector Cells. Biol. Blood Marrow Transplant. 25, 
625–638 (2019).

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Appendix 1 Performance Status Criteria
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence 
of disease
0
Normal activity
Fully active, able to carry on all 
pre-disease performance 
without restriction
90
Able to carry on normal activity; 
minor signs or symptoms of disease
80
Normal activity with effort; some 
signs or symptoms of disease
1
Symptoms, but ambulatory
Restricted in physically 
strenuous activity, but 
ambulatory and able to carry out 
work of a light or sedentary 
nature (e.g., light housework, 
office work)
70
Cares for self, unable to carry on 
normal activity or to do active work
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs
2
In bed < 50% of the time
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities
Up and about more than 50% of 
waking hours
50
Requires considerable assistance 
and frequent medical care
40
Disabled, requires special care and 
assistance
3
In bed > 50% of the time
Capable of only limited self-
care, confined to bed or chair 
more than 50% of waking hours
30
Severely disabled, hospitalization 
indicated
Death not imminent
20
Very sick, hospitalization indicated
Death not imminent
4
100% bedridden
Completely disabled
Cannot carry on any self-care
Totally confined to bed or chair
10
Moribund, fatal processes 
progressing rapidly
5
Dead
0
Dead

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Appendix 2 Data and Safety Monitoring Plan for a Phase II or III Institutional Trial
1.
Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for auditing data quality and participant safety for 
all HDFCCC institutional clinical trials.  A summary of DSMC activities for this trial includes: 

Semiannual auditing (depending on trial accrual)

Review of serious adverse events

Minimum of biennial regulatory auditing
2.
Monitoring and Reporting Guidelines
Investigators will conduct a continuous review of data and participant safety at monthly site 
committee meetings where the results of each participant’s treatment are discussed and 
documented in the site committee minutes.  
All institutional Phase II and III therapeutic trials are audited on a semiannual basis, with all data 
from twenty percent of the enrolled participants audited by the DSMC Monitor/Auditor.  The 
assigned DSMC Monitor/Auditor will review no more than a total of 10 participant charts during 
the course of auditing this trial. DSMC Monitor/Auditors will send a follow-up report to the study 
team within 20 business days after the auditing visit is complete for the PI and the study team to 
resolve all action items from this report within 20 business days.  An abbreviated regulatory 
review (i.e., reviewing protocol and consent versions, SAEs, PVs, DOA logs, 1572 forms, etc.) 
will occur at each participant monitoring review; however, a full regulatory review will occur on a 
biennial basis by the DSMC for regulatory compliance.
Auditing of all enrolled participants in these trials will be complete after 20% of enrolled 
participants have been audited through five cycles of treatment.  However, regulatory reviews of 
the trial, safety reviews (i.e., Serious Adverse Event (SAE) reviews and Protocol Violation (PV) 
reviews), and audit/inspection preparation (as applicable) will continue until the trial is closed by 
the IRB.  
3.
Review and Oversight Requirements
3.1
Adverse Event Monitoring 
All Grade 3-5 adverse events (AEs), whether or not considered to be expected or 
unexpected and whether or not considered to be associated with the use of the 
investigational agent(s) or study procedure, will be entered into OnCore®, UCSF’s 
Clinical Trial Management System.  
Adverse events are graded according to the Common Terminology Criteria for Adverse 
Events (CTCAE) as developed and revised by the Common Therapy Evaluation 
Program (CTEP) of the National Cancer Institute.  Adverse events are further given an 
assignment of attribution or relationship to investigational agent or study procedure.  
Attribution categories are:

Definite – The adverse event is clearly related to the investigational agent(s) or 
study procedure.

Probable – The adverse event is likely related to the investigational agent(s) or 
study procedure.

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
Possible – The adverse event may be related to the investigational agent(s) or study 
procedure.

Unrelated – the adverse event is clearly not related to the investigational agent(s) or 
study procedure.
All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis 
at the Site Committee meetings.  The Site Committee will review and discuss the 
selected toxicity, the toxicity grade, and attribution assignment.
3.2
Serious Adverse Event Reporting
By definition, an adverse event is defined as a serious adverse event (SAE) according to 
the following criteria:

Death.

Life-threatening (i.e., results in an immediate risk of death).

Requires inpatient hospitalization or prolongation of existing hospitalization,

Permanent or significant disability/incapacity

Gives rise to a congenital anomaly/birth defect, or cancer, or any experience that 
suggests a significant hazard, contraindication, side effect, or precaution that may 
require medical or surgical intervention to prevent one of the outcomes listed above. 

Event occurring in a gene therapy study.

Event that changes the risk/benefit ratio of a study.

Any other event the Principal Investigator judges to be serious or which would 
suggest a significant hazard, contraindication, side effect, or precaution.
Serious adverse event reporting will be in accordance with all IRB regulations. For trials 
conducted under an investigational new drug (IND) application, the SAE will be reported 
in accordance with Code of Federal Regulation Title 21 Part 312.32 and will be reported 
on a Med Watch form.  
UCSF IRB website for guidance in reporting serious adverse events:
https://irb.ucsf.edu/adverse-event 
Med Watch forms and information:
www.fda.gov/medwatch/getforms.htm 
All serious adverse events are entered into OnCore®, as well as submitted to the IRB 
(per IRB guidelines).  The SAEs are reviewed and monitored by the Data and Safety 
Monitoring Committee on an ongoing basis and discussed at DSMC meetings, which 
take place every six weeks.  The date the SAE is sent to all required reporting agencies 
will be documented in OnCore®. 
If the SAE involves a subject death and is determined to be possibly, probably, or 
definitely related to the investigational drug or any research-related procedure, the event 
must be reported to the DSMC Chair (or Vice-Chair) and DSMC Director within one 
business day.  
3.3
Review of Adverse Event Rates
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported 
in the Investigator Brochure or package insert) is noted in the study, the Principal 
Investigator will notify the DSMC via report at the time the increased rate is identified.  

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The report will indicate if the incidence of adverse events observed in the study is above 
the range stated in the Investigator Brochure or package insert.
If at any time the Investigator voluntarily holds enrollment or stops the study due to 
safety issues, the DSMC Chair (or Vice-Chair) and the DSMC Director must be notified 
within one business day and the IRB must be notified as per IRB reporting regulations.
Data and Safety Monitoring Committee Contacts:
Katie Kelley, MD (DSMC Chair)
Katie.kelley@ucsf.edu
UCSF HDFCCC
San Francisco, CA 94158
John McAdams (DSMC Director) 
Box 0981
UCSF HDFCCC
San Francisco, CA 94143

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Appendix 3 Contraceptive Guidance and Pregnancy Testing
Contraception
Pembrolizumab may have adverse effects on a fetus in utero.  Refer to below for approved 
methods of contraception.
For this study, male participants will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).
Pregnancy
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, the 
participant will be immediately discontinued from study intervention(s).  The site will contact the 
participant at least monthly and document the participant’s status until the pregnancy has been 
completed or terminated.  The outcome of the pregnancy will be reported to Merck within 2 
working days 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 Merck.  
If a male participant impregnates his female partner, the study personnel at the site must be 
informed immediately and the pregnancy must be reported to Merck and followed as described 
in Section 8.7.
Breastfeeding
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, participants who are breastfeeding are not eligible for enrollment.
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below) 
Women in the following categories are not considered WOCBP:

Premenarchal

Premenopausal female with 1 of the following:
o
Documented hysterectomy
o
Documented bilateral salpingectomy
o
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.

Postmenopausal female
o
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 

A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception 

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or hormone replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with two FSH measurements in the postmenopausal range 
is required. 
o
Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment.
CONTRACEPTION REQUIREMENTS
Male Participants
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to one of the following during the protocol defined time frame in Section 3.1.1: 

Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent

Use a male condom plus partner use of a contraceptive method with a failure rate of 
<1% per year as described in Table A3 when having penile-vaginal intercourse with 
a woman of childbearing potential who is not currently pregnant.
o
Note: Men with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile-vaginal intercourse or use a male condom during each 
episode of penile penetration
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table A3 
during the protocol-defined time frame in Section 3.1.1. 

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Table A3
Highly Effective Contraception Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly.

Combined (estrogen- and progestogen- containing) hormonal contraception b, c
o
Oral 
o
Intravaginal 
o
Transdermal 
o
Injectable

Progestogen-only hormonal contraception b, c
o
Oral 
o
Injectable 
Highly Effective Methods That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly.

Progestogen-only contraceptive implant b, c 

Intrauterine hormone-releasing system (IUS) b 

Intrauterine device (IUD)

Bilateral tubal occlusion

Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP, and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used. 

Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatment. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.) 
Notes: Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies.
a)
Typical use failure rates are lower than perfect-use failure rates (i.e. when used consistently and 
correctly.
b)
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable hormonal contraceptives are limited to those which inhibit ovulation. 
Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test. 
Following initiation of treatment, pregnancy testing will be performed whenever an expected 
menstrual cycle is missed or when pregnancy is otherwise suspected; at the time points 
specified in the Schedule of Activities, and as required locally.

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Appendix 4 ASTCT Consensus Grading System for CRS

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Appendix 5 ASTCT Consensus Grading System for ICANS
Immune Effector Cell-Associated Encephalopathy (ICE) score
Score 10: no impairment
Score 7 – 9: consistent with Grade 1 ICANS
Score 3 – 6: consistent with Grade 2 ICANS
Score 0 – 2: consistent with Grade 3 ICANS
Score 0 due to patient unarousable and unable to perform ICE assessment, consistent with 
grade 4 ICANS

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Appendix 6 IMWG Uniform Response Criteria
Response
IMWG criteria46 
Stringent complete 
response (sCR)
CR as defined below plus normal FLC ratio and absence of clonal plasma cells by 
immunohistochemistry or flow cytometry
Complete response 
(CR)
Negative immunofixation of serum and urine and disappearance of any soft tissue 
plasmacytomas and < 5% plasma cells in bone marrow.
For patients without measurable serum and urine M-protein levels at baseline: a normal 
FLC ratio (0.6 –  1.65) is necessary in addition to the above criteria 
Very good partial 
response (VGPR)
Serum and urine M-component detectable by immunofixation but not on electrophoresis or 
≥90% reduction in serum M-component plus urine M-component < 100 mg/24 hours
For patients without measurable serum and urine M-protein levels at baseline: ≥90% 
decrease in the difference between involved and uninvolved free light chains
Partial response 
(PR)
≥ 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥ 90% 
to < 200 mg/24 hours. 
If serum and urine M-protein are not measurable, a decrease ≥50% in the difference 
between involved and uninvolved FLC levels is required in place of the M-protein criteria. 
If serum and urine M-protein are not measurable, and serum-free light assay is also not 
measurable, ≥ 50% reduction in bone marrow plasma cells is required in place of M-
protein, provided baseline percentage ≥ 30%. 
In addition to the above criteria, if present at baseline,  ≥50% reduction in the size of soft 
tissue plasmacytomas is also required. 
Stable Disease (SD)
Not meeting criteria for CR, VGPR, PR, or PD
Progressive disease 
(PD)
Meeting one of the following criteria:
1)
Increase of 25% from lowest response value in any of the following: 
a)
serum M-protein (absolute increase must be ≥ 0.5 g/dL) 
b)
Urine M-component (absolute increase must be ≥ 200 mg/24h)
c)
Only in patients without measurable serum and urine M-protein levels: the 
difference between involved and uninvolved FLC levels (absolute increase 
must be > 10 mg/dL) 
d)
Only in patients without measurable serum and urine M-protein levels and 
without measurable disease by FLC levels: bone marrow plasma cell 
percentage (absolute percentage must be ≥ 10%) 
2)
Definite development of new bone lesions or soft tissue plasmacytomas or 
definite increase in the size of existing bone lesions or soft tissue plasmacytomas
3)
Development of hypercalcemia (corrected serum calcium 11.5 mg/dL) that can 
be attributed solely to the plasma cell proliferative disorder. 
All response categories (CR, sCR, VGPR, PR, and PD) require 2 consecutive assessments made at any time before the institution of any new therapy 
for confirmation; CR, sCR, VGPR, PR, and SD categories also require no known evidence of progressive or new bone lesions if radiographic studies 
were performed. VGPR and CR categories require serum and urine studies regardless of whether disease at baseline was measurable on serum, 
urine, both, or neither. Radiographic studies are not required to satisfy these response requirements. Bone marrow assessments need not be 
confirmed. For PD, serum M-component increases of more than or equal to 1 g/dL are sufficient to define relapse if starting M-component is ≥ 5 g/dL.

UCSF Helen Diller Family Comprehensive Cancer Center
Version date: 04/21/22
Protocol CC#: 212530
Phase II – pembrolizumab
Page 78 of 78
Appendix 7 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. Laboratory tests for hematology, chemistry, and others are specified in Table 
A7 below.
Participants will have laboratory evaluations (CBC, basic metabolic panel (BMP), liver function 
tests (LFT), uric acid, magnesium, thyroid function tests, β-hCG for WOCBP) prior to the 
administration of pembrolizumab for each cycle to ensure adequate organ function. Results 
must be reviewed by the investigator or qualified designee and found to be acceptable prior to 
each dose of trial treatment. After Cycle 1, pre-dose laboratory procedures can be conducted up 
to 72 hours prior to dosing.
Table A7
Laboratory Tests
Hematology
Chemistry
Other
Hematocrit
Albumin
Serum or urine β-human chorionic 
gonadotropin†
Hemoglobin
Alkaline phosphatase
  (β-hCG)†
Platelet count
Alanine aminotransferase (ALT)
Total triiodothyronine (T3)
WBC (total and differential)
Aspartate aminotransferase 
(AST)
Free thyroxine (T4)
Red Blood Cell Count
Carbon Dioxide 
Thyroid-stimulating hormone (TSH)
Absolute Neutrophil Count
  (CO2 or bicarbonate)
Serum protein and immunofixation 
electrophoresis (SPEP/SPIE)
Absolute Lymphocyte Count
Uric Acid
Urine protein and immunofixation 
electrophoresis (UPEP/UPIE) – 24-
hour collection
Calcium
Free light chain assay (FLC)
Chloride
Lymphocyte subsets
Glucose
Phosphorus
 
Potassium  
 
Sodium
 
Magnesium
Total Bilirubin
 
Direct Bilirubin
 
Total protein
 
Blood Urea Nitrogen
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum 
pregnancy test will be required.