A Phase II Pilot Study of Avelumab in Combination With Hypofractionated Radiotherapy in Patients With Relapsed Refractory Multiple Myeloma
Phase: PHASE2
Conditions: Myeloma, Multiple, Myeloma-Multiple
Sponsor: National Cancer Institute (NCI)

Abbreviated Title:  Avelumab plus XRT in RRMM 
  
Version Date:  09/01/2020   
 
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  Abbreviated Title:  Avelumab plus XRT for RRMM 
 
CC Protocol #:  19-C-0078 D 
 
Version Date: 09/01/2020 
 
NCT Number: NCT03910439 
 
A Phase II Pilot Study of Avelumab in Combination with Hypofractionated Radiotherapy 
in Patients with Relapsed Refractory Multiple Myeloma 
 
 
 
NCI Principal Investigator: Dickran Kazandjian, M.D. 
Joint appointment: 
• Lymphoid Malignancies Branch (LYMB) 
 
Center for Cancer Research (CCR)  
 
National Cancer Institute (NCI) 
• Office of Hematology and Oncology Products (OHOP) 
Food and Drug Administration (FDA) 
10 Center Drive 
Building 10, Room 4N115 
National Institutes of Health (NIH) 
Bethesda, MD 20892 
Phone: 301-480-0532  
Email:  kazandjiandg@mail.nih.gov  
 
 
Investigational Agents:   
Drug Name: 
Avelumab (MSB0010718C) 
IND Number: 
142027 
Sponsor: 
Center for Cancer Research 
Manufacturer: EMD Serono, Inc. 
(Company Study/Tracking #:  MS100070-0037) 
 
Commercial Agents:  None 

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PRÉCIS 
Background: 
• Multiple Myeloma (MM) is a hematologic neoplasm of the plasma cells defined by an M-
protein ≥ 3.0 g/dL or bone marrow plasma cells ≥ 10% and presence of end-organ 
disease. 
• Although significant advances in treatment have been made in the past decade, MM 
remains incurable with median survivals of 5-8 years.  
• While therapeutic strides have been made with approvals of immunomodulatory drugs 
(IMiDs), proteasome inhibitors, and monoclonal antibodies, treatment of relapsed 
refractory MM (RRMM) remains an unmet need for patients who have exhausted 
available therapies. 
• Extramedullary plasmacytomas arising either from focal bone involvement or from 
hematogenous spread occur in 7-18% of newly diagnosed MM (NDMM) with an 
additional 6-20% in RRMM. 
• Immune checkpoint inhibitors are being evaluated in combination regimens and evidence 
exists that radiation therapy (XRT) may synergize with immune checkpoint inhibitors. 
Objectives: 
• To assess the response rate of avelumab in combination with XRT (BavXRT) in RRMM 
patients with plasmacytomas or lytic lesions 
Eligibility: 
• Patients must have previously treated RRMM refractory to, ineligible for, or intolerant of 
available therapeutic regimens known to provide clinical benefit (e.g, immunomodulatory 
[IMiD], proteasome inhibitor, and anti-CD38 monoclonal antibody-based treatments). 
• Presence of ≥ 1 extramedullary plasmacytoma and/or lytic lesion amenable to XRT 
• Age ≥ 18 years 
• Adequate organ function, and without serious comorbidity or disease (e.g., autoimmune 
disease), that would preclude concurrent systemic treatment or radiotherapy. 
Design: 
• Treatment will consist of a 4-week lead-in with avelumab, followed by concurrent XRT 
5Gy x 5 days).  Monotherapy avelumab will continue indefinitely until progressive 
disease (PD) or unacceptable toxicity; 28-day cycles. 
• Routine safety and MM-specific clinical labs will be assessed. Additional research bloods 
will be collected for evaluating immune-subsets, endosomes, and peripheral blood T cell 
repertoire prior to and following treatment (lead-in and prior to XRT, at disease re-
evalutions at at time of response [i.e., CR/PD]). 
• Bone marrow biopsies will be evaluated for PD-1/L1 expression, and B and T cell 
subsets using IHC. Flow cytometry will also be used to evaluate stimulatory and 
inhibitory immune subsets along with endosomes. Standard clinical histopathology and 
flow cytometry will also be evaluated.  
• Single arm, Simon minimax two-stage phase II trial design. The first stage will enroll 13 
patients; if futility is not met, second stage will enroll another 14 patients to define the 
response rate to BavXRT in this population. Early stopping rules for safety will also be 
applied. 

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TABLE OF CONTENTS  
PRÉCIS .................................................................................................................................. 2 
TABLE OF CONTENTS ......................................................................................................... 3 
1 
INTRODUCTION ........................................................................................................... 6 
1.1 
Study Objectives .................................................................................................... 6 
1.2 
Background and Rationale ...................................................................................... 7 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ................................................... 21 
2.1 
Eligibility Criteria ................................................................................................ 21 
2.2 
Screening Evaluation............................................................................................ 25 
2.3 
Participant Registration and Status Update Procedures........................................... 26 
2.4 
Baseline Evaluation .............................................................................................. 27 
3 
STUDY IMPLEMENTATION....................................................................................... 28 
3.1 
Study Design........................................................................................................ 28 
3.2 
Drug Administration............................................................................................. 29 
3.3 
Radiation Therapy Administration ........................................................................ 30 
3.4 
Dose Modifications .............................................................................................. 31 
3.5 
On Study Evaluations ........................................................................................... 32 
3.6 
Post-Treatment Evaluations .................................................................................. 32 
3.7 
Study Calendar..................................................................................................... 34 
3.8 
Criteria for Removal from Protocol Therapy and Off Study Criteria ....................... 36 
4 
CONCOMITANT MEDICATIONS/MEASURES .......................................................... 36 
4.1 
Acceptable Medications........................................................................................ 36 
4.2 
Prohibited Medications ......................................................................................... 36 
5 
CORRELATIVE STUDIES ........................................................................................... 37 
5.1 
Summary ............................................................................................................. 37 
5.2 
Sample Collection and Processing......................................................................... 40 
5.3 
Biomarker and Research Methods......................................................................... 43 
5.4 
Sample Storage, Tracking and Disposition ............................................................ 47 
5.5 
Samples for Genetic/Genomic Analysis ................................................................ 50 
5.6 
Exploratory/Research Radiation Exposure............................................................. 51 
6 
DATA COLLECTION AND EVALUATION ................................................................ 51 
6.1 
Data Collection .................................................................................................... 51 
6.2 
Data Sharing Plans ............................................................................................... 52 
6.3 
Response Criteria ................................................................................................. 53 
6.4 
Toxicity Criteria ................................................................................................... 53 

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NIH REPORTING REQUIREMENTS / DATA SAFETY MONITORING PLAN ........... 54 
7.1 
Definitions ........................................................................................................... 54 
7.2 
OHSRP Office of Compliance and Training / IRB Reporting ................................. 54 
7.3 
NCI Clinical Director Reporting ........................................................................... 54 
7.4 
NIH Required Data and Safety Monitoring Plan .................................................... 54 
8 
SPONSOR SAFETY REPORTING................................................................................ 54 
8.1 
Definitions ........................................................................................................... 54 
8.2 
Assessment of Safety Events ................................................................................ 56 
8.3 
Reporting of Serious Adverse Events .................................................................... 56 
8.4 
Waiver of Expedited Reporting to CCR ................................................................ 56 
8.5 
Safety Reporting Criteria to the Pharmaceutical Collaborators ............................... 56 
8.6 
Reporting Pregnancy ............................................................................................ 57 
8.7 
Regulatory Reporting For Studies Conducted Under CCR Sponsored IND ............. 58 
9 
CLINICAL MONITORING ........................................................................................... 58 
10 STATISTICAL CONSIDERATIONS ............................................................................ 58 
10.1 
Study Endpoints ................................................................................................... 58 
10.2 
Statistical Hypothesis and Sample Size Determination........................................... 59 
10.3 
Populations for Analyses ...................................................................................... 60 
10.4 
Statistical Analyses .............................................................................................. 60 
11 COLLABORATIVE AGREEMENTS ............................................................................ 62 
11.1 
Cooperative Research and Development Agreement (CRADA) ............................. 62 
11.2 
Material Transfer Agreement (MTA) .................................................................... 62 
12 HUMAN SUBJECTS PROTECTIONS .......................................................................... 62 
12.1 
Rationale For Subject Selection ............................................................................ 62 
12.2 
Participation of Children....................................................................................... 62 
12.3 
Participation of Subjects Unable to Give Consent .................................................. 62 
12.4 
Evaluation of Benefits and Risks/Discomforts ....................................................... 63 
12.5 
Consent Process and Documentation ..................................................................... 64 
12.6 
Inclusion of Women and Minorities ...................................................................... 64 
13 PHARMACEUTICAL INFORMATION ........................................................................ 65 
13.1 
Avelumab (IND #142027) .................................................................................... 65 
14 REFERENCES .............................................................................................................. 67 
15 APPENDICES ............................................................................................................... 74 
15.1 
Appendix A: Performance Status Criteria .............................................................. 74 

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15.2 
Appendix B: Treatment Modification for Symptoms of Infusion-Related Reactions 75 
15.3 
Appendix C: Management of Immune-Mediated Adverse Reactions ...................... 76 
15.4 
Appendix D: Peripheral Blood and Urine Collection and Storage ........................... 84 
15.5 
Appendix E: CD138+ Cell Sorting: Calvo Lab ...................................................... 86 
15.6 
Appendix F: IMWG Response Criteria.................................................................. 87 
15.7 
Appendix G: Patient Reported Outcome Instrument – PROMIS ............................. 89 
 
 

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1 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objective 
To determine the response rate (IMWG 2016 criteria[1]) of avelumab in combination 
with XRT (BavXRT) in RRMM patients with plasmacytomas or lytic lesions  
1.1.2 Secondary Objectives 
• To determine complete response (CR) and minimal residual disease negative (MRD) 
negative CR (MRDnegCR) rates 
• To determine reductions in bone marrow (BM) and peripheral blood (PD) plasmacytosis 
• To determine systemic radiographic response by FDG PET/CT 
• To determine local responses in non-irradiated plasmacytomas and/or FDG avid lytic 
lesions (abscopal effect)  
• To determine progression-free survival (PFS) 
• To determine overall survival (OS) 
• To determine the safety and tolerability of BavXRT combination 
• To determine the activity of avelumab monotherapy after 1 cycle of treatment  
1.1.3 Exploratory Objectives 
Studies may be performed in select patients where adequate samples and resources are available: 
To assess: 
• Peripheral blood mononuclear cells (PBMCs):  
o Changes in 123 immune subsets including CD4 and CD8 T cells, natural killer 
(NK) cells, NK-T cells, regulatory T cells (Tregs), myeloid-derived suppressor 
cells (MDSCs), and dendritic cells and 114 refined subsets relating to 
maturation/function using multicolor flow cytometry 
o Changes in the function of select immune cell subsets (e.g. CD4 and CD8 effector 
T cells, NK cells, Tregs, and MDSCs) 
o Changes in tumor antigen specific T cells (e.g. brachyury, MUC1, and CEA) 
using intracellular cytokine staining for IFNg, TNF, and IL2 and the 
degranulation marker CD107a 
o Changes in T cell clonality/repertoire score using Adaptive Biotechnologies, Inc. 
TCRseq assay 
o Changes in inflammatory gene signature using Nanostring’s nCounter Human 
PanCancer Immune Profiling Panel 
• Peripheral Blood/Plasma/Serum: 
o Changes in the neutrophil to lymphocyte ratio (NLR) 
o Changes in circulating tumor DNA (ctDNA) by Adaptive Biotechnologies, Inc. B 
cell VDJseq assay 
o Changes in sCD27, sCD40L 

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o Changes in cytokines (IFN-γ, IL-10, IL-12, IL-2, IL-4, etc.), chemokines, 
antibodies, tumor-associated antigens, and/or other markers 
• Bone Marrow: 
o Changes in BM aspirate immune subsets by multicolor flow cytometry to evaluate 
Tregs, MDSC subsets, monocyte subsets, CD8+ T-cells and CD4+Foxp3- T-cells 
and functional markers including PD-1, Ki-67, Tim3, CTLA-4 and/or CD40 
o Expression patterns in BM biopsy of PD-1 and PD-L1 by immunohistochemistry 
(IHC ) 
o Evaluate known recurrent MM mutations and other genetic alterations including 
tumor mutational load (TML) by the MSKCC myTYPE next generation 
sequencing (NGS) assay 
o Evaluate tumor mutational burden (TMB) and Microsatellite Instability (MSI) 
status 
• Imaging, Diffusion Weighted MRI (DW-MRI): 
o To evaluate radiographic changes (signal intensity) in bone marrow heterogeneity 
and focal lesions by DW-MRI at baseline and over time 
• To evaluate the changes in quality of life (QoL) of patients treated on this protocol using 
the validated patient reported outcome (PRO) tool developed by the NCI, PROMIS® 
(Patient-Reported Outcomes Measurement Information System) 
1.2 
BACKGROUND AND RATIONALE 
1.2.1 Introduction 
Multiple myeloma (MM) is a neoplasm characterized by the proliferation and accumulation of 
malignant plasma cells in the bone marrow that lead to the overproduction of monoclonal 
proteins in the serum or urine. There was an estimated 30,280 new cases in the US, accounting 
for 1.8% of all new cancer cases with 12,590 deaths in 2017.[2] In 2014, there were an estimated 
118,539 people living with myeloma in the United States.[2] End-organ damage and hence 
myeloma defining criteria resulting from this disorder includes hypercalcemia, renal 
insufficiency, anemia, and lytic bone lesions (CRAB).[3]  Myeloma remains incurable, with a 
median survival of 5-8 years (previously 3-4 years) in the United States, although newer 
therapies appear to be improving survival.[4-10]  Importantly, two recent studies have provided 
evidence that all cases of MM are preceded by a premalignant state, monoclonal gammopathy of 
undetermined significance (MGUS) or smoldering multiple myeloma (SMM), although at this 
time the biological mechanism of this progression is not understood.[11, 12] 
MM is diagnosed when BM C138+ plasma cells are ≥ 10% in number and/or monoclonal band 
(M-spike) on serum electrophoresis (SPEP) ≥ 3 g/dL with with the addition of CRAB-defined 
end-organ damage and/or MM defining biomarkers of 1) Involved/un-involved serum free light 
chain ratio ≥ 100, 2) ≥ 2 focal lesions on spinal MRI, or 3) BM plasmacytosis of ≥60%.[3] Two 
major criteria have been used in the past to risk stratify patients in terms of prognosis, 
fluorescent in situ hybridization (FISH)/cytogenetics and International Staging System (ISS) 
which more recently have been combined into the revised ISS (R-ISS).[13] The table below 
describes the R-ISS:[13]  

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R-ISS 
Criteria 
Prognosis 
I 
ISS I (Serum 2-microglobulin < 3.5 mg/L, 
serum albumin ≥ 3.5 g/dL) & non-high risk FISH 
& normal LDH 
mOS not reached 
HR: 1 
II 
Not R-ISS Stage I or III 
mOS 83 months 
HR: 3.68 (95%CI: 2.75,4.92) 
III 
ISS III (Serum 2-microglobulin > 5.5 mg/L) & 
High Risk FISH or LDH 
mOS 43 months 
HR: 9.95 (95%CI: 6.45,15.36) 
 
1.2.2 Current standard of care and FDA approved therapies for RRMM 
The last decade has revolutionized the treatment and management of MM. Key milestones 
include the development of autologous stem cell transplant (ASCT), immunomodulatory drugs 
(IMiD), proteasome inhibitors (PI), monoclonal antibodies (MAb) directed against SLAMF7 and 
CD38 and more recently with promising results of chimeric antigen receptor T cell therapy 
(CART), bispecific T cell engager therapy (BiTE), and antibody drug conjugates (ADC). In the 
context of  newly diagnosed multiple myeloma (NDMM) and upfront RRMM treatment, 3 drug 
combinations are superior to 2 drug combinations. However, ultimately patients exhaust 
available combinations and succumb to disease.[7] Current available therapies are listed below: 
Drug class 
Drug 
FDA: approved indication 
Line of Therapy 
PI 
Bortezomib 
NDMM and RRMM 
≥1st 
Carfilzomib 
Monotherapy or in combo 
with d or Rd for RRMM 
≥2nd 
Ixazomib 
In combo with Rd for RRMM 
≥2nd 
IMiD 
Thalidomide 
In combo with d for NDMM 
1st 
Lenalidomide 
In combo with d for NDMM, 
RRMM, maintenance 
≥1st 
Pomalidomide 
In combo with d for RRMM 
≥3rd 
DNA 
intercalator 
Liposomal 
doxorubicin 
In combo with V for RRMM 
≥2nd  
(no prior V) 
HDACi 
Panobinostat 
In combo with Vd for RRMM 
≥3rd 
(PI, IMiD) 
Anti-CD38 
Daratumumab 
Monotherapy, or with Rev, 
Velcade, or Pom for RRMM 
≥2nd 
(PI, IMiD) 
Anti-
SLAMF7 
Elotuzumab 
In combo with Rd for RRMM 
2-4th 
 
1.2.3 Extramedullary plasmacytomas and lytic bone lesions in MM and treatment 
Extramedullary plasmacytomas (EMPs) in MM patients is a relatively uncommon clinical 
manifestation and tends to occur in later stages of disease. Soft-tissue extramedullary 
plasmacytomas (EMPs) can develop either by direct invasion from the medullary compartment 
disrupting the cortical bone or less commonly by hematogenous metastasis.[14] In a series of 

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1003 patients, overall, 13% of patients had extramedullary disease (EMD), 7% at diagnosis (85% 
of cases surrounded the axial skeleton and 15% involved hematogenous spread) and 6% 
later.[15] Up to 45% of patients with EMD at diagnosis developed EMPs at relapse. In another 
series of 459 NDMM patients, 16.3% had EMD.[16] More than one site was involved in 20% of 
patients and in a third EMD patients, the presenting symptoms were mainly due to EMD 
(palpable masses and neurologic symptoms). Regardless of therapy, extramedullary disease was 
associated with shorter progression-free and overall survival, as well as the presence of anemia, 
thrombocytopenia, elevated serum lactate dehydrogenase, and cytogenetic abnormalities in a 
series of 936 patients with EMD.[17] As evidenced by the above studies, EMD is a major 
contributor to morbidity in MM.  
Lytic bone lesions in MM patients is a relatively common clinical manifestation. In fact, bone 
lesions are one of the MM defining criteria in CRAB. MM bone disease may manifest in the 
form of a conventional discrete lytic lesion, radiolucent with underlying plasmacytoma, 
widespread osteopenia, or multiple lytic lesions affecting any part of the skeleton, preferably 
spine, skull, and long bones and occurs in up to 80% of patients.[18] As a result of bone disease, 
patients may suffer from bone pain (70–80%), fractures (50–60%), hypercalcemia (15%), spinal 
cord compression (2–3%), decreased quality of life, and poor mobility.[19] 
Management of both EMD and bone lesions requires multiple disciplines which may include 
conventional systemic MM agents, radiation therapy, bisphosphonates, pain control, and a 
subgroup of patients who may need surgical interventions. Radiotherapy, in particular, has been 
an important aspect of treatment. Upfront external beam radiation is used for patients with EMP 
or cord compression. Indications include pain control, spinal cord compression, pathological 
fractures, soft tissue plasmacytomas, and control of local neurological symptoms. Approximately 
a third of patients will require radiation therapy at some point in their treatment and is most 
commonly used for pain control with a very high success rate.[20-22] Palliation of lytic bone 
lesions may be accomplished with up to 30 Gy administered in 5 to 10 fractions, however, a 
single 8- to 10-Gy fraction is generally recommended as single fractions are increasingly 
preferred to fractionated treatment.[23] Limited evidence-based data exists regarding the ideal 
dose, however in a series of 101 patients treated at a single site, the total dose ranged from 3.0 to 
60 Gy, with a mean of 25 Gy.[20] Symptom relief was obtained in 97% of the symptomatic sites 
(92% with < 10 Gy and 98% when ≥ 10 Gy used, respectively) but no dose-response could be 
demonstrated.  
1.2.4 Immune checkpoint inhibitors, approved agents and indications 
The last 5 years of drug development have brought the advent of highly successful and 
efficacious immunotherapies in the treatment of cancer. Newer therapeutic modalities have 
focused on targeting the immune system.[24] Pathways involved in inhibiting antitumor T-cell 
responses (activation of the inhibitory coreceptors cytotoxic T-lymphocyte-associated protein 4 
[CTLA-4] and programmed cell death 1 [PD-1] on T cells) are thought to allow tumors to evade 
the immune system. PD-1 inhibitors, a new class of immune checkpoint inhibitors, are thought to 
block T-cell inhibitory signal pathways by preventing engagement of PD-1 to its ligands (PD-
L1/2). Program death-1 (PD-1) protein is a co-T -cell regulatory receptor that mediates 
immunosuppression by binding to the programmed death ligand 1 (PD-L1) normally expressed 
on stromal cells, T cell, B cells, macrophages and dendritic cells. Some tumors upregulate PD-L 
1 expression as a means of immune evasion. Preclinical data demonstrates that inhibition of the 

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PD-1/PD-L 1 interaction leads to an enhanced T -cell response and increased tumor killing, and 
clinical data show promising efficacy with this approach. 
The PD-1 pathway can also be blocked by PD-L1 inhibitors. Inhibitors to PD-L1 may be more 
advantageous than PD-1 inhibitors because they block not only PD-1 but also B7.1, another cell 
surface receptor involved in inhibition of T-cell activity and priming. Moreover, blocking PD-Ll 
leaves the PD-1/PD-L2 interaction intact which may be important in maintaining immune 
homeostasis and preventing autoimmunity.  
The PD-1 inhibitors pembrolizumab and nivolumab were the first approved in 2014 for the 
treatment of melanoma followed by the PD-L1 inhibitors atezolizumab and durvalumab for 
urothelial cancer and avelumab for Merkel Cell Carcinoma. The table below lists indications that 
various PD-1/L1 inhibitors are currently approved for. 
 
Agent 
FDA Approved Disease Indications 
Melanoma 
NSCLC 
RCC 
SCCHN 
UC 
MSI-
CRC 
HCC 
GC/ 
CC 
MCC 
HD 
PMBCL 
Atezolizumab 
(1200 mg q3 
wk) 
 
XXX 
 
 
XXX 
 
 
 
 
 
 
Avelumab  
(10 mg/kg q2 
wk) 
 
 
 
 
XXX 
 
 
 
XXX 
 
 
Durvalumab  
(10 mg/kg q2 
wk) 
 
XXX 
 
 
XXX 
 
 
 
 
 
 
Nivolumab  
(240 mg q2 wk; 
480 mg q4 wk) 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
 
 
XXX 
 
Pembrolizumab 
(200 mg q3 wk) 
XXX 
XXX 
 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
Abbreviations: NSCLC, non-small cell lung cancer; RCC: renal cell carcinoma; SCCHN, Squamous Cell Carcinoma of the 
Head and Neck; UC, Urothelial Carcinoma; MSI-CRC, Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient 
(dMMR) Metastatic Colorectal Cancer; HCC, Hepatocellular Carcinoma; GC, gastric cancer; CC, cervical cancer; MCC, 
Merkel Cell Carcinoma; HD, Classical Hodgkin Lymphoma; PMBCL, Primary Mediastinal Large B-Cell Lymphoma; 1 Anti-
PD-L1 antibody; 2 Anti-PD-1 antibody 
 
1.2.5 Immune checkpoint combinations with XRT and abscopal effect 
T cells recognize tumor antigens expressed by cancer cells and induce tumor rejection as self. 
Although many times tumor infiltrating CD8+ T cells are observed, more often than not, tumor 
regression in advanced malignancy is not observed due to negative immunoregulatory pathways 
that inhibit anti-tumor responses.[25] Immune checkpoint inhibitors have revolutionized the 
treatment of many malignancies with unprecedented clinical benefit in terms of duration of 
response and overall survival. However, not all patients derive clinical benefit from treatment 
due to a variety of reasons and therefore there is considerable interest in developing synergistic 
combinations with other therapies to increase efficacy. Radiotherapy is one potential “drug” 
candidate. Radiation causes tumors to release (neo)antigens and can modulate the immune 
system without significant immunosuppression. In addition to direct tumoricidal effect, 

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radiotherapy interacts with the immune system by inducing the immunogenic recruitment of anti-
tumor T cells locally, in addition, it can induce MHC I expression and finally can promote T cell 
repertoire diversity in terms of anti-tumor antigens.[26] For example, radiotherapy induced cell 
death generates signals that target Toll-like receptor 4 (TLR4) on dendritic cells (DC), leading to 
antigen processing and cross-presentation.[27] Additional mechanisms include increased PD-L1 
expression, interferon gamma production, tumor vasculature normalization, “danger signals” 
triggering inflammation and destruction of immunosuppressive stromal cells including Tregs and 
myeloid derived suppressor cells (MDSC).[27]  
The abscopal effect is used to define systemic anti-tumor responses at sites distant from a locally 
irradiated site. Limited non-clinical animal studies evaluating the abscopal effect exist, however, 
Camphausen et al., an investigator on this study, showed that irradiation of the leg of 
immunocompetent mice bearing a syngeneic tumor (lung carcinoma or fibrosarcoma) resulted in 
tumor growth inhibition.[28] The effect was dose-dependent and more effective with 
hypofractionation (10 Gy x 5) compared to conventional dosing (2 Gy x 12). Clinical reports of 
an abscopal effect after radiotherapy alone are not common but a recent report identified 46 
cases in the literature including lymphoma, melanoma, and carcinomas.[29] Interestingly, a case 
report of a RRMM patient who failed multiple treatments including ASCT subsequently 
achieved a sustained CR after palliative XRT to a gastric plasmacytoma and remained in 
remission for >15 years.[30]  
In terms of immunotherapy/radiation combinations, radiation has been shown to have a 
synergistic effect with various immunomodulating agents.[31] Synergy with CTLA-4 inhibitors 
led to decreases in tumor growth in murine mesothelioma, breast cancer, melanoma, pancreatic, 
and glioblastoma models.[32, 33] These responses have been reported not only in animal models, 
but in the clinic as well.[34] Synergy between radiation and PD-1 pathway inhibitors have been 
observed in breast, colon, melanoma, and glioma models.[34-38] A variety of doses have been 
used including 12 Gy x 1, 20 Gy x 1, 2 Gy x 5, 4 Gy x 5, 8 Gy x 3, and 10 Gy x 1.  
1.2.6 PD-1/L1 inhibitors in MM 
Despite the overwhelming success of monotherapy PD-1/L1 inhibitors in the treatment of solid 
tumors, their monotherapy activity is marginal and disappointing in MM. For example, in the 
phase 1b study of nivolumab treatment in various hematologic malignancies, the response rate in 
the MM cohort was a modest 4% compared to B and T cell lymphomas.[39] Interestingly, in that 
study, the one response which was observed occurred in a patient who had received palliative 
radiation. Combination regimens blocking the PD-1 pathway however, have generated initial 
excitement. In MM, tumor cells, pDCs, and MDSCs express PD-L1,while the microenvironment 
of the bone marrow including resident cytotoxic T, NK, and NK-T cells express PD-1.[40, 41] 
Preclinical studies have shown that inhibition of the PD-1/PD-L1 interaction inhibits accessory 
cell induced MM proliferation and survival while activating host T- and NK-cell anti-MM tumor 
responses which can be augmented by the addition of lenalidomide.[42] These preclinical data 
led to a series of single arm clinical studies with reported response rates of 33 to 76%.[41, 43, 
44] Two important phase 3 randomized studies evaluated lenalidomide or pomalidomide, dex, 
and +/- pembrolizumab. Unfortunately, at an interim analysis, the PD-1 inhibitor containing arms 
were associated with a detriment in overall survival leading to placing the study on hold and 
release of an FDA statement including Kaplan-Meier graphs.[45] The reasons and mechanisms 
of action leading to this detriment with the combination is currently unknown, however, it is 
unlikely that combinations with IMiDs will move forward. 

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1.2.7 Avelumab drug product, preclinical and clinical pharmacology 
Avelumab (company code: MSB0010718C) binds PD-L1 and blocks the interaction between 
PD-L1 and PD-1. This removes the suppressive effects of PD-L1 on anti-tumor CD8+ T cells, 
resulting in the restoration of cytotoxic T cell response. The active pharmaceutical ingredient in 
avelumab drug product is a fully human antibody (calculated molecular weight of 143,832 
Dalton) of the immunoglobulin G (IgG) 1 isotype that targets PD-L1, the ligand for PD-1.[46] 
The nonclinical pharmacology studies have shown that avelumab functionally enhances T cell 
activation in vitro and significantly inhibits the growth of PD-L1 expressing tumors in vivo. 
Avelumab binds to human PD-L1 with a high affinity of 0.7 nM and not to any other B7 family 
proteins, and competitively blocks the interaction of PD-L1 with PD-1.[46] The in vitro study 
results have shown that by binding to PD-L1, avelumab effectively enhances T cell activation as 
measured by interleukin (IL)-2 or interferon-gamma production. In addition, as a fully human 
IgG1 antibody, avelumab has the potential to trigger the antibody-dependent cell-mediated 
cytotoxicity (ADCC) against target cells expressing PD-L1. As a monotherapy, avelumab has 
demonstrated anti-tumor activity against murine MC38 colon carcinoma tumors that are 
characterized by a high level of PD-L1 expression. A dose-dependent trend was observed, and 
400 μg per dose (20 mg/kg) was identified as the optimally effective dose when given every third 
day for 3 total doses.[46] 
Full pharmacokinetic (PK) profiles were evaluated in mice and cynomolgus monkeys, since 
these species have similar binding affinity to PD-L1 to humans, and therefore these species are 
likely to have similar target-mediated clearance. The anti-PD-L1 antibodies from research 
batches and precursor molecules tested in single-dose PK studies demonstrated pronounced 
nonlinear PK characteristics in mice and cynomolgus monkeys in single-dose studies at doses 
below 20 mg/kg, suggesting a combination of first order catabolic clearance and saturable target-
mediated clearance. Similar terminal half-lives (t1/2) ranging from 58 to 70 hours at doses 
between 20 and 140 mg/kg were observed in toxicity studies in mice and monkeys. Since 
avelumab represents a foreign protein to the immune system of animals, anti-avelumab 
antibodies in rodents and nonhuman primates were observed and have been considered in 
interpreting the nonclinical data, with higher doses generally resulting in lower immunogenicity 
incidence. This is potentially due to the interference of avelumab trough concentrations with the 
measurement of antidrug antibody (ADA), and did not affect exposure or impact the conclusions 
of the toxicity studies. The immunogenicity incidence against the human antibody avelumab in 
animals is not deemed predictive for human subjects. 
Unlike mouse models, neither in the pilot 4-week IV repeat-dose toxicity study nor in the pivotal 
13-week study were clinical signs of hypersensitivity or avelumab-related infusion reactions seen 
in cynomolgus monkeys after repeated treatment with avelumab at dose levels of 20, 60, and 140 
mg/kg, respectively. For the pilot 4-week study as well as for the pivotal 13-week IV repeat-dose 
toxicity study, a no observed adverse effect level (NOAEL) of 140 mg/kg for systemic toxicity 
was established. 
Clinical Pharmacology: Human PK of avelumab have been characterized using both on 
compartmental analyses (NCA) and population PK (Pop PK) analysis. The PK profile of 
avelumab is typical for a human antibody, i.e. with a low clearance and volume of distribution. 
Based on the NCA after the first dose, maximum plasma concentration observed post-dose 
(Cmax) and area under the serum concentration-time curve (AUC) increased dose-proportionally 
at 3 mg/kg and higher, while concentration at the end of the dose interval (Ctrough) increased 

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13 
dose-proportionally at 10 mg/kg and higher. Based on Pop PK analysis, serum clearance (CL) of 
avelumab was estimated to be 0.0246 L/hr [95% confidence interval (CI): 0.0239, 0.0252] for a 
typical subject. The volume of distribution at steady state (Vss) was estimated to be 4.72 L (95% 
CI: 4.63, 4.82). The half-life (t1/2) was estimated to be 6.1 days [146 hour (95% CI: 140, 152)]. 
Avelumab accumulation on Cmax and AUC was estimated to be 1.25-fold when given once 
every 2 weeks. Pop PK analysis and simulations demonstrated that age, race, baseline tumor PD-
L1 status, urothelial carcinoma (UC) tumor type, or hepatic impairment had no influence on the 
avelumab CL or the central and peripheral volumes of distribution, and no influence of renal 
impairment on CL. Body weight was found to positively correlate with PK exposure. Baseline 
albumin, sex, the 3 mg/kg dose level, baseline tumor burden, and metastatic Merkel cell 
carcinoma (mMCC) tumor type in the final Pop PK model reduced the unexplained variability in 
CL by 5.1%, but none of those parameters is expected to have a clinically meaningful effect on 
PK. 
Avelumab PK are not expected to be affected by concomitant administration of other drugs. 
Avelumab did not induce cytokines in vivo for human subjects to concentrations needed to affect 
transporters involved in the distribution or CYP450 metabolism for small molecule drugs. The 
10 mg/kg dose once every 2 weeks achieved the high target occupancy (mean TO > 90%) of  PD-
L1 in PBMC during the whole dose interval as determined from ex vivo studies. Based on the in 
vitro TO data and the observed trough serum avelumab levels, TO was predicted to reach or 
exceed 95% throughout the entire dose interval for more subjects in 10 mg/kg dose group than 
those in 3 mg/kg dose group from the dose escalation cohorts of Study EMR100070-001. 
Immunogenicity assessment included all subjects from Studies EMR100070-001 and 
EMR100070-003 treated with 10 mg/kg of avelumab once every 2 weeks and who had at least 
one valid ADA result. Treatment-emergent ADA incidence was 64 of 1558 subjects (4.1%) 
across the integrated safety analysis population. No apparent clinically meaningful impact of 
immunogenicity on PK, efficacy or safety of avelumab was observed. 
1.2.8 Avelumab clinical safety and efficacy 
Avelumab is currently in clinical development across multiple Phase 1-3 clinical studies, 
however, as of the date of Investigator Brochure v7 (10/2016), there are no completed clinical 
trials to report. [46]  The safety data summarized in the Investigator’s Brochure include data 
from all subjects treated with 10 mg/kg every 2 weeks from studies JAVELIN Solid Tumor 
(1650 patients) and JAVELIN Merkel 200 Part A (88 subjects) as pooled safety dataset with a 
data cutoff of 09 June 2016. Most of the observed adverse events (AEs) were either in line with 
those expected in patients with advanced solid tumors or with class effects of monoclonal 
antibody (mAb) blocking the PD-1/PD-L1 axis. Infusion-related reactions including drug 
hypersensitivity reactions and immune-mediated adverse reactions (immune-related pneumonitis, 
immune-related colitis, immune-related hepatitis, immune-related endocrinopathies (thyroid 
disorders, adrenal insufficiency, new onset type I diabetes mellitus, pituitary disorders), immune-
related nephritis and renal dysfunction and other immune-related AEs (myositis, myocarditis, 
Guillain-Barré syndrome, uveitis) have been identified as important risks for avelumab. The 
tables below list the appropriate treatment emergent AEs (TEAE). 

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Most Frequently Reported (≥ 5%) Treatment-Related TEAEs in the Pooled Safety Dataset 
Body System or Organ Class 
Preferred term 
(N=1738) 
N (%) 
Number of Subjects With At Least One Event 
1164 (67.0) 
Endocrine disorders 
Hypothyroidism 87 (5.0) 
111 (6.4) 
87 (5.0) 
Gastrointestinal disorders 
Nausea 
Diarrhea 
356 (20.5) 
150 (8.6) 
123 (7.1) 
General disorders and administration site conditions 
Fatigue 
Chills 
Pyrexia 
554 (31.9) 
307 (17.7) 
116 (6.7) 
106 (6.1) 
Injury, poisoning and procedural complications 
Infusion related reaction 
302 (17.4) 
295 (17.0) 
Investigations 
200 (11.5) 
Metabolism and nutrition disorders 
Decreased appetite  
149 (8.6) 
90 (5.2) 
Musculoskeletal and connective tissue disorders  170 (9.8) 
Nervous system disorders  
132 (7.6) 
Respiratory, thoracic and mediastinal disorders  104 (6.0) 
Skin and subcutaneous tissue disorders  
253 (14.6) 
 
Grade ≥ 3 treatment-related TEAEs were observed in 177 subjects (10.2%) in the pooled safety 
dataset. The most frequently reported (at least 3 subjects, 0.2%) Grade ≥ 3 treatment-related 
TEAEs were fatigue, lipase increased (17 subjects each; 1.0%), GGT increased, infusion related 
reaction (10 subjects; 0.6%), AST increased (8 subjects; 0.5%), pneumonitis (7 subjects; 0.4%), 
anemia, blood CPK increased (6 subjects each; 0.3%), diarrhea, asthenia (5 subjects each; 0.3%), 
autoimmune hepatitis, ALT increased, amylase increased, hyponatremia, hypophosphatemia (4 
subjects each; 0.2%). Other Grade ≥ 3 treatment-related TEAEs that were observed in 3 subjects 
(0.2%) included lymphopenia, adrenal insufficiency, hypothyroidism, colitis, vomiting, 
autoimmune disorders, lymphocyte count decreased, transaminase increased, decreased appetite 
and hypokalemia. In the pooled safety dataset, overall, a total of 4 deaths (0.2%) were due to 
TEAEs related to study treatment. The causes of death included pneumonitis, hepatic failure, and 
respiratory distress. 
In the pooled safety dataset (N=1738), a total of 247 patients (14.2%) experienced immune 
related adverse events (irAEs). The median time to first onset of an irAE was 11.7 weeks. The 
most frequent irAEs were thyroid disorders including hypothyroidism (5.2%), hyperthyroidism 
(0.4%) and thyroiditis (0.2%), immune-related rash (5.2%), immune-related colitis (1.5%), 

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immune-related pneumonitis (1.2%), immune-related hepatitis (0.9%), adrenal insufficiency 
(0.5%), and immune-related myositis (0.5%). In addition, irAEs reported in 0.1% of patients in 
the pooled safety dataset included: Type 1 diabetes mellitus, immune-related nephritis and renal 
dysfunction, pituitary disorder, uveitis, and Guillain-Barré syndrome. The majority of irAEs 
were Grade 1 or Grade 2 in severity, with 39 (2.2%) being of Grade ≥ 3 severity. Fatal outcome 
was reported in 1 (0.1%) patient with immune-related pneumonitis, and 2 (0.1%) patients with 
immune-related hepatitis.  
Clinical efficacy as provided in the USPI for approved indications: 
JAVELIN Merkel 200 trial 
Efficacy Endpoints 
Results (N=88) 
Overall Response Rate (ORR) 
 
Overall response rate, (95% CI) 
33.0% (23.3%, 43.8%) 
Complete response (CR) rate, (95% CI) 
11.4% (6.6%, 19.9%) 
Partial response (PR) rate, (95% CI) 
21.6% (13.5%, 31.7%) 
Duration of Response (DOR) 
N=29 
Range in months 
2.8 to 23.3+ 
Patients with DOR ≥ 6 months, n (%) 
25 (86%) 
Patients with DOR ≥ 12 months, n (%) 
13 (45%) 
 
JAVELIN Solid Tumor Trial: urothelial carcinoma cohorts 
Efficacy Endpoints 
≥ 13 Weeks Follow-Up 
(N=226) 
≥ 6 Months Follow-Up 
(N=161) 
Confirmed Overall Response Rate (ORR) 
Overall Response Rate n (%) 
30 (13.3%) 
26 (16.1%) 
(95% CI) 
(9.1, 18.4) 
(10.8, 22.8) 
Complete Response (CR) n (%) 
9 (4.0%) 
9 (5.6%) 
Partial Response (PR) n (%) 
21 (9.3%) 
17 (10.6%) 
Duration of Response (DOR) 
Median, months (range) 
NE (1.4+ to 17.4+) 
NE (1.4+ to 17.4+) 
 
1.2.9 Rationale for combining PD-L1 inhibitor with XRT in RRMM 
Pre-clinical models suggest that methods involving the restoration of robust anti-tumor innate 
immune activation may overcome resistance to checkpoint inhibitors. Therefore, we hypothesize 
that targeted radiation can change the MM microenvironment niche to sensitize myeloma cells to 
PD-1 inhibitors and activate systemic anti-tumor T cell and immune responses. The rationale for 
using radiation as the synergistic partner to induce an abscopal effect is that radiation:  

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1. Induces tumor cell death through DNA damage and creates neoantigens 
2. Increases PD-L1 expression on MM cells and immune cells 
3. Increases secretion of IFN gamma 
4. Enhances MHC class I surface expression and induces neo-antigen presentation on MM 
cells 
5. Activates dendritic cells and cross presentation of antigens 
6. Increases density of tumor infiltrating lymphocytes and modulates Treg’s to create the 
“inflamed phenotype” which plays major role in XRT efficacy 
7. Induces cell adhesion molecules and modifies the tumor vasculature to enhance immune 
cell extravasation 
Furthermore, patients will receive radiation at sites of disease (plasmacytomas and bone lesions) 
and will therefore also derive direct benefit from the local therapy. 
A second potential mechanism of action for avelumab is the induction of ADCC. Myeloma cells 
have been well characterized as having increased PD-L1 expression.[47, 48] As a fully human 
IgG1 antibody, avelumab has the potential to trigger the antibody-dependent cell-mediated 
cytotoxicity (ADCC) against target cells expressing PD-L1 which has been shown in preclinical 
models.  
In summary, preclinical models of PD-1 pathway blockade in MM have shown promising results 
as this pathway appears to play an important role as the tumor cells express relatively high levels 
of PD-L1 and T cells which show increased PD-1 expression not observed in normal plasma 
cells.[49-51] We hypothesize that the addition of local radiotherapy will synergize with systemic 
PD-L1 inhibition to lead to clinical benefit by priming the immune system. In support of this, 
using a 5T33 murine mouse multiple myeloma model, it has been shown that radiation therapy in 
combination with blocking the PD-L1 pathway with an antibody resulted in longer survival 
compared to a control IgG antibody.[52] In another preclinical J558L myeloma model, the 
authors showed that PD-L1 blockade with an antibody elicited rejection of murine myeloma 
when combined with radiation.[50] The term abscopal effect was coined to describe an immune-
mediated anti-tumor response to radiation by malignant cells located distant from the irradiated 
site and has been demonstrated in various solid tumors including melanoma, renal cell 
carcinoma, breast cancer, and hepatocellular carcinoma amongst others.[53] Recently, more and 
more studies are indicating that combining radiation with immunotherapy may boost abscopal 
response rates. The table below describes the preclinical studies supporting the combination of 
immunotherapy. 
Selected preclinical studies demonstrating the abscopal effect with the combination of 
radiotherapy and immunotherapy (adapted from Ngwa et al.)[53] 
Tumor model 
Radiation 
dose 
Immunotherapy type, dose, 
timing, route 
Boosting the abscopal effect: 
conclusion 
Subcutaneous MC38 colon 
adenocarcinoma[54] 
3 × 8 Gy  
Anti-PD1, anti-CD137 or both; 
300 μg; after each radiotherapy 
fraction; intraperitoneal  
Brachytherapy with 
immunotherapy can potentiate 
the abscopal effect  
Subcutaneous CT26 
colorectal carcinoma[55]  
20 Gy  
Anti-CTLA4; 250 μg; before 
radiotherapy; intraperitoneal 
Anti-TNFRSF4; 250 μg; after 
radiotherapy; intraperitoneal 
In combining radiotherapy and 
immunotherapy, ideal timing 
of radiotherapy is dependent 
on the mechanism of action of 

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Tumor model 
Radiation 
dose 
Immunotherapy type, dose, 
timing, route 
Boosting the abscopal effect: 
conclusion 
the respective immunotherapy 
utilized  
Subcutaneous Lewis lung 
carcinoma[56]  
6 Gy  
Anti-CD40; 20 μg; after 
radiotherapy; intratumoural  
Intratumoural administration 
of anti-CD40 boosts the 
abscopal effect, and further 
research on the use of SRBs to 
boost this effect is justified  
Subcutaneous 67NR 
mammary carcinoma[57]  
3 × 8 Gy  
FLT3L; 10 μg × 10; after 
radiotherapy; intratumoural  
Fractionated radiotherapy with 
FLT3L induces abscopal 
effects  
Subcutaneous B16-F10 
melanoma & Subcutaneous 
TSA mammary 
adenocarcinoma [58]  
20 Gy; 3 × 
8 Gy 
Anti-CTLA4, anti-PD1, 
anti-PDL1; 200 μg per mouse; 
before, concurrent with and after 
radiotherapy; intraperitoneal  
The combination of 
radiotherapy, anti-CTLA4 and 
anti-PDL1 promotes response 
and immunity through distinct 
mechanisms  
Subcutaneous TUBO 
mammary carcinoma  & 
MCA38 colon 
carcinoma[35]  
12 Gy  
Anti-PDL1; 200 μg × 4; before, 
concurrent with and after 
radiotherapy; intraperitoneally  
There is close interaction 
between radiotherapy, T cells 
and PDL1 in boosting the 
abscopal effect  
Subcutaneous colon26 
adenocarcinoma[59]  
2 Gy × 5 
consecutive 
days per 
cycle × 2 
cycles  
IL-2; 20,000 IU in 0.1 mL of PBS; 
after radiotherapy; intratumoural  
Intratumoural injection of IL-2 
boosts both the local and 
abscopal effects of local 
radiotherapy  
Subcutaneous TSA 
mammary adenocarcinoma 
& MCA38 colon 
carcinoma[60]  
 
20 Gy × 1, 
8 Gy × 3 or 
6 Gy × 5  
Anti-CTLA4 antibody (9H10); 
200 μg × 3; concurrent with or 
after radiotherapy; intraperitoneal  
Fractionated but not single-
dose radiotherapy in 
combination with anti-CTLA4 
boosts the abscopal effect  
Subcutaneous SCCVII[61]  4–10 Gy  
DC; 1 × 106 cells; after 
radiotherapy; intratumoural  
A combination of 
intratumoural DCs and 
radiotherapy can induce strong 
local and abscopal responses  
Subcutaneous 4T1 
mammary carcinoma[62]  
12 × 2 Gy  
Anti-CTLA4; 200 μg × 3; after 
radiotherapy; intraperitoneal  
Combining local radiotherapy 
with anti-CTLA4 is a 
promising new strategy 
against poorly immunogenic 
metastatic cancers  
Subcutaneous 67NR 
mammary carcinoma[63]  
2–6 Gy  
FLT3L; 0.5 mg per kg body 
weight × 10; after radiotherapy; 
intraperitoneal  
T cells mediate the abscopal 
effect  
Subcutaneous C3 sarcoma 
and MethA 
fibrosarcoma[64]  
10 Gy × 3–
5 cycles  
DC; 2–4 × 106 cells per mouse; 
after radiotherapy; intravenous  
The combination of 
radiotherapy and DC 
administration may be an 
attractive new approach to 
treat advanced cancer  

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Tumor model 
Radiation 
dose 
Immunotherapy type, dose, 
timing, route 
Boosting the abscopal effect: 
conclusion 
B16 melanoma[65] 
2, 5, 10, 20 
Gy 
Anti-PD-1 antibody, pre and post 
radiation 
Combination of PD-1 inhibitor 
and radiation produces 
persistent abscopal effect 
 
In conclusion, both animal models and clinical anectodal cases support the current study of 
combining radiation with checkpoint blockade. 
1.2.10 Avelumab and XRT dose and schedule rationale  
Avelumab is currently approved for 2 indications at a dose of 10 mg/kg and schedule of every 2 
weeks. We propose to use a fixed or flat dose of 800 mg IV given every 2 weeks. Per personal 
communication with the manufacturing sponsor (EMD Serono) this is the equivalent appropriate 
flat dose per their data. As most PD-1/L1 drug sponsors are developing or have developed flat 
doses, we have proposed to do the same with avelumab for this study.  
In terms of radiation, an ideal dose and schedule should activate the immune system and 
decrease the level of immunosuppression. Thus far there is some discrepancy based on 
preclinical studies of the optimal dose and regimen of XRT to be used in conjunction with 
immunotherapy.[66, 67] However, it appears that hypofractionated doses of XRT improve 
synergy with immune-oncology drugs compared to conventional doses or one time high doses. 
For example, in preclinical models, hypofractionated XRT in daily doses of 6 to 8 Gy times 5 or 
3 days, over a single high dose treatment of 20 Gy, were more effective in generating an anti-
tumor immune response with anti-CTLA-4 inhibitors.[60] Since human tumor cells are generally 
more sensitive to radiation than mouse cells, and since hematologic tumors are generally more 
sensitive to radiation than epithelial tumors, daily doses of 5 Gy over 5 days to a multiple 
myeloma lesion are expected to produce similar immunological sequelae to the aforementioned 6 
to 8 Gy over 3 to 5 days. In addition, delayed anti-CTLA-4 inhibition was inferior to concurrent 
administration. Moreover, the most impressive clinical results with solid tumors have been 
observed when preclinical XRT hypofractionated doses (i.e. 6 Gy x 5) with ipilimumab were 
used.[68, 69] Based on successful preclinical results combining XRT with PD-1/L1 inhibition, 
many early phase and a couple of late phase clinical trials have been initiated with results 
pending. A review by Kang et al, identified 19 phase 1, 29 phase 1/2, and 2 phase 3 registered 
clinical trials encompassing a variety of both hematologic and solid cancers.[66] The results of 
these trials are much anticipated as they will give clinical insight regarding the various XRT 
schema used including 6 Gy × 5, 8 Gy × 1, 2, or 3 and 20 Gy × 1, 2, or 3.  
In terms of our proposed study in RRMM, the chosen XRT regimen of 5 Gy for 5 days is 
generally aligned with both preclinical work and ongoing clinical studies to activate an anti-
myeloma immune response. Furthermore, a 5 Gy x 5 fraction regimen can be considered an 
ablative palliative dose that is likely to provide local control of the lesion (without recurrence in 
the treatment field) and restoration of function in as many cases as radiation is expected to 
restore. Thus, this regimen is sufficient to provide direct local palliation to plasmacytoma and 
lytic lesions; it is expected to be well-tolerated with minimal risk of toxicity; and it is a dose and 
fractionation scheme similar to dose/fractionation approaches which can be radiobiologically 
synergistic with concurrent immunotherapy.  

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The study design incorporates a lead-in period of one cycle (two doses) of avelumab prior to 
radiotherapy. The rationale for this study design is to ensure that maximal PD-L1 blockade and T 
cell priming occurs prior to radiation to induce tumor cell immunogenicity. Preclinical studies 
have shown that a delay in PD-L1 inhibition does not lead to synergy. Therefore, concurrent 
administration of the combination is essential for synergy by converting the irradiated tumor into 
an in situ vaccine for systemic disease control.[66] For example, in a mouse model, delay of PD-
L1 pathway inhibition was ineffective in enhancing long term survival of the mice.[36] 
Furthermore, the majority of clinical trials are evaluating the concomitant administration of 
radiation and checkpoint blockade.[66] To ensure maximal PD-1 pathway inhibition, the lead-in 
period will ensure a study state concentration of avelumab. In human repeated dosing studies, 
avelumab reached the steady state between the second and third dose.[46] Furthermore, Pop PK 
modeling confirmed that the steady state is expected to be reached by the third dose.[46] 
Therefore, it is expected that at 1 cycle of avelumab treatment, drug levels will reach study state 
and with the addition of radiation then, maximal synergy will occur. 
1.2.11 Rationale for performing exploratory studies  
Immunotherapies including PD-1/L1 inhibitors have revolutionized treatment paradigms for 
many malignancies. However, not all patients respond to therapy and the most appropriate 
biomarker has not yet been identified. Although, PD-L1 expression has been associated with 
improved clinical responses, in itself it may not be adequate.[70] Newer biomarkers have been 
discovered and are currently being developed.[71] For example, tumor mutational burden (TMB) 
and micro-satelite instability (MSI) have been found to be important in predicting response to 
checkpoint blockade.[72, 73] Along these lines, T cell repertoire, clonality, and diversity have 
been shown to be important in predicting response to checkpoint blockade.[74, 75] It has been 
suggested that immune gene signatures may play an important role in predicting response to 
immunotherapy. For example, two signatures, the “Interferon-gamma 10-gene” and the 
“Expanded-immune 28-gene,” were found to be associated with ORR and PFS in a validation 
cohort of PD-1 inhibitor treated patients.[76] The Nanostring Human Pan Cancer Gene 
Expression Panel is a gene expression panel which combines components involved in the 
interaction between the tumor, microenvironment and immune response in cancer for 
characterization of disease biology. Furthermore, immune subset populations in the micro 
environment and tumor infiltrating lymphocytes are important mediators of final clinical activity 
of checkpoint inhibitors.[71, 74] This entails the balance in the micro environment and periphery 
of activating (CD4 and CD8 T cells, natural killer (NK) cells, NK-T cells) and inhibitory subsets 
(regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs)). Other studies have 
shown that the neutrophil to lymphocyte ratio (NLR) may be an important predictor of 
checkpoint inhibitor response.[77] Tumor antigen specific T cells play an important role in anti-
myeloma responses. For example, brachyury expression has been shown to be increased in 
MM.[78] MUC1 and CEA also appear to be important T cell anti-myeloma tumor antigens.[79, 
80]  
It is now well known that mismatch repair defects (MMRd) and MSI-High tumors forecast a 
response to checkpoint blockade not only in colon cancer but in multiple other solid tumors as 
well. For example, in a study of 68 patients with 12 different solid tumor types with evidence of 
MMRd were given a PD-1 inhibitor which was associated with an ORR of 53%.[81] 
Pembrolizumab is now approved for second line treatment of any MMRd and MSI-H solid 
tumor. This approval was based on data from five single-arm multi-cohort trials (KEYNOTE-

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016, KEYNOTE-164, KEYNOTE-012, KEYNOTE-028, and KEYNOTE-158) including 15 
cancer types. Among all patients, ORR was 39.6% with 78% of responders having a duration of 
6 months or greater. Studies have investigated the frequency of microsatellite instability in MM, 
for example, Velangi et al. reported MSI phenotype in 54% of 26 newly diagnosed MM 
patients.[82] Timuragaoglu et al. examined 98 patients with plasma cell dyscrasias and found 
that MMRd became more frequent as the disease progressed from MGUS/SMM (7.7%) to 20.7% 
in MM/plasma cell leukemia.[83] More recently, Miyashita et al. used high-resolution florescent 
MSI assay to demonstrate MSI in 2 of 20 patients with myeloma.[84] The Illumina TruSight 
Oncology 500 (STO 500) NGS assay is able to target multiple variant types, including TMB and 
MSI. Evaluating for MMRd/MSI-High, along with TMB in this study is of upmost clinical 
significance.  
The purpose of our proposed exploratory studies is to evaluate weather the above stated markers 
at baseline will correlate with a clinical response in RRMM. Secondly, we would like to evaluate 
these markers as patients go into a clinical response and/or have progressive disease to evaluate 
whether clinical changes are associated with biologic changes presumably due to activation of 
the immune system and/or failure of overcoming myeloma-mediated immunosupression. 
1.2.12 Imaging – DW-MRI 
DW-MRI has recently been found as a potential complementary imaging modality that focusses 
on the actual myeloma plasmacytoma disease rather than subsequent bone destruction. The MY-
RADS group state that because skeletal survey and CT predominantly help to detect the 
destructive effects of myeloma on trabecular and cortical bone rather than disease within the 
bone marrow space, sensitivity and capability as a restaging tool are inherently limited. [81] 
Myeloma infiltrates within bone marrow can be observed on CT if they lie within the marrow 
spaces adjacent to fatty bone marrow. However, in trabecular bone spaces (i.e., vertebral bodies), 
myeloma infiltrates are difficult to evaluate given factors including the trabeculae, degenerative 
changes, benign lesions, and osteoporosis. In contrast, MRI allows direct imaging of the bone 
marrow given its superb sensitivity, soft-tissue contrast, and early detection of focal myeloma 
lesions. Although PET/CT can also detect myeloma lesions, MRI is more sensitive especially 
with newer techniques; in particular, DW-MRI have shown a sensitivity of 77% compared to 
47% for PET/CT. [82] Current whole-body MRI protocols can incorporate DW- MRI sequences 
that are sensitive to cellular density and viability, and are important for disease detection and 
monitoring. Another benefit of DW-MRI sequences are that they are quick to perform 
(approximately 30-45 minutes) and interpret. Finally, the relationship of apparent diffusion 
coefficient values with cell density has the potential to assess response to treatment and response 
heterogeneity prior to changes in lesion size. [83, 84] The recent MY-RADS recommendations 
were published in an attempt to promote standardization and decrease variations in the 
acquisition, interpretation, and reporting of whole-body MRI, and to allow better response 
assessments across cancer centers. MY-RADS recommendations do require validation within 
clinical trials, including assessments of reproducibility and, therefore, we will be guided by the 
group’s recommendations especially in regard to MRI data acquisition and analysis protocols. 
[81]  
1.2.13 Patient Reported Outcome/Quality of Life:  PROMIS 
Patient-Reported Outcomes Measurement Information System (PROMIS) is a health-related 
patient reported outcome (PRO) quality of life measurement instrument that was developed by 
NIH/NCI to standardize patient-reported outcomes for national use by research clinicians. Two 

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versions of PROMIS are available to researchers: computer-adaptive tests (CATs) and short 
forms.[85-90] The short forms are brief, static instruments that have demonstrated similar 
reliability to the longer, dynamic CATs, which provide precise measures for studying 
populations with widely varied responses and longitudinal self-report data. Each short form 
includes 4 to 8 items, measures reported health outcomes in the past 7 days on a Likert type scale 
and takes less than 5 minutes each to complete; collectively we anticipate the questionnaires 
chosen for this study to take approximately 20 minutes in total.   
PROMIS instruments, measuring a broad range of health domains, have been validated for adults 
(>18) with a variety of health conditions. Results of PRO for patients with RRMM treated with 
the carfilzomib, lenalidomide, dexamethasone regimen have been published before as, which is a 
significantly different drug combination than the this study.[91] In addition, recently, QoL and 
other EORTC PROs were published in patients post salvage HDM-ASCT.[92] In the current 
study, we hope to gain insight into PROs when a monoclonal antibody drug is combined with 
radiation therapy. 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria 
2.1.1.1 Patients must have a documented diagnosis of multiple myeloma defined by the 
International Myeloma Working Group Criteria (IMWG)[3]. Patients at initial 
diagnosis must have had a serum M-protein ≥3 g/dL and/or bone marrow plasma cells 
≥10%, and at least one of the following: 
• Anemia: Hemoglobin ≤10 g/dL, or 
• Renal failure: serum creatinine ≥ 2.0 mg/dL, or 
• Hypercalcemia: Ca ≥10.5 mg/dL, or 
• Lytic bone lesions on X-ray, CT, or PET/CT, or 
• ≥2 focal lesions on spinal MRI, or 
• ≥60% bone marrow plasma cells, or  
• Involved/un-involved serum free light chain ratio ≥ 100 
2.1.1.2 Have at least one extramedullary plasmacytoma or lytic lesion which at the discretion of 
the investigators is amenable to and clinically indicated for localized radiation therapy 
2.1.1.3 Must have Relapsed or Relapsed and Refractory Multiple Myeloma. Patients must have 
documented evidence of progressive disease (PD) as defined by the IMWG criteria on 
or after their last regimen and must have achieved a minimal response (MR) or better to 
at least one prior regimen. Definitions by the IMWG:[93] 
• Relapsed and refractory: disease that is nonresponsive while on salvage therapy or 
progresses within 60 days of last therapy in patients who have achieved minor 
response (MR) or better 
• Relapsed: disease that progresses and requires the initiation of salvage therapy but 
does not meet criteria for either primary refractory or relapsed and refractory 
MM categories 

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22 
2.1.1.4 Patients must have been previously treated for MM and be refractory to, not a candidate 
for (ineligible), or intolerant of available therapeutic regimens known to provide 
clinical benefit including immunomodulatory (IMiD), proteasome inhibitor, and anti-
CD38 monoclonal antibody-based treatments. 
2.1.1.5 Documented measurable disease within the 4 weeks prior to registration defined by any 
one of the following: 
• Monoclonal Bone marrow plasma cells ≥5%  
• Serum monoclonal protein ≥0.2 g/dl 
• Urine monoclonal protein >200 mg/24 hour  
• 
Serum immunoglobulin free light chain >10 mg/dL AND abnormal kappa/lambda 
ratio 
• 
A measurable lesion on PET/CT or MRI  
2.1.1.6 Be  18 years of age on day of signing informed consent 
Note: The estimated 2017 US incidence of MM of patients under the age of 20 is 0.0%; 
therefore, children are excluded from enrollment in this study.[2] 
2.1.1.7 ECOG performance status <2 (Appendix A) 
2.1.1.8 Adequate organ function as evidenced by the following laboratory parameters:   
• Absolute neutrophil count (ANC) ≥ 1000 /mcL 
• Platelets 
≥ 75,000 / mcL 
• Hemoglobin 
≥ 8 g/dL (transfusions permitted)  
• Serum creatinine  
OR 
Measured CrCl or eGFR by CKD-
EPI formula may be used to 
estimate CrCl/eGFR 
≤ 1.5 X ULN (except if due to myeloma) 
OR 
≥ 30 mL/min/1.73 m2 for subject with creatinine levels 
> 1.5 X ULN  
• Serum total bilirubin 
≤ 1.5 X ULN OR  
Direct bilirubin ≤ ULN for patients with total bilirubin 
levels > 1.5 ULN (except if due to myeloma) 
• AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN (except if due to myeloma) 
 
2.1.1.9 The effects of avelumab on the developing human fetus are unknown, however, given 
the known role of PD-1/PD-L1 in maintaining the maternal/fetal tolerance, avelumab 
can be expected to have an adverse effect on pregnancy, including embryo-lethality. 
Women of child-bearing potential (WOCBP) and men must agree to use highly 
effective contraception (such as implants, injectables, combined oral contraceptives, 
IUDs, sexual abstinence or vasectomised partner) prior to study entry and for the 
duration of study treatment, and for at least 30 days after the last dose of avelumab.  
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. 
NOTE:  WOCBP is defined as any female who has experienced menarche and who has 
not undergone successful surgical sterilization or who is not postmenopausal.   

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23 
2.1.1.10 Negative serum or urine pregnancy test at screening for WOCBP. 
2.1.1.11 Ability of patient to understand and the willingness to sign a written informed consent 
document 
2.1.2 Exclusion Criteria 
2.1.2.1 Patients with clinically unstable lesions (e.g., impending cord compression) where a 
delay in receiving XRT would be detrimental are not eligible 
2.1.2.2 Current or prior anti-cancer treatment prior to the first dose of avelumab as defined 
below: 
• Chemotherapy, targeted small molecule therapy, or other anti-cancer treatment 
not otherwise specified below within 2 weeks 
• Radiation therapy within 2 weeks 
• Anti-cancer monoclonal antibody (mAb) treatment within 4 weeks 
• Use of an investigational agent (e.g., biologic, drug, or other) within 4 weeks 
• Allogeneic stem cell transplant 
2.1.2.3 No autoimmune disease, as follows:  
• Active (acute or chronic) autoimmune disease that might deteriorate when 
receiving an immuno-stimulatory agent. Patients with type I diabetes, vitiligo, 
psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive 
treatment may be eligible. 
• History of serious autoimmune-related disorders including immune colitis, 
inflammatory bowel disease, pneumonitis, or pulmonary fibrosis whether drug-
mediated or not. 
2.1.2.4 Current use of immunosuppressive medication, EXCEPT for the following: 
• Intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular 
injection) 
• Systemic corticosteroids at physiologic doses 
• Steroids as premedication for hypersensitivity reactions (e.g., CT scan 
premedication) 
2.1.2.5 Uncontrolled intercurrent illness including, but not limited to the following that may 
limit interpretation of results or that could increase risk to the patient in the judgment of 
the investigator: 
• Patients with a positive hepatitis B core antibody [HBcAb] and negative surface 
antigen (HBsAg) may be included if HBV DNA is undetectable 
• Patients who are positive for HCV antibody must be negative for HCV by 
polymerase chain reaction (PCR) to be eligible for study participation 
• Known acquired immunodeficiency syndrome (AIDS). Controlled and stable HIV 
positivity is allowed  
• Prior organ transplantation including allogenic stem-cell transplantation 
• Clinically significant cardiovascular disease: cerebral vascular accident/stroke (< 

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24 
6 months prior to enrollment), myocardial infarction (< 6 months prior to 
enrollment), unstable angina, congestive heart failure (≥ New York Heart 
Association Classification Class III), or serious cardiac arrhythmia requiring 
medication. Mild arrhythmias, e.g. stable atrial fibrillation, may be allowed at the 
discretion of the investigator 
• Active infection requiring systemic therapy (minor infections may be allowed at 
the discretion of the investigator) 
• Known mental or physical illness that would interfere with cooperation with the 
requirements of the trial or confound the results or interpretation of the results of 
the trial and, in the opinion of the treating investigator, would make the patient 
inappropriate for entry into the study. 
2.1.2.6 Persisting toxicity related to prior therapy (Grade > 1); however, alopecia, sensory 
neuropathy Grade  ≤ 2, or other Grade  ≤ 2 not constituting a safety risk based on 
investigator’s judgment are acceptable. 
2.1.2.7 Vaccination with live vaccines within 4 weeks of the first dose of avelumab and while 
on study is prohibited (inactivated vaccines may be administered). 
2.1.2.8 Pregnant or lactating females. Because there is an unknown but potential risk for 
adverse events in nursing infants, on-study breastfeeding is not allowed. 
2.1.2.9 History of allergic reactions or hypersensitivity to avelumab or any component in its 
formulations, including known severe hypersensitivity reactions to monoclonal 
antibodies (Grade ≥ 3) unless felt to be in the best interests of the patient at the 
discretion of the investigator. 
2.1.2.10 Known additional malignancy that is symptomatic or requires active systemic treatment 
(at the discretion of the PI, exceptions may be made if in the best interest of the 
patient). 
2.1.2.11 Other severe acute or chronic medical conditions including  immune colitis, 
inflammatory bowel disease,  immune pneumonitis, pulmonary fibrosis or psychiatric 
conditions including recent (within the past year) or active suicidal ideation or 
behavior; or laboratory abnormalities that may increase the risk associated with study 
participation or study treatment administration or may interfere with the interpretation 
of study results and, in the judgment of the investigator, would make the patient 
inappropriate for entry into this study. 
2.1.3 Recruitment Strategies 
Study participants will be recruited from the population of patients screened in the lymphoid 
malignancies clinic of the National Institutes of Health. These will include both referrals from 
outside physicians as well as patient self-referrals. Of note, our outside physician referral 
network has a high representation of minorities. 
This study will be posted on NIH websites and on NIH social media forums. Study-specific 
public service announcements and informational fliers will be used for recruitment activities.  All 
information to be posted or distributed publicly will be submitted to the IRB for review and 
approval in advance of use. 

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25 
2.2 
SCREENING EVALUATION 
2.2.1 Screening activities performed prior to obtaining informed consent 
Minimal risk activities that may be performed before the subject has signed a consent include the 
following: 
• Email, written, in person or telephone communications with prospective subjects 
• Review of existing medical records to include H&P, laboratory studies, etc.   
• Review of existing  MRI, x-ray, or CT images 
• Review of existing photographs or videos 
• Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes 
2.2.2 Screening activities performed after a consent for screening has been signed 
The following activities will be performed only after the subject has signed the study consent or 
the consent for study 01-C-0129 (provided the procedure is permitted on that study) on which 
screening activities will be performed. Assessments performed at outside facilities or on another 
NIH protocol within the timeframes below may also be used to determine eligibility once a 
patient has signed the consent. 
NOTE: Assessments and procedures to confirm study eligibility should be completed within 28 
days prior to registration (unless otherwise noted). 
2.2.3 Clinical Evaluations 
• Confirmation of disease diagnosis (i.e., review of pathology and/or hematopathology, 
as required) 
• Disease history, including:  diagnosis, treatment (e.g., systemic treatments, radiation 
and surgeries), status, and significant prior/ongoing side effects and symptoms 
• Complete medical history, including:  all active conditions considered to be clinically 
significant by the treating investigator 
• Physical examination, including:  height (screening only), weight, vital signs (i.e., 
temperature, pulse, respiratory rate, and blood pressure); review of concomitant 
medications and symptoms/side effects; and, assessment of performance status  
2.2.4 Laboratory Evaluations  
NOTE:  Results from outside NIH are accepted. 
• CBC with differential 
• Chemistry panels: Acute Care (sodium, potassium, chloride, CO2, glucose, BUN, 
creatinine), Mineral (serum calcium, phosphate, magnesium and albumin) and 
Hepatic (alkaline phosphatase, ALT, AST, total and direct bilirubin) and 24-hour 
urine creatinine clearance (if needed to measure CrCl in cases where serum creatinine 
> 1.5 X ULN) 
• Thyroid function tests, including: thyroid stimulating hormone (TSH), total 
triiodothyronine (T3), free thyroxine (T4) 

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26 
• Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody, Hepatitis C antibody 
(HCV) [qualitative]) (within 3 months). If Anti HCV is positive, will follow with 
HCV RNA PCR 
• Anti-HIV-1/2 Antibody (within 3 months) 
• Urine and/or serum HCG in WOCBP (within 3 days prior to enrollment and initiation 
of study therapy)  
• Uric acid, LDH, and Beta-2 Microglobulin  
• Serum protein electrophoresis (SPEP) and immunofixation to assess for presence and 
quantity of monoclonal protein (M-protein)  
• Random urine sample for protein electrophoresis (UPEP) and immunofixation to 
assess for monoclonal protein in the urine (Bence-Jones proteinuria). Collect a 24 
hour urine sample if patient’s serum monoclonal protein is ≤ 0.2 g/dL.   
• Serum free light-chain studies 
• Quantitative immunoglobulins 
2.2.5 Imaging Studies  
NOTE:  For the purposes of screening, outside radiology may be used, however, a 
baseline performed at NIH will be needed. 
• 
18F-FDG PET/CT to confirm extramedullary disease and/or lytic lesions (in certain 
scenarios, at the discretion of the investigator, a chest, abdomen and pelvis CT or 
MRI without contrast may substitute). 
2.2.6 Other Procedures 
• 12-lead EKG 
• Optional:  Bone marrow biopsy for screening may be done if patient does not have 
measurable disease otherwise (see eligibility). If done for screening/eligibility 
purposes, it does not have to repeated as a baseline measure. 
2.3 
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES 
Registration and status updates (e.g., when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found here..  
2.3.1 Treatment Assignment Procedures 
2.3.1.1 Cohorts 
Number 
Name 
Description 
1 
RRMM  
Patients with relapsed/refractory multiple myeloma (RRMM), including 
at least one extramedullary plasmacytoma or lytic lesion amenable to and 
clinically indicated for localized radiation therapy  
2.3.1.2 Arms 
Number 
Name 
Description 
1 
Experimental 
therapy  
Avelumab 800 mg IV every two weeks in combination with radiation 
therapy 

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27 
2.3.1.3 Arm Assignment 
Single arm/group assignment; open-label and non-randomized (i.e., subjects in Cohort 1 directly 
assigned to Arm 1). 
2.4 
BASELINE EVALUATION 
The following should be performed within 28 days prior to the first dose of avelumab unless 
otherwise noted; tests performed as part of screening do not need to be repeated if they were 
performed within the specified window prior to the first dose of avelumab.  
NOTE:  Results from an outside NIH institution are accepted at the discretion of the 
investigator. 
2.4.1 Clinical Evaluations 
• Medical history (interim) 
• Physical examination, including weight, and vital signs (i.e., temperature, pulse, 
respiratory rate, and blood pressure); review of concomitant medications and 
symptoms/side effects; and, assessment of performance status 
2.4.2 Peripheral Blood/Urine Laboratory Evaluations  
NOTE:  Results from outside NIH are accepted. 
• Required within 3 days:   
o Urine and/or serum HCG in WOCBP 
• Required within 14 days: 
o CBC with differential; reticulocyte count 
o Chemistry panels, including:  Acute Care Panel (sodium, potassium, chloride, 
CO2, glucose, BUN, creatinine), Mineral Panel (serum calcium, phosphate, 
magnesium and albumin), and Hepatic Panel (alkaline phosphatase, ALT, 
AST, total and direct bilirubin) 
o Others:  LDH, Uric acid, Total protein, Beta-2 Microglobulin  
o Serum protein electrophoresis (SPEP) and immunofixation to assess for 
presence and quantity of monoclonal protein (M-protein). Random urine 
sample for protein electrophoresis (UPEP) and immunofixation to assess for 
monoclonal protein in the urine (Bence-Jones proteinuria). Collect a 24 hour 
urine sample if patient’s serum monoclonal protein is < 1.0 g/dl.   
o Serum free light-chain studies 
o Quantitative serum immunoglobulins 
o Coagulation panel, including:  PT/INR and aPTT  
o Thyroid function tests, including: thyroid stimulating hormone (TSH), total 
triiodothyronine (T3), free thyroxine (T4) 
• Required within 28 days:   
o Lymphocyte Phenotype: T, B and NK cell subsets 
2.4.3 Bone Marrow Biopsy and Aspirate Evaluations 
• Histopathological evaluation on bone marrow aspirate and biopsy (DLM) 

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28 
• Immunophenotyping of aberrant clonal plasma cells by multiparametric flow 
cytometry (LP: Stetler-Stevenson Lab) 
• 
Interphase FISH (Mayo Laboratories) 
2.4.4 Imaging Studies 
NOTE:  The following required to be done at NIH. 
• 
18F-FDG PET/CT  
• Diffusion Weighted Whole Body MRI (DW-MRI) (exception: patients with a contra-
indication or inability to perform due to administrative or logistical reasons) (MIP) 
• Skeletal Survey (CC) 
NOTE:  Results from NIH only. In certain scenarios, at the discretion of the 
investigator, a CT chest, abdomen and pelvis may substitute or be in addition to 
the above diagnostic imaging modalities. 
• 
Radiation therapy imaging for planning and treatment position verification purposes, 
per institutional standards and treating radiation oncologist (must be done locally by 
ROB). 
2.4.5 Research Correlates 
NOTE:  See Section 5 for additional information.  
2.4.6 Questionnaires/Patient-Reported Outcomes (PROs) 
NOTE:  See Section 5.3.6 and Appendix G 
3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
This is a single-arm, open-label,  single institution phase 2 study of avelumab in combination 
with hypofractionated radiation therapy (BavXRT) in up to 27 patients with relapsed/refractory 
multiple myeloma (RRMM) with extramedullary disease who have progressed on 2 or more 
prior lines of therapy.  Avelumab monotherapy will continue after cycle 2 (concurrent avelumab 
and radiotherapy) until disease progression, unacceptable toxicity, or other criteria meeting 
stopping criteria (see Section 3.8).   
The primary endpoint of ORR per IMWG criteria will be augmented with secondary endpoints 
including safety and tolerability of BavXRT and exploratory correlative studies.  
All ongoing testing and procedures will take place per the Study Calendar (Section 3.7).  
NOTE: Treatment is planned to be administered on an outpatient basis. At the investigator’s 
discretion (e.g., for additional monitoring, patient social reasons, scheduling logistics, etc.), 
patients may be treated on an inpatient basis. Any cases of planned hospitalization are not 
considered reportable serious adverse events per Section 6.1.2. 
3.1.1 Cycle 1 and 3 and beyond 
• Patients will receive avelumab 800 mg IV every two weeks  
3.1.2 Cycle 2 only 
• Patients will receive XRT to at least one extramedullary plasmacytoma or lytic lesion 
daily for 5 days starting day 1. 

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29 
• Patients will receive avelumab 800 mg IV every two weeks  
 
 
 
 
3.2 
DRUG ADMINISTRATION 
3.2.1 Avelumab (MSB0010718C) Dosage  
Patients will receive avelumab 800 mg IV over 60 minutes (+/- 20 minutes) on days 1 and 15 of 
each 28-day or 4-week cycle. If radiation therapy on Day 1 of Cycle 2 is delayed (+/- 5 days), 
subsequently, Day 15 of Cycle 2 will occur 14 days after.  Any avelumab administration day 
may be adjusted +/- 5 days as needed due to scheduling or other administrative reasons.  The 
maximum window between cycles is 14 days.  
3.2.2 Avelumab Preparation 
Visually inspect vial for particulate matter and discoloration. Avelumab is a clear, colorless to 
slightly yellow solution. Discard vial if the solution is cloudy, discolored, or contains particulate 
matter. 

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Withdraw the required volume of avelumab from the vial(s) and inject it into a 250 mL infusion 
bag containing either 0.9% Sodium Chloride Injection or 0.45% Sodium Chloride Injection. 
Gently invert the bag to mix the diluted solution and avoid foaming or excessive shearing. 
Inspect the solution to ensure it is clear, colorless, and free of visible particles. 
Discard any partially used or empty vials. 
3.2.3 Avelumab Administration 
• Infusion: Administer the diluted solution over 60 minutes through an intravenous line 
containing a sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 
micron). Do not co-administer other drugs through the same intravenous line. 
• Premedication: To mitigate infusion related reactions, premedication with an 
antihistamine and paracetamol (acetaminophen) 30 to 60 minutes prior to the first 4 
infusions of avelumab is mandatory (e.g., 25-50 mg diphenhydramine and 650 mg 
acetaminophen). At the discretion of the investigator, ranitidine 150 mg PO or IV 30-
60 minutes prior to avelumab may also be administered. Premedication should be 
administered for subsequent avelumab infusions based upon clinical judgment and 
presence/severity of prior infusion reactions. This may be modified based on local 
treatment standards and guidelines, as appropriate.  
• Setting: Avelumab should be administered in a setting that allows for immediate 
access to an intensive care unit or equivalent environment and administration of 
therapy for anaphylaxis, such as the ability to implement immediate resuscitation 
measures. Steroids (dexamethasone 10 mg), epinephrine (1:1,000 dilution), allergy 
medications (IV antihistamines), bronchodilators, or equivalents, and oxygen should 
be available for immediate access. 
• 
Observation period:  Following avelumab infusions, patients must be observed for 30 
minutes post infusion for potential infusion related reactions. Infusions may be done 
peripherally or via central venous access device (not required by study), etc.  
3.3 
RADIATION THERAPY ADMINISTRATION 
3.3.1 Personnel 
Radiation therapy to extramedullary and/or lytic lesions will be administered by Radiation 
Oncology investigators from the Radiation Oncology Branch of the CCR/NCI/NIH. 
3.3.2 Radiation Dosage and Schedule 
At any given lesion, selected as a target for this study, 5 Gy per fraction will be delivered on 5 
consecutive treatment days (although consecutive days are ideal, a treatment may be delayed up 
to 3 days for administrative purposes) for a total dose 25 Gy. Treatment will be administered on 
Cycle 2 Day 1-5 (+/- 7 days). Radiation Oncology Branch Associate Investigators will be the 
points of contact (1st: Dr. Jennifer Jones; 2nd: Dr. Kevin Camphausen). Depending on the 
radiation field for a given lesion, alternate dosing and schedules will be allowed.  
3.3.3 Radiation Sites 
Only lesions which are safely amenable to radiation will be considered for radiation. Sites may 
include lytic or extramedullary lesions of the long bones, axial skeleton, and soft tissue. At the 

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31 
discretion of the investigator, more than a single site may be irradiated if clinically indicated. 
Doses to critical structures, including spinal cord, bowel, kidneys, lungs, heart, and brain, will be 
limited to standard dose constraints that are known to be associated with lower than 2-5% 
average risk of long term radiation-related side effects. Lesions that normally would not have a 
clinical indication for radiation will not be irradiated. In addition, we will treat all lesions that 
clinically require it. 
3.3.4 Additional Irradiation 
At the discretion of the investigator, a patient may receive palliative radiation to additional sites 
of disease. 
3.4 
DOSE MODIFICATIONS 
3.4.1 Avelumab 
• Dose reductions are not allowed. 
• Doses should be delayed in general for Grade ≥ 3 toxicity until toxicity resolves to 
Grade ≤ 1 unless otherwise stated in the protocol. Management should follow 
accepted medical and institutional standards. 
• Dose delays should only be instituted for adverse reactions that are at least possibly 
due to (suspected) avelumab. 
• Laboratory abnormalities which are clinically insignificant and/or unrelated to 
avelumab in the judgement of the investigator will not lead to dose delays. 
• Grade 3 fatigue, local reactions, headache, nausea, emesis that resolves to Grade ≤ 1 
with medical management will not lead to dose delays. 
• Management guidelines for infusion-related adverse reactions are found in Appendix 
B: Treatment Modification for Symptoms of Infusion-Related Reactions and 
should be followed along with institutional standards. 
• Immune-related adverse reactions (irAE) should lead to treatment modifications and 
management per Appendix C.  
• Patients may temporarily suspend study treatment for up to 28 days from the last dose 
if they experience toxicity that is considered related to the study drug and requires a 
dose to be held.  
• Local tumor flare phenomenon defined as local pain, irritation, or rash localized at 
sites of known or suspected myelomatous lesions will not be considered adverse 
events or lead to dose interruptions. 
3.4.2 Radiation Therapy 
• Very limited toxicity is expected with the planned dose and schedule of XRT (Section 
3.3)  and delays in XRT are not expected. However, both dose delays and dose 
adjustments (increase or decrease) are allowed at the discretion of the treating 
radiation oncologist in conjunction with the Principal Investigator and ROB Associate 
Investigators. 
• Any local toxicity (i.e. rash, pain) will be managed per institutional standards. 
• Local tumor flare phenomena defined as local pain, irritation, or rash localized at sites 
of known or suspected tumor, , may occur within days of the radiation treatment. 

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These responses are typically self-limited and are able to be managed by standard 
supportive measures, including topical Aquaphor and/or other institutional standards. 
3.5 
ON STUDY EVALUATIONS 
Upon confirmation of eligibility and successful registration, and following completion of the 
Screening/Baseline visits, patients will begin treatment with BavXRT.  
After Cycle 1, pre-dose assessments may be performed up to 3 days prior to Day 1 of a cycle, 
except where otherwise noted. The results from all applicable procedures/tests must be reviewed 
prior to initiation of each cycle of treatment for consideration of dose modifications. Additional 
clinical and other appropriate evaluations may be performed as clinically indicated. 
Treatment will continue indefinitely until disease progression, unacceptable treatment-related 
toxicity, or other reasons outlined in Section 3.8.1.  
Refer to the Study Calendar (Section 3.7) for all tests and procedures to be conducted during 
screening/baseline, on study/during treatment, and upon discontinuation of treatment and during 
follow-up.   
3.5.1 Cycle 2 Day 1 Evaluation 
We hypothesize that avelumab monotherapy will not be sufficient and that concomitant 
administration of XRT will be needed for synergy and clinical responses. Therefore, at the Cycle 
2 Day 1 evaluation, if the patient meets criteria for biochemical progression per IMWG, the 
patient will remain on treatment if clinically stable and without overt clinical progression in the 
judgement of the investigator. In terms of evaluating best response, PD on Cycle 2 Day 1 and 
treatment continuation will not be included. 
3.5.2 Treatment Past Progression (“Pseudo-progression”) 
Patients will not be allowed to remain on treatment past IMWG defined PD unless per the 
investigator they are receiving objective clinical benefit. 
3.6 
POST-TREATMENT EVALUATIONS 
The following evaluations are required after the decision to discontinue protocol treatment.  Any 
other evaluations and tests should be performed as clinically indicated. Any adverse events 
which are present at the time of study discontinuation should be followed in accordance with the 
safety requirements. 
3.6.1 Safety Follow-Up Visit 
The following will be performed at the end of treatment (+2 weeks), about 30 days following the 
last dose of treatment (+7 days), and post-treatment prior to (or at) disease progression. If a 
subject initiates a new anti-cancer therapy within 30 days after the last dose of trial treatment, the 
30-day safety follow-up visit must occur before the first dose of the new therapy. 
3.6.2 Extended Safety Follow-Up 
Given the potential risk for delayed immune-related toxicities, in addition to above, safety 
follow-up must be performed 90 (+14) days after the last dose of avelumab administration. This 
may be performed either via a clinic visit or via a telephone call/email with subsequent clinic 
visit requested in case any concerns are noted during the telephone call/email.  

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3.6.3 Follow-Up – Prior to Disease Progression 
If a patient discontinues treatment for a reason other than disease progression, or unless 
otherwise noted, follow-up post treatment will occur at the following time points:  every 3 
months (+/- 2 weeks) for first year after completion of therapy, every 6 months for years 2-5 (+/- 
4 weeks), and then annually thereafter (+/- 6 weeks) at the discretion of the investigator. All 
effort will be made to follow up patients in clinic to include relevant blood work and response 
assessment. However, these follow ups may be performed by phone/email if patients are unable 
to attend clinic at the discretion of the investigator.  
3.6.4 Follow-Up – Survival/Post-Disease Progession 
Upon disease progression, contact will be for survival evaluation about every 3 months only 
while the patient is on study unless otherwise indicated at the judgement of the investigator. See 
Study Calendar (Section 3.7) for additional information.  

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3.7 
STUDY CALENDAR  
Procedure 
Screening 1 
Baseline2 
Treatment Cycles3 
Disease 
Evaluations4 
End of 
Treatment5 
Post-Treatment 
Follow-Up 
Cycle 
1 
Cycle 
2 
Cycle 
3 + 
Safety6 
Follow-
Up 
(Prior to 
PD)7 
Study Cycle Day: (1 cycle = 28 days or 4 weeks) 
1 
8 
15 
22 
1 
158 
1 
Physical Exam (including, history, vitals, weight, and 
height [screening only]); ECOG PS 
X 
X* 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Confirmation of Diagnosis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
X 
X* 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Reticulocyte Count 
 
X* 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Chemistry Panels (i.e., Acute care, Mineral. Hepatic) 
X 
X* 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
LDH, Uric Acid, Total Protein 
 
X* 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
PT/INR and aPTT 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Thyroid Function (i.e., TSH, T3, T4) 
X 
X* 
 
 
 
X 
X 
X 
 
X 
X 
X 
Urinalysis 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Pregnancy Test (urine/serum HCG; WOCBP)9 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
Hepatitis B and C Testing (within 3 months) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Antibody Testing (within 3 months) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Myeloma Tests10 
X 
X* 
 
 
 
X 
X 
X 
 
X 
X 
X 
12-lead EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
T/B/NK cell subsets 
 
X 
X 
 
 
 
X 
X 
X 
 
X 
X 
X 
Skeletal Survey 
 
X 
 
 
 
 
 
X# 
 
X 
(X) 
X 
X 
18F-FDG-PET/CT Scan11 & DW MRI 
X 
X 
 
 
 
 
 
X# 
X11 
X 
(X) 
X 
X 
Radiation Therapy Imaging 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Bone Marrow Aspiration/Biopsy12 
 
X 
 
 
 
 
 
X# 
 
X 
(X) 
(X) 
 
Symptoms/Toxicity Assessment, 
Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Research Samples#13 
 
X 
See Table in Section 5.1 
PROs/Questionnaires# 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
Survival 
 
 
 
 
 
 
 
 
 
 
 
 
X (Post-PD) 
 
(X) = Optional.  NOTE:  Other tests/assessments may be performed at the discretion of the investigator as clinically indicated.   

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#See Section 5, Correlative Studies for Research, for additional information on the research blood, urine, bone marrow sampling, and questionnaires..
1 Screening evaluations should be performed within 28 days, with the following exceptions:  Confirmation of diagnosis (no time limit); HIV antibody, Hepatitis 
B surface antigen and Hepatitis C antibody (within 3 months).  NOTE:  Screening tests performed within the time frame for baseline do not need to be repeated. 
2  Baseline evaluations should be performed within 28 days prior to first dose of avelumab unless otherwise noted, tests performed as part of screening do not 
need to be repeated if performed within the specified window.  NOTE:  Items marked with an asterick (*) are required within 14 days prior to first dose. 
3 14 day maximum window between cycles due to scheduling or other administrative reasons. Cycle 1 (monotherapy): Avelumab Day 1, 1 5; Cycle 2 (dual 
therapy): Avelumab Day, 15, Radiation therapy Day 1,2,3,4,5; Cycle3+ (monotherapy): Avelumab Day 1, 15. Treat indefinitely until disease progression, or 
unacceptable toxicity. After Cycle 1 pre-dose assessment may be performed up to 3 days prior to Day 1 of a cycle except when otherwise noted. If radiation 
therapy on Day 1 of Cycle 2 is delayed (±5 days), subsequently, Day 15 of Cycle 2 will occur 14 days after. Any avelumab administration day may be adjusted 
±5 days as need for administrative or logistical reasons. 
4 During treatment, if and when patient reaches partial response (PR), complete response (CR), and/or progressive disease (PD), and at the end of treatment 
which is optional. 
5 Within 2 weeks after last treatment 
6 30 days (+7) following last dose (via clinic/in person, preferred), and 90 days (+14) after last dose of avelumab (via clinic or phone/email). If initiating new 
anti-cancer therapy within 30 days after last dose of avelumab, 30-day safety follow-up visit must occur before first dose of new therapy.  
7 Post-treatment follow-up to be done every 3 months (±2 weeks) for first year after therapy completion, every 6 months for years 2-5 (±4 weeks), and then 
annually thereafter (±6 weeks) at the discretion of the investigator. Follow-ups may be done by phone/email or by clinic visit at the discretion of the investigator.  
In cases of remote follow-up (i.e., phone/email), routine outside blood, urine, bone marrow, imaging results may be collected and used for analysis at the 
discretion of the PI; otherwise, follow-up will involve verbal reporting and survival follow-up only. Any other evaluations and tests should be performed as 
clinically indicated.  Upon progression or start of new therapy, survival follow-up may take place about every 3 months (±28 days) (i.e., phone/email preferred). 
8At Cycle 2 Day 15, disease evaluations/re-assessment should be performed ±5 days; if radiation therapy is delayed, perform 14 days (±5 days) after start of 
radiation therapy.  NOTE:  This applies to all items marked with “#;” the timing of other C2D15 assessment may also be adjusted at the discretion of the PI in 
the case of radiation delay(s).   
9 Urine and/or serum HCG in women of childbearing potential (at screening/baseline and within 3 days prior to initiation of study therapy). 
10 Myeloma tests include serum protein electrophoresis (SPEP) and serum immunofixation to assess M-protein quantity and presence, random urine sample for 
urine protein electrophoresis (UPEP) and urine immunofixation (Bence-Jones proteinuria- M- protein in urine), serum free light chains, quantitative 
immunoglobulins and beta-2 microglobulin 
11 In certain scenarios, at the discretion of the investigator, a chest, abdomen and pelvis CT or MRI may substitute for PET.  At Cycle 2 Day 15, re-assessment 
should be performed +/- 5 days; if radiation therapy is delayed, perform 14 days (±5 days) after start of radiation therapy. Patients will also receive PET/CT 
imaging at cycle 4 day 1 (±5 days) and at any point per the disrection of the investigator for non-reasearch clinical reasons. Diffusion weighted MRI (DW-MRI) 
will also be performed at the discretion of the PI. DW-MRI will be performed by standard techniques in the NCI Molecular Imaging Program. In follow-up, 
PET/CTs and DW-MRIs will be done approximately annually, if feasible. 
12Histopathological evaluation, multiparametric flow cytometry- immunotyping of aberrant clonal plasma cells, Interphase FISH (only at baseline) 
13 Samples for correlative research, including optional biopsy based on investigator discretion and safety (see Section 5). 
 
 

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3.8 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
Prior to removal from study, effort must be made to have all patients complete a safety visit 
approximately 30 and 90 days following the last dose of study therapy. Additional safety visits 
and follow-up will continue as per Section 3.6. 
3.8.1 Criteria for removal from protocol therapy 
• Confirmed disease progression not including exceptions outlined in Section 3.5  
• Unacceptable toxicity  
• Intercurrent illness that prevents further administration of treatment 
• Requirement for use of prohibited therapies as listed in Section 4.2 
• Pregnancy 
• Patient withdrawal from protocol therapy 
• Noncompliance with trial treatment or procedure requirements 
• Investigator’s decision to withdraw patient 
• Study is cancelled for any reason 
3.8.2 Off-Study Criteria 
• Patient requests to be withdrawn from study 
• Patient is lost to follow-up 
• Death 
• Study is cancelled for any reason 
• Screen failure  
4 
CONCOMITANT MEDICATIONS/MEASURES 
Medications or vaccinations specifically prohibited in the exclusion criteria (see Section 2.1.2) 
are not allowed during the ongoing trial. If there is a clinical indication for a prohibited 
medication/measure during the trial, discontinuation from trial therapy may be required.  
4.1 
ACCEPTABLE MEDICATIONS 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications and 
fluids. If changes occur during the trial period, documentation of drug dosage, frequency, route, 
and date may also be included on the CRF. Bisphosphonates (e.g. zolidronic acid) or other bone 
modifying agents may be given to treat myeloma bone disease at the discretion of the 
investigator per institutional standards. 
All concomitant medications received starting from the first dose of trial treatment and 30 days 
after the last dose of trial treatment should be recorded.  
4.2 
PROHIBITED MEDICATIONS 
Patients are prohibited from receiving the following therapies during treatment on this trial: 

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• Other therapy for the disease under study not specified in this protocol, unless 
specifically noted as permitted 
• Investigational agents outside of this clinical study protocol   
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  
Patients who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the protocol treatment but may 
remain on study for follow up. Patients may receive other medications that the investigator 
deems to be medically necessary. 
5 
CORRELATIVE STUDIES 
5.1 
SUMMARY 
Research correlatives listed below are not all inclusive and may or may not be performed based 
on investigator discretion and available resources. Of note, the table below lists the optimal 
collection methods/tubes but may be modified at the discretion of the investigator. The following 
sample types will be collected for correlative research studies:  
 

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Research Samples and Questionnaire Calendar: 
 
Sample 
Collection Details* 
Time Points 
Supervising 
Laboratory/ 
Investigator 
Baseline C2 
D1 
C2 
D15 
D1,C3 & 
beyond ≥ PR ≥ CR PD 
End of  
Treatment 
Safety/ 
Follow-
Up 
Blood Samples 
 
 
 
 
 
 
 
 
 
 
 
Biobank Storage 
(ctDNA, gDNA, exosomes) 
2 x 10 mL Streck tubes 
X 
X 
X 
X 
X 
X 
X 
(X) 
 
X 
Figg Lab 
2 x 7-10 mL K2EDTA tubes 
Circulating Tumor Cells 
(CTCs) 
2 x 10 mL in NaHep tubes 
X 
X 
X 
 
X 
X 
X 
(X) 
X 
Stetler-Stevenson 
Lab 
PBMCs, Immune Markers, 
Functional Studies 
4-6 x 10 mL NaHep tubes   
and 
1-2 x 8 mL SST tubes 
X 
 
X 
 
X 
X 
X 
(X) 
X 
Schlom Lab 
Immunoseq T cell Repertoire 
Inflammatory Gene Signature 
Bone Marrow Biopsy/Aspirate 
 
 
 
 
 
 
 
 
 
 
Histology/IHC  
FFPE  
X 
 
X 
 
X 
X 
X 
(X) 
 
CC/DLM 
Multiparametric Flow 
Cytometry 
1 x 3 mL in heparinized 
syringe 
X 
 
X 
 
X 
X 
X 
(X) 
(X) 
Stetler-Stevenson 
Lab 
CD138+ sorting/VDJ seq 
1 x 2-5 mL K2EDTA tube 
X 
 
X 
 
X 
X 
X 
(X) 
(X) 
Calvo Lab 
BMMCs/Immune Subsets 
1 x 1 mL CPB (or EDTA) tube 
X 
 
X 
 
X 
X 
X 
(X) 
(X) 
Trepel Lab 
FISH 
1 x 1-2 mL in NaHep tube 
X 
 
 
 
 
 
 
 
(X) 
Mayo send out 
myTYPE NGS 
Aspirate sections 
(standard media/ handling) 
X 
 
 
 
 
 
 
 
 
CC/DLM;  
MSKCC 
Landgren 
Urine 
 
 
 
 
 
 
 
 
 
 
 
Biobank Storage 
Sterile Container 
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
Figg Lab 
Other Procedures 
 
 
 
 
 
 
 
 
 
 
 
Plasmacytoma Biopsy 
FFPE 
Optional: up to 3 anytime on study at discretion of PI based 
on safety 
 
Laboratory of 
Pathology 
PROMIS Questionnaires+ 
Electronic (tablet) 
X 
X 
X 
X 
 
 
 
(X) 
 
Study Team 

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(X) = Optional 
*Tubes/media may be adjusted at the time of collection based upon materials available or to ensure the best samples are collected for planned 
analyses. Any of the above collections may also be performed at the discretion of the investigator at monthly time points for patients who may 
be off-treatment but not off-study. 
+The electronic PROMIS questionnaire can be accessed by designated study team members at https://scribe.cancer.gov/ 
 

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TIME POINTS FOR CORRELATIVE RESEARCH/SELECT CLINICAL MYELOMA SAMPLES: 
 
 
5.2 
SAMPLE COLLECTION AND PROCESSING  
5.2.1 Summary 
The planned analyses described below may be done on leftover and/or shared sample portions 
from the respective laboratories, as needed. In addition to the prospectively collected samples 
below, leftover portions of samples sent for routine laboratory testing (e.g., plasma from 
CBC/hematologies) may also be retrieved for research tests prior to being discarded. The 
planned prospective analyses are identified below; laboratories may share resources or 
collaborate on analyses, if appropriate (e.g., isolation/analysis of DNA is not prospectively 
planned by the Trepel lab, yet may be incorporated if needed during the planned analyses). 
Portions of all samples may be banked for future research analyses; prospective consent will be 
obtained during the informed consent process.  
For adult subjects:  The amount of blood that may be drawn from adult patients for research 
purposes shall not exceed 10.5 mL/kg or 550 mL, whichever is smaller, over any eight-week 
period. Correlative studies associated with blood/bone marrow/urine specimens will be 
performed and related to clinical outcome if the results of the study indicate a clinical or 
translational rationale for analyzing the samples. Such studies may include but are not limited to 
the following: 
5.2.2 Peripheral Blood and Urine Samples 
• Biobanking and Storage: CPP/Figg Lab 
For questions, please contact Dr. Figg’s Clinical Pharmacology Program (CPP) at 240-
760-6180; additionally, for pre-notification of planned samples (at least 24 hours in 
advance, the Friday before is preferred) email NCIBloodcore@mail.nih.gov.  After 
sample collection, please page 102-11964 for immediate pick-up. For any questions 
MIP

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regarding sample processing, you may also contact NCIBloodcore@mail.nih.gov by e-
mail or at 240-760-6180. For processing see Appendix D. 
• Circulating Plasma Cells (CTCs): LP/ Stetler-Stevenson Lab 
For questions about processing, please contact the Flow Cytometery Section of the 
Laboratory of Pathology (LP). Collect two 10 ml of blood in Sodium heparin tubes. Mix 
by gentle inversion 5-6 times. Label tube with patient name, unique identifier number and 
date. Deliver immediately to the Flow Cytometry Laboratory 3S240 (specimens 
containing hematopoietic neoplasms have a tendency to clot and must be processed 
immediately). Call for STAT Escort pickup and delivery if you cannot deliver the 
specimen yourself (301-496-9295). Flow Cytometry will be performed per LP’s standard 
processing.  
• Immune Subsets/Function, T cell repertoire, Inflammatory Signature: LTIB:/Schlom Lab 
Ideally, 6 Na heparin (green top) 10 ml and 2 serum separator (8 ml SST) tubes should be 
collected, however, 4 Na heparin 10 ml and 1 SST 8ml red top tubes is the very minimum 
acceptable. Please notify the Frederick laboratory when specimens are being shipped and 
email Frederick prior to shipping to notify the lab. Emails should be sent to Theresa 
Burks, burkst@mail.nih.gov and Caroline Jochems, jochemscm@mail.nih.gov. Once 
samples are drawn in phlebotomy, send to OP12 clinic via escort for courier pickup. 
On days samples are drawn, Jen Bangh at the Clinical Support Laboratory should be 
notified (phone: [301] 846-5893; fax [301] 846-6222). She will arrange same-day courier 
delivery of the specimens to be delivered to Frederick National Laboratory. All samples 
will be labeled with the following identifier system: 
o Patient’s enrollment #  
o Trial number  
o Patient’s initials Example: 01-ABC  
These labels are used only to send the samples from the NIH Clinical Center to the 
Clinical Support Laboratory at the Frederick National Laboratory for Cancer Research. 
The Clinical Support Laboratory will process all samples, appropriately discard the label 
on the blood tube, except for one label that is kept on the original paperwork, and then 
store the samples with unique identifiers, to which only NCI study personnel will have 
the code to link to patient specific clinical information. 
5.2.3 Bone Marrow Biopsy and Aspirate Samples 
• Immunohistochemistry of FFPE Bone Marrow Core Biopsy: CC/DLMP 
Per standard protocol of the Hematopathology Section of CC/DLM, Dr. Maric will lead 
the effort of characterizing expression of markers including PD-1 and PD-L1 by IHC of 
FFPE Bone Marrow core sections. No special collection is required for this. 
• Immunophenotyping by Flow Cytometry Aspirate: LP/Stetler-Stevenson Lab 
For questions about processing, please contact the Flow Cytometery Section of the 
Laboratory of Pathology (LP). Collect 3 mL of aspirate in one heparinized (0.5 ml) 
syringe. Mix by gentle inversion 5-6 times. Label tube with patient name, unique 
identifier number and date. Deliver immediately to the Flow Cytometry Laboratory 
3S240 (specimens containing hematopoietic neoplasms have a tendency to clot and must 
be processed immediately). Call for STAT Escort pickup and delivery if you cannot 

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deliver the specimen yourself (301-496-9295). Flow Cytometry will be performed per 
LP’s standard processing. 
• Aspirate CD138 +/- Sorting, VDJ and Microenvironment: DLM/Calvo Lab 
For aspirate designated for potential CD138 sorting, Illumina TMB/MSI sequencing (see 
5.3.2.1), VDJ sequencing, exome sequencing, and microenvironment studies, send 2-5 
mL aspirate sample in K2EDTA tube to the Calvo Laboratory in the Department of 
Laboratory Medicine Clinical Center (Attn: Dr. Weixin Wang (Building 10 Room 
2C418A). Place aspirate sample in EDTA syringe immediately on ice. Transfer within 30 
minutes of sampling to the lab for processing. For baseline samples, cells will be sorted 
in CD138+ and – fractions. Cells will be viably frozen at -20ºC and batched. See 
Appendix E for detailed laboratory protocol regarding CD138 sorting. 
• BMMCs and Immune Subsets by Flow Cytometry: DTB/Trepel Lab 
Upon subject scheduling and immediately after sample collection, contact the Trepel Lab, 
Developmental Therapeutics Branch, NCI for pick-up:  Jane Trepel:  
trepelj@mail.nih.gov; Min-Jung Lee: min-jung.lee@nih.gov; Akira Yuno: 
akira.yuno@nih.gov; and, Sunmin Lee:  leesun@mail.nih.gov; and/or 240-760-6330.  
Bone Marrow Mononuclear Cells (BMMCs) will be isolated from fresh Bone Marrow 
aspirate samples. Collect aspirate in sodium citrate tubes (e.g., CPB, blue/black speckled 
top tubes); gently invert tubes 8-10 times immediately after collection. BMMCs will be 
isolated per routine laboratory techniques. 
• Standard Fish Cytogenetics: Mayo Clinical Labs 
For baseline bone marrow aspirates, samples will be sent for standard clinical interphase 
Fluorescent In Situ Hybridization (FISH) through the CC/DLM routine processing to 
Mayo Clinical Labs. Optionally, at the discretion of the investigator, outside documented 
FISH/Cytogenetics results may be used to substitute. The name of the specific assay is 
Plasma Cell Proliferative Disorder, FISH (Test ID: PLASF) 
• myTYPE Targeted NGS Assays:  Landgren Lab (MSKCC) 
Clot sections and/or aspirate based DNA will be sent to Dr. Landgren under an MTA to 
conduct a specific myeloma targeted NGS panel.  Only coded, linked samples and data 
will be shared for these assays.   
5.2.4 Other Tissue Samples/Extramedullary plasmacytoma 
• Optionally and the discretion of the investigator, a core needle biopsy (or similar) 
procedure may be performed on extramedullary soft tissue or bone plasmacytomas. The 
procedure will only be performed on amenable lesions where the procedure will only be 
minimal risk for the patient (i.e., non-significant risk). The biopsy will be performed per 
routine standard of care, by Surgery Consultants or Interventional Radiology, as 
appropriate; with imaging guidance, if appropriate (e.g., CT-guided). A procedure-
specific consent form will be signed by the patient prior to the procedure. If a biopsy 
procedure is performed, more than one lymph node and at more than one anatomic site 
may be collected, provided the additional procedures are acceptable risk to the patient. In 
the event of core needle biopsy, these are obtained typically by using a 16-18G needle at 
the discretion of the provider performing the procedure. Conscious sedation may be used, 
if warranted, and the use and risks are acceptable to the patient.  

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Potential site(s) of biopsy include, but are not limited to: bone lesions, extramedullary 
disease/masses, and lymph nodes. The type of procedure to be done and manner in which 
it will proceed (e.g., excision/core, single vs. multiple sites of biopsy) will be discussed 
with the patient prior to the biopsy procedure.  The patient will be reminded that all 
sampling for research is voluntary.  
No more than three (3) optional biopsies will take place in any patient during the study.   
• Sample handling/processing  
When performed, biopsies will be placed in sterile collection/core cylinder tubes (e.g., 
formalin); gently invert/inspect tubes with media 8-10 times immediately after collection 
to ensure the core(s) is completed immersed in the media. 
Tissue samples will be handled/processed as below prior to planned analyses, as 
appropriate: 
Any required routine review for histopathologic confirmation of diagnosis and/or grade 
will occur per standard of care (e.g., H&E, immunohistochemistry), if required. Formalin 
samples will be fixed and paraffin-embedded per routine techniques.  
5.3 
BIOMARKER AND RESEARCH METHODS 
The technology platforms that are able to interrogate genomic structure and function are 
constantly in flux; therefore, the exact nature of the methodologies that will be employed will be 
assessed at the time that the samples are collected and ready for analysis. All of the below 
biomarker and research methods will be considered exploratory. 
5.3.1 Immune Subset Analysis 
IHC and flow cytometry will be used to evaluate bone marrow immune subsets. Bone marrow 
aspirates will be processed, stored, and assessed by the Trepel Lab using multiparameter flow 
cytometry for immune subsets including but not necessarily limited to Tregs, MDSC subsets, 
monocyte subsets, CD8+ T-cells and CD4+Foxp3- T-cells. Assessment will include functional 
markers, i.e. PD-1, Ki-67, Tim3, CTLA-4 and/or CD40 (Trepel Lab). Cell analysis and 
histological (e.g., H&E), immunohistochemical review and analysis will be performed per 
standard and established research techniques (e.g., PD-1/PD-L1, -L2 expression [Dako], CD20, 
Bcl-2, and other IHC analyses)(CC/DLM). 
The following immune assays may be performed at the Laboratory of Tumor Immunology and 
Biology at the NCI’s Center for Cancer Research (CCR) in select patients where adequate 
samples are available: 
PBMC: 
1. PBMCs may be analyzed for changes in standard immune cell types (CD4 and CD8 T 
cells, natural killer [NK] cells, regulatory T cells [Tregs], myeloid-derived suppressor 
cells [MDSCs], and dendritic cells) as well as 123 immune cell subsets, as per established 
methods.   

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2. PBMCs from selected subjects may be analyzed for function of specific immune cell 
subsets, including CD4 and CD8 T cells, NK cells, Tregs, and MDSCs. 
3. PBMCs may be analyzed for tumor antigen-specific immune responses to CEA, MUC-1 
and Brachyury using an intracellular cytokine staining assay. PBMCs will be stimulated 
in vitro with overlapping 15-mer peptide pools encoding the tumor-associated antigens 
listed above; control peptide pools will involve the use of human leukocyte antigen 
peptide as a negative control and CEFT peptide mix as a positive control. CEFT is a 
mixture of peptides of CMV, Epstein-Barr virus, influenza, and tetanus toxin. Post-
stimulation analyses of CD4 and CD8 T cells will involve the production of IFN-γ, IL-2, 
TNF, and the degranulation marker CD107a. If sufficient PBMCs are available, assays 
may also be performed for the development of T cells to other tumor-associated antigens.  
4. To determine T-cell receptor clonality, DNA may be extracted from cryopreserved 
PBMC or tumor tissue (if available) using the Qiagen DNeasy Blood and Tissue 
Kit.  TCR Vb CDR3 sequencing will be performed at the NCI genomic core facility using 
the Immunoseq kit from Adaptive Biotechnologies at the survey (tumor) or deep (PBMC) 
resolution. In this assay, a multiplex PCR system amplifies and quantifies the rearranged 
CDR3b sequences from sample DNA.  Analysis of the sequences will be performed using 
the ImmunoSeq ANALYZER from Adaptive Biotechnologies. 
5. To determine changes in inflammatory gene signatures, RNA may be extracted from 
cryopreserved PBMC or tumor tissue (if available) using the Qiagen RNeasy Plus Kit.  
Nanostring will be performed at the NCI genomic core facility using Nanostring’s 
nCounter Human PanCancer Immune Profiling panel that quantifies expression of 770 
genes. 
Analyses of soluble factors: 
1. Sera may be analyzed pre- and post-therapy for the following soluble factors: sCD27, 
sCD40 ligand using commercial ELISA kits. 
Sera may be analyzed for changes in cytokines (IFN-γ, IL-10, IL-12, IL-2, IL-4, etc.), 
chemokines, antibodies, tumor-associated antigens, and/or other markers using ELISA or 
multiplexed assays (e.g. Mesoscale, Luminex, cytokine bead array). 
5.3.2 Circulating Myeloma Cells (CTCs) and Bone Marrow Myeloma Cells 
CTCs and bone marrow plasma cell will be isolated and evaluated per established flow 
cytometry techniques. Immunophenotyping of aberrant plasma cells by flow cytometry currently 
involves, but is not limited to, the use of the following reagents: CD138, CD19, CD45, CD38, 
and CD56. Characteristic changes in immunophenotypically abnormal plasma cells (CD138 
positive) include but are not limited to absent CD19 and CD45, decreased CD38, and increased 
CD56.  These studies will be performed under the direction of Maryalice Stetler-Stevenson of 
the flow cytometry unit in the NCI Laboratory of Pathology 
5.3.2.1 Bone Marrow, CD138+/- Fractions 
Bone Marrow CD138 positive (plasma cells) and negative (microenvironment cells) will be 
fractioned per routine methods in the Calvo Lab. DNA from CD138+ fractions may be sent to 
Adaptive Biotechnologies for amplification and sequencing of the VDJ segment of the 
immunoglobulin receptor to determine clonality using well established NGS techniques. In 

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addition, CD138+ fractions may be sent to Dr. Raffeld’s Lab (NCI/LP) to undergo targeted 
sequencing using the Illumina TSO500 assay which LP is currently clinically validating to detect 
TMB and MSI status of tumor tissues. Negative fractions will be evaluated for 
microenvironmental changes in response to therapy in the Calvo Lab. 
5.3.2.2 Myeloma Targeted NGS Panel: myTYPE 
As resources allow, baseline and/or other bone marrow clot section slides may be sent to 
Memorial Sloan Kettering Cancer Center (MSKCC) for NGS targeted sequencing of myeloma 
cells using the myTYPE assay under the direction of Ola Landgren, MD, PhD. myTYPE 
captures 120 genes including driver mutations, signaling pathways, therapeutic targets, IGH 
translocations, and copy number variations. Baits were designed to capture the entire IgH locus 
where majority of the chromosome 14 breakpoints occur, genome wide single nucleotide 
polymorphisms (SNPs) for hyperdiploidy and other CNAs, as well as exons of 120 frequently 
mutated somatic genes in multiple myeloma. The target regions from bone marrow samples are 
amplified and then sequenced using 126 bp paired end reads using Illumina HiSeq with a mean 
target depth of ~600x. Data is analyzed using validated bioinformatic algorithms including 
CNVkit, Brass and Delly. This will not include sequencing matched controls. 
5.3.3 Figg Lab Biobanked Samples (ctDNA, gDNA, and exosomes) 
Blood research samples will also be collected for biobanking purposes and future experiments. 
The purpose of these assays will be to further characterize underlying biology and correlate with 
clinical outcomes in an exploratory manner. Future experiments and research work not discussed 
in this protocol will first be incorporated into the protocol prior to initiation. Appropriate 
Material Transfer Agreements (MTA) will be executed prior to sample shipment. These 
exploratory studies are not limited to but may include the following: 
Peripheral blood nanoscale particle analysis (exosome profiling, microparticles, and other 
extracellular vesicles): 
Dr. Jennifer Jones will lead studies based on profiling exosomes and changes with treatment. 
Samples will be isolated, batched, and stored in Dr. Figg’s lab. At the time of analysis, samples 
will be pulled and delivered to Dr. Jones’ lab to perform studies per routine lab procedures. 
Next Generation Sequencing (NGS) collaboration with Office of Hematology and Oncology 
Products (OHOP) FDA : 
This study may be incorporated in to the multi-protocol CCR collaborations with OHOP/FDA in 
terms of the translational and correlative aspects utilizing OHOP’s NGS laboratory to perform 
NGS assays on various human samples enrolled on a variety of CCR clinical trials. The transfer 
of samples will be performed under a CCR “umbrella” MTA. The samples will be locally 
biobanked in the Figg Lab and batched at the NIH until time for shipment, at which time, the 
samples will be sent to: 
ATTN: Elliot Rosen, Ph.D. 
DBRR III/OBP/OPQ/CDER 
Food and Drug Administration 
10903 New Hampshire Ave, 
Bldg. 52/72, Room 2248, 
Silver Spring, MD 20993 
Tel: 240-402-7353 

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Email:  elliot.rosen@fda.hhs.gov 
The correlative NGS assays to be performed will be dependent on final agreement in 
investigating mutually important questions of interest with our collaborators.  These include but 
are not limited to all or some of the following but are all optional: 
1. Germline single nucleotide polymorphisms (SNP) and copy number variations (CNV) 
DNAseq: Whole exome or genome sequencing will be performed on peripheral blood to 
determine baseline germline SNPs and CNVs. Whole blood  samples will be collected at 
baseline for germline DNA extraction. This DNA will be used to analyze and compare 
germline vs. somatic/tumor genetic alterations based on sequence data. Furthermore, 
germline normal polymorphic variation will be analyzed as genome-wide association 
study (GWAS) to determine whether certain normal variations predispose patients with 
treated SMM to progress to biochemical or overt symptomatic disease. Additionally, 
these germline variations may be analyzed for association with treatment related adverse 
events. 
2. ctDNA: Targeted DNAseq will be performed on ctDNA for assessment of changes in 
myeloma clone copy numbers. This may be performed by Adaptive Biotechnologies by 
their well established assay. Alternatively, a novel assay may be developed in 
collaboration with the FDA. This assay, in addition to the VDJ targeted commercial assay 
to determine presence of the malignant clone, the library will also include other known 
recurrent genetic aberrations. Approximately 45% of myeloma patients have 
hyperdiploidy of one of the odd numbered chromosomes, the other 45% have specific 
translocations/deletions, well characterized, including translocations of 6;14, 11;14, 4;14, 
14;16, 16;18, 17p del, and cMYC.  Therefore, the assay will focus on both VDJ as with 
other hematologic malignancies and recurrent genetic alterations similar to the approach 
used in solid malignancies. Blood collection will involve two 10 mL EDTA tubes, 
alternatively, Streck tubes may be used if processing of the sample will be delayed by 
more than 2 hours. 
3. Gene expression profiling: RNAseq will be performed on CD138+ myeloma cells and 
correlated with DNAseq results. If performed, samples will be processed in collaboration 
with the Calvo Lab. 
5.3.4 Future Use 
Any blood, tissue, or other human tissues or portions leftover from other analyses will be stored 
for future research.   
5.3.5 Imaging – DW-MRI 
5.3.5.1 Schedule 
Whole body DW-MRI scans will be performed on patients at baseline, on day 15 of cycle 2, 
cycle 4, if and when patient reaches a PR, CR, and/or PD, and at the end of treatment.  During 
follow-up period, scans may be done at any time point at the discretion of the investigator. 
5.3.5.2 Procedures 
DW-MRI exploits differences in the diffusion of water in various tissues to internal physiology. 
The image contrast in reflects the difference in rate of diffusion between tissues. All attempts 
will be made to perform the DW-MRI scans on the same day as PET/CTs, but is not mandatory. 

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For DW-MRI, no external contrast will be used and fasting is not required. Standard clinical 
operating procedures will be used for image collection. 
5.3.5.3 Results 
Patients will be given the results of the DW-MRI scans.  But given the exploratory and research 
nature of the scans, these results will not be used for clinical decision-making purposes. 
5.3.6 Patient Reported Outcomes 
The PROMIS QoL instrument will be administered to all consenting patients who speak English 
or Spanish. These instruments will be administered at baseline; at cycle 2 day 1 and 15; and start 
of every cycle beginning with cycle 3. Since the measures have not been validated in other 
languages, participation in this portion of the study will be limited to subjects who speak either 
English or Spanish.  
PROMIS, the Patient Reported Outcome Measurement Information System (PROMIS®), is 
funded by the National Institutes of Health and provides clinicians and researchers access to 
efficient, precise, valid, and responsive measures of health and well–being in clinical trial 
patients. The short forms that will be implemented in this study involve questions in the domains 
of physical function, anxiety, depression, fatigue, sleep disturbance, ability to participate in 
social roles and activities, pain interference, pain intensity, and cognitive function (see 
Appendix G). A computer tablet-based application also exists which can utilize computer 
adaptive tests (CAT) which can lower patient burden; that is, adapting the template 37 questions 
presented on the paper short forms based on patient response. The questionnaires are not 
expected to take more than 20 minutes to complete.   
As feasible, the PROMIS data may be captured based on this CAT PROMIS tablet application; 
alternatively, the paper short forms presented in the appendix will be used. Data will be secured 
on the tablet based on 2 passwords. When results are ready for analysis, they will be exported in 
excel format and submitted for storage in C3D or Labmatrix, as appropriate. Patients already 
enrolled onto the study may begin completion of PROs at the next scheduled visit after 
amendment activation at the discretion of the investigator. 
5.4 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
5.4.1 General 
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system.  
Should a CRIS screen not be available, the CRIS downtime procedures will be followed.  
Samples will not be sent outside NIH without appropriate approvals and/or agreements, if 
required. 
All specimens obtained in the protocol are used as defined in the protocol. Any specimens that 
are remaining at the completion of the protocol will be stored in the conditions described below.  
The study will remain open so long as sample or data analysis continues.  Samples from 
consenting patients will be stored until they are no longer of scientific value or if a subject 
withdraws consent for their continued use, at which time they will be destroyed.   The PI will 
record any loss or unanticipated destruction of samples as a deviation. Reporting will be per the 
requirements of section 7.2. 
If the patient withdraws consent his/her data will be excluded from future distributions, but data 
that have already been distributed for approved research use will not be able to be retrieved. 

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5.4.2 Laboratory of Tumor Immunology and Biology (Schlom Lab) 
All data associated with the patient samples is protected by using a secure database. All Clinical 
Support Laboratory Staff receive annual training in maintaining records’ confidentiality. All 
samples drawn at the NIH Clinical Center will be transported to the Clinical Support Laboratory 
at the Frederick National Laboratory for Cancer Research by couriers.  
Samples will be tracked and managed by Central Repository database, where there is no link to 
personal identifiable information. All samples will be stored in either a -80˚C freezer or vapor 
phase liquid nitrogen. These freezers are located at NCI Frederick Central Repository in 
Frederick, Maryland.  
The NCI Frederick Central Repositories is managed under subcontract to Leidos Biomedical, 
Inc., Frederick, Inc. NCI Frederick Central Repositories store, among other things, biological 
specimens in support of NIH clinical studies. All specimens are stored in secure, limited-access 
facilities with sufficient security, backup, and emergency support capability and monitoring to 
ensure long-term integrity of the specimens for research.  
Specimens are stored in accordance will applicable HHS and FDA Protection of Human Subjects 
Regulations in accordance with the subcontactors Federal-wide Assurance. The subcontractor’s 
role limited to clinical research databases and repositories containing patient specimens. The 
subcontractor does not conduct or have any vested interest in research on human subjects, but 
does provide services and support the efforts of its customers, many of which are involved in 
research on human subjects. The subcontractor’s IRB reviews policies and procedures for 
labeling, data collection and storage, access, and security. The IRB will review protection of 
privacy issues prior to acceptance of any new work and in the event of change impacting privacy 
issues in existing work.  
It is the intent and purpose of the subcontractor to accept only coded (linked) samples and 
sample information. To the limit of our ability, every effort will be made to ensure that protected 
information is not sent electronically or by hard copy or on vial labels.  
Sample data is stored in the BioSpecimen Inventory System II (BSI). This inventory tracking 
system is used to manage the storage and retrieval of specimens, as well as to maintain specimen 
data. BSI is designed for controlled, concurrent access. It provides a real-time, multi-user 
environment for tracking millions of specimens. The system controls how and in what order 
database updates and searches are performed. This control prevents deadlocks and race 
conditions. For security, BSI has user password access, 3 types of user access levels, and 36 user 
permissions (levels of access) that can be set to control access to the system functions. BSI 
provides audit tracking for processes that are done to specimens including shipping, returning to 
inventory, aliquoting, thawing, additives, and other processes. BSI tracks the ancestry of 
specimens as they are aliquoted, as well as discrepancies and discrepancy resolution for 
specimens received by the repository. If a specimen goes out of the inventory, the system 
maintains data associated with the withdraw request. Vials are labeled with a unique BSI ID 
which is printed in both eye-readable and bar-coded format. No patient-specific information is 
encoded in this ID.  
Investigators are granted view, input, and withdraw authority only for their specimens. They may 
not view specimen data or access specimens for which they have not been authorized. Access to 
specimen storage is confined to repository staff. Visitors to the repositories are escorted by 
repository staff at all times.  

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Samples will be used for research analysis, including immunologic monitoring as outlined 
previously. All specimens for analysis will be requested from Leidos Biomedical, Inc. and will 
be delivered by Leidos Biomedical, Inc. couriers to the Laboratory of Tumor Immunology and 
Biology.  
The samples will be processed/stored through: 
Leidos Biomedical Research 
Attn: Ms. Theresa Burks 
1050 Boyles Street 
Bldg. 469/Room 121 
Frederick, MD 21702 
Phone 301-846-5125 
On days samples are drawn, Jen Bangh at the Clinical Support laboratory should be notified 
(phone: [301] 846-5893; fax [301] 846-6222). She will arrange same-day courier delivery of the 
specimens.  
5.4.3 Developmental Therapeutics Branch (Trepel Lab) 
Under the direction of Dr. Trepel, all samples processed by the Developmental Therapeutics 
Branch Laboratory will be uniquely barcoded, with data entered using a secure computerized 
database and backup hardcopy process per standard laboratory practice. All lab personnel with 
access to patient information annually complete the NIH online Protection of Human Subjects 
course. 
Samples are stored in labeled boxes in secured freezers (i.e., -20ºC to -80ºC, or other, as 
appropriate) according to stability requirements; these freezers are located onsite.  Access to 
stored clinical samples is restricted and limited to research personnel for approved analyses only 
(as per the IRB approved protocol). 
Upon completion of planned analyses by the Trepel lab, leftover samples may be stored for 
future analyses at the Clinical Support Laboratory, Leidos Biomedical Research, Inc.in 
Frederick, MD (see below).   
5.4.4 Clinical Pharmacology Program (Figg Lab) 
5.4.4.1 Sample Data Collection 
All samples sent to the Blood Processing Core (BPC) of the Clinical Pharmacology Program 
under the direction of Dr. Figg will be barcoded, with data entered and stored in Labmatrix 
utilized by the BPC. This is a secure program, with access to Labmatrix limited to defined Figg 
lab personnel, who are issued individual user accounts. Installation of Labmatrix is limited to 
computers specified by Dr. Figg. These computers all have a password restricted login screen.  
Labmatrix creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to patients without Labmatrix access. The data recorded for each sample includes the 
patient ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, 
as well as box and freezer location. Patient demographics associated with the clinical center 
patient number are provided in the system. For each sample, there are notes associated with the 
processing method (delay in sample processing, storage conditions on the ward, etc.). 

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5.4.4.2 Sample Storage  
Barcoded samples are stored in barcoded boxes in a locked freezer at appropriate temperatures 
(e.g., -20ºC to -80ºC) according to stability requirements.  These freezers are located onsite in the 
BPC and offsite at NCI Frederick Central Repository Services in Frederick, MD. Visitors to the 
laboratory are required to be accompanied by laboratory staff at all times.  
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in Labmatrix. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused 
samples must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to 
ensure that the samples requested are being used in a manner consistent with IRB approval. 
Sample barcodes are linked to patient demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
LABrador. It is critical that the sample remains linked to patient information such as race, age, 
dates of diagnosis and death, and histological information about the tumor, in order to correlate 
genotype with these variables. 
5.4.5 Hematopathology Section of Laboratory of Pathology (other tissue samples) and 
Department of Laboratory Medicine (Bone Marrow) 
Archival and/or freshly collected and processed tumor tissue may be stored in the 
Hematopathology Section of Laboratory of Pathology until ready for planned and/or future 
research assays if the patient has agreed to allowing specimens to be used in future research 
studies.  IRB approval will be obtained before using any samples to conduct studies that are not 
described within this protocol.  Samples will be stored under conditions appropriate to the type 
of sample and processing (e.g., ambient or frozen).   
Tissue that is given to the technician will be assigned an accession number (HP#) in the HP Case 
Log book; sample tracking also takes place with a FileMaker Pro database called HP Patient 
Information and Specimen Inventory.  A Patient background sheet may be filled out and filed 
with any accompanying paperwork, with final reports and any supplemental reports that follow 
added as completed.  
5.4.6 Adaptive Biotechnologies Corp. 
Only coded (linked) samples will be shared with Adaptive Biotechnologies Corporation for the 
studies as described (see Sections 5.3.1, 5.3.2.1 and 5.3.3.  The samples and data will sent in 
batches at the address listed below: 
Adaptive Biotechnologies Corp. 
1551 Eastlake Ave E 
Suite 200  
Seattle WA 98102 
5.5 
SAMPLES FOR GENETIC/GENOMIC ANALYSIS 
5.5.1 Scope of genetic/genomic analysis 
The research correlates for this study are expected to include DNA/RNA sequencing of tumors, 
including circulating tumor (ct) DNA.  In addition, whole exome sequencing may include 
evaluation for known lymphoma mutations.  For any genetic studies performed, the results will 

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be deposited in a database such as dbGaP per NIH requirements.  Although there is controlled 
access to such a database, such a submission carries theoretical risks of revealing the identity of 
the subject.  This is discussed in the consent. 
5.5.2 Privacy and confidentiality of medical information/biological specimens  
Confidentiality for genetic samples will be maintained as described (Section 5.4).  In addition, a 
Certificate of Confidentiality has been obtained for this study. 
5.5.3 Management of Results 
These NGS exploratory investigations will be performed solely for research purposes, as these 
assays are not as sensitive as the tests that are performed in a laboratory that is certif ied to 
perform genetic testing. There is no plan for looking for incidental findings that are relevant to 
other diseases. Therefore, results will not be shared with patients or referring physicians. 
Subjects will be contacted if a clinically actionable gene variant is discovered.  Clinically 
actionable findings for this study are defined as disorders appearing in the American College of 
Medical Genetics and Genomics recommendations for the return of incidental findings that is 
current at the time of primary analysis. (A list of current guidelines is maintained on the CCR 
intranet: https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists). 
5.5.4 Genetic Counseling 
Subjects will be contacted with a request to provide a blood sample to be sent to a CLIA certified 
laboratory.  If the research findings are verified in the CLIA certified lab, the subject will be 
offered the opportunity to come to NIH to have genetic education and counseling to explain this 
result; at the time of any such event(s), these activities will be funded by the NCI/CCR in 
consideration of the specific circumstances.  If the subject does not want to come to NIH, a 
referral to a local genetic healthcare provider will be provided (at their expense). 
This is the only time during the course of the study that incidental findings will be returned. No 
interrogations regarding clinically actionable findings will be made after the primary analysis. 
5.6 
EXPLORATORY/RESEARCH RADIATION EXPOSURE 
An exploratory objective of this study is to describe the effects of the study treatment in tumor 
tissue with optional biopsies.  To satisfy this exploratory objective, subjects will receive 
radiation from up to three (3) CT-guided biopsies for research purposes on this protocol. 
CT-guidance may be used for up to three (3) optional tumor biopsies during the study.  The 
procedures for performing each biopsy will follow clinical policies, no special procedures apply 
to the additional procedures for research purposes (see Section 5.2.4). 
   
6 
DATA COLLECTION AND EVALUATION  
6.1 
DATA COLLECTION 
6.1.1 Summary 
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system (C3D) and ensuring data accuracy, consistency and timeliness.  The principal 
investigator, associate investigators/research nurses and/or a contracted data manager will assist 
with the data management efforts.  All data obtained during the conduct of the protocol will be 

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kept in secure network drives or in approved alternative sites that comply with NIH security 
standards.  Primary and final analyzed data will have identifiers so that research data can be 
attributed to an individual human subject participant. 
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event.   
Document AEs from the first study intervention, Study Day 1 through 90 days after last 
treatment. Beyond the 90 day period after the last drug was administered, only adverse evnts 
which are serious and related to the study intervention need to be recorded. 
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 7.2.1. 
6.1.2 Data Collection/Recording Exceptions 
6.1.2.1 Abnormal Laboratory Values 
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following: 
• Results in discontinuation from the study 
• Is associated with clinical signs or symptoms  
• Requires treatment or any other therapeutic intervention 
• Is associated with death or another serious adverse event, including hospitalization.  
• Is judged by the Investigator to be of significant clinical impact 
• If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome. 
6.1.2.2 Hospitalizations 
Any cases of planned or prolonged hospitalization are not considered reportable serious adverse 
events if for the following reasons: 
• Closer monitoring and/or prophylaxis of TLS at any cycle 
6.2 
DATA SHARING PLANS 
6.2.1 Human Data Sharing Plan 
What data will be shared? 
I will share human data generated in this research for future research as follows: 
_X_ Coded, linked data in an NIH-funded or approved public repository.   
_X_ Coded, linked data in another public repository 
_X_ Coded, linked data in BTRIS (automatic for activities in the Clinical Center) 
_X_ Coded, linked or identified data with approved outside collaborators under appropriate 
agreements. 

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How and where will the data be shared?  
Data will be shared through: 
_X_ An NIH-funded or approved public repository.  Insert name or names: ClinicalTrials.gov, 
dbGaP. 
_X_ BTRIS (automatic for activities in the Clinical Center) 
_X_ Approved outside collaborators under appropriate individual agreements.   
_X_ Publication and/or public presentations. 
When will the data be shared? 
_X_ Before publication. 
_X_ At the time of publication or shortly thereafter. 
6.2.2 Genomic Data Sharing Plan 
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy. 
6.3 
RESPONSE CRITERIA  
Patient response and overall response rates (ORR) will be assessed according to the 2016 
International Myeloma Working Group (IMWG) response criteria.[1] (See Appendix F.) 
6.3.1 Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence per IMWG criteria.  
6.3.2 Duration of Response 
The duration of response (DoR) is measured from the time measurement criteria are met for a 
response of PR or better until the first date that recurrent or progressive disease is objectively 
documented. Patients without a progression event will be censored at the date response 
assessment was last evaluated. 
6.3.3 Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from the date of study 
enrollment until time of disease progression, or death, whichever occurs first. Patients without a 
progression or death event will be censored at the date response assessment was last evaluated.  
Note that, a progression or death event occurring up to cycle 2 day 1 will not be included in the 
definition as patients have not had received combination therapy until that time. 
6.3.4 Overall Survival 
Overall survival (OS) is defined as the duration of time from the date of study enrollment until 
time of death. Patients without a death event will be censored at the date survival assessment was 
last evaluated (e.g., clinic visit, phone call). 
6.4 
TOXICITY CRITERIA 
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study.  The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 

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5.0.  A copy of the CTCAE version 5.0 can be downloaded from the CTEP website 
(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_50).  
7 
NIH REPORTING REQUIREMENTS / DATA SAFETY MONITORING PLAN 
7.1 
DEFINITIONS 
Please refer to definitions provided in Policy 801: Reporting Research Events found here. 
7.2 
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING 
7.2.1 Expedited Reporting  
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found here. Note: Only IND Safety Reports that 
meet the definition of an unanticipated problem will need to be reported per these policies. 
7.2.2 IRB Requirements for PI Reporting at Continuing Review 
Please refer to the reporting requirements in Policy 801: Reporting Research Events found here.  
7.3 
NCI CLINICAL DIRECTOR REPORTING   
Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical 
Director.  A separate submission is not necessary as reports in iRIS will be available to the 
Clinical Director. 
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to 
progressive disease.   
To report these deaths, please send an email describing the circumstances of the death to Dr. 
Dahut at NCICCRQA@mail.nih.gov within one business day of learning of the death. 
7.4 
NIH REQUIRED DATA AND SAFETY MONITORING PLAN 
7.4.1 Principal Investigator/Research Team  
The clinical research team will meet approximately weekly when patients are being actively 
treated on the trial to discuss each patient.  Decisions about trial continuation will be made based 
on the efficacy data from prior patients at appropriate time points per the statistical plan.   
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator.  Events meeting requirements for expedited reporting as described in 
section 7.2.1 will be submitted within the appropriate timelines.   
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy.  The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
8 
SPONSOR SAFETY REPORTING 
8.1 
DEFINITIONS 
8.1.1 Adverse Event  
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pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product (ICH E6 (R2)) 
8.1.2 Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• 
Death, 
• 
A life-threatening adverse event (see section 8.1.3) 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
o A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event. 
o A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient convenience) is not considered a serious adverse event.  
o Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria. 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
8.1.3 Life-threatening  
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. (21CFR312.32) 
8.1.4 Severity 
The severity of each Adverse Event will be assessed utilizing the CTCAE version 5. 
8.1.5 Relationship to Study Product 
All AEs will have their relationship to study product assessed using the terms:  related or not 
related.   
• 
Related – There is a reasonable possibility that the study product caused the adverse event. 
Reasonable possibility means that there is evidence to suggest a causal relationship between the 
study product and the adverse event. 

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• 
Not Related – There is not a reasonable possibility that the administration of the study product 
caused the event. 
8.2 
ASSESSMENT OF SAFETY EVENTS  
AE information collected will include event description, date of onset, assessment of severity 
and relationship to study product and alternate etiology (if not related to study product), date of 
resolution of the event, seriousness and outcome. The assessment of severity and relationship to 
the study product will be done only by those with the training and authority to make a diagnosis 
and listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  AEs 
occurring during the collection and reporting period will be documented appropriately regardless 
of relationship.  AEs will be followed through resolution. 
SAEs will be: 
• 
Assessed for severity and relationship to study product and alternate etiology (if not related to 
study product) by a licensed study physician listed on the Form FDA 1572 as the site principal 
investigator or sub-investigator. 
• 
Recorded on the appropriate SAE report form, the medical record and captured in the clinical 
database. 
• 
Followed through resolution by a licensed study physician listed on the Form FDA 1572 as the 
site principal investigator or sub-investigator. 
For timeframe of recording adverse events, please refer to section 6.1. All serious adverse events 
recorded from the time of first investigational product administration must be reported to the 
sponsor with the exception of any listed in section 8.5. 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS  
Any AE that meets protocol-defined serious criteria or meets the definition of Adverse Event of 
Special Interest that require expedited reporting must be submitted immediately (within 24 hours 
of awareness) to OSRO Safety using the CCR SAE report form. Any exceptions to the expedited 
reporting requirements are found in section 8.5. 
All SAE reporting must include the elements described in section 8.2. 
SAE reports will be submitted to the Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  CCR SAE report form 
and instructions can be found at: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=157942842  
Following the assessment of the SAE by OSRO, other supporting documentation of the event 
may be requested by the OSRO Safety and should be provided as soon as possible. 
8.4 
WAIVER OF EXPEDITED REPORTING TO CCR 
There are no execeptions to expedited reporting requirements.   
8.5 
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS  
All events listed below must be reported in the defined timelines to OSROsafety@mail.nih.gov.  
The CCR Office of Regulatory Affairs will send all reports to the manufacturer(s) as described 
below, unless otherwise noted. 

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The investigational agent, avelumab, is being supplied by EMD Serono and the following are 
their requirements for safety reporting. 
The following reportable events must be submitted to EMD Serono within 2 business days or 3 
calendar days (whichever comes first) using the applicable safety report form provided. The 
Principal Investigator/study team will submit reportable events to the Sponsor as well as ensure 
that any other local reporting requirements are completed, if required (e.g., IRB).  The Sponsor 
will assume responsibility for submitting the reportable event(s) to EMD Serono. 
The reportable events to EMD Serono include:   
• Serious Adverse Events 
• Exposure during Pregnancy or Breastfeeding (even if not associated with an adverse 
event) 
• Occupational exposure (even if not associated with an adverse event) 
• Potential drug-induced liver injury (Hy's Law cases): These events are considered 
important medical events and should be reported as SAEs. 
Contact information for submission of reportable events to EMD Serono: 
Fax: +49 6151 72 6914 
OR 
E-mail: GlobalDrugSafety@merckgroup.com, specifying: 
• PROTOCOL Number and/or Title 
• EMD Serono assigned Study Number 
• SUBJECT Number 
• SITE Number/PI Name 
8.6 
REPORTING PREGNANCY 
8.6.1 Maternal exposure 
If a patient becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of 
when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later 
than 24 hours of when the outcome of the Pregnancy become known, 
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (section 8.1.2) should be reported as 
SAEs.  
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth, or congenital abnormality) should be followed up and documented. 
8.6.2 Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 30 
days after study drug.  
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 30 days after the last dose 
should, if possible, be followed up and documented. 

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8.7 
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR SPONSORED IND  
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected.  CCR will report an AE as a suspected 
adverse reaction only if there is evidence to suggest a causal relationship between the study 
product and the adverse event.  CCR will notify FDA and all participating investigators (i.e., all 
investigators to whom the sponsor is providing drug under its INDs or under any investigator’s 
IND) in an IND safety report of potential serious risks from clinical trials or any other source, as 
soon as possible, in accordance to 21 CFR Part 312.32.  
All serious events will be reported to the FDA at least annually in a summary format. 
9 
CLINICAL MONITORING  
As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring 
program. The CCR’s program allows for confirmation of: study data, specifically data that could 
affect the interpretation of primary and secondary study endpoints; adherence to the protocol, 
regulations, ICH E6, and SOPs; and human subjects protection. This is done through 
independent verification of study data with source documentation focusing on: 
• 
Informed consent process 
• 
Eligibility confirmation 
• 
Drug administration and accountability 
• 
Adverse events monitoring 
• 
Response assessment. 
The monitoring program also extends to multi-site research when the CCR is the coordinating 
center. 
This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified 
by training and experience to monitor the progress of clinical trials. Personnel monitoring this 
study will not be affiliated in any way with the trial conduct.   
10 STATISTICAL CONSIDERATIONS   
10.1 STUDY ENDPOINTS 
• Primary Endpoint:  
o The primary endpoint of this study is to determine the overall response rate 
(ORR) in patients with multiple myeloma treated with avelumab and irradiation. 
• Secondary Endpoints: 
o The secondary endpoints are to determine: 
▪ Complete Response (CR) rate and Minimal Residual Disease (MRD) 
negative CR rate, 
▪ Reductions in bone marrow (BM) and peripheral blood (PD) 
plasmacytosis,  
▪ Radiographic reduction in size, and/or FDG avidity (PET/CT) of 
extramedullary lesions, 

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▪ Radiographic reduction in size, and/or FDG avidity (PET/CT) of non-
irradiated extramedullary lesions (abscopal effect) 
▪ Progression-free survival (PFS) 
▪ Overall survival (OS) 
▪ All Grade, Grade 3-4, and serious adverse events, and 
▪ ORR post cycle 1 (prior to XRT) 
• Exploratory Endpoints 
o Correlative Studies may be performed in select patients where adequate samples 
are available: 
▪ Peripheral blood mononuclear cells (PBMCs):  
• Changes in 123 immune subsets including CD4 and CD8 T cells, 
natural killer [NK] cells, NK-T cells, regulatory T cells [Tregs], 
myeloid-derived suppressor cells [MDSCs], and dendritic cells and 
114 refined subsets relating to maturation/function using 
multicolor flow cytometry 
• Changes in the function of select immune cell subsets (e.g. CD4 
and CD8 effector T cells, NK cells, Tregs, and MDSCs)   
• Changes in tumor antigen specific T cells (e.g. brachyury, MUC1, 
and CEA) using intracellular cytokine staining for IFNg, TNF, and 
IL2 and the degranulation marker CD107a 
• Changes in T-cell clonality score using adaptive biotechnologies 
TCRseq assay 
• Changes in inflammatory gene signature using Nanostring’s 
nCounter Human PanCancer Immune Profiling Panel 
▪ Plasma/Serum: 
• Changes in sCD27, sCD40L 
• Changes in cytokines (IFN-γ, IL-10, IL-12, IL-2, IL-4, etc.), 
chemokines, antibodies, tumor-associated antigens, and/or other 
markers 
• Changes in VDJ copy number of MM clones 
▪ Bone Marrow: 
• Changes in immune subsets 
• Changes in VDJ copy number of MM clones 
• DNA genetic alterations and TMB of MM cells 
10.2 STATISTICAL HYPOTHESIS AND SAMPLE SIZE DETERMINATION 
Historically, anti-PD-1 monotherapy in MM has an overall response rate (PR+VGPR+CR+sCR) 
of approximately 5%. It would be desirable to demonstrate that the combination of avelumab and 
irradiation has a substantially higher response rate, of at least 10-15%. As such, this study will be 
conducted using a Simon minimax two-stage phase II trial design to rule out an unacceptably 
low ORR of 5% (p0=0.05) in favor of an improved response rate of 20% (p1=0.20). With 
alpha=0.05 (probability of accepting a poor treatment=0.05) and beta = 0.20 (probability of 
rejecting a good treatment=0.20), the first stage will enroll 13 evaluable patients, and if 0 of the 

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13 have a clinical response, then no further patients will be accrued in this trial.  If 1 or more of 
the first 13 patients have a response, then accrual would continue until a total of 27 evaluable 
patients have been treated. As it may take up to several months to determine if a patient has 
experienced a response, a temporary pause in the accrual may be necessary to ensure that 
enrollment to the second stage is warranted. If there are 1 to 3 patients with a response out of 27 
patients, this would be an uninterestingly low response rate. If there were 4 or more of 27 
(14.8%) who experienced a response, this would be sufficiently interesting to warrant further 
study in later trials. Under the null hypothesis (5% response rate), the probability of early 
termination is 51.3%. 
It is expected that approximately 8-10 patients per year may enroll onto this trial. Thus, it is 
expected that 3 years may be required to enroll up to 27 evaluable patients. To allow for a small 
number of inevaluable patients and screen failures, the accrual ceiling will be set at 30 patients. 
10.3 POPULATIONS FOR ANALYSES 
Modified intention to treat: all patients who receive at least one dose of avelumab will be 
included in the statistical analyses performed. 
10.3.1 Evaluable for toxicity:  
All patients will be evaluable for toxicity from the time of their first treatment with avelumab. 
10.3.2 Evaluable for objective response:  
Only those patients who have measurable disease present at baseline and have received at least 
one dose of therapy will be considered evaluable for response.  
10.4 STATISTICAL ANALYSES 
10.4.1 General Approach 
Response fractions, and time to event endpoints will be reported along with appropriate 
confidence intervals.  
10.4.2 Analysis of the Primary Endpoints 
The fraction of patients who experience a PR, VGPR, CR, or sCR using the study treatment will 
be determined by dividing the number of responders by the total evaluable patients. The fraction 
will be reported along with 90% and 95% two-sided confidence intervals 
10.4.3 Analysis of the Secondary Endpoints 
• CR rate: the fraction of patients who experience a CR or sCR using the study treatment 
will be determined by dividing the number of these responders by the total evaluable 
patients. The fraction will be reported along with 90% and 95% two-sided confidence 
intervals. 
• MRDnegCR rate: the fraction of patients who experience an MRDnegCR using the study 
treatment will be determined by dividing the number of these responders by the total 
evaluable patients. The fraction will be reported along with 90% and 95% two-sided 
confidence intervals.  
• Reduction of BM and PD plasmacytosis: Percent change in plasma cells in the PB and 
BM from baseline will be reported descriptively. 

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• Reduction of size, and/or FDG avidity of extramedullary lesions: Percent reduction of 
size, and/or FDG avidity, radiographicaly, of extramedullary lesions compared to 
baseline will be reported descriptively. 
• PFS: will be determined using the Kaplan-Meier method, considering  those who 
progress or die without progression as failures, and censoring those who do not. 
• OS: will be determined using the Kaplan-Meier method. 
• Safety and tolerability: overall tolerability in terms of adverse events will be evaluated 
with descriptive statistics to determine the safety of receiving avelumab in the context of 
irradiation in RRMM patients. NCI CTCAE v.5 will be used to grade adverse events. 
• ORR post cycle 1: a milestone ORR at start of cycle 2 will be calculated as above to 
determine ORR of avelumab monotherapy after 1 cycle of therapy. 
Each of these will be calculated starting from the date the patient enrolled onto the trial which 
corresponds to the date the patient signed the informed consent document. Appropriate 
confidence intervals will be reported for each of these measures. (Only PFS events occurring 
during the initiation and of the combination of irradiation and avelumab and after will be counted 
as this proof of principal study hypothesis is that the combination of BavXRT will be active.) 
10.4.4 Safety Analyses 
Early stopping rules for toxicities will be put in place. Specifically, if within the first 6 patients, 
there are two Grade ≥ 3 toxicities, or if at any time after 6 patients have been treated, the 
cumulative fraction with Grade ≥ 3 toxicity is 33% or greater, then the trial will suspend accrual 
and will only reopen following review of the safety data and amendment to modify the treatment 
appropriately. Adverse events which are clinically insignificant or can be resolved with 
conservative measures (e.g. laxatives for constipation) or which are not at least possibly due to 
the experimental treatment will not be included in this early stopping strategy. 
10.4.5 Baseline Descriptive Statistics 
Demographic and baseline clinical characteristics of all patients will be reported. 
10.4.6 Planned Interim Analyses 
As indicated above futility will be determined using the Simon two-stage design, after the 
required number of evaluable patients have been enrolled in the first stage, an analysis of the 
response rate will be undertaken to determine if there are sufficient responses to proceed to the 
second stage. 
10.4.7 Sub-Group Analyses 
None will be performed 
10.4.8 Tabulation of Individual Participant Data 
None will be performed 
10.4.9 Exploratory Analyses 
All exploratory objectives listed above will be analyzed using descriptive statistics. Various 
percentile confidence intervals and nominal P-values may be determined. 
Changes in QoL/PROs based on the PROMIS instrument will be evaluated relative to any degree 
of response and summary statistics will be described over time. As these evaluations may be 
performed in a post hoc manner based on the response results obtained, the findings will need to 

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be carefully presented in the context of the exploratory nature of the analyses undertaken; results 
will not be evaluated in “real-time.” 
11 COLLABORATIVE AGREEMENTS 
11.1 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA) 
This study will be incorporated into an existing CRADA between the National Cancer Institute 
and EMD Serono (#02666/iMTA #44957-18). 
11.2 MATERIAL TRANSFER AGREEMENT (MTA) 
11.2.1 Memorial Sloan Kettering Cancer Center (MSKCC) 
An MTA will be established between the National Cancer Institute (NCI ) and Dr. C. Ola 
Landgren at Memorial Sloan Kettering Cancer Center (MSKCC) prior to the sharing of any 
data/samples (see Section 5.2.3).  (MTA # [PENDING]) 
11.2.2 Food and Drug Administration (FDA) 
12 AN MTA WILL BE EXECUTED/REVISED TO ALLOW THE SAMPLES 
DESCRIBED IN SECTION 5 TO BE SHIPPED TO THE OFFICE OF 
BIOTECHNOLOGY AT THE FDA AS PART OF THE COLLABORATIVE 
EFFORT. THE MTA WILL BE A GLOBAL CCR MTA TO INCLUDE MULTIPLE 
PROTOCOLS, HOWEVER, DR. KAZANDJIAN WILL BE THE RESPONSIBLE PI 
REGARDING THE MULTIPLE MYELOMA PROTOCOLS BOTH AT THE NIH 
AND FDA SITE.  (MTA #43656)HUMAN SUBJECTS PROTECTIONS  
12.1 RATIONALE FOR SUBJECT SELECTION 
MM is an almost always incurable plasma cell neoplasm that comprises approximately 10%  
of all hematologic malignancies, affecting 30,000 patients annually. Recent studies have shown 
that MM is preceded by MGUS and SMM. Rate of progression at 5 years from high risk SMM to 
MM is 72-76% at 5 years with a median TTP of < 2 years. MM affects all genders and races. 
Incidence rates of myeloma is higher among African Americans (AA) compared to Caucasian 
Americans (CA), affecting 14.3 AA males per 100, 000 males and 10.0 AA females per 100,000 
females compared to 6.7 CA males per 100, 000 males and 4.1 CA females per 100, 000 women. 
The median age at death for myeloma is 75 years of age. As such, we expect that the majority of 
patients enrolled in this trial will be older adults of either gender or race. MM patients enrolled 
on this study will consist of patients referred to and screened at the NIH Clinical Center. There 
will be no subject selection bias with regard to gender, ethnicity, or race. This protocol excludes 
lactating and pregnant women from receiving this investigational drug to avoid any possible 
risks to the fetus or newborn. 
12.2 PARTICIPATION OF CHILDREN 
Pediatric patients with RRMM are extremely rare. Patients under the age of 18 are excluded from 
this study because inclusion of a rare younger patient will not provide adequate generalizable 
information to justify their inclusion in this study. Based on the most recent SEERS data, the 
incidence of MM in people less than the age of 20 was 0.0%. 
12.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT 
Adults unable to give consent  are excluded from enrolling in the protocol. However, re-consent 

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may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (Section 12.4),  all subjects deemed capable of doing so by the PI will be 
offered the opportunity to fill in their wishes for research and care, and assign a substitute 
decision maker on the “NIH Advance Directive for Health Care and Medical Research 
Participation” form so that another person can make decisions about their medical care in the 
event that they become incapacitated or cognitively impaired during the course of the study.   
NOTE:  The PI or AI will contact the NIH Ability to Consent Assessment Team (ACAT) for 
evaluation as needed for the following: an independent assessment of whether an individual has 
the capacity to provide consent; assistance in identifying and assessing an appropriate surrogate 
when indicated; and/or an assessment of the capacity to appoint a surrogate.  For those subjects 
that are incapacitated or become incapacitated and do not have pre-determined substitute 
decision maker, the procedures described in NIH HRPP SOP 14E for appointing a surrogate 
decision maker for adult subjects who are (a) decisionally impaired, and (b) who do not have a 
legal guardian or durable power of attorney, will be followed. 
In cases where the subject’s LAR is unable to be present in person, obtaining informedconsent 
via technology and/or electronic processes is permissible.   
12.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
Currently, MM is an incurable malignancy with frequent complications of skeletal fractures, 
anemia, renal failure and hypercalcemia. Conventional radiographs reveal that 79% of patients 
will have observed skeletal abnormalities at time of diagnosis. Treatment of patients with 
RRMM and extramedullary disease with avelumab and XRT may not only treat/reduce 
skeletal/soft tissue related events and prevent morbidity from irreversible bone damage seen with 
MM but also by synergizing together, the combination may cause a systemic abscopal effect. 
Therefore, not only will patients benefit from local radiation but may also benefit in terms of the 
other symptoms caused by systemic and diffuse myeloma including the CRAB criteria. Although 
effective treatments exist for MM, once a patient progresses through IMiD and PI based 
therapies, available drug options become limited. Risks of the study include exposing patients to 
immune-related adverse drug reactions seen with anti-PD-L1 inhibitors without potential benefit 
of a systemic response. However, patients will still benefit from the well-established modality of 
XRT locally. Of importance, the relative adverse drug reaction profile of avelumab is favorable 
compared to other newer cell-based therapies or older cytotoxic chemotherapy regimens. 
Procedures required for obtaining samples/data for experimental purposes (venipuncture, urine 
collection, PET/CT scan, DW-MRI, bone marrow biopsy, and potential radiation from CT-
guided biopsy procedures) are of limited risk to the patient. Although patients will suffer some 
additional pain or discomfort from the PET/CT scans and annual bone marrow biopsies, clinical 
experience has shown that the medical risk is limited. 
12.4.1 Risks Related to Imaging  
 
[18F]-FDG PET/CT (alternatively, CT scans), MRIs, CT-guided biopsies, and skeletal surveys 
may be used to monitor a patient’s disease on this study. Some of these scans expose a patient to 
radiation as discussed below.  

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In addition, [18F]-FDG PET/CT involve use of contrast (oral and/or IV).  The [18F]-FDG PET/CT 
scans will entail the injection of 10mCi dose for all ages and body sizes. An IV line may need to 
be inserted for administration of the contrast agent and can cause pain at the site where the IV is 
placed.  There is also a small risk of bruising or infection. If a contrast agent is given with the 
scan there is a small risk of having a reaction to the contrast.  In the small group of patients who 
have a reaction, the most common symptoms are nausea, pain in the vein where the contrast was 
given, headache, a metallic or bitter taste in the mouth, and a warm or flushing feeling that lasts 
from 1-3 minutes.  Rarely, these symptoms may require treatment.  In very rare cases, people 
have had more severe allergic reactions that result in skin rashes, shortness of breath, wheezing, 
or lowering of the blood pressure. 
12.4.2 Radiation Exposure  
The primary source radiation exposure on the study is from 5x5Gy of radiation therapy to bone 
lesions.  In addition, a much smaller amount of radiation will be derived from up to 9 FDG/PET 
CT scans, 5 skeletal surveys and 3 CT guided biopsies.  The risks of radiation are as described in 
the consent form.  
12.5 CONSENT PROCESS AND DOCUMENTATION 
The informed consent document will be provided to the participant or consent designee(s) (e.g., 
legally authorized representative [LAR] if participant is an adult unable to consent) for review 
prior to consenting.  A designated study investigator (see NOTE at the bottom of this section) 
will carefully explain the procedures and tests involved in this study, and the associated risks, 
discomforts and benefits. In order to minimize potential coercion, as much time as is needed to 
review the document will be given, including an opportunity to discuss it with friends, family 
members and/or other advisors, and to ask questions of any designated study investigator. A 
signed informed consent document will be obtained prior to entry onto the study. 
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms)  per discretion of the 
designated study investigator and with the agreement of the participant/consent designee(s).  
Whether in person or remote, the privacy of the subject will be maintained. Consenting 
investigators (and participant/consent designee, when in person) will be located in a private area 
(e.g., clinic consult room). When consent is conducted remotely, the participant/consent designee 
will be informed of the private nature of the discussion and will be encouraged to relocate to a 
more private setting if needed.  
NOTE: Please note that consent for treatment (consent labeled Affected Patient) must be 
obtained by a designated appropriately licensed study investigator (e.g., MD, NP, PA, DO). 
However, study investigators not falling into this category (e.g. RNs) who are designated as able 
to obtain consent, may do so for non-treatment procedures such as screening. 
Consent for the optional biopsies performed on this study will be obtained at the time of the 
procedure. If the patient refuses the optional biopsy at that time, the refusal will be documented in the 
medical record and in the research record. 
12.6  INCLUSION OF WOMEN AND MINORITIES 
Both men and women and members of all races are eligible for this trial.  

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13 PHARMACEUTICAL INFORMATION   
This investigation of avelumab requires an IND as investigational, not commercial, drug supply 
lots are being provided for this clinical trial by the pharmaceutical collaborator (EMD Serono). 
13.1 AVELUMAB (IND #142027) 
13.1.1 Source  
Investigational supplies of Avelumab will be provided by EMD Serono for use by subjects in 
this clinical trial.   
13.1.2 Toxicity  
The following immune-related adverse events have occurred in patients receiving Avelumab as a 
single agent (1,738 patients):  
• Immune-related hypothyroidism/hyperthyroidism (6%) 
• Immune-related colotis (1.5%) 
• Immune-related pneumonitis (1.2%)  
• Immune-related hepatitis (0.9%) 
• Immune-related adrenal insufficiency (0.5%) 
• Immune-related Type 1 Diabetes Mellitus (0.1%) 
• Immune-related nephritis and renal dysfunction (0.1%) 
 
Other following clinically significant, immune-related adverse reactions have been reported. The 
following occurred at an incidence of less than 1%: immune-related myocarditis including fatal 
events, immune-related pancreatitis including fatal events, immune-related myositis, 
hypopituitarism, uveitis, myasthenia gravis/myasthenic syndrome, and Guillain-Barré syndrome. 
Please refer to the IB for more detailed toxicity information. 
13.1.3 Formulation and Preparation  
Avelumab drug product is a sterile, clear, and colorless concentrate for solution presented at 
concentration of 20 mg/mL in European Pharmacopeia (Ph. Eur.) and United States 
Pharmacopeia (USP) type I glass vials closed with a rubber stopper and sealed with an aluminum 
Flip Off® crimp seal closure. 
Each single-use vial contains 200 mg of avelumab as a preservative-free acetate-buffered 
solution (pH 5.2) containing Mannitol, and Polysorbate 20 (Tween 20). 
For avelumab drug product, only excipients that conform to the current Ph. Eur. and/or the 
current USP are used. 
13.1.4 Stability and Storage  
Supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label.  Receipt and dispensing of trial supplies must be recorded by an 
authorized person at the trial site. Supplies may not be used for any purpose other than that stated 
in the protocol. 
Avelumab drug product must be stored at 2°C to 8°C until use. Store diluted solution at room 
temperature up to 77°F (25°C) for no more than 8 hours from the time of dilution OR under 
refrigeration at 36°F to 46°F (2°C to 8°C) for no more than 24 hours from the time of dilution. If 

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refrigerated, allow the diluted solution to come to room temperature prior to administration. The 
storage condition is based on data from ongoing long term stability studies with avelumab. 
Avelumab drug product stored at room (23°C to 27°C) or higher temperatures for extended periods 
of time might be subject to degradation. Avelumab drug product must not be frozen. Rough 
shaking of the solution must be avoided. 
13.1.5 Administration procedures 
For administration in clinical trials, avelumab drug product may be diluted with 0.9% saline 
solution (sodium chloride injection) supplied in an infusion bag; alternatively, a 0.45% saline 
solution can be used if needed. The chemical and physical in-use stability for the infusion 
solution of avelumab in 0.45% or 0.9% saline solution has been demonstrated for a total of 24 
hours at room temperature. However, from a microbiological point of view, the diluted solution 
should be used immediately. If not used immediately, it can be considered that the diluted 
product is sufficiently stable from a microbiological perspective for up to 8 hours when stored at 
ambient room temperature or up to 24 hours at 2°C to 8°C. The in-use storage times and 
conditions prior to administration are the responsibility of the user. 
Prior to the preparation of the dilution for final infusion, allow each vial to equilibrate to room 
temperature. Use a disposable syringe equipped with a needle of suitable size to remove a 
volume of sodium chloride solution to be replaced by avelumab from the infusion bag and 
discard the removed solution. Use a new disposable syringe equipped with a needle of suitable 
size to inject a volume of avelumab drug product identical to the discarded volume of sodium 
chloride solution into the infusion bag. Gently invert the mixture 10 times. Infusion bags must 
not be shaken, in order to avoid foaming or excessive shearing of the protein solution. The 
preparation must be carefully inspected as it should result in a homogeneous looking clear 
solution, free of visible particles. 
13.1.6 Returns and Reconciliation 
Unused investigational products will be destroyed per routine pharmacy procedure. 
 
 

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15 APPENDICES 
15.1 APPENDIX A: PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-
care, but unable to carry out any work activities.  Up and about 
more than 50% of waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-care, 
confined to bed or chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any 
self-care.  Totally confined to bed or chair. 
5 
Dead. 
 
 
 

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15.2 APPENDIX B: TREATMENT MODIFICATION FOR SYMPTOMS OF INFUSION-RELATED 
REACTIONS  
 
NCI-CTCAE Grade 
Treatment Modification for Avelumab 
Grade 1 – mild 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated. 
Decrease the avelumab infusion rate by 50% and 
monitor closely for any worsening. 
Grade 2 – moderate 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (for 
example, antihistamines, NSAIDs, narcotics, IV 
fluids); prophylactic medications indicated for  
24 h. 
Temporarily discontinue avelumab infusion. 
Resume infusion at 50% of previous rate once 
infusion-related reaction has resolved or decreased to 
at least Grade 1 in severity and monitor closely for 
any worsening. 
Grade 3 or Grade 4 – severe or life-threatening 
• 
Grade 3: Prolonged (for example, not rapidly 
responsive to symptomatic medication and/or 
brief interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for clinical sequelae. 
• 
Grade 4: Life-threatening consequences; 
urgent intervention indicated. 
Stop avelumab infusion immediately and disconnect 
infusion tubing from the subject. 
Subjects have to be withdrawn immediately from 
study avelumab and must not receive any further 
avelumab treatment. 
- If avelumab infusion rate has been decreased by 50% or interrupted due to an infusion reaction, it must 
remain decreased for the next scheduled infusion.  If no infusion reaction is observed in the next 
scheduled infusion, the infusion rate may be returned to baseline at the subsequent infusions based on 
investigator’s medical judgment.- If hypersensitivity reaction occurs, the subject must be treated 
according to the best available medical practice.  
IV = intravenous; NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for Adverse 
Event; NSAIDs = nonsteroidal anti-inflammatory drugs. 
 
 
 

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15.3 APPENDIX C: MANAGEMENT OF IMMUNE-MEDIATED ADVERSE REACTIONS 
15.3.1 Gastrointestinal irAEs 
 
Severity of Diarrhea/Colitis 
(NCI-CTCAE v5) 
Initial Management 
Follow-up Management 
Grade 1 
Diarrhea: increase < 4 stools/day 
over Baseline; mild increase in ostomy 
output compared to baseline 
Colitis: asymptomatic  
Continue avelumab therapy 
Symptomatic treatment (e.g. 
loperamide) 
Close monitoring for worsening symptoms 
Educate subject to report worsening 
immediately 
 
If worsens: 
Treat as Grade 2, 3 or 4.  
Grade 2  
Diarrhea: 4 to 6 stools per day over 
Baseline; moderate increase in ostomy 
output compared to baseline; limiting 
instrumental ADL  IV fluids indicated 
< 24 hours; not interfering with 
ADL 
Colitis: abdominal pain; mucus or 
blood in stool  
 
Withhold avelumab therapy 
Symptomatic treatment 
If improves to Grade ≤ 1:  
Resume avelumab therapy 
 
If  persists > 5-7 days or recurs: 
Treat as Grade 3 or 4. 
Grade 3 to 4 
Diarrhea (Grade 3):increase of ≥ 7 
stools per day over Baseline; 
hospitalization indicated; severe 
increase in ostomy output compared to 
baseline; limiting self care ADL 
incontinence; IV fluids ≥ 24 h; 
interfering with ADL 
Grade 4: Life-threatening 
consequences; urgent intervention 
indicated 
Colitis (Grade 3):  severe abdominal 
pain, medical intervention indicated, 
peritoneal signs 
Grade 4: life-threatening, urgent 
intervention indiacted perforation 
Withhold avelumab for 
Grade 3. 
Permanently discontinue 
avelumab for Grade 4 or 
recurrent Grade 3. 
1.0 to 2.0 mg/kg/day 
prednisone IV or equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
Consider lower endoscopy  
If improves:  
Continue steroids until Grade ≤ 1, then taper 
over at least 1 month; resume avelumab 
therapy following steroids taper (for initial 
Grade 3).  
 
If worsens, persists > 3 to 5 days, or recurs 
after improvement: 
Add infliximab 5mg/kg (if no 
contraindication). Note: infliximab should not 
be used in cases of perforation or sepsis.  
 
 
 

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15.3.2 Dermatological irAEs 
 
Grade of Rash 
(NCI-CTCAE v5) 
Initial Management 
Follow-up Management 
Grade 1 to 2  
Covering ≤ 30% body surface area  
Continue avelumab therapy 
Symptomatic therapy (for 
example, antihistamines, 
topical steroids)  
If persists > 1 to 2 weeks or recurs:  
Withhold avelumab therapy  
Consider skin biopsy  
Consider 0.5-1.0 mg/kg/day prednisone or 
equivalent. Once improving, taper steroids 
over at least 1 month, consider prophylactic 
antibiotics for opportunistic infections, and 
resume avelumab therapy following steroids 
taper. 
 
If worsens:  
Treat as Grade 3 to 4.  
Grade 3 to 4 
Grade 3: Covering > 30% body 
surface area;  
Grade 4: Life threatening 
consequences  
Withhold avelumab for 
Grade 3. 
Permanently discontinue for 
Grade 4 or recurrent Grade 3.  
Consider skin biopsy  
Dermatology consult  
1.0 to 2.0 mg/kg/day 
prednisone  or equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month; resume 
avelumab therapy following steroids taper 
(for initial Grade 3). 
 
 
 

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15.3.3 Pulmonary irAEs 
 
Grade of Pneumonitis 
(NCI-CTCAE v5) 
Initial Management 
Follow-up Management 
Grade 1 
Radiographic changes only  
Consider withholding 
avelumab therapy  
Monitor for symptoms every 
2 to 3 days  
Consider Pulmonary and 
Infectious Disease consults  
Re-assess at least every 3 weeks 
If worsens:  
Treat as Grade 2 or Grade 3 to 4.  
Grade 2 
Mild to moderate new symptoms  
Withhold avelumab therapy 
Pulmonary and Infectious 
Disease consults 
Monitor symptoms daily; 
consider hospitalization  
1.0 to 2.0 mg/kg/day 
prednisone  or equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
Consider bronchoscopy, lung 
biopsy  
Re-assess every 1 to 3 days  
If improves:  
When symptoms return to Grade ≤ 1, taper 
steroids over at least 1 month, and then 
resume avelumab  therapy following steroids 
taper  
 
If not improving after 2 weeks or worsening:  
Treat as Grade 3 to 4.  
Grade 3 to 4 
Grade 3: Severe new symptoms; 
New/worsening hypoxia; 
Grade 4:  Life-threatening  
Permanently discontinue 
avelumab therapy. 
Hospitalize. 
Pulmonary and Infectious 
Disease consults. 
1.0 to 2.0 mg/kg/day  
prednisone or equivalent  
Add prophylactic antibiotics 
for opportunistic infections  
Consider bronchoscopy, lung 
biopsy  
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month  
 
If not improving after 48 hours or worsening:  
Add additional immunosuppression (for 
example, infliximab, cyclophosphamide, IV 
immunoglobulin, or mycophenolate mofetil)  
 
 
 

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15.3.4 Hepatic irAEs 
 
Grade of Liver Test Elevation 
(NCI-CTCAE v5) 
Initial Management 
Follow-up Management 
Grade 1 
Grade 1 AST or ALT > ULN to 3.0 
x ULN and/or Total bilirubin > 
ULN to 1.5 x ULN  
Continue avelumab therapy 
Continue liver function monitoring  
If worsens:  
Treat as Grade 2 or 3 to 4.  
Grade 2 
AST or ALT > 3.0 to ≤ 5 x ULN 
and/or total bilirubin > 1.5 to ≤ 3 x 
ULN  
Withhold avelumab therapy 
Increase frequency of 
monitoring to every 3 days. 
 
If returns to Grade ≤ 1: 
Resume routine monitoring; resume 
avelumab therapy. 
 
If elevation persists > 5 to 7 days or worsens:  
Treat as Grade 3 to 4. 
Grade 3 to 4 
AST or ALT > 5 x ULN and/or total 
bilirubin > 3 x ULN  
Permanently discontinue 
avelumab therapy  
Increase frequency of 
monitoring to every 1 to 
2 days  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics 
for opportunistic infections  
Consult gastroenterologist/ 
hepatologist 
Consider obtaining MRI/CT 
scan of liver and liver biopsy 
if clinically warranted  
If returns to Grade ≤ 1:  
Taper steroids over at least 1 month  
 
If does not improve in > 3 to 5 days, worsens 
or rebounds:  
Add mycophenolate mofetil 1 gram (g) twice 
daily  
 
If no response within an additional 3 to 5 
days, consider other immunosuppressants per 
local guidelines. 
 
 
 

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15.3.5 Renal irAEs 
 
Grade of Creatinine Increased  
(NCI-CTCAE v5) 
Initial Management 
Follow-up Management 
Grade 1 
Creatinine increased > ULN to 1.5 x 
ULN 
Continue avelumab therapy 
Continue renal function monitoring 
If worsens: 
Treat as Grade 2 to 3 or 4. 
Grade 2 to 3 
Creatinine increased > 1.5 and ≤ 6 x 
ULN 
 
 
 
 
 
Withhold avelumab therapy 
Increase frequency of  monitoring to 
every 3 days 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent. 
Add prophylactic antibiotics for 
opportunistic infections 
Consider renal biopsy 
If returns to  Grade ≤1: 
Taper steroids over at least 1 month, 
and resume avelumab therapy 
following steroids taper. 
 
If worsens:  
Treat as Grade 4. 
 
 
Grade 4 
Creatinine increased > 6 x ULN 
 
 
 
 
 
 
 
Permanently discontinue avelumab 
therapy 
Monitor creatinine daily 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent. 
Add prophylactic antibiotics for 
opportunistic infections 
Consider renal biopsy 
Nephrology consult 
If returns to Grade ≤1: 
Taper steroids over at least 1 month. 
 
 
 
 
 
 
 
 
 
 

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15.3.6 Cardiac irAEs 
 
Myocarditis 
(All grades) 
Initial Management 
Follow-up Management 
New onset of cardiac signs or 
symptoms and / or new laboratory 
cardiac biomarker elevations (e.g. 
troponin, CK-MB, BNP) or cardiac 
imaging abnormalities suggestive 
of myocarditis.  
Withhold avelumab therapy. 
Hospitalize. 
In the presence of life threatening cardiac 
decompensation, consider transfer to a 
facility experienced in advanced heart 
failure and arrhythmia management. 
Cardiology consult to establish etiology 
and rule-out immune-mediated 
myocarditis.  
Guideline based supportive treatment as 
per cardiology consult.* 
Consider myocardial biopsy if 
recommended per cardiology consult. 
If symptoms improve and 
immune-mediated etiology is ruled 
out, re-start avelumab therapy. 
 
If symptoms do not 
improve/worsen, viral myocarditis 
is excluded, and immune-mediated 
etiology is suspected or confirmed 
following cardiology consult, 
manage as immune-mediated 
myocarditis. 
Immune-mediated myocarditis 
Permanently discontinue avelumab. 
Guideline based supportive treatment as 
appropriate as per cardiology consult.* 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent 
Add prophylactic antibiotics for 
opportunistic infections. 
Once improving, taper steroids 
over at least 1 month. 
 
If no improvement or worsening, 
consider additional 
immunosuppressants (e.g. 
azathioprine, cyclosporine A). 
*Local guidelines, or e.g. ESC or AHA guidelines  
ESC guidelines website:  https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines 
AHA guidelines website: 
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001 
 
 
 

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15.3.7 Endocrine irAEs 
 
Endocrine Disorder 
(NCI-CTCAE v5) 
Initial Management 
Follow-up Management 
Grade 1 or Grade 2 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
Continue avelumab therapy 
Endocrinology consult if needed 
Start thyroid hormone replacement therapy (for 
hypothyroidism), anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for adrenal 
insufficiency) or insulin (for Type I diabetes 
mellitus) as appropriate.   
Rule-out secondary endocrinopathies (i.e. 
hypopituitarism / hypophysitis) 
Continue hormone 
replacement/suppression 
and monitoring of 
endocrine function as 
appropriate. 
Grade 3 or Grade 4 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
Withhold avelumab therapy 
Consider hospitalization 
Endocrinology consult 
Start thyroid hormone replacement therapy (for 
hypothyroidism), anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for adrenal 
insufficiency) or insulin (for type I diabetes 
mellitus) as appropriate.   
Rule-out secondary endocrinopathies (i.e. 
hypopituitarism / hypophysitis) 
Resume avelumab once 
symptoms and/or 
laboratory tests improve to 
Grade ≤ 1 (with or without 
hormone 
replacement/suppression). 
Continue hormone 
replacement/suppression 
and monitoring of 
endocrine function as 
appropriate.  
Hypopituitarism/Hypophysitis, 
all grades (secondary 
endocrinopathies) 
If secondary thyroid and/or adrenal insufficiency 
is confirmed (i.e. subnormal serum FT4 with 
inappropriately low TSH and/or low serum 
cortisol with inappropriately low ACTH) : 
• 
Refer to endocrinologist for dynamic testing 
as indicated and measurement of other 
hormones (FSH, LH, GH/IGF-1, PRL, 
testosterone in men, estrogens in women)  
• 
Hormone replacement/suppressive therapy as 
appropriate  
• 
Perform pituitary MRI and visual field 
examination as indicated 
 
If hypophysitis confirmed: 
• 
Continue avelumab if mild symptoms with 
normal MRI. Repeat the MRI in 1 month 
• 
Withhold avelumab if moderate, severe or 
life-threatening symptoms of hypophysitis 
and/or abnormal MRI. Consider 
hospitalization. Initiate corticosteroids (1 to 2 
mg/kg/day prednisone or equivalent) 
followed by corticosteroids taper during at 
least 1 month. 
• 
Add prophylactic antibiotics for opportunistic 
infections. 
Resume avelumab once 
symptoms and hormone 
tests improve to Grade ≤ 1 
(with or without hormone 
replacement). 
In addition, for 
hypophysitis with 
abnormal MRI, resume 
avelumab only once 
shrinkage of the pituitary 
gland on MRI/CT scan is 
documented.  
Continue hormone 
replacement/suppression 
therapy as appropriate. 
 

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15.3.8 Other irAEs 
NOTE:  This pertains to “other” irAEs (i.e., not described above). 
 
Grade of other irAEs  
(NCI-CTCAE v5) 
Initial Management 
Follow-up Management 
Grade 2 or Grade 3 clinical signs 
or symptoms suggestive of a 
potential irAE 
Withhold avelumab therapy pending 
clinical investigation 
If irAE is ruled out, manage as 
appropriate according to the 
diagnosis and consider re-starting 
avelumab therapy 
If irAE is confirmed, treat as Grade 
2 or 3 irAE. 
Grade 2 irAE   
or  
first occurrence of Grade 3 irAE 
Withhold avelumab therapy 
1.0 to 2.0 mg/kg/day prednisone  or 
equivalent   
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult as appropriate 
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month 
and resume avelumab therapy 
following steroids taper. 
Recurrence of same Grade 3 
irAEs 
Permanently discontinue avelumab 
therapy 
1.0 to 2.0 mg/kg/day prednisone  or 
equivalent 
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult as appropriate 
If improves to Grade ≤ 1:  
Taper steroids over at least 1 
month. 
Grade 4  
 
Permanently discontinue avelumab 
therapy 
1.0 to 2.0 mg/kg/day prednisone  or 
equivalent and/or other 
immunosuppressant as needed 
Add prophylactic antibiotics for 
opportunistic infections  
Specialty consult. 
If improves to Grade ≤ 1:  
Taper steroids over at least 1 month 
Requirement for 10 mg per day 
or greater prednisone or 
equivalent for more than 12 
weeks for reasons other than 
hormonal replacement for 
adrenal insufficiency 
Persistent Grade 2 or 3 irAE 
lasting 12 weeks or longer 
Permanently discontinue avelumab 
therapy 
Specialty consult 
 
 
 
 

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15.4 APPENDIX D: PERIPHERAL BLOOD AND URINE COLLECTION AND STORAGE 
 
Blood Processing Core Figg Lab 
Refer to Sections 3.7 (Study Calendar) and 5.1 for research blood and urine collection time points. 
Contact: For questions, please contact Dr. Figg’s Clinical Pharmacology Program (CPP) at 240-
760-6180; additionally, for pre-notification of planned samples (at least 24 hours in advance, the 
Friday before is preferred) email NCIBloodcore@mail.nih.gov.  After sample collection, please 
page 102-11964 for immediate pick-up.  For any questions regarding sample processing, you 
may contact NCIBloodcore@mail.nih.gov or at 240-760-6180. 
Venipuncture 
• 
Approximately 40 ml of peripheral blood will be collected into EDTA (lavender) and Streck 
(brown/black) tubes.  The amount of blood collected will be dictated by the number of 
experiments to be performed. Although, above tubes are ideal for the collection, they may 
be substituted at the discretion of the investigator. 
• cfDNA  
1. Collect blood in two 10 ml Streck Tubes 
2. Keep at room temperature until processing (Samples are stable for up to five days at 
room temperature and can be batched with other samples drawn on different days)  
3. All steps for plasma separation should be done in a clean space, preferably in a separate 
room dedicated for this procedure, but minimally without the presence of molecular 
biology reagents such as PCR products, plasmids or any other low complexity DNA, 
which will contaminate the plasma. The centrifuge used for this should not be used if 
the centrifuge is also used for bacteria, plasmid purification etc. Use of a 1% bleach 
solution to wipe down areas before and after processing (inside and outside the 
workspace) can greatly cut down on contamination issues. (Clorox Healthcare Bleach 
Germicidal Wipes - Wipe - 6" Width x 5" Length - 150 / Canister - 1 Each – White 
Item # 129202)  
4. In hood: transfer blood to 15 mL conical tube 
5. Centrifuge 15 mL conical tubes for 10 minutes at 1500 ± 150xg (=1500RCF) 
6. Transfer supernatant to a fresh 15 ml tube without disturbing the leukocyte layer 
7. Centrifuge plasma a second time for 10 min at 3000 ± 150xg (=3000 RCF) 
8. Transfer supernatant to a fresh 15 ml centrifuge tube without disturbing the cellular 
layer. Leave a residual volume of about 0.3 ml (~7 mm) on the bottom of the 15 ml 
tube to avoid cellular contamination. 
9. After transferring the plasma to a new 15 ml centrifuge tube as described, gently mix 
plasma and record total plasma volume (typically ~ 4 ml plasma per 10 ml blood). 
10. Make 1 mL aliquots into standard cryovials 
11. Barcode as plasma 
12. Enter sample note: cfDNA 
13. Store plasma at -80C freezer, ship without thawing 
• gDNA 
1. Collect blood in one 10 ml Lavender EDTA tube 

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2. Keep at room temperature until processing 
3. Follow standard procedures for DNA isolation per Figg Lab 
4. Store at -80C freezer 
• PBMC  
1. Collect blood in one 10 ml Lavender EDTA tube 
2. Keep at room temperature until processing 
3. Follow standard procedures for PBMC pellet preparation per Figg Lab 
4. Store at -80C freezer 
Urine (spot) Sample Collection 
• Approximately 45 mL of urine will be collected into a standard urine collection cup for 
further analysis.  The amount of urine collected will be dictated by the number of 
experiments to be performed.   
• Transfer to two 50 ml  screw-cap conical tubes 
• Freeze immediately at -20C or lower 
• Maintain in -80C freezer for storage until shipment 
Labeling of Samples 
All specimens are to be labeled per the local site’s standard procedures. The following 
information, if not provided on the specimen label, must be linked to the specimen label and 
provided on the inventory sheet:  
• Patient study ID #  
• Sample type 
• Date/time of draw (DD/MMM/YY 24:00) 
• Time point (ex. C1D1 pre, C1D1 24hr post) 
• Any collection issues (short draw, delayed processing, etc.) 
• Protocol title/number 
• Institute name 
• Contact information 
• Do not include the patient name, medical record number, or initials. 
 
 
 

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15.5 APPENDIX E: CD138+ CELL SORTING: CALVO LAB 
 
The following is example protocol which may be modified as needed: 
1. Pour all the bone marrow aspirate into 50 ml tube. Add PBS to about 24 ml as diluted BM 
2. Prepare six 15ml tubes. Add 3 ml Ficoll into each tube. SLOWLY add 4 ml diluted BM on the wall of 
each tube with Ficoll. Try not to disturb the bottom Ficoll. Spin at 2200rpm for 20min. 
3. Carefully pipette 1ml top clean solution as diluted BM plasma into 1 cryovial. Collect 2 vials and 
label on cryovial with patient ID number on the first row, “diluted BM plasma” as second row, and 
date as third row. Then transfer the medium part BMMCs after Ficoll from each tube combined into 
one 50ml tube. Spin at 1250rpm for 10min. 
4. Discard supernatant. Resuspend the pellet with 10ml PBS and transfer all the suspension into a new 
50 ml tube through the cell strainer on the top of the tube. Use 20 ul for counting cell number. 
5. Spin at 1250 rpm for 10min. Discard supernatant. 
If only total BMMCs is needed (i.e. MM patient is in CR), resuspend the pellet in 0.5ml PBS, and 
transfer all the suspension into 1 new 1.5 ml Eppendorf tube. Spin at 5000 rmp for 5min. Aspirate 
supernatant, and store it at -20ºC freezer. I usually label on 1.5ml Eppendorf tube with patient ID 
number on the first row, “total BMMCs” as second row, cell number as third row, and date as fourth 
row.   
If CD138+ selection is needed, resuspend the pellet with 2ml “MACS + BSA” buffer. Calculate the 
volume of “MACS + BSA” buffer and CD138+ microbeads. Use 80 ul “MACS + BSA” buffer and 
20 ul CD138+ microbeads for 20 million total BMMCs. Scale up accordingly. If the total BMMCs 
number is below 20 million, use 80 ul buffer and 20 ul beads as minimum. Spin at 1250 rpm for 
10min. Discard supernatant. Resuspend the pellet at the calculated volume of buffer and beads. Mix 
the pellet well by tapping the tube. Put in 4ºC refrigerator for 20 min incubation. Tap the tube gently 
every 5 minutes. 
6. After incubation, add 2 ml “MACS + BSA” buffer in the tube. Spin at 1250 rpm for 10 min. 
Meanwhile, set up two LS columns for selection. Label three 15 ml tubes as “-”; “+1”; “+2”. Put “-” 
tube under first LS column. Add 0.5 ml “MACS + BSA” buffer on the column to wash. Repeat 
adding 0.5 ml buffer two times, i.e. in total, wash 3 times.  
7. Discard supernatant of the 50 ml tube. Resuspend the pellet in 0.5 ml “MACS + BSA” buffer. 
Transfer all to the top of LS column until no elution out, repeat to use 0.5 ml “MACS + BSA” buffer 
to wash the 50 ml tube and transfer on the top of first column for three times, i.e. in total 2 ml. 
8. Until no elution out of column, put the “-” 15 ml tube under second LS column. Pull out first LS 
column and insert it into the new “+1” 15 ml tube. Add 1 ml “MACS + BSA” buffer on top of the 
column. Insert syringe and quickly plunge it down. Transfer all the elution from “+1” tube on the top 
of second LS column. Until no elution out, repeat to use 0.5 ml “MACS + BSA” buffer to wash the 
“+1” tube and transfer on the top of second column for three times, i.e. in total 2 ml. 
9. Until no elution out of column, pull out first LS column and insert it into the new “+2” 15 ml tube. 
Add 1 ml “MACS + BSA” buffer on top of the column. Insert syringe and quickly plunge it down. 
Use 20 ul resuspension from “+2” tube to count CD138+ cell number and 20 ul resuspension from “-“ 
tube to count CD138- cell number. 
10. Spin both “-“ and “+2” tubes at 1250 rpm for 10 min. Resuspend in 0.5 ml “MACS + BSA” buffer 
and transfer to new 1.5 ml Eppendorf tubes as CD138- and CD138+ cells respectively. 
11. Spin at 5000 rmp for 5 min. Aspirate supernatant and store it in -20ºC freezer. Label on 1.5 ml 
Eppendorf tube with patient ID number on the first row, “CD138-” or “CD138+” as second row, cell 
number as third row, and date as fourth row.   
 
 

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15.6 APPENDIX F: IMWG RESPONSE CRITERIA 
 
NOTE:  The following are taken from the International Myeloma Working Group (IMWG) 
response criteria, 2016 (adapted).[1] 
 
IMWG MRD criteria (requires a complete response as defined below) 
Sustained MRD-
negative (Sustained 
MRDnegCR) 
MRD negativity in the marrow (NGF or NGS, or both) and by imaging as 
defined below, confirmed minimum of 1 year apart. Subsequent evaluations 
can be used to further specify the duration of negativity (e.g., MRD-negative at 
5 years) 
Flow MRD-negative 
(Flow MRDnegCR) 
Flow MRD-negative Absence of phenotypically aberrant clonal plasma cells 
by NGF on bone marrow aspirates using the EuroFlow standard operation 
procedure for MRD detection in multiple myeloma (or validated equivalent 
method) with a minimum sensitivity of 1 in 10⁵ nucleated cells or higher 
Sequencing MRD-
negative (Seq 
MRDnegCR) 
 
Absence of clonal plasma cells by NGS on bone marrow aspirate in which 
presence of a clone is defined as less than two identical sequencing reads 
obtained after DNA sequencing of bone marrow aspirates using the 
LymphoSIGHT platform (or validated equivalent method) with a minimum 
sensitivity of 1 in 10⁵ nucleated cells or higher 
Imaging plus MRD-
negative (Img 
MRDnegCR) 
 
MRD negativity as defined by NGF or NGS plus disappearance of every area 
of increased tracer uptake found at baseline or a preceding PET/CT or decrease 
to less mediastinal blood pool SUV or decrease to less than that of surrounding 
normal tissue 
 
Standard IMWG response criteria 
Stringent 
complete 
response (sCR) 
Complete response as defined below plus normal FLC ratio and absence of clonal 
cells in bone marrow biopsy by immune-histochemistry (κ/λ ratio ≤4:1 or ≥1:2 for 
κ and λ patients, respectively, after counting ≥100 plasma cells) 
Complete 
response (CR) 
Negative immunofixation on the serum and urine and disappearance of any soft 
tissue plasmacytomas and <5% plasma cells in bone marrow aspirates 
Very good 
partial response 
(VGPR) 
Serum and urine M-protein detectable by immunofixation but not on 
electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level 
<100 mg per 24 h 
Partial response 
(PR) 
≥50% reduction of serum M-protein plus reduction in 24 h urinary M-protein by 
≥90% or to <200 mg per 24 h; If the serum and urine M-protein are unmeasurable, 
a ≥50% decrease 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 
unmeasurable, and serum-free light assay is also unmeasurable, ≥50% reduction in 
plasma cells is required in place of M-protein, provided baseline bone marrow 
plasma-cell percentage was ≥30%. In addition to these criteria, if present at 
baseline, a ≥50% reduction in the size (SPD)§§ of soft tissue plasmacytomas is also 
required 

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Standard IMWG response criteria 
Minimal 
response (MR) 
≥25% but ≤49% reduction of serum M-protein and reduction in 24-h urine M-
protein by 50–89%. In addition to the above listed criteria, if present at baseline, a 
≥50% reduction in the size (SPD) of soft tissue plasmacytomas is also required 
Stable disease 
(SD) 
Not recommended for use as an indicator of response; stability of disease is best 
described by providing the time-to-progression estimates. Not meeting criteria for 
complete response, very good partial response, partial response, minimal response, 
or progressive disease 
Progressive 
disease (PD) 
Any one or more of the following criteria: 
Increase of 25% from lowest confirmed response value in one or more of the 
following criteria: Serum M-protein (absolute increase must be ≥0·5 g/dL); Serum 
M-protein increase ≥1 g/dL, if the lowest M component was ≥5 g/dL; Urine M-
protein (absolute increase must be ≥200 mg/24 h); 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); In patients without measurable 
serum and urine M-protein levels and without measurable involved FLC levels, 
bone marrow plasma-cell percentage irrespective of baseline status (absolute 
increase must be ≥10%); Appearance of a new lesion(s), ≥50% increase from nadir 
in SPD of >1 lesion, or ≥50% increase in the longest diameter of a previous lesion 
>1 cm in short axis; ≥50% increase in circulating plasma cells (minimum of 200 
cells per μL) if this is the only measure of disease 
 

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15.7 APPENDIX G: PATIENT REPORTED OUTCOME INSTRUMENT – PROMIS 
 
NOTE:  The English versions of the paper short forms are shown here for illustration purposes; Spanish versions are available and 
will be used for Spanish-speaking subjects, if applicable.  The use of electronic versions (e.g., iPad) is preferred.     
 
Please respond to each question or statement by marking one box per row. 
 
Physical Function 
In the past 7 days… 
Without 
any 
difficulty 
With a 
little 
difficulty 
With some 
difficulty 
With 
much 
difficulty 
Unable 
to do 
PFA11 
 
Are you able to do chores such as vacuuming or yard 
work?.......................... 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
 
 
 
 
 
PFA21 
 
Are you able to go up and down stairs at a normal 
pace?.............................................. 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
 
 
 
 
 
PFA23 
 
Are you able to go for a walk of at least 15 
minutes?................................ 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
 
 
 
 
 
PFA53 
 
Are you able to run errands and shop?....... 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
 
 
 
 
 
PFC7r1 
Are you able to run five miles (8 km)? .... 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
 
 
 
 
 
PFM17  
Are you able to remove a heavy suitcase (50 lbs/25 kg) from 
an overhead bin on an airplane or bus? ..................................... 
 
5 
 
4 
 
3 
 
2 
 
1 
 

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Anxiety 
In the past 7 days… 
Never 
Rarely 
Sometimes 
Often 
Always 
EDANX01 
 
I felt fearful……………………………… 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 
 
 
 
 
EDANX40 
 
I found it hard to focus on anything other than my 
anxiety………………………… 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 
 
 
 
 
EDANX41 
 
My worries overwhelmed me………… 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 
 
 
 
 
EDANX53 
 
I felt uneasy……………………………… 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 

Abbreviated Title:  Avelumab plus XRT in RRMM 
  
Version Date:  09/01/2020   
 
91 
 
Depression 
In the past 7 days... 
Never 
Rarely 
Sometimes 
Often 
Always 
 
EDDEP04 
 
I felt worthless……………………………  
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 
 
 
 
 
 
EDDEP06 
 
I felt helpless…………………………… 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 
 
 
 
 
 
EDDEP29 
 
I felt depressed…………………………... 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 
 
 
 
 
 
EDDEP41 
 
I felt hopeless……………………………. 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 

Abbreviated Title:  Avelumab plus XRT in RRMM 
  
Version Date:  09/01/2020   
 
92 
 
 
Fatigue 
During the past 7 days… 
Not at all 
A little bit 
Somewhat 
Quite a 
bit 
Very 
much 
HI7 
 
I feel fatigued…………………………… 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 
 
 
 
 
AN3 
 
I have trouble starting things because I am 
tired…………………………………. 
 
1 
 
2 
 
3 
 
4 
 
5 
In the past 7 days… 
 
 
 
 
 
FATEXP41 
 
How run-down did you feel on average?.. 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 
 
 
 
 
FATEXP40 
 
How fatigued were you on average?......... 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 
 
 
 
 
FATEXP35 
How much were you bothered by your fatigue on 
average? ................................ 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 
 
 
 
 
FATIMP49 
To what degree did your fatigue interfere with your physical 
functioning? ............. 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 

Abbreviated Title:  Avelumab plus XRT in RRMM 
  
Version Date:  09/01/2020   
 
93 
 
 
Sleep Disturbance 
In the past 7 days… 
Very poor 
Poor 
Fair 
Good 
Very 
good 
Sleep109 
 
My sleep quality was…………………… 
 
5 
 
4 
 
3 
 
2 
 
1 
 
In the past 7 days… 
Not at all 
A little bit 
Somewhat 
Quite a 
bit 
Very 
much 
Sleep116 
 
My sleep was refreshing……………....... 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
 
 
 
 
 
Sleep20 
 
I had a problem with my sleep………… 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 
 
 
 
 
Sleep44 
 
I had difficulty falling asleep…………… 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 

Abbreviated Title:  Avelumab plus XRT in RRMM 
  
Version Date:  09/01/2020   
 
94 
 
 
Ability to Participate in Social Roles and Activities 
In the past 7 days… 
Never 
Rarely 
Sometimes 
Usually 
 
Always 
 
SRPPER11_CaPS 
 
I have trouble doing all of my regular leisure activities with others
 ............................................................. 
 
 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
 
 
 
 
 
 
SRPPER18_CaPS 
 
I have trouble doing all of the family activities that I want to do  
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
 
 
 
 
 
 
SRPPER23_CaPS 
 
I have trouble doing all of my usual work (include work at home)
 ............................................................. 
 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
 
 
 
 
 
 
SRPPER46_CaPS 
 
I have trouble doing all of the activities with friends that I want to 
do ......................................................... 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
 

Abbreviated Title:  Avelumab plus XRT in RRMM 
  
Version Date:  09/01/2020   
 
95 
 
 
Pain Interference 
In the past 7 days… 
Not at all 
A little bit 
Somewhat 
Quite a 
bit 
Very 
much 
PAININ9 
 
How much did pain interfere with your day to day 
activities?................................. 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 
 
 
 
 
PAININ22 
 
How much did pain interfere with work around the 
home?...................................... 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 
 
 
 
 
PAININ31 
 
How much did pain interfere with your ability to participate in 
social activities? ......................................  
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 
 
 
 
 
PAININ34 
 
How much did pain interfere with your household 
chores?................................ 
 
1 
 
2 
 
3 
 
4 
 
5 
 
Pain Intensity 
In the past 7 days… 
 
 
 
 
 
Global07 
 
How would you rate your pain on 
average………………………….. 
 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
 
 
No   
pain 
 
 
 
 
 
 
 
 
Worst pain 
imaginable 
 
 
 

Abbreviated Title:  Avelumab plus XRT in RRMM 
  
Version Date:  09/01/2020   
 
96 
 
 
Cognitive Function  
In the past 7 days… 
Never 
Rarely 
(Once) 
Sometimes 
(Two or 
three times) 
Often 
(About 
once a 
day) 
Very 
Often 
(Several 
times a 
day) 
PC8r 
I have had trouble concentrating.............. 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
 
 
 
 
 
PC11r 
I have had trouble remembering where I put things, like my keys 
or my wallet...... 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
 
 
 
 
 
 
PC25r 
I have had to work really hard to pay attention or I would make a 
mistake…… 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
 
 
 
 
 
PC-CaPS25r 
I have had difficulty multi-tasking……. 
 
5 
 
4 
 
3 
 
2 
 
1