Denosumab for Smoldering Multiple Myeloma
Phase: PHASE2
Conditions: Smoldering Multiple Myeloma
Sponsor: University of Rochester

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Denosumab for Smoldering Multiple Myeloma
Date: 15Jul2021
NCT 03839459
Protocol version/Date: 
Protocol #: 
UMMY18121 
Reference # 20187179
TITLE: Denosumab for Smoldering Multiple Myeloma
Study Chair:
Brea Lipe, MD 
University of Rochester
601 Elmwood Ave, Box 704
Rochester NY 14642
IND Number:
Denosumab:
Study Collaborator:
Andrea Baran, MS biostatistician
Protocol Version: 6
Date: 15Jul2021
This document is a confidential communication of the University of Rochester. Acceptance of this 
document constitutes agreement by the recipient that no unpublished information contained herein shall 
be published or disclosed without prior written approval, except that this document may be disclosed to 
the appropriate Institutional Review Boards/ Independent Ethics Committees under the condition that they 
keep it confidential.

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T A B L E O F C O N T E N T S
STUDY SYNOPSIS...........................................................................................................................................5
1. Background............................................................................................................................................11
1.1SMM.................................................................................................................................................11
1.2Bone Disease.....................................................................................................................................12
1.3Exploratory endpoints......................................................................................................................13
1.4Study drug.........................................................................................................................................14
1.4.1Pharmacokinetics...............................................................................................................................................................15
1.4.2Denosumab Dose Selection................................................................................................................................................15
1.5Hypothesis........................................................................................................................................15
2OBJECTIVES AND ENDPOINTS..................................................................................................................16
2.1Primary Objective.............................................................................................................................16
2.2Secondary Objectives.......................................................................................................................16
3ELIGIBILITY CRITERIA................................................................................................................................16
3.1Inclusion Criteria...............................................................................................................................17
3.2Exclusion Criteria..............................................................................................................................17
4STUDY DESIGN.........................................................................................................................................20
4.1Overview of Study Design.................................................................................................................20
4.2Registration.......................................................................................................................................21
4.3Discontinuation from Study Treatment............................................................................................21
4.4Criteria for Study termination...........................................................................................................21
5STUDY ASSESSMENTS AND TREATMENT SCHEDULE...............................................................................22
6Agent Administration...............................................................................................................................24
6.1Denosumab.......................................................................................................................................24
6.1.1Form...................................................................................................................................................................................25
6.1.2Storage and Stability..........................................................................................................................................................25
6.1.3Preparation........................................................................................................................................................................25
6.1.4Administration....................................................................................................................................................................25
6.1.5Ordering.............................................................................................................................................................................25
6.1.6Safety..................................................................................................................................................................................26

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6.1.7Destruction and Return......................................................................................................................................................27
6.1.8Dosage adjustments and discontinuation of denosumab..................................................................................................28
6.2concomitant/ excluded Medications................................................................................................28
7MEASUREMENT OF EFFECT.....................................................................................................................29
7.1Method of Assessment.....................................................................................................................29
7.1.1Serum.................................................................................................................................................................................29
7.1.2Free Light Chain Testing.....................................................................................................................................................29
7.1.3Urine...................................................................................................................................................................................29
7.1.4Bone Marrow Examination.................................................................................................................................................29
7.1.5DXA scans...........................................................................................................................................................................31
7.1.6Assessment of response.....................................................................................................................................................31
8STATISTICAL CONSIDERATIONS...............................................................................................................31
8.1design................................................................................................................................................32
8.2Patient Disposition............................................................................................................................33
8.3Patient Demographics and Baseline Characteristics.........................................................................33
8.4Extent of Exposure............................................................................................................................33
8.5Statistical Analyses............................................................................................................................33
9SAFETY REPORTING..................................................................................................................................34
9.1Adverse Event Characteristics..........................................................................................................35
9.2Definitions of Adverse Events...........................................................................................................35
9.3Adverse Events (AEs) and Treatment Emergent Adverse Events (TEAEs).........................................36
9.4Adverse Events/Serious Adverse Event Causality Assessment.........................................................36
9.4.1Handling of Adverse Events................................................................................................................................................36
9.5Serious Adverse Events.....................................................................................................................37
9.5.1Definitions of Serious Adverse Events................................................................................................................................37
9.5.2Serious Adverse Event Reporting by Investigators.............................................................................................................38
9.6Recording of Adverse Events and Serious Adverse Events...............................................................39
9.6.1Persistent or Recurrent Adverse Events.............................................................................................................................39
9.6.2Deaths................................................................................................................................................................................39
9.6.3Hospitalization, Prolonged Hospitalization, or Surgery......................................................................................................39
9.7Safety Reporting to Amgen...............................................................................................................40
Table 9.7.1.  Expedited Reporting Requirements for Interventional Studies.......................................................................40

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Table 9.7.2. Aggregate Reports..........................................................................................................................................40
10CLINICAL DATA COLLECTION..................................................................................................................41
10.1Amendments to the Protocol.........................................................................................................41
10.2Financial Disclosures and Ethical Considerations...........................................................................41
10.3IRB and Regulatory approval..........................................................................................................41
10.4Informed Consent...........................................................................................................................42
10.5Confidentiality................................................................................................................................42
10.6Study Documentation and Storage.................................................................................................43
10.7Data Collection and Safety..............................................................................................................44
10.8Publication Policy............................................................................................................................45
11Planned correlative analyses.................................................................................................................45
12REFERENCES...........................................................................................................................................46
13Appendix A: IMWG response criteria....................................................................................................50
14Appendix B: Abbreviations....................................................................................................................53

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STUD Y SYNOP SIS
Protocol no.
Study Title
Denosumab for Smoldering Multiple Myeloma
Principle 
Investigator and 
Study Chair
Brea Lipe, MD
Wilmot Cancer Institute, University of Rochester, Rochester NY USA
Study Site & 
Enrollment
University of Rochester Medical Center 
20 evaluable patients
Study Rationale
Smoldering multiple myeloma (SMM) is a premalignant condition conveying a 
variable risk of progression to multiple myeloma, but with a median time to 
progression of 2 years for high risk patients [1]. While the exact mechanisms of 
transformation from SMM to multiple myeloma (MM) are not known, 
alterations in bone metabolism are seen in both patients with SMM and MM 
and are 
in part mediated through altered bone metabolism leading to increased 
bone destruction [2]. Recently, changes 
in markers for bone-turnover have been 
associated with disease progression from monoclonal gammopathy of 
undetermined significance (MGUS) to MM [3]. As MM remains an incurable 
disease, therapies aimed to prevent disease progression of SMM are needed.
Denosumab is a monoclonal antibody targeting receptor activator of nuclear 
factor kappa-B ligand (RANKL) that correlates to improved bone 
microarchitecture and strength [4], but whose biologic effects also make 
denosumab of particular interest in SMM and MM. In patients with MM, RANKL 
is up regulated while OPG is suppressed. This dysregulation correlates with 
clinical disease activity, severity of bone disease, and decreased survival [5]. In 
patients with MGUS and SMM, RANKL, and the RANKL/OPG ratio are increased 
compared to healthy controls, but to a lesser extent than in patients with frank 
MM [5]. Through actions via RANKL, denosumab also causes a reduction 
in DKK1 
levels which is implicated in disease progression and skeletal dysregulation and 
provides further rationale for the use of denosumab in patients with SMM who 
are both at risk for skeletal events and disease progression [6]. We therefore 
propose to study the impact of denosumab on bone architecture and markers 
of bone metabolism in patients with SMM.

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Study Objectives
Primary objective:
To determine the change in risk for progression to MM in patients with 
SMM treated with denosumab for one year.
Secondary objectives:
To measure the change in monoclonal (M) serum protein or free light chain 
(FLCs) as appropriate to assess response per IMWG criteria listed in 
Appendix A.
Determine the rate of skeletal related events (SREs)
To assess the rate of disease progression to MM
Determine the progression free survival (PFS)
Define the rate of adverse events (AEs)
Determine the change in bone mineral density
Exploratory objectives:
To determine the impact of denosumab on soluble factors of bone activity 
including MIP-1α, DKK1, Notch signaling, sclerostin, RANKL, and OPG.
To describe the changes in mesenchymal and osteolineage populations and 
osteoprogenitor function
To determine the 
impact of denosumab discontinuation on markers of bone 
turnover and bone formation including serum bone alkaline phosphatase, 
total osteocalcin, procollagen type 1 N-terminal propeptide, serum C- 
terminal cross-linked telopeptides, and urinary N and C-terminal cross- 
linked telopeptides.
Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for 
participation in this study:
1. Patient has confirmed SMM according to the definition of the 
International 
Myeloma Working Group (IMWG) definition: serum M-protein ≥3 g/dL or 
BMPC >10% but less than 60%, or both, along with no plasma-cell related 
abnormal organ and marrow function (CRAB related to a plasma cell 
disorder) within 24 weeks prior to baseline, without new evidence of 
disease progression to multiple myeloma.
C: Absence of hypercalcemia, evidenced by a calcium ≤11 mg/dL, 
R: Absence of renal failure, evidenced by a creatinine ≤ 2.0mg/dL, 
A: Absence of anemia, evidenced by a hemoglobin ≥10 g/dL
B: Absence of lytic bone lesions per IMWG recommendations:
One of either PET-CT, 
low-dose whole-body CT (LDWBCT) or MRI of the 
whole body or spine. Increased uptake on PET-CT alone 
is not adequate 
for the diagnosis of multiple myeloma; evidence of underlying 

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osteolytic bone destruction is needed on the CT portion of the
examination.

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2. One of the risk factors below that portends for an increased risk of 
progression to MM:
An abnormal free light chain ratio
M-spike ≥ 2 g/dL
≥ 20% bone marrow plasma cells
Immunoparesis 
≥ 20% 
less than the 
institutional normal standard of 
the uninvolved immunoglobulins
3. Serum calcium or albumin-adjusted serum calcium ≥ 2.1 mmol/L (8.4 
mg/dL) and ≤ 2.9mmol/L (11.5 mg/dL) (Reference range 8.5-10.8 mg/dL)
4. Able to tolerate daily supplementation of calcium and vitamin D
5. Must have a vitamin D level ≥ 30 ng/mL or have a level 12ng/mL to 30ng/mL 
and be on active repletion with cholecalciferol 50,000 IU po weekly or 
equivalent.
6. Participants must have normal organ as defined below:
Total bilirubin ≤ 2.0 x institutional upper limit of normal (ULN); 
patients diagnosed with Gilbert’s syndrome can enroll with a total 
bilirubin > 2 after review of the principal investigator

AST(SGOT) ≤2.5 × institutional ULN

ALT(SGPT) ≤2.5 × institutional ULN
7. Age ≥ 18 years.
8. ECOG PS ≤1
9. Life expectancy greater than 12 months
10.Subjects with reproductive potential must be willing to use, in combination 
with his/her partner, 2 highly effective methods of effective contraception 
or practice sexual abstinence throughout the study and continue for 5 
months after the study duration. Subjects who are surgically sterile (e.g. 
history of bilateral tubal ligation, hysterectomy) or whose sexual partner is 
sterile (e.g. history of vasectomy) are not required to use additional 
contraceptive measures.
11.Ability to understand and the willingness to sign a written informed 
consent document.
1. Patient is willing and able to comply with the protocol for the duration of 
the study including undergoing treatment and scheduled visits and 
examinations including follow up.
12.Statement on Inclusion of Women and Minorities
Men and women of all ethnicities and racial backgrounds are 
eligible for this study.

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Exclusion Criteria
Patients who meet any of the following exclusion criteria are not to be enrolled 
to this study:
1. Prior administration of denosumab.
2. Any history of IV bisphosphonate use prior to or during the study
3. Prescription oral fluorides or bisphosphonate usage > 3 months within 
the past 2 years
4. Systemic corticosteroids > 10mg prednisone per day
5. Patient has symptomatic MM, as defined by any of the following related 
to the plasma cell disorder:
Lytic lesions or pathologic fractures.
Anemia (hemoglobin <10 g/dL)
Hypercalcemia (corrected serum calcium > 11.0 mg/dL)
Renal insufficiency (creatinine > 2.0 mg/dL).
Clonal bone marrow plasma cells > 60%
An involved serum free light chain (kappa or Lambda) > 
100mg/L with the ratio of the involved/uninvolved free light 
chains also > 100 mg/L
One or more osteolytic lesions on radiography, but more than 
one lesion is required if < 10% marrow plasma cells. From MRI 
imaging, there must be more than one lesion of > 5mm in size.
6. Other: symptomatic hyperviscosity, amyloidosis, plasma cell leukemia, 
POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, 
monoclonal protein)
7. Prior history or current evidence of osteonecrosis/osteomyelitis of the 
jaw.
8. Active dental or 
jaw condition that requires oral surgery, 
including tooth 
extraction.
9. Non-healed dental/oral surgery, including tooth extraction.
10.Planned invasive dental procedures during the course of study.
11.Evidence of any of the following conditions per subject self-report or 
medical chart review:
Any prior invasive malignancy within 3 years of enrollment that 
may affect outcome of study
Any non-invasive malignancy not treated with curative 
intent or 
with known active disease within 3 years before enrollment 
that may affect outcome of study
Major surgery or significant traumatic injury occurring within 4 
weeks before enrollment
Active infection with Hepatitis B virus or Hepatitis C virus

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Known infection with human immunodeficiency virus (HIV) 
requiring IV anti-infective therapy
13.Subject is pregnant or breast feeding, or planning to become pregnant 
within 5 months after the end of treatment.
14.Female subject of child-bearing potential is not willing to use, in 
combination with her partner, 2 methods of highly effective 
contraception during treatment and for 5 months after the end of 
treatment.
15.Clinically significant hypersensitivity to denosumab or any components 
of denosumab 120mg.
16.Known sensitivity to any of the products to be administered during the 
study (e.g., calcium, or vitamin D).
17.Subject is receiving or is less than 14 days since ending other 
experimental drug (no marketing authorization for any 
indication).
18.Any major medical or psychiatric disorder that, in the opinion of the 
investigator, might prevent the subject from completing the study or 
interfere with the interpretation of the study results.
Efficacy Endpoints
The primary objective of the study is to determine the rate of downgraded risk 
for the progression to multiple myeloma as defined by a reduction in the risk 
category for progression. The risk categories will be 
identified as 
in section 7.1.6 
using the Mayo clinic and PETHEMA criteria [7, 8].
Study Design
Single center, open 
label, Phase II single-arm trial of denosumab 
in patients with 
smoldering multiple myeloma. The trial will aim to enroll 10 patients per year 
with 2 years of follow up after completion of therapy for a total study duration 
of 5 years.
Dosing
Regimen &
All cycles will be 28 days.
Denosumab: 120mg will be administered subcutaneously once every 4 weeks,
Treatment
+/- one week.
Study Visits
SCHEMA

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1. BACKG ROUND
1.1SMM
Plasma cell dyscrasias exist as a spectrum of diseases, from the asymptomatic precursors monoclonal 
gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to the 
malignancy multiple myeloma (MM). MM is relatively rare with 30,000 new cases estimated in 2018 
[9],and with 14% of those patients expected to have SMM [10]. MGUS is a relatively common finding with 
increasing incidence with age, seen in up to 3% of patients over age 50 and 5% of patients over age 70 
[11]. MM is an incurable cancer causing significant morbidity and mortality characterized by 
hypercalcemia, renal insufficiency, anemia, and lytic bone lesions (CRAB criteria), and is felt to be 
preceded by precursor plasma cell dyscrasias 
in the form of MGUS or SMM [12]. Most patients with MGUS 
or SMM do not develop MM, providing an opportunity to both study and understand who is at risk to 
progress and to investigate strategies aimed at preventing the devastating consequences for the patients 
destined to get MM.
SMM requires the absence of myeloma defining events related to the plasma cell disorder; CRAB criteria 
(hypercalcemia, anemia, renal insufficiency, bone lesions, and an involved serum light chains< 100mg/L and a 
light chain ratio < 100), and the presence of between 10%-60% clonal plasma cells 
in the bone marrow, and/ or 
a serum M protein level ≥3 g/dL, and /or a urine monoclonal protein level ≥500 mg/24 hours [13]. While 
patients with SMM are by definition, asymptomatic, they carry a lifelong risk of progressing to the incurable 
malignancy, multiple myeloma (MM). The average risk of progression to MM from SMM is 10% per year for 
the first five years, and the risk decreases with the passage of time to a maintained risk of 1% per year [14]. 
Amongst patients with SMM, risk factors that predispose a higher than average risk of progression have been 
identified and include a serum monoclonal protein level ≥ 4g/dL, a bone marrow plasma cell percentage > 50% 
or between 20-50%, 
immunoparesis, and an abnormal free 
light chain ratio of 
involved to uninvolved chains of 
>8 or elevated from normal [1, 7]. A more recent risk stratification system was presented at ASCO, 2019 and 
predicts a higher risk of disease progression to MM for patients with a paraprotein of at least 2g/ dL and at 
least 20% bone marrow plasma cells [60].  Stratification of SMM using risk factors for progression has allowed 
greater precision in identifying patients more likely to get MM.     This is an exploratory study and will 
include any patient with SMM with an increased risk of progression to      MM.. SMM is differentiated from 
MGUS by a higher plasma cell burden and increased risk of progression to MM [11]. Patients with MGUS have 
clonal bone marrow plasma cells < 10%, an M-protein < 3g/dL, urine monoclonal proteins < 500 mg/24 hours, 
and the absence of myeloma defining events or CRAB criteria and an average risk of progression to MGUS of 
1% per year [15].

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*Risk factors included in the model include monoclonal protein levels ≥3g/dL, Bone marrow plasma cells ≥10%, and having an 
abnormal free light chain ratio
The current standard of care for patients with SMM or MGUS is observation without active treatment 
because early trials for the treatment of SMM did not demonstrate a survival advantage and 
demonstrated toxicity [16, 17]. Initial results with thalidomide demonstrated response rates, but 
widespread adaptation of early treatment was limited by the risks involved with treating patients who 
may never develop an active disease[18, 19]. A randomized trial of thalidomide + zoledronic acid versus 
zoledronic acid alone showed improved PFS, but no difference in the rate of PFS as defined by CRAB 
criteria or OS [20]. More recently, the PETHEMA group reported results on the treatment of patients with 
SMM at high risk for disease progression who were randomized to treatment with lenalidomide and 
dexamethasone versus observation alone. Patients on the treatment arm had improvements in the 3- 
year overall survival and lower rates of disease progression [21]. However, generalizability of the 
PETHEMA study has been questioned based on the use of flow markers for risk stratification, and on the 
choice of salvage therapy in the observation arm that did not include lenalidomide, and the way the trial 
dealt with biochemical progression. Despite this, the PETHEMA study has regenerated interest in the 
optimal management of patients with SMM and has lead the way for multiple ongoing clinical trials, 
including this proposed study supported by Amgen.
1.2BONE DISEASE
While the exact mechanisms of transformation from MGUS to MM are not known, alterations in bone 
metabolism are seen in patients with MGUS and MM and are in part mediated through altered bone 
metabolism leading to increased bone destruction [2]. Throughout life, bone remodeling is an ongoing 
balance between cells that make and breakdown bone, namely osteoblasts, osteoclasts, and osteocytes. 
In patients with MM, the balanced coupling of bone modeling cells is disrupted and leads to increased 
osteoclast activity and subsequent bone destruction [22]. The increased bone turnover seen in myeloma 
is also thought to contribute to disease pathogenesis and can be correlated with advanced disease stage

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and an 
increased risk of death [23]. Recently, changes in markers for bone-turnover have been associated 
with disease progression from MGUS to MM [3]. A meta-analysis has also demonstrated an 
increased risk 
of fracture and 
lower bone mineral density 
in patients with MGUS, demonstrating that alterations in bone 
metabolism precede the malignant disease phase and further supports a contributory role [24].
The perturbations of bone metabolism seen amongst patients with plasma cell dyscrasias are mediated in 
part through the Receptor Activator of Nuclear Factor- κB (RANK) and RANK Ligand (RANKL) pathway. 
RANKL 
is a membrane bound protein expressed on cells of osteoblast 
lineage that binds the RANK receptor 
on osteoclast precursors to induce osteoblastic resorption and increase osteoclast survival [2]. 
Osteoprotegrin (OPG), is a decoy receptor for RANK and limits osteoclastogenesis. In patients with MM, 
RANKL 
is up regulated while OPG 
is suppressed. This dysregulation correlates with clinical disease activity, 
severity of bone disease, and decreased survival [5]. In patients with MGUS, RANKL, and the RANKL/OPG 
ratio are increased compared to healthy controls, but to a lesser extent than in patients with frank MM 
[5]. MM cells are felt to directly participate in the bone dysregulation as MM cells can directly produce 
both RANKL and degrade OPG [25-27].
Clinically, the RANK/RANKL/OPG pathway has been exploited to alter bone modeling and decrease tumor 
burden. In the SCID-hu-MM mouse model of human MM, a RANKL antagonist limited bone destruction 
and reduced tumor burden [28]. Another study demonstrated the ability of OPG to decrease serum 
paraprotein levels and inhibit bone destruction in mouse models using the 5T2MM cell line [29]. In 
humans, targeting bone remodeling with bisphosphonates decreases skeletal related events [30, 31]. In 
vitro, bisphosphonates have a direct cytotoxic effect [32, 33]. It has been suggested as well that more 
potent bisphosphonates can improve overall survival rates [34, 35]. Overall, the animal and human 
experience demonstrates the therapeutic potential in targeting bone remodeling to modulate myeloma 
disease activity.
Given the early perturbations in bone modeling seen in patients with MGUS and SMM, bisphosphonates 
have been studied. Bisphosphonates are pyrophosphate analogs that bind bone hydroxyapatite and 
inhibit osteoclast function and bone resorption during remodeling [36]. In pamidronate and zoledronic 
acid, the most commonly used bisphosphonates for plasma cell disorders, the mechanism of action is 
through inhibition of the enzyme farnesyl pyrophosphate synthase, causing cytoskeleton abnormalities in 
osteoclasts [37]. The action of bisphosphonates translates to improvement in bone mineral density in 
patients with MGUS when given zoledronic acid [38]. However, randomized studies have evaluated the 
impact of bisphosphonates on SMM and found that while bisphosphonates decrease the risk of skeletal 
events, the progression free survival was not improved with the use of a bisphosphonate [39, 40].
1.3EXPLORATORY ENDPOINTS
In patients with MGUS, altered bone architecture has also been linked to elevated DKK1, sclerostin, and 
MIP-1a levels [41]. DKK1 is a key regulator of osteoblast activity thought to play a role in myeloma bone 
disease through action via the Wnt pathway on RANKL and OPG [42]. DKK1 is also thought to play a role 
in disease progression and relapse in MM. Therapies targeting DKK1 (BHQ880) are in development for the 
treatment of MM and SMM [43, 44]. Denosumab causes a reduction in DKK1 levels and further study

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into correlation of the clinical 
impact of denosumab with DKK1 
levels and osteoprogenitors evaluation are 
needed [6]. Notch signaling is also implicated in the progression of MM from precursor states through 
upregulation of RANKL and alterations in the bone marrow stromal environment [45]. The impact of 
denosumab on bone signaling pathways requires further study given the importance of these signaling 
pathways at the interface between bone RANKL expression, bone health, and MM disease pathogenesis.
In addition to altered bone modeling, MM involved alterations in bone cell function. Patients with MM 
have decreased osteocytes and impaired ability of bone marrow stromal cells to differentiate into 
osteoblasts [46, 47]. Cell to cell interactions within the bone marrow stromal compartment are important 
for MM cell homing and these altered stromal compartments in myeloma are important for disease 
pathogenesis [48]. The impact of denosumab on the precursor stromal environment is not known, but the 
importance of osteoprogenitors and the stromal compartment in MM pathogenesis make further study 
of potential denosumab impacts of particular importance. We therefore propose to study the impact of 
denosumab on bone architecture and markers of bone metabolism in patients with MGUS and SMM.
1.4STUDY DRUG
Denosumab is a fully human monoclonal IgG2 antibody targeting RANKL in soluble and membrane bound 
forms. Denosumab binds with high affinity and specificity without binding to other related proteins of the 
TNF family [52]. A key difference between denosumab and bisphosphonates is that denosumab can exert 
effect within the extracellular milieu versus requiring internalization, allowing a more broad impact for 
denosumab on the development and survival of osteoclasts [53]. Furthermore, the activity of circulating 
denosumab allows for broader impact on bone versus at the bone mineral surface [54, 55]. Clinically, 
the 
differences between bisphosphonates and denosumab have been observed. In women with low bone 
mineral density, denosumab increased bone mineral density compared to a bisphosphonate [56] . 
Another study demonstrated the ability of denosumab to increase bone mineral density in patients 
already treated with a bisphosphonate [57]. In malignancy, a randomized phase 3 study demonstrated 
non-inferiority of denosumab compared to zoledronic acid in delaying time to first skeletal related event, 
but showed denosumab had greater ability to suppress bone turnover [58]. A phase 3 trial in MM also 
showed non-inferiority of denosumab compared to zoledronic acid, but demonstrated an improvement 
in progression free survival for patients treated on the denosumab arm [50]. Overall, the preclinical and 
clinical data suggests that denosumab exerts a fundamentally different impact on bone remodeling via a 
different mechanism of action from bisphosphonates and offers a novel opportunity to further explore 
the impact of RANKL inhibition in patients with plasma cell dyscrasias.
Case reports have suggested a rare risk of multiple vertebral fractures in women who discontinue 
denosumab[49]. The described case reports demonstrate the risk of multiple vertebral fractures 
in women 
undergoing treatment for breast cancer or with a history of osteoporosis, with longer duration of use 
seeming to correlate with the 
increased risk. There are no reports of multiple vertebral fractures 
in women 
treated with denosumab for multiple myeloma [50]. The exact mechanism of this increased risk is not 
known, but a rebound increase in bone resorption and resultant decrease in bone mineral density is 
thought to be the likely culprit [51]. In this study, we propose to follow markers of bone resorption

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and DXA scans for 2 years after the discontinuation of denosumab to determine the long-term effects of 
denosumab withdrawal in patients with SMM.
Denosumab is currently FDA approved for the prevention of skeletal-related events in patients with 
multiple myeloma. Additional and updated information can be found in the Investigator’s Brochure for 
additional and updated information on safety, background, and clinical experience.
1.4.1PHARMACOKINETICS
Denosumab displays dose-dependent, nonlinear pharmacokinetics at doses below 60mg in healthy 
patients and patient populations evaluated. However, dose-proportional increases in exposure (based on 
area under the serum concentration-time curve and maximum serum denosumab concentration) are seen 
at higher doses. Bioavailability is 62%. In patients with newly diagnosed MM, 120 mg denosumab 
subcutaneously every 4 weeks (Q4W), up to 2.8-fold accumulation in serum denosumab concentrations 
was observed at steady-state (at 6 months) and these steady-state exposures were maintained with 
continued dosing. These results are consistent with a lack of change in pharmacokinetics with time upon 
multiple dosing. The mean elimination half-life was 28 days. Median reductions in uNTx/Cr of 
approximately 75% were observed by week 5. Reductions in bone turnover markers were maintained, 
with median reductions of 74% to 79% for uNTx/Cr from weeks 9 to 49 of continued 120mg q4w dosing.
1.4.2DENOSUMAB DOSE SELECTION
As mentioned above, multiple phase 3 studies have demonstrated the efficacy and safety of the 120 mg 
SC Q4W dose regimen, with non-inferiority in the risk of SREs compared with zoledronic acid observed in 
subjects with advanced malignancies involving bone. In addition, this dose regimen led to significantly 
greater (p < 0.0001) suppression of uNTx/Cr when compared to zoledronic acid; this result and the robust 
SRE data for denosumab suggest that targeting maximal suppression of uNTx/Cr is an appropriate strategy 
for dose selection.
Denosumab administered at a dose of 120 mg SC Q4W has been well tolerated in the pivotal phase 3 
studies. Therefore, 120 mg SC Q4W has been selected as the dose in subjects with SMM in this study
1.5 HYPOTHESIS
Current standard of care for patients with SMM is close observation despite the risk of developing an 
incurable malignancy. While the exact mechanisms for disease progression from SMM to MM are not 
known, perturbations in bone modeling are linked to disease progression biologically and clinically. 
Specifically, the RANKL pathway is postulated to play a role in the development of MM and inhibition of 
this pathway has led to tumor reduction in animal models. Denosumab is an FDA approved agent that has 
proven safe and effective in modulating bone modeling and preventing skeletal related events in

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patients with MM. The unique mechanism of action and strong safety profile make denosumab an ideal 
drug to target disease progression in SMM. We therefore hypothesize that denosumab will result in 
reduced disease activity and a decreased risk of progression to MM. We further hypothesize that the 
alterations in bone remodeling will 
lead to 
increased bone mineral density, and 
lower than expected rates 
of disease progression and prolonged progression free survival when compared to historical averages. 
Additionally, the ultimate effects of denosumab on osteoprogenitor numbers, function and the impact on 
modulators of MM disease activity as it interacts with the bone marrow stromal compartment are not 
known but bear further investigation.
2OBJECT 
IVES AND E ND P O 
INTS
2.1PRIMARY OBJECTIVE
To determine the change 
in risk for progression to MM 
in patients with SMM treated with denosumab 
for one year.
2.2SECONDARY OBJECTIVES
To measure the change in monoclonal (M) serum protein or free light chain (FLCs) as appropriate to 
assess for disease response per the IMWG criteria in Appendix A.
Determine the rate of skeletal related events (SREs)
To assess the rate of disease progression to MM
Determine the progression free survival (PFS)
Define the rate of adverse events (AEs)
Determine the change in bone mineral density as measured by bone densitometry (DXA scanning)
Exploratory objectives:
To determine the impact of denosumab on soluble factors of bone activity including MIP-1α, Notch 
signaling, DKK1, sclerostin, RANKL, and OPG.
To describe the changes in mesenchymal and osteolineage populations and osteoprogenitor function
To determine the impact of denosumab discontinuation on markers of bone turnover and bone 
formation including serum bone alkaline phosphatase, total osteocalcin, procollagen type 1 N- 
terminal propeptide, serum C-terminal cross-linked telopeptides, and urinary N and C-terminal cross- 
linked telopeptides.
3EL 
IGIB 
IL 
IT Y CR 
ITERI A
Patients must meet all of the following inclusion criteria and none of the exclusion criteria to be eligible 
for participation in this study.

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3.1INCLUSION CRITERIA
Patients must meet all of the following inclusion criteria to be eligible for participation in this study:
1. Patient has confirmed SMM according to the definition of the International Myeloma Working 
Group (IMWG) definition: serum M-protein ≥3 g/dL or BMPC >10% but less than 60%, or both, 
along with no plasma-cell related abnormal organ and marrow function (CRAB related to a plasma 
cell disorder) within 24 weeks prior to baseline, without new evidence of disease progression to 
multiple myeloma.
C: Absence of hypercalcemia, evidenced by a calcium ≤11 mg/dL. 
R: Absence of renal failure, evidenced by a creatinine ≤ 2.0mg/dL 
A: Absence of anemia, evidenced by a hemoglobin ≥10 g/dL.
B: Absence of lytic bone lesions per IMWG recommendations:
One of either PET-CT, low-dose whole-body CT (LDWBCT) or MRI of the whole body or spine. 
Increased uptake on PET-CT alone 
is not adequate for the diagnosis of multiple myeloma; evidence 
of underlying osteolytic bone destruction 
is needed on the CT portion of the examination.
2. One of the risk factors below that portends for an increased risk of progression to MM:
• An abnormal free light chain ratio
• M-spike ≥ 2 g/dL
• ≥ 20% bone marrow plasma cells
• Immunoparesis ≥ 20% 
less than the 
institutional normal standard of the uninvolved 
immunoglobulins
3. Serum calcium or albumin-adjusted serum calcium ≥ 2.1 mmol/L (8.4 mg/dL) and ≤ 2.9mmol/L 
(11.5 mg/dL) (Reference range 8.5-10.8 mg/dL)
4. Able to tolerate daily supplementation of calcium and vitamin D
5. Must have a vitamin D level ≥ 30 ng/mL or have a level 12ng/mL to 30ng/mL and be on active repletion with 
cholecalciferol 50,000 IU po weekly or equivalent.
6. Participants must have normal organ as defined below:
Total bilirubin ≤ 2.0 x institutional upper limit of normal (ULN); patients diagnosed with 
Gilbert’s syndrome can enroll with a total bilirubin > 2 after review of the principal 
investigator
AST (SGOT) ≤2.5 × institutional ULN 
ALT (SGPT) ≤2.5 × institutional ULN
7. Age ≥ 18 years.
8. ECOG PS ≤1
9. Life expectancy greater than 12 months
10.Subjects with reproductive potential must be willing to use, in combination with his/her partner, 
2 highly effective methods of effective contraception or practice sexual abstinence throughout 
the study and continue for 5 months after the study duration. Subjects who are surgically sterile 

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(e.g. history of bilateral tubal 
ligation, hysterectomy) or whose sexual partner 
is sterile (e.g. history 
of vasectomy) are not required to use additional contraceptive measures.
11.Ability to understand and the willingness to sign a written informed consent document.
12.Patient must be willing and able to comply with the protocol for the duration of the study 
including undergoing treatment and scheduled visits and examinations including follow up.
13. Men and women of all racial and ethnic origins are eligible for this study.
3.2EXCLUSION CRITERIA
Patients who meet any of the following exclusion criteria are not to be enrolled to this study:

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1. Prior administration of denosumab.
2. Any history of IV bisphosphonate use prior to or during the study
3. Prescription oral fluorides or bisphosphonate usage > 3 months within the past 2 years
4. Systemic corticosteroids > 10mg prednisone per day
5. Known secondary cause for osteopenia or osteoporosis
6. Patient has symptomatic MM, as defined by any of the following related to the plasma cell disorder:
Lytic lesions or pathologic fractures.
Anemia (hemoglobin <10 g/dL)
Hypercalcemia (corrected serum calcium > 11.0 mg/dL)
Renal insufficiency (creatinine > 2.0 mg/dL).
Clonal bone marrow plasma cells > 60%
An involved serum free light chain (kappa or Lambda) > 100mg/L with the ratio of the 
involved/uninvolved free light chains also > 100 mg/L
One or more osteolytic lesions on radiography, but more than one lesion is required if < 10% 
marrow plasma cells. From MRI imaging, there must be more than one lesion of > 5mm in 
size.
7. Other: symptomatic hyperviscosity, amyloidosis, plasma cell leukemia, POEMS syndrome 
(polyneuropathy, organomegaly, endocrinopathy, monoclonal protein)
8. Prior history or current evidence of osteonecrosis/osteomyelitis of the 
jaw.
9. Active dental or jaw condition that requires oral surgery, including tooth extraction.
10.Non-healed dental/oral surgery, including tooth extraction.
11.Planned invasive dental procedures during the course of study.
12.Evidence of any of the following conditions per subject self-report or medical chart review:
Any prior invasive malignancy within 3 years of enrollment that may affect outcome of study
Any non-invasive malignancy not treated with curative intent or with known active disease 
within 3 years before enrollment that may affect outcome of study
Major surgery or significant traumatic injury occurring within 4 weeks before enrollment
Active infection with Hepatitis B virus or Hepatitis C virus
Human immunodeficiency virus (HIV) requiring IV anti-infective therapy
13.Subject is pregnant or breast feeding, or planning to become pregnant within 5 months after the end 
of treatment.
14.Female subject of child-bearing potential is not willing to use, in combination with her partner, 2 
methods of highly effective contraception during treatment and for 5 months after the end of 
treatment.
15.Clinically significant hypersensitivity to denosumab or any components of denosumab 120mg.
16.Known sensitivity to any of the products to be administered during the study (e.g., calcium, or vitamin 
D).
17.Subject is receiving or is less than 14 days since ending other experimental drug (no marketing 
authorization for any 
indication).

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18.Any major medical or psychiatric disorder that, in the opinion of the investigator, might prevent the 
subject from completing the study or interfere with the interpretation of the study results.

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4STUD Y D ESIG N
4.1 OVERVIEW OF STUDY DE SIGN
This is an open label, Phase II trial of denosumab 120mg subcutaneous (SC) for patients with smoldering 
multiple myeloma (SMM). Subjects will be recruited from the James P. Wilmot Cancer Center, University 
of Rochester 
in Rochester, New York. Patients seen 
in the 
inpatient or outpatient setting with histologically 
confirmed SMM will be evaluated for this study.
20 patients will be treated as follows:
Denosumab: day 1 = 120mg SC every 4 weeks for 12 cycles. Cycles will be 28 days in length. Patients will 
be followed after completion of the study per standard of care for progression free survival for an 
additional 2 years after the last dose of denosumab. All patients will take daily vitamin D and calcium 
supplements of at least 1200mg elemental calcium and 800IU of vitamin D unless documented 
hypercalcemia develops on study. Pre-existing hypocalcemia must be corrected prior to initiating therapy 
with denosumab.
Serum vitamin D levels will be checked during screening and patients with hydroxyvitamin D level < 
30ng/mL prior to denosumab administration must take at least 50,000 IU cholecalciferol weekly during 
treatment or equivalent until hydroxyvitamin D 
level ≥ 30ng/mL at which time patients can continue 800IU 
vitamin d daily. Hydroxyvitamin D levels < 30ng/mL will be repeated at least every 12 weeks or more 
frequently at investigator’s discretion.
Correlates:
Clinical labs including CBC, CMP, and SPEP with IFE, FLC, quantitative immunoglobulins, and phosphorous 
levels will be collected at baseline, monthly during treatment, and at 13 months. A UPEP with IFE will be 
collected at baseline and at 13 months and additionally as per clinically indicated. Other clinical labs will 
be collected during the study per standard of care of the 
investigator.
Investigational Labs (peripheral blood and urine) to be collected at baseline, 13 months, 24 months, and 
36 months will be analyzed in the laboratory of Brea Lipe
DXA scans will be conducted at baseline, 13 months, 24 months, and 36 months
Bone marrow and aspirate samples will be analyzed for baseline disease assessment and disease response 
in the clinical pathology laboratory at the University of Rochester Medical Center with additional aspirate 
samples to be analyzed in the Lipe laboratory.
Patients may discontinue therapy early for unacceptable toxicity or withdrawal from the study due to 
investigator decision or other reasons.

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4.2REGISTRATION
4.3PATIENTS 
MUST NOT START ANY PROTOCOL INTERVENTION PRIOR TO 
REGISTRATION THROUGH THE WILMOT CANCER INSTITUTE. REGISTRATI ONS ARE 
CAPTURED IN THE WILMOT CANCER INSTITUTE REDCAP DATABASE AT THE UNIVERSITY 
OF ROCHESTER. SITE PERSONNEL WILL BE RESPONSIBLE FOR ENTERING THE PATIENT 
DATA INTO REDCAP WITHIN 24 HOURS OF THE SIGNING OF INFORMED CONSENT. 
DISCONTINUATION FROM STUDY TREATMENT
Patients will be discontinued from study treatment for any of the following reasons:
Partial withdrawal of consent meaning that a patient declines further denosumab, but consents 
to continued data and sample collection.
Full withdrawal of consent meaning a patient does not wish to receive further denosumab and 
does not wish to continue any further study participation.
Pregnancy in a female patient
Inability of the patient to comply with study requirements
Use of bisphosphonates or commercial use of denosumab
Non-compliance/lost to follow-up
Investigator discretion
Study termination
Patients who discontinue from study treatment will continue to be followed for progression and late 
toxicities for one year. After withdrawal from protocol treatment, patients will be followed for AEs for 30 
calendar days after their last dose of study drug. All new AEs occurring during this period will be reported 
and followed until resolution, unless, in the opinion of the investigator, these values are not likely to 
improve because of the underlying disease. In this case the investigator must record his or her reasoning 
for this decision in the patient’s medical records. All patients who have CTCAE Grade 3 or 4 laboratory 
abnormalities at the time of withdrawal should be followed until the laboratory values have returned to 
Grade 1 or 2, unless in the opinion of the investigator, it is not likely that these values are to improve 
because of the underlying disease. In this case, the investigator must record his or her reasoning for 
making this decision in the patient’s medical records.
4.4CRITERIA FOR  STUDY T ERMINATION
This study will be considered terminated when 1 of the following conditions are met:
All subjects have completed all required study visits;
All subjects have discontinued from the study;

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The University of Rochester Data Safety Monitoring Committee or 
Institutional Review Board (IRB) 
discontinues the study because of safety considerations.
5STUD Y AS SES SM ENTS AN D TREATM E NT SC HE D UL E
Table 5.1 below 
lists all of the required assessments that should be performed at the corresponding study 
visit.
TABLE 5.1: STUDY ASSESSMENTS AND TREATMENT SCHEDULE

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Procedure
Pre-
study
1
Study
Day 12
Weeks
2-4
C2-C12
Off
Treatment
16
24 months
36
months
Informed Consent
X
Inclusion/Exclusion
Criteria
X
X
Medical and Treatment
History
X
Physical Exam3
X
X
X
X
Oral Examination4
X
X
X
X
ECOG Performance
Status
X
X
X
X
CBC with diff3
X
X
X
Serum Chemistries
3,5
X
X
X
Serum Calcium
6
X
X
X
X
7sCTX, MIP-1α, DKK1,
sclerostin, NOTCH 
RANKL, and OPG7
X
X
7Markers of bone 
resorption and turnover
X
X
X
X
uNTX8
X
X
X
X
SPEP with IFE
X
X
X
UPEP with IFE9
X
X
Free light chain testing
X
X
X
Vitamin D level
X
x
Pregnancy Test10
X
Bone marrow biopsy/
aspirate 
11
X
X
PET-CT, low-dose whole-
body CT or MRI of the 
whole body or spine
X
Denosumab (SC)12
X
X
DXA
X
X
X
X
Adverse Event
Evaluation
13
X
X
X
Skeletal Event
Recording14
X
X
X
Concomitant
Meds/Treatment15
X
X
X
X
1Screening: All screening assessments must be completed and results obtained (e.g., chemistry, 
hematology) before entry into the study. Assessments conducted as standard of care do not require 
informed consent and may be provided as screening data. Imaging tests done as standard of care within 
the 12 months prior to enrollment will be considered within the screening window.  Other screening 
assessments will have a 30 day window.

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2Study Day 1: The first day that disease-related treatment is administered will be study day 1.
3Physical Exam, Vital Signs, Hematology and Chem: visit days have - 8 day window

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4Oral Examination: A visual examination of the oral cavity, including teeth, mucosa to establish baseline 
oral health conditions and to identify any new abnormalities or changes in pre-existing conditions.
5Serum Chemistries: To include Na, K, CL, CO2, Mg, Phosphorus, BUN, creatinine, glucose, albumin, total 
protein, alkaline phosphatase, total bilirubin, AST, ALT
6Serum Calcium: Monitored weekly for first 4 weeks then every cycle thereafter with a +/-3 day window. 
Calcium level willbe assessed prior to the administration of denosumab.
7Soluble markers of bone turnover: to be drawn after fasting to be analyzed in the laboratory of Brea 
Lipe, MD
8Urinary markers: to be collected from second morning void and to be analyzed in the laboratory of Brea 
Lipe, MD
9UPEP: Twenty-four hour urine samples for quantitation of M-protein and assessment of M-protein by 
immunofixation are to be requested from all patients during screening and will be analyzed in the local 
laboratory. Patients may refuse to provide urine samples.
10Serum pregnancy test: prior to Cycle 1 / Day 1 for females of childbearing potential. If patient has 
experienced menopause or no longer has uterus / ovaries this can be omitted.
11Bone marrow biopsy and aspirate: routine processing per pathology with aspirate and marrow samples 
sent to the laboratory of Brea Lipe, MD. Baseline bone marrow biopsy/aspirate not needed if recent 
sample within 3 months.
12Treatment administration: +/- 8 day window, but must have a minimum of 3-week intervals for 
administration of denosumab.
13Adverse event reporting: Adverse events must be assessed and documented at each scheduled clinic 
visit. Subjects must be followed for adverse events for 30 days after the last dose of denosumab, or until 
all denosumab-related toxicities and ongoing serious adverse events have resolved or are considered 
stable, whichever is later.
14Skeletal event (SE) recording: SEs will 
include all pathologic fractures, radiation to bone, surgery to bone 
for fracture or stabilization. SEs will be confirmed by imaging.
15Concomittant medications: Type and timing of concomitant medications will be collected. Calcium and 
vitamin D supplementation will be recorded.
16Off treatment: 4 weeks + 30 days following completion of cycle 12 or upon discontinuation of therapy. 
Follow AEs for 30 days after discontinuation of protocol treatment; after 30 days only AEs related to 
protocol must be followed. Follow-up survival and safety data will be collected per routine of care clinic 
visits for 2 years after the last dose of denosumab.
6AGENT AD M 
INI STRAT 
I ON
6.1DENOSUMAB

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Denosumab is a human IgG2 monoclonal antibody that binds to human RANKL. Denosumab has an 
approximate molecular weight of 147 kDa and is produced in genetically engineered mammalian 
(Chinese hamster ovary) cells.
Onset of action: Decreases markers of bone resorption by ~85% within 3 days; maximal reductions 
observed within 1 month
Duration: Markers of bone resorption return to baseline within 12 months of discontinuing therapy
Bioavailability: SC: 62%
Half-life elimination: ~25-28 days
Time to peak, serum: 10 days (range: 3-21 days
6.1.1FORM
Denosumab will be provided as a sterile, clear, colorless to slightly yellow, preservative free liquid, in 
single-use 3.0 mL glass vials containing a deliverable dose of 1.7mL
Denosumab will be packaged in boxes containing single-use vials of denosumab of 120mg/ 1.7mL 
(70mg/mL).
6.1.2STORAGE AND STABILITY
Store denosumab in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. Do not freeze. 
Once removed from the refrigerator, denosumab must not be exposed to temperatures above 
25°C/77°F or direct light and once removed from the refrigerator must be used within 24 hours. 
Discard denosumab if not used within 24 hours. Do not use denosumab after the expiry date printed 
on the label. Avoid vigorous shaking.
6.1.3 PREPARATION
Each box of denosumab will contain one 1.7 mL vial. A single use syringe should be used to prepare 
the dose. There are no other special preparations required prior to denosumab administration.
6.1.4ADMINISTRATION
Subcutaneous injections are to be given at different locations. There are no other special preparations 
required prior to denosumab administration.
6.1.5ORDERING

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Denosumab will be shipped to the responsible investigational pharmacist at the University of 
Rochester, who will check the amount and condition of the drug and enter these data into the Proof 
of Receipt Form. If any abnormality on the bottles is observed, the Pharmacist or the appropriate 
person must document that on the acknowledgement of receipt and contact that Sponsor and/or 
Sponsor designee. The Proof of Receipt Form should then be returned to Amgen Inc., and the original 
retained at the site.
6.1.6SAFETY
A complete list of the adverse events and potential risks associated with the denosumab administered in 
this study can be found at http://pi.amgen.com/unitedstates/xgeva/xgevapi.pdf
Hypocalcemia: Denosumab can cause severe symptomatic hypocalcemia, and fatal cases have been 
reported. Hypocalcemia needs to be corrected prior to initiating denosumab. Monitor calcium levels 
and administer calcium, magnesium, and vitamin D as necessary. Calcium levels have to be monitored 
weekly for the first 4 weeks of treatment then every cycle thereafter. All subjects need to be 
adequately supplemented with calcium and vitamin D (see Section 5.1). If hypocalcemia occurs, 
additional short-term calcium supplementation may be necessary.
Osteonecrosis of the jaw (ONJ): can occur in patients receiving denosumab, manifesting as jaw pain, 
osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or 
gingival erosion. The risk of ONJ is associated with the length of the exposure and risk factors for ONJ. 
Subjects should be monitored for ONJ as part of routine clinical practice. Subjects should be 
instructed 
to maintain good oral hygiene while on treatment with denosumab.
A dental examination with appropriate preventive dentistry should be considered prior to treatment 
with denosumab in subjects with risk factors for ONJ. Subjects who are suspected of having or who 
develop ONJ while on denosumab should receive care by a dentist or an oral surgeon. Expert 
evaluation of patients with potential ONJ cases should be based on the American Association of Oral 
and Maxillofacial Surgeons (AAOMS) guidelines for ONJ. In subjects who develop ONJ during treatment 
with denosumab 120 mg, a temporary interruption of treatment should be considered based on 
individual risk/benefit assessment until the condition resolves. While on treatment with denosumab, 
subjects should be instructed to avoid invasive dental procedures, if possible. For subjects in whom 
invasive dental procedures cannot be avoided, the clinical judgment of the treating physician should 
guide the management plan of each patient based on individual benefit/risk assessment.
In three phase III active-controlled clinical trials in subjects with advanced malignancies involving 
bone, ONJ was conformed in 1.8% of patients in the denosumab group treated with 120 mg 
subcutaneously every 4 weeks. The trials in patients with breast and prostate cancer included 
denosumab extension treatment phase (median overall exposure of 14.9 months; range

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0.1 – 67.2). The patient-year adjusted incidence of confirmed ONJ was 1.1% during the first year of 
treatment and 4.1% thereafter. The median time to ONJ was 20.6 months (range: 4-53).
Atypical femoral fracture (AFF): has been reported with denosumab. These fractures can occur 
anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare 
and are transverse or short oblique in orientation without evidence of comminution. AFF most 
commonly occur with minimal or no trauma to the affected area. They may be bilateral and many 
patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, 
weeks to months before a complete fracture occurs. During denosumab treatment, subjects should 
be advised to report new or unusual thigh, hip, or groin pain. Subjects presenting with such symptoms 
should be evaluated for an incomplete femoral fracture, and the contralateral femur should also be 
examined. Expert evaluation of patients with potential AFF cases should be based on the American 
Society for Bone and Mineral Research (ASBMR) guidelines for A FF.
Hypersensitivity: Clinically significant hypersensitivity including anaphylaxis has been reported with 
use of denosumab. Reactions may include hypotension, dyspnea, upper airway edema, lip swelling, 
rash, pruritus, and urticaria. Clinically significant hypersensitivity has been identified as a 
contraindication for treatment with denosumab. If an anaphylactic or other clinically significant 
allergic reaction occurs, initiate appropriate therapy and discontinue denosumab therapy 
permanently
Multiple vertebral fractures: There is a risk of multiple vertebral fractures (MVF) following 
denosumab discontinuation. When denosumab is discontinued, evaluate the individual patient’s risk 
for vertebral fractures.
Musculoskeletal pain: Including severe cases, has been identified as an adverse drug reaction based 
on data from the post-marketing setting.
6.1.7DESTRUCTION AND RETURN
A Denosumab Accountability Record for the denosumab mandated by the protocol must be kept current 
and should contain:
Dates and quantities of denosumab received from Amgen 
Inc.
Manufacturing lot number AND box numbers for product received
Subject’s identification (subject number and initials)
Date and box number of denosumab dispensed
Initials of the dispenser

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Used vials will not be returned to Amgen. Any partial or remaining drug at the time of use will be discarded 
per institutional safe handling procedure. Drug accountability will be maintained within the institutional 
system.
At the end of the study, or as directed, all denosumab supplies will be discarded per institutional 
standards. For each medication destroyed, documentation will be filed and kept in the appropriate 
protocol file. Documentation will include, medication destroyed, quantity, protocol number, and date 
drug is placed in Biohazard container.
6.1.8DOSAGE ADJUSTMENTS AND DISCONTINUATION OF DENOSUMAB
There will be no dose adjustments for the SC denosumab.
Administration of SC denosumab will be withheld for any subject who experiences a grade 3 or 4 
adverse event (refer to Common Terminology Criteria for Adverse Events [CTCAE] Version 5.0) 
reported by the investigator as related to denosumab, or osteonecrosis of the jaw (ONJ) as 
determined by the investigator or by an independent expert panel. Denosumab will be held for 
albumin-adjusted serum calcium levels less than 8.4 mg/dL. Re-exposure to denosumab may occur 
only when the event resolves to grade 1 or less or to the subject’s baseline and if the investigator and 
sponsor agree subject safety will not be compromised.
If any scheduled dose after study day 1 is delayed for more than 8 calendar days from the scheduled 
visit date, this will be considered a missed dose and recorded as such on the case report form (CRF). 
The next dose is to be given on the next scheduled visit date (based on study day 1). There must be a 
minimum of a 3-week interval between administrations of denosumab. If subjects are delayed for 
more than 5 weeks, then subjects will be removed from study at the treating physician’s discretion.
Administration of the denosumab is recommended to be withheld 30 days prior to any elective 
invasive oral/ dental procedure. Denosumab administration is recommended to be withheld until 
documented evidence of complete mucosal healing following any invasive oral/dental procedure.
Invasive dental procedures should be avoided, if possible. If a subject undergoes an invasive dental 
procedure while on study, a clinical decision to continue the subject on the denosumab must be 
documented in the medical chart.
6.2 CONCOMITANT/ EXCLUDED MEDICATIONS
Calcium and vitamin D supplements will not be provided as part of the trial, but will be prescribed by 
the investigator as a concomitant medication per standard of care as described previously.
No formal drug –drug interaction trials have been conducted with denosumab.

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Bisphosphonates (oral or IV) are not permitted during the study period or until the end of study 
assessments are completed.
7 M EASUREM ENT O F EF F EC T
7.1 METHOD OF ASSESSMENT
In addition to clinical examination, laboratory-based evaluation will be used in this study for all patients 
enrolled.
7.1.1SERUM
Blood samples for quantitation of Ig (IgA, IgG, and IgM are required; IgD and IgE are optional)
and M-protein and assessment of M-protein by immunofixation in serum are to be collected from 
all patients during Screening. Such samples also are to be collected at the time points designed in 
Table 5.1.
All samples will be analyzed by the local laboratory.
7.1.2FREE LIGHT CHAIN TESTING
Serum samples for FLC testing are to be collected from all patients during screening and at the 
time points designed in Table 5.1. The free kappa/lambda ratio is to be recorded in the eCRF. 
A serum sample for FLC testing also is to be collected in order to confirm stringent complete 
response (sCR).
All samples will be analyzed by the local laboratory.
7.1.3URINE
Twenty-four hour urine samples for quantitation of M-protein and assessment of M-protein by 
immunofixation are to be requested from all patients during screening. Patients may refuse to provide 
urine samples.
All samples will be analyzed by the local laboratory.
7.1.4BONE MARROW EXAMINATION
Bone marrow aspiration and trephine biopsy per institution standard are to be performed for all patients 
during screening prior to study treatment administration and the end of study. If a bone marrow biopsy 
has been done within 3 months before screening, this does not need to be repeated. Bone
marrow aspiration and biopsy are to be repeated during treatment as clinically indicated, at the

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Investigator’s discretion, in order to confirm complete response (CR).
A portion of the pre-treatment sample and the end of treatment sample will be used for correlative 
studies.

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7.1.5DXA SCANS
DXA scans are to be performed during screening and at the end of study. All scans will be performed at 
the local radiology facility. Bone density will be measured at the 
lumbar spine, femoral neck, total hip, and 
distal 1/3 of the radius.
7.1.6ASSESSMENT OF RESPONSE
Patients will be assigned a baseline category of SMM risk for progression as below in Table 7.1.6. Patients 
will be determined to have a downgraded risk of progression if the risk category decreases. Patients with 
low risk SMM will have a downgraded risk if they no longer meet the criteria for SMM, but have MGUS 
instead. MGUS will be defined per IWMG criteria as an M-protein < 3g/dL and clonal bone marrow plasma 
cells < 10% and urine monoclonal protein < 500mg/24 hours [14].
Table 7.1.6
Risk Factors
Low risk
Low-
intermediate risk
High-
intermediate risk
High risk
BM plasma cell %
≥50
M-protein ≥ 3g/dL
Involved/uninvolved
free light chains ≥ 8
Patient has SMM, 
but none of the 
listed risk factors
1 risk factor is 
present
2 risk factors are 
present
3 risk factors are 
present
Immunoparesis
Not present
Present
without
other risk factors
Disease progression and the response rate will be determined by the International Myeloma Working 
Group Criteria (IMWG) [13] (Appendix A). Investigators will assess response and progression on the basis 
of analyses of M-protein in serum or urine that will be performed locally and according to methods and 
frequencies consistent with local standard of care. It is recommended to monitor serum (or urine) M- 
protein every 4 weeks until first progression.
Disease progression in bone and outside of the bone (extra osseous) will be determined by the 
investigator based on local review of images and/or clinical observations according to methods and 
frequencies consistent with local standard of care. The criteria for disease progression are described 
herein. Disease progression will be documented on the CRF.
Changes in bone mineral density will be determined by bone densitometry (DXA). 
8 STATI STIC AL CON SID E R ATION S

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8.1 DESIGN
This is a single center, single-arm prospective open-label trial of denosumab in patients with smoldering 
multiple myeloma (SMM). We aim to establish preliminary estimates of downgrade rate after denosumab 
treatment in this population. The downgrade rate will be estimated from twenty enrolled subjects. Exact 
binomial methods will be used to calculate an associated 90% two-sided confidence interval. The 
maximum possible width of a 90% two-sided confidence interval using 20 subjects is 0.396, when the rate 
is 0.50. We anticipate a downgrade rate much lower than 0.50. If the downgrade rate were 0.10, the 
resulting 90% two-sided confidence interval would have a width of 0.265 (from 0.018 to 0.283). Table 8.1 
highlights 90% confidence interval limits based on the number of downgrades seen in twenty enrolled 
patients. Despite the wide confidence intervals produced due to limited sample size, this information is 
still critical to obtain prior to investigating this regimen in a larger definitive trial. This study will produce 
pilot data that will be used to plan future larger definitive studies. 2 or more downgrade events will be 
considered sufficient rationale for moving forward with a larger trial.
Table 8.1: 90% Confidence Intervals for a range of possible event counts
Number of downgrade events 90% confidence interval limits
1
(0.003, 0.216)
2
(0.018, 0.283)
3
(0.042, 0.344)
4
(0.071, 0.401)
5
(0.104, 0.456)
8.2EARLY STOPPING RULE FOR SAFETY
This study will be continuously monitored for grade 4 or higher adverse events (AEs) related (possibly, 
probably or definitely) to denosumab using a Pocock-style boundary for repeated testing. {Ivanova, 2005
#1764}Using the table below, the trial will be stopped and data reviewed if the boundary number of 
related grade 4 or higher AE events is reached or exceeded. Only points where stopping is possible are 
listed. If the true rate of such events is 5% (maximum-tolerated rate), there is a 7% chance of early 
termination (type I error). If the true rate is as high as 25%, there is an 86% chance of stopping the trial 
early.
Table 8.2: Early Stopping Boundary
# Patients
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
# Events
2 2 2 2 2 2 3 3 3
3
3
3
3
3
3
4
4
4
4

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8.3PATIENT DISPOSITION
The disposition of patients includes the number and percentage of patients for the following categories: 
patients enrolled, patients treated (safety population), patients in the intent to treat population, and 
patients discontinued from the study. The reasons for study discontinuation will also be summarized in 
this table. Only one primary reason for study discontinuation will be reported in the summary. However, 
all reasons will be presented in the listing. A listing will present data concerning patient disposition.
8.4PATIENT DEMOGRAPHICS AND BASELINE CHARACTERISTICS
Baseline demographic and clinical characteristics will be summarized as medians and interquartile ranges 
(IQR) for continuous variables, and as counts and proportions for categorical variables.
8.5EXTENT OF EXPOSURE
The dose (mg) of study drug administered, the total number of doses of study drug, and the duration of 
treatment (number of study cycles) will be summarized with descriptive statistics. The number and 
percentage of patients whose dose is modified at any time will be summarized by each type of 
modification by cycle and overall. The proportion of patients completing each cycle of treatment will be 
summarized.
8.6STATISTICAL ANALYSES
The treated population is defined as all enrolled subjects who received at least 1 dose of denosumab. 
Efficacy and safety analysis will be based on this population. The downgrade rate (DR) is defined as the 
proportion of patients for whom risk of progression from SMM to MM is lower after denosumab 
treatment. The criteria defining risk are defined in Table 7.1.6. Patients who cannot be assessed for any 
reason will be considered not downgraded and will be included in the denominator when calculating the 
DR.
Secondary endpoints will be analyzed as follows. Medians and interquartile ranges (IQR) will be reported 
for continuous variables and counts and proportions will be reported for categorical variables. The non- 
parametric Wilcoxon signed rank test will be used to compare pre- and monthly measures of monoclonal
(M) serum protein levels, free light chain (FLC) levels, and bone mineral density (baseline and each post- 
treatment point). If the normality assumption is valid or can be met with transformation, linear mixed 
models will be used compare changes in each measure across all time points simultaneously, and will 
include a subject-specific 
intercept to account for correlations 
in data coming from the same subject. Time 
will be treated as a categorical fixed effect. A separate model will be fit for each outcome: M serum protein 
levels, FLC levels and bone mineral density. Rates of skeletal related events will be calculated and

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presented with associated 95% two-sided exact binomial confidence intervals. Cumulative incidence for 
progression to MM from treatment initiation (Study Day 1 in Table 5.1) through 1 year will be calculated, 
treating death as a competing risk. PFS is defined as the time to progression or death from any cause, 
whichever occurs first. PFS from treatment initiation (Study Day 1 in Table 5.1) through 3 years will be 
summarized using the Kaplan-Meier method. Safety and toxicity data will be summarized at the event 
level and at the subject level. Adverse event level data will be tabulated and summarized as frequency, 
type and severity of each adverse event. Subject level data will be tabulated and summarized as subject 
incidence of each adverse event. The safety population includes all subjects who received at least 1 dose 
of denosumab.
9SAFETY REP ORTIN G
Study Investigators will conduct continuous review of data and patient safety. The 
Investigator will submit 
semi-annual progress reports of these data to the Data Safety Monitoring Committee for review. The 
review will 
include: the number of patients enrolled, withdrawals, significant toxicities as described in the 
protocol, serious adverse events both expected and unexpected, dose adjustments, and responses 
observed. The PI maintains a database of all adverse events with toxicity grade and information regarding 
treatment required, complications, or sequelae. The Investigator will submit a copy of the AE spreadsheet 
along with a Progress Report to the Data Safety Monitoring Committee (DSMC) for review. Actual review 
dates will be assigned when the 1st patient is accrued.
The DSMC at the Wilmot Cancer Institute, University of Rochester provides oversight of study progress 
and safety by review of accrual and adverse events at semi-annual meetings or more often if concerns 
arise. Any adverse event requiring expedited review per protocol, will be submitted to the Safety 
Coordinator of the DSMC at the University of Rochester for determination as to whether further action is 
required. When patient safety is of concern, an interim meeting may be called
Any serious adverse event that is serious, related AND unexpected must be reported within 5 
calendar days to both the DSMC Safety Coordinator and the RSRB (see RSRB guidelines). The 
DSMC Chair will determine whether further action is required, and when patient safety is of 
concern, an interim meeting may be called.
Serious adverse events that are related AND expected or unrelated AND unexpected will be 
reported to the DSMC for review. SAE reports are expected to include sufficient detail so that the 
DSMC can determine the severity, toxicity grade, expectedness, treatment required, and a follow 
up report documenting resolution or if there are sequelae. Serious adverse events that require 
detailed reports (but not necessarily expedited) are expected, related, non-hematologic toxicities 
of grades 3, 4 or 5.
Safety data and aggregate reports will be reported to Amgen as in section 9.7.
The Safety Coordinator administratively coordinates reports and data collection and prepares documents 
for the DSMC Chair and committee review. The Safety Coordinator will administratively monitor adverse

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event rates utilizing the report from the study database. If any study has had two or more of the same 
SAE’s reported in a month or more than six of the same SAE’s in six months, the DSMC will review the 
summary of SAEs, discuss events with Study Chair, and conduct a more detailed review with the Study 
Chair. The Data Safety Monitoring Chair will determine if further action is required.
9.1ADVERSE EVENT CHARACTERISTICS
CTCAE term (AE description) and grade: 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 investigators should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 
can be downloaded from the CTEP web site: 
http://ctep.cancer.gov/protocolDevelopment/electronicapplications/ctc.htm.
‘Expectedness’: AEs can be 
‘Unexpected’ or 
‘Expected’ for expedited reporting purposes only. Please refer 
to the denosumab prescribing information for a listing of expected AEs.
9.2 DEFINITIONS OF ADVER SE EVENTS
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product. An AE does not necessarily have to have a causal relationship 
with this treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign 
(including an abnormal 
laboratory finding, for example), symptom, or disease temporarily associated with 
the use of a medicinal product, whether or not considered related to the medicinal product. This includes 
any occurrence that is new in onset or aggravated in severity or frequency from the baseline condition.
In clinical studies, an AE can 
include an undesirable medical condition occurring at any time, 
including run- 
in or washout periods, even if no study treatment has been administered. The NCI Common Terminology 
Criteria for Adverse Events (CTCAE) v5.0 is to be used for the grading of severity of symptoms and 
abnormal findings. For adverse events not covered by the NCI-CTCAE Version 5.0 grading system, the 
following definitions will be used:
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated.
Grade 2: Moderate; minimal, local or non-invasive intervention 
indicated.
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated.
Grade 4: Life-threatening consequences; urgent intervention indicated.
Grade 5: Death related to AE.

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9.3ADVERSE EVENTS (AES) AND TREATMENT EMERGENT ADVERSE EVENTS ( TEAES)
All AEs and SAEs occurring on study will be listed by patient. The frequency and percentages of patients 
with treatment-emergent adverse events (TEAEs) will be tabulated by system organ class (SOC) and 
preferred term (PT), where treatment-emergent is defined as any AE that:
Occurs after first dosing of study medication and through the end of the study or up through 30 
days after the last dose of study treatment, or
Is considered treatment-related regardless of the start date of the event, or
Is present before first dosing of study medication but worsens in intensity or the investigator 
subsequently considers treatment-related.
TEAEs that are considered at least possibly related to study treatment will be tabulated as well as deaths, 
SAEs, and events resulting in treatment discontinuation.
At each level of summarization, a patient will be counted only once for each AE, SOC, or PT experienced 
within that level. In the summation for AE severity, within each level of AE, SOC, or PT experienced, the 
one with the highest severity will be included. In the summation for AE’s relationship to the study drug, 
within each level of AE, SOC, or PT experienced, the one with the closest relationship to the study drug 
will be included.
9.4ADVERSE EVENTS/SERIOUS ADVERSE EVENT CAUSALITY ASSESSMENT
The Investigator must also assess the relationship of any adverse event to the use of study drugs based 
on available information, using the following guidelines:
Not Related: Clear-cut temporal and/or mechanistic relation to a cause other than the study 
drug(s).
Doubtful: There is no reasonable possibility that the event is related to the study drug(s) but a 
definite cause cannot be ascertained.
Possible: There is still a reasonable possibility that the cause of the event was the study drug(s) 
but there exists a more likely cause of the event such as complications of progressive disease.
Probable: The most likely cause of the event is the study drug(s) but other causes cannot be 
completely excluded.
Definite: Clear cut temporal and/or mechanistic relation to the study drug(s). All other causes 
have been eliminated. Events classified as definite will often be confirmed by documenting 
resolution on discontinuation of the study drug and recurrence upon resumption.
9.4.1 HANDLING OF ADVERSE EVENTS
All adverse events resulting in discontinuation from the study will be followed until resolution or 
stabilization. Patients will be followed for AEs for 30 calendar days after discontinuation or completion of 
protocol-specific treatment. All new AEs occurring during this period will be reported and followed until

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resolution unless, in the opinion of the investigator, these values are not likely to improve because of the 
underlying disease. In this case, the investigator will record or her reasoning for this decision in the 
patient’s medical record and as a comment on the CRF. After 30 days, only AEs, SAEs, or deaths assessed 
by the investigator as treatment related are to be reported.
9.5SERIOUS ADVERSE EVENTS
9.5.1DEFINITIONS OF SERIOUS ADVERSE EVENTS
The definitions of serious adverse events (SAEs) are given below. The investigator is responsible for 
ensuring that all staff involved in the study are familiar with the content of this section.
An SAE or reaction is defined as any untoward medical occurrence that:
Results in death, is immediately life-threatening,
Requires at least a 24-hour in-patient hospitalization or prolongation of existing hospitalization,
Results in persistent or significant disability/incapacity, and/or
Causes a congenital anomaly/birth defect.
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately life- 
threatening or result in death or hospitalization, but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the previous definition. These should also 
usually be considered serious. Examples of such events are intensive treatment in an emergency room or 
at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
Progression of malignancy (including fatal outcomes), if documented by use of appropriate method (for 
example, as per IWCLL Hallek et al. 2008, should not be reported as a serious adverse event.
A suspected unexpected serious adverse reaction (SUSAR) is defined as an SAE that is suspected to be at 
least possibly related to study medication(s) and is an unexpected event.
Treatment within or admission to the following facilities does not meet the criteria of “in-patient 
hospitalization” (although if any other SAE criteria are met, the event must still be treated as an SAE):
Emergency Department or Emergency Room
Outpatient or same-day surgery units
Observation or short-stay unit
Rehabilitation facility
Hospice or skilled nursing facility
Nursing homes, Custodial care or Respite care facility

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Hospitalization during the study for a pre-planned surgical or a medical procedure (one which was planned 
prior to entry in the study), does not require reporting as a serious adverse event.
9.5.2SERIOUS ADVERSE EVENT REPORTING BY 
INVESTIGATORS
It is important to distinguish between serious and severe adverse events, as the terms are not 
synonymous. Severity is a measure of intensity; however, an AE of severe intensity need not necessarily 
be considered serious. For example, nausea which persists for several hours may be considered severe 
nausea, but may not be considered an SAE. On the other hand, a stroke which results in only a limited 
degree of disability may be considered only a mild stroke, but would be considered an SAE. Severity and 
seriousness should be independently assessed when recording AEs and SAEs on the CRF.
Adverse events classified by the treating investigator as serious require expeditious handling and 
reporting to the Sponsor in order to comply with regulatory requirements. Serious adverse events may 
occur at any time from the signing of the informed consent form through the 30-day follow-up period 
after the last study treatment. Sponsor or designee should be notified of all SAEs, regardless of causality, 
within 24 hours of the first knowledge of the event by the treating physician or research personnel.
All SAEs (regardless of causality assessment) occurring on study or within 30 days of last study treatment 
should be immediately reported to the sponsor as SAEs within the CRF and followed until resolution (with 
autopsy report if applicable).
SMM progression or death due to SMM progression should be reported by the investigator as a serious 
adverse event only if it is assessed that the study drugs caused or contributed to the SMM progression 
(i.e. by a means other than lack of effect). Unrelated events of SMM progression should be captured on 
the appropriate CRF.
The investigator must review and sign off on the SAE data on the SAE report. The SAE should be reported 
to the Sponsor.
When an SAE is reported to the sponsor or designee, the same information should be entered on the CRF 
within 24 hours (1 business day).
Follow-up information for SAEs and information on non-serious AEs that become serious should also be 
reported to the sponsor or designee as soon as it is available; these reports should be submitted using the 
appropriate SAE form, MedWatch3500A.
The sponsor is responsible for reporting relevant SAEs to the competent authority, other applicable 
regulatory authorities, and participating 
investigators, 
in accordance with ICH guidelines, FDA regulations, 
and/or local regulatory requirements.
The sponsor is responsible for reporting unexpected fatal or life-threatening events associated with the 
use of the study drugs to the regulatory agencies and competent authorities within 7 calendar days after 
being notified of the event. The Sponsor will report all related but unexpected SAEs including non-

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death/non-life-threatening related but unexpected SAEs (SUSAR) associated with the use of the study 
medications to the regulatory agencies and competent authorities by a written safety report within 15 
calendar days of notification. Following the submission to the regulatory agencies and competent 
authorities, Investigators and trial sites will be notified of the SUSAR. Investigators must report SUSARs 
and follow-up information to their responsible Institutional Review Board (IRBs)/Independent Ethics 
Committee according to the policies of the responsible IRB (Research Ethics Committee).
SUSARs and pregnancy or lactation will be reported to Amgen per section 9.7.
9.6RECORDING OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
Investigators should use correct medical terminology/concepts when recording AEs or SAEs on the SAE 
Report Forms and AE CRF. Avoid colloquialisms and abbreviations.
All AEs, 
including those that meet SAE reporting criteria, should be recorded on the AE CRF; AEs that meet 
the definition of an SAE should additionally be reported.
9.6.1PERSISTENT OR RECURRENT ADVERSE EVENTS
A persistent AE is one that extends continuously, without resolution, between patient evaluation time 
points. Such events should only be recorded once on the SAE Report Form and/or the AE CRF. If a 
persistent AE becomes more severe (changes from a Grade 1 or 2 AE to a Grade 3 or 4 AE) or lessens in 
severity (changes from a Grade 3 or 4 AE to a Grade 1 or 2 AE), it should be recorded on a separate SAE 
Report Form and/or AE CRF.
A recurrent AE is one that occurs and resolves between patient evaluation time points, and subsequently 
recurs. All recurrent AEs should be recorded on an SAE Report Form and/or AE eCRF for each recurrence.
9.6.2DEATHS
Deaths that occur during the protocol-specified AE reporting period that are attributed by the 
investigator 
solely to progression of the patient’s SMM for up to 30 days post the last dose of study drug will be 
recorded on the appropriate study CRF and reported on the Adverse Event page of the CRF, i.e. are 
exempted from expedited reporting. All other on-study deaths, regardless of attribution, will be recorded 
on an SAE Report Form and expeditiously reported to the Sponsor.
When recording a serious adverse event with an outcome of death, the event or condition that caused or 
contributed to the fatal outcome should be recorded as the single medical concept on the Adverse Event 
page of the CRF. If the cause of death is unknown and cannot be ascertained at the time of reporting, 
record “Death NOS” on the CRF Adverse Event page.
9.6.3HOSPITALIZATION, PROLONGED HOSPITALIZATION, OR SURGERY

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Any AE that results in hospital admission of >24 hours or prolongs hospitalization should be documented 
and reported as an SAE unless specifically instructed otherwise in this protocol. There are some 
hospitalization scenarios that do not require reporting as an SAE when there is no occurrence of an AE.
9.7SAFETY REPORTING TO AMGEN
The Sponsor/Investigator is responsible for compliance with expedited reporting requirements for 
serious, unexpected and related adverse events (SUSARs), for generation of SAE reports including 
narratives, and for periodic reporting to Amgen of SAEs as outlined in Table 9.7.1 and Table 9.7.2 below. 
Individual safety reports (Table 9.7.1) should be accompanied by the Safety Fax Cover Form and sent to 
Amgen Global Safety, utilizing the fax or email information provided on the cover page. Aggregate safety 
reporting (Table 9.7.2) including listings, tabulations and summary reports should be scanned and 
accompanied by the Data Reconciliation Fax Cover Form, and sent to Amgen NASCR, utilizing the email 
information provided on the cover page.
Table 9.7.1. Expedited Reporting Requirements for Interventional Studies
Safety Data
Timeframe for Submission to Amgen
Suspected Unexpected Serious Adverse Reaction 
(SUSARs)
Individual reports sent to Amgen at time of 
expedited reporting to IRB and/or FDA.
Pregnancy/Lactation
Individual reports sent within 10 calendar days of 
Sponsor/Investigator awareness.
Individual reports should be faxed to 
 or scanned and sent via email to
Table 9.7.2. Aggregate Reports
Safety Data
Timeframe for submission to Amgen
US IND Annual Safety Report
Annually
Other Aggregate Analyses
(any report containing safety data generated 
during the course of a study)
At time of ISS sponsor submission to any body 
governing research conduct (eg, FDA, IRB, etc)

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Final (End of Study Report), including:
Unblinding data for blinded studies
Reports of unauthorized use of a 
marketed product
At time of ISS sponsor submission to any body 
governing research conduct (eg, FDA, IRB, etc) but 
not 
later than 1 calendar year of study completion
Aggregate reports should be submitted via email to the Amgen NASCR manager, accompanied by the Data 
Reconciliation Fax Cover Form
10CL 
INI CAL D ATA COL L E C TION
10.1 AMENDMENTS TO THE PR OTOCOL
Amendments to the protocol shall be planned, documented, and signature authorized prior to 
implementation.
All amendments require review and approval of the Principal Investigator. The written amendment must 
be submitted to the IRB at the investigator’s facility for the board’s approval.
Amendments specifically involving change to study design, risk to patient, increase to dosing or exposure, 
patient number 
increase, addition or removal of new tests or procedures, shall be reviewed and approved 
by the IRB.
The amendment will be submitted formally to the FDA or other regulatory authorities by the investigator 
as applicable, and specifically when an increase to dosing or patient exposure and/or patient number has 
been proposed; or, when the addition or removal of an Investigator is necessitated.
10.2FINANCIAL DISCLOSURE S AND ETHICAL CONSIDERATIONS
This study will be conducted according to the standards of Good Clinical Practice outlined in the ICH E6 
Tripartite Guideline and CFR Title 21 part 312, applicable government regulations, institutional research 
policies and procedures and any other local applicable regulatory requirement(s).
10.3IRB AND REGULATORY APPROVAL
The study protocol, ICF, IB, available safety information, patient documents, patient recruitment 
procedures, information about payments and compensation available to the patients and documentation

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evidencing the PI’s qualifications must be submitted to the IRB for ethical review and approval prior to 
the study start and in accordance with institutional guidelines.
The PI/Sponsor and/or designee will follow all necessary regulations to ensure initial and ongoing, IRB 
study review. The PI must submit and, when necessary, obtain approval from the IRB for all subsequent 
protocol amendments and changes to the informed consent document. Investigators will be advised by 
the sponsor or designee whether an amendment 
is considered substantial or non-substantial and whether 
it requires submission for approval or notification only to an IRB. Sites must follow institutional IRB 
guidelines for submission requirements.
If applicable, the PI will notify the IRB within 90 days of the end of the study, or if the study terminates 
early, the PI must notify the IRB within 15 days of the termination. A reason for the early termination must 
be provided (as defined in Directive 2001/20/EC).
10.4INFORMED CONSENT
Informed consent is a process by which a patient voluntarily confirms his or her willingness to participate 
in a particular study, after having been informed of all aspects of the study that are relevant to the 
patient's decision to participate. Informed consent is documented by means of a written, signed, and 
dated informed consent form.
The ICF will be submitted for approval to the IRB that is responsible for review and approval of the study. 
Each consent form must include all of the relevant elements currently required by the responsible 
regulatory authority, as well as local county authority or state regulations and national requirements.
Before recruitment and enrollment into the study, each prospective candidate will be given a full 
explanation of the study. Once the essential information has been provided to the prospective candidate, 
and the investigator is sure that the individual candidate understands the implications of participating in 
this study, the candidate will be asked to give consent to participate in the study by signing an informed 
consent form. A notation that written informed consent has been obtained will be made in the patient’s 
medical record. A copy of the informed consent form, to include the patient’s signature, will be provided 
by the investigator to the patient.
If an amendment to the protocol substantially alters the study design or the potential risks to the patients, 
the patient’s consent to continue participation in the study must be obtained.
10.5 CONFIDENTIALITY
Confidentiality of patient’s personal data will be protected in accordance with the Health Insurance 
Portability and Accountability Act of 1996 (HIPAA), and national data protection laws. HIPAA regulations 
require that, in order to participate in the study, a patient must sign an authorization from the study that 
he or she has been informed of following:

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What protected health information (PHI) will be collected from patients in this study;
Who will have access to that information and why;
Who will use or disclose that information;
That health information may be further disclosed by the recipients of the information, and that if 
the information is disclosed the information may no longer be protected by federal or state 
privacy laws;
The information collected about the research study will be kept separate from the patient’s 
medical records, but the patient will be able to obtain the research records after the conclusion 
of the study;
Whether the authorization contains an expiration date; and
The rights of a research patient to revoke his or her authorization. In the event that a patient 
revokes authorization to collect or use his or her PHI, the investigator, by regulation, retains the 
ability to use all 
information collected prior to the revocation of patient authorization. For patients 
that have revoked authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at 
least vital status (i.e., that the patient 
is alive) at the end of their scheduled 
study period. In compliance with ICH GCP guidelines and applicable parts of 21 CFR it is a 
requirement that the investigator and institution permit authorized representatives of the 
Sponsor, the regulatory authorities and the IRB direct access to review the patient’s original 
medical records at the site for verification of study-related procedures and data.
Measures to protect confidentiality include: only a unique study number and initials will identify patients 
on the CRF or other documents submitted to the Sponsor. This information, together with the patient’s 
date of birth, will be used in the database for patient identification. Patient names or addresses will not 
be entered 
in the CRF or database. No material bearing a patient’s name will be kept on file by the Sponsor. 
Patients will be informed of their rights within the ICF.
10.6STUDY DOCUMENTATION AND STORAGE
The PI must maintain a list of appropriately qualified persons to whom he/she has delegated study duties 
and should ensure that all persons assisting in the conduct of the study are informed of their obligations. 
All persons authorized to make entries and/or corrections on the CRFs are to be included on this 
document. All entries in the patient’s CRF are to be supported by source documentation where 
appropriate. Source documents are the original documents, data, records and certified copies of original 
records of clinical findings, observations and activities from which the patient’s CRF data are obtained. 
These can include, but are not limited to, hospital records, clinical and office charts, laboratory, medico- 
technical department and pharmacy records, diaries, microfiches, EKG traces, copies or transcriptions 
certified after verification as being accurate and complete, photographic negatives, microfilm or magnetic 
media, X-rays, and correspondence.
The PI and study staff are responsible for maintaining a comprehensive and centralized filing system (Site 
Study File/SSF or ISF) of all study-related (essential) documentation, suitable for 
inspection at any time by

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representatives from the Sponsor and/or applicable regulatory authorities. The ISF/SSF must consist of 
those documents that individually or collectively permit evaluation of the conduct of the study and the 
quality of the data produced. The ISF/SSF should contain as a minimum all relevant documents and 
correspondence, including key documents such as the IB and any amendments, protocol and any 
amendments, signed ICFs, IRB approval documents, Financial Disclosure forms, patient identification lists, 
enrollment logs, delegation of authority log, staff qualification documents, laboratory normal ranges, 
records relating to the study drug including accountability records. Drug accountability records should, at 
a minimum, contain information regarding receipt, shipment, and disposition. Each form of drug 
accountability record, at a minimum, should contain PI name, date drug shipped/received, date, quantity 
and batch/code, or lot number for identity of each shipment. In addition, all original source documents 
supporting entries in the CRF must be maintained and be readily available.
The IRB shall maintain adequate documentation / records of IRB activities for at least 3 years after 
completion of the research.
The Investigator shall maintain adequate records of drug disposition, case histories and any other study- 
related records for no less than 2 years after the last marketing application has been approved by FDA; 
or, in the event that the marketing application has not been approved by FDA, for no less than 2 years 
after the last shipment / delivery of the drug for investigational use is discontinued and FDA has been 
notified of the discontinuation.
To enable evaluations and/or audits from regulatory authorities or from the Sponsor or 
its representative, 
the investigator additionally agrees to keep records, including the identity of all participating patients 
(sufficient information to link records e.g., medical records), all original, signed informed consent forms, 
and copies of all CRFs, SAE Reporting forms, source documents, detailed records of treatment disposition, 
and related essential regulatory documents. The documents listed above must be retained by the 
investigator for as long as needed to comply with national and 
international regulations (generally 2 years 
after discontinuing clinical development or after the last marketing approval). The Sponsor or its 
representative will notify the investigator(s)/institutions(s) when the study-related records are no longer 
required.
10.7 DATA COLLECTION AND SAFETY
The study CRF is the primary data collection instrument for the study. An electronic case report form will 
be utilized for the collection of all data and all data will be entered into the RedCap database using the 
English language and should be kept current to enable review of the patients’ status throughout the 
course of the study.
In order to maintain confidentiality, only study number, patient number, initials, and date of birth will 
identify the patient in the CRF. If the patient’s name appears on any other document (e.g. laboratory 
report), it must be obliterated on the copy of the document to be supplied to the investigator site and 
replaced instead with the patient number and patient’s initials. The investigator will maintain a personal 
patient 
identification 
list (patient numbers with corresponding patient 
identifiers) to enable records to be

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identified and verified as authentic. Patient data/information will be kept confidential, and will be 
managed according to applicable local, state, and federal regulations.
The University of Rochester Data and Safety Monitoring Committee (DSMC) will be the data safety 
monitoring committee of record for the conduction of this study. Please refer to the Wilmot Cancer 
Institute (WCI) University of Rochester Policy and Procedures for Data and Safety Monitor document for 
details.
10.8PUBLICATION POLICY
All information provided regarding the study, as well as all information collected/documented during 
the 
course of the study, will be regarded as confidential.
A clinical study report will be prepared upon completion of the study. The PI will disclose the study results, 
in the form of a clinical study report synopsis, to the applicable regulatory authorities within one year of 
the end of the study.
11P L ANNED CORREL ATIV E ANAL Y SES
At URMC, peripheral blood will be collected from fasting patients within 30 days of the first treatment and 
at the end of treatment at the times of a regularly scheduled blood draw. The second morning void will 
be collected for assessment of uNTx measurements via immunoassay at the time of a regularly scheduled 
lab collection. These assays will include measurement of sRANKL, sCTx, NOTCH signals, sclerostin, DKK1, 
MIP-1α, and OPG via enzyme-linked immunosorbent assay (ELISA). These specimens will be collected, 
processed and analyzed by the Lipe laboratory as below.
Peripheral blood:
1. 10 mL of Whole blood will be collected in 2 green top tubes
2. Centrifuge at 1800xg for 30 minutes in a swing bucket centrifuge (not a fixed angle) within 24 
hours of collection
3. 10mL of Whole blood will be collected in 2 red top tubes
4. Blood will be allowed to clot prior to centrifugation at 4000 x g for 10 minutes
5. Blood will be stored at -80 degrees centigrade until analysis 
Bone marrow:
1. 40mL of Bone marrow aspirate will be collected first in 2 Sodium Heparin (green top with 10mL
each) and then 2 lavender top collection tubes (10mL each).
a. Samples will undergo Ficoll separation for the collection of mononuclear cells. 
Mononuclear cells will be grown and analyzed in the Lipe laboratory.
2. Bone marrow samples will be collected and processed in the Lipe 
laboratory.

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12
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induce apoptosis 
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Sanfilippo, K.M., et al., Comparative effectiveness on survival of zoledronic acid versus 
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Morgan, G.J., et al., Effects of zoledronic acid versus clodronic acid on skeletal morbidity 
in patients 
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Dunford, J.E., et al., Structure-activity relationships for 
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Berenson, J.R., et al., Zoledronic acid markedly improves bone mineral density for patients with 
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Musto, P., et al., A multicenter, randomized clinical trial comparing zoledronic acid versus 
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D'Arena, G., et al., Pamidronate versus observation in asymptomatic myeloma: final results with 
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Drake, M.T., Unveiling Skeletal Fragility in Patients Diagnosed with MGUS: No Longer a Condition 
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Qiang, Y.-W., et al., Dkk1 blocks Wnt-induced osteoprotegerin production 
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in multiple myeloma. Cancer Research, 2007. 67(9 Supplement): p. 2050-2050.
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Mabille, C., et al., DKK1 and sclerostin are early markers of relapse in multiple myeloma. Bone, 
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challenges for therapeutic intervention. Blood Rev, 2013. 27(6): p. 261-7.
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Colombo, M., et al., Notch-directed microenvironment reprogramming in myeloma: a single path 
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Fowler, J.A., et al., Bone marrow stromal cells create a permissive microenvironment for myeloma 
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Lamy, O., et al., Severe Rebound-Associated Vertebral Fractures After Denosumab 
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Raje, N., et al., Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed 
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Kostenuik, P.J., et al., Denosumab, a fully human monoclonal antibody to RANKL, inhibits bone 
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Masarachia, P., et al., Comparison of the distribution of 3H-alendronate and 3H-etidronate in rat 
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McClung, M.R., Inhibition of RANKL as a treatment for osteoporosis: preclinical and early clinical 
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Brown, J.P., et al., Comparison of the effect of denosumab and alendronate on BMD and 
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Kendler, D.L., et al., Effects of denosumab on bone mineral density and bone turnover in 
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Henry, D.H., et al., Randomized, Double-Blind Study of Denosumab Versus Zoledronic Acid in the 
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Perez-Persona, E., et al., New criteria to identify risk of progression in monoclonal gammopathy of 
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60. 
 Updated risk stratification model for smoldering multiple myeloma (SMM) incorporating the revised 
IMWG diagnostic criteria.  Jesus San Miguel, Maria-Victoria Mateos, Veronica Gonzalez, Meletios A. 
Dimopoulos, Efstathios Kastritis, Roman Hajek, Carlos Fernández de Larrea Rodríguez, Gareth John 
Morgan, Giampaolo Merlini, Silvia Mangiacavalli, Hartmut Goldschmidt, Michele Cavo, Charalampia 
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and Shaji Kumar. Journal of Clinical Oncology 2019 37:15_suppl, 8000-8000

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13APPENDIX A : IMWG RESPONSE CRIT ERIA
INTERNATIONAL MYELOMA WORKING GROUP (IMWG) UNIFORM RESPONSE CRITERIA FOR MULTIPLE MYELOMA
Response
IMWG criteria
sCR
CR as defined below plus normal FLC ratio and absence of clonal cells in 
bone marrow3 by immunohistochemistry or immunofluorescence4
CR
Negative immunofixation on the serum and urine and disappearance of any 
soft tissue plasmacytomas and < 5% plasma cells in bone marrow3
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/24 h
> 50% reduction of serum M-protein and reduction in 24 hours urinary M-
protein by >90% or to < 200 mg/24 h
If the serum and urine M-protein are unmeasurable,⁵ 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 not measurable, and serum free 
light assay 
is also not measureable, > 50% reduction in plasma cells is required in place 
of M- protein, provided baseline bone marrow plasma cell percentage was
> 30%
PR
In addition to the above listed criteria, if present at baseline, a > 50% 
reduction in the size of soft tissue plasmacytomas is also required
MR
NA
No change/Stable disease
Not meeting criteria for CR, VGPR, PR, or progressive disease
Plateau
NA

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Progressive Disease⁵
Increase of > 25% from lowest response value in any one or more of the 
following:
Serum M-component and/or (the absolute increase must be >0.5 g/dL)⁶ 
Urine M-component and/or (the absolute increase must be > 200 mg/24 h)
Only in patients without measurable serum and urine M-protein levels; the 
difference between involved and uninvolved FLC levels. The absolute 
increase must be > 10 mg/dL
Bone marrow plasma cell percentage; the absolute percentage must be > 
10%⁷
Definite development of new bone lesions or soft tissue plasmacytomas or 
definite increase in the size of existing bone lesions or soft tissue 
plasmacytomas
Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL or
2.65 mmol/L) that can be attributed solely to the plasma cell proliferative 
disorder
Relapse
Clinical relapse requires one or more of:
Direct indicators of increasing disease and/or end organ dysfunction (CRAB 
features).⁶ It 
is not used 
in calculation of time to progression or progression- 
free survival but is 
listed as something that can be reported optionally or for 
use in clinical practice
Development of new soft tissue plasmacytomas or bone lesions
Definite increase in the size of existing plasmacytomas or bone lesions. A 
definite increase is defined as a 50% (and at least 1 cm) increase as 
measured
serially by the sum of the products of the cross-diameters of the measurable 
lesion

Hypercalcemia (> 11.5 mg/dL) [2.65 mmol/L] Decrease in hemoglobin of > 2 
g/dL [1.25 mmol/L]
Rise in serum creatinine by 2 mg/dL or more [177 mmol/L or more]
Relapse from CR5 (To be used 
only if the end point studied is 
DFS)8
Any one or more of the following:
Reappearance of serum or urine M-protein by immunofixation or 
electrophoresis
Development of > 5% plasma cells in the bone marrow7
Appearance of any other sign of progression (i.e., new plasmacytomas, lytic 
bone lesion, or hypercalcemia)
1 BGM Durie et al. International uniform response criteria for multiple myeloma. Leukemia (2006) 1-7.
Adapted from Durie BGM, et al. Leukemia 2006; 20: 1467-1473; and Kyle RA, Rajkumar SV. Leukemia 2008;23:3-9.
Note: A clarification to IMWG criteria for coding CR and VGPR in patients in whom the only measurable disease is 
by serum FLC 
levels: CR 
in such patients 
is defined as a normal FLC ratio of 0.26–1.65 
in addition to CR criteria 
listed 
above. VGPR in such patients is defined as a >90% decrease in the difference between involved and uninvolved 
free light chain (FLC) levels.
3 Confirmation with repeat bone marrow biopsy not needed.
4 Presence/absence of clonal cells is based upon the kappa/lambda ratio. An abnormal kappa/lambda ratio by 
immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells for analysis. An 
abnormal ratio reflecting presence of an abnormal clone is kappa/lambda of > 4:1 or < 1:2.
5 All relapse categories require two consecutive assessments made at any time before classification as relapse or 
disease progression and/or the institution of any new therapy. In the IMWG criteria, CR patients must also meet 
the criteria for progressive disease shown here to be classified as progressive disease for the purposes of 
calculating time to progression and progression-free survival. The definitions of relapse, clinical relapse and relapse 
from CR are not to be used in calculation of time to progression or progression-free survival.
6 For progressive disease, serum M-component increases of >1 gm/dL are sufficient to define relapse if starting M- 
component is >5 g/dL.
7 Relapse from CR has the 5% cut-off versus 10% for other categories of relapse.
8 For purposes of calculating time to progression and progression-free survival, CR patients should also be 
evaluated using criteria listed above for progressive disease.
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14APPENDIX B: ABBREVIA TIONS
Abbreviation
Unabbreviated
AE
Adverse events
BMPC
Bone marrow plasma cell
Cbc
Complete blood chemistry
Cmp
Comprehensive metabolic profile
Cr
Creatinine
CR
Complete response
CRF
Case report form
CRF
Case report form
CTCAE
Common Terminology Criteria for Adverse 
Events
DKK1
Dickkopf-related protein 1
dL
Deciliter
DR
Downgrade rate
DSMC
Data safety monitoring committee
DXA
Dual energy x-ray abrorptiometry scan
FLC
Free light chain
G
Gram
HIV
Human immunodeficiency virus
IFE
Immunofixation
IMWG
International myeloma working group
IQR
Interquartile range
kDa
kilodaltons
L
liter
M
monoclonal

Mg
Milligram
MGUS
Monoclonal gammopathy of undetermined 
significance
MM
Multiple myeloma
Mmol
millimoles
Ng
Nanograms
ONJ
Osteonecrosis of the jaw
OPG
osteoprotegrin
PFS
Progression free survival
PS
Performance status
Q4w
Every 4 weeks
RANK
Receptor activator of nuclear factor kappa-B
RANKL
Receptor activator of nuclear factor kappa-B 
ligand
SAE
Serious adverse events
SC
subcutaneous
sCR
Stringent complete response
SMM
Smoldering multiple myeloma
SPEP
Serum protein electrophoresis
SRE
Skeletal related events
SUSAR
suspected unexpected serious adverse 
reaction
ULN
Upper limit of normal
uNTx
Urinary N-telopeptide
UPEP
Urine protein electrophoresis
.