Smoldering Myeloma High-Risk Patient Observation and Longitudinal Insight Trial
Conditions: Smoldering Multiple Myeloma
Sponsor: University of Utah

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Protocol name: Smoldering myeloma High-Risk Patient Observation Longitudinal Insight Trial 
Version date: 30OCT2024  
Principal Investigator: Dr. Ghulam Mohyuddin 
 
 
 
 
 
SPOTLIGHT: Smoldering myeloma 
High-risk Patient Observation and 
Longitudinal Insight Trial 
 
 
Principal Investigator 
Ghulam Rehman Mohyuddin, MD 
Assistant Professor, Division of Hematology, 
Huntsman Cancer Institute 
1950 Circle of Hope Drive 
Salt Lake City, Utah, 84093 
Email: g.mohyuddin@hci.utah.edu 
(801) 585-6387 
Sponsor 
Huntsman Cancer Institute 
Coordinating Center 
Huntsman Cancer Institute 
2000 Circle of Hope 
Salt Lake City, UT 84112 
Email: spotlight@hci.utah.edu 
HCI IRB number 
170107 
Protocol Version 
Version 1: 30NOV2023 
Version 2: 19MAR2024 
Version 3: 30OCT2024 

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Protocol name: Smoldering myeloma High-Risk Patient Observation Longitudinal Insight Trial 
Version date: 30OCT2024  
Principal Investigator: Dr. Ghulam Mohyuddin 
 
 
DOCUMENT HISTORY 
 
Document 
Date 
Overall Rationale 
Original Protocol 
30NOV2023 
Not applicable 
Amendment 1 
19MAR2024 
Protocol clarifications   
Amendment 2 
30OCT2024 
Schedule of Events 
Clarifications 

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Protocol name: Smoldering myeloma High-Risk Patient Observation Longitudinal Insight Trial 
Version date: 30OCT2024  
Principal Investigator: Dr. Ghulam Mohyuddin 
 
 
Table of Contents
Table of Contents 
DOCUMENT HISTORY ................................................................................................................ 2 
STATEMENT OF COMPLIANCE ................................................................................................. 6 
PROTOCOL SIGNATURE ........................................................................................................... 7 
ABBREVIATIONS ........................................................................................................................ 8 
1 
PROTOCOL SUMMARY..................................................................................................... 11 
1.1 Synopsis ............................................................................................................................................... 11 
Schema ......................................................................................................................................................... 14 
Schedule of Events ..................................................................................................................................... 15 
2 
OBJECTIVES AND ENDPOINTS ....................................................................................... 16 
2.1 Primary Objective ................................................................................................................................ 16 
2.2 Secondary Objective ........................................................................................................................... 16 
3 
BACKGROUND AND RATIONALE .................................................................................... 16 
3.1 Patient Population Background ......................................................................................................... 16 
4 
STUDY DESIGN ................................................................................................................. 18 
4.1 Description ........................................................................................................................................... 18 
4.2 Study Duration ..................................................................................................................................... 19 
4.3 End of Study ........................................................................................................................................ 19 
5 
STUDY POPULATION ........................................................................................................ 20 
5.1 Inclusion Criteria ................................................................................................................................. 20 
5.2 Exclusion Criteria ................................................................................................................................ 21 
5.3 Screen Failures .................................................................................................................................... 22 

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Protocol name: Smoldering myeloma High-Risk Patient Observation Longitudinal Insight Trial 
Version date: 30OCT2024  
Principal Investigator: Dr. Ghulam Mohyuddin 
 
 
5.4 Strategies for Recruitment .................................................................................................................. 22 
5.4.1 
Number of Subjects ..................................................................................................................... 22 
6 
STUDY PLAN ..................................................................................................................... 22 
6.1 Duration of Study ................................................................................................................................. 22 
6.1.1 
Criteria for the Discontinuation of Study .................................................................................. 22 
6.1.2 
Withdrawal of consent ................................................................................................................ 23 
 
Lost to Follow-Up ..................................................................................................................... 23 
7 
STUDY ASSESSMENTS .................................................................................................... 23 
7.1 General Assessments ......................................................................................................................... 23 
7.2 PROMIS-29 v. 2.1 ................................................................................................................................. 24 
7.3 Chart Review and Morbid Event Assessment .................................................................................. 24 
7.3.1 
Criteria for Progression to MM and Nuances of Assessment ................................................. 25 
7.3.2 
Criteria for Morbid Progression Events .................................................................................... 27 
7.3.3 
Use of PET/CT as alternative to MRI .......................................................................................... 27 
7.4 Remote Visits/Telehealth .................................................................................................................... 27 
8 
STATISTICAL CONSIDERATIONS .................................................................................... 27 
8.1 Sample size determination ................................................................................................................. 27 
8.2 Primary Endpoint ................................................................................................................................. 28 
8.3 Secondary Endpoints .......................................................................................................................... 28 
9 
ETHICAL AND REGULATORY CONSIDERATIONS .......................................................... 28 
9.1 Informed Consent ................................................................................................................................ 28 
9.2 Human Subjects Protection ................................................................................................................ 28 
9.2.1 
Personal Data Protection ............................................................................................................ 29 
9.3 Institutional Review ............................................................................................................................. 29 
9.4 Investigator Responsibilities .............................................................................................................. 29 
9.5 Protocol Amendments ........................................................................................................................ 29 
9.6 Protocol Deviations ............................................................................................................................. 29 
10 
DATA HANDLING ....................................................................................................... 30 
10.1 Recording and Collection of Data ...................................................................................................... 30 

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Protocol name: Smoldering myeloma High-Risk Patient Observation Longitudinal Insight Trial 
Version date: 30OCT2024  
Principal Investigator: Dr. Ghulam Mohyuddin 
 
 
10.2 Data Management ................................................................................................................................ 30 
10.3 Clinical Trials Data Bank ..................................................................................................................... 30 
11 
PUBLICATION PLAN .................................................................................................. 30 
12 
REFERENCES ............................................................................................................. 31 
 

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Protocol name: Smoldering myeloma High-Risk Patient Observation Longitudinal Insight Trial 
Version date: 30OCT2024  
Principal Investigator: Dr. Ghulam Mohyuddin 
 
 
STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with International Conference on Harmonization Good 
Clinical Practice (ICH GCP), applicable United States (US) Code of Federal Regulations (CFR). 
The Principal Investigator will assure that no deviation from, or changes to the protocol will take 
place without prior agreement from the Investigational New Drug (IND) or Investigational Device 
Exemption (IDE) sponsor, funding agency and documented approval from the Institutional 
Review Board (IRB), except where necessary to eliminate an immediate hazard(s) to the trial 
participants. All personnel involved in the conduct of this study have completed Human Subjects 
Protection and ICH GCP Training. 
The protocol, Informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
form must be obtained before any participant is enrolled. Any amendment to the protocol will 
require review and approval by the IRB before the changes are implemented to the study. All 
changes to the consent form will be IRB approved; a determination will be made regarding 
whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form. 

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Protocol name: Smoldering myeloma High-Risk Patient Observation Longitudinal Insight Trial 
Version date: 30OCT2024  
Principal Investigator: Dr. Ghulam Mohyuddin 
 
 
PROTOCOL SIGNATURE 
I confirm that I have read this protocol, and I will conduct the study as outlined herein and 
according to the ethical principles stated in the latest version of the Declaration of Helsinki, the 
applicable ICH guidelines for good clinical practice, and the applicable laws and regulations of the 
federal government. I will promptly submit the protocol to the IRB for review and approval. Once 
the protocol has been approved by the IRB, I understand that any modifications made during the 
study must first be approved by the IRB prior to implementation except when such modification is 
made to remove an immediate hazard to the subject. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study. I will discuss this material with them to ensure that 
they are fully informed regarding the study treatment, the conduct of the study, and the obligations 
of confidentiality. 
This document is signed electronically through submission and approval by the Principal 
Investigator at Huntsman Cancer Institute in the University of Utah IRB Electronic Research 
Integrity and Compliance Administration (ERICA) system. For this reason, the Principal 
Investigator at Huntsman Cancer Institute will not have a hand-written signature on this signature 
page. 
 
 
 
 
 
 
Signature of Principal Investigator 
Date 
 
 
 
 
 
 
Principal Investigator Name (Print) 
 
 
 
 
 
 
 
 
 
 
 

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Protocol name: Smoldering myeloma High-Risk Patient Observation Longitudinal Insight Trial 
Version date: 30OCT2024  
Principal Investigator: Dr. Ghulam Mohyuddin 
 
 
ABBREVIATIONS 
 
Abbreviation 
Definition/Explanation 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase 
AV 
Atrioventricular 
BCVA 
Best-corrected distance visual acuity 
BICR 
Blinded Independent Central Review 
β-HCG 
Beta-human chorionic gonadotropin 
BID 
Twice daily 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CHF 
Congestive heart failure 
CI 
Confidence interval 
CLIA 
Clinical Laboratory Improvement Amendments 
CLcr 
Creatinine clearance 
Cmax 
Maximum observed concentration 
Cmin 
Trough observed concentration 
CMP 
Comprehensive metabolic panel 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
ctDNA 
Circulating tumor DNA 
CYP 
Cytochrome P450 
CQ 
Chloroquine 
DILI 
Drug-Induced Liver Injury 

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Protocol name: Smoldering myeloma High-Risk Patient Observation Longitudinal Insight Trial 
Version date: 30OCT2024  
Principal Investigator: Dr. Ghulam Mohyuddin 
 
 
 
Abbreviation 
Definition/Explanation 
DoR 
Duration of Response 
DSMB 
Data Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
Eg 
Exempli Gratia (for example) 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GGT 
Gamma-glutamyltransferase 
GI 
Gastrointestinal 
GMP 
Good Manufacturing Practice 
hBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
i.e. 
Id est (that is) 
IEC 
Independent ethics committee 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional review board 
LDH 
Lactate dehydrogenase 
MRI 
Magnetic resonance imaging 
NIH 
National Institute of Health 
PD 
Pharmacodynamic(s) 
PDAC 
Pancreatic Ductal Adenocarcinoma 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetic(s) 
PO 
Per os (administered by mouth) 
PR 
Partial response 

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Protocol name: Smoldering myeloma High-Risk Patient Observation Longitudinal Insight Trial 
Version date: 30OCT2024  
Principal Investigator: Dr. Ghulam Mohyuddin 
 
 
 
Abbreviation 
Definition/Explanation 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QTc 
QT interval corrected 
QTcF 
QT interval corrected using Fredericia equation 
RBC 
Red blood cell 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious adverse event 
SD 
Stable disease 
SD-OCT 
Spectral-domain ocular coherence tomography 
T1/2 
Terminal elimination half-life 
TdP 
Torsades de Pointes 
Tmax 
Time of maximum observed concentration 
ULN 
The upper limit of normal 
VF 
Visual field 
WBC 
White blood cell 

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Protocol name: Smoldering myeloma High-Risk Patient Observation Longitudinal Insight Trial 
Version date: 30OCT2024  
Principal Investigator: Dr. Ghulam Mohyuddin 
 
 
1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
 
Title: 
SPOTLIGHT: Smoldering myeloma High-risk Patient Observation 
and Longitudinal Insight Trial 
Protocol Short Title 
SPOTLIGHT 
Study Description: 
Single arm, prospective cohort, non-interventional study 
Objectives: 
Primary Objective: 
Ascertain the frequency and nature of progression events in a 
prospective cohort of patients with smoldering myeloma undergoing 
active surveillance with diffusion weighted whole body MRI. 
Secondary Objectives: 
To determine longitudinal Quality of Life as assessed by the 
PROMIS-29 instrument- physical function, pain interference, and 
anxiety at enrollment and every 6 months during this study 
Endpoints: 
Primary Endpoint: 
The primary endpoint is the cumulative incidence of morbid 
progression events at two years of follow-up (defined as death 
attributed to plasma cell dyscrasia, fracture attributed to plasma cell 
dyscrasia, lack of achievement of renal complete response defined 
as achievement of GFR≥ 60ml/min within 4 weeks in the event of 
new onset renal insufficiency attributable to plasma cell dyscrasia, 
lytic bone lesions, development of AL Amyloidosis or development of 
plasma cell leukemia). 
Secondary Endpoints: 
Change in the quality of life as measured by physical function, pain 
interference, and anxiety domains on the PROMIS-29, from baseline 
to the end of study at 24 months of follow-up. 
Study Population: 
Key Inclusion Criteria (see section 5. Study Population for additional 
criteria): 
• 
Diagnosis of High-Risk Smoldering Myeloma made within 
365 days of enrollment in the study. See section 5. Study 
Population for additional criteria.  

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Protocol name: Smoldering myeloma High-Risk Patient Observation Longitudinal Insight Trial 
Version date: 30OCT2024  
Principal Investigator: Dr. Ghulam Mohyuddin 
 
 
Key Exclusion Criteria (see section 5. Study Population for 
additional criteria): 
• 
Presence of any features that would meet diagnostic criteria 
for myeloma as per the IMWG Criteria  
• 
Presence of extramedullary plasmacytomas 

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Protocol name: Smoldering myeloma High-Risk Patient Observation Longitudinal Insight Trial 
Version date: 30OCT2024  
Principal Investigator: Dr. Ghulam Mohyuddin 
 
 
 
• 
Presence of any focal bone marrow lesions or lytic bone 
lesions on imaging done prior to screening or on 
screening 
Number of subjects: 
100 evaluable subjects 
Study Duration: 
5 years 
Participant Duration: 
2 years 
Enrollment Duration: 
 3 years 

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Protocol name: Smoldering myeloma High-Risk Patient Observation Longitudinal Insight Trial 
Version date: 30OCT2024 
Principal Investigator: Dr. Ghulam Mohyuddin 
 
 
 
Schema 
 
 

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Protocol name: Smoldering myeloma High-Risk Patient Observation Longitudinal Insight Trial 
Version date: 30OCT2024 
Principal Investigator: Dr. Ghulam Mohyuddin 
 
 
 
Schedule of Events 
 
Protocol Procedures1 
SCREENING 
Follow-Up Period 
(+/- 2 month) 
- 2 Months 
Month 6 
Month 12 
Month 18 
Month 24 
Progression 
Consent2 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Eligibility 
X 
 
 
 
 
 
PROMIS-29 v.2.13 
X 
X 
X 
X 
X 
X 
Chart Review and Morbid Event Assessment 
 
X 
X 
X 
X 
X 
Complete Blood Count (CBC) with Platelet Count, 
Differential 
Per SOC 
Per SOC 
 
Comprehensive Metabolic Panel (CMP) 
Per SOC 
Per SOC 
 
Urine 24 Hour Immunofixation/electrophoresis 
(recommended within 1 year prior to enrollment) 
Per SOC 
Per SOC 
 
Tumor Markers (serum monoclonal protein, serum 
kappa/lambda light chains, serum immunoglobulin levels. 
Recommended within 2 months prior to enrollment) 
Per SOC 
Per SOC 
Bone Marrow Biopsy (recommended within 6 months 
prior to enrollment) 
Per SOC 
Per SOC 
 
Diffusion weighted whole body MRI (recommended within 3 
months prior to enrollment) 
Per SOC 
Per SOC 
 
 
 
 
1 Standard of care assessments completed prior to enrollment, unless otherwise specified, should be used for screening.  
2 See Section 7.1.1. 
   3 Completion window is +/- 2 months for optional PROMIS-29 V.2.1. See section 4.1 for further details. 

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Protocol name: Smoldering myeloma High-Risk Patient Observation Longitudinal Insight Trial 
Version date: 30OCT2024 
Principal Investigator: Dr. Ghulam Mohyuddin 
 
 
2 
OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objective 
Ascertain the frequency and nature of progression events in a prospective cohort of patients 
with smoldering myeloma undergoing active surveillance with diffusion weighted whole body 
MRI. 
Primary Endpoint: The primary endpoint is the cumulative incidence of morbid progression 
events at two years of follow-up (defined as death attributed to plasma cell dyscrasia, fracture 
attributed to plasma cell dyscrasia, lack of achievement of renal complete response defined as 
achievement of GFR≥ 60ml/min within 4 weeks in the event of new onset renal insufficiency 
attributable to plasma cell dyscrasia, lytic bone lesions, development of AL Amyloidosis or 
development of plasma cell leukemia). 
2.2 
Secondary Objective 
To determine longitudinal Quality of Life as assessed by the PROMIS-29 instrument- physical 
function, pain interference, and anxiety at enrollment and every 6 months during this study. 
Secondary Endpoint: Change in the quality of life as measured by physical function, pain 
interference and anxiety domains on the PROMIS-29, from baseline to the end of study at 24 
months of follow-up. 
3 
BACKGROUND AND RATIONALE 
3.1 
Patient Population Background 
Smoldering myeloma (SMM) is a precursor stage of multiple myeloma (MM), which is a cancer of 
the plasma cells that is characterized by the accumulation of malignant plasma cells in the bone 
marrow, and characteristic features of end-organ damage referred to as the CRAB criteria 
(hypercalcemia, renal dysfunction, anemia and bone lytic lesions)4. SMM is associated with a 
higher risk of progression to multiple myeloma than monoclonal gammopathy of undetermined 
significance (MGUS)3 and is present in one in 200 individuals over the age of 405. Historically, the 
diagnosis of MM has required the presence of end-organ damage, however changes to diagnostic 
criteria in 2014 led to reclassification of some patients previously classified as ultra- high risk SMM 
as MM4. These included patients with more than one focal lesion on magnetic resonance imaging 
(MRI), bone marrow plasma cells more than 60%, and serum free light chain ratio more than 1004. 
These patients were estimated to have an 80% risk of progression to MM at 2 years from 
diagnosis and thus reclassified as MM based on this risk4. As such, external validity of trials that 
enrolled patients with SMM prior to 2014 remains uncertain. 
Historically, lytic lesions seen on a skeletal survey was part of the standard diagnostic workup for 
MM. However, a skeletal survey can miss up to 40% of lytic lesions that can be picked up by more 
advanced detection modalities such as whole-body diffusion weighted MRI (WB DW-MRI) or 
PET/CT6,7. Widespread usage of these modalities can thus lead to reclassification of patients to 
MM, who would have previously been diagnosed as SMM based on a negative skeletal survey. 
Numerous criteria exist today to stratify patients with SMM into different risk status. These models 
include the Spanish PETHEMA model that incorporates the ratio of plasma cells ≥95% with an 
atypical immunophenotype on flow cytometry of the bone marrow aspirate and the presence of 

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Protocol name: Smoldering myeloma High-Risk Patient Observation Longitudinal Insight Trial 
Version date: 30OCT2024 
Principal Investigator: Dr. Ghulam Mohyuddin 
 
 
serum immunoparesis8, the 2008 Mayo Clinic model that involves serum monoclonal protein ≥30 
g/l, BMPCs ≥10%, and an abnormal serum free light chain ratio [κ/λ] of either ≤0.125 or ≥8.09, the 
2018 Mayo Clinic (a M-spike greater than 2 g/dL, an involved/uninvolved free light chain ratio 
greater than 20, and bone marrow plasmacytosis greater than 20%) model3 and the most recent 
International Myeloma Working Group scoring model2. Unfortunately, these models have 
significant discordance with each other10. Furthermore, they also lack prospective validation in 
clinical trials. 
Although two trials have shown that early intervention with lenalidomide (with or without 
dexamethasone) can decrease the likelihood of progression for patients with high-risk SMM to 
MM11,12, these trials have important limitations that limit broad applicability to today’s landscape. 
The first trial by the Spanish Group began enrolling in 2007, well before the use of advanced 
imaging and diagnostic reclassification of ultra-high risk SMM and MM12. As such, a substantial 
proportion of participants in that trial would have MM today. Although an overall survival 
advantage was seen in this trial upon extended follow-up, most patients in the control arm did not 
receive lenalidomide (or other contemporary therapies) when they experienced disease 
progression, and this trial was not statistically powered for overall survival either13. 
The E3A06 trial comparing lenalidomide to observation also began enrolling prior to the 
reclassification of SMM to MM, although the diagnostic reclassification occurred during the trial 
period11. This trial demonstrated that there was a decreased risk of progression with early therapy 
with lenalidomide compared to observation, the exact nature of progression events was not clearly 
defined in these studies. It is thus unclear whether early treatment led to prevention of 
asymptomatic bone lesions picked up on imaging or whether actual fractures or irreversible end 
organ damage was prevented. Furthermore, this trial is not powered for, or has shown an overall 
survival difference either at latest follow-up, with approximately 70% of patients in the observation 
arm without evidence of disease progression at three years of follow-up. Thus, although it is 
known that treatment for high risk SMM comes with increased financial toxicity, side effects, and 
secondary malignancies- whether patients live longer or better with early intervention in the 
modern era is unknown. 
The most recent data on progression events for smoldering myeloma comes from the German 
group in their observational study of 96 patients14. Utilizing WB DW-MRI, they demonstrated that 
most progression events did not involve catastrophic end-organ damage. Out of a total of 22 
patients who progressed, three developed osteoporotic compression fractures, and in all three, 
moderate or severe diffuse infiltration was present on MRI before onset of fracture. Only one 
patient presented with worsening renal function as the progression feature14. However, this study 
was not designed a priori to ascertain how progression events happened, and this study did not 
limit enrollment to high-risk SMM. Also, the reversibility of events like anemia or renal damage 
was not described, and quality of life was not evaluated. Furthermore, while myeloma and 
precursor diseases disproportionately affect Blacks/African Americans, they remain under- 
represented in clinical trials, and further data is needed for this patient population in a prospective 
fashion. As risk stratification models have been devised from predominantly White populations, 
there is a need to prospectively ascertain the risk of progression in a contemporary diverse patient 
population. 
In summary, there is an unmet need for a rigorous prospective cohort study with an a priori defined 
threshold of detection of end-organ damage and longitudinal quality of life assessment to truly 

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Protocol name: Smoldering myeloma High-Risk Patient Observation Longitudinal Insight Trial 
Version date: 30OCT2024 
Principal Investigator: Dr. Ghulam Mohyuddin 
 
 
establish the natural history of smoldering myeloma in the modern era of advanced imaging, as 
well as demonstrate prospectively that patients with high-risk SMM can be safely observed. 
4 
STUDY DESIGN 
4.1 
Description 
This is a prospective, non-interventional study of a cohort of patients with high-risk smoldering 
myeloma (HR-SMM). 
We will conduct a prospective single-arm study of 100 evaluable patients with high-risk SMM. 
We hypothesize that the event probability of morbid progressions is less than 0.08 (in 8 or less 
enrolled patients) at two years of follow-up. 
Subjects enrolled in this prospective cohort study are expected to receive standard of care 
procedures as outlined below in section 4.1. As these procedures are considered non-research 
related, departure from the expected frequency will not be considered a protocol deviation. 
Standard of care assessments should be used for screening.  
In cases where follow-up assessments are completed outside of the expected timeframe, the 
study PI should be notified and an individual decision will be made on a case-by-case basis to 
keep patients on that study or consider them unevaluable. 
 
It is recommended, but not mandated that the following procedures be done prior to enrollment 
to the study.  
• 
A bone marrow biopsy within 6 months of enrollment 
• 
A diffusion weighted MRI within 3 months prior to enrollment 
• 
A 24-hour urine protein electrophoresis/immunofixation 1 year prior to enrollment 
• 
Serum myeloma assessment (electrophoresis/immunofixation and light chains within 2 
months of enrollment) 
• 
Routine blood work (complete blood count (CBC) and complete metabolic panel (CMP) 
within 2 prior of enrollment) 
 
                  If a patient has had the following procedures done outside the recommended 
window, they may still be enrolled on the trial, as long as they meet inclusion criteria, namely a 
diagnosis of high-risk smoldering myeloma within the past year. It is especially important to 
have a recent diffusion weighted MRI prior to enrollment (or PET for those who are 
claustrophobic and/or have a contraindication to MRI), as the presence of focal lesions on MRI 
precludes enrollment. For patients who have smoldering myeloma but have not yet undergone 
MRI, it is recommended that enrollment be delayed until after a baseline MRI is obtained and 
confirmed to show no focal lesions. 
 
 
All patients on the study are recommended to undergo the following standard of care 
surveillance protocol: 
• 
Complete Blood Count (CBC), Complete Metabolic Panel (CMP), myeloma blood tests 
(serum kappa/lambda light chains, monoclonal protein evaluation, immunoglobulin 

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Protocol name: Smoldering myeloma High-Risk Patient Observation Longitudinal Insight Trial 
Version date: 30OCT2024 
Principal Investigator: Dr. Ghulam Mohyuddin 
 
 
levels), to be done monthly for first year, and then every two months for the second year. 
• 
WB DW-MRIs every 6 months during the study period.  
• 
24-hour urine Immunofixation/electrophoresis is expected to be completed 
approximately every 6 months.  
• 
Bone marrow biopsy will be performed annually during the study time-period.  
The primary objective is the occurrence of morbid progression events defined in section 7.2.2. 
Chart review and assessment of morbid events will occur every 6 months during the follow-up 
period. Staff will document every 6 months and retroactively complete when progression 
occurred and how it occurred. A patient will be considered as having progressed to MM, if they 
meet criteria for progression to MM, as per the IMWG 2014 diagnostic criteria for myeloma.4 
Secondary endpoints will include longitudinal measurement of quality of life. This will be done at 
baseline and at 6, 12, 18, and 24 months using the optional PROMIS-29 questionnaire15. The 
domains of interest on the PROMIS-29 instrument would be physical function, pain interference, 
and anxiety. The PROMIS-29 instrument may be completed +/- 2 months for each time point. If 
a patient progresses to MM, the details of how their progression occurred will be recorded, they 
will be taken off the clinical study, the PROMIS-29 may be completed, and standard of care 
treatment at the local institution would be offered to them. 
4.2 
Study Duration 
5 years (3 years to enroll patients, two years of follow-up) 
 
4.3 
End of Study 
A subject is considered to have completed the study if he or she has completed all phases of 
the study including the last visit (two years of follow-up) or they experience disease progression 
to MM. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol name: Smoldering myeloma High-Risk Patient Observation Longitudinal Insight Trial 
Version date: 30OCT2024 
Principal Investigator: Dr. Ghulam Mohyuddin 
 
 
5 
STUDY POPULATION 
5.1 
Inclusion Criteria 
1.  
 Adult subject aged ≥ 18 years. 
2.  
Diagnosis of smoldering myeloma as per the IMWG criteria, specifically: 
• 
Serum monoclonal protein (IgG or IgA) of 30g/L or greater per 24 hours or 
urinary monoclonal protein of 500mg or greater per 24 hours 
and/or 
• 
Clonal bone marrow plasma cells 10-59% with the absence of myeloma-defining 
events or amyloidosis  
 
Percentage of clonal bone marrow  
 
plasma cells (if applicable) ________% 
Date bone marrow results 
(DD/MMM/YYYY):  
 
__________________________ 
 
3.  
 High-risk smoldering myeloma defined as two or more out of four of the following 
criteria: 
• 
M-spike greater than 2 g/dL 
• 
An involved/uninvolved free light chain ratio greater than 20 
• 
Bone marrow plasmacytosis greater than 20% 
• 
Presence of any of translocation (4;14), deletion 17p, deletion 13q or 1q gain by 
conventional cytogenetics/fluorescence in situ hybridization (FISH) studies)10 
and/or 
• 
 An IMWG SMM score of 9 or greater14 according to the IMWG risk model for 
smoldering multiple myeloma (SMM) 
 
4.     Diagnosis of high-risk SMM made within 365 days of enrollment in the study. 
Note: If a patient previously had MGUS or low/intermediate SMM- the date at which 
high-risk SMM was diagnosed would have to be within 365 days of enrollment in the 
study. 
 
 
 
 
        
 
 
_______________ Date of Diagnosis 
(DDMMMYYYY) 
 

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Protocol name: Smoldering myeloma High-Risk Patient Observation Longitudinal Insight Trial 
Version date: 30OCT2024 
Principal Investigator: Dr. Ghulam Mohyuddin 
 
 
5.2 
Exclusion Criteria 
1.  
 Presence of any features that would meet diagnostic criteria for myeloma as per 
the IMWG Criteria 
2.  
 Presence of extramedullary plasmacytomas 
3.  
 Presence of any focal bone marrow lesions, or lytic bone lesions on imaging done 
prior to screening or on screening. However, presence of diffuse or patchy infiltration of 
the marrow (without any clear lesions) on MRI, will not be an exclusion criteria. Patients 
with 1 focal marrow lesion on MRI that is attributable to plasma cell dyscrasia, will be 
excluded from study, even if they do not meet criteria for myeloma. 
4.  
 Creatinine clearance of less than 40ml/min. 
5.  
 Presence of AL Amyloidosis (the amount of workup necessary to exclude AL 
Amyloidosis is per the discretion of the treating investigator, however the investigator 
must attest that they do not believe AL Amyloidosis to be present at time of enrollment. 
Serum nt-PROBNP is recommended as part of evaluation in order to ascertain for 
cardiac amyloidosis). 
6.  
 Hemoglobin of less than 11g/dl, unless a clearly reversible reason for anemia is 
identified, at which point they can be rescreened in two months if Hgb is greater than 
11g/dl. 
 
Note: The Hgb cut-offs can vary between institutions (lower cut-off for Hgb University of 
Utah for men is a Hgb of 14.8, rendering a patient with Hgb of 12.7 as having a CRAB 
feature). If the Hgb is above 10g/dl but the patient meets the definition of anemia 
according to the IMWG criteria, by virtue of this being more than 2 g/dl below the limit of 
normal, the investigator can decide whether to call a patient being considered for 
screening as having multiple myeloma OR smoldering myeloma and allow enrollment on 
this study. 
 
I certify that this patient meets all inclusion and exclusion criteria for enrollment onto 
this study. 
 
 
 
Investigator Signature 
Date 
Time 
 
 
 
 
 
 
 
 
 
 
 

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Principal Investigator: Dr. Ghulam Mohyuddin 
 
 
5.3 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but do 
not meet subject eligibility criteria. These subjects will not be entered into the study or begin 
study intervention. However, minimal information is required to ensure transparent reporting of 
screen failure participants to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements. Minimal information includes, but may not be limited to, demography 
(including zip codes), screen failure details, eligibility criteria. Individuals who do not meet the 
criteria for participation in this trial (screen failure) may be rescreened at the Investigator’s 
discretion. 
5.4 
Strategies for Recruitment 
This trial allows for enrollment procedures to be done virtually. Participants are identified by their 
providers during clinic visits at HCI and/or  through referral by their local physician. Participants 
may also self-refer themselves to the study team. A brochure may also be utilized for promoting 
the study, as well as social media. Participants receiving care at HCI may also be identified 
through their participation in Total Cancer Care (IRB 89989). Demographic, name, date of birth, 
and medical record numbers, when possible, will be documented in the research database for 
potentially eligible patients to ensure the study approaches all eligible patients. This information 
will remain confidential and within the research database for patients who refuse participation in 
order for study staff to 1) ensure patients are not re-approached after refusal and 2) identify 
potential solutions to address refusals. Patients enrolled virtually will receive the consent or 
consent cover letter electronically via REDCap or mail. An email or paper template will be 
included (see documents for reference). 
Additionally, a recruitment letter may be sent to other oncologists with high-risk smoldering 
myeloma patients. Those providers could then refer potentially eligible patients to the study 
team at HCI. This study will be posted on clinicaltrials.gov. In situations where a patient 
contacts HCI to participate in the study, the patient will be encouraged to inform their provider of 
their interest. Staff may use the personalized dear doctor letter to facilitate communication with 
their provider after receiving approval from the participant to do so. After consent, the study 
staff will send the local physician a questionnaire regarding their typical routine monitoring 
schedule to confirm if his/her standard of care monitoring schedule is compatible with the MRI 
frequency outlined in the study protocol. The patient will no longer be considered if the MRI 
frequency is not compatible.  
5.4.1 Number of Subjects 
We plan to enroll 100 evaluable patients over approximately three years. 
 
6 
STUDY PLAN 
6.1 
Duration of Study 
Subjects will be consented, screened, and then followed for two years. 
 
6.1.1 Criteria for the Discontinuation of Study 
Subjects may withdraw from the study overall at any time at their request, or they may be 
withdrawn at the discretion of the Investigator or an oncologist/hematologist clinician. 
Subjects will be taken off study for the following: 

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Protocol name: Smoldering myeloma High-Risk Patient Observation Longitudinal Insight Trial 
Version date: 30OCT2024 
Principal Investigator: Dr. Ghulam Mohyuddin 
 
 
• 
Completed study follow-up period. 
• 
Participant or legally authorized representative requests to be fully withdrawn from the 
study. 
• 
If, in the investigators or oncologist/hematologist clinician opinion, the continuation of the 
study would be harmful to the subject's well-being. 
• 
The subject is lost to follow-up. 
• 
Screen failure. 
• 
Death. 
• 
Documented and confirmed progression to MM 
o Should worsening of kidney function be the sole reason for progression to MM, 
progression will not be confirmed until standard of care follow up has been 
performed for at least four additional weeks beyond initiation of MM treatment to 
ascertain reversibility of kidney dysfunction. 
6.1.2 Withdrawal of consent 
Subjects are free to withdraw from the study at any time without any prejudice. If a subject 
withdraws consent, they will be specifically asked if they are withdrawing consent to all further 
participation in the study including any further follow-up (e.g., survival contact telephone calls). 
Survival status may be obtained from public records for subjects who have withdrawn from any 
further follow-up contact. 
 Lost to Follow-Up 
Subjects will be considered lost to follow-up only if no contact has been established by the time 
the study is completed, such that there is insufficient information to determine the subject’s 
status at that time. Subjects who refuse to continue participation in the study, including 
telephone contact, should be documented as “withdrawal of consent” rather than “lost to follow- 
up.” Investigators should document attempts to re-establish contact with missing subjects 
throughout the study period. If contact with a missing subject is re-established, the subject 
should not be considered lost to follow-up and evaluations should resume according to the 
protocol. 
When a subject is lost to follow-up, site personnel should check hospital records, the subjects’ 
current physician, and a publicly available death registry to obtain a current survival status. 
In the event that the subject has actively withdrawn consent, the survival status of the subject 
can be obtained by site personnel from publicly available death records. 
7 
STUDY ASSESSMENTS 
Every effort should be made to ensure that the protocol-required procedures are completed as 
described. However, it is anticipated that there may be circumstances, outside of the control of 
the Investigator that may make it unfeasible to perform the test. In these cases, the Investigator 
will take all steps necessary to ensure the safety and well-being of the subject. When a protocol- 
required test cannot be performed, the Investigator will document the reason for this and any 
corrective and preventive actions that he or she has taken to ensure that normal processes are 
adhered to as soon as possible. 
7.1 
General Assessments 

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Version date: 30OCT2024 
Principal Investigator: Dr. Ghulam Mohyuddin 
 
 
 
7.1.1 Participant Consent 
As this is a non-interventional study there are minimal risks to being enrolled. However, all 
potential subjects or their legal representative must be fully informed of the risks and potential 
benefits of trial participation and demonstrate understanding. For patients not enrolled in Total 
Cancer Care (IRB 89989), an informed consent document must be signed and dated by the 
participant or their legal representative indicating that they understand the risks and consent to 
participation and treatment on the study. A copy of the signed document should be provided to 
the subject. 
Procedures, laboratory tests, or imaging performed as part of the standard of care prior to 
subject consent may contribute to the assessment of eligibility and/or screening procedures if 
performed during the screening period. Participants will also be asked to complete the NIH 
Demographic Form. 
 HCI Patients Enrolled in Total Cancer Care 
HCI patients who have previously consented to the Total Cancer Care protocol (IRB 89989) will 
be provided with a cover letter for this study if eligible. A Waiver of Informed Consent Request 
will be submitted for Total Cancer Care consented patients whose samples and data are 
utilized. This will reduce patient burden in filling out two separate consent forms. Individuals 
under this criteria will be considered consented once PROMIS questionnaire is completed per 
the cover letter. The PROMIS questionnaire is highly recommended, but not mandatory for 
enrollment. For potential patients that are unable/unwilling to complete the questionnaire, they 
will receive the cover letter consent, review the cover letter with study staff, and will be enrolled 
after their verbal agreement to participate in the study. Potential subjects who are not enrolled 
in Total Cancer Care will be provided with a study specific consent, if they wish to participate.  
7.2 
PROMIS-29 v. 2.1 
The optional PROMIS-29 questionnaire may be administered according to the time points 
indicated in the Study Calendar and if a participant progresses to MM. Administration may be 
completed either with pen and paper or electronically and is available in a variety of languages. 
Study staff may document participant responses on the participant’s behalf if the participant 
needs assistance to complete the form. Participants may be reminded by phone or email to 
complete the questionnaire. This questionnaire is strongly encouraged, but it will not be 
considered a deviation if the patient is unable or unwilling to complete the assessment. 
7.3 
Chart Review and Morbid Event Assessment 
Chart review and Morbid Event Assessment should occur at the time points indicated in the 
Study Calendar. The following items will be documented in REDCap and UBox and evaluated 
as possible morbid events: 
• 
Death attributed to plasma cell dyscrasia, 
• 
Fracture attributed to plasma cell dyscrasia, 
• 
Lack of achievement of renal complete response defined as achievement of GFR≥ 
60ml/min within 4 weeks in the event of new onset renal insufficiency attributable to 
plasma cell dyscrasia, 
• 
Lytic bone lesions, 
• 
Development of AL Amyloidosis 
• 
Development of plasma cell leukemia 

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Additionally, information pertaining to demographics, bone marrow biopsies, 24-hour urine, tumor 
markers, CMP, CBC, and MRI/PET results may be abstracted from the participants record. Electronic 
health record information will be stored in REDCap.  
 
7.3.1 Criteria for Progression to MM and Nuances of Assessment 
Specifically, for our study: Any of the following criteria will qualify as progression to MM. 
Note: Progression does not automatically qualify as an event towards primary endpoint of study. 
1) Evidence of end organ damage that can be attributed to the underlying plasma cell 
proliferative disorder, specifically: 
a) Hypercalcemia: serum calcium >0.25 mmol/L (>1mg/dL) higher than the upper limit 
of normal or >2.75 mmol/L (>11mg/dL) 
b) Renal insufficiency: creatinine clearance <40 mL per minute or serum creatinine 
>177mol/L (>2mg/dL) 
c) Anemia: hemoglobin value of >20g/L below the lowest limit of normal, or a 
hemoglobin value <100g/L. The Hb cut-offs can vary between institutions (lower cut- 
off for Hb University of Utah for men is a Hb of 14.8, rendering a patient with Hb of 
12.7 as having a CRAB feature). If the Hb is above 10g/dl but the patient meets the 
definition of anemia according to the IMWG criteria, by virtue of this being more than 
2 g/dl below the limit of normal, the investigator can decide whether to call a patient 
as having progressed to MM or still refer as SMM. 
d) Bone lesions: one or more osteolytic lesion on skeletal radiography, MRI, CT, or 
PET/CT. If bone marrow has <10% clonal plasma cells, more than one bone lesion is 
required to distinguish from solitary plasmacytoma with minimal marrow involvement 
NOTE: These lab findings have to be attributable to a plasma cell dyscrasia by the investigator 
in order to be considered as progression to MM, as there may be other reasons that can cause 
hypercalcemia, anemia and renal insufficiency etc. 
2) Any one or more of the following biomarkers of malignancy, or myeloma-defining events 
(MDEs): 
a) 60% or greater clonal plasma cells on bone marrow examination 
b) Serum involved / uninvolved free light chain ratio of 100 or greater, provided the 
absolute level of the involved light chain is at least 100mg/L (a patient's involved free 
light chain is the one that is produced by the aberrant plasma cells, and is the one 
that is typically higher than upper limit of normal, whereas the uninvolved light chain 
is made by normal plasma cells and typically falls in or below the normal range) 
c) More than one focal bone marrow lesion on MRI that is at least 5mm or greater in 
size. 
As documentation of the nature of progression is critical to primary endpoint ascertainment of 
our study, the characteristics of tumor progression will be clearly documented and recorded. 
With respect to MRI imaging, the following caveats must be noted. 
1) Development of “new” focal bone marrow lesions on an MRI will not be counted as a 
morbid progression event, but if there is more than one focal bone marrow lesion on an 
MRI that is at least 5mm or greater in size, this will be considered as progression to MM, 
and patients will be taken off the study. If only one focal bone marrow lesion on MRI 
develops, patients will not be considered as having progressed to MM, but a follow-up 
MRI in three months may be considered as per standard of care per the investigator’s 
discretion. Patients progressing with new focal lesions on MRI should have a CT or 

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Protocol name: Smoldering myeloma High-Risk Patient Observation Longitudinal Insight Trial 
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Principal Investigator: Dr. Ghulam Mohyuddin 
 
 
PET/CT as per investigators discretion to evaluate for lytic lesions definitively. 
2) Development of “diffuse or focal bone marrow infiltration” on MRI will not be counted as 
a progression event to MM, or as a morbid progression event. 
Development of new ‘lytic” bone lesions on MRI or any other form of imaging will be counted as 
a morbid progression event, and patient will be taken off the study. Patients progressing with 
new focal lesions on MRI should have a CT or PET/CT as per investigators discretion to 
evaluate for lytic lesions definitively. 
Anemia considerations may require assessment by the investigator, as the Hgb cut-offs can 
vary between institutions (lower cut-off for Hgb University of Utah for men is a Hgb of 14.8, 
rendering a patient with Hgb of 12.7 as having a CRAB feature). If the Hgb is above 10g/dl but 
the patient meets the definition of anemia according to the IMWG criteria, by virtue of this being 
more than 2 g/dl below the limit of normal, the investigator can decide whether to call a patient 
as having progressed to MM, or still be considered as SMM. 
If an indication develops for plasma cell directed therapy (such as development of myeloma), 
the decision to pursue such therapy will be done as per the treating physicians discretion.  
 

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Nevertheless, should an investigator decide to pursue plasma cell directed therapy for 
rising/abnormal lab values (such as a rising light chain level), in the absence of any clear MM 
defining feature, this will not count towards the primary endpoint of the study. This will be 
documented as initiation of MM therapy, and similar to the process for when patients are 
diagnosed with MM- these patients will then be taken off study and removed from further- 
follow-up. We will not enroll additional patients (beyond target of 100) to adjust for this situation, 
as these patients would be considered eligible for primary endpoint ascertainment and would be 
considered to have not met the primary endpoint.  
7.3.2 Criteria for Morbid Progression Events 
The primary endpoint is the cumulative incidence of morbid progression events at two years of 
follow-up defined as any of the following: 
• 
Death attributed to plasma cell dyscrasia 
• 
Fracture attributed to plasma cell dyscrasia, 
• 
Lack of achievement of renal complete response defined as achievement of GFR≥ 
60ml/min within 4 weeks in the event of new onset renal insufficiency attributable to 
plasma cell dyscrasia, 
• 
Lytic bone lesions 
• 
Development of AL Amyloidosis 
• 
Development of plasma cell leukemia 
7.3.3 Use of PET/CT as alternative to MRI 
Use of MRI for imaging surveillance is strongly preferred. In cases where an MRI result is 
unavailable or MRI could not be performed as per standard of care for reasons such as 
claustrophobia or metallic device, PET/CT results may be utilized at the discretion of the PI. 
 
7.4 
Remote Visits/Telehealth 
 
Patients may choose to complete their study related and routine visits remotely or via telehealth 
as per their discretion. The method of telehealth should be documented in the participants’ 
charts. 
8 
STATISTICAL CONSIDERATIONS 
8.1 
Sample size determination 
Our primary research hypothesis is that event probability morbid progressions is less than 0.08 
at two years of follow-up. If the true probability of progression is 0.08 or less, then a 1-sided 
hypothesis test with 𝛼𝛼𝛼𝛼 =0.10 will achieve at least 82% power. This 1-sided hypothesis test is 
based on the rule that if we observe 10 or fewer morbid progressions, then we reject the null 
hypothesis that the progression probability is ≥ 0.15 in favor of the alternative hypothesis that 
the progression probability is < 0.15. In addition, with 100 evaluable patients, the margin of error 
corresponding to the upper 95% confidence bound (one-sided) for the true progression 
probability is approximately 0.05. 

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Principal Investigator: Dr. Ghulam Mohyuddin 
 
 
Descriptive analysis will be conducted to explore the characteristics of the patient population 
using means (standard deviations) and numbers (percentages) for quantitative and qualitative 
variables. Patients who die before the 24-month endpoint ascertainment due to disease 
progression will be regarded as “failures” and will count towards the event. Patients lost to 
follow-up will be censored. Subjects who withdraw prior to 1-year post-enrollment will be 
censored and replaced. Using the Wilson’s score-based proportion confidence interval 
technique, a one-sided 95% confidence bound for the rate of morbid progression events will be 
constructed. 
Pitfalls: Shortcomings of this approach include a lack of a control arm to ascertain whether 
treatment could lower the risk of progression further, although this approach is being 
investigated in other randomized trials. The follow-up is limited to two years of follow-up, and 
overall survival will not be ascertained as that would require a longer follow-up. Further funding 
in the future could be used to extend follow-up on this study. 
8.2 
Primary Endpoint 
The primary endpoint of this study is rate of morbid progression events. We hypothesize that 
most progression to MM that occurs during our study follow-up, will be asymptomatic 
biochemical changes in labs, or development of bone marrow lesions on imaging, rather than 
lytic lesions, fracture, or irreversible renal failure. We hypothesize that the primary endpoint is 
the cumulative incidence of morbid progression events at two years of follow-up (defined as 
death attributed to plasma cell dyscrasia, fracture attributed to plasma cell dyscrasia, lack of 
achievement of renal complete response defined as achievement of GFR≥ 60ml/min within 4 
weeks in the event of new onset renal insufficiency attributable to plasma cell dyscrasia, lytic 
bone lesions, development of AL Amyloidosis or development of plasma cell leukemia). With 
100 patients, we will ensure that a 95% confidence bound (one-sided) can be estimated with a 
margin of error ≤0.05. 
If a patient progresses to MM, the details of how their progression occurred will be recorded, 
they will be taken off the study, and standard of care treatment would be offered to them. 
8.3 
Secondary Endpoints 
Secondary endpoints will include longitudinal measurement of quality of life. This will be done at 
baseline and at 6, 12, 18 and 24 months using the PROMIS-29 questionnaire15. The domains of 
interest on the PROMIS-29 instrument would be physical function, pain interference, and 
anxiety. We hypothesize that there will not be a significant change from baseline in any of the 
patient reported outcome domains at follow-up. 
9 
ETHICAL AND REGULATORY CONSIDERATIONS 
9.1 Informed Consent 
Informed consent will be obtained from all research participants prior to performing any study 
procedures using the most recent IRB approved version. 
9.2 
Human Subjects Protection 
The study will be conducted in accordance with the protocol, 21 CFR, HIPAA regulations, the 
Belmont Principles, ICH Guidelines for Good Clinical Practice (GCP), and the Declaration of 
Helsinki. Informed consent will be obtained from all research participants or their legally 

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Protocol name: Smoldering myeloma High-Risk Patient Observation Longitudinal Insight Trial 
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Principal Investigator: Dr. Ghulam Mohyuddin 
 
 
authorized representative before performing any study procedures using the most recent IRB 
approved version. 
9.2.1 Personal Data Protection 
All parties will take all necessary actions required for the protection of subject personal data. 
Subjects enrolled in the study will be assigned a subject number and will be referenced by this 
number. Directly identifiable data will be omitted from reports, publications, and other 
disclosures. All personal data will be stored at the study site in encrypted electronic and/or 
paper form stored in a locked and secured facility. The site will be responsible for maintaining a 
list of subjects linking each subject with their subject number. Data will only be accessed by 
appropriate personnel and will be password protected or securely stored in a locked room. In 
the case of a potential breach of personally identifiable data, the site will take responsibility to 
ensure appropriate action is taken according to institutional practice and applicable laws and 
regulations. 
9.3 
Institutional Review 
Before the initiation of the study, the Investigator will have prospective approval of the study 
protocol, protocol amendments, informed consent documents, and other relevant documents, 
(e.g., recruitment advertisements, questionnaires, if applicable), from the IRB. All 
correspondence with the IRB should be retained in the Investigator’s regulatory file. Changes to 
the protocol or approved documents may not be made until IRB approval has been received. 
However, if a change is necessary to eliminate immediate hazards to the subjects, prospective 
approval is not necessary. 
The investigator or designee should provide the IRB with reports, updates and other information 
(e.g., expedited safety reports, amendments, and administrative letters) according to regulatory 
requirements or institution procedures. 
9.4 
Investigator Responsibilities 
The Investigator is responsible for ensuring the trial is conducted in compliance with the current 
IRB approved version of the protocol, GCP, the Declaration of Helsinki, and any applicable 
national and local laws and regulations. 
9.5 
Protocol Amendments 
Any amendments or administrative changes to an IRB approved protocol will not be initiated 
without submission of an amendment for IRB review and approval. However, prospective IRB 
approval will not be sought when an amendment is required to eliminate immediate risk to 
subjects on study. In these cases, amendments will be retrospectively submitted to the IRB for 
review and approval. 
Any amendments to the protocol that significantly affect the safety of subjects, the scope of the 
investigation, or the scientific quality of the study will be submitted to the FDA for review. 
9.6 
Protocol Deviations 
A deviation will be defined as any noncompliance with ICH GCP or the clinical protocol 
requirements. The noncompliance may be either on the part of the participant, the Investigator, 
or the study staff. As a result of the deviation, a corrective action must be implemented to 

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Protocol name: Smoldering myeloma High-Risk Patient Observation Longitudinal Insight Trial 
Version date: 30OCT2024 
Principal Investigator: Dr. Ghulam Mohyuddin 
 
 
ensure future deviation does not occur. It is the Investigator’s responsibility to identify and report 
deviations from ICH GCP or protocol requirements. These deviations and corrective action 
should be documented in the subject’s research chart, the associated eCRF, and reported to 
the IRB per their policy. 
10 DATA HANDLING 
10.1 Recording and Collection of Data 
Primary source documentation will come directly from the subject’s medical record. All source 
documentation should be attributable, legible, contemporaneous, original, accurate, complete, 
and available. All documentation should be signed and dated by applicable personnel. Relevant 
source data will be transcribed into the electronic case report forms (eCRFs) and should be 
completed as soon as possible after data availability. The eCRFs will be part of a computerized 
database grounded in the protocol requirements and study objectives. The database will be 
designed to comply with 21 CFR Part 11. 
The Investigator has ultimate responsibility for ensuring that all data collected and recorded is 
accurate and consistent. 
10.2 Data Management 
To accommodate evaluations, inspections, and/or audits from regulatory authorities, the 
Investigator must maintain all study records including subject identity, source documentation, 
original signed consent form, safety reporting forms, monitoring logs, relevant correspondence 
(e.g., letters, emails, meeting minutes, etc.), and any other documents pertaining to the conduct 
of the study. For the duration of record maintenance, records must be stored in a secure 
location and protected from the elements.  
10.3 Clinical Trials Data Bank 
The study will be registered on http://clinicaltrials.gov and the NCI CTRP (Clinical Trials 
Reporting Program). 
11 PUBLICATION PLAN 
In accordance with U.S. regulations and the best interest of research ethics and transparency, 
this study will be registered on ClinicalTrials.gov before subject enrollment. US Basic Results 
will also be reported and available on ClinicalTrials.gov within one year of the primary 
completion date, regardless of formal journal publication. All results will be reported objectively, 
accurately, balanced, and completely, regardless of the study outcome. We will plan on 
submitting the results within three months of study completion to a major journal (Lancet 
Hematology). Our study outline/plan may also be published in a journal for wider dissemination. 

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12 REFERENCES 
1. 
Cowan A, Ferrari F, Freeman SS, et al: Personalised progression prediction in 
patients with monoclonal gammopathy of undetermined significance or smouldering multiple 
myeloma (PANGEA): a retrospective, multicohort study. Lancet Haematol 10:e203-e212, 2023 
2. 
Mateos MV, Kumar S, Dimopoulos MA, et al: International Myeloma Working 
Group risk stratification model for smoldering multiple myeloma (SMM). Blood Cancer J 10:102, 
2020 
3. 
Lakshman A, Rajkumar SV, Buadi FK, et al: Risk stratification of smoldering 
multiple myeloma incorporating revised IMWG diagnostic criteria. Blood Cancer J 8:59, 2018 
4. 
Rajkumar SV, Dimopoulos MA, Palumbo A, et al: International Myeloma Working 
Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 15:e538-48, 2014 
5. 
Thorsteinsdottir S, Gislason GK, Aspelund T, et al: Prevalence of smoldering 
multiple myeloma based on nationwide screening. Nat Med 29:467-472, 2023 
6. 
Hillengass J, Moulopoulos LA, Delorme S, et al: Whole-body computed 
tomography versus conventional skeletal survey in patients with multiple myeloma: a study of 
the International Myeloma Working Group. Blood Cancer J 7:e599, 2017 
7. 
Siontis B, Kumar S, Dispenzieri A, et al: Positron emission tomography- 
computed tomography in the diagnostic evaluation of smoldering multiple myeloma: 
identification of patients needing therapy. Blood Cancer J 5:e364, 2015 
8. 
Perez-Persona E, Vidriales MB, Mateo G, et al: New criteria to identify risk of 
progression in monoclonal gammopathy of uncertain significance and smoldering multiple 
myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells. Blood 
110:2586-92, 2007 
9. 
Dispenzieri A, Kyle RA, Katzmann JA, et al: Immunoglobulin free light chain ratio 
is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma. 
Blood 111:785-9, 2008 
10. 
Hill E, Dew A, Morrison C, et al: Assessment of Discordance Among Smoldering 
Multiple Myeloma Risk Models. JAMA Oncol 7:132-134, 2021 
11. 
Lonial S, Jacobus S, Fonseca R, et al: Randomized Trial of Lenalidomide Versus 
Observation in Smoldering Multiple Myeloma. J Clin Oncol 38:1126-1137, 2020 
12. 
Mateos MV, Hernandez MT, Giraldo P, et al: Lenalidomide plus dexamethasone 
for high-risk smoldering multiple myeloma. N Engl J Med 369:438-47, 2013 
13. 
Mateos MV, Hernandez MT, Salvador C, et al: Lenalidomide-dexamethasone 
versus observation in high-risk smoldering myeloma after 12 years of median follow-up time: A 
randomized, open-label study. Eur J Cancer 174:243-250, 2022 
14. 
Wennmann M, Goldschmidt H, Mosebach J, et al: Whole-body magnetic 
resonance imaging plus serological follow-up for early identification of progression in 
smouldering myeloma patients to prevent development of end-organ damage. Br J Haematol 
199:65-75, 2022 
15. 
Hays RD, Spritzer KL, Schalet BD, et al: PROMIS((R))-29 v2.0 profile physical 
and mental health summary scores. Qual Life Res 27:1885-1891, 2018 
16. 
Oken MM, Creech RH, Tormey DC, et al: Toxicity and response criteria of the 
Eastern Cooperative Oncology Group. American journal of clinical oncology 5:649-655, 1982 

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17. 
Hays RD, Spritzer KL, Schalet BD, et al: PROMIS(®)-29 v2.0 profile physical and 
mental health summary scores. Qual Life Res 27:1885-1891, 2018 

Appendix 2: PROMIS–29 Profile v2.1 
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Principal Investigator: Dr. Ghulam Mohyuddin 
 
 
 
Please respond to each question or statement by marking one box per row. 
 
 
Physical Function 
Without 
any 
difficulty 
With a 
little 
difficulty 
With 
some 
difficulty 
With 
much 
difficulty 
Unable 
to do 
PFA11 Are you able to do chores such 
as vacuuming or yard work? ..... 
 
5 
 
4 
 
3 
 
2 
 
1 
PFA21 Are you able to go up and down 
stairs at a normal pace? ........... 
 
5 
 
4 
 
3 
 
2 
 
1 
PFA23 Are you able to go for a walk of 
at least 15 minutes? ................. 
 
5 
 
4 
 
3 
 
2 
 
1 
PFA53 Are you able to run errands and 
shop? ...................................... 
 
5 
 
4 
 
3 
 
2 
 
1 
Anxiety 
In the past 7 days… 
Never 
Rarely 
Sometimes 
Often 
Always 
EDANX 
01 
I felt fearful. .............................. 
 
1 
 
2 
 
3 
 
4 
 
5 
EDAN 
X40 
I found it hard to focus on 
anything other than my anxiety. 
 
1 
 
2 
 
3 
 
4 
 
5 
EDAN 
X41 
My worries overwhelmed me. ... 
 
1 
 
2 
 
3 
 
4 
 
5 
EDAN 
X53 
I felt uneasy.............................. 
 
1 
 
2 
 
3 
 
4 
 
5 

Appendix 2: PROMIS–29 Profile v2.1 
Page 34 of 36 
Protocol name: Smoldering myeloma High-Risk Patient Observation Longitudinal Insight Trial 
Version date: 30OCT2024 
Principal Investigator: Dr. Ghulam Mohyuddin 
 
 
 
 
Depression 
In the past 7 days... 
Never 
Rarely 
Sometimes 
Often 
Always 
EDDE 
P04 
I felt worthless........................... 
 
1 
 
2 
 
3 
 
4 
 
5 
EDDE 
P06 
I felt helpless.............................. 
 
1 
 
2 
 
3 
 
4 
 
5 
EDDE 
P29 
I felt depressed.......................... 
 
1 
 
2 
 
3 
 
4 
 
5 
EDDE 
P41 
I felt hopeless............................ 
 
1 
 
2 
 
3 
 
4 
 
5 
Fatigue 
During the past 7 days… 
Not at all 
A little bit 
Somewhat 
Quite a bit 
Very much 
HI7 
I feel fatigued.............................. 
 
1 
 
2 
 
3 
 
4 
 
5 
AN3 
I have trouble starting things 
because I am tired.................. 
 
1 
 
2 
 
3 
 
4 
 
5 
FATEXP 
41 
How run-down did you feel on 
average? ................................ 
 
1 
 
2 
 
3 
 
4 
 
5 
FATEXP 
40 
How fatigued were you on 
average?................................. 
 
1 
 
2 
 
3 
 
4 
 
5 

Appendix 2: PROMIS–29 Profile v2.1 
Page 35 of 36 
Protocol name: Smoldering myeloma High-Risk Patient Observation Longitudinal Insight Trial 
Version date: 30OCT2024 
Principal Investigator: Dr. Ghulam Mohyuddin 
 
 
 
 
Sleep Disturbance In 
the past 7 days… 
Very poor 
Poor 
Fair 
Good 
Very 
good 
Sleep109 My sleep quality was....................... 
 
5 
 
4 
 
3 
 
2 
 
1 
 
In the past 7 
days..................................... 
Not at all 
A little bit 
SomewhatQuite a bit Very much
Sleep116 My sleep was refreshing. ................ 
 
5 
 
4 
 
3 
 
2 
 
1 
 
Sleep20 
I had a problem with my sleep.......... 
 
1 
 
2 
 
3 
 
4 
 
5 
 
Sleep44 
I had difficulty falling asleep. ............ 
 
1 
 
2 
 
3 
 
4 
 
5 
 
Ability to Participate in Social Roles and 
Activities 
Never 
Rarely Sometimes
Usually 
Always 
SRPPER 
11_CaPS 
I have trouble doing all of my 
regular leisure activities with others 
 
5 
 
4 
 
3 
 
2 
 
1 
 
SRPPER 
18_CaPS 
I have trouble doing all of the 
family activities that I want to do.... 
 
5 
 
4 
 
3 
 
2 
 
1 
 
SRPPER 
23_CaPS 
I have trouble doing all of my usual 
work (include work at home)........... 
 
5 
 
4 
 
3 
 
2 
 
1 
 
SRPPER 
46_CaPS 
I have trouble doing all of the 
activities with friends that I want to 
do...................................................... 
 
5 
 
4 
 
3 
 
2 
 
1 
 

Appendix 2: PROMIS–29 Profile v2.1 
Page 36 of 36 
Protocol name: Smoldering myeloma High-Risk Patient Observation Longitudinal Insight Trial 
Version date: 30OCT2024 
 
Principal Investigator: Dr. Ghulam Mohyuddin 
 
 
 
 
Pain Interference In 
the past 7 days… 
Not at all 
A little bit 
Somewhat 
Quite a 
bit 
Very 
much 
PAININ9 How much did pain interfere with 
your day to day activities? 
......................... 
 
1 
 
2 
 
3 
 
4 
 
5 
 
PAININ2 
2 
How much did pain interfere with 
work around the home? .................. 
 
1 
 
2 
 
3 
 
4 
 
5 
 
PAININ3 
1 
How much did pain interfere with 
your ability to participate 
in social activities? ........................... 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
Pain Interference 
In the past 7 days… 
Not at all 
A little bit 
Somewhat 
Quite a bit
Very much 
PAININ34 
How much did pain interfere 
with your household chores? ...... 
 
1 
 
2 
 
3 
 
4 
 
5 
 
Pain Intensity 
In the past 7 days… 
Global07 
How would you rate your pain 
on average? ................................. 
 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
No 
pain 
Worst pain 
imaginable