1. SCREENING FOR MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE A population-based randomized clinical trial
Sigurður Yngvi Kristinsson, MD, PhD
Professor of Hematology
University of Iceland

2. iStopMM Iceland Screens, Treats or Prevents Multiple Myeloma

3. Monoclonal gammopathies
Multiple myeloma
Malignant plasma cells in the bone marrow
Survival improving in recent years due to novel drugs
Monoclonal gammopathy of undetermined significance (MGUS)
M-protein on protein electrophoresis or pathological free light chain ratio with no underlying lymphoproliferative malignancy
Prevalence in >40 years is approximately 4%
Constantly precedes multiple myeloma
1.5% progression to a malignant disorder per year

4. Natural history

5. Probability of progression
Kyle et al. NEJM 2007 5

6. MGUS
We are unaware of the underlying causes of monoclonal gammopathies
We cannot predict which individuals with precursor states will progress to full-blown malignancy
There is no evidence from prospective studies to guide clinicians and patients for the optimal follow-up
The impact of hereditary factors, genetics, imaging, and other molecular markers on transformation is unknown
All individuals with MGUS are identified out of pure coincidence because of another unrelated sickness

7. Survival is really improving in myeloma
Thorsteinsdottir S et al. Haematologica 2018

8. Why is it improving? High-dose therapy with stem cell support
Novel drugs
Improved supportive care
Prognostic factors
Earlier treatment?

9. Does follow-up for MGUS matter?

10. The Role of Diagnosis and Clinical Follow-up of Monoclonal Gammopathy
of Undetermined Significance on Survival in Multiple Myeloma
Sigurdardottir EE, et al and Kristinsson SY. JAMA Oncol. 2015

11. The Role of Diagnosis and Clinical Follow-up of Monoclonal Gammopathy
of Undetermined Significance on Survival in Multiple Myeloma
Sigurdardottir EE, et al and Kristinsson SY. JAMA Oncol. 2015

12. Follow-up of MGUS is important

13. Because of early treatment?

14. Treating smoldering myeloma
Mateos MV et al. NEJM 2013

15. Kristinsson SY, et al. NEJM 2013

16. How do we find asymptomatic people to treat?
By chance? By screening?

17. Should we screen for MGUS?

18. Benefits of screening
Early detection
Early treatment
Prevent rather that treat
Improved survival?

19. Potential harm of screening
Cost
Psychological harm
Low risk of progression
Unnecessary evaluations
Bone marrow, X-ray, MRI etc
Only non-aggressive disease is captured

20. Overall aims of iStopMM
Evaluate the impact of screening for MGUS
Obtain evidence for optimal work-up and follow-up
Integration biological, imaging, and germline genetic markers in risk models for progression
Evaluate the impact of screening on quality of life
Biobanking
Evaluate the effect of early detection and early treatment

21. All Icelanders > 40 years
Ca 3600 with MGUS/SMM
Without MGUS/SMM R
No further work-up
N=1200
IMWG
Recommendations
N=1200
Intervention arm
N=1200

22. How does this work? All Icelanders born 1975 and earlier
A purple envelope sent to their home address

23. mgus.is

24. All 35 laboratories in Iceland participate

25. Innovative aspects Electrical informed consent in a whole population
Unique way of obtaining samples without drawing blood
Using germline genetic variants in risk model in a prospective study
Quality of life measurement in cancer screening programs
Prospective nationwide screening randomized clinical trial (RCT)
Personal identification numbers for complete outcome measures in RCT
Theoretical change on how risk models are conducted
Imaging
Hereditary factors
Comorbidity
Correlative studies

26. R Ca 3600 with MGUS Without MGUS/SMM Smoldering myeloma N=200
No further work-up
N=1200
IMWG
Reccommendations
N=1200
Intervention arm
N=1200
Followed for progression to multiple myeloma or another malignancy (Cancer Registry)
Followed for all diagnoses in inpatient and outpatient clinics throughout Iceland (Patient Registry)
Followed for vital status every 2 months (Population Registry)
All prescriptions throughout Iceland (Prescription registry)
Regular quality of life assessments

27. R Ca 3600 with MGUS Without MGUS/SMM Smoldering myeloma N=200
No further work-up
N=1200
IMWG
Recommendations
N=1200
Intervention arm
N=1200
Medical history and clinicial examination
Blood work-up in all individuals
Intervention arm:
Extensive blood work, bone-marrow, low-dose CT in all patients
Annual follow-up
More intense bone marrow evaluations

28. R Integrating germline genetic variants
Ca 3600 with MGUS
Without MGUS/SMM
Smoldering myeloma
N=200 R
No further work-up
N=1200
IMWG
Recommendations
N=1200
Intervention arm
N=1200
Integrating germline genetic variants
Flow cytometry of bone marrow and peripheral blood
Control group form non-MGUS
Biobanking

29. Biobanking Bone marrow; Biopsy -> formalin fixed, stored at LHS
Bone marrow smear -> stored in lab
BM aspirate -> plasma + cell sorting
Blood and urine;
Plasma (LiHep tube)
Cell free Plasma (EDTA tube)
Buffy coat from the EDTA tube
EDTA tube (DeCode)
Serum (SST tube)
Mononuclear cells (CPT tube)
RNA (PAXgene tube)
Urine

30. Flow cytometry in iStopMM
MM-MRD panel
Immunophenotyping of normal/abnormal plasma cells in bone marrow and peripheral blood
Deep Immune profiling
B cell panel
NK cell panel
T cell panel
Myeloid cell panel
Intensive track
Baseline: BM and PB samples
4 month follow-up: PB sample
Annual follow-up: BM and PB samples
Baseline: BM and PB samples
Annual follow-up: PB sample
End of follow-up: BM and PB samples

31. Early results Prevalence of smoldering myeloma
Quality of life in MGUS (and in the whole population)
New germline genetic variants associated with risk of MGUS

32. An important part of the iStopMM study is to evaluate the psychological aspects of screening:
Regular Quality of life, anxiety, and well being assessments in all participants

33. Quality of life assessment

34. Quality of Life Questionnaires
Patient Health Questionnaire (PHQ-9)
Generlized Anxiety Disorder (GAD-7)
Satisfaction with Life Scale (SWLS)
Happiness Question
Question of Well Being
At visits to the clinical study center
Background questions (only at first visit)
Physical and Mental Health Questionnaires
Brief Pain Inventory
Neuropathy Symptom Score
Douleur Neuropathique 4 (DN-4)
Generalized Anxiety Disorder (GAD-7)
36-Item Short Form Survey (SF-36)
Perceived Stress Scale (PSS-10)
Posttraumatic stress disorder checklist for DMS-5 (PCL-5)
Yearly for all participants providing an address
Background questions (only at first round)
Generlazed Anxiety Disorder (GAD-7)
Nutrition questions – will be sent out to all participants within the next 2 years.

35. Key outcomes The impact of screening for M-protein/MGUS
On overall survival
On MM specific survival
On quality of life
Cost-effectiveness
Evidence for optimal follow-up strategy in MGUS
New prognostic model for progression
Biobanking
Unique possibility of an early intervention on asymptomatic individuals
Cure by early treatment?

36. Population-based nationwide clinical trial with early intervention

38. Nilsson B et al. Nat Comm 2015
Houlston R et al. Nat Comm 2016

39. Tumor microenvironment
Renal amyloidosis
Pain
Genetics
Neuropathy
Correlative science
Psychological impact
Cardiac amyloidosis