SCREENING FOR MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE A population-based randomized clinical trial Sigurður Yngvi Kristinsson, MD, PhD Professor of Hematology University of Iceland Email: sigyngvi@hi.is Twitter: @sykristinsson

iStopMM Iceland Screens, Treats or Prevents Multiple Myeloma

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

Natural history

Probability of progression Kyle et al. NEJM 2007 5

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

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

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

Does follow-up for MGUS matter?

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

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

Follow-up of MGUS is important

Because of early treatment?

Treating smoldering myeloma Mateos MV et al. NEJM 2013

Kristinsson SY, et al. NEJM 2013

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

Should we screen for MGUS?

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

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

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

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

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

mgus.is

All 35 laboratories in Iceland participate

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

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

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

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

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

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

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

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

Quality of life assessment

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 e-mail 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.

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?

Population-based nationwide clinical trial with early intervention

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

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