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Mayo Clinic College of Medicine
Mayo Clinic Comprehensive Cancer Center
Risk Stratification of Smoldering Multiple
Myeloma
Shaji Kumar, M.D.
Professor of Medicine
Mayo Clinic
Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida
DISCLOSURES
• Advisory Board Participation:
– Janssen, Takeda, Sanofi, Celgene, Abbvie, BMS, Merck, Genentech, Oncopeptides
• Clinical Trial Support:
– Janssen, Takeda, Sanofi, Novartis, Abbvie, Celgene, Merck, Roche-Genentech, KITE
Smoldering multiple myeloma
Ultra-high risk SMM (aka MM)
High risk of progression: Redefine as MM? Intervene?
When is risk of progression too much?
MRI SpineFree Light Chain RatioBone marrow PC%
Ratio >= 100
Ratio < 100
Revised MM criteria
Classical Definition
• HyperCalcemia
• Renal Insufficiency
• Anemia
• Bone Disease
Expanded definition
• BMPC >= 60%
• >1 PET/MRI lesions
• FLC ratio > 100
Predicts an 80% or more risk of progression in 2 years
SMM: Current Definition
• Asymptomatic
• Increased clonal burden as shown by
– Serum monoclonal protein (IgG or IgA) ≥3 g/dL
– Or urinary monoclonal protein ≥500 mg per 24 h
– Or clonal bone marrow plasma cells 10–60%
• No lytic lesions, none or one lesion on MRI, no anemia, or no hypercalcemia.
• Evolution into overt myeloma @ ~3 percent per year.
Progression to Symptomatic MM
Kyle et al, NEJM, Volume 356:2582-2590, June 21, 2007
15%
1%
1%
3%
Quantitative progression
Increasing levels of monoclonal protein
Increasing marrow plasma cell percentage
Development of End Organ Damage
Qualitative progression
MGUS SMM SymptomaticMM
Clonal Clonal PCs Clonal “malignant’ PCs
Tumor microenvironment
Risk factors for progression
Quantitative spectrum
• Serum M spike
• Bone marrow PC%
• MRI marrow abnormalities
Qualitative spectrum
• FISH abnormalities
• Mutations
• GEP profile
• Proliferation rate
• FLC ratio abnormality• Immunoparesis• Circulating tumor cells• Evolving phenotype
Impact of Bence Jones proteinuria
Gonzalez-Calle, Leukemia 2016
Imaging
Zamagni et al, Leukemia, 2016
FISH Abnormalities
High risk: any of del(17p13), t(4;14), or 1q21
Neben et al, JCO 2013; Rajkumar et al, Leukemia 2013
Gene expression Profiles
Khan et al, Haematologica 2015
Dispenzieri A et al. Blood 2008;111:785-789
FLC ratio and risk of progression
Polyclonal PCs
Perez-Persona et al, Blood 2007
Circulating plasma cells
Bianchi et al, et al, Leukemia, 2012
Evolving parameters
• ≥10% in M-protein and/or involved Ig in first 6mths of diagnosis (only if M ≥3g/dL) AND/OR
• ≥25% in M-protein and/or involved Ig within first 12mths
• Minimum required of 0.5g/dL in M-protein and/or 500mg/dL in Ig (or both)
• ≥0.5g/dL in Hb within first 12mths of diagnosis
mTTP0 (n=54): 12.3yrs1 (n=58): 5.1yrs2 (n=32): 2.0yrs3 (n=22): 1.0yrs
p<0.001
Evolving MRI findings
Merz et al, Leukemia 2014
Dispenzieri A et al. Blood 2008;111:785-789
Risk of progression in SMM
>95% aPC/BMPC or paresis
>95% aPC/BMPC + paresis
No adverse factors
Pérez E. Blood 2007; 110:2586-92
Revised risk stratification (20/20/20)
Factors• BMPC >20%• M Spike >20g/L • FLC ratio >20
Stratification
Low-risk: 0 Intermediate-risk: 1high-risk: >=2
Lakshman et al, BCJ, 2018
Subset with advanced imaging and FISH
• TTP in patients with none (low risk), one (intermediate risk), and two or more (high risk): BMPC% > 20%, FLCr > 20, and high-risk cytogenetics [del17p, t(4;14) or hyperdiploidy].
• The estimated median TTP in the three groups were not reached (95% CI, 33.3 months–NR), 63.0 months (95% CI, 29.8–NR), and 14.5 months (95% CI, 10.7–25.4), respectively (p < 0.0001).
New model Old model
Why risk stratify?
• Tow phase 3 trials have shown improved susrvivalwith prevention approaches
High-risk: Early therapy as with MM?
Intermediate risk: prevention of progression strategies
Low risk: Observation? Clinical trials?
FUTURE
SMM is not a true biological entity
• Transitional stage (MGUS →MM)
• Represent a mix of true MGUS with polyclonal but benign PCs and MM with “malignant” PCs
• No molecular marker available and morphological distinction not possible
• Future technologies such as single cell approaches may play a key role
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