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

THANK YOU

kumar.shaji@mayo.edu