Elisabet Manasanch M.D., M.H.Sc.Assistant Professor, Department of

Lymphoma/Myeloma Division of Cancer Medicine

Should we treat smoldering myeloma? Is the data

convincing?

Disclosures

Nothing to disclose

Monoclonal Gammopathies

MM

SMM

MGUSM protein < 3 g/dL

Bone marrow

plasma cells <10%

No end organ

damage. No other

LPD.M protein ≥ 3 g/dL

Bone marrow

plasma cells ≥ 10%

No end organ

damage

M protein in the

serum or urine

Bone marrow clonal

plasma cells

Presence of end organ damage

Tumor BurdenDurie et al. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003.

SMM Risk StratificationHigh risk SMM median time to progression is < 2 years

PETHEMA Group Criteria (n=89)

No. of risk factors

No. of patients, n (%)

Progression at 5 years

0 28 (31) 4%

1 22 (25) 46%

2 39 (44) 72%

Risk factors:• ≥95% abnormal plasma cells • Immunoparesis

Pérez-Persona 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 2007

SMM Risk Stratification

Dispenzieri et al. Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma. Blood 2008

Risk factors:• BMPCs >10%• M-protein >3 g/dL • FLC-ratio <0.125 or >8

No. of risk factors

No. of patients, n (%)

Progression at 5 years

1 76(28) 25%

2 115 (42) 51%

3 82 (30) 76%

Mayo Clinic Criteria (n=273)

SMM Risk Stratification

Risk factors:• GEP70 score > -0.26• M-protein >3 g/dL• Involved sFLC > 25 mg/dL

No. of risk factors

No. of patients, n (%)

Progression at 2 years

0 76(28) 3%

1 115 (42) 22%

≥ 2 82 (30) 68%

SWOG Criteria (n=117)

Dhodapkar et al. Clinical, genomic and imaging predictors of malignancy: analysis of the first prospective clinical trial inAsymptomatic monoclonal gammopathies (SWOG S0120). Blood. 2014.

0%

20%

40%

60%

80%

100%

0 12 24 36 48 60

Months from Registration

2+ RF1 RFNo RF

Events / N12 / 189 / 392 / 60

24-MonthEstimate66.7%21.9%3.4%

SWOG CriteriaVariable % (n=117) HR (95% CI)

GEP 70-gene risk > -0.26 27 6.81 (2.90, 15.97)Serum M-protein ≥ 3 g/dL 15 6.49 (2.78, 15.18)Involved serum FLC > 25 mg/dL 23 3.15 (1.40, 7.08)

Dhodapkar et al. Clinical, genomic and imaging predictors of malignancy: analysis of the first prospective clinical trial inAsymptomatic monoclonal gammopathies (SWOG S0120). Blood. 2014.

Risk of Clinical MM Requiring Therapy Based on Molecular Subtypes in Asymptomatic Monoclonal Gammopathy

0%

20%

40%

60%

80%

100%

0 12 24 36 48 60Months from Registration

PRMSHYCD-2MFLBCD-1

Events / N3 / 54 / 118 / 314 / 282 / 173 / 280 / 6

24-MonthEstimate60.0%40.0%22.6%15.7%11.8%10.7%

.%

Dhodapkar et al. Clinical, genomic and imaging predictors of malignancy: analysis of the first prospective clinical trial inAsymptomatic monoclonal gammopathies (SWOG S0120). Blood. 2014.

Ultra high risk SMM1) ≥ 60% bone marrow plasma cell infiltration2) iFLC/uFLC ratio >1003) More than 1 lesion on whole body MRI (may be substituted by PETCT)

Larsen JT et al. Serum free light chain ratio as a biomarker for high-risk smoldering multiple myeloma. Leukemia. 2013.Rajkumar SV et al. Diagnosis of smoldering multiple myeloma. N Engl J Med. 2011;365(5):474-475Kastritis E et al. Extensive bone marrow infiltration and abnormal free light chain ratio identifies patients with asymptomatic myeloma at high risk for progression to symptomatic disease. Leukemia. 2013. Hillengas et al. Prognostic significance of focalLesions in whole-body magnestic resonance imaging in patients with asymptomatic multiple myeloma. JCO. 2010

n=21

n=634

iFLC/uFLC>100

iFLC/uFLC<100

MRI

Risk of progression to MM of about 80% at 2 years

Lenalidomide and Dexamethasone in SMMRandomized phase III clinical trial

117 patientsTreatment (n=57) Maintenance (n=50)

Observation (n=62)

Mateos et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. NEJM.2013.

Treatment of high risk SMM: first randomized trial showing benefit in

treatment arm

LenDex

LenDex

119 high risk SMM patients randomized to:- Lenalidomide plus dexamethasone for 9 cycles (28 days each)

followed by Len Maintenance for 2 years- Observation only (currently recommended by guidelines)

Mateos et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. NEJM.2013.

Carfilzomib, Lenalidomide andDexamethasone in SMM

Landgren et al. Pilot study: Carfilzomib, lenalidomide and dexamethasone in high-risk smoldering multiple myeloma. ASH.2013.

Carfilzomib, Lenalidomide andDexamethasone in high-risk

SMM

Landgren et al. Pilot study: Carfilzomib, lenalidomide and dexamethasone in high-risk smoldering multiple myeloma. ASH.2013.

Deep level of remission

4/5 patients achievingsCR/CR/nCR were MRDnegative

Using mutiparameterflow cytometry

Analyzing 3-4 x 106 million cells

Monoclonal Gammopathies

MM

SMM

MGUSM protein < 3 g/dL

Bone marrow plasma cells <10%

No end organ damage. No other LPD.

M protein ≥ 3 g/dL

Bone marrow plasma cells ≥ 10%

No end organ damage

HIGH-RISK

HIGH-RISK HIGH-RISK

ULTRA HR ULTRA HR ULTRA HRM protein in the serum or urine

Bone marrow clonal plasma cells

Presence of end organ damageTumor Burden

Durie et al. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003.

Manasanch et al. Smoldering multiple myeloma: special considerations surrounding treatment on versus off clinical trials. Haematologica. 2014. In press.

Summary

BENEFITS

RISKS

Delay of symptomatic diseaseRelief of psychological burdenPossibility of cure

Clonal evolutionToxicityCostOvertreatment

YES

Dr. Robert OrlowskiDr. Jatin Shah

Dr. Donna WeberDr. Sheeba ThomasDr. Michael Wang

Dr. ParmarDr. Qazilbash

Dr. ShahDr. Bashir

Stem Cell Transplant Department

Support staff, nurses, coordinators

Patients

MDACC Myeloma Center