Post on 02-Nov-2014
description
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