Should we treat smoldering myeloma? Is the data convincing? Yes: Elisabet Manasanch, MD No: Prantar Chakarbarty, MD

1. Should we treat smoldering
myeloma? Is the data convincing?
Elisabet Manasanch M.D., M.H.Sc.
Assistant Professor, Department of Lymphoma/Myeloma
Division of Cancer Medicine

2. Disclosures
Nothing to disclose

3. Monoclonal Gammopathies
MGUS
SMM
MM
M 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 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.

4. SMM Risk Stratification
High 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

5. SMM Risk Stratification
Mayo Clinic Criteria (n=273)
risk factors
No. of patients,
n (%)
1 76(28) 25%
2 115 (42) 51%
3 82 (30) 76%
Risk factors:
• BMPCs >10%
• M-protein >3 g/dL
• FLC-ratio <0.125 or >8
No. of
Progression
at 5 years
Dispenzieri et al. Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering
(asymptomatic) multiple myeloma. Blood 2008

6. SMM Risk Stratification
SWOG Criteria (n=117)
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%
Dhodapkar et al. Clinical, genomic and imaging predictors of malignancy: analysis of the first prospective clinical trial in
Asymptomatic monoclonal gammopathies (SWOG S0120). Blood. 2014.

7. 100%
80%
60%
40%
20%
0%
SWOG Criteria
0 12 24 36 48 60
Months from Registration
2+ RF
1 RF
No RF
Events / N
12 / 18
9 / 39
2 / 60
24-Month
Estimate
66.7%
21.9%
3.4%
Variable
%
(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
23 3.15 (1.40, 7.08)
mg/dL
Dhodapkar et al. Clinical, genomic and imaging predictors of malignancy: analysis of the first prospective clinical trial in
Asymptomatic monoclonal gammopathies (SWOG S0120). Blood. 2014.

8. Risk of Clinical MM Requiring Therapy Based on Molecular
Subtypes in Asymptomatic Monoclonal Gammopathy
100%
80%
60%
40%
20%
0%
0 12 24 36 48 60
Months from Registration
PR
MS
HY
CD-2
MF
LB
CD-1
Events / N
3 / 5
4 / 11
8 / 31
4 / 28
2 / 17
3 / 28
0 / 6
24-Month
Estimate
60.0%
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 in
Asymptomatic monoclonal gammopathies (SWOG S0120). Blood. 2014.

9. Ultra high risk SMM
1) ≥ 60% bone marrow plasma cell infiltration
2) iFLC/uFLC ratio >100
3) More than 1 lesion on whole body MRI (may be substituted by PETCT)
n=634
n=21
iFLC/uFLC>100
iFLC/uFLC<100
MRI
Risk of progression to MM of about 80% at 2 years
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):474-475
Kastritis 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 focal
Lesions in whole-body magnestic resonance imaging in patients with asymptomatic multiple myeloma. JCO. 2010

10. Lenalidomide and Dexamethasone in SMM
Randomized phase III clinical trial
117 patients
Treatment (n=57)  Maintenance (n=50)
Observation (n=62)
Mateos et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. NEJM.2013.

11. 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.

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

13. Carfilzomib, Lenalidomide and
Dexamethasone in high-risk SMM
Deep level of remission
4/5 patients achieving
sCR/CR/nCR were MRD
negative
Using mutiparameter
flow cytometry
Analyzing 3-4 x 106 million
cells
Landgren et al. Pilot study: Carfilzomib, lenalidomide and dexamethasone in high-risk smoldering
multiple myeloma. ASH.2013.

14. Monoclonal Gammopathies
MGUS
SMM
MM
M 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 HR
M protein in
the serum or
urine
Bone marrow
clonal plasma
cells
Presence of
end organ
damage
Tumor 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.

15. YES
Summary
BENEFITS
RISKS
Delay of
symptomatic
disease
Relief of
psychological
burden
Possibility of cure
Clonal evolution
Toxicity
Cost
Overtreatment
Manasanch et al. Smoldering multiple myeloma: special considerations surrounding treatment on versus off
clinical trials. Haematologica. 2014. In press.

16. MDACC Myeloma Center
Dr. Robert Orlowski
Dr. Jatin Shah
Dr. Donna Weber
Dr. Sheeba Thomas
Dr. Michael Wang
Dr. Parmar
Dr. Qazilbash
Dr. Shah
Dr. Bashir
Stem Cell Transplant Department
Support staff, nurses, coordinators
Patients