Mayo Clinic College of MedicineMayo Clinic Comprehensive Cancer Center
Smoldering Multiple Myeloma
S. Vincent RajkumarProfessor of Medicine
Mayo Clinic
Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida
Disclosures
No conflicts to disclose
Kyle RA et al. N Engl J Med 2007;356:2582-2590
SMM verus MGUS
• <10% BMPC AND • <3gm/dL M protein AND• No CRAB
• ≥10% BMPC OR• ≥3 gm/dL M protein AND• No CRAB
• Clonal PCPD• CRAB attributable
to the PCPD
CRAB= Hypercalcemia, renal failure, anemia, or lytic bone lesions attributable to a clonal plasma cell disorder
MGUS SMM MM
Rajkumar SV. Cecil Textbook of Medicine, 25th Edition, 2016
Previous Disease Definitions
No CRAB CRAB
Rajkumar SV. Cecil Textbook of Medicine, 25th Edition, 2015
Catch-22
Paradigm shift in diagnosis of myeloma
• <10% BMPC AND • <3 gm/dL M protein AND• No MDE
• ≥10%-60% BMPC OR• ≥3 gm/dL S. M protein OR• ≥500 mg/24h Ur. M protein AND• No MDE
• PCPD, AND• 1 or more MDE• CRAB• ≥60% BMPC• ≥100 FLC ratio• >1 MRI focal lesion
MDE, myeloma-defining events
MGUS SMM MM
Rajkumar SV, et al. Lancet Oncol. 2014;15(12):e538-e548.
Revised IMWG Criteria
Light Chain SMM
Kyle RA, et al. Lancet Haematol 2014;1:e28-36
Kyle R et al. N Engl J Med 2007;356:2582-2590
SMM verus MGUS
SMM Paradigm Shift
MGUS Myeloma
Exclude Multiple Myeloma
Low-dose Whole Body CT or PET-CT
Rajkumar SV, Dispenzieri A. In: Niederhuber JE, et al, eds. Abeloff’s Clinical Oncology, 5th Edition; 2013.Rajkumar SV. In: Goldman L and Schafer AI, eds. Goldman’s Cecil Medicine, 25th Edition. 2016.
Exclude Lytic Lesions
Bone Marrow Plasma Cell Estimation
Rajkumar SV et al. N Engl J Med 2011; N Engl J Med 2011; 365:474-475
• Regular (Wright’s, H & E)• Not immunostaining • Not flow
• Highest value
>100
<100
FLC Ratio >100 and Risk of progression to myeloma
Larsen J, et al. Leukemia advance online publication 27 November 2012; doi: 10.1038/leu.2012.296
Impact of renal failure
Gonsalves W. Blood Cancer J. 2015;5:e296.
Using the FLC ratio ≥100
• Measurable level of involved FLC: • ≥100 mg/L (≥10 mg/dL)
• Be wary of• Longstanding history• Minimal urine 24 hour M protein
• Assay
Rajkumar SV, Landgren O, Mateos MV. Blood 2015
Images courtesy of Jens Hillengass MD. University Hospital Heidelberg, S.D.G.;Hillengass J, Landgren O. Leuk Lymphoma 2013;54:1355–63.
MRI Focal Lesions
• 23/149 patients had >1 lesion; median TTP not patients with <= 1 FL and 13 months for those with >1 FL
Jens Hillengass et al. JCO 2010;28:1606-1610
MRI
• Definite focal lesions – at least 2• ≥5mm• Repeat in 3-6 months if in doubt
Rajkumar SV, Landgren O, Mateos MV. Blood 2015
Evolving MRI findings
Merz et al, Leukemia 2014
Diagnosis of Myeloma
• Judgment • Hypercalcemia• Renal Failure• Anemia• Bone
• Judgment • Interpreting FLC ratio• Clinical course• Imaging studies
Rajkumar SV, Dimopoulos M, Palumbo A, et al. Lancet Oncol. 2014;15(12):e538-e548.
©2012 MFMER | 3206302-23
Smoldering Multiple Myeloma
Low-risk SMM:
High-Risk SMM
MM
• >60% BMPC
• FLCr >100
• >1 MRI focal lesions
©2012 MFMER | 3206302-24
Smoldering Multiple Myeloma
Low-risk SMM: 5%/yr risk of MM
High-Risk SMM
25%/year risk of MM
High Risk SMM: Median TTP ~2 years
≥10% PCs plus:•SMM with M protein ≥3 gm/dL •Absence (<5%) of normal PCs by immunophenotyping plus Immunoparesis •Abnormal FLC ratio 8-100•Del(17p), t4;14, gain(1q21)•M protein ≥4 gm/dL•IgA SMM•Evolving pattern•Increased circulating plasma cells
Rajkumar SV, Landgren O, Mateos MV. Blood 2015
Copyright ©2008 American Society of Hematology. Copyright restrictions may apply.
Dispenzieri, A. et al. Blood 2008;111:785-789
FLC Ratio and risk of progression in SMM
Bianchi, et al. Leukemia advance online publication 18 September 2012; doi: 10.1038/leu.2012.237
High Circulating Plasma Cells and Risk of progression to myeloma
Follow up from diagnosis of smoldering multiple myeloma (years)
Per
cent
pro
gres
sing
PCLI <1
PCLI ≥1
Madan S. Mayo Clin Proc 2010
High Plasma Cell Proliferative Rate and Risk of progression to myeloma
Risk Cytogenetic Abnormalities % of patients
(N=351)
Median TTP to
Multiple Myeloma(months) a
Median TTP to Multiple
Myeloma or related
disorder(months) b
High-Risk t(4;14)Del(17p)Gain(1q21)*
13% 24 24
Intermediate-Risk
Trisomies 42% 34 34
Standard-Risk t(11;14), t(14;16), t(14;20), combined IgH translocations and trisomies†, and isolated monosomy 13
30% 55 54
Low-Risk No abnormalities detected on FISH‡ 15% Not reached
101
Rajkumar SV et al Leukemia. 2013 Aug;27(8):1738-44; Neben et al. J Clin Oncol 2013
Cytogenetic Abnormalities and risk of progression in SMM
FISH Abnormalities
High risk: any of del(17p13), t(4;14), or 1q21
Neben et al, JCO 2013
Risk factor Progression within 2 years eMP only 64%eHb only 65%Both eMP and eHb 82%eMP, eHb, and BMPC ≥20% 91%
eMP: 10% increase in M protein within 6 months (if M-protein ≥3 g/dl) or ≥25% increase in M protein within 12 months (minimum 0.5 g/dl)
Evolving M protein Levels
Ravi P, et al. Blood Cancer J 2016;6:e454-
eHb: ≥0.5 g/dL decrease within 12 months
Fernández de Larrea C, et al. Leukemia 2018 (ePub)
Management of SMM
When Should Treatment Be Initiated?
Potential New Myeloma or Smoldering Myeloma
Observation
Rajkumar SV, Landgren O, Mateos MV. Blood 2015
Any Myeloma Defining Events?• CRAB, • >60% PC, • FLC >100, • MRI >1 focal
No Myeloma Defining Events (SMM)
Treat as Myeloma
High Risk SMM(Median TTP ~2 years)
Low Risk SMM(~5% per year PD)
To Treat or Not to Treat?
Especially Evolving, or Many high risk
factors
