1. Cancer Education Day Approach to Paraproteinemia or Why did I order that SPE?#!
May 13, 2016
Dr Sindu Kanjeekal MD FRCPC
Hematology and Medical Oncology

2. Disclosures
No relevant disclosures

3. Objectives Epidemiology of MGUS Review of common tests
Hypergammaglobulinemia vs MGUS
Definition of MGUS, SMM, active MM
Risk stratification of MGUS
Special considerations for IgM MGUS

4. What are the most common reasons you order SPE? Evaluation of…
Anemia
Neuropathy
reduced EGFR
Proteinuria
Connective tissue disease

5. Do you ever wish you hadn’t ordered that SPE?
Yes No

6. Case #1 72 yo man. Lawyer. Phx: HTN, type II DM
Presented with mild asymptomatic normocytic anemia for ~3 years.
Jan 2014 Hb=111
Upper and lower endoscopy normal
Jan 2016 Hb=117. (normal iron, B12/folate/TSH)
Creat=122
SPE shows ill-defined band in gammaglobulin region
IFE=IgG kappa protein

7. Case #1 Investigations Results
Because of unexplained anemia, mild elevation of creatinine
BM Biopsy
SFLC ratio
24hr urine collection for protein and IFE
Skeletal survey
BMB-3% plasma cells
SFLC ratio-normal
24hr urine normal
Skeletal survey normal

8. 1. What is this patient’s risk of progression to multiple myeloma at 20 years?
B 5%
C 20%
D 60%

9. MGUS…
Benign monoclonal proteins were first described by Dr. Jan Waldenström in 1960 after he detected abnormal narrow hypergammaglobulinemia bands in serum protein electrophoresis (SPEP) samples from healthy individuals
SPEP often performed as a result of screening
primary care for anemia
nephrologists for renal insufficiency or proteinuria
neurologists for peripheral neuropathy

10. Monoclonal Gammopathies Mayo Clinic 2011
Lymphoproliferative 1% (25)
Amyloidosis (AL) 10% (174)
SMM 5% (81)
Solitary or extra- medullary 2% (34)
Multiple myeloma 20% (348)
Macro 3.5% (62)
Other 7.5% (130)
MGUS 51% (879)

11. What is MGUS?
An asymptomatic plasma cell dyscrasia present in 3-5% of adults >50 yo
Non IgM MGUS
IgM MGUS
Light chain MGUS
Twice as common in African American population and more common in men than women
Average risk of progression to MM=1%/year

13. Diagnostic Tests

14. Normal SPEP
TBG
haptoglobin
CRP
immunoglobulins
transferrin

15. Abnormal SPEP Monoclonal protein

16. Serum Immunofixation

17. UPEP
UPEP is used to detect Bence-Jones protein (BJP), which is a Kappa or Lambda light chain found dissociated from the regular Ig conformation
The light chains are sufficiently small that they can be excreted by the kidneys once they reach a sufficient concentration in the blood.
In 15% of multiple myeloma cases the only identifiable monoclonal product is BJP
Ref: (Beetham et al., 2007; Merlini and Bellotti, 2003).

18. Serum Free Light Chain Assay

19. Other Conditions Associated with M-protein
POEMS
Rare paraneoplastic associated with plasma cell disorder (Lambda light chain)
Rare skin disease
Immune suppression-
seen transiently post transplant
Neurologic disorder
sensorimotor peripheral neuropathy
Renal
Idiopathic focal glomerulonephrosclerosis
hematologic
Lymphoma/CLL
Connective tissue disorders
RA/SLE/PMR/AS

20. Most cases of MM are preceded by MGUS
Why do we follow?

21. We want to avoid this…

22. Biological events related to progression to multiple myeloma.
Biological events related to progression to multiple myeloma. The biologic transition from normal plasma cells to multiple myeloma precursor disease (monoclonal gammopathy of undetermined significance [MGUS] and smoldering myeloma) to multiple myeloma consists of many overlapping oncogenic events. These events do not all occur in each affected individual, for example, hyperdiploidy is present in approximately 50% of precursor and multiple myeloma tumors. In this illustration, solid lines approximate the period during which the oncogenic event is likely to occur; dashed lines indicate less certainty in the timing. Once an oncogenic event occurs, it almost always persists. The 2 major types of early events include IgH translocations [most commonly: t(4;14), t(14;16), t(6;14), t(11;14), and t(14;20)] and hyperdiploidy, although most tumor cells have only one of these two events. Either of these can coexist with deletion of chromosome 13, although this abnormality most commonly (> 80% to 90% of patients) occurs with the t(4;14), t(14;16), and t(14;20) IgH translocations.38,39 A unifying early event in most, perhaps all, precursor and multiple myeloma tumors is the dysregulation of a cyclin D gene. Secondary translocations, sometimes involving an Ig locus, can occur at any stage of myelomagenesis. Activating mutations of NRAS and KRAS are each present in about 15% of multiple myeloma tumors; NRAS mutations are present in MGUS tumors and KRAS mutations are absent from MGUS tumors. Constitutive activation of the nuclear factor κB (NFκB) pathway is mediated by mutations in some tumors during progression.38 Other events, such as Rb gene inactivation or deletion of p53 or p18 genes, are mostly seen at the level of advanced intramedullary or extramedullary multiple myeloma.38,65 Through the stage of intramedullary multiple myeloma, the tumor cells are strongly dependent on the bone marrow microenvironment.66 The reciprocal interaction of the bone marrow microenvironment and the tumor cells results in changes in the bone marrow microenvironment, which are responsible for the lytic lesions that are characteristic of multiple myeloma. Extramedullary tumor cells have developed features that make them independent of the bone marrow microenvironment. (Reprinted with permission.37)‏
Neha Korde et al. Blood 2011;117:
©2011 by American Society of Hematology

23. Definitions IMWG 2014 MGUS 1%/year SMM 10%/year Active MM Asymptomatic
M-protein<30g/L
Plasma cells<10%
No CRAB criteria
M-protein>=30g/L
and/or
Plasma cells>=10-60%
No CRAB criteria or MDE
(myeloma Defining Events)
May or may not have symptoms
M-protein in serum or urine
And/or
>=10% plasma cells
and
Presence of CRAB criteria or
Myeloma defining events
60%>plasma cells
SFLC ratio>100
2 or more focal lesions on MRI>=5mm
(indicates focal BM abnormalities)

24. MGUS Prognostic Score Risk Factors Prognosis at 20 years
M-protein >15g/L
non IgG MGUS
Abnormal SFLC ratio
# Risk Factors
Risk of progression at 20 years 5% 1
21% 2
37% 3
58%

25. Initial testing and follow-up

26. low risk MGUS (5% risk of progression at 20 years)
Low risk MGUS (40% of MGUS)
IgG subtype
M-protein<15g/L
normal SFLC ratio
in the absence of concerning symptoms such as anemia or poor renal function
no further initial evaluation is required

27. Low Risk MGUS At 6m follow with SPEP, CBC, Calcium, creatinine Or
If stable then every 2-3 years Or
Alternatively only if concerning symptoms arise

28. Intermediate and high risk MGUS (20-60% at 20 years)
Consider Baseline BMB
Bone imaging
skeletal survey
consider MRI (for high risk MGUS) because may show focal BM lesion which is a Myeloma Defining Event (MDE)
Hx/Px, SPEP, CBC, Calcium, creatinine, q3-6m for 1st year then q6-12m

29. Case #2 Presentation Investigations
73 yo woman mild anemia and fatigue
Past med Hx: osteoarthritis
Presented in July 2013 after work-up for fatigue and back pain showed IgA M-protein
BMB 7% atypical plasma cells. Normal cytogenetics
Normal calcium, creatinine, skeletal survey
SPE IgA 35g/L IgA kappa
UPE IgA kappa
SFLC ratio=3 ( )

30. Question #2 What is the diagnosis? Low risk MGUS High risk MGUS
Smoldering Myeloma
Active myeloma

31. Myeloma Smoldering MM~10%/year risk of progression Active MM
M-protein>30g/L
and/or 10-60% plasma cells
No end organ damage or MDE
Active MM
Usually an M-protein
Often >10% plasma cells but not necessary
End organ damage
CRAB
Myeloma defining events
SFLC ratio >100
>60% plasma cells
2 or more focal bone lesions on MRI

32. Probability of Progression SMM verus MGUS
Figure 2. Probability of Progression to Active Multiple Myeloma or Primary Amyloidosis in Patients with Smoldering Multiple Myeloma or Monoclonal Gammopathy of Undetermined Significance (MGUS). I bars denote 95% confidence intervals.
1% per year vs 10% per year
Kyle R et al. N Engl J Med 2007;356:

33. SMM Prognostic Score Risk Factors Prognosis at 10 years
>10% plasma cells
M-protein >30g/L
Abnormal SFLC
Risk Factors
Risk of progression at 10 years 1
50% 2
65% 3
84%
In a retrospective review of 276pt at Mayo
Risk of progression to malignancy was 10%/year for the first 5 years
Then 3%/year for next 5 years
Then 1%/year thereafter

34. The case for observation…
50% of low risk SMM remain progression free after 5 years
Only Alkylators and Steroids…until recently
Hjorth M, Eur J Haematol 1993;50(2):
Riccardi A, Br J Cancer 2000;82(7):

35. Case #3 In 1999 a 62yo man presents with IgM MGUS
Discharged from WRCC 2010 stable M-protein~15g/L
In 2013 at age 73
diffuse adenopathy
bilateral peripheral sensory neuropathy
IgM ~17g/L
LN biopsy-amyloid deposits
BMB-lymphoplasmacytic lymphoma

36. IgM MGUS is associated with which of the following?
Amyloidosis
Waldenstrom’s Macroglobulinemia
Isolated Peripheral neuropathy
A and B
All of the above

37. Special Case of IgM MGUS
Association with neuropathy
Neuropathy of IgM MGUS usually bilateral, peripheral sensory. EMG shows demyelinating pattern biopsy can show axonal loss
Association with AL amyloid
WM-IgM M-proten, lympadenopathy, hepatosplenomegaly, BMB plasmacytoid lymphocytes, hyperviscocity
IgM Myeloma very rarely

38. IgM M-protein

39. Summary

40. For Low risk MGUS, what is this risk of progression to multiple myeloma at 20 years?
B 5%
C 20%
D 60%

41. Low risk MGUS High risk MGUS Smoldering Myeloma Active myeloma
If pt presents with M-protein=35g/L, BMB=7% plasma cells, no end organ damage. What is the diagnosis?
Low risk MGUS
High risk MGUS
Smoldering Myeloma
Active myeloma

42. IgM MGUS is associated with which of the following?
Amyloidosis
Waldenstrom’s Macroglobulinemia
Isolated Peripheral neuropathy
A and B
All of the above

43. Summary Low Risk MGUS Intermediate and High risk MGUS Smoldering MM
risk of progression 5% at 20 years
do not need BMB
short follow-up to ensure stable
Intermediate and High risk MGUS
consider BMB, bone imaging, MM labs
Ongoing follow-up q6m then annually
Smoldering MM
need careful ongoing follow-up q6m
but at 5 years 50% will not progress
IgM MGUS needs special attention

44. Useful References
September-october 2014, vol 11. Issue 5. Ask the Hematologist. A diagnostic Approach to Patients with IgM monoclonal protein
Blood Reviews 23 (2009) S Madan and P Greipp. Review:The incidental monoclonal protein: Current approach to management of MGUS
Lancet Oncology. Nov International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma

45. Order that SPE...