1. Asymptomatic plasma cell dyscrasias –Smoldering myeloma & MGUS
Aric Hall, MD
Assistant Professor – UW Health

2. Objectives To discuss pathophysiology of plasma cell disorders
To define and describe the asymptomatic plasma cell dyscrasias
To discuss prognosis
To discuss management
Questions and further directions

3. Plasma cell origin and function
Plasma Cells are terminally differentiated B cells whose function is the production of antibodies (=immunoglobulin = Ig)
Immunoglobulin is a Y shaped protein that binds and helps neutralize pathogens
This is the key portion of the adaptive immune system (part that recognizes stuff you’ve seen before)
Immunoglobulins provide a major mechanism of durable immunity

4. Functionality requires flexibility
Best “fit” variable region for pathogen
Appropriate heavy chain for needed function / location

5. Flexibility requires physiologic DNA alteration
Immune system needs to be ready for unknown unknowns
Goal is to create most avid, least self reactive, most functional antibody possible
Three points of physiologic double stranded breaks in DNA
Presumed to be a point of trouble

6. Protein testing for clonality- what is a M-spike
Normal  diverse plasma cell population, small amounts of many immunoglobulins
Neoplastic transformation  specific plasma cell gains a growth and proliferation advantage (single clone of plasma cells predominating & secreting a single immunoglobulin)
Clonal plasma cell ≠ Cancer
One way we assess this clonality is by looking at the products of plasma cells  immunoglobulins in the blood
Monoclonal protein (M-spike) indicator of a clonal plasma cell, unless you just make light chains

7. Protein Electrophoresis

8. SPEP Examples
Normal
Monoclonal gammopathy

9. Symptomatic multiple myeloma
Presence of clonal plasma cell population + end organ damage.
Organ damage is typically defined by CRAB
HyperCalcemia
Renal disease
Anemia
Bone Disease
Or now just by a very high burden of clonal plasma cells with presumed near 100% risk of ultimately causing organ damage

10. What are we talking about – MGUS
MGUS : “a clinically asymptomatic premalignant clonal plasma cell or lymphoplasmacytic proliferative disorder. It is defined by the presence of a serum monoclonal protein (M-protein) at a concentration <3 g/dL, a bone marrow with <10 percent monoclonal plasma cells, and absence of end-organ damage (lytic bone lesions, anemia, hypercalcemia, renal insufficiency, hyperviscosity) related to the proliferative process”

11. What are we talking about – Smoldering MM
SMM: “a clinically asymptomatic premalignant clonal plasma cell or lymphoplasmacytic proliferative disorder. It is defined by the presence of a serum monoclonal protein (M-protein) at a concentration >3 g/dL or a bone marrow with >10 percent monoclonal plasma cells but <60%,
and absence of end-organ damage related to the proliferative process and NOT involved/uninvolved light chains ration < 100:1 or > 2 bone lesions on advanced imaging > 5 mm in diameter

12. What we are NOT talking about…
“Asymptomatic” symptomatic multiple myeloma: No bone lesions, no anemia, no hypercalcemia, no osteoporosis, no kidney issues but biomarker criteria for MM
Solitary plasmacytoma, Plasmacytoma with minimal marrow involvement
Dangerous small clone diseases – Low burden of plasma cells but clinically significant and causing organ injury
AL amyloidosis, light chain and heavy chain deposition disease
Monoclonal gammopathy of clinical significance

13. AL amyloidosis

14. Amyloid Manifestations
If we can prove it, we should treat it

15. Monoclonal gammopathy of clinical significance
“dangerous small B-cell clone”
Low burden of abnormal plasma cells, low burden of monoclonal immunoglobulin
Usually felt to be due to direct deposition and injury from immunoglobulin or immunologic activation
Most common organs are kidneys, skin, peripheral nerves
Likely all rare, but we don’t really know how rare
If we can prove it, we should treat it
Fermand et al. Blood

16. Asymptomatic Plasma Cell Disorders- Very simple
MGUS : A low number of abnormal plasma cells that we can detect on monoclonal protein testing
SMM: More abnormal plasma cells that we can discuss on monoclonal protein testing but still short of the level where we think they are destined to get MM and there is no injury
These are neoplasms (“new growths”) that are cells proliferating under own guidance; therefore they have the potential to become cancer but are not harmful yet
Similar to polyps on colonoscopy or premalignant skin lesions

17. Epidemiology of asymptomatic plasma cell disorders
MGUS
Quite common – estimate about 3% of population > 50 years old
Perhaps as high as 10% of octogenerians
Main risks
Age
Male > Female
African American Ethnicity
Lower rates in East Asia
Smoldering MM- likely much rarer
< 1: 100, 000
Landgren et al. Leukemia 2014.

18. Diagnostic work - up
Full paraprotein evaluation (blood and urine labs)
Assess for anemia / high calcium / renal failure
If low risk MGUS (M-spike < 1.5 g/dL, Nl light chain ratio, IgG M-spike) and no evidence of lab abnormalities above can stop and watch without any further work up
If not, bone marrow biopsy to determine if smoldering myeloma vs MGUS (i.e. are there 10% plasma cells or less)

19. Further work up…
Smoldering MM – Need skeletal imaging, start with skeletal survey and if negative move on to advanced cross sectional imaging to exclude bone disease (CT-PET, MRI total spine and pelvis, whole body CT)
If weird organ dysfunction you can’t otherwise explain (i.e. heart failure, kidney injury, skin lesions) consider biopsy of target organ as this will be usually necessary to look for amyloid or monoclonal gammopathy of clinical significance

20. Cross Sectional Imaging

21. Risk Stratification

22. Risk of developing MM from MGUS – Very low
Historic cohort followed at Mayo Clinic
241 patients with at least 5 years of follow up where nothing bad had happened (no MM or WM)
Amount of monoclonal protein
corresponded to risk of progression
Kyle, R. Am J Med 1978: 815

23. Holds up over time… 22 years follow up
There are a few more progressions
But…
Rate of progression reduces with time
Young patients are likely harder to predict

24. MGUS - Stratification When we break down MGUS even clearer
Risk factors
Non-IgG subtype
Abnormal FLC ratio
M-spike > 1.5 g/dL
Stratify based on 1,2, or 3 risks
Rajkumar et al. Blood

25. Risk with SMM is MUCH, MUCH Higher
These are series of fewer patients, however, that are contaminated with patients we would now call symptomatic MM
Still, huge difference
Kyle et al. NEJM

26. Risk Stratification SMM- Old Mayo Model
Risk factors-
Marrow > 10% infiltrated
M-spike > 3 gm/dL
FLC ratio abnormal
Kyle et al. Leukemia

27. Risk Stratification MM- Spanish Model
2 risk factors
>95% “aberrant” plasma cells
Immunoparesis (Low “good” immunoglobulins)

28. Risk Stratification MM-Newer model?
Mayo : reviewed 421 SMM pts for factors that correlate with TTP to symptomatic myeloma
Bone marrow plasma cells >20% (HR CI )
M spike >2.0 g/dl at time of diagnosis (HR 1.56 CI )
FLC ratio>20 (HR 2.13, CI )
0 factors-110 months
1 factor 68 months
> 2 factors 29 months

29. “Other” High risk Features
High risk CG including t(4:14), -17p, and +1q
More urine protein rather than less
Rapidly increasing M-spike
Abnormal cross-sectional imaging even if not sufficient for diagnosis of symptomatic MM
Less clear how this predicts on its own (i.e. if I have otherwise low risk SMM and have high risk CG)

30. Difficulties with current risk stratification
Unfortunately, concordance between risk factors is not great
As definitions are shifting rapidly, the cohort we are diagnosing people in now will probably do differently than those we defined
Biggest strength is probably targeting high risk patients for potential intervention

31. Asymptomatic Plasma cell disorders- Management

32. MGUS – no interest in medical treatment
Standard of care remains periodic follow up
SEER data indicates that F/U is beneficial to avoid morbidity and death
No indication (yet) that early intervention will improve outcomes
Go et al. Clin Lymph Myelo

33. Non-pharmacologic interventions?
Unfortunately, not a lot of things we have to offer
There are small analyses that suggest obesity is a risk factor for early progression after transplant and remission and for MGUS  MM
This could actually represent many patterns of causality, there is no evidence any natural product prevents /slows progression

34. Smoldering MM- Interest in treating for a long time
Ref
Intervention N
PFS OS 1
Mel-Pred: early vs delayed 50
12 mo ND
2,3
145
~12mo
64mo vs 71 mo
4,5
Pamidronate vs Obs
174
5yr 53%; SRE 74% vs 39% (p<.01)
46 vs 48 mo 6
Zol vs Obs
169
67 vs 59 m, p=NS
SRE 55% vs 78% (p<.05) 7
Thal-Zol vs Zol 68
29m vs 14m (p<.01)
6 yr>70% 8
Silituximab vs Obs 85
1 yr PFS 84.5% vs 74.4%
Not reached
1.Horth M, EJH :
2. Riccardi A BJC :
3. Riccardi A BJC :
4. Musto P Leuk Lymph 44:
5. D’Arena G. Leuk Lymph : 771
6. Musto P Cancer :88
7. Witzig T Leukemia :220
8. Brighton B Clin Canc Res 2019 ePub

35. Targeting High Risk SMM
Now MM
People above the line are those still at risk of developing MM
Trying to target and help the group in the green box is probably highest value
Kyle et al. NEJM

36. 1st Successful Phase III trial - QuiReDex
125 high risk patients in Spain or Portugal
Randomized to Lenalidomide (Revlimid)/ Dexamethasone X 9 mos then lenalidomide versus observation
High risk defined by Spanish system (unclear how mirrors our patients)
Surprising Results
Unsurprising Results
Mateos et al. Lancet Onc

37. Why didn’t Lenalidomide / Dex become standard of care?
They did not do cross sectional imaging did not have biochemical criteria for disease, concern contaminated with “real” MM
Median PFS in control arm 23 mos, shorter than even really high-risk people in Mayo risk or Spanish risk papers
Unclear need for dexamethasone – Hated by patients
Aberrant plasma cell testing not usually standard in US

38. US study to look at high risk smoldering MM
E3A06: Phase III – Asymptomatic Myeloma*(PI: Sagar Lonial)
Lenalidomide vs. observation:
Does dexamethasone make a difference?
Observation
Lenalidomide
CR/PR/
Stable
Prog.
anytime
Continue therapy
till prog. or toxicity
Off Rx
RANDOMI
ZAT
ION
N=226 pts
10/23 ACTION LETTER DSMB: PFS favors lenalidomide group!
ASCO Sunday June 3, 2019 – PFS at 3 years 91% vs 66%

39. EA306 Results – Still questions
66% PFS at 3 years is still pretty good, puts the control arm between low and intermediate on the old Mayo hierarchy (is this what we see with “real” smoldering where we’ve ruled out the people we’d now call MM)
No survival advantage (wouldn’t expect to see yet)
Lenalidomide is expensive, and there are toxicities
Alongside these efforts there is a new idea…. “cure” of smoldering MM

40. KRD/R maintenance for high-risk SMM*
*FLC ratio >8; or<0.125
Korde N JAMA Onc : 746

41. GEM-CESAR (Curativo Estrategia Smouldering Alto Riesgo): Phase II Study Design
Multicenter, open-label trial
Consolidation 2 x 28-day cycles
Maintenance 24 x 28-day cycles
Induction 6 x 28-day cycles
Carfilzomib IV 20/36 mg/m2 Days 1, 2, 8, 9, 15, 16
Lenalidomide 25 mg Days 1-21
Dexamethasone 40 mg Days 1, 8, 15, 22
High-dose Melphalan 200 mg/m2 followed by ASCT
Carfilzomib IV 20/36 mg/m2 Days 1, 2, 8, 9, 15, 16
Lenalidomide 25 mg Days 1-21
Dexamethasone 40 mg Days 1, 8, 15, 22
Lenalidomide 10 mg Days 1-21
Dexamethasone 20 mg Days 1, 8, 15, 22
Patients with high-risk* smoldering MM
(N = 90)
ASCT, autologous stem cell transplantation; MM, multiple myeloma; MRD, minimal residual disease; sCR, stringent CR; TTP, time to progression.
Primary endpoint: MRD negative rate (by flow cytometry) after induction, ASCT, consolidation/maintenance, and 3 and 5 yrs after maintenance
Secondary endpoints: response, TTP, PFS, OS, safety
*High risk defined per Mayo and/or Spanish models (pre-2014 diagnostic criteria)
Pts with both BM PCs ≥ 10% and serum M- protein ≥ 3g/dL, or 1 plus > 95% aberrant BM PCs by immunophenotyping plus immunoparesis
Pts w/ bone disease on CT or PET/CT at screening excluded
Mateos MV, et al. ASH Abstract 402.

42. GEM-CESAR: PFS and OS Median follow-up: 10 mos (range: 1-28) PFS OS
1.0
1.0
0.8
0.8
0.6
0.6
Proportion Remaining Alive
Proportion Without Progression
0.4
0.4
0.2
0.2
94% PFS at 28 mos
98% OS at 28 mos 5 10 15 20 25 30 10 20 30
Mos
Mos
2 deaths: 1 due to progression after relapse from CR, 1 due to ischemic stroke during induction
2 pts relapsed from CR during induction, proceeded to subsequent therapy
Mateos MV, et al. ASH Abstract 402.

43. EA173: Phase III –Daratumumab to Enhance Therapeutic Effectiveness
of Revlimid in Smoldering Myeloma (DETER-SMM)(PI: NC)
Lenalidomide
+ Dex
Daratumumab
+ Lenalidomide
CR/PR/
Stable
Prog.
anytime
Continue therapy
For 2 years
Off Rx
RANDOMI
ZAT
ION
N = 288
PI: Natalie Callander (Activated – just s starting)

44. Summary – MGUS
MGUS is a common condition associated with age in which the majority of patients will never develop a plasma cell cancer
Higher or non IgG M-spike as well as abnormal free light chain ratio are main indicators of risk of progression
Regular surveillance of paraprotein (at least yearly) seems to be associated with better outcomes

45. Summary - SMM
The actual prevalence of smoldering myeloma is unknown and given shifts in diagnosis it is somewhat unclear how high the risk of progression is
Bone marrow plasma cell burden >20%, M-spike > 2 gm/dL, and FLC ratio >200 are all associated with worse risks of progression
Studies of treatment of high-risk SMM have had mixed results but lenalidomide with or without dexamethasone seem to be associated with a progression free survival advantage though overall survival unclear

46. Summary - General
The best therapeutic management of high-risk SMM at the moment is a clinical trial
Patients may choose between lower intensity type protocols to prolong time to progression vs “nuclear option” type trials to attempt cure
Clinical suspicion and curiosity as well as possible biopsy of target organ are the major paths to finding pathologic small clone diseases