1. University of Wisconsin Carbone Cancer Center
MGUS and Smoldering Myeloma: Risk stratification and Therapeutic Options
Natalie S. Callander, M.D.
University of Wisconsin Carbone Cancer Center

2. 1. MGUS definition
2. Factors associated with MGUS progression
3. Appropriate evaluation
4. SMM definition
5. Factors associated with SMM progression
6. Are we ready to treat SMM outside of a clinical trial?

3. Monoclonal gammopathy (MGUS)
SPEP Longsworth Shedlovsky and MacInnes reported on method to separate and quantitate serum and plasma proteins
1944- Waldenstrom reports on 3 patients with “essential hyperglobulinemia”2,possibly “premyeloma”
Scattered reports in 1960s of patients with excess immunoglobulins
Also called benign monoclonal gammopathy
Longsworth L et al J Exp Med :355
2Waldenstrom J Acta Med Scan97

4. Letters sent to every pt (!), death certificates obtained if relevant
Identified 241 pts who had at least 5 years of follow up and no evidence of myeloma or Waldenstrom’s
Letters sent to every pt (!), death certificates obtained if relevant
Some of his original observations remain true:
Amount of monoclonal protein associated with progression to MM
Presence of proteinuria not always indicative of progression to MM
Kyle, R. Am J Med 1978: 815

5. What happens to people with MGUS

6. MGUS Estimates 3% of general population age 50 (US, Sweden)
8-10% of octogenarians
Lower rates Japan, China, Thailand,
Current definition:
<3g/dl monoclonal protein (IgG, IgA, rarely IgD)
<10% monoclonal plasma/lymphoplasmacytic cells
No SLIM-CRAB
No “SLiM CRAB”

7. Other MGUS variants1 All MM starts as MGUS
Light-chain MGUS
Abnormal FLC ratio (<0.26 or >1.65); increased level of involved LC; no Ig found on IFE
<10% plasma cells
<500mg/24 hours LC
IgM MGUS:
Serum M protein <3g/dl
LPL cells<10% in marrow
no end organ damage
Rajkumar Lancet Oncol :538
Langren Blood 117: 5127

8. Obesity and Ethnicity contribute to risk of progression
Chang S JNCI 2017https://

9. MGUS more common in African-Americans and appears at younger age
Landgren O Leukemia :1572
Landgren O Blood CanJ :e618
Recent study of CoMPASS samples identified higher incidence of p53 and IRF4 mutations in CA versus higher rate
of BCL7A, BRWD3, AUTS2 mutations in AA samples Manojlovic Z Plos Genet :e

10. AGENT ORANGE EXPOSURE AND MGUS RISK
OR 2.37 ( ) for AO exposure; 47% had detectable
Dioxin; higher levels associated with higher MGUS risk
Langren JAMA Onc :1061

11. MGUS risk increased in 9/11 First Responders HR 1. 8 overall, 3
MGUS risk increased in 9/11 First Responders HR 1.8 overall, 3.0 for LC MGUS
Landgren JAMA Oncol. 2018;4(6):821

12. Serum Free Light Chain Ratio as Independent Risk Factor for Progression in MGUS
Baseline serum samples obtained within 30 days of diagnosis were available in 1148 of 1384 MGUS patients seen at the Mayo Clinic from 1960 to 1994
Malignant progression occurred in 87 (7.6%) patients at a median follow-up of 15 years
An abnormal free light chain (FLC) ratio (κ:λ ratio <0.26 or >1.65) was detected in 379 (33%) patients. The risk of progression in patients with an abnormal FLC ratio was significantly higher compared with patients with a normal ratio (P<.001) and was independent of the size and type of the serum monoclonal (M) protein
Patients with an abnormal serum FLC ratio, non-IgG MGUS, and a high serum M-protein level (≥15 g/L) had a risk of progression at 20 years of 58% (high-risk MGUS) vs 37% with any 2 of these risk factors (high-intermediate risk), 21% with 1 risk factor (low-intermediate risk), and 5% when none of the risk factors were present (low risk)
Rajkumar SV et al. Blood. 2005;106:812 12

13. Do Cytogenetic/FISH/Molecular alterations in MGUS predict progression?
Often Seen at presentation
Acquisition may be associated with progression to SMM or MM
(14q32) IgH rearrangements common and likely early event (40-50%)1,2
Alteration in 13 (30-50%)
Hyperdiploidy
t(11;14) (q13q32) about 20%
t(4;14) (p16.3q32), t(14;16)q32;q23 less common, 5%
t(14;20) 5% -better course?4
MYC alterations
1q21 amplification (infrequent in MGUS)
Kras, Nras
Del 1p
Del 17 p
Increase in Hypomethylation?
1Fonseca Blood :1417; 2Chesi M In J Hem 97:313 3Hanomura Blood : Ross Haematol 5: 1221

14. No treatment indicated but F/U advisable
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 R. Clin Lymph Myelo :

15. Follow up 6 months or sooner if new sx/signs develop
SUGGESTED EVALUATION FOR MGUS
Monoclonal protein <1.5g/dl
FLC ratio <8 or >0.125
IgG paraprotein
Monoclonal protein
>1.5 g/dl
FLC ratio >8 or <0.125
Non IgG paraprotein
Symptoms?
Significant comorbidities?
No other symptoms: anemia, renal insufficiency, osteoporosis or sclerosis, neuropathy, GI (e.g. chronic diarrhea), CHF, fatigue, weight loss
Bone Marrow Biopsy with FISH/Cyto
Bone imaging
Urine for total protein, UPEP:
Still MGUS?
Rule out amyloidosis POEMS, active MM
Monitor in 6 months for any change
If none, consider annual F/U with PCP/heme
Exercise, weight loss?
After 6 mo., significant increase (25-50) in M spike, FLC, new symptom or sign?
Follow up 6 months or sooner if new sx/signs develop

16. Tale of 2 MGUS pts
56 y.o. female with treated
for “osteoporosis”; known compression fx; osteoporosis seems to be worsening over yrs, hgb 11.5 g/dl-
had been 13g/dl 2 yrs previously
Found to have small serum IgG lambda, 0.8g/dl M spike;
referred
67 year old male referred due to concerns of “vasculitis” in 2009-transiently cold toes
Previous history CAD, aortic stenosis, HTN, DM II, CKD stage II, s/p DCP for arrhythmia
Asymptomatic, exam showed obese male, no skin lesions, purpura
Labs: nl WBC, Hgb 15g/dl, IgG lambda M protein 0.4g, λ light chains 12mg/dl; bone marrow biopsy 9% plasma cells; no amyloid; cryo neg; EMG neg
After 8 yrs-M protein still 0.4g/dl; cold toe symptoms never recurred

17. Smoldering myeloma Term coined by Kyle and Elveback (1976)
Kyle and Griepp in reviewed 334 cases of MM (10% PC, >3 g/dl M spike) prior to 1974
Identified 6 pts who did not develop MM over at least a five year observation period,
Suggested that PCLI was best way to discriminate SMM from MM
SMM entity adopted by IMWG in 20032
1NEJM : Br J Haemato 2003: 749

18. Current definition of SMM: still some debate on definition:
rare entity (0.44 /100,000)1
>10% but <60% monoclonal plasma cells in marrow AND
No SLiM-CRAB (i.e. FLC ratio >100, no more than 1 lesion by MRI)
>3g/dl of monoclonal protein OR
>500mg/24 hours of monoclonal protein2
95% phenotypically aberrant plasma cells (CD19-/dim CD 45-/dim CD38low CD 56high)
with immunoparesis of > 1 uninvolved Ig class3
>1g/24 hours of urinary monoclonal protein
>2g/dl of IgA monoclonal protein
Kristinsson NEJM :1762.2Rajkumar Sv. Lancet : Perez-Persona E. Blood :2586.

19. Increased risk of progression to MM confirmed by examination
of 3549 pts, of whom 276 pts
(8%) met definition of SMM
83% had “immunoparesis”
84% had <0.1g/24h proteinuria
Kyle RA NEJM :2582

20. Ultra high risk SMM-shifted over to MM definition
These patients moved over to myeloma category
Risk of progression between % in two years
>60% plasma cells
>100 FLC κ/λ ratio1
Larson JT Leuk : Waxman J Leuk : 751

21. “Evolving” monoclonal protein may increase progression risk
Evaluated 53 pts with SMM
Separated those whose M protein increased 2/2 consecutive visits, vs those with stable M protein
Evolving pattern was associated with 66% and 88% 2 and 5 yr. rate of progression vs 12% and 58%, respectively
Rosinol L Br J Amatol :631

22. Imaging studies that help discriminate SMM from Myeloma (much better than skeletal survey!)
Whole Body MRI: >1 focal lesion
Pelvic/Spine MRI
Low dose whole body CT
18FDG-PET/CT
Helps appropriately classify patients with true myeloma who should be treated

23. 18FDG-PET may help determine SMM risk of progression
120 pts with SMM
About 10% had MM by current definitions (i.e. osteocytes lesions present)
16% of pts had positive PET without evidence of lytic bone disease or diffuse marrow involvement
Relative risk of skeletal progression was 3.0 (95% CI , P= 0.013) if PET scan was abnormal
Zamagni E Leukemia :417

24. Can we better define SMM progression risk through cytogenetics and FISH?
Increased risk of progression to MM seen with deletion 17p13, t(4;14) and 1q21+, found in 6.1%, 8.9% and 29.8% respectively
Hazard ratios 2.9, 2.3 and 1.7, respectively
Hyperdiploidy also associated with risk of progression (HR1.7), found in 43.3% of pts (somewhat different from MM2)
Presence of lambda light chains, higher PC% in marrow also associated with progression to MM
Neben K JCO :4325; 2 Chreitien M Blood :2713

25. Presence of circulating plasma cells (cPCs) associate with progression to MM
Detection by FC of clonal cPCs with abnormal CD 19/CD45 in peripheral blood are correlated with progression to MM
Pts with highest levels (>150/150,000 events) are at highest risk
Gonsalves W Leuk :130

26. Molecular/Genetic Evolution in SMM
WGS in 11 pts with SMM that progressed to MM
Translocation of MYC found in 5/11 pt samples-important driver
Pts exhibited “static progression” (i.e. all genomic alterations present) or “spontaneous evolution”, where subclonal population appeared to evolve1
Bolli N et al. Nature Comm :3363

27. Are we ready to treat SMM as part of standard of care if certain features are present?
Level of bone marrow plasmacytosis
Level of and rate of increase of M protein
Abnormal FLC ratio
Circulating plasma cells
Aberrant PC on flow cytometry
Bence Jones proteinuria
CONCORDANCE BETWEEN THESE
RISK FACTORS IS UNCLEAR
Immunoparesis
Presence of 17p53 deletion, 1q21 amplification, t(4;14)
Radiographic features by PET or MRI
Gene expression profiling (GEP70) signature
Dhodapkar MV et al. Blood 2014 Fernández Larrea C et al. ASH Khan RC et al. Haematologica 2015 Neben et al. JCO 2013; 31: ; Rosinol BrJ Haematol 2003; Gonsalves W Leuk :130; Dispenzieri A Blood :785

28. Landscape of SMM
Observation still
appropriate
Redefined as MM
High risk SMM: Standard of care to treat off protocol?

30. Can you improve upon these results?
Early treatment was associated with improved survival
BUT….
49% experience biochemical or symptomatic progression
While on len maintenance, 39% (22/57)
ultimately developed symptomatic myeloma
10% vs 2% subsequent cancers
Can you improve upon these results?
Mateos V Lanc Oncol :1127

31. 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
This trial has completed accrual, results awaited

32. KRD/R maintenance for high-risk SMM*
*FLC ratio >8; or<0.125
Mailankody S, Blood Adv :1911; Korde N JAMA Onc : 746

33. 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.

34. GEM-CESAR: Baseline Characteristics
Pts (N = 90)
Median age, yrs (range)
59 (33-70)
Serum/urine M protein, g/dL / g/24 hr
2.77 / 0.43
BMPC, % (range)
22 (10-80)
High risk, n (%)
Mayo Clinic model only
Spanish model only
Both
19 (21)
47 (52)
24 (27)
Ultrahigh risk (≥ 1 biomarker), n (%)
sFLC > 100
> 1 focal lesion on MRI
≥ 60% BMPC
30 (33)
18 (20)
11 (12)
7 (8)
PET positive with no lytic lesions, n (%)
5 (6)
Cytogenetic abnormalities, n (%)
Standard risk
High risk
Unknown risk
56 (62)
21 (23)
13 (14)
BMPC, bone marrow plasma cell; sFLC, serum free light chain.
Mateos MV, et al. ASH Abstract 402.

35. 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
Mos 5 10 15 20 25 30
Mos 5 10 15 20 25 30
Mos
Mos
2 pts relapsed from CR during induction, proceeded to subsequent therapy
2 deaths: 1 due to progression after relapse from CR, 1 due to ischemic stroke during induction
Mateos MV, et al. ASH Abstract 402.

36. Actively accruing trials for SMM
Elo Len Dex
Ixazomib/Len/Dex
Ibrutinib
SQ daratumumab vs Obs
Silituximab vs Placebo
Daratumumab, single arm, different dosing schedules
Carfilzomib, Len, Dex (continuing)
Multipeptide vaccines
Discontinued/no effect:
Nivolumab/Len/Dex (PD-1 concern)
fenofibrate

37. Smoldering MM
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 (Awaiting activation)

38. Trial design
Statistical considerations: median OS from 6y on the Rd control arm to 25y on the DRd experimental arm
Accrual duration is estimated to be 4y, given an accrual rate target of 72 patients per year (6 patients per month).
ASSESS MRD by NGF and NGS at baseline, 12 mo, and end of study; correlate with PFS and OS
FDG-PET at baseline, 12 mo and EOT: correlate with PFS and OS
Important QoL measures: PRO-CTCAE, ASK-12, FACT-G

39. Key entry criteria
Asymptomatic high risk SMM, diagnosed within 12 mo. of enrollment
Bone marrow aspirate and biopsy with >10% plasma cells
Any one of the following criteria:
Abnormal free light chain ratio(<.125 or >8)
M protein >3 g/dl
t(4;14), del17p or gain of 1q
M spike at least >1g/dl or monoclonal protein in urine of >200 mg/24 hours

40. Conclusions
MGUS is a common and often benign entity of unknown etiology
More common in Northern European, AA populations
Bone marrow biopsy can be deferred in asymptomatic pts with low levels (<1.5g/dl) of M protein, normal/low FLC ratio, expected short survival
Low risk MGUS patients should be followed serially, but infrequently (PCP)
Pts with higher M protein, FLC level and non IgG protein, suggestive symptoms more likely to progress and require full evaluation and more frequent follow up

41. Conclusions
Smoldering myeloma carries higher risk of progression to myeloma; lower risk SMM may not require Rx ( pending ECOG E3A06)-M protein, FLC, nonIgG, FISH
SMM patients should be evaluated with imaging in order to rule out MM;
High risk smoldering myeloma should be treated as part of a clinical trial, pending mature results of CESAR, other trials