1. Smoldering Myeloma: Who and When to Treat; Should Smoldering High Risk Myeloma be Immediately Treated?
Raymond L. Comenzo, MD
Professor of Medicine and Pathology
Tufts University School of Medicine
Boston, Massachusetts

2. Case 1 52 year-old woman, asymptomatic Elevated total protein
IgGλ M-protein 3.6g/dL
FLC λ 123mg/L, Ratio 0.08
190mg BJP
30% PCs, standard risk cyto/FISH
Hemoglobin 11.8 g/dL
SS and spinal MRI negative
GFR and creatinine normal
NTX:Creat 102 units

3. Case 2 69 year-old man, asymptomatic Elevated total protein
IgGλ M-protein 3.6g/dL
FLC λ 123mg/L, Ratio 0.08
190mg BJP
30% PCs, del13q (6%) by CD138-FISH
Hemoglobin 11.0 g/dL
SS Negative, spinal MRI 2 lesions
CKD3
NTX:Creat Ratio 82 units

5. Smoldering Myeloma
Kyle NEJM 1980 (6 cases): We believe that a patient whose illness fulfills the criteria for the diagnosis of multiple myeloma should be observed off therapy if there is no anemia, bone lesions, hypercalcemia, or renal insufficiency Therapy may lead to leukopenia [And] unnecessary chemotherapy causes unnecessary expense, and it is a source of concern to the patient.
NEJM 1980;302:1347

6. Monthly Wholesale Acquisition Cost
Drug
Cost ($)
Carfilzomib (BSA 1.8)
5,936 (cycle 1)
8,013 (cycle 2)
Pomalidomide
10,437
Bortezomib (BSA 1.8)
4,106
Lenalidomide
8,673
Thalidomide
8,092

7. Asymptomatic Myeloma
Alexanian Blood 1980 (20 cases): Since asymptomatic patients with higher tumor mass grades are even less common chemotherapy should not be withheld in those rare asymptomatic patients with intermediate or high tumor mass. Also, the presence of an IgA myeloma protein or the excretion of more than 200 mg/day of Bence Jones protein favored the need for early chemotherapy. . . Serial assessments of myeloma protein level provided a useful index of changing tumor load and the need for chemotherapy.
Blood 1980;56:521

8. Progression of Asymptomatic Myeloma
Blood 2000;96:2037

9. Two Patterns of Changes in M-Ig Level During Progression to MM
Blood 2009;113:5418

10. Traditional Elements Traditional variables
Monoclonal protein status
Bone marrow plasmacytosis
Symptoms
Time
Traditional clinical philosophies
Minimalists vs. Intensivists
Palliation
Prolong survival

11. Modern Elements Translational science Modern clinical philosophy
Serum free light chains
New platforms for clonal genetics
New metrics of organ damage
Modern clinical philosophy
Incurable but treatable
Safety of high-dose melphalan
Effective less toxic new drugs
Patient involvement and advocacy
Changing view of risk

12. Would you consider treatment for High Risk Smoldering multiple myeloma?
PostPosted: Thu Feb 28, :23 pm
by DanaH
I would welcome the community's thoughts on early treatment of High Risk Smoldering multiple myeloma (high risk for progression to active disease) in the clinical trial setting. I am aware of early clinical trial intervention studies with Revlimid w/ Dex (Spanish study group as well as some centers in the US, I believe Dr. Emory ) and carfilzomib, Revlimid w/ Dex (NIH w/ Dr. Landgren). Have any smolderers considered this and actually participate(d) in these trials? Or would anyone currently under treatment for active multiple myeloma have or had considered this option prior to commencing treatment once their multiple myeloma became active, had you known you were at high risk for progression ? All opinions will be very much appreciated.

13. Re: Would you consider treatment for High Risk Smoldering mu
PostPosted: Thu Feb 28, :19 pm
by mrsv118
Dana H,
I am in the NIH trial. I went to the NIH and had all the testing done planning to enter the natural history study. My testing showed that i was a high risk smolderer according to the both the Italian and Spanish study protocol. Dr Landgren felt that I had a 75% chance of converting to active myeloma in the next two years. They had introduced the CRD for smolderers at a previous visit so I was already considering it and those odds were not for me. I didn't want to wait to be symptomatic before starting to fight it.
They are having great results thus far!
You need to meet them and have an evaluation before you think too much about this. Nothing wrong with standard therapy. Lots involved in making a decision like this besides the labs.
Can you get there easily, (its an eight month treatment, almost weekly). You may or may not be able to work depending on your response to the meds and what kind of job you have. Expenses are not totally covered. Your comfort level with the docs.
Good luck with your eval and your decision.

14. Symptomatic
Nature
of the Clone
Organs
at risk

15. Conditional Models Time to Event Risk of Event Predictive Tests

16. Mayo Clinic Risk Factors for Progression
The IMWG guidelines use the factors developed by the Mayo Clinic from their longitudinal study of 273 patients with a median follow-up of about 12 years.
The Mayo Clinic There are three risk factors for progression to MM or a related disease in patients who have SMM
BM PC infiltration greater than 10%
M-protein concentration greater than 3 gm/dL
And a skewed sFLC ration of either <0.125 or >8
These factors comprise three groups with increasing risks of developing MM with the risk at 10 years 50%, 65% and 84%.
You will notice that in SMM the two higher risk groups have the highest risk in the first 5-10 years, whereas following that they appear to platuea, whereas the lower riskgroup appears more like the pattern of MGUS wher there is a steady, in definite risk ofprogression. Thus, there appears to be an indefinite risk of progression and also importantly not all patients with these myeloma precursors states ill develop MM or a related dorsorder.
Mayo Clinic Risk Factors for Progression
BM PC >10%
M-protein > 3 g/dL
Skewed sFLC ratio <0.125 or >8.0
Leukemia 2010;24:1121
Seminars Hematol 2011;48:4 16

17. PETHEMA Risk Factors for Progression
The IMWG guidelines use the factors developed by the Mayo Clinic from their longitudinal study of 273 patients with a median follow-up of about 12 years.
The Mayo Clinic There are three risk factors for progression to MM or a related disease in patients who have SMM
BM PC infiltration greater than 10%
M-protein concentration greater than 3 gm/dL
And a skewed sFLC ration of either <0.125 or >8
These factors comprise three groups with increasing risks of developing MM with the risk at 10 years 50%, 65% and 84%.
You will notice that in SMM the two higher risk groups have the highest risk in the first 5-10 years, whereas following that they appear to platuea, whereas the lower riskgroup appears more like the pattern of MGUS wher there is a steady, in definite risk ofprogression. Thus, there appears to be an indefinite risk of progression and also importantly not all patients with these myeloma precursors states ill develop MM or a related dorsorder.
PETHEMA Risk Factors for Progression
aBMPC > 95%
Immunoparesis
Blood 2007;110:2586
Seminars Hematol 2011;48:4 17

18. Criteria for Diagnosis
Smoldering MM
3 g M-protein
or 10% PC
Symptomatic MM
M-protein
10% PC
MGUS
<3 g M-protein
<10% PC
No related organ or
tissue impairment
(no end-organ damage
including bone lesions)
or no symptoms
Related organ or
tissue impairment
(end-organ damage, including
bone lesions)
“CRAB”
BJH 2003;121:749
Leukemia 2010;24:1121

19. Waiting For The

20. Clinical Trials in SMM
Adapted from Clin Cancer Res 2013;19:985

21. QuiReDex Induction phase 28d cycles x 9 cycles Maintenance
Lenalidomide 25 mg/d D1-21
Dexamethasone 20 mg/d
D1-4, 12-15
Lenalidomide 10 mg/d
D1-21 every 2 mos
High risk SMM*
Observation
*High risk SMM
Both BMPC≥10% AND M-protein≥ 3 gm/dL OR
one of the above plus aPC >95% and immunoparesis
Mateos ASH 2011

25. QuiReDex SMM within the past 5 years Combined Mayo/PETHEMA high risk
Stratified
Combined Mayo/PETHEMA high risk
But no serum FLC
Asymptomatic
Skeletal survey at screening
Repeated only with symptoms
No MRI

26. QuiReDex Absolute risk reductions at 3 years Progression 82% Death 69%
Overall survival at 3 years
94% with LenDex
80% with observation
Number needed to treat
Two to prevent 1 progression
Seven to prevent 1 death
NEJM 2013;369:5
BMJ 1999;307:1492

27. IMWG Guidelines for SMM
Preventive clinical trials need to be considered for
patients with high risk smoldering myeloma.
Patients with smoldering myeloma with FLC ratio <0.125
or > 8 plus > 10% plasma cells in the marrow
are at high risk of progression in the first 2 years
following recognition.
These patients should be considered candidates for
chemoprevention trials. However, off-study,
observation is still the standard even in this group.
Leukemia 2010;24:1121

28. Numerous SMM Trials

29. Monthly Wholesale Acquisition Cost
Drug
Cost ($)
Carfilzomib (BSA 1.8)
5,936 (cycle 1)
8,013 (cycle 2)
Pomalidomide
10,437
Bortezomib (BSA 1.8)
4,106
Lenalidomide
8,673
Thalidomide
8,092

30. Case 1 52 year old-woman, asymptomatic Elevated total protein
IgGλ M-protein 3.6g/dL
FLC λ 123mg/L, Ratio 0.08
190mg BJP
30% PCs, standard risk cyto/FISH
Hemoglobin 11.8g/dL
SS and spinal MRI negative
GFR and creatinine normal
NTX:Creat 102 units

31. Wb-MRI in SMM
“End organ damage currently is the most important factor for the classification and the
decision to treat systemically in monoclonal plasma cell disease. Therefore, serum calcium,
renal damage, anemia, and bone destruction (ie, osteoporosis or focal lytic bone lesions)
are the most important parameters (ie, CRAB criteria).”
JCO 2010;28:1606

32. NTX:Creatinine Ratio
Leukemia 2010;24:1700

33. Case 2 69 year-old man, asymptomatic Elevated total protein
IgGλ M-protein 3.6g/dL
FLC λ 123mg/L, Ratio 0.08
190mg BJP
30% PCs, del13q (6%) by CD138-FISH
Hemoglobin 11.0g/dL
SS Negative, spinal MRI 2 lesions
CKD3
NTX:Creat Ratio 82 units

34. QuiReDex CD138-FISH abnormal in 91/123 (74%)
41% gain 1q
42% del 13q
9% del 17p
17% t(11;14)
12% t(4;14), 6% t(14;16)
8% 14q32 with unknown partner
No group or grouping predicted POD
11 before and at progression
Suggestive GEP
haematologica 2012;97:1439

35. E3A06 Groups 1 and 2 if the FLC ratio is <0.125 or >8.0
Within 12 months of diagnosis
SS negative
Serum FLC monthly
GEP
MRI spine and pelvis
NEJM 2007;356:25
Blood 2008; 111:785

36. CRd at NIH for High-risk SMM
Pilot study
8 cycles of CRd then 12 cycles lenalidomide extended dosing
Stem cell harvest after > 4 cycles
Primary objective is response rate
Correlative studies: GEP, proteasome activity, MRD by flow, FDG PET-CT

37. CRd at NIH for High-risk SMM
During screening for the trial many SMM patients had bone lesions detectable by CT or PET-CT; these patients were ineligible for the trial (due to multiple myeloma)
Among SMM without bone lesions, about 30% had increased PET uptake in the bone marrow
Depending on the extent of imaging, SMM for E3A06 but MM for CRd?

38. Cases Case 1 Case 2 Vaccinate Observe at 3 month intervals
Bisphosphonate
Offer E3A06
Case 2
Manage co-morbid conditions
Offer CRd or E3A06
Observe expectantly

39. Who and When to Treat
Not newly diagnosed patients with no evidence of evolving organ damage
Vaccinate
Observe at 3 month intervals
Offer E3A06
Observation
Follow clonal proliferation based on increasing M-protein or FLC
Follow for trends in organ damage
Biomarkers, including NT-proBNP

40. Should all high risk SMM patients be treated immediately?
Not as standard of care
Determine what the patient wants
Offer E3A06 or NIH CRd trial
Use best metrics for clone and organ damage
Follow trends
Image appropriately
MRI, PET/CT

41. Changing Landscape Up-dated IMWG guidelines will be forthcoming
How rational are our definitions?
How radically should they be changed?
Should we
re-define myeloma needing treatment?
re-group plasma cell diseases?
risk from clone and from organ damage
We must improve criteria for SMM trials
We must keep foremost in mind the urgency of relapsed refractory disease as the major driver