1. How Should High Risk AMM be treated? Treat Now
Sagar Lonial, MD Professor, Winship Cancer Institute
Director of Translational Research,
B-cell Malignancy Program

2. Real Case 52 year old healthy surgeon presents with knee pain
MRI done shows marrow infiltration, no bone disease. Has extensive workup that shows no m protein, normal renal and chemistries, CBC shows Hgb of Freelight ratio of >100, UPEP ufix only.
PET and MRI shows no lytic disease
Marrow shows 40% plasma cells, normal cyto, negative FISH panel

3. Additional details Hgb 1 month ago was 14 B2M is 2.2, albumin is 3.9
Would you treat this patient?
What are you waiting to happen before you treat him?
Does something bad have to happen before you start treatment? Why???

4. Our ‘Case’
Male with no anemia, >10% plasma cells, and m protein of >3gm/dl
What does this mean in terms of his risk of progression?

5. Criteria for Diagnosis of Myeloma
SMM
≥ 3 g M spike
≥ 10% plasma cells
Active MM
≥ 10% plasma cells
M spike +
AND
MGUS
< 3 g M spike
< 10% plasma cells
AND
No anemia, bone lesions,
normal calcium, and
kidney function
Anemia, bone lesions,
high calcium, or
abnormal kidney function
MGUS = monoclonal gammopathy of unknown significance; SMM = smoldering multiple myeloma.
Kyle et al, 2009.

6. We were not given specifics on risk
SMM “Conversion”
Clearly not all patients are the same with SMM
Is there a way to identify ‘Some’ of the patients such that…
“Should patients with high risk Asymptomatic or Smoldering MM (AMM) receive treatment as routine care?”
We were not given specifics on risk

7. Smoldering Multiple Myeloma
27% will convert in 15 years
Roughly 2% per year
Kyle R et al. N Engl J Med 2007;356:

8. Initial Risk Stratification
2 yr
19 yr
8 yr
Patients with >10% plasma cells and >3gm/dl M protein are at higher risk
Kyle R et al. N Engl J Med 2007;356:

9. Free Light is Useful for Risk Assessment in AMM
Dispenzeri et al Blood 2008

10. This is all well and good, but can we know more?
How can we differentiate from those just stopping by AMM on their way to MM vs those who really have AMM?
Mayo team suggests patients with freelight ratio >100 or >60% plasma cells have a much higher risk and should be treated
No prospective data to support this analysis

11. Freelight Ratio >100 predicts risk
Larsen et al, Leukemia 2013

12. There are patients with higher risk of progression to MM
These patients can be defined by the use of simple testing
There is a subset of high risk AMM patients that progress to MM on average within 2 years.
Can we change the natural history of their disease for these patients?

13. Trials with old treatments
Use of MP was tested in 3 small trials in the past
No improvement in outcomes was noted
Risk of MDS among early treated patients.

14. The use of Thalidomide in SMM
3 trials have been done to date (MDACC, Mayo, UAMS)
2 showed longer TTP for responders to thal,
UAMS trial showed shorter TTP for responders to thal.
No improvement in OS

15. What was the Price of Early Therapy
Toxicity of therapy was significant
Significant PN was noted
Median duration of thal was short in Mayo study
“Despite our results and those reported by others, we do not recommend the use of thalidomide for SMM.”
Detweiler-Short et al, AMJ 2010

16. Smoldering multiple myeloma: aberrant PCs by immunophenotype plus immunoparesis
1.0
p = 0.003
>95% aPC/BMPC + paresis
n = 39 (28 progr.)
Median 23 months
0.8
82%
> 95% aPC/BMPC or paresis
n = 22 (10 progr.)
0.6
Median 73 months
TTP (%)
42%
No adverse factors
n = 28 (1 progr.)
0.4
0.2
Median not reached 8%
0.0 24 48 72 96
120
Months
Perez-Persona E, et al. Blood. 2007;110:

17. Schedule of therapy (n:126 pts)
Treatment arm (n = 60)
Control arm (n = 66)
Lenalidomide
25 mg/daily during 21d every 28 d
Dexamethasone
20 mg D1-D4 and D12-D15 every 28 d
Induction
Nine 4-week cycles
Therapeutic abstention
Lenalidomide
10 mg/daily during 21 d
every month*
Therapeutic abstention
Maintenance
Ammendment on August 2011: Stop treatment at 2 years of treatment
* Low-dose Dex will be added at the moment of biological progression

18. PFS for Early treatment
Mateos et al, NEJM 2013

19. Len-dex: toxicity profile during induction (n:57)
Anemia
15 (28%)
1(2%)
Neutropenia
11 (20%)
3 (5%)
Thrombocytopenia
7 (13%)
1 (2%)
Asthenia
4 (7%)
Constipation
10 (18%) -
Diarrhea
13 (24%)
Rash
18 (33%)
2 (4%)
Parestesias
Tremor
Infection*
25 (46%)
4 (6%)
DVT**
One infection was Grade 4
**DVT prophylaxis with Aspirin (100mg) in 1 pt, oral anticoagulation in 1 pt with low INR levels and no px in the other one

20. OS from study entry
Mateos et al, NEJM 2013

21. Initial Review of the data
Very impressive effect of a novel treatment approach
Treatment with modest toxicity
Preliminary encouraging data demonstrates a change in the natural history for early treatment
If we presume the patient has high risk AMM, then this data supports early intervention.

22. Treat or not to Treat? For low risk AMM, observation is reasonable
For patients with concerns for high risk disease, what are you waiting for?
For intermediate risk, may be able to alter the natural history of disease
For all cases, close follow up and tempo of disease is critical

23. ECOG/SWOG: Phase III – Asymptomatic Myeloma*(PI: SL)
Lenalidomide vs. observation
No Dex to isolate the effect of len
Observation
Lenalidomide
CR/PR/
Stable
Prog.
anytime
Continue therapy
till prog. or toxicity
Off Rx
RANDOMIZATION
Control/standard arm

24. So Where does that Leave us?
Preliminary data looks encouraging.
This patient meets criteria for high risk AMM and thus should be treated before irreversible toxicity sets in

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