1. Smoldering Myeloma: To Treat or not to Treat
Ruben Niesvizky MD Myeloma Center Myelomacenter.org

2. CASE
A 47-year-old man is diagnosed with smoldering multiple myeloma. He has 14% phenotypically aberrant plasma cells in his bone marrow and an IgG-lambda monoclonal protein measuring 3.6 gm/dl. Blood counts, renal function, and serum calcium levels are normal. He has no detectable bone lesions.
Observe and withhold treatment until his disease meets CRAB criteria ??

3. No glomerular proteinuria: ? AL amyloid
CASE: Observe vs Treat
No CRAB
IgG lambda
M-protein 3.6 gm/dl.
14% phenotypically aberrant plasma cells
Evolution of disease?
Free light chains?
Cytogenetics/FISH?
Uninvolved Ig ?
Doubling time?
No glomerular proteinuria: ? AL amyloid

4. Gompertzian Growth 1012 Precursor Disorders MGUS Smoldering 109 105
Renal Failure Myelosuppression
Bone disease Hypercalcemia
109
Mol CR, IF CR: MRD
105
Surviving clone

5. Kyle R. N Engl J Med 2007; 356:

6. CASE: Observe vs. Treat No CRAB IgG lambda M-protein 3.6 gm/dl.
14% phenotypically aberrant plasma cells
Evolution of disease?
Free light chains?
Cytogenetics/FISH?
Uninvolved Ig ?
Doubling time?

7. Kyle RA et al. N Engl J Med 2007;356:2582-2590.
Risk Factors for Disease Progression among 276 Patients with Smoldering Multiple Myeloma (1970–1995).
Kyle RA et al. N Engl J Med 2007;356:

8. CASE: Observe vs. Treat No CRAB IgG lambda M-protein 3.6 gm/dl.
14% phenotypically aberrant plasma cells
Evolution of disease?
Free light chains?
Cytogenetics/FISH?
Uninvolved Ig ?
Doubling time?

9. Kyle RA et al. N Engl J Med 2007;356:2582-2590.
Risk Factors for Disease Progression among 276 Patients with Smoldering Multiple Myeloma (1970–1995).
Kyle RA et al. N Engl J Med 2007;356:

10. Smoldering multiple myeloma: aberrant PCs by immunophenotype
Gating strategy for PC analysis by multiparametric flow cytometry.
Pérez-Persona E et al. Blood 2007;110:

11. Smoldering multiple myeloma: aberrant PCs by immunophenotype
Aberrant Plasma Cells
CD45 CD19 CD56 % − − − − − 24 −/dim − + 11 − Dim − − 5 − + − 1 + Dim ++ 1
Paiva et al., Leukemia (2013) 27, 2056–2061

12. Smoldering multiple myeloma: aberrant PCs by immunophenotype
Time to progression in MGUS and SMM according to the percentage of immunophenotypically aberrant plasma cells.
MGUS
Smoldering MM
Pérez-Persona E et al. Blood 2007;110:
©2007 by American Society of Hematology

13. Smoldering multiple myeloma: aberrant PCs by immunophenotype
Paiva et al., Leukemia (2013) 27, 2056–2061

14. CASE: Observe vs. Treat No CRAB IgG lambda M-protein 3.6 gm/dl.
14% phenotypically aberrant plasma cells
Evolution of disease?
Free light chains?
Cytogenetics/FISH?
Uninvolved Ig ?
Doubling time?

15. Smoldering Multiple Myeloma
M- protein in serum ≥ 30 g/L AND/OR
Bone Marrow clonal plasma cells ≥ 10%
No CRAB
10% 3% 1%
IMWG Br J Haematol 2003; 21:749-57
Kyle R. N Engl J Med 2007; 356:

16. CASE: Observe vs. Treat No CRAB IgG lambda M-protein 3.6 gm/dl.
14% phenotypically aberrant plasma cells
Evolution of disease?
Free light chains?
Cytogenetics/FISH?
Uninvolved Ig ?
Doubling time?

17. Free Light Chains as a Predictor
Dispenzieri et al, Blood 2008 Jan 15;111(2): Epub 2007 Oct 17.

18. Probability of Progression (%)
Smoldering MM: PCs BM infiltration and serum M-component level plus sFLC ratio
100
p < 0.001
Gr 1:TTP 1.9 y 80
Gr 2: TTP: 5 y 60
Gr 3: TTP 10 y
Probability of Progression (%) 40
No. of risk factors No. Rel risk
1 81 1
(1.2–2.9)
(2.6–6.1) 20 5 10 15
Years
PCsBM Infiltration ≥ 10%
Serum M protein ≥ 3 g/dL
Serum FLC ratio < 1/8 or > 8
Kyle RA, et al. N Engl J Med. 2007; 356:
Dispenzieri A, et al. Blood. 2008;111:785-9.

19. CASE: Observe vs. Treat No CRAB IgG lambda M-protein 3.6 gm/dl.
14% phenotypically aberrant plasma cells
Evolution of disease?
Free light chains?
Cytogenetics/FISH?
Uninvolved Ig ?
Doubling time?

20. Impact of gain 1q, del(17p13), t(4;14), and ploidy status on time to progression in patients with smoldering multiple myeloma.
Neben K et al. JCO 2013;31:
©2013 by American Society of Clinical Oncology

21. CASE: Observe vs. Treat No CRAB IgG lambda M-protein 3.6 gm/dl.
14% phenotypically aberrant plasma cells
Evolution of disease?
Free light chains?
Cytogenetics/FISH?
Uninvolved Ig ?
Doubling time?

22. Kyle RA et al. N Engl J Med 2007;356:2582-2590.
Risk Factors for Disease Progression among 276 Patients with Smoldering Multiple Myeloma (1970–1995).
Kyle RA et al. N Engl J Med 2007;356:

23. 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:

24. Risk of SMM progression to active MM according to different prognostic systems as compared with risk of progression of MGUS to active MM. Gray shading includes 2-year time point.
Dispenzieri A et al. Blood 2013;122:

25. Ultra High Risk Smoldering

26. Smoldering multiple myeloma: early treatment
Conventional agents
Initial MP vs
Deferred MP1,2,3
No benefit in ORR/TTP/OS
Novel agents
Thalidomide4,5
~ 30% ≥ PR; high toxicity;
patients achieving PR had a shorter time to treatment
Bisphosphonates vs abstention 6,7
Lower incidence of skeletal related events
4. Rajkumar SV, et al. Am J Hematol 2010; 85(10):737-40
5. Barlogie B, et al. Blood. 2008;112:
6. Musto P, et al. Leuk Lymphoma. 2011;52(5):
7. Musto P, et al. Cancer. 2008;113:
1.Hjorth M, et al. Eur J Haematol. 1993;50:
2.Grignani G, et al. Br J Cancer. 1996;73:
3.Riccardi A, et al. Br J Cancer. 2000;82:

27. ORIGINAL ARTICLE
Lenalidomide plus Dexamethasone for High-Risk Smoldering
Multiple Myeloma
María-Victoria Mateos, M.D., Ph.D., et al
N Engl J Med 2013; 369: August 1, 2013

28. 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

29. Len-dex vs. no treatment: TTP to active disease (n = 119)
ITT analysis
Median follow-up: 32 months (range 12–49)
Lenalidomide + dex
Median TTP: NR
9 Progressions (15%)
5 pts:early disc followed by DP
4 pts:symptomatic DP
Proportion of patients alive
No treatment
Median TTP: 23m
37 Progressions (59%)
20 patients: bone disease
7 patients: renal failure
HR: 6.0; 95% IC (2.9–12.6); p <
Time from inclusion

30. Len-dex vs. no treatment: OS from inclusion (n = 119)
Median follow-up: 32 months (range 12–49)
Lenalidomide + Dex
No treatment
Lenalidomide + Dex: 93% at 3 years
No treatment: 76% at 3 years
Time from inclusion
Proportion of patients alive
p=0.04 50 45 40 35 30 25 20 15 10 5
1.0
0.8
0.6
0.4
0.2
0.0

31. Critique Unbalanced arms
excess mortality in control arm: intervention only at CRAB
asymptomatic biologic progression: intervention with dex (and increase the dose of lenalidomide) in the intervention group
testing intensity differ between the two groups?
Flow availability

32. CASE: Observe vs. Treat No CRAB IgG lambda M-protein 3.6 gm/dl.
14% phenotypically aberrant plasma cells
Median TTP 75 months
Median TTP 117 months

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