Smoldering Myeloma: To Treat or not to Treat Ruben Niesvizky MD Myeloma Center Myelomacenter.org run9001@med.cornell.edu

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 ??

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

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

Kyle R. N Engl J Med 2007; 356:2582-90

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?  

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;356:2582-2590.

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?  

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;356:2582-2590.

Smoldering multiple myeloma: aberrant PCs by immunophenotype Gating strategy for PC analysis by multiparametric flow cytometry. Pérez-Persona E et al. Blood 2007;110:2586-2592

Smoldering multiple myeloma: aberrant PCs by immunophenotype Aberrant Plasma Cells CD45 CD19 CD56 % − − ++ 50 − − − 24 −/dim − + 11 − + ++ 8 Dim − − 5 − + − 1 + Dim ++ 1 Paiva et al., Leukemia (2013) 27, 2056–2061

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;110:2586-2592 ©2007 by American Society of Hematology

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

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?  

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; 356:2582-90

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?  

Free Light Chains as a Predictor Dispenzieri et al, Blood 2008 Jan 15;111(2):785-9. Epub 2007 Oct 17.

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 2 114 1.9 (1.2–2.9) 3 78 4.0 (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; 356:2582-90 Dispenzieri A, et al. Blood. 2008;111:785-9.

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?  

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;31:4325-4332 ©2013 by American Society of Clinical Oncology

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?  

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;356:2582-2590.

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;110:2586-92.

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;122:4172-4181

Ultra High Risk Smoldering

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;112:3122-25. 6. Musto P, et al. Leuk Lymphoma. 2011;52(5):771-775 7. Musto P, et al. Cancer. 2008;113:1588-95. 1.Hjorth M, et al. Eur J Haematol. 1993;50:95-102. 2.Grignani G, et al. Br J Cancer. 1996;73:1101-07. 3.Riccardi A, et al. Br J Cancer. 2000;82:1254-60.

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; 369:438-447 August 1, 2013

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

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 < 0.0001 Time from inclusion

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

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

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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