Smoldering Myeloma To Treat or not to Treat Ruben Niesvizky MD Myeloma Center Myelomacenterorg run9001medcornelledu CASE A 47yearold man is diagnosed with smoldering multiple myeloma He has ID: 762642
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Smoldering Myeloma: To Treat or not to Treat Ruben Niesvizky MD Myeloma CenterMyelomacenter.orgrun9001@med.cornell.edu
CASEA 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 ??
CASE: Observe vs TreatNo CRABIgG lambdaM-protein 3.6 gm/dl. 14% phenotypically aberrant plasma cellsEvolution of disease?Free light chains? Cytogenetics/FISH?Uninvolved Ig ?Doubling time? No glomerular proteinuria: ? AL amyloid
Gompertzian Growth Renal Failure Myelosuppression Bone disease Hypercalcemia Mol CR, IF CR: MRD 10 5 10 9 10 12 Surviving clone Surviving clone Precursor Disorders MGUS Smoldering
Kyle R. N Engl J Med 2007; 356:2582-90
CASE: Observe vs. TreatNo CRABIgG lambdaM-protein 3.6 gm/dl. 14% phenotypically aberrant plasma cellsEvolution of disease?Free light chains?Cytogenetics/FISH?Uninvolved Ig ?Doubling time?
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. TreatNo CRABIgG lambdaM-protein 3.6 gm/dl. 14 % phenotypically aberrant plasma cellsEvolution of disease?Free light chains?Cytogenetics/FISH?Uninvolved Ig ?Doubling time?
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.
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
Smoldering multiple myeloma: aberrant PCs by immunophenotype Aberrant Plasma CellsCD45 CD19 CD56 % − − ++ 50 − − − 24 −/dim − + 11 − + ++ 8 Dim − − 5 − + − 1 + Dim ++ 1 Paiva et al., Leukemia (2013) 27, 2056–2061
Time to progression in MGUS and SMM according to the percentage of immunophenotypically aberrant plasma cells. Pérez-Persona E et al. Blood 2007;110:2586-2592 ©2007 by American Society of Hematology Smoldering multiple myeloma : aberrant PCs by immunophenotype MGUS Smoldering MM
Smoldering multiple myeloma: aberrant PCs by immunophenotype Paiva et al., Leukemia (2013) 27, 2056–2061
CASE: Observe vs. TreatNo CRABIgG lambdaM-protein 3.6 gm/dl. 14% phenotypically aberrant plasma cellsEvolution of disease?Free light chains?Cytogenetics/FISH?Uninvolved Ig ?Doubling time?
Smoldering Multiple Myeloma Kyle R. N Engl J Med 2007; 356:2582-90 IMWG Br J Haematol 2003; 21:749-57 M - protein in serum ≥ 30 g/ L AND / OR Bone Marrow clonal plasma cells ≥ 10% 10% 3% 1% No CRAB
CASE: Observe vs. TreatNo CRABIgG lambdaM-protein 3.6 gm/dl. 14% phenotypically aberrant plasma cellsEvolution 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.
Kyle RA, et al. N Engl J Med. 2007; 356:2582-90Dispenzieri A, et al. Blood. 2008;111:785-9 . Smoldering MM: PCs BM infiltration and serum M- component level plus sFLC ratio Gr 1:TTP 1.9 y Gr 2: TTP: 5 y Gr 3: TTP 10 y p < 0.001 100 80 60 40 20 0 0 5 10 15 Probability of Progression (%) Years 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) PCsBM Infiltration ≥ 10% Serum M protein ≥ 3 g/ dL Serum FLC ratio < 1/8 or > 8
CASE: Observe vs. TreatNo CRABIgG lambdaM-protein 3.6 gm/dl. 14% phenotypically aberrant plasma cellsEvolution 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. TreatNo CRABIgG lambdaM-protein 3.6 gm/dl. 14% phenotypically aberrant plasma cellsEvolution of disease?Free light chains?Cytogenetics/FISH?Uninvolved Ig ?Doubling time?
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.
Perez -Persona E, et al. Blood. 2007;110:2586-92. Smoldering multiple myeloma : aberrant PCs by immunophenotype plus immunoparesis > 95% aPC/BMPC or paresis n = 22 (10 progr.) >95% aPC/BMPC + paresis n = 39 (28 progr.) No adverse factors n = 28 (1 progr.) 120 96 72 48 24 0 1.0 0.8 0.6 0.4 0.2 0.0 Months TTP (%) Median not reached Median 73 months p = 0.003 Median 23 months 8% 42% 82%
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 MP 1,2,3 No benefit in ORR/TTP/OS Novel agents Thalidomide 4,5 ~ 30% ≥ PR; high toxicity; patients achieving PR had a shorter time to treatment Bisphosphonates vs abstention 6,7 No benefit in ORR/TTP/OSLower incidence of skeletal related events 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. 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):771-7757. Musto P, et al. Cancer. 2008;113:1588-95.
ORIGINAL ARTICLELenalidomide plus Dexamethasone for High-Risk Smoldering Multiple MyelomaMaría-Victoria Mateos, M.D., Ph.D., et alN Engl J Med 2013; 369:438-447 August 1, 2013
Lenalidomide 25 mg/daily during 21d every 28 d Dexamethasone20 mg D1-D4 and D12-D15 every 28 d Therapeutic abstention Induction Nine 4-week cycles Maintenance Lenalidomide 10 mg/daily during 21 d every month* Therapeutic abstention Schedule of therapy (n:126 pts) Treatment arm (n = 60) Control arm (n = 66) * Low-dose Dex will be added at the moment of biological progression Ammendment on August 2011: Stop treatment at 2 years of treatment
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 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 Proportion of patients alive
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 0 1.0 0.8 0.6 0.4 0.2 0.0
CritiqueUnbalanced armsexcess 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. TreatNo CRABIgG lambdaM-protein 3.6 gm/dl. 14% phenotypically aberrant plasma cells Median TTP 75 monthsMedian TTP 117 months
Morton Coleman Roger N Pearse Tomer MarkAdriana RossiKoen Van BesienLinda Tegnestam Kathleen Pogonowski Joseph Lane Alan Weinstein Selina Chen-Kiang Monica Guzman Scott Ely John Allen Yashpal Agrawal David S. Jayabalan Stanley Goldsmith Paul Christos Susan MathewLaura Prescod MyelomaCenter. org