Smouldering Myeloma: to treat or not to treat?

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1 Smouldering Myeloma: to treat or not to treat? Massimo Offidani Clinica di Ematologia Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona

2 Definitions and epidemiology new SMM/year in USA (underestimate)

3 Rationale for treating SMM Uncurability of Multiple Genetic instability of MM Myeloma More intraclonal and subclonal heterogeneity in MM Sudden evolution of precursor in MM Higher tumor burden in MM

4 Tumor burden and outcome CLL DLBCL Risk Group Patients (all ages) Risk Factors, n CR, % 5-Yr OS, % Low Low intermediate High intermediate High Older than 60 yrs of age, LDH > normal, PS 2, Ann Arbor stage III/IV, Extranodal involvement > 1 site ALL COLON CANCER

5 Why we do not treat SMM? Toxic drugs Unsatisfactory results No selection of patients

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7 Len-Dex vs no treatment in High-Risk SMM Mateos MV et al, NEJM 2013

8 QuiRedex: Time to progression to symptomatic disease Mateos MV et al, NEJM 2013

9 QuiRedex: OS since study inclusion Mateos MV et al, NEJM 2013

10 QuiRedex: OS since diagnosis Mateos MV et al, NEJM 2013

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12 Have we suitable tools to treat patients with SMM? Is this study sufficient to change our clinical practice?

13 Robust biomarkers that identify patients who will inevitably progress to MM Treatments so effective that they cure MM or lead to its control No selection of resistant clones Appropriate end-points Treatments with no early and long-term toxicities Advanced methods to define disease eradication

14 Behavior of SMM and markers of progression

15 The different behavior of the myeloma precursor diseases The clinical dilemma of smoldering myeloma MM-like (early myeloma) MGUS-like SMM Landgren O, Hematology 2010 Roschewski M, Blood 2013

16 Smoldering multiple myeloma: risk of progression to active disease Probability of progression (%) % 10% 51 Smoldering MM 1% Years since diagnosis MGUS Are there any risk factors predicting progression to active disease? Kyle RA, et al. N Engl J Med. 2007

17 Smouldering multiple myeloma: serum immunoglobulin free-light chain (FLC) ratio Probability of Progression (%) 100 Serum FLC ratio > or < p < FLC ratio < 100 median TTP = 55 months FLC ratio 100 median TTP = 15 months Years Dispenzieri A, et al. Blood 2008 Larsen JT, et al. Leukemia 2013

18 BM plasma cells Rajkumar SV et al, NEJM 2011 Kastritis et al, Leukemia 2013 Increase of MC Circulating plasma cells Rosinol L, et al Br J Haematol 2003 Bianchi G, et al. Leukemia 2013

19 TTP (%) p < Gr 1:TTP 1.9 y Gr 2: TTP: 5 y Gr 3: TTP 10 y No. of risk factors No. Rel risk ( ) ( ) Years PETHEMA Model >95% apc/bmpc + paresis > 95% apc/bmpc or paresis No adverse factors Risk-stratification models Perez-Persona E, et al. Blood 2007 TTP (%) p = Mayo Clinic Model PCsBM Infiltration 10% Serum M protein 3 g/dl Serum FLC ratio < 1/8 or > 8 Dispenzieri A, et al. Blood years 82% 42% 8% Months Median 23 months Median 73 months Median not reached

20 Risk-stratification models comparison There was significant discordance in overall patient risk classification (~30% concordance) Cherry BM et al, Leuk Lymphoma 2013

21 Smouldering multiple myeloma: MRI and 18 F-FDG PET/CT In 12 cases of SMM PET/CT detected focal increased FDG uptake at diagnosis and upstaged the disease (25%) Abnormal areas corresponded to bone lesion later identified by MRI (n = 10) or TC (n = 2) Hillengass et al. J Clin Oncol 2010 Za T et al. EHA 2013

22 Smouldering multiple myeloma:del (17p), t(4;14) and 1q21predict progression from smoldering to symptomatic MM (n = 248)

23 Cytogenetics FL, MC, BM plasma cells??????????????????

24 Disease assessment

25 How long skeletal X-ray?

26 Effective and nonearly or long-term toxic therapies

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28 Carfilzomib, Lenalidomide, and Dexamethasone in High-Risk Smouldering Multiple Myeloma Landgren O, IMW 2013

29 Objectives of study

30 Response rates and Mean M-protein concentration

31 Toxicity

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33 No unexpected SPM

34 No dysplastic features observed

35 Clonal dinamics of multiple myeloma

36 Pathways to myeloma

37 A model of MM disease progression A model based on the random acquisition of genetic hits and Darwinian Initiation selection Progression Germinal centre Bone marrow Peripheral blood Post-GC B cell MGUS Smouldering myeloma Myeloma Plasma cell leukaemia Inherited variants Primary genetic events IgH translocations Hyperdiploidy Secondary genetic events Copy number abnormalities DNA hypomethylation Acquired mutations COMPETITION AND SELECTIVE PRESSURE MIGRATION AND FOUNDER EFFECT CLONAL ADVANTAGE Myeloma progenitor cell TUMOUR CELL DIVERSITY GENETIC LESIONS Morgan G, et al. Nat Rev Cancer. 2012;12:

38 Accumulation of abnormalities throughout disease CNV, SNV, methylation changes Walker et al, Leukemia 2013

39 Median percentage of PC with genetic abnormalities Lopez-Corral et al, Clin Cancer Res 2011

40 Theoretically possible scenarios resulting from early treatment of smouldering myeloma Landgren O. Clin Cancer Res 2011

41 From Noncurable to Curable Malignancy Asymptomatic Symptomatic M-Protein (g/l) Treatment SMM ACTIVE MYELOMA 1. RELAPSE 2. RELAPSE REFRACTORY RELAPSE Chronic disease Cure Time

42 Theoretically possible scenarios resulting from early treatment of smouldering myeloma Early treatment may facilitate selection of aggressive clones that are more capable of competing in the treatment-altered microenvironment

43 Clonal dynamics over multiple relapses Don t allow genetic evolution to occur in this hideously complex disease. Ken Anderson Lenalidomide/ dexamethasone Clone 1.1 Clone 1.2 Clone 2.1 Clone 2.2 Misc Remission ~2N Relapse 1 ~2N Relapse 2 ~2N Diagnosis ~2N Plasmacytoid Phenotype 66% Plasmacytoid Phenotype 37% Relapse 3 ~2N Bortezomib SGN-40 Lymphoid Phenotype 34% Plasma cell leukaemia ~3N Relapse 4 ~3N Lymphoid phenotype 63% Melphalan/prednisone/ bortezomib (MPV) Keats JJ, et al. Blood. 2012;120:

44 Curative blueprint for early Myeloma Roschewski M. et al. Blood 2013