I nuovi fa*ori di classificazione e di rischio del Mieloma smouldering.

Transcription

1 Dipartimento di Scienze Biomediche e Oncologia Umana Unità per lo Studio e la Terapia delle Gammopatie Monoclonali I nuovi fa*ori di classificazione e di rischio del Mieloma smouldering. Roberto Ria, M.D.

2 Disclosures Research Support/P.I. Employee Consultant Major Stockholder Speakers Bureau Honoraria ScienHfic Advisory Board Yes (CLS Behring) No No No No Yes (Janssen, Celgene, NovarHs, Italfarmaco) Yes (Janssen, Celgene, Italfarmaco) PresentaFon includes discussion of the off- label use of a drug or drugs Department of Hematooncology, Ostrava University Hospital and Faculty of Medicine

3 Am J Med, 42: , June 1967

4 Premalignant precursor of mulhple myeloma (MM) is stable and not associated with the presence of secondary clinical manifestahons (<30 g/l serum M- Ig, <10% bone marrow clonal PCs) PROGNOSTIC FACTORS MGUS SMM MM 1 32 years Permanently higher risk of malignant disorder development MGUS and MMS consistently precedes MM Landgren, O. et al Blood 113(22): Weiss, B. M. et al Blood 113(22): Kyle, R. A. et al Leukemia 24:

5 Smouldering Myeloma DefiniHon of smoldering myeloma 1 Serum monoclonal IgG or IgA 3 g/dl and/or clonal bone marrow plasma cells 10% AND Absence of end- organ damage (ie, hypercalcemia, renal insufficiency, anemia, or bone lesions agributed to plasma cell proliferahve disorder) Overall risk of progression 2 10% per year in years 0-5 3% per year in years % per year in years Risk strahficahon Mayo Clinic analysis 3 strahfies pahents according to their 5- yr risk of progression into 3 groups: 25% risk, 51% risk, and 76% risk PETHEMA Study Group analysis 4 strahfies pahents according to their 5- yr risk of progression into 3 groups: 4% risk, 46% risk, and 72% risk 1 Kyle RA, et al. Leukemia. 2010;24: Kyle RA, et al. N Engl J Med. 2007;356: Dispenzieri A, et al. Blood. 2008;111: Perez- Persona E, et al. Blood. 2007;110:

6 Criteria for Diagnosis of Myeloma IMWG 2003 MGUS < 3 g M spike < 10% plasma cells SMM 3 g M spike 10% plasma cells AcFve MM ( 10%) plasma cells M spike + AND AND No anemia, bone lesions, normal calcium, and kidney funchon Anemia, bone lesions, high calcium, or abnormal kidney funchon

7 Multiple myeloma No myeloma No myeloma

8 MGUS and SMM risk of progression to acfve disease 100 Smoldering MM Probability of progression (%) 80 1% 3% % Years since diagnosis MGUS Kyle RA, et al. N Engl J Med. 2007; 356:

9 Image- guided biopsies: early disease, pre- therapy and post- therapy Normal Focal myeloma infiltration Multiple myeloma (n=149) Minimal Diffuse Focal 8% 28% 64% Smoldering myeloma (n=142) Minimal Diffuse Focal 46% 26% 28% Multiple focal biopsies in individual patients

10 Generic factors Other factors Variable N HR 95% CI P-value Median TTP in years TTP rate % at 3-years Gender male female Age 60 years >60 years Serum heavy chain IgA 61 NA 20 IgG Immunoparesis 0 73 NA 19 1 or Serum light chain kappa lambda NA 28 Neben, JCO 2013

11 t 1 t 2 Tumor mass & TTP m crit m 2 m 1 TTP TTP Neben, JCO 2013

12 Tumor load Tumor load Variable N HR 95% CI P-value Median TTP in years TTP rate % at 3-years Tumor mass surrogate** low high < Aberrant plasma cells*** 95% >95% < Monoclonal protein 20 g/l < g/l < Bone marrow plasma cells 10% % % NA FLC ratio**** normal 54 NA 8 abnormal ISS I II/III Rajkumar et al., NEJM 2011 Neben, JCO 2013

13 Tumour mass & enfty? Variable Line N TTP rate at 3- years (%) HR [95% CI] P- value P- value* Time to progression (%) Years since BM assessment Malignant plasma cells 95% CytogeneHc risk low Malignant plasma cells 95% CytogeneHc risk high Malignant plasma cells >95% CytogeneHc risk low Malignant plasma cells >95% CytogeneHc risk high [ ] 1.92 [ ] 4.51 [ ] 6.75 [ ] <.001 < Neben, JCO 2013

14 PredicFng progression with current clinical risk model Mayo Clinic The Mayo Clinic model emphasizes clonal plasma cell burden with monoclonal protein values and skewed free light- chain rafos. Mayo Clinic (n=273) No. of risk factors No. of patients, n (%) Progression at 5 years SMM risk factors for progression: bone marrow plasma cells > 10% serum M- protein concentrahon > 3 g/dl, skewed FLC- raho (normal reference: ) CumulaHve risk of progression at 10 years for SMM pahents with 1, 2, and 3 risk factors is 50%, 65%, and 84%, respechvely 1 76 (28) 25% (42) 51% 3 82 (30) 76% Risk factors: BMPCs >10% M- protein >3 g/dl FLC- raho <0.125 or >8 Rajkumar SV,Blood Aug 1; 106(3):812-7, Dispenzieri A, Blood Jan 15; 111(2):785-9

15 PredicFng progression with current clinical risk model Mayo Clinic Dispenzieri A, Blood Jan 15; 111(2):785-9

16 PredicFng progression with current clinical risk model Mayo Clinic Dispenzieri A, Blood Jan 15; 111(2):785-9

17 PredicFng progression with current clinical risk models- Spanish study group The Spanish study group uses mulfparametric flow cytometry techniques to idenhfy aberrant plasma cell populahons SMM risk factors for progression: apc/bmpc > 95% immunoparesis (decreased uninvolved gammaglobulin levels) At 5 years, progression free survival for SMM pahents with 0, 1, and 2 risk factors is 4%, 46%, and 72%. PETHEMA Study Group (n=89) No. of risk factors No. of patients, n (%) Progression at 5 years 0 28 (31) 4% 1 22 (25) 46% 2 39 (44) 72% Risk factors: 95% abnormal plasma cells* Immunoparesis *Incl decreased CD38 expression, expression of CD56, and absence of CD19 and/or CD45 Pérez- Persona E, Blood. 2007;110:

18 Smoldering mulfple myeloma: aberrant PCs by immunophenotype plus immunoparesis TTP (%) p = % 42% Median 23 months Median 73 months >95% apc/bmpc + paresis n = 39 (28 progr.) > 95% apc/bmpc or paresis n = 22 (10 progr.) No adverse factors n = 28 (1 progr.) 0.2 8% Median not reached Months 120 Pérez- Persona E, Blood. 2007;110:

19 Smoldering mulfple myeloma: aberrant PCs by immunophenotype plus immunoparesis 1.0 p = % Median 23 months Early MM TTP (%) % Median 73 months 0.2 MGUS 8% Median not reached Months 120 Pérez- Persona E, Blood. 2007;110:

20 Mayo Clinic versus PETHEMA risk models for SMM Cherry et al. Leukemia and Lymphoma 2013

21 M- protein ( 30g/l) +/- 10% plasma cells +/- FLC < 1/8 or 8 < FLC 2-year progression (Mayo) Guide to treatment? Immunoparesis +/- 95% aberrant plasma cells (flow) 2-year progression (PETHEMA) 30% 42% % 52% 52% 32% % 37% fraction of patients 28% 0 12% 4% 0 26% Perez- Persona, Blood 2007 Dispenzieri, Blood 2008

22 Using RNA- Seq to characterize mechanisms of progression Precursor disease Precursor disease Precursor disease Multiple myeloma Platform to discover somatic mutations and chromosomal translocations as well as to provide digital gene expression. Aim is to identify treatment targets delay or prevent multiple myeloma

23 Copy number gains and losses in MGUS, SMM and MM MGUS (n=20), high-risk SMM (n=20) and newly diagnosed MM (n=34) by highdensity 6.0 SNP array Median frequency (per case) of copy number abnormalities (CNA) increased from MGUS (n=5) to SMM (n=7.5) and to MM (n=12); P=0.006 Although MM have more CNA, MGUS is as genetically aberrant as MM, the transition from MGUS to MM is not associated with a particular chromosomal imbalance, but rather with an expansion of altered clones that are already present in MGUS Lopez- Corral et al. Leukemia 2012

24 EnFty - Chromosomal aberrafons Variable N HR 95% CI P-value Chromosomal aberrations Median TTP in years TTP rate % at 3-years del(17p13) no yes t(4;14) no yes q21 no 172 NA 27 yes Cytogenetic risk* low 157 NA 24 high Ploidy status non-hyperdiploidy 139 NA 29 hyperdiploidy t(11;14) no yes NA 27 del(13q14) no yes NA 28 Neben, JCO 2013

25 EnFFes intrinsic - risk (ifish) Time to progression (%) t(4;14) no t(4;14) Time to progression (%) del 17p no del 17 p Time to progression (%) q no +1q 0 P = Years since BM assessment 0 P = Years since BM assessment 0 P = Years since BM assessment Time to progression (%) hyperdiploidy non-hyperdiploidy Time to progression (%) high-risk cytogenetics no high-risk cytogenetics 0 P = Years since BM assessment 0 P = Years since BM assessment Neben, JCO 2013

26 EnFFes intrinsic - risk (ifish) Fraction not progressed) del17p, t(4;14) trisomies only t(11;14), t(xx;14), del13q none Years since BM assessment Rajkumar et al. Leukemia 2013

27 From MGUS to MM: linear versus branching pathways? Key molecular events leading to evolution are represented as diamonds Walker et al. Nature Reviews Cancer 2012

28 MM: Oncology perspecfve Early intervention Smoldering MM

29 Guide to treatment? Time to progression (%) Years since BM assessment Variable Line N M- protein < 20 g/l CytogeneHc risk low M- protein < 20 g/l CytogeneHc risk high M- protein 20 g/l CytogeneHc risk low M- protein 20 g/l CytogeneHc risk high TTP rate at 3- years (%) HR [95% CI] 1 [ ] 3.1 [ ] 4.50 [ ] ] 7.55 [ ] P- value <.001 <.001 P- value* Neben, JCO 2013

30 Treatment goals for high- risk smoldering (early) myeloma Landgren et al. Clin Cancer Research 2011

31 Smouldering mulfple myeloma: early treatment 1.Hjorth M, et al. Eur J Haematol. 1993;50: Grignani G, et al. Br J Cancer. 1996;73: Riccardi A, et al. Br J Cancer. 2000;82: Rajkumar SV, et al. Am J Hematol 2010; 85(10): Barlogie B, et al. Blood. 2008;112: Musto P, et al. Leuk Lymphoma. 2011;52(5): Musto P, et al. Cancer. 2008;113:

32 Smoldering mulhple myeloma at high- risk of progression to symptomahc disease: a randomized trial of len- dex as induchon followed by maintenance therapy with len alone vs no treatment High risk smoldering MM Both Bone marrow plasma cells >10% High M- spike IgG >3g/dL, IgA >2g/dL, Bence Jones >1g/day Or one of the above plus both: 95% phenotypically aberrant PCs by flow cytometry Immunoparesis ReducHons in 1 or more uninvolved immunoglobulins of >25% Mateos et al, EHA 2012 abstract 283

33 First Randomized Phase III Trial for Smoldering Myeloma Randomization of high-risk smoldering MM patients: Lenalidomide 25 mg/day, D1-21 Dexamethasone 20 mg D1-D4 and D12-D15 Induction: Nine 28-day cycles Therapeutic abstention Lenalidomide 10 mg/day, D1-21 every 2 months Maintenance: Until progression Therapeutic abstention Primary endpoint: time to progression to symptomatic MM Secondary endpoints: ORR, DOR, PFS, OS, and safety and tolerability Median time to symptomatic progression Len/dex: not yet reached Observation: 21 months 4-year overall survival Len/dex: 94% Observation: 85% HR = 5.67; P <.0001 HR = 3.5; P <.01 Mateos MV, et al. ASH Abstract 991.

34 Smoldering mulhple myeloma at high- risk of progression to symptomahc disease: a randomized trial of len- dex as induchon followed by maintenance therapy with len alone vs no treatment Group A (57 pahents) Lenalidomide 25mg d1-21 Dexamethasone 20mg d1-4, Lenalidomide 10mg d1-21 AddiHon of Dex 20mg d1-4 for biochemical progression Group B (62 pahents) No treatment x 9 cycles x 15 cycles Mateos et al, EHA 2012 abstract 283

35 Smoldering mulhple myeloma at high- risk of progression to symptomahc disease: a randomized trial of len- dex as induchon followed by maintenance therapy with len alone vs no treatment Induction ORR 81% PR 56% VGPR 11% CR 7% scr 7% After maintenance scr 16% Mateos et al, EHA 2012 abstract 283

36 Smoldering mulhple myeloma at high- risk of progression to symptomahc disease: a randomized trial of len- dex as induchon followed by maintenance therapy with len alone vs no treatment Progression Median f/u 32m Median TTP Len-dex 9/57 (16%) Not reached 93% 3-year OS Observation 37/61 (59%) 23 months 76% (p<0.04) Conclusion: High-risk SMM has a high mortality with observation that can be abrogated by early treatment Mateos et al, EHA 2012 abstract 283

37 Monitoring SMM watch and wait strategy no current standardized treatment ophons for MGUS and SMM Beger understanding of pathogenesis from MGUS to myeloma needed: To develop beger biological markers To predict a pahent s risk of progression To develop early intervenhon strategies - For SMM: acfve clinical trials

38 Head: Prof. A. Vacca Dipartimento di Scienze Biomediche e Oncologia Umana R. Ria, MD Unità per lo Studio e la Terapia delle Gammopatie Monoclonali A. Melaccio, MD A. Reale, MD E. Settimo, MD A. Sportelli