Incidence: ~4/100,000 persons/year Prevalence: 60,000 patients (Europe) Incidence increases with age: 80% of patients > 60 years (rare in < 35 y.

Size: px

Start display at page:

Download "Incidence: ~4/100,000 persons/year Prevalence: 60,000 patients (Europe) Incidence increases with age: 80% of patients > 60 years (rare in < 35 y."

Joshua Lynch
5 years ago
Views:

Multiple myeloma Second most common hematological malignancy

(Europe) Incidence increases with age: 80% of patients > 60 years

) Clinical Course: Remitting and Relapsing disease - In spite of the

1 Multiple myeloma Second most common hematological malignancy Incidence: ~4/100,000 persons/year Prevalence: 60,000 patients (Europe) Incidence increases with age: 80% of patients > 60 years (rare in < 35 y.) Clinical Course: Remitting and Relapsing disease - In spite of the progress in survival with novel agents. eventually refractory state (incurable) With current treatment 5-year surival 50% - 70% Potentially cured ~ 10%

2 IMWG criteria for the classification of monoclonal gammopathies Monoclonal Gammopathy of uncertain significance (MGUS) Smoldering Multiple Myeloma (SMM) Symptomatic Multiple Myeloma (MM) Monoclonal component < 30 g/l serum AND 30 g/l serum AND/OR Present (serum/urine) AND Bone Marrow Plasma Cells (%) < 10% AND 10% AND 10% AND End Organ Damage a Absent Absent Present -Calcium levels increased: serum calcium >11 mg/dl ( > 2 75 mmol/l) -Renal insufficiency: creatinine > 2mg/dl (>173 mmol/l) -Anemia: hemoglobin 2 g/dl below the lower limit of normal or hemoglobin <10 g/dl -Bone lesions: lytic lesions or osteoporosis with compression fractures (MRI or CT may clarify) Other: symptomatic hyperviscosity, amyloidosis, recurrent bacterial infections (> 2 episodes in 12m) Dimopoulos et al. Blood 2011;117:

3 DEFINITIONS OF MYELOMA AND EARLY MYELOMA FEATURES MM CRAB Criteria Ultra-HR-SMM Pre-CRAB PC>60% High FREELITE MRI/Other Changes HR-SMM Spanish Criteria Mayo Criteria LR-SMM MGUS

MGUS Smoldering MM MM Multiple Myeloma: A model for

pre-malignant into a malignant disease MM is preceded by MGUS in

malignant or to remain dormant for >30years?

clone or is it also drived by the dialogue between the PC clone

4 MGUS Smoldering MM MM Multiple Myeloma: A model for investigation of mechanisms involved in the transition form a pre-malignant into a malignant disease MM is preceded by MGUS in most patients* What dictates a clonal benign PC to become malignant or to remain dormant for >30years? Is this drived by the specific characteristics of the malignant clone or is it also drived by the dialogue between the PC clone and its microenvironment?... selection of a dominant clone *Weiss et al Bood 2009; Landgren et al Blood 2009

5 Multiple Myeloma: From Biology to Therapeutics MM Pathogenesis Treatment - Genetic abnormalities of MM cell - MM cell & microenvironment Novel drugs with Singular Mechanism of Action Prognostic Factors Myeloma Subtypes

Numerical abnormalities in MM Structural abnormalities in MM Trisomies p 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 X

6 Numerical abnormalities in MM Structural abnormalities in MM Trisomies p X Y X Monosomies q Genomic chaos of MM: Almost all cases are cytogenetically abnormal Mutations of N, K-RAS Del/Mutat de p53 Secondary IGH Transl: C-MYC Primary IGH Translocations 11q13 6p21 16q23 20q11 4p16 Chesi, Blood 1998; Avet-Loiseau, GCC 1999; Gutiérrez et al, Haematologica 2000 y Leukemia 2001 IGH q32

7 MM Pathogenesis: Host-tumor interactions Direct contact & soluble molecules IL-6 MM cell IGF-1 CD138 CD44 VEGF TNF ICAM-2 CXCR4 1-integrins LFA-1 ICAM- 1 VLA-4 VCAM- 1 SDF1 ECM (Fibronectin, laminin) BMSC 1-integrins: VLA-4 (CD49d), VLA-5 (CD49e), VLA-6 (CD49f) Cell adhesion induces a drug resistance phenotype in the Myeloma cell: 1) cell cycle arrest ( p27); 2) apoptosis inhibition ( FLIP-1 FAS inhibitor-); 3) protection from drug-induced DNA damage PC adhesion to Fn induces overexpresion of 53 genes ( 11 regulated by NFkB) San Miguel, Hematol J. 2003

Cell count -> Age ECOG Prognostic Factors

CD19/81, CD117 ISS B2micro+albúmine P <.

0 Mateo JCO 2008, Paiva Leukemia 2012 P53

8 Cell count -> Age ECOG Prognostic Factors G 0 G 1 S-phase PATOGENIA Cómo se desarrolla el tumor? S G 2 San Miguel, et al Blood 1999 CD28, CD19/81, CD117 ISS B2micro+albúmine P < Mateo JCO 2008, Paiva Leukemia 2012 P53 deletion Greip P, San Miguel J et al JCO 2005 p= Perez-Simon Blood 1996, Gutierrez, Leukemia 2007

9 Genetic markers with prognostic significance FISH analysis IGH translocations t(4;14) t(14;16) t(11;14) SNP-based mapping array Gene expression profiling TC classification Genomic imbalances Non-hyperdiplid 1q gains 1p deletions Monosomy 13 17p deletions 16q deletions 12p deletions 1q gains 5q gains Molecular classifications (UAMS & Hovon) 17 gene-model (Arkansas group) 15 gene-model (Intergroupe Francophone) Perez-Simon, Blood 1999; Fonseca Blood 2003; Chang Blood 2005; Gutierrez Leukemia 2007; Avet- Loiseau JCO 2010 & Blood 2011; Boyd Leukemia 2011, Kumar Blood 2012; Zhan Blood 2006, Saughnessy Blood 2007; Deacaux Blood 2008; Broyl Blood 2010; Tapper JCO 2011:

10 Cumulative Proportion Event Free Surviving Cumulative Proportion Surviving Response to Therapy:depth of response correlates with EFS & OS PETHEMA-GEM 2000: Outcome according to post-transplant response EFS OS 1,0 0,9 CR vs VGPR or PR P<10-5 1,0 0,9 CR vs VGPR VS PR P= ,8 0,7 0,6 0,8 0,7 0,5 0,4 CR 0,6 0,5 0,3 0,2 0,1 0,0 PD VGPR PR Months from diagnosis 0,4 0,3 0,2 0, Months from diagnosis CR, n=278 VGPR, n=124 PR, n=280 PD, n=25 Lahuerta et al. JCO 2008;26:

11 The definition of CR is suboptimal and requires further improvements CR Negative Inmunofixation & < 5% PC in BM (+normal FLC for stringent) Outside BM..Imaging techniques (MRI & CT-PET). BM Level...Immunophenotypic remission (by multiparametric flow) Molecular remission (by RT-PCR): (Sensitivity ) *

12 MRI & FDG-PET in MM Sagittal STIR MRI Sagittal FDG PET Ant MIP FDG PET - 3m post-asct: Complete FDG suppression at PET/CT Longer PFS & OS Zamagni et al. Blood 2011;118(23):

13 Immunophenotypic Remission The better the quality of the response the longer the survival: - GEM2000 & PFS OS Immunop. CR vs CR: P = Immunop. CR vs CR: P < Immun. CR Immun. CR CR ncr PR CR ncr PR months months Immunophenotypic CR, n=193 CR, 292 ncr, n=164 PR, n=364 Median f/u: 46 months (updated) Paiva et al; Blood. 2008, JCO 2011

14 Multiple Myeloma: From Biology to Therapeutics MM Pathogenesis Treatment - Genetic abnormalities of MM cell - MM cell & microenvironment Novel drugs with singular Mechanism of Action Prognostic Factors Myeloma Subtypes

15 TREATMENT OF MULTIPLE MYELOMA: Should all patients be treated? PATIENTS WHO SHOULD NOT BE TREATED "Smoldering MM (MC >3 g/dl &/or PC > 10%) - Asymptomatic & NO: bone lesions, anemia, renal insufficiency or hypercalcemia Early MP vs deferred MP 1,2,3.No benefit Thalidomide 4,5 only 30% PR & No benefit in TTP/OS Bisphosponates 6,7.No benefit in OR/TTP/OS 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 4. 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:

16 TTP (%) Smoldering multiple myeloma: Risk of transformation into Symptomatic MM based on the % of aberrant PCs by immunophenotype plus immunoparesis 1.0 p = High Risk % Median 23 months >95% apc/bmpc + paresis n = 39 (28 progr.) % Median 73 months > 95% apc/bmpc or paresis n = 22 (10 progr.) 0.2 No adverse factors n = 28 (1 progr.) 0.0 8% Median not reached Low Risk Months Perez-Persona E, et al. Blood. 2007;110:

17 Randomized trial Lenalidomide+dex vs no treatment in High Risk SMM (n = 120) ITT analysis TTP OS 1.0 Len+dex 1.0 Len+ Dex No treatment HR: 5.6; 95% IC (2.9 11); p < No treatment 0.4 TTP: 21m 46 Progressions (74%) 0.4 HR: 3,5; 95% IC (1 10); p=0.01 Bone disease (21); RI (8) Lenalidomide + Dex: 94% at 5 y No treatment: 78% at 5 y Median follow-up: 40 m Time from inclusion Time from inclusion Mateos et al NEJM 2013

18 Myeloma Treatment - Newly diagnosed - Transplant candidates (Young) - Non-Transplant candidates (Elderly) - Relapsed patient - Experimental Agents

19 Old Transplant candidate patient approach Induction (VAD or TD) ASCT (Mel 200) Maintenance (IFN +/- Predn)

20 Percent Response Do we have something better than VAD or TD?: Response obtained with Novel Induction Regimens ORR CR VAD TD TAD LD BzD BzTD BzLD Induction Regimen VRD BzCD BzLCD VCD VRDC This translates into prolonged PFS: VTD or PAD >VAD or TD - Adapted from: How I treat MM in younger patients by Stewart K, Richardson P, San Miguel JF. Blood 2009; 114:

intensive and repetitive therapies Significant increase in CR rate together with a long treament-free

21 ASCT Upfront or at Relapse: Intensive vs. gentle approaches: Arguments in favor of intensive upfront treatment The patient is more fit to tolerate intensive and repetitive therapies Significant increase in CR rate together with a long treament-free interval & good quality of life..& cost Relapses after MEL200 are sensitive to novel agents but we don t know the long term effcicacy of the opposite (Mel200 after novel agents)

22 Maintenance treatment with Thalidomide* 6 Randomized trials have compared Thalidomide +/- Pred... vs Nothing or Pamidronate or Prednisone or IFN > PFS in all 6.. but OS in only 3 Meta-analysis: modest benefit in PFS & OS (+/- 6 m) Attal (Blood 2006; 108:3289); Spencer (JCO 2008;26:3735 ); Barlogie (NEJM 2006; 354:1021); Lokhorst (Blood 2010; 115:1113); Morgan (ASH 2010, Abstr 623); Stewart (ASH 2010, Abstr 39)

23 Lenalidomide vs Placebo after ASCT: PFS from randomization IFM CALGB PFS PFS P < Placebo Revlimid P < 10-7 OS: 75% at 5y in both arms Lena 41 m Placebo 23 m Secondary Malignancies: 6,5% vs 2%; (Hemtol: 3,6% vs 1%; solid: 3,9% vs 1%) P < 10-8 Lena 46 m Placebo 27 m OS: 35 vs 59 deaths, p=0.03 Secondary Malignancies: 8 vs 3 % ; (Hematol: 3,46% vs 0%; solid: 4,3% vs 2,1%) Attal M. NEJM 2012, 366: McCarthy P, NEJM 2012, 366:

24 Auto/Allo-RIC vstandem Auto 4 studies (IFM 1, HOVON 2, PETHEMA 3, BMTCTN 4 ).. No benefit 2 studies (GIMEMA 5, EBMT 6 ) Significant benefit (EFS, OS) The role of Allo should be revisited in the era of novel drugs: integrated programs...early relapses (after optimize induction & ASCT) + high risk cytogenetics 1.Garban, Blood 2006 and Moreau, Blood 2008; 2. Lokhorst ASH 2008 (Abstr 461); 3.Rosinol, Blood 2008; 4. Krishnan, ASH 2010 (abst 41) 5. Bruno, NEJM 2007 (updated EBMT 2009); 5. Gahrton, ASH 2009 (Abst 52) 6. Knop, ASH 2009 (abst 51)

25 Transplant candidate patient: standard treatment from tomorrow Induction (VAD) ASCT (Mel 200) Maintenance (IFN +/- Predn)

26 Transplant candidate patient: standard treatment from tomorrow Induction (Bz-Thal-Dx) ASCT (Mel 200) Maintenance (IFN +/- Predn)

27 Transplant candidate patient: standard treatment from tomorrow Induction (Bz-Thal-Dx) ASCT (Mel 200 +Bz) Maintenance (IFN +/- Predn)

28 Transplant candidate patient: standard treatment from tomorrow Induction (Bz-Thal-Dx) ASCT (Mel 200 +Bz) CR Maintenance (Len +/- Bz )

29 Transplant candidate patient: standard treatment from tomorrow Induction (Bz-Thal-Dx) ASCT (Mel 200 +Bz) CR No CR Consolidation(Bz-Len-Dx) Maintenance (Len +/- Bz )

30 Transplant candidate patient: standard treatment from tomorrow Induction (Bz-Thal-Dx) VRD CR ASCT No CR (Mel 200 +Bz) Consolidation(Bz-Len-Dx) VRD VRD..... Maintenance (Len +/- Bz )

31 Transplant candidate patient: standard treatment from tomorrow Induction (Bz-Thal-Dx) VRD CR ASCT No CR (Mel 200 +Bz) Consolidation(Bz-Len-Dx) VRD VRD..... Maintenance (Len +/- Bz ) Late ASCT

32 Myeloma Treatment - Newly diagnosed - Transplant candidates (Young) - Non-Transplant candidates (Elderly) - Relapsed patient - Experimental Agents

33 Thalidomide + MP (MPT) vs MP: Efficacy in Newly Diagnosed Elderly Patients With Myeloma 6 Randomized trials.. > PFS in 5 >OS in 3 PFS: 20,4 vs 15 m (6 m)..hr 0,67 OS: 39,3 vs 33 m (6 m)..hr 0,82 Thal maintenance in Italian, Nordic, Hovon 1 Facon. Lancet. 2007;370: ; 2 Hulin. J Clin Oncol. 2009; 27(22): ; 3 Wijermans. J Clin Oncol. 2010; 28: ; 4 Palumbo. Blood. 2008; 112: ; 5 Beksac. Eur J Haematol. 2010; 86:16-22; 6 Waage. Blood. 2010;116(9): & ASCO 2010 (abstr 8130); Kapoor. Leukemia

34 Patients (%) Lenalidomide + MP (MPR): MPR-R vs MPR vs MP 100 MPR-R PFS 31 m Overall Survival MPR 14 m 75 MP 13 m 100 MPR-R MPR 50 HR P< MP Time (months) HR P= year overall survival: 92-93% 70%, 62%, 66% 2-year overall survival: 75-82% Time (months) Small number of events, median follow-up of 21 months Palumbo. NEJM 2012, 366:

35 FIRST: Phase 3 trial of Lenalidomide + low-dose Dex vs MPT (IFM 07-01; MM-020) Inclusion criteria N = 1,623 Previously untreated MM Age 65 years or not eligible for a transplant No neuropathy of grade > 2 R A N D O M IZ A TI O N Rd (28-day cycle; until disease progression) Lenalidomide 25 mg/day, days 1 21 Dexamethasone* 40 mg/day, days 1, 8, 15, and 22 Rd (28-day cycle; up to 18 cycles) Lenalidomide 25 mg/day, days 1 21 Dexamethasone* 40 mg/day, days 1, 8, 15, and 22 MPT (6-week cycle; up to 12 cycles ) Melphalan* 0.25 mg/kg/day, days 1 4 Prednisone 2.0 mg/kg/day, days 1 4 Thalidomide* 200 mg/day Primary end-point: PFS PFS: 28% reduction in the risk of DP/death for Rd (til DP) vs MPT OS: 22% reduction in the risk of death for Rd (til DP) vs MPT Len-dex will be a new standard of care for elderly newly diagnosed MM pts, or... new backbone *In patients aged > 75 years: Dex 20 mg/day, melphalan 0.20 mg/kg/day, thalidomide 100 mg/day Facon T, et al. Blood. 2013;122:abstract 2.

36 72 wks Patients (%) FIRST Trial: PFS Continuous Rd reduced the risk of disease progression by 28% vs. MPT Rd (n= 535) Rd18 (n= 541) MPT (n= 547) Hazard ratio Rd vs. MPT: 0.72; P = Rd vs. Rd18: 0.70; P = Rd18 vs. MPT: 1.03; P = Median PFS 25.5 mos 20.7 mos 21.2 mos Time (months) Rd Rd MPT mos, months; MPT, melphalan, prednisolone, thalidomide; PFS, progression-free survival; Rd, Lenalidomide plus low-dose dexamethasone. Facon T, et al. Blood. 2013;122:abstract 2.

37 Patients (%) FIRST Trial: Overall Survival Interim Analysis deaths (35%) 4-year OS Rd (n= 535) 59.4% Rd18 (n= 541) 55.7% MPT (n= 547) 51.4% Rd Rd18 MPT Hazard ratio Rd vs. MPT: 0.78; P = ( 22% risk of death with Rd) Rd vs. Rd18: 0.90; P = Rd18 vs. MPT: 0.88; P = Overall survival (months) Facon T, et al. Blood. 2013;122:abstract 2.

38 Patients without event (%) Patients without event (%) Bortezomib + MP (VMP) vs MP: Efficacy Data (682 Patients) Time to Progression Overall Survival TTP VMP MP OS: 13,3 months benefit VMP MP VMP: 24.0 months MP: 16.6 months, P< Median follow-up 60,1 m VMP: 56,4m MP: 43m, P= Time (months) Time (months) San Miguel. N Engl J Med. 2008;359:906; Mateos MV. J Clin Oncol. 2010;28:2259.

39 Weekly VMP (VTP) followed by maintenance (VT/VP): GEM2005 spanish trial Biweekly VMP Weekly VMP Significant reduction of PN 13% 5% Improved CR rate 30% 42% Prolonged PFS 21m 35m Similar results reported with VMPT+VT (Palumbo et al JCO 2010, 28:5101-9) * Subcutaneous administration of Bortezomib Mateos MV et al. Lancet Oncology. 2010;10(11):934-42

40 Myeloma Treatment - Newly diagnosed - Transplant candidates (Young) - Non-Transplant candidates (Elderly) - Relapsed patient - Experimental Agents

41 Strategies at Relapse: How to make the right choice? Type of relapse Efficacy of previous treatments Toxicity of previous treatments Further options

42 2 nd Generation of Novel Drugs in MM Derivatives from the already approved Novel Proteasome Inhibitors: Carfilzomib, Ixazomib Novel IMIDs: Pomalidomida Novel Alkylators:Bendamustina Novel Mechanisms of action MoAb: anti CS1 & anti-cd38 Deacetylase Inhibitors: Panobinostat KSP inhibitors

43 Current Treatment Approaches in Multiple Myeloma Progress in MM Cell Biology Discovery of New Drugs Prognostic factors & Myeloma subtypes* Singular Mechanism of action Individualize & Tailor Treatment * MM sould not be considered a single entity

Should we treat Smoldering MM patients? María-Victoria Mateos University Hospital of Salamanca Salamanca. Spain

Should we treat Smoldering MM patients? María-Victoria Mateos University Hospital of Salamanca Salamanca. Spain Should we treat some patients with Stage I MM? Len-dex is a promising and atractive option