Il trattamento del Mieloma su stratificazione di rischio: è oggi possibile? Francesca Gay, MD Divisione Ematologia 1 AO Città della Salute e della Scienza, Torino, Italy Focus sul MM 2014 Cagliari, 30-31 Maggio 2014 25min 30m
Survival improvement Where we come from Median age 61 5-year OS with MP: 24% where we are now Median age 59 5-year OS with TT3: 73% OS OS CR duration P<0.0001 P<0.0001 0 years years years Myeloma Trialists Collaborative Group JCO 1998;16:3832 Usmani SZ, et al. Leukemia 2012,10:1038
Biological events Korde N, et al Blood 2011
Different molecular mechanisms in early and late stage disease.treatment targeted to the subtype of the disease. Morgan G J, and Kaiser M F Hematology 2012;2012:342-349
PREDICTIVE vs PROGNOSTIC markers Marker Informative on example Prognostic Predictive Outcome risk stratification Outcome w specific th Individualized treatment ISS stage, Del17, t(4;14), LDH level TRAF bortezomib response 1 Cereblon IMIDs resistance 2 TRAF: TNF receptor associated factor; IMIDs: immunomodulatory drugs 1. Keats JJ, et al. Cancer Cell 2007;12:131-44 2. Zhu YX, at al. Blood 2011;118: 4771-79 Chng WJ et al, Leukemia 2014, 269-77
What is the best riskstratification?
RISK STRATIFICATION several prognostic markers! Marker Informative on example Host Fitness to receive Age, frailty therapy Tumor byology Genetic aberration (FISH) GEP signatures burden ISS Stage response Degree Duration ISS, international Staging System; FISH, fluorescent in situ Ibridization, GEP, gene expression profile,
ISS Tumor related markers t(4;14) LDH del17 Greipp PR, JCO 2005; 23(15) 3412-20, Gkotzamanidou, M et al. Clin Lymphoma Myeloma Leuk. 2011, Avet Loiseau H, JCO 2013, 31:2806-9
Tumor response Analysis of 1175 elderly patients OS Stringent CR OS Molecular CR OS 100 75 CR 100 80 87% SMR 50 VGPR PR 60 40 59% Medians: NR No SMR 25 20 0 0 P =.009 0 10 20 30 40 50 60 70 80 0 20 40 60 80 100 120 140 months months Gay F et al. Blood. Blood. 2011;117:3025-31 Paiva et al. Blood. 2008;112:4017 4023 Ladetto M, et al. ASH 2011 Abstract 827
Importance of achieving durable CR Hoering et al. Blood 2009;114:1299-1305)
Parameters RISK FACTORS not just one staging! Combined genetic-iss models GRADE 1 Low-Risk ISS I/II No t(4;14), 17p13 del +1q21 GRADE 2 Std-Risk GRADE 3 High-Risk ISS II/III and Others t(4;14) * or Age<55 years 17p13 del Median OS >10 years 7 years 2 years % Patients 20% 60% 20% ISS, international Staging System; OS, overall survival; *Survival of t(4;14) patients is improved with the use of bortezomibbased therapy; Chng WJ et al, Leukemia 2014, 269-77.
RISK FACTORS not just one staging! Combined genetic-iss-ldh models Score 0 1 2 3 Definition Absence of adverse factors (neither high LDH, nor ISS 3, nor t (4;14) and/or del 17p) Presence of only 1 adverse factor (either high LDH or ISS3 or t (4;14) and/or del 17p) Presence of high LDH plus ISS 3 in the absence of t(4;14) and/or del 17p Presence of t (4;14) and/or del 17 in addition to either ISS 3 or high LDH Overall population Outcome (4 years OS) 57 % 89 % 32 % 73 % 6 % 68 % 5 % 24 % Moreau P asbtract ASH 2012
RISK STRATIFICATION why? Prognosis Research Optimize patient management and outcome Comprehensive evaluation
Can we recommend riskadapted therapy?
RISK ADAPTED THERAPY in CURABLE DISEASES GOOD PROGNOSIS LESS INTENSIVE THERAPY BAD PROGNOSIS HIGH-DOSE THERAPY
RISK ADAPTED THERAPY Tansplant eligible Not Tansplant eligible Mayo Clinic Proceedings 2013 88, 360-376DOI: (10.1016/j.mayocp.2013.01.019)
RISK ADAPTED THERAPY in CURABLE DISEASES GOOD PROGNOSIS LESS INTENSIVE THERAPY BAD PROGNOSIS HIGH-DOSE THERAPY But MM is INCURABLE
Outcome improved in standard risk VTD, VMP, VMPT by FISH PFS TT3 by GEP EFS 100 80 60 P<0.0001 TT3/Low-risk TT2/Low-risk OS 40 20 0 100 80 60 P=0.02 TT3/High-risk TT2/High-risk 0 2 4 6 8 10 OS TT3/Low-risk TT2/Low-risk 40 TT3/High-risk 20 0 TT2/High-risk 0 2 4 6 8 10 Cavo M, et al. ASH 2010;116:781 Barlogie B, et al. IMW Paris 2011:96 VTD, bortezomib-thalidomide-dexamethasone; VMP, bortezomib-melphalan-prednisone; VMPT, VMP plus thalidomide; TT, total therapy; FISH, fluorescence in situ hybridization; GEP, gene expression profile; PFS, progression-free survival; EFS, event-free survival; OS, overall survival
Can we optimize patients management? May be
Getting to Minimal Residual Disease (MRD): New Definitions for CR Newly diagnosed 1 10 12 CR Stringent CR 1 10 8 Molecular/Flow CR 1 10 4 Cure? 0.0 Bortezomib Lenalidomide Combinations Courtesy of Dr S. Lonial
Tumour burden Treatment Strategy Continuous therapy Prolongs PFS Improve Quality of lyfe Combinational therapy Increases CR rate Time Safe Consolidation and Maintenance to improve outcome
Impact of genetic evolution Morgan G, et al ASH 2012
Early vs late intensification Sensitive disease CR rate 56% PFS 67% @ 5 yr OS 73% @ 5 yr Progression Combination therapy + maintenance 2nd-line 3rd-line Progression Single agent or non-novel drug combo 2nd-line 3rd-line 5thline 4thline CR rate 2% PFS 50% @ 5 mo Resistant disease OS 50% @ 9 mo Usmani SZ, et al. Leukemia 2012:1 [Epub]; Kumar SK, et al. Leukemia 2012;26:149
How: young fit patients
Current standard inductions for young patients Induction regimen Bortezomib- Dexamethasone 1 (223 patients) Bortezomib- Cylophosphamide- Dexamethasone 2 (63 patients) Dexamethasone 3 (413 patients) Bortezomib-Doxorubicin- Bortezomib- Thalidomide- Dexamethasone 4 (241 patients) Bortezomib- Lenalidomide- Dexamethasone 5 (66 patients) Schedule Four 21-day cycles Bor: 1.3 mg/m 2, d 1-4-8-11 Dex: 40 mg, d 1-4, 9-12 Four 28-day cycles Bor: 1.3 mg/m 2 d 1-4-8-11 or 1.5 mg/m 2 d 1-8-15-22 Cycl: 300 mg/m 2 d 1-8-15-22 Dex: 40 mg d 1-4, 9-12, 17-20 Three 28-day cycles Bor: 1.3 mg/m 2 d 1-4-8-11 Dox: 9 mg/m2 d 1-4 Dex. 40 mg d 1-4, 9-12, 17-20 Three 21-day cycles Bor: 1.3 mg/m 2 d 1-4-8-11 Thal: 100 mg/d for the first 14 days and 200 mg/d thereafter Dex: 40 mg/d on 8 of the first 12 days, but not consecutively; total of 320 mg per cycle Eight 28-day cycles Bor: 1.3 or 1 mg/m 2 d 1-4-8-11 Len: 15 or 25 mg d 1-21 Dex: 40 or 20 mg d 1-2, 4-5, 8-9, 11-12 DLT: Bor: 1.3mg/m 2, Len: 25 mg, Dex: 20 mg Response post-induction (%) PFS OS CR/nCR VGPR 15* 38 50% @ 3 yr 81% @ 3 yr 12* 35 50% @ 2.7 yr 88% @ 3 yr 11 42 50% @ 3 yr 61% @ 5 yr 31 62 68 @ 3 yr 86 @ 3 yr 39 67 75% @ 1.5 yr 97% @ 1.5 yr 1 Harousseau JL, et al. JCO 2010;28:4621; 2 Reeder CB, et al. Blood 2010;115:3416; 3 Sonneveld P, et al. JCO. 2012;30:2946; 4 Cavo M, et al. Lancet. 2010;376:2075; 5 Richardson PG, et al. Blood 2010; 116:679; CR, complete response; ncr, near complete response; PFS, progression-free survival; OS, overall survival; NA, not available; * CR rate only
VAD - ASCT Median follow-up 75 months EFS Single vs double ASCT 100 VAD - ASCT Median follow-up 62 months EFS VAD - ASCT - T maint no random Median follow-up 41 months Median 30 months Double ASCT Median 25 months P=0.03 Single ASCT OS 75 Median 35 months 50 Double ASCT 25 Median 23 months P=0.0051 Single ASCT 0 0 12 24 36 48 60 72 84 96 108 120 OS ASCT Single Double PFS median 24 mo 31 mo Median 48 months P=0.01 Cochrane: Median 58 months Double ASCT Single ASCT 100 75 50 25 Median 67 months Median 71 months P=0. 8832 0 0 12 24 36 48 60 7 2 Koreth M, et al. NEJM 2003;349:2495 Cavo M, et al. JCO 2007;25:2434 Double ASCT Single ASCT 84 96 108 120 - no study was sufficiently informative for treatment decisions - no trial integrated "novel agents" OS @ 5 yr 55% 70% Sonneveld P, et al. JCO 2012;30:2946 Cochrane Database Syst Rev. 2012 Oct 17
Consolidation improves response VTD 1 TD 2 before after CR: 15% 49% before after CR: 40% 47% before after VTD 2 R 5 before after V 3 (n)cr: 20% 45% before after VTD 4 CR: 33% 52% CR: 49% 61% before after 1 1 2 3 VGPR: 58% 69% V:Bortezomib (Velcade) T:Thalidomide D:Dexamethasone R:Lenalidomide (Revlimid) 0 10 20 30 40 50 60 70 80 Percentage 1 Ladetto M, et al. JCO 2010;28:2077-84; 2 Cavo M, et al. Blood 2012 Epub; 3. Mellqvist UH, et al. Blood 2013. 4. Leleu X, et al. Leukemia 2013. 5 Attal M, et al. NEJM 2012;366:1782-91
Lenalidomide maintenance IFM 05-02 CALGB 100104 Median follow-up 45 months PFS Median follow-up 34 months PFS Median 41 months Median 46 months Median 23 months Median 27 months P<0.001 OS OS 84%@ 3 yr 88%@ 3 yr 80%@ 3 yr 80%@ 3 yr P=0.03 Attal M, et al. NEJM 2012;366:1782 McCarthy PL, et al. NEJM. 2012;366:1770
How: Elderly patients
Standard therapies AEs and discontinuation Grade 3-4 AEs (%) Discontinuation for toxicity (%) PFS OS MPT 1 60 40 25% at 3 yr 69% at 3 yr VMP twice-weekly 2 91 34 50% at 2 yr 68% at 3 yr VMP once-weekly 3 51 17 46% at 3 yr 87% at 3 yr RD high-dose Dex 4 52 27 48% at 2 yr 78% at 2 yr Rd low-dose Dex 4 35 19 52% at 2 yr 88% at 2 yr 1 Waage A, et al. ASCO 2010; 2 San Miguel JF, et al. N Engl J Med 2008; 3 Bringhen S, et al. Blood. 2010; 4 Rajkumar SV, et al. Lancet Oncol 2010 AE, adverse events; PFS, progression free survival; OS, overall survival; MPT, melphalan-prednisone-thalidomide; VMP, bortezomib-melphalan-prednisone; RD, lenalidomide plus high-dose dexamethasone; Rd, lenalidomide plus low-dose dexamethasone.
IMID-based combination PFS All Patients 60% Reduced Risk of Progression 65-75 Years of Age 69% Reduced Risk of Progression Median PFS Median PFS 100 MPR-R MPR MP 31 months 14 months 13 months 100 MPR-R MPR MP Not reached 14.7 months 12.4 months Patients (%) 75 50 HR 0.395 P <.001 75 50 HR 0.315 P <.001 25 HR 0.796 P =.135 25 HR 0.675 P =.030 0 0 5 10 15 20 25 30 35 40 Time (Months) 0 0 5 10 15 20 25 30 35 40 Time (Months) Palumbo A, NEJM 2011 MPR-R: melphalan-prednisone-lenalidomide lenalidomide continuous treatment; MPR: melphalan-prednisone-lenalidomide; MP: melphalan-prednisone
IMID-based combination PFS and OS Rd continuous vs Rd18 vs MPT Significant PFS advantage for Rd continuous vs Rd 18 vs MPT ( Rd continuous vs MPT: HR=0.72; p= 0.00006) Significant PFS advantage for Rd continuous vs Rd 18 vs MPT ( Rd continuous vs MPT: HR=0.78, p=0.01685) Facon T, ASH 2013 meeting Abstract
Patients (%) PI-Based combination OS VMPT VT Maintenance Off therapy 1.00 5-years OS Median OS 0.75 VMPT-VT VMP 61% Not reached 51% 60.6 months 0.50 0.25 0.00 0 10 20 30 40 50 60 70 80 90 Palumbo A, ASH 2012 meeting Abstract Time (months) HR 0.70, 95% CI, 0.52-0.92, P = 0.01
Overall survival Landmark analysis 1.00 Age < 75 years 1.00 ISS 1-2 1.00 CR 0.75 0.75 0.75 0.50 0.50 0.50 0.25 0.25 0.25 HR 0.60, 95% CI, 0.41-0.89, p=0.009 0.00 0 10 20 30 40 50 60 70 0.00 HR 0.66, 95% CI, 0.43-1.00, p =.05 0 10 20 30 40 50 60 70 0.00 HR 0.45, 95% CI, 0.24-0.86, p =.01 0 10 20 30 40 50 60 70 1.00 Age 75 years 1.00 ISS 3 1.00 VGPR/PR 0.75 0.75 0.75 0.50 0.50 0.50 0.25 0.25 0.25 HR 0.76, 95% CI, 0.42-1.37, p =.36 HR 0.64, 95% CI, 0.31-1.31, p =.22 HR 0.80, 95% CI, 0.54-1.20, p =.28 0.00 0.00 0.00 0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70 VMPT VT maint. VMPT VT maint. VMPT VT maint. Off therapy Off therapy Off therapy VMP No maint. VMP No maint. VMP No maint.
How can we improve? Tomorrow
PRAMEF12 NRAS USH2A ASXL2 NCKAP5 PLS1 ACOT12 PCDHB6 CDKAL1 COL9A1 TIAM2 LRRC69 TRPM3 Whole Genome Sequencing New genomic frontier 1,2 1 0,8 Early mutation not in late sample New mutations in late sample PD4301 0,6 0,4 0,2 %MutLate %MutEarly 0 Early Tumor Late Tumor Early Tumor Late Tumor EARLY LATE (Munshi NC et al, ASH 2012 Abs. 276)
Carfilzomib, Lenalidomide, Dexamethasone (CRd) Patients (%) 53 newly diagnosed transplant eligible and ineligible MM patients enrolled at 4 US centers CRd Cycles 1-8 C: 20/27/36 mg/m 2, d 1,2,8,9,15,16 R: 25 mg/m 2, d 1-21 d: 40 mg (cycles 1-4) 20 mg (cycles 5-8), d 1,8,15,22 For ASCT eligible: Stem cell collection after cycle 4 M AI N T E N A N C E CRd Cycles 9-24 C: 20/27/36 mg/m2, d 1,2, 15,16 R: 25 mg/m2, d 1-21 d: 20 mg, d 1,8,15,22 R E C O M M E N D E D R (off protocol) Cycles 25+ L: 25 mg/day on days 1-21 Progression-free survival Median follow-up 13 months (range 1-20) 1-year rate 97% 2-year rate 92% 100 80 60 40 20 0 Best response Median 12 cycles (range 1-25) PR VGPR ncr scr 98 81 62 42 CRd, cyclophosphamide-lenalidomide-dexamethasone; R, lenalidomide; ASCT, autologous stem cell transplantation; PR, partial response; VGPR, very good partial response; CR, complete response; scr, stringent complete response. Jakubowiak AJ, et al. Blood 2012.
Patients (%) Patients (%) Carfilzomib, Cyclophosphamide, Dexamethasone (CCyd) 58 newly diagnosed elderly MM patients enrolled at 10 Italian centers CCyd Cycles 1-9 C: 20 mg/m 2 d 1,2 followed by 36 mg/m 2 d 8,9,15,16,22 (cycle 1); 36 mg/m 2 d 1,2,8,9,15,16,22 (cycle 2-9); Cy: 300 mg/m 2 d 1,8,15 d: 40 mg d 1,8,15,22 Progression-free survival M A I N T E N A N C E C Until progression/intolerance C: 36 mg/m 2 d 1,2,15,16 Best response 100 75 50 25 1-year rate 86% 13 15 0 0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 0 Cycle 2 Cycle 6 Cycle 9 Time (months) CCyd, cyclophosphamide-cyclophosphamide-dexamethasone; C, carfilzomib; PR, partial response; VGPR, very good partial response; CR, complete response; scr, stringent complete response; ncr, near complete response. Bringhen S, et al. EHA 2013 100 80 60 40 20 scr scr/ncr/cr VGPR PR 41 63 89 46 72 94 96 24 76 64
Bortezomib in patients with t(4;14) VD induction in t(4;14) pts VD vs VAD induction in t(4;14) pts Avet-Loiseau H et al. JCO 2010;28:4630-4634
Predictive markers in MM Cereblon primary teratogenic thalidomide targe Depletion resistance to Lenalidomide and Pomalidomide Acquired CRNB deletion resistance to Lenalidomide and Pomalidomide TRAF gene mutation causing inactivation of TRAF results in constitutive activation of NF-KB PIs target the NF-KB pathway
Conclusions 1 Risk stratification based on host and tumor factor Early is better than late Good prognosis major benefit Best available treatment Prospective collection of risk-assignement in clinical trials retrospective evaluation
Predictive markers Conclusions 2 Genomic driven therapy Newer agents/combo Risk stratification in the trial design in order to specifically answer questions on treatment within each risk group.
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