Terapia del paziente non candidato a trapianto

Gammapatie monoclonali e mieloma multiplo Varese, 14 novembre 2011 Terapia del paziente non candidato a trapianto Luca Baldini UO Ematologia 1-CTMO 1 Università degli studi di Milano Fondazione IRCCS Cà Granda OM Policlinico, Milano

Elderly patients with MM MM is predominantly a disease of the elderly In the US, two-thirds of pts is 65 years old ASL TORINO: 902.000 people Median age at diagnosis: 69.4 years 65-75 years 36% 31% 25-64 years 33% 75-101 years Regione Piemonte, Assessorato Sanità 2006,15

Major milestones in Multiple Myeloma Therapy Other CCT regimens = MP ASCT Single vs double ASCT Bortezomib Melph-Pdn HDMelphalan Thal Lenalidomide 1962 1986 1996 1999 2003 2005 Quality of response PF survival Overall survival LB UNIMI

LESSON FROM NEW AGENTS IN MM Role of CR New toxicities Different subsets of elderly pts

LESSON FROM NEW AGENTS IN MM Role of CR Different subsets of elderly pts New toxicities

What disease response is best? Depth of response Time to progression Treatment initiation MR PR VGPR ncr CR scr icr mcr Time Depth of response is related to TTP Niesvizky et al. Br J Haematol 2008; 143(1): 46-53; Harousseau et al. Blood 2009; 114(15): 3139-3146 Chanan-Khan et al. J Clin Oncol 2010; 28(15): 2612-2624

CR correlates with survival International MyelomaWorking Group criteria (2009) Retrospective analysis of three randomized studies from GIMEMA and HOVON (n=1175; median age: 72 yrs) MP (n=332), MPT (n=332), VMP (n=257), or VMPT-VT VT (n=254) CR CR (195) VGPR (212) VGPR PR PFS PR (397) OS p<0.001 p<0.001 Median follow-up: 29 months Gay et al. Blood 2011; 117(11): 3025-3031

CR associata a miglior PFS e OS anche nei pazienti >75 anni CR VGPR PR 3y PFS 79% 24% 23% 3y OS 88% 65% 57% 3y PFS 3y OS Gay et al. ASH Gay et 2010 al. Blood (Abs 2010 1949)

La miglior qualità della risposta è associata a miglior QoL Progressive disease Stable disease Partial response Complete response Study details n=292 newly diagnosed MM Prospective comparison: Continuous prednisone + VMCP Intermittent prednisone + VMCP Collection of quality of life data using EORTC QLQ-C30 0 20 40 60 80 Quality of life score 100 Ludwig et al. IMW 2007; (Abs 1103)

LESSON FROM NEW AGENTS IN MM Role of CR New toxicities Different subsets of elderly pts

Summary Table of Selected Therapy-Related Adverse Effects Peripheral Neuropathy Thalidomide [1] Lenalidomide [2] Bortezomib [3] (50%): grade 3-4: 5-8%; may be irreversible DVT More with dex (4-15%) More with dex (7%) Myelosuppression Hypotension Neutropenia Neutropenia (21%), thrombocytopenia (10%) anemia (20-30%); grade 3-4: 4-8%; painful, usuallyreversible Thrombocytopenia (20%) Fatigue, weakness (70%) (38%) Sedation Rash (30%) GI Disturbance Constipation (50%) Constipation (39%) diarrhea (29%) Nausea and vomiting, diarrhea (8%) 1. Thalidomide [package insert]. 2. Lenalidomide [package insert]. 3. Bortezomib [package insert]. 4. Orlowski RZ, et al. J Clin Oncol. 2007;25:3892-3901. L. Baldini -UniMI

LESSON FROM NEW AGENTS IN MM Role of CR New toxicities Different subsets of elderly pts

10-Yr Relative Survival (%) Improvements in Survival by Age Period Estimates of 10-Yr Survival by Major Age Groups in Defined Calendar Periods 50 45 40 35 30 25 20 15 10 5 0 Age, yrs 1984-1986 1987-1989 1990-1992 1993-1995 Years 1996-1998 1999-2001 2002-2004 < 50 50-59 59 60-69 69 70-79 79 80+ Improvements in survival for elderly patients expected with longer follow-up of ongoing trials Brenner H, et al. Blood. 2008;111:2521-2526.

Management of elderly patients The NCCN guidelines on treating older adults with cancer recommend using Comprehensive Geriatric Assesment tools to asses the patient s likely tolerance of treatment by formally assessing: - comorbidities, - functional status - geriatric syndromes - polypharmacy,nutrition - socioeconomic status and personal preferences Toxicity Comorbidities Depth of response Niesvizky R et al. Oncology 24:3; March 2010

Len + High- or Low-Dose Dex (E4A03 trial) Low-dose Dex = 40 mg/day PO, on Days 1, 8, 15, 22 High-dose Dex = 40 mg/day PO, on Days 1-4, 9-12, 17-20 High Dose Low Dose P Value Best overall response, % 81 70.009 VGPR, % 50 40.040 OVERALL SURVIVAL Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37.

Nel paziente > 75 aa,, il raggiungimento della miglior risposta possibile è auspicabile, ma altri parametri devono essere considerati TTNT (time to next treatment): è il tempo dall inizio di un trattamento all inizio del successivo TFI (treatment free interval): è il tempo dalla fine di un trattamento all inizio del successivo QoL TWiST (time without symptoms disease or toxicity related) LB UNIMI

Terapia con nuovi agenti a dose ridotta o terapia convenzionale Terapia con nuovi agenti a dose piena

Expanding treatment options in front-line therapy for elderly myeloma pts MP/CTX + novel agents MPT (GIMEMA, IFM, NMSG, HOVON, Turkish study group) CTD (MRC Myeloma IX) VMP (VISTA, PETHEMA, GIMEMA) VMPT-VT (GIMEMA) VMP-VT/VP (PETHEMA) MPR-R (GIMEMA) Dex + novel agents Bortezomib/Dex-based (UPFRONT study) Thal/Dex-based (ECOG, Celgene 003, CEMSG, MRC Myeloma IX) Len/Dex (ECOG, SWOG others) Len/Bortezomib/Dex (DFCI)

CONVENTIONAL THERAPY MP, Dex,, VAD or VAD-like regimens ORR ~ 50% CR < 5% Median DFS: 18 mos Median OS: 3 yrs LB MM 30.10.08

Farmaci concessi dal SSN in Italia per la terapia di prima linea del paziente non ASCT candidabile MP, HCTX, VAD MP+Thalidomide (MPT) Frontline therapy in elderly pts (FDA, EMEA,AIFA march 2009) MP+Bortezomib (MPV) Frontline therapy in elderly pts (FDA and EMEA 2008, AIFA july 2009) L. Baldini -UniMI

ALKILATING + NOVEL AGENTS without maintenance

MP vs MPT Studies Patient Characteristics and MPT Regimens GIMEMA [1,2] IFM 99-06 [3] IFM 01-01 [4] NMSG [5] HOVON [6] Patients, n (MPT) 331 (167) 447 (125) 232 (113) 362 (182) 301 (152) Age, yrs Median 72 69 78.5 75 (mean) 72 Range 60-85 65-75 76-91 49-92 N/A WHO grade 3/4, % 5 8 7 30 4 MPT regimen Cycles, n 6 12 12 Until plateau Until plateau M dosing 4 mg/m 2 Days 1-7 0.25 mg/kg Days 1-4 0.2 mg/kg Days 1-4 0.25 mg/kg Days 1-4 0.25 mg/kg Days 1-5 Thal dosing, mg/day 100 Up to 400 100 Up to 400 200 Maintenance + - - + + 1. Palumbo A, et al. Lancet. 2006; 367:825-831. 2. Palumbo A, et al. Blood. 2008;112:3107-3114. 3. Facon T, et al. Lancet. 2007;370:1209-1218. 4. Hulin C, et al. JCO 2009, 27: 3664-3670. 5. Waage A, et al. Blood 2010, 116: 1405-12 6. Wijermans P, et al. JCO 2010, 28:3160-66

Summary of MPT phase III trials in the upfront setting Regimen GIMEMA Thal/MP MP IFM 99-06 Thal/MP MP MEL 100 n. Pts (median FU) 129 (18) 126 (15) 191 124 121 ( 1 5 ) (51) CR (%) 15 2 13 2 18 CR+VGPR (%) 29 11 47 7 PFS (mos) 21.8 14.5 27.5 17.8 19.4 OS (mos) 45 47.6 51.6 33.2 38.3.0006 Reference Palumbo et al. Blood 2008; 112:3107-14 Facon, et al. Lancet 2007; 370:1209 18 IFM 01-01 Thal/MP MP NMSG Thal/MP MP 113 116 182 181 (47) (42) 7 1 13 3 21 7 23 7 24.1 18.5 15 14 44.3 29.1 29 32.028 Hulin, et al. JCO 2009; 27:3664-3670 Waage A et al. Blood 2010 116(9):1405-12 HOVON Thal/MP MP 165 (nr) 168 (nr) 4 2 23 8 15 11 40 31 Wijermans P, et al. JCO 2010, 28:3160-66

Toxicities of THAL combined with melphalan in phase III trials Toxicity grade 3-4 (%) MPT (n=167) Palumbo et al. (GIMEMA) MPT (n=124) Facon et al (IFM) MPT (n=113) Hulin et al. (IFM) - Infections 10 17 n./a. - Neutropenia 22 41 20 - DVT 12 12 7 - Neuropathy 8 6 2 Thal Discontinuation / Treatment withdrawal (%) 46.5* 45* 53* * Due to adverse events LB UNIMI

Valutazione del rischio trombotico in pazienti trattati con talidomide Fattori di rischio individuali Fattori di rischio associati alla terapia Pregressa trombosi Trombofilia ereditaria Obesità CVC Comorbidità (diabete, infezioni..) Interventi chirurgici Desametasone ad alte dosi Doxorubicina Polichemioterapia Fattori di rischio associati al mieloma Trombosi nel MM: ~5% LB UNIMI

Aspirina Profilassi antitrombotica in pazienti trattati con IMiD Se 1 1 FR individuali o associati al mieloma Eparina a basso peso molecolare Se 2 2 FR individuali o associati al mieloma Se talidomide + HD dexa, doxorubicina, poli-ct Palumbo et al, Leukemia 2008; Palumbo et al, EHA 2008 LB UNIMI

CTD vs MP : MRC Myeloma IX Phase III, Study in Elderly Patients with Newly Diagnosed MM RANDOMIZATION 849 pts (median age 73 yrs; ; 57-89) 100 P<.001 CTD CTX 500 mg po,, days 1,8,and 15; THAL 50-200 mg/day; Dex 20 mg/day days 1-41 and 15-18 18 q 4 wk RANDOMIZATION MP Response, % 80 60 40 20 0 63.8 13 17 32.6 28.6 33.8 2.4 1.7 CTD (n = 426) MP (n = 423) PR VGPR CR Thal +Thal 100 mg/day No differences in terms of OS and PFS (36 and 12 mos) Correlation with quality of response and cytogenetic profile) VTE 16% vs 4.5% Morgan et al. Blood, 2011

VISTA - Velcade as Initial Standard Therapy in newly diagnose multiple myeloma (> 65 yrs or not transplant eligible): Assessment with melphalan and prednisone 54 weeks 682 pts Bort 1.3 mg/m 2 IV on Days 1, 4, 8, 11, 22, 25, 29, 32 during first four 6-week cycles + MP* (n = 344) Bort 1.3 mg/m 2 IV on Days 1, 8, 22, 29 for five 6-week cycles + MP* (n = 344) Melphalan (9 mg/sm) and Prednisone (60 mg/sm) on days 1-4 for nine 6-week cycles (n = 338) DOSE/INTENSITY OF BORTEZOMIB: 52 doses/54 wks Primary end point: TTP San Miguel J, NEJM 2008; 359:906 LB Unimi

VISTA: response rates and TTP Responses Time to progression p < 0.001 100 74% PR VGPR CR 39% Event-free patients (%) 80 60 40 20 0 Median TTP MPV: 24 months MP: 16.6 months HR 0.48; p < 0.001 0 3 6 9 12 15 18 21 24 27 Time (months) San Miguel JF, et al. N Engl J Med. 2008;359:906-17.

VISTA: overall survival 3-year OS rates: MPV 68.5%, MP 54.0% Surviving patients (%) 100 80 60 40 20 0 Median follow-up: 36.7 months Median OS MPV: not reached (109 deaths) MP: 43.1 months (148 deaths) HR 0.653 (95% CI 0.508 0.840); p = 0.0008 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 Time (months) Mateos MV, et al. J Clin Oncol. 2010;28:2259-66.

VISTA - Adverse events VMP (N=340) MP (N=337) AE, % Grade 3 Grade 4 Grade 3 Grade 4 Neutropenia 30 10 23 15 Thrombocytopenia 20 17 16 14 Anemia 16 3 20 8 GI 19 1 5 <1 Peripheral sensory neuropathy 13 <1 0 0 Fatigue 7 1 2 0 Asthenia 6 <1 3 0 Pneumonia 5 2 4 1 Herpes zoster 3 0 2 0 Overall rate of peripheral sensory neuropathy with VMP was 44%, including 14% grade 1, 17% grade 2 At data cut-off 74% of peripheral neuropathy (PN) events had resolved to baseline (56%) or decreased by at least one toxicity grade (18%) in a median of 2 months Herpes zoster was more frequent with VMP (13% vs 4%); rate with VMP only 3% among patients receiving antiviral prophylaxis Rate of DVT was low and similar with VMP vs MP (1% vs 2%) LB UNIMI

Raccomandazioni per la gestione della neuropatia da Bortezomib Segni e sintomi di PN Grado 1 (parestesie e/o perdita dei riflessi senza dolore nè deficit funzionali) Azione Se bisettimanale passare a monosettimanale; se monosettimanale ridurre di un livello Grado 2 (non interferisce con lo svolgimento delle normali attività quotidiane) Grado 3 e 4 (disabilitante) Se bisettimanale passare a monosettimanale; se monosettimanale ridurre di un livello o sospendere temporaneamente. Se migliora riprendere monosettimanale con dose ridotta a 1 mg/m 2 Sospendere definitivamente La presenza di dolore neuropatico innalza di 1 grado Riduzione dose livello 1 =: 1 mg/sm; livello 2= 0.7 mg/sm Delforge et al, Lancet Oncol 2010

Bortezomib planned dose: 67.6 mg/sm sm; administreded dose: 38.5 mg/sm Bortezomib planned dose: 36.4 mg/sm sm; administreded dose: na Bortezomib planned dose: 46.8 mg/sm sm; administreded dose: 40 mg/smn

MM-015: phase 3 trial of MPR vs MP for longterm control in newly diagnosed MM R A N D O M I Z A T I O N 51 centres in Europe, Australia, and Israel (N = 459) MPR-R Melphalan 0.18 mg/kg, days 1 4 Prednisone 2 mg/kg, days 1 4 Lenalidomide 10 mg/day p.o., days 1 21 MPR Cycles (28-day) 1 9 Melphalan 0.18 mg/kg, days 1 4 Prednisone 2 mg/kg, days 1 4 Lenalidomide 10 mg/day p.o., days 1 21 MPSecondary comparison Melphalan MPR-R 0.18 vsmg/kg, MPR days 1 4 Prednisone Addition of 2 MPR mg/kg, arm days per 1 4 PlaceboEMEA days advice 1 21 Cycles 10+ Lenalidomide continued 10 mg/day days 1 21 Placebo Placebo P R O G R E S S I O N Len (25 mg/day) ± Dex Double-blind treatment phase Stratification by age ( 75 vs > 75 years) and ISS stage (1, 2, or 3) Open-label extension and follow-up phase Palumbo A, et al. Blood. 2010;116:[abstract 622]. Updated data presented at ASH 2010.

MM-015: response rates significantly higher with MPR vs MP Best overall response* MPR (n = 153) ORR ( PR) (%) 67 50 CR ** (%) 13 4 VGPR*** (%) 32 12 Median time to first response (months) 2 3 MP (n = 154) *As measured using EBMT criteria. 1 **Immunofixation negative with or without bone marrow confirmation. ***VGPR: > 90% reduction in M protein. Palumbo A, et al. Blood. 2010;116:[abstract 622]. 1. Bladé J, et al. Br J Haematol. 1998;102:1115-23.

MM-015: MPR vs MP progressionfree survival 100 Patients (%) 75 50 25 MPR MP Median PFS 14 months 13 months 0 0 5 10 15 20 25 30 35 40 Time (months) Median follow-up 25 months p = 0.153 *Analysis based on data up to May 2010. Palumbo A, et al. Blood. 2010;116:[abstract 622]. Updated data presented at ASH 2010.

Treatment Initial 9 cycles MPR MP Discontinuation rate (%) 65-75 years of age 17 10 > 75 years of age 34 16 Cumulative dose intensity (%) 65-75 years of age 88 97 > 75 years of age 56 97 Discontinuation due to AEs or withdrawal of consent Cumulative dose intensity of melphalan and lenalidomide/placebo

DEX + NOVEL AGENTS

Lenalidomide + High (RD) vs Low-Dose Dex (Rd) in Elderly Patients with Newly Diagnosed MM: ECOG (E4A03 phase III study) Four 28-day cycles 445 pts Median age 66 yrs (51-88) RD Arm A Lenalidomide 25 mg/day orally on Days 1-21 + Dexamethasone 40 mg orally on Days 1-4, 9-12, 17-20 (Dex tot 480) (n = 223) Rd Arm B Lenalidomide 25 mg/day orally on Days 1-21 + Dexamethasone 40 mg orally on Days 1, 8, 15, 22 (Dex tot 160) (n = 222) CR/PR < PR ASCT or RD/Rd Rd or no further therapy CR/PR 4 cycles thal + dex LB MM UniMi

Phase III ECOG Trial: RD vs Rd After 4 induction cycles: VGPR 51% with RD vs 40% with Rd PR 81% with RD vs 70% with Rd PFS: 24-26 26 months (P P =.08. log-rank; P =.04 Pepe-Fleming) OS: 75% at 3 years Although initial findings suggested better OS with Rd; OS at 3 years identical for both treatment arms (P P =.46. log-rank rank; ; P =.01 Pepe-Fleming) Rajkumar SV, et al. Lancet Oncol. 2009

Novel agents in combination as primary treatment (without maintenance) Study n Median age, years VGPR, % PR, % PFS or TTP (mos) Median MPT 1 IFM 99-06 125 69 47 76 28 MPT 2,3 MPT vs MP 167 72 29 69 22 MPV 4,5 VISTA 337 71 41 74 TTP: 24 MPR 6 MPR 153 71 33 67 14 Rd 7 ECOG-E4A03 65 years 222 65 40 70 26 CTDa 8,9 MRC Myeloma IX NA 73 40 50 12 1. Facon T, et al. Lancet. 2007;370:1209-18. 2. Palumbo A, et al. Lancet. 2006;367:825-31. 3. Palumbo A, et al. Blood. 2008;112:3107-14. 4. San Miguel JF, et al. N Engl J Med. 2008;359:906-17. 5. Mateos MV, et al. Blood. 2009;114:[abstract 3859]. 6. Palumbo A, et al. Blood. 2009;114:[abstract 613]. 7. Rajkumar SV, et al. Lancet Oncol. 2009. 8. Morgan GJ, et al. Blood. 2007;110:[abstract 3593]. 9. Owen RG, et al. Presented at IMW 2009 [abstract 547].

Outcomes from randomized phase 3 trials in elderly NDMM Regimen Median age CR rate % Median PS Median OS, mos Stop rate, % MPT (5 studies) 69-78 10-23 15-28 26-52 40-55 VMP (VISTA) 71 30 na nr 34 VMP (Palumbo( Palumbo) 71 24 23 nr 17 Rd (Rajkumar) 66 4 25 nr 19 VMPT (Palumbo) 71 38 nr nr 23 MPR-R (Palumbo) 71 16 nr nr 13 CTDa (Morgan) 73 13 13 33 NA

Novel agents as primary treatment: safety Grade 3 or 4 adverse events, % IFM MPT VISTA MPV GIMEMA MPR ECOG Rd Neutropenia 48 40 52 20 Thrombocytopenia 14 37 24 5 Anaemia 14 19 5 7 Neuropathy 6 13 0 2 DVT 12 1 5 12 Infection 10 7 9.5 9 Herpes zoster 2.5 3 NR NR Moreau P, et al. Blood Rev. 2008;22:303-9. Rajkumar SV, et al. Lancet Oncol. [Epub ahead of print 2009 Oct 21.]

OPEN QUESTIONS ABOUT NEW AGENTS IN MM Role of CR Different subsets of elderly pts New toxicities Fixed doses or continuos therapy Identification of the best synergistic effect New-new agents

Approach to MM cells control Progression free Survival MM cells TARGET OF EFFICACY Improvement Citostatici convenzionali of quality of response Improvement or ofifn/dex OS Continuous terapy (continuous ther. vs ther. at relapse) Nuovi farmaci ± CT Overall Survival time

Phase III Study of Bortezomib, Melphalan, Prednisone (VMP) ± Thalidomide (VMPT) in elderly patients with Newly Diagnosed MM: GIMEMA Trial Newly diagnosed symptomatic MM 65 yr or <65 yr and not transplanteligible (N=393) R A N D O M I Z A T I O N VMP Bortezomib 1.3 mg/m2 IV days 1,8,15,22* Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1 4 VMPT Bortezomib 1.3 mg/m2 IV days 1,8,15,22* Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1 4 Thalidomide 50 mg/d continuously NO MAINTENANCE MAINTENANCE Bortezomib 1.3 mg/m2 IV days 1,15 Thalidomide 50 mg/day 9 5-wk cycles in both arms Until relapse *61 VMP patients and 70 VMPT patients were treated with biweekly infusions of bortezomib Palumbo A, et al. J Clin Oncol. 2010;28:5101-9.

GIMEMA (MPVT-VT vs MPV): efficacy Response MPVT-VT (n = 250) Patients (%) MPV (n = 253) p value CR 42 24 < 0.0001 VGPR 64 50 0.001 PR 90 81 0.007 OS at 3 years 85 80 0.35 Palumbo A, et al. J Clin Oncol. 2010;28:5101-9.

GIMEMA (MPVT-VT vs MPV): PFS and TTNT Progression-free survival Median follow-up: 32 months Time to next therapy 41% reduced risk of progression 48% reduced risk of progression 3-year PFS Median PFS 3-year TTNT Median TTNT 1.00 MPVT MPV 51% 37.2 months 32% 27.4 months 1.00 MPVT MPV 70% Not reached 51% 37.6 months Patients (%) 0.75 0.50 0.25 0.00 HR 0.59 p < 0.0001 0 10 20 30 40 50 60 Time (months) Patients (%) 0.75 0.50 0.25 0.00 HR 0.52 p < 0.0001 0 10 20 30 40 50 60 Time (months) Palumbo A, et al. J Clin Oncol. 2010;28:5101-9.

PETHEMA/GEM study phase 3 trial of MPV and VTP in elderly patients with previously untreated MM Untreated MM; age > 65 years (N = 253) R A N D O M I Z A T I O N MPV (n = 130) Bortezomib 1.3 mg/m 2 for one 6-week cycle, days 1, 4, 8, 11, 22, 25, 29, 32; then for five 5-week cycles, days 1, 8, 15, 22 Melphalan 9 mg/m 2 and Prednisone 60 mg/m 2, days 1 4 of each cycle VTP (n = 130) Bortezomib as above, continuous Thalidomide 100 mg/day, Prednisone as above Maintenance Bortezomib 1.3 mg/m 2, days 1, 4, 8, 11 every 3 months Prednisone 50 mg every other day Maintenance Bortezomib 1.3 mg/m 2, days 1, 4, 8, 11 every 3 months Thalidomide 50 mg/day Maximum 6 cycles Up 3 years Mateos MV, et al. Lancet Oncology. 2010;11:934-41.

VMP vs VTP VT vs VP in Elderly Newly Diagnosed Myeloma Patients: Responses Outcome Following Induction, % VMP VTP After a median follow-up (n = of 130) 32 months from (n = 130) first randomization ORR 80 81 CR (if negative) 20 27 CR (if median positive) PFS for all patients 12 was 31 months 10 PR 48 46 MR median TTP was 35 months 10 6 SD 8 11 Outcome 3-year Following OS was 70% VT VP Maintenance Therapy, % (n = 91) (n = 87) CR/nCRno significant differences between the MPV and CR (if negative) 44 39 CR VTP (if positive) groups in PFS (p = 15 0.1) and 3-year OS 16 (p = PR 0.3) 39 44 MR 2 1 Overall CR rate (if negative) increased from 23% following induction to 42% after maintenance Mateos MV, et al. Lancet Oncol. 2010;11:934-941.

Toxicity of Maintenance in Elderly MM Patients Grade 3/4 adverse events significantly increased in VMPT VT vs VMP arms (Neutropenia (P =.02); Cardiologic (P =.04); Deep vein thrombosis/pulmonary embolism (P =.05) More patients in VMPT VT vs VMP arm discontinued treatment due to adverse events: 21% vs 16% Palumbo A, et al. J Clin Oncol. 2010;28:5101-9. MPV treatment produced more haematological adverse events than VTPV (particularly grade 3 or worse neutropenia and thrombocytopenia) VTP was associated with severe cardiac complications (11 patients (8%) compared with none in those receiving MPV) Rate of infections was higher with MPV than with VTP Mateos MV, et al. Lancet Oncology. 2010;11:934-41.

MM-015: phase 3 trial of MPR vs MP for longterm control in newly diagnosed MM R A N D O M I Z A T I O N 51 centres in Europe, Australia, and Israel (N = 459) MPR-R Melphalan 0.18 mg/kg, days 1 4 Prednisone 2 mg/kg, days 1 4 Lenalidomide 10 mg/day p.o., days 1 21 MPR Cycles (28-day) 1 9 Melphalan 0.18 mg/kg, days 1 4 Prednisone 2 mg/kg, days 1 4 Lenalidomide 10 mg/day p.o., days 1 21 MPSecondary comparison Melphalan MPR-R 0.18 vsmg/kg, MPR days 1 4 Prednisone Addition of 2 MPR mg/kg, arm days per 1 4 PlaceboEMEA days advice 1 21 Cycles 10+ Lenalidomide continued 10 mg/day days 1 21 Placebo Placebo P R O G R E S S I O N Len (25 mg/day) ± Dex Double-blind treatment phase Stratification by age ( 75 vs > 75 years) and ISS stage (1, 2, or 3) Open-label extension and follow-up phase Palumbo A, et al. Blood. 2010;116:[abstract 622]. Updated data presented at ASH 2010.

MM-015: response rates significantly higher with MPR-R vs MP Best overall response* MPR-R (n = 152) MP (n = 154) p value (MPR-R vs MP) ORR ( PR) (%) 77 50 < 0.001 CR ** (%) 16 4 < 0.001 VGPR*** (%) 32 12 < 0.001 Median time to first response (months) 2 3 < 0.001 *As measured using EBMT criteria. 1 **Immunofixation negative with or without bone marrow confirmation. ***VGPR: > 90% reduction in M protein. Palumbo A, et al. Blood. 2010;116:[abstract 622]. 1. Bladé J, et al. Br J Haematol. 1998;102:1115-23.

MM-015: MPR-R significantly improved progression-free survival Patients (%) 100 75 50 0 Time (months) Median follow-up 25 months *Analysis based on data up to May 2010. MPR 0 5 10 15 20 25 30 35 40 MP p < 10-7 Median PFS low incidence of adverse events MPR-R during lenalidomide continuous treatment but p = 0.153 31 months 14 months 13 months maintenance 25 therapy should performed only in clinical trials! Palumbo A, et al. Blood. 2010;116:[abstract 622]. Updated data presented at ASH 2010.

COSA è CAMBIATO CON LE NUOVE ASSOCIAZIONI? La THAL e il Bortezomib si potenziano in associazione con MP Il patner ideale per la Len non sembra essere MP ma il Dex/dex La scelta dell uno vs l altro l dipende da considerazioni specifiche sul singolo paziente (PS/comorbidit comorbidità,, rischio genetico, PNP all esordio etc) Le dosi dei nuovi agenti devono essere aggiustate in relazione all et età Non ci sono dati a favore che l utilizzo l contemporaneo dei nuovi agenti possa comportare ad un miglioramento della risposta in grado di incisìdere sulla OS rispetto ad un uso sequenziale volto ad ottenere il massimo da ogni singolo agente Mantenimento/Extended therapy migliora la qualità della risposta e la PFS. Non ci sono dati a favore di un incremento della OS (soprattutto vs un trattamento alla recidiva). Il mantenimento con Bortezomib o Thal aumentano la tossicità.. MPR-R: R: secondo tumore?

VULNERABILITY OF ELDERLY PATIENTS Frailty grade Description Fraility: weakness, regularly poor or occasionally endurance, weight loss, low physical activity, Patients not, slow regularly gait active speed beyond Very fit Moderately fit Active, energetic patients, who exercise routinely walking Comorbidity: At concurrent presence of 2 least 2 comorbidities in US: medically diagnosed diseases. Vulnerable Mildly frail Moderately frail Severely frail Patients who can perform limited activities but yet do not need help from other people - 60-69 69 yrs: : 35% in M and 45% in F Patients who need help for household tasks (shopping, walking several blocks, managing their finances, and medications) - 80 yrs: : 53% in M and 70% in F Disability: difficulty in activities essential to independent living (personal care, household tasks) Patients who need partial help for their personal care (dressing, bathing, toileting, eating) Patients completely dependent on other people for their personal care Palumbo et al, Blood 2011

Report of European Myeloma Network (EMN) on personalized therapy in MM according to age and vulnerability Palumbo et al, Blood oct 2011

CR, PFS and OS CR and PFS QoL

PROPOSAL OF THERAPEUTIC ALGORITHM FOR PTS NOT CANDIDATE FOR ASCT > 75 yrs or frail < 75 yrs or fit Specific complications Low-dose MPT Low-dose Bz ± MP MP Low-dose Dex Low dose Len/Dex CDT Ctx-Pdn NO MPT MPV CTD Rd MPR-R R? Renal: Bz-based YES Thrombophilic status, cardiovascular events: Bz-based Poor genetic risk: Bz-based History of PN: Len-based

Future Directions (Continued)? Tuning of tested combinations Newer combinations. Novel agent sequences (second generation PIs, HDAC inhibitors, other small molecules, 3rd generation IMiDs, MoAbs)? Tailored approach to therapy: Identify groups of pts in whom combinations are required versus pts in whom doublets and/or sequences should be used Use of GEP, Proteomics Risk adaptation

In the Absence of Data Quality of Life Response CLINICAL TRIALS!!!!!! and Risk Based Therapy

IMWG response criteria Durie et al., Leukemia 2006 scr: : CR più normale rapporto FLC,, assenza di cellule clonali midollari all analisi analisi citofluorimetrica ed immunoistochimica CR: : IF negativa nel siero e nelle urine, scomparsa di localizzazioni tessutali da plasmacitoma e <5% di plasmacellule midollari VGPR: : negatività all elettroforesi o riduzione di della CM sierica 90% e BJ proteinuria <100 mg/24h PR: riduzione della CM sierica 50% e della BJ 90% o < 200 mg/24h; nei MM non secernenti, riduzione 50% del rapporto FLC e della plasmocitosi midollare 50% (partendo da un infiltrato iniziale 30%; nei plasmacitomi solitari, riduzione 50% delle dimensioni SD: se non soddisfatti i criteri della CR, VGPR, PR e della progressione sione (non criterio di risposta; utile per calcolare TTP) LB UNIMI

IMiDs, bortezomib Dex Bortezomib Hsp90 inh HDAC inh Alkylators Anthracyclines Mitochondria Caspase-8 Cytochrome-c Caspase 9 Smac NFκB Transcriptional changes Caspase-3 PARP Proteasome Aggresome TUMOR CELL DEATH TUMOR CELL DEATH The Future: Synergistic anti-mm activity Proteasome Inhibitor/IMiD-based Novel Agent Combos