Cure versus control: Which is the best strategy?

Cure versus control: Which is the best strategy? Barcelona 8-9-2012 Mario Boccadoro DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

MULTIPLE MYELOMA Cure versus control Young patients HIGHER CR LONGER SURVIVAL DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

RATIONALE Young ASCT patients EFS OS Haurousseu JL et al, J Clin Oncol 2009

MULTIPLE MYELOMA Cure versus control Young patients HIGHER CR LONGER SURVIVAL Elderly patients HIGHER CR LONGER SURVIVAL DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

RATIONALE Elderly patients MP MPT 5 VMP 6 VMPT-VT 6 No Pts 126 129 253 250 CR 3% 16% 24% 38% VGPR 5% 9% 26% 21% PR 52% 84% 81% 89% V= Velcade; M= Melphalan; P= Prednisone; T= Thalidomide; R= Lenalidomide

STUDY DESIGN Patients with newly diagnosed MM, 65 years enrolled in phase III trials : GISMM-2001 MP vs MPT, HOVON MP vs MPT, GIMEMA MM0305 VMP vs VMPT-VT Phase III MP vs MPT N=331 Phase III MP vs MPT N=344 Phase III VMP vs VMPT-VT N=511 Best response available in 1,136 patients CR N=195 VGPR N=212 PR N=397 Gay F et al, Blood. 2011 Mar 17;117(11):3025-31

SURVIVAL ACCORDING TO RESPONSE OS@3 yr: CR 91% vs VGPR 70% vs PR 67% Gay F et al, Blood. 2011 Mar 17;117(11):3025-31

AGE OVER 75:OVERALL SURVIVAL OS@3yr: CR 88% vs VGPR 65% vs PR 57% Gay F et al, Blood. 2011 Mar 17;117(11):3025-31

MULTIPLE MYELOMA Cure versus control Young patients HIGHER CR Elderly patients HIGHER CR LONGER SURVIVAL Tx intensification CURE LONGER SURVIVAL DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

MULTIPLE MYELOMA Cure versus control Tx intensification CURE TOXICITY DISCONTINUATION DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

MPT and VMP Severe AEs and early discontinuation ITT Doses Grade 3-4 AEs Early Discontinuation MPT 1 Thalidomide 400 mg/d 50% 45% MPT 2 Thalidomide 100 mg/d 50% 41% VMP 3 Bortezomib 1.3mg/m 2 d1,4,8,11 91% 34% 1. Facon T, et al. Lancet. 2007; 370:1209-18. 2. Palumbo A, et al. Lancet. 2006;367:825-31. 3. San Miguel J, et al. N Engl J Med. 2008;359:906-17.

VMPT-VT vs VMP: discontinuation and dose intensity 1.00 1.00 65-75 Years of Age > 75 Years of Age 0.75 0.75 EFS (%) 0.50 0.25 VMPT- VT VMP EFS (%) 0.50 0.25 VMPT-VT VMP 0.00 HR 0.51, p<0.0001 HR 0.63, p=0.25 0.00 0 10 20 30 40 0 5 10 15 20 25 30 35 40 Months Months VMPT VT VMP Discontinuation from induction < 9 cycles due to AE (%) 65 75 years 27 16 > 75 years 37 18 Median cumulative dose intensity (mg/m 2 ) 65 75 years 61 42 > 75 years 31 37 Palumbo A, et al. Blood. 2010;116:[abstract 620]. Updated data presented at ASH 2010.

Patients (%) MM-015: discontinuation and dose intensity 100 75 50 25 HR 0.850 Log rank P = 0.307 All patients MP MPR-R MPR Discontinuation from induction < 9 cycles due to AE (%) 65 75 years 12 4 > 75 years 19 8 Cumulative dose intensity (%) MPR Patients (%) HR 0.423 Log rank P < 0.001 0 0 5 10 15 20 25 30 35 40 Time (months) 100 65 75 years 88 97 > 75 years 56 97 75 50 25 65-75 Years of Age MP MP MPR-R MPR HR 0.315 Log rank P < 0.001 HR 0.675 Log rank P = 0.031 0 0 5 10 15 20 25 30 35 40 Time (months)

Lower dose regimens may benefit elderly patients Treatments that give good results in patients between 65 and 75 years of age can give poor results in patients over 75 years due to toxicity and discontinuation lower dose of conventional treatments can improve outcomes for elderly, frail patients 1 lower doses of novel agents or appropriate prophylaxis may be indicated in older patients 1,2 1. Haematological Malignancies in the Elderly. 2010. Proceedings of the First International Conference; Ch4:52-61. 2. NCCN Guidelines: Multiple Myeloma v1.2011.

Lenalidomide + Dexamethasone in NDMM: ECOG Trial Study Design Lenalidomide + High-Dose Dexamethasone (RD) a Len: 25 mg/day, days 1-21 Dex: 40 mg/day, days 1-4, 9-12, 17-20 (n = 223) Lenalidomide + Low-Dose Dexamethasone (Rd) Len: 25 mg/day, days 1-21 Dex: 40 mg/day, days 1, 8, 15, 22 (n = 222) 4 cycles b Transplant-eligible patients can proceed to SCT Continue therapy until disease progression Objective: to assess if a reduced dose of dexamethasone decreases toxicity while maintaining efficacy Primary endpoint: ORR after first 4 cycles a Based on the superiority of the Rd regimen, the study was stopped at a median follow-up of 12.5 months and patients in the RD arm crossed over to Rd therapy. b Every 28 days; N = 445. ECOG, Eastern Cooperative Oncology Group; NDMM, newly diagnosed multiple myeloma; ORR, overall response rate; SCT, stem cell transplant. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37.

Lenalidomide + Dexamethasone in NDMM: ECOG Trial Progression-Free Survival Progression-free survival was higher in the Rd arm than in the RD arm ECOG, Eastern Cooperative Oncology Group; NDMM, newly diagnosed multiple myeloma; Rd, lenalidomide, low-dose dexamethasone; RD, lenalidomide, high-dose dexamethasone. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37.

MULTIPLE MYELOMA Cure versus control Dose reduction and tumor control is the best strategy particularly in elderly patients or with comorbilities DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

Tailored therapy efficacy toxicyty DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY