Quadruplet Regimens in Multiple Myeloma Jeffrey A. Zonder, MD Associate Professor, Oncology and Medicine Karmanos Cancer Institute

Objectives Review the results of VMPT-VT vs VMP trial Come out against EVOLUTION (Sorry Mom) Discuss CYCLONE regimen www.amyloidplanet.com

Commonly Voiced Concerns “More toxic” Prohibitively? “Not more effective” Mixed results “Costs more” “Less convenient”

EVOLUTION Trial VDCR (n=48) VRD (n=42) VCD (n=43) VCD-mod (n=17) Len 15 mg/d x 14 BTZ d1,4,8,11 CTX: 500 mg/m2 d1,8 CTX: 500 mg/m2 d1,8,15 ORR 88% 85% 75% 100% VGPR+ 58% 51% 41% 53% CR 25% 24% (10pts) 22% 47% (8 pts) 1-yrOS 92% 1y-PFS* 83% 68% 97% D/C for AE’s 21% 14% 12% 6% Gr 1-2 PN 56% 55% 49% 47% Kumar S, et al. Blood 2012;119(19):4375

Observations about EVOLUTION Not powered to detect modest differences in efficacy (or toxicity) BTZ schedule and route not optimal Kumar S, et al. Blood 2012;119(19):4375

VMPT-VT vs VMP n=229 Mel 9 mg/m2 d1-4 Pred 60 mg/m2 d1-4 Vel 1.3 mg/m2 d1,8,15,22* Observation New MM > 65 yo nine 35-day cycles Mel 9 mg/m2 d1-4 Pred 60 mg/m2 d1-4 Vel 1.3 mg/m2 d1,8,15,22* Thal 50 mg q day Vel 1.3 mg/m2 d1,15 Thal 50 mg q day n=221 71 pts on MPV-T and 64 pts on MPV got twice-weekly VEL Palumbo AP et al. J Clin Oncol 2010;28(34):5101

EFFICACY: VMPT-VT better Median PFS* 35.3 mos 24.8 mos 3y-PFS* 56% 41% ORR* 89% 81% CR* 38% 24% 3y-OS 5y-OS* 61% 51% Palumbo AP et al. J Clin Oncol 2010;28(34):5101 Palumbo AP et al. J Clin Oncol 2014;32(7):634

TOXICITY: Nothing Surprising VMPT-VT VMP Gr 3-4 PN* 11% Gr 3-4 ANC* 38% 28% Gr 3-4 PLT* 22% 5% Any DVT* 2% Gr 3-4 Cardiac 10% Palumbo AP et al. J Clin Oncol 2010;28(34):5101

TWICE WEEKLY vs ONCE WEEKLY BORTEZOMIB VMPT† VMP† 2×/wk (n=71) 1×/wk (n=150) (n=64) (n=165) CR 38% 32% 27% 20% Grade 3–4 PN 18% 2% 14% Dose Reduction* 42% 11% 35% 13% Discontinuation* 10% 3% 15% 4% (13%)* *VISTA Palumbo AP et al. ASCO 2009, abstract #8515 9

Observations Regarding VMPT-VT The induction portion of the therapy resulted in improved disease control The maintenance portion resulted in improved time-to-event endpoints, including 5-year OS Major criticism of the study (but not by me) Toxicity can be reduced by adjusting BTZ dosing schedule

CYCLONE Regimen Builds off of CTD1,2 (used overseas) by adding carfilzomib 1Morgan et al. Haematologica 97:442, 2012. 2Morgan et al. Blood 118:1231, 2011

CYCLONE: Outcomes & Commentary 100% response rate after 4 cycles (n=27) 83% VGPR+ Gr 3-4 fatigue, thrombosis, somnolence 20% Gr 1 PN (only) Historical expectations for CTD lower 63-83% ORR with 30-40% VGPR+ In terms of developing regimen, control arm is potential problem in USA Mikhael JR, et al. ASCO 2012

Conclusions One large randomized study showed superior outcomes with quadruplet followed by maintenance in older MM pts Dose modification makes combination regimens more tolerable MRD technology will mature and provide further insight about 4-drug combos

Think Outside of the Box Immunotherapeutics may make quadruplet therapy STANDARD in a few years Elotuzumab (+RVD, currently in trials) Daratumumab or SAR650984 (anti-CD38 mAbs) Response modifiers may improve triplets Clarithromycin?