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

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

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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

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

12. 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

13. 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

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