1. Karmanos Cancer Institute
VRD as Frontline Therapy for Transplant-Eligible Patients with Multiple Myeloma
Jeffrey A. Zonder, MD
Associate Professor,
Oncology and Medicine
Karmanos Cancer Institute

2. Objectives
Beat Bob

3. Important Questions
Are the response rates achieved with VRD and CRd similar?
How toxic is each regimen?
How convenient is each regimen?
How much does each regimen cost?
What’s “Plan B?”

4. The Regimens VRD (q 21d) x 8 VRD (q 28d) x 4 CRd (q 28d) x 8
Richardson, et al
Blood 2010
Chari AJ, et al
ASH 2011
Jakubowiak, et al
Blood 2012 PI
IV BTZ 1.3 mg/m2
d 1,4,8,11
d 1,4,11,18
CFZ 36 mg/m2
d 1,2,8,9,15,16
Len
25 mg/d x 14d
25 mg/d x 21d
Dex
40 mg/wk x 4 cycles
20 mg/wk x 4 cycles
20 or 40 mg
d1,4,11,18

5. EFFICACY: SIMILAR
VRD (q 21d)
VRD (q 28d)
VRD (EVOLUTION)
CRd (q28d)
Richardson, et al
Blood 2010
Chari AJ, et al
ASH 2011
Kumar S, et al
Blood 2012
Jakubowiak, et al
N (Ph 2) 35 38 42 36
ORR
100%
97%
85%
VGPR+
74%
63%
51%
72% CR
37%
24% (10pts)*
39% OS
18 mo
N/A
1 yr
PFS
18 mo
9 mo
1 yr
12 mo
* 6 of 10 MRD(-)
No problems mobilizing stem cells and performing ASCT with either VRD or CRd

6. What do the Experts Say? NCCN (Version 2.2014) mSMART (Version 2013)1
RVD “preferred regimen” for ASCT-eligible pts
CRd mentioned but not in “preferred column”
Both based on level 2A evidence
Neither mentioned for non-ASCT pts
mSMART (Version 2013)1
VRd for high-risk ASCT or non-ASCT pts
CRd not currently recommended for any pt grp
1. Mikhael JR, et al. Mayo Clin Proc 2013;88(4):360-76

7. What Would Jesus Do?
He’d pick CRd if it could be proved that it increased rate of MRD(-) CR

8. MRD Testing No standardized methodology thus far
Multiparametric flow cytometry (IMF/EuroFlow)
Deep sequencing (LymphoSIGHT)
Allele-specific PCR
Variable concordance and sensitivity
~85% concordance between techniques1
2-log intra-center differences in sensitivity2
Too early to declare CRd the “winner” 1.
2. Flanders A, et al. Blood. 2013;122(6):

9. Presented by O Landgren in Kyoto, Japan at the 2013 International Myeloma Workshop

10. TOXICITY: “Less Neuropathy”
RVD (q 21d)
CRd (q 28d)
VTD (sq BTZ; Thal100 mg/d)
Richardson, et al
Blood 2010
Jakubowiak, et al
Blood 2012
Lok A., et al
Haematologica 2014
Any Gr 3+
N/A
48%
37%
Any PN
80%
23%
24%
Gr 3-4 PN 2% 0% 4%
Gr 3-4 ANC 9%
17%
Gr 3-4 PLT 6%
Any DVT
11%
PI Dose 
44%
19%
Dex Dose 
31%

11. “You say Tomato….” In actual practice, “VRD” not standard
Bortezomib often adjusted for tolerability
Research to Practice ASH Friday Satellite Symposium, New Orleans, LA. December 6th, 2013

12. CONVENIENCE goes to VRD
VRD (q 21d) x 8
CRd (q 28d) x 8
Richardson, et al
Blood 2010
Jakubowiak, et al
Blood 2012
Weeks of Rx 24 32 PI
32 doses
48 doses
Len
112 days
168 days
Dex
960 total mg
(Unless on S0777: 1280mg)
(Thanks, Bob!)

13. Dollars and Sense VRD:~$66K/six 21-day cycles (~$88K/8 cycles)1
$11K/cycle: $5.5K each for LEN and BTZ/cycle
Estimating cost of CRd
28-day cycles
CFZ costs $10K/cycle2 (IF you use standard dose!)
1.5 times as much LEN/cycle = ~$8K/cycle
$18K/cycle x 8 cycles = $144K
Excess cost of CRd for 10K NDMM pts? $560M
1. Kumar S, et al. ASH 2013, abstract

14. Sound Familiar?

15. What’s “Plan B?”
2nd PFS
CFZ approval based in part on efficacy after prior BTZ-containing therapy
No evidence that BTZ can be used after CFZ

16. Conclusions
VRD has ~100% ORR, is more cost effective, and more convenient
Neurotoxicity of VRD can be reduced with subQ and/or weekly BTZ dosing
Neither regimen has yet been proven in a randomized Phase 3 study
S0777: Rd vs VRd (Closed)
E1A11: VRd vs CRd (Active)
Farber/IFM: VRd +/- Early ASCT (Active)