1. Should Alkylators be used Upfront in Transplant-Ineligible Patients? NO!! Lymphoma-Myeloma October 2013
Scottsdale, Arizona
Rochester, Minnesota
Jacksonville, Florida
Joseph Mikhael, MD, MEd, FRCPC, FACP
Staff Hematologist, Mayo Clinic Arizona

2. Objectives
Review the emerging data regarding replacing “MP” as backbone in upfront therapy
Provide practical advice as to initiating therapy in older patients with myeloma
Unequivocally defeat my friend Antonio in this debate 
Concede that cyclophosphamide may be an exception to this general rule

3. Summary Points – Why Melphalan is no longer standard of initial care in elderly patients
Novel agents are equivalent if not superior to MP+novel agent
MP+ results in greater short term toxicity
As survival is extended in myeloma, using melphalan upfront is not desirable due to marrow toxicity
Melphalan can lead to increased second primary malignancies

4. mSMART 2.0: Classification of Active MM
High-Risk 20%
Intermediate-Risk 20%
Standard-Risk 60%
FISH
Del 17p
t(14;16)
t(14;20)
GEP
High risk
signature
FISH
t(4;14)*
Cytogenetic Deletion 13 or hypodiploidy
PCLI >3%
All others including:
Hyperdiploid
t(11;14)
t(6;14)
3 years years years
Mikhael et al Mayo Clinic Proceedings April 2013 4 4

5. Transplant Ineligible Bortezomib maintenance
mSMART – Off-Study
Transplant Ineligible
High Risk
Intermediate Risk
Standard Risk*
VRd
MP + weekly Bortezomib
or weekly CyBorD Rd
Bortezomib maintenance
Observation
Mikhael et al Mayo Clinic Proceedings April 2013 5

6. Argument #1
Novel agents are equivalent if not superior to MP+novel agent

7. Newly Diagnosed, Patients SCT Ineligible
MPT1
N = 129
VMP2
N = 337
MPR3
N = 153
MPR-R4
N = 152
VTP5
N = 130 CR
16%
30%
11%
27%
> VGPR
29%
Not reported
33%
32%
37%
> PR
69%
71%
68%
77%
81%
PFS
21.8 mo
TTP: 24.0 mo
14 mo
31 mo
23 mo
Median follow-up
31.8 mo
36.7 mo
25 mo
22 mo
MPT: melphalan, prednisone, thalidomide; VMP: bortezomib, melphalan, prednisone; MPR: melphalan, prednisone, lenalidomide; MPR-R: MPR with maintenance lenalidomide; VTP: bortezomib, thalidomide, prednisone.
1Palumbo A, et al. Blood. 2008;112: ;
2Mateos MV, et al. Blood. 2009;114(22). Abstract 3859;
3,4Palumbo A, et al. Blood. 2010;116(21). Abstract 622 and Abstract 566;
5Mateos MV, et al. Blood. 2009;114(22). Abstract 3. 7

8. Primary Study Schema lenalidomide plus RD versus
lenalidomide plus Rd in newly diagnosed MM R A N D O M I Z T
445 patients RD
x 4 cycles Rd
Less than PR
CR/PR
Thal + Dex
Patients can go off and proceed to SCT
CR/PR/stable
Rajkumar et al

9. BEST RESPONSE: > PR*
RD [n]
Rd [n]
Odds
Ratio
Fisher's
Exact
Overall
81.3% [214]
70.2% [208]
1.85
p=0.009
< 65
85.4% [103]
66.0% [103]
3.02
p=0.002
> 65
77.5% [111]
74.3% [105]
1.19
p=0.634
> 70
74.6% [71]
73.8% [65]
1.04
p=1.000
> 75
77.8% [36]
70.4% [27]
1.47
p=0.566
*Same observations with VGPR except age > % vs 47.7% 9

10. Second Interim Analysis RD vs. Rd
Results
Second Interim Analysis RD vs. Rd RD Rd
CR + PR
79%
68%
1 year OS
87%
96%
Grade 3 or worse AE
52%
35%
RD did not result in superior TTP, PFS, or OS compared to Rd
OS at 1-year was significantly better with Rd than RD,
resulting in early closure of the trial
Rajkumar et al, 2010. 10

11. Overall Survival-ITT Age > 65 yrs Age < 65 Age > 70
Status RD
N=223
(%) Rd
N=220
Total*
N=443
Treatment End by Mandatory Crossover
Yes
195
(87.4)
169
(76.8)
364 No 28
(12.6) 51
(23.2) 79 11

12. 12 month survival probability (95%CI)
Survival Rate by Age N
12 month survival probability (95%CI)
24 month
survival
probability
(95%CI)
Age <65
Len-High Dex
104
0.92 ( )
0.86 ( )
Len-Low Dex
108
0.96 ( )
0.92 ( )
Age ≥65
119
0.84 ( )
0.72 ( )
114
0.95 ( )
0.85 ( ) 12

13. 14/04/2017
Median age 71 y; 30% >75 y; Median KPS 80%; 63% IgG; 33% B2M > % albumin < 35 g/L 13

15. 15

16. Larocca A, et al. Gr. Emat. Milano 2012

17. Conclusion #1
MP is not necessary
Lenalidomide-dexamethasone and bortezomib-dexamethasone are effective and viable options

18. Argument #2
MP+ results in greater short term toxicity

21. 21 21

24. Conclusion #2
3 drug regimens that include melphalan are more toxic (and not necessarily more effective)
Dose reduction is critical in the elderly

25. Argument #3
As survival is extended in myeloma, using melphalan upfront is not desirable due to marrow toxicity

26. Multiple Myeloma 1971-2006 n=2,981 Proportion surviving
Survival, med
44.8 mo
Proportion surviving
Survival, med
29.9 mo
Diagnosis after 1996
Diagnosis during/ before 1996
Time from diagnosis (months)
Kumar et al: Blood 111:2516, 2008 CP 26

27. Multiple Myeloma Mayo Patients
66%
P <
47%
S. Kumar, 2012

28. Argument #4
Melphalan can lead to increased second primary malignancies

33. The “NEW” CyBorD All three drugs given weekly
Cyclophosphamide 300mg/m2 PO
Bortezomib 1.5 mg/m2 IV or SQ
Dexamethasone 40mg PO
We consider one cycle a 4 week course
No “week off”
Less neuropathy, more convenience, equal efficacy
Always give viral prophylaxis
Comment – I see CyBorD as a slight modification to VMP

34. Summary Points – Why Melphalan is no longer standard of initial care in elderly patients
Novel agents are equivalent if not superior to MP+novel agent
MP+ results in greater short term toxicity
As survival is extended in myeloma, using melphalan upfront is not desirable due to marrow toxicity
Melphalan can lead to increased second primary malignancies

35. Quote – ASCO 2013 – Dr. Antonio Palumbo
“Gli Americani avevano ragione: non dobbiamo usare melphalan come terapia iniziale nei pazienti anziani”
“The Americans were right – we should not use melphalan upfront in elderly patients”