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Case Presentations
S. Vincent Rajkumar
Professor of Medicine
Mayo Clinic
Scottsdale,
Scottsdale Arizona
Rochester,
Rochester Minnesota
Jacksonville,
Jacksonville Florida
Mayo Clinic College of Medicine
Mayo Clinic Comprehensive Cancer Center

Case Presentation
· 55 yr old executive
· Newly diag
ygnosed MM
· Multiple lytic lesions
· Hb
Hb 105g
10.5 m/dL
gm/dL
· Normal Ca, creatinine
· Normal cytogenetics
· FISH: t11;14
t11;14

www.msmart.org
mSMART : Classification of
of Active
Active MM
MM
High-
High Risk
-
(25%)
Standard-
Standard Risk
-
(75%) *
FISH
Del 17p
All others
others including:

including:
t(4;14)*

t(14;16)
Hyperdiploid
Cytogenetic Deletion
Deletion 13
13
t(11;14)
Cytogenetic
t(6;14)
hypodiploidy
PCLI >3%
*P ti
a
t
en s i
w th
ith t(4 14)
;
, b2M<4 mg/l/l and Hb
Hb 10g/dl may have int
di
erme
t
a e ri k
s di
disease
Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; v4 Revised and updated: June 2008

MM 003: Thal/Dex versus Placebo/Dex: (A) TTP and (B) PFS
of patients receiving Thal/dex (yellow) versus Placebo/dex (blue)
Rajkumar, S. V. et al. J Clin Oncol; 26:2171-2177 2008
Copyright © American Society of Clinical Oncology

IFM: VAD vs Vel-Dex
VAD
Vel-Dex
P value
Evaluable patients
N=219
N=223
CR
3.2%
9.9%
0.004
CR+nCR
7.8%
19.3%
0.0004
> VGPR
19.2%
9%
46.6%
66%
< 0 0001
.
> PR
65.8%
82.5%
< 0.0001
Harousseau JL, ASCO 2008

IFM: VAD vs
vs Vel-
Vel Dex
PROGRESSION-FREE SURVIVAL
VAD
Vel/Dex
N. of events
29
22
1-yr PFS
87.5
90.7
18m PFS
85.1
89.5
p=0.38
Traitement ----- VAD - - - Vel/Dex
Days
Harousseau JL, ASCO 2008

VTD versus TD
TD
%o
% fp
of atients
patients
VTD
RESPONSE
TD
(
129)
(n=127)
P value
(n=129)
(n=127)
CR+nCR
36
9
<0.001
VGPR
60
27
<0.001
<P
< R
PR
7
20
0 003
.
Progression
0
5.5
0.008
EBMT criteria (with added nCR and VGPR categories)
Cavo ASH 2007

S0232: Progression Free Survival
Len-Dex
p=0.002
Dex
1-yr PFS
LD:
77%
Len-Dex
Dex:
55%
Dex
Zonder J. ASCO 2008

Overall Survival
Survival
100
Rd
80
75%
3-yr OS rate
y
RD
yilit 60
robab
lP
vivaur 40
S
20
P=0.46 log-rank;
P=0.01
01 Pepe Fleming
-
0
0
6
12
18
24
30
36
Time in Months
Nu
N mbers
ber at
at Ri
Risk
s
RD
223
208
195
184
173
123
78
Rd
222
217
212
201
192
146
83

Initial Therapy in Transplant
Candidate
· Th l/D
a
ex
· Vel/Dex
· VTD
· Len/dex
· Other

Choice of Initi
itial Th
Therapy
Transplant Candidates
Significant
Use in
Regimen
Route
DVT Risk
Neuropathy
Renal
risk
Failure
TD
Oral
Yes
Yes
Yes
Rd
Oral
Yes
No
No
Vd
IV
No
Yes
Yes
VTD, CyBorD
CyBorD, etc
etc
IV
Yes
Yes
Yes
In aggressive extramedullary plasmacytomas, plasma cell leukemia:
leukemia: VDT
VDT PACE
P
Rajkumar SV. ASCO ED. Book 2008

www.msmart.org
mSMART Off-Study
Transplant Eligible
High
g Risk
Standard Risk
4-6 cycles of bortezomib
4 cycles of Rd*
containing regimen (CBD, VRd, VTD etc)
Collect Stem Cells**
Collect Stem Cells
If not in CR, consider autologous stem
Autologous stem cell
OR
Continue
cell transplant (ASCT)
transplant (ASCT)
Rd
All pati
ti
t
en s receive Rd
Rd
If not in CR/VGPR after

til
If not in CR/VGPR
until
progression
1st ASCT, consider
consolidation (eg.,
second ASCT or IMiD)
* Bortezomib containing regimens preferred in
renal failure
failure or if rapid response
response needed
needed
Continuing Rd is an option for patients
(**If age >65 or > 4 cycles of Rd
responding well to induction with low toxicities;
Consider G-CSF plus cytoxan or plerixafor )
Dex is usually discontinued after first year
Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; v5 Revised and updated: Jan 2009

VRD
· 66
l
eva
b
ua l
ble pts
· CR
26%
· nCR
11%
71%
· VGPR
35%
· PR (27%)
· Overall response rate: 98%
(95% CI: 87 4
. 99

9%)
.
Richardson PG. ASCO 2008

SWOG: Rd versus VRd
SWOG S0777: Phase III New MM
R
A
N
Continue therapy
CR/PR/
D
Rd
till prog. or
Stable
O
toxicity
M
I
Z
A
Prog.
VRd
Off Rx
T
VRd
Rx
T
anytime
I
O
N

ECOG: VRd versus Vd
E1A05: Phase III Novel non-transplant consolidation
R
A
VRd
C
t
on i
tinue th
therapy till
N
CR/PR/
till
D
Stable
progression or
O
toxicity
M
I
Z
A
Progression
anytime
Off prescription
T
prescription
I
Vd
O
N
CTEP and CIRB approved

Evolution: Study design
VDCR: 36% CR
t
ra e i l
nc d
u i
ding 20% CR
s
R
VDR
A
(Vc, Dex, Rev)
N
Up to eight 21-day cycles
D
O
VDCR
M
Vc
(Vc, Dex, Cy, Rev)
I
Up to four 42-day cycles
Up to eight 21-day cycles
Z
A
VDC
T
(Vc, Dex, Cy)
I
Up to eight 21-day cycles
O
N
Induction
Maintenance
· Eligible patients could undergo ASCT after 4 cycles

Case Presentation
· 75 yr old reti d
re teacher
· Newly diag
ygnosed MM
· Multiple lytic lesions
· Hb
Hb 95g
9.5 m/dL
gm/dL
· Normal Ca, creatinine
· Normal cytogenetics
· FISH: Trisomy
Trisomy 3, 5, 9, 11

Initial Therapy in Non-Transplant Candidates: MP
MTCG. J Clin Oncol 1998; 16:3832

IFM 99-06: OS
Facon T. Lancet 2007;370:1209

Treatment of elderly MM
MM patients
patients (Phase
(Phase III MPT trials)
trials)
TTP
Study
Regimen
N
Overall
Study
Regimen
N
PFS/EFS
Survival
Palumbo
MPT
129
22
45 vs 48
(Blood 2008)
MP
126
15
P=0.79
Facon
MPT
125
28
52 vs 33
(Lancet 2007)
MP
196
18
P=0.0006
Hulin
MPT
113
24
45 vs 28
(ASH 2007)
MP
116
11
19
P=00
0. 3
03
Wijermans
MPT
165
13
37 vs 30
(ASH 2008)
MP
168
10
P=0.16
Gulbrandsen
MPT
363
20
29 vs 33
(EHA 2007)
MP
18
P=0.46

VISTA Trial: VMP vs MP: Overall Survival
San Miguel J et al. N Engl J Med 2008;359:906-917

VMP- VISTA Trial
Trial
TTP
OS
VMP standard
standard risk
VMP standard risk
VMP high risk
VMP high risk
VMP standard risk (N=142): 23.1 months (34 events)
VMP standard risk (N=142): not reached (16 events)
VMP high risk (N=26): 19.8 months (7 events)
VMP high risk (N=26): not reached (3 events)
HR = 1.297 (95% CI: 0.55, 3.06)
HR = 1.009 (95% CI: 0.278, 3.663)
San Miguel J et al. N Engl J Med 2008;359:906-917

VISTA TRIAL: Adverse Events (Safety Population)
VMP
MP
San Miguel J et al. N Engl J Med 2008;359:906-917

Choice of Initi
itial Th
Therapy
Non-Transplant Candidates
Si
ifi
gn
t
can
Ui
Use in
Neuropathy
Renal
Regimen
Route
DVT Risk
risk
Failure
MPT
Oral
Yes
Yes
Yes
VMP
IV
No
Yes
Yes
Rajkumar SV. ASH 2007

Treatment of elderly MM patients (Phase III trials)
TTP
Study
Regimen
N
Overall Survival
Survival
PFS/EFS
MPT
125
28
Facon
MP
196
18
3yr OS ~65% with MPT
(Lancet 2007)
()
San Miguel
VMP
344
24
3y OS 72% with VMP
(ASH 2008)
MP
338
17
RD
445
22
3y OS
OS: 75% with Rd
Rd
Rajkumar
Rd
23
in elderly patients >65
(ASH 2008)

www.msmart.org
mSMART Off-Study
Transplant Ineligible
High Risk
Standard Risk*
MP + Bortezomib**
MP + Thalidomide** or Rd
Observation
Ob
i
servat on
*Bortezomib containing regimens preferred in
renal failure or if rapid response needed
Continuing Rd is an option for patients
responding well to induction with low toxicities;
** In patients in whom administration of
Dex is usually discontinued after first year
thalidomide or bortezomib is of concern,
consider MP or Rd
Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; v5 Revised and updated: Jan 2009

ECOG: MPT vs
vs MPR
MPR
E1A06: Phase III New
N
MM, non-transplant
candidates
R
A
CR/PR/
Continue therapy
N
MPT
Stable
till prog. or toxicity
D
O
M
IZ
A
Prog.
TI
MPR
Off Rx
R
anytime
O
N

MPR: Event-free survival and overall survival
Palumbo, A. et al. J Clin Oncol; 25:4459-4465 2007
Copyright © American Society of Clinical Oncology

MM 020 Clini l
ca T i
r l
a
MPT (18 months)
Rd (18 months)
Rd (indefinite)

Case Presentation
· 72 yr ld
o
lawyer
· Newly diagnosed MM
· Multiple lytic lesions
· Hb 9 gm/dL
· Ca 11 mg/dl, S. creatinine 5.2
mg/dL
· Normal cytogenetics
· FISH t11;14

Pi
Pri
i
nc ples of Initi
itial Th
Therapy
· T
t
rea
ibl
revers
e causes of renal failure
· Plasma exchange (controversial)
· Rapid reduction in tumor burden

Fl
Fo lllow up
· Rl
Renal f i
a lilure does
t
no improve
· Long-term hemodialysis
· Relapse: 6 months later while on VTD
· No response to chemotherapy with VBMCP

Recommendations for Starting Dose in
Patients with Impaired Renal Function
· For patients with normal renal function/mild renal impairment (CLCr 60 mL/min), the
recommended starting dose is lenalidomide 25 mg/day with water, days 1-21 + dexamethasone
40 mg/day, days 1-4, 9-12, and 17-20 of repeated 28-day cycles*
· Adjustment of the starting dose of lenalidomide is recommended in patients with moderate or
severe renal impairment and in patients on dialysis
Renal function
function
Recommended starting
starting
Categoriesb
(Cockcroft-Gault CL c
Cr )
dose of lenalidomided
Moderate renal impairment
30 CLCr <60 mL/min
10 mg every 24 hours
Severe renal impairment
CLCr <30 mL/min,
not requiring dialysis
15 mg every 48 hours
CL
Ed
End-stl
tage renal di
Cr <30 mL/min,
5 mg once daily. On dialysis
disease
Cr
30 mL/min,
dd
h
ld b
d i i t
d
requiring dialysis
days, dose should be administere
following dialysis
*After first 4 cycles, dexamethasone is administered only on days 1-4 of repeated 28-day cycles.
aLenalidomide is primarily excreted unchanged by the kidney. These recommendations are based on a pharmacokinetic study in patients
with renal impairment due to nonmalignant conditions. Starting dose adjustment is recommended for patients with
with
CLCr <60 mL/min. Nondialysis patients with CLCr <11 mL/min and dialysis patients with CLCr <7 mL/min have not been studied.
bNational Kidney Foundation criteria. cCLCr, creatinine clearance.
dlenalidomide is administered days 1-21 of repeated 28-day cycles.
National Kidney Foundation. K/DOQI Clinical Practice Guidelines. Available at: http://www.kidney.org/Professionals/kdogi/.
Accessed January 8, 2009.