This document discusses current approaches to managing multiple myeloma. It provides an overview of multiple myeloma, including its definition as a malignancy of plasma cells, epidemiology, natural history from preceding monoclonal gammopathy of undetermined significance stage through risk of progression. It also reviews diagnostic criteria, prognostic factors, cytogenetic abnormalities, treatment approaches including initial therapy options and transplant candidacy, and response criteria.

1. Mayo Clinic College of Medicine
Mayo Clinic Comprehensive Cancer Center
Current Approaches to Managing
Multiple Myeloma
Shaji Kumar, M.D.
Associate Professor of Medicine
Mayo Clinic
Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida

2. Mul$ple
Myeloma
• Malignancy
of
terminally
differen$ated
plasma
cells
• Age
standardized
incidence
rate
of
0.7-­‐2.2
per
100,000
worldwide
and
death
rate
of
0.6-­‐1.3
per
100,000
• Second
most
common
hematological
malignancy;
2%
of
all
cancers
• Median
Age
at
diagnosis
67
years,
male
predominance
• Twice
as
common
among
African
Americans,
less
common
in
Asians

3. Plasma
cells
• Plasma
cells
are
terminally
differen$ated,
non-­‐dividing,
effector
cells
of
B-­‐cell
lineage
• They
synthesize
an$gen
specific
immunoglobulins
• Abnormali$es
of
plasma
cells
are
responsible
for
– autoimmune
diseases
– Plasma
cell
neoplasms
• The
development
and
func$on
are
$ghtly
regulated

4. The
immune
response
and
plasma
cell
forma$on

5. Monoclonal
Gammopathies
MGUS
58% (23,179)
Multiple
myeloma
17.5% (6,974)
Amyloidosis
9.5% (3,781)
Lymphoproliferative
3% (1,298)
SMM 4% (1,494)
Solitary or extramedullary
2% (774)
Macro 2% (940)
Other 4% (1,489)
n=39,929
Mayo Clinic 1960-2008

6. Natural
History
Kyle et al, NEJM, Volume 356:2582-2590, June 21, 2007

7. Preceding
MGUS
• MM
is
always
preceded
by
MGUS
stage
• Among
77
469
healthy
adults
from
PLCO
Cancer
Screening
Trial:
71
subjects
developed
MM
• Serially
collected
pre-­‐diagnos$c
serum
samples
studied
• MGUS
was
present
in
100.0%,
98.3%,
97.9%,
94.6%,
100.0%,
93.3%,
and
82.4%
at
2,
3,
4,
5,
6,
7,
and
8+
years
prior
to
MM
diagnosis
Landgren O, Blood. 2009 :5412-7.

8. Progression
to
Symptoma$c
MM
• MGUS:
up
to
2
percent
of
persons
50
years
of
age
or
older
and
about
3
percent
of
those
older
than
70
years
• For
SMM,
maximum
risk
in
the
first
5
years
• Risk
factors:
Higher
M
spike,
higher
plasma
cell
burden,
type
of
M
protein,
Abnormal
free
light
chain
ra$o,
circula$ng
plasma
cells
Kyle et al, NEJM, Volume 356:2582-2590, June 21, 2007

9. Risk
factors
for
monoclonal
gammopathies
• Race:
Higher
risk
in
African
Americans
– Similar
risk
in
a
popula$on
from
Ghana
• Chemical
and
radia$on
exposure
– Increased
risk
among
those
with
pes$cide
exposure
• Familial
risk
– Increased
risk
among
first
degree
rela$ves

10. Stages
of
myeloma
treatment
1. Diagnose
and
determine
need
for
treatment
2. Risk
stra$fy
3. Control
disease
and
treat/
reverse
complica$ons
4. Consolidate
ini$al
response
5. Maintain
response
6. Iden$fy
disease
relapse
and
treat
7. Suppor$ve
care
at
all
stages!

11. Diagnosis
of
Mul$ple
Myeloma
• Clonal
bone
marrow
plasma
cells
≥
10%
• Serum
and/or
urinary
monoclonal
protein
and
• “End-­‐organ
Damage”
or
CRAB
features
– HyperCalcemia
– Renal
Insufficiency
– Anemia
– Bone
Disease

12. Detec$on
of
Clonal
Plasma
Cells
Bone
marrow
Plasmacytoma
Peripheral
blood

13. Demonstra$ng
Monoclonal
Protein
0.1
1
10
100
1000
10000
100000
0.1 1 10 100 1000 10000 100000
Serum Kappa (mg/L)
SerumLambda(mg/L)
Normal sera
Kappa LCMM
Lambda LCMM
Renal impairment
Serum or Urine
Protein Electrophoresis
Serum or Urine
Immunofixation
Serum Free Light Chain Assay

14. Intact Immunoglobulin
Exposed surface
Hidden surface
Kappa
Free Light Chain
Binding Site®, free light chain assay
Previously
hidden
surface
FLC reference range:
κ 3.3 – 19.4 mg/L
λ 5.7 – 26.3 mg/L
κ/λ ratio 0.26 - 1.65

15. Prognos$c
Factors
• Interna'onal
Staging
System
Stage
• Cytogene'c
Abnormali'es
– Dele'on
13,
hypodiploidy
– (FISH)
t(4;14),
t(14;16),
or
del(17p)
• Poor
performance
status
• Plasma
cell
labeling
index
(>1%)
• Abnormal
free
light
chain
ra$o
• Circula$ng
myeloma
cells
• Plasmablas$c
morphology
• High
LDH,
CRP
levels

16. Stage Criteria Median Survival (months)
I Serum ß2-microglobulin < 3.5 mg/L 62
Serum albumin > 3.5 g/dL
II Not stage I or III* 44
III Serum ß2-microglobulin > 5.5 mg/L 29
Greipp, P. R. et al. J Clin Oncol; 23:3412-3420 2005
Interna$onal
Staging
System
(ISS)

17. Cytogene$c
Abnormali$es
Hyperdiploid Non-hyperdiploid
IgH (chr 14) translocations
1. 11q13 (CCN D1):16%
2. 6p21 (CCN D3):3%
3. 16q23 (MAF): 5%
4. 20q12 (MAFB): 2%
5. 4p16 (FGFR3 and MMSET): 15%
Multiple trisomies
Chromosomes 3, 5, 7, 9, 11,
15, 19, and 21
Chromosome 13 abnormalities
P53 mutations
Ras mutations

18. High
Risk
Myeloma
High-risk abnormality
% of patients with newly
diagnosed MM
Conventional cytogenetics
Deletion of chromosome 13 (monosomy) 14
Hypodiploidy 9
Either hypodiploidy or deletion of chromosome
13 17
Fluorescence in situ hybridization (FISH)
t(4;14) 15
t(14;16) 5
17p– 10
Plasma cell labeling index ≥3% 6
Any 1 of the high-risk abnormalities 25-30

19. General
approach
to
treatment
Not a transplant candidate Transplant candidate
Melphalan-based regimens
Observation
Induction therapy
Auto transplant
Newly diagnosed MM
Continue induction
and
delayed transplant
at relapseMaintenance
options?

20. Ini$al
Therapy
The
ideal
ini$al
therapy
should:
• Rapidly
and
effec$vely
control
disease
• Reverse
disease
related
complica$ons
• Decrease
the
risk
of
early
death
• Be
easily
tolerated
with
minimal/manageable
toxicity
• Not
interfere
with
the
ability
to
collect
stem
cells
for
transplanta$on

21. Recent
advances
The
old
• Dexamethasone
• VAD
– Vincris$ne
– Adriamycin
– dexamethasone
The
New
• Thalidomide
• Lenalidomide
• Bortezomib

22. Response
criteria
in
myeloma
PR VGPR nCR CR sCR
Serum Protein
electrophoresis
> 50% > 90% 0 0 0
Serum Protein
electrophoresis
>90% < 100
mg/24
hrs
0 0 0
Serum/Urine
Immunofixation
Positive Negative Negative
Bone marrow PC <5% <5% <5%
Bone marrow
immunoflourescence
Negative
Serum Free light chain
ratio
Normal
Durie et al, Leukemia. 2006 Sep;20(9):1467-73

23. Thalidomide
(Thalomid®)
• Mul$ple
mechanisms,
Response
rates
of
25-­‐35%
when
used
alone
in
relapsed
MM
• Seda$on,
Fa$gue
• Cons$pa$on
• Peripheral
neuropathy
• Rash
• DVT
in
combina$on
with
steroids
or
chemotherapy
• Teratogenicity
–
contracep$on
required

24. Rajkumar SV, et al. J Clin Oncol. 2008;26:2171-7.
Thal
+
Dex
vs.
Dex
in
newly
diagnosed
MM
(MM-­‐003):
response
rates
Patients(%)
p = 0.001
0
20
40
60
63
Thal + Dex
46
Dex
19.2
7.7
30.2
2.6
PR
CR
80
VGPR
36.1
13.2
CR + VGPR
p < 0.001

25. Patients(%)
Time (weeks)
Thal + Dex
Placebo + Dex
Censored
MM-­‐003:
$me
to
progression
and
overall
survival
Time to progression Overall survival
HR (95% CI): 0.43 (0.32–0.58)
Thal + Dex: median time to progression 22.6 months
Placebo + Dex: median time to progression 6.5
months
Thal + Dex: median overall survival not reached
Placebo + Dex: median overall survival 32 months
HR (95% CI): 0.82 (0.57–1.16)
p < 0.0001
Progression-freepatients(%)
Time (weeks)
Thal + Dex
Placebo + Dex
Censored
Rajkumar SV, et al. J Clin Oncol. 2008;26:2171-7.

26. Thalidomide
combina$ons
vs
VAD
TD vs VAD1 TD vs VAD2 TAD vs VAD3 CTD vs CVAD4
4 months 4 months 3 cycles NA
Patients, n 200 204 402 251
Response before ASCT, %
CR 10 vs 8 12.5 4 vs 2 20 vs 12
> VGPR 19 vs 14 35 vs 13 33 vs 15 38 vs 26
> PR 76 vs 52 – 72 vs 54 96 vs 83
Response after ASCT, %
CR – – 16 vs 11 58 vs 41
> VGPR – 44 vs 42 49 vs 32 67 vs 43
> PR – – 79 vs 76 99 vs 96
Deep-vein thrombosis 15 vs 2 23 vs 7.5 8 vs 4 NA
1. Cavo M, et al. Blood. 2005;106:35-39. 2. Macro M, et al. Blood. 2006;108:[abstract 57].
3. Lokhorst HM, et al. Haematologica. 2008;93:124-7. 4. Morgan GJ, et al. Blood. 2007;110:[abstract 3593].
ASCT = autologous SCT; CTD = cyclophosphamide + thalidomide + dexamethasone; CVAD = cyclophosphamide +
VAD; TAD = thalidomide + doxorubicin + dexamethasone; TD = thalidomide + dexamethasone.

27. Bortezomib
(PS
341;
Velcade®)
• Proteasome
inhibitor
• Intravenous
administra$on
• Common
side
effects
– Neuropathy
– Thrombocytopenia
– Flu
like
syndrome
– Fever
– Increased
risk
of
infec$on,
zoster
reac$va$on

28. IFM
2005-­‐01:
bortezomib
+
dexamethasone
vs
VAD
Response
VAD Bortezomib + Dex
Post induction, % Final, %* Post induction, % Final, %*
CR 1 NR 6 NR
CR + nCR 7 32 15 39
≥ VGPR 16 47 39 68
≥ PR 65 NR 82 NR
*Best response, including second ASCT.
Harousseau JL, et al. Presented at ASH/ASCO symposium, ASH 2008.NR = not reported.

29. IFM
2005-­‐01:
progression-­‐free
survival
Harousseau JL, et al. JCO October 20, 2010; 28 (30) 4621-4629
VAD: 101 events
Median PFS 28 months;
2-year PFS 60%
Bortezomib + Dex (B1 + B2)
VAD (A1 + A2)
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40
Time (months)
Patients(%)
Bortezomib + Dex: 71 events
Median PFS not reached;
2-year PFS 69%
Log-rank p = 0.0115
80
60
40
20
0

30. Lenalidomide
(CC-­‐5013;
Revlimid®)
• More
“potent”
immunomodulator
than
thalidomide
• Fewer
side
effects:
no
significant
cons$pa$on,
neuropathy,
or
seda$on
• Common
side
effects:
anemia,
leukopenia,
thrombocytenia,
skin
rash,
thrombosis
• Not
teratogenic
in
animal
studies
N
N
H
O
O
NH

31. SWOG
S0232:
phase
III
trial
of
Len
+
Dex
vs
Dex
in
transplant-­‐eligible
pa$ents
CR
VGPR
PR
Zonder J, et al. Blood December 23, 2010, p 5838.
Outcome Len + Dex, % Dex, % p value
1-Year PFS 77 55 0.002
1-Year OS 93 91 NS
Len + Dex Dex
0
20
40
60
80
100
Patients(%)
14
47
15
29
17
2
75
48
p = 0.001

32. Zonder J, et al. Blood December 23, 2010, p 5838.
SWOG
S0232:
prolonged
progression-­‐free
survival
with
Len
+
Dex
0
20
40
60
80
100
0 6 12 18 24 30 36
Progression-freepatients(%)
Time since registration (months)
Len + Dex
Dex alone
p = 0.002
1-year PFS
Len + Dex: 77%
Dex: 55%

33. ECOG-­‐E4A03:
phase
III
trial
of
Len
+
high-­‐dose
Dex
vs
Len
+
low-­‐dose
Dex
RD, % Rd, % p value
Response (≥ PR) in 4 cycles 79 68 0.008
≥ VGPR within 4 cycles 42 24 < 0.008
Best overall response (≥ PR) 81 70 0.009
≥ VGPR 51 40 0.040
CR (IF−) 17 14 0.428
Any non-haematological adverse
event (grade ≥ 3)
66 8 < 0.001
Adverse event of any type (grade ≥ 4) 21 14 < 0.001
Rajkumar SV, et al, Lancet Oncology; 11 (1), 29-37

34. ECOG-­‐E4A03:
overall
survival
RD 223 208 195 184 173 123 78
Rd 222 217 212 201 192 146 83
3-year OS rate 75%
Numbers at risk
0
Patients(%)
Time (months)
20
40
60
80
100
0 6 12 18 24 30 36
Log-rank p = 0.46
Pepe-Fleming p = 0.01
RD
Rd
Rajkumar SV, et al, Lancet Oncology; 11 (1), 29-37

35. VTD
(n = 226)
TD
(n = 234)
p value
Induction
CR + nCR, % 32 12 < 0.001
VGPR, % 62 29 < 0.001
PR, % 94 79 < 0.001
Post-SCT
CR + nCR, % 55 32 < 0.001
CR, % 43 23 < 0.001
VGPR, % 76 58 < 0.001
Cavo M, et al, Lancet 2010; 376 (9758), 2075–2085
Neuropathy and skin rash were more common with VTD
Phase
III
trial
of
VTD
vs
TD
in
transplant-­‐eligible
pa$ents:
response
rates

36. Cavo M, et al. Blood. 2008;112:[abstract 158];
updated data presented at ASH 2008.
VTD
versus
TD:
progression-­‐free
survival
and
overall
survival
Progression-free survival
0 5 10 15 3020 25
p = 0.009
2-Year rates
VTD (n = 226) 90%
TD (n = 234) 80%
0
40
60
80
100
20
Time (months)
Progression-freepatients(%)
Overall survival
p = 0.2
2-Year rates
VTD (n = 226) 96%
TD (n = 234) 91%
0 5 10 15 3020 25
0
40
60
80
100
20
Time (months)
Patients(%)

37. Phase
I/II:
New
Combina$ons
Efficacy
Len/Cyc/
Dex1
N = 53
Len/Bort/aDex2
N = 65
Bort/Dex/Cyc/
Len3
N = 25
Bort/Cyc/Dex →
Bort/Thal/Dex4
N = 44
Best response
ORR
≥ nCR
≥ VGPR
45 (85%)
NR
17 (32%)
65 (100%)b
29 (44%)
49 (74%)b
25 (100%)
9 (36%)c
17 (68%)
41 (90%)
15 (35%)
24 (60%)
aDexamethasone, 20 mg Days 1–2, 4–5, 8–9, 11–12.
bIndependent of ISS and high-risk cytogenetics.
c≥ CR.
Len = lenolidomide; ORR = overall response rate; NR = not reached; ISS = International Staging System.
1Kumar, Hayman, et al, 2008; 2Richardson, Lonial, et al, 2008; 3Kumar, Flinn, et al, 2008; 4Bensinger, 2008.
aDexamethasone, 20 mg Days 1–2, 4–5, 8–9, 11–12.
bIndependent of ISS and high-risk cytogenetics.
c≥ CR.
Len = lenolidomide; ORR = overall response rate; NR = not reached; ISS = International Staging System.
1Kumar, Hayman, et al, 2008; 2Richardson, Lonial, et al, 2008; 3Kumar, Flinn, et al, 2008; 4Bensinger, 2008.

38. Efficacy
improvements
with
novel
induc$on
regimens
Regimen
Patientswith≥VGPR(%)
Cavo M, et al. Blood. 2008;112:[abstract 158]. Harousseau J-L, et al. ASH/ASCO symposium at ASH, 2008. Lokhorst HM, et al. Haematologica. 2008;93:124-7. Macro M, et
al. Blood. 2006;108:[abstract 57]; updated data from ASH 2006. Morgan G, et al. Blood. 2007;110:[abstract 3593]; updated data from ASH 2007. Rajkumar SV, et al. ASH/
ASCO symposium at ASH 2008. Richardson P, et al. Blood. 2008;112:[abstract 92]. Sonneveld P, et al. Blood. 2008;112:[abstract 653].

39. Ini$al
treatment
and
early
deaths
Regimen* Response, % Early deaths, %
Dex (ECOG-E1A00) 41 11
Dex ± IFN (IFM 95-01) 41 10.5
MP (IFM 99-06) 35 8
Thal + Dex (ECOG-E1A00) 63 7
MPT (IFM 99-06) 76 3
Len + high-dose Dex (ECOG-E4A03) 81 4.5
Len + low-dose Dex (ECOG-E4A03) 70 0.5
* Recent phase III trials that did not restrict entry to transplant candidates.
Facon T, et al. Blood. 2006;107:1292-8. Facon T, et al. Lancet. 2007;370:1209-18.
Rajkumar SV, et al. J Clin Oncol. 2006;24:431-6. Rajkumar SV, et al. ASH/ASCO symposium at ASH 2008.

40. Stages
of
myeloma
treatment
1. Diagnose
and
determine
need
for
treatment
2. Risk
stra$fy
3. Control
disease
and
treat/
reverse
complica$ons
4. Consolidate
ini$al
response
5. Maintain
response
6. Iden$fy
disease
relapse
and
treat
7. Suppor$ve
care
at
all
stages!

41. Attal M. N Engl J Med. 1996;335:91-7.
Transplant
vs.
Conven$onal
chemotherapy
Patients (95% CI), %
Conventional dose 63 (53–73) 35 (22–50) 12 (1–40)
High dose 69 (58–78) 61 (50–71) 52 (36–67)
Time (months)
0
25
50
75
100
Overallsurvival(%)
0 15 30 45 60
High dose
Conventional dose

42. What
does
transplant
add?
Regimen
Patientswith≥VGPR(%)
Cavo M, et al. Blood. 2008;112:[abstract 158]; updated data presented at ASH 2008. Harousseau J-L, et al. ASH/ASCO symposium at ASH 2008.
Lokhorst HM,et al. Haematologica 2008;93:124-7. Macro M, et al. Blood. 2006;108:[abstract 57]; updated data from ASH 2006. Morgan G, et al. Blood.
2007;110:[abstract 3593]; updated data from ASH 2007. Sonneveld P, et al. Blood. 2008;112:[abstract 653]; updated data from ASH 2008.

43. Depth
of
response
improves
over
$me
with
lenalidomide
Lacy MQ, et al. Mayo Clin Proc. 2007;82:1179-84.
Mayo clinic phase II
CR
VGPR
PR
Patientsrespondingto
treatment(%)
4 cycles
(n = 34)
19 cycles
(n = 21)
0
20
40
60
80
100
43
19
24
53
6
32

44. HDT
and
ASCT
in
MM
pa$ents
<
55
years
old:
up-­‐front
or
rescue
treatment
Fermand J-P, et al. Blood. 1998;92:3131-6.
0
0.2
0.4
0.6
0.8
1.0
0 20 40 100
Survivalprobability
60 80
Time (months)
Early HDT
Late HDT
0
0.2
0.4
0.6
0.8
1.0
0 20 40 50 70 90 100
EFSprobability
10 30 60 80
Time (months)
TWiSTT
TWiSTT
OS
Post-HDT EFS
Post-CCT EFS
Late HDT
Early HDT
0
0.2
0.4
0.6
0.8
1.0
0 20 40 50 70 90 100
EFSprobability
10 30 60 80
Time (months)
TWiSTT
OS
EFS
HDT = high-dose therapy; TWiSTT = time without
symptoms, treatment, or treatment toxicity.

45. Single
vs
double
ASCT
for
newly
diagnosed
MM
Study ASCT n CR, %
Median EFS,
months
Median OS,
months
IFM941 Single
Double
199
200
42*
50*
25
30
48
58
MAG952 Single 94 42‡ No difference No difference
Double 99 37‡
HOVON 243 Single 148 13 20 55
Double 155 28 22 50
Bologna 964 Single
Double
115
113
33§
47§
Significant
prolongation
of EFS with
double SCT
46% at 7 years
43% at 7 years
1. Attal M, et al. N Engl J Med. 2003;349:2495-502. 2. Fermand JP, et al. Blood. 2001;98:815a:[abstract 3387].
3. Sonneveld P, et al. Blood. 2005;106:715a:[abstract 2545]. 4. Cavo M, et al. J Clin Oncol. 2007;25:2434-41.
* CR + VGPR; p = NS by ITT.
‡ CR + minimum residual disease; p = NS.
§ CR + nCR; ITT analysis.
NS
NS
p = 0.002
p = 0.008
p = 0.03
p = 0.02
p = 0.01
NS
NS

46. Thalidomide
maintenance:
IFM
99-­‐02
Attal M, et al. Blood. 2006;108:3289-94.
Event-free survival
4-Year EFS 36% vs 26%
+ Thal
Time since randomization (months)
0
10
20
30
40
50
60
70
80
90
100
1 13 25 37 49
Event-freepatients(%)
− Thal
Overall survival
4-Year OS 87% vs 75%
+ Thal
0
10
20
30
40
50
60
70
80
90
100
1 13 25 37 49
Time since enrolment (months)
Patients(%)
− Thal

47. What
about
the
transplant
‘ineligible’
popula$on?

48. Melphalan
+
Prednisone
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6+
Estimatedpercentagestillalive
24.4
%
23.0
19.4
%
18.0
1.4% SD 1.4
(log-rank
2P > .1; NS)– Allocated CCT (% ± SD)
– Allocated MP (% ± SD)
Myeloma Trialists' Collaborative Group. J Clin Oncol. 1998;16;12:3832
Years
27 randomized trials

49. MPT Arm
Melphalan, 4 mg/m2 (7 days per month)
Prednisone, 40 mg/m2 (7 days per month)
Thalidomide, 100 mg/d (continuously)*
(n=129)
MP Arm
Melphalan, 4 mg/m2 (7 days per month)
Prednisone, 40 mg/m2 (7 days per month)
(n=126)
→ ×6 courses
Newly
diagnosed MM patients,
Age >65 years
(median age: 72 years)
n=255
*Thalidomide dose reduced to 50% if grade 2 toxicity. Enoxaparin prophylaxis added to protocol in
December 2003.
GIMEMA Phase III
Randomized
Controlled Trial
Palumbo et al. Lancet 2006;367:825-831
MP
vs
MP-­‐thalidomide
(MPT)
in
Elderly
Pa$ents

50. Palumbo et al. Lancet 2006;367:825-831
MPT vs MP: Survival Rates
EFS
49% ↓ in risk of event for MPT
OS
65% ↓ in risk of death at >9 mo
for MPT
0 6 12 18 24
HR 0.51 (95% CI 0.35–0.75) P=0.0006
ProportionofPatients
0
01
02
03
04
05
06
07
08
09
1.0
Months
0
01
02
03
04
05
06
07
08
09
1.0
0 6 12 18 24 30
HR 0.68 (95% CI 0.38–1.22) P=0.19
ProportionofPatients
Months
MP
MPT

51. Arm A
MP X 12
cycles
Arm C
VAD X 2
Cyclophosphamide 3g/m2
+ G-CSF
+ PBSC harvest
MEL 100 mg/m2
+ PBSC + G-CSF
MEL 100 mg/m2
+ PBSC + G-CSF
Arm B
MP X 12
cycles
+ Thal
≤ 400 mg/d
Facon T et al. The Lancet 2007; 370:1209-1218
IFM
99-­‐06:
Newly
Diagnosed
MM
65-­‐75
years

52. IFM
99-­‐06:
Overall
Survival
Facon T et al. The Lancet 2007; 370:1209-1218

53. MP (12 cycles q 6 weeks)
• Melphalan: 0.2 mg/kg/d Day 1-4
• Prednisone:2 mg/kg/d Day 1-4
MP + Placebo
18 months, continuos
MP + Thalidomide (100 mg/d)
18 months, continuos
Clodronate
was
given
to
all
pts.
No
an3-­‐coagulant
prophylaxis
was
planned.
Hulin C, et al. Blood. 2007;108:78a, abstract 75
IFM
01/01:
Pa$ents
Over
75
Years

54. 1117273140658096105116
1626364557708096101113
0,00
0,20
0,40
0,60
0,80
1,00
0 6 12 18 24 30 36 42 48 54
Months
Proportionofsurvivingpatients
MP
MP+Thalidomide
IFM 01-01: Overall survival
44 vs 29.1 months, p = 0.001
Hulin C, et al, J Clin Oncol. 2009; article in press.

55. MP
vs
MPT:
progression-­‐free
survival
and
overall
survival
GIMEMA1,2 IFM 99-063 IFM 01-014 Nordic5 HOVON6
Median PFS, months
MP
MPT
15
22
18
28
19
24
14
16
10*
13
p value 0.0004 < 0.0001 0.001 TTP‡ < 0.001
Median OS, months
MP
MPT
48
45
33
52
29
44
39
29
30
37
p value NS 0.0006 0.028 NS NS
1. Palumbo A, et al. Lancet. 2006;111:825-31. 2. Palumbo A, et al. Blood. 2008;112:3107-14. 3. Facon T, et al. Lancet. 2007;370:1209-18.
4. Hulin C, et al. J Clin Oncol. 2009; in press. 5. Waage A, et al. Blood. 2007;110:[abstract 78].
6. Wijermans P, et al. Blood. 2008;112:[abstract 241]; updated data presented at ASH, 2008.
*Event-free survival.
‡ Significant.
In 5 of 5 studies, MPT was superior to MP in terms of PFS or TTP (or both)
In 2 of 5 studies, MPT was superior to MP in terms of OS

56. VMP
Cycles 1-4
Bortezomib 1.3 mg/m2 IV: days 1,4,8,11,22,25,29,32
Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4
Cycles 5-9
Bortezomib 1.3 mg/m2 IV: days 1,8,22,29
Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4
MP
Cycles 1-9
Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4
R
A
N
D
O
M
I
Z
E
9 x 6-week cycles (54 weeks) in both arms
• Previously untreated MM patients who were not candidates for HDT-ASCT
• 682 patients randomized from December 2004 to September 2006
VISTA:
Randomized,
Phase
III
Trial
of
VMP
vs
MP
San Miguel et al. NEJM. 359 (9): 906

57. VISTA:
Survival
San Miguel et al. NEJM. 359 (9): 906
24.0 months for bortezomib vs.
16.6 months in the control group

58. Melphalan/
Prednisone/
Lenalidomide
MPR
any dose
(n=53)
MTD
(n=21)
1-Year event-free survival, % 92 95
1-Year overall survival, % 100 100
MTD = maximum tolerated dose (melphalan 0.18 mg/kg + lenalidomide 10 mg/day + prednisone
2 mg/kg/day)
Palumbo et al. J Clin Oncol 2007;25:4459-65

59. mSMART – Off-Study
Transplant Eligible
* Bortezomib containing regimens preferred in
renal failure or if rapid response needed
Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; v5 Revised and updated: Jan 2009
Collect Stem Cells
High Risk Standard Risk
If not in CR, consider autologous stem
cell transplant (ASCT)
All patients receive Rd† until
progression
Autologous stem cell
transplant (ASCT)
If not in CR/VGPR after
1st ASCT, consider
consolidation (eg.,
second ASCT or IMiD)
4-6 cycles of bortezomib
containing regimen (CBD, VRd, VTD etc)
4 cycles of Rd*
Collect Stem Cells**
† Continuing Rd is an option for patients
responding well to induction with low toxicities;
Dex is usually discontinued after first year
OR
Continue
Rd
†
(**If age >65 or > 4 cycles of Rd
Consider G-CSF plus cytoxan or plerixafor )

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

61. Suppor$ve
care
• Bisphosphonates
• An$bio$cs
• Renal
failure
management
• Erythropoie$c
agents/
Anemia
management
• Preven$on
of
thrombo$c
events

62. Bisphosphonate
Guidelines
• In
general
18
months
to
24
months
• Beyond
18-­‐24
months,
individualized
decision
based
on
disease
status
• Beneficial
in
all
pa$ents,
irrespec$ve
of
ly$c
disease
• Calcium
and
vitamin
D
supplementa$on
• Baseline
dental
evalua$on
• Careful
monitoring
for
ONJ

63. Pamidronate
• 90
mg
IV
given
over
2-­‐4
hours
every
month
• Renal
abnormali$es
(Albuminuria,
azotemia)
infrequently
reported
with:
– Long
term
use
with
• Higher
doses
(>
90
mg
q3-­‐4
wks)
• Faster
infusion
$mes
(<
1
hour)
• Reversible
– Hold
dose
un$l
albuminuria/Cr
improves
– Then
try
slower
infusion
$me
(>
2
hours)

64. Zoledronic
acid
• Zoledronic
acid
is
a
highly
potent
bisphosphonate
• 4
mg
IV
over
at
least
15
minutes
• Monitor
renal
func$on-­‐
risk
of
acute
renal
failure
• Not
recommended
in
pa$ents
with
severe
renal
impairment

65. Infec$ous
disease
prophylaxis
• No
randomized
data
on
outcome
• Infec$ons
common
in
the
ini$al
phase
of
disease
• Bactrim/
quinolone
prophylaxis
can
be
considered
on
an
individual
basis
• Zoster
prophylaxis
in
pa$ents
on
bortezomib
• PJP
prophylaxis
for
those
on
steroids
• Role
of
IVIG
not
clear,
may
reduce
infec$ons
in
those
severely
hypogammoglobulinemic

66. Management
of
anemia
• Anemia
common
• Mul$factorial,
several
mechanisms
• Usually
improve
with
effec$ve
therapy
• Persistent
anemia
may
reflect
treatment
agent
• Erythropoie$n
use
may
increase
risk
of
thrombosis

67. Renal
Failure
• Nearly
a
third
of
pa$ents
with
MM
have
some
degree
of
renal
insufficiency
• 5-­‐10%
have
severe
renal
insufficiency
• Mul$factorial:
cast
nephropathy,
hypercalcemia,
hyperuricemia,
amyloidosis
• Effec$ve
therapy
cri$cal,
bortezomib
based
• PLEX
may
benefit
selected
pa$ents
• Suppor$ve
renal
management

68. Thromboprophylaxis
• Risk
of
thrombosis
about
5%
among
pa$ents
with
MM
• Increased
risk
associated
with
IMiDs,
high
dose
steroids
and
cytotoxic
drugs
• Aspirin
decreases
risk
among
pa$ents
receiving
IMiDs
• Selected
pa$ents
may
benefit
from
coumadin/
heparin

69. What
about
when
these
fail?

70. Relapsed
disease:
factors
to
consider
• Risk
factors,
including
cytogene$cs
• Dura$on
of
first
response
• Previous
therapies
and
response
• Toxicity
from
previous
therapies
• Residual
hematological
func$on
• Performance
status

71. Have
we
made
progress?
Kumar SK, et al. Blood. 2008;111:2516-20.
Overall survival in 6-year intervals from time of diagnosis
Time (months)
Proportionofpatients
0
0.2
0.4
0.6
0.8
1.0
0 20 40 60 80 100 120 140
2001–2006
1995–2000
2001–2006
1989–1994
1983–1988
1977–1982
1971–1976

72. Thank
You!