Front Line Therapy for Newly
Diagnosed Multiple Myeloma
VISHAL KUKRETI, M.D., FRCPC
P R I N C E S S M A R G A R E T H O S P I TA L
S E P T E M B E R 2 4 , 2 0 11
Objectives
 Overview of Myeloma
 Treatment options First Line Therapy
 Transplant Eligible
 Non-Transplant Eligible
Multiple Myeloma
 Incurable cancer of plasma cells
 Medullary and extra-medullary disease
Antibodies/Immunoglobulins
Plasma cells make antibodies (immunoglobulins, Igs)
which consist of 2 heavy chains and 2 light chains
One type of antibody is made to bind with one foreign
substance (virus, bacteria, etc.)
Patterns of Antibody Production
Serum Protein Electropheresis

Normal SPEP

Multiple Myeloma
Types of Multiple Myeloma
Diagnostic Criteria


Diagnosis based on finding over 10% plasma cells
(antibody forming cells) in bone marrow
Symptomatic myeloma characterized by “CRAB”
 Anemia (<100 or 20g/L below normal)
 Bone lesions - lytic
 Kidney damage (Creatinine 176 umol/L)
 Elevated blood calcium (>2.8mmol/L)
Findings at diagnosis - MM
 Anemia – 80%
 Renal dysfunction – 20%
 Hypercalcemia – 25%
 Bone destruction – 75%
 Hyperviscosity - <5%
 M-protein Identification
 Serum – 80%
 Urine – 20%
 Neither (non-secretory) – 1-2%
Age-specific incidence of MM
Ineligible
Transplant candidates
70
Male cases
Female cases
Male rates
Female rates
50
40
200
30
20
100
10
Age at diagnosis
http://info.cancerresearchuk.org/cancerstats/types/multiplemyeloma
85+
80-84
75-79
70-74
65-69
60-64
55-59
50-54
45-49
40-44
35-39
30-34
25-29
20-24
15-19
10-14
0
5-9
0
0-4
Number of cases
300
60
Rate per 100,000 population
400
Staging of Myeloma
International Staging System
Risk Category
1
2
3
Characteristics
 2 M  3.5 mg/L + albumin  35 g/L
 2 M  3.5 mg/L+ albumin  35 g/L
or
 2 M  3.5 – 5.5 mg/L
 2 M  5.5 mg/L
Survival and ISS score
FISH Cytogenetics in Myeloma
t(4;14)=15%
(dysregulation of FGFR3 and MMSET)
p53 deletion=10%
(loss of tumor suppressor gene)
Combining Beta 2-Microglobulin and
FISH Identifies 3 Prognostic Groups
No t(4;14), no del17p,
b2m£4 mg/L, no del13
35%
50%
No t(4;14), no del17p,
b2m£4 mg/L, del13
No t(4;14), no del17p,
b2m>4 mg/L, no del13
No t(4;14), no del17p,
b2m>4 mg/L, del13
p=2.10-13
15%
t(4;14) or del17p, b2m£4
mg/L
t(4;14) or del17p, b2m>4
mg/L
Avet-Loiseau H. Blood. 2007;109:3489-3495.
Treatment – Principles
 Bisphosphonates
◦ Osteonecrosis of the jaw – 1.8 to 12.8%
◦ Duration of therapy
 Vertebroplasty/Kyphoplasty
 Infections
 Induction Therapy – Transplant Eligible vs
Ineligible
 Autologous Stem Cell Transplant
 Maintenance therapy post-stem cell transplantation
Autologous Stem Cell Transplant
Patient
Priming
Therapy
Collect PBSCs
High-dose
Chemotherapy
Reinfuse
PBSCs
+/- Post-ASCT
therapy
Freeze
Where We’ve Been with Initial Therapy
ASCT
 Preceded by VAD, Dex





Melphalan + Prednisone
 Overall response rate 40-50%
alone or Thal/Dex x 4 cycles  CR/nCR 5%
Melphalan 200 mg/m2
 Median PFS 12-15 mos
Overall response rate 80%  Median OS 30-36 mos
CR/nCR rate 20%
Median PFS 20-36 mos
Median OS 48-60 mos
Novel Agents in Multiple Myeloma
Thalidomide
Bortezomib
Lenalidomide
Agent
Class
Effects
Toxicity
Thalidomide
(Thalomid®)
IMiD
Immunomodulatory effects
- inhibits TNFa, inhibits
angiogenesis, stimulates Tcells (CD8), alters cytokine
production, impedes
binding to stromal cells
Teratogenicity, PN,
sedation, rash,
constipation, DVT
Bortezomib
(VelcadeTM)
Proteasome
inhibitor
Decreased adhesion,
cytokine production,
angiogenesis, NFkB,
DNA repair
Fatigue, PN, GI toxicity
Decrease in neutrophils,
platelets and
lymphocytes
Lenalidomide
(CC-5013;
Revlimid®)
IMiD
Stimulate T-cell
proliferation, upregulate
IL-2 and IFN-g, inhibit
TNFa and IL-6Decreased
adhesion, alter synthesis of
cytokines, induce growth
arrest and caspase
dependent apoptosis
NK cell cytotoxicity
Myelosuppression, DVT
Strategies to Improve ASCT Results
 Improved induction therapy
 Risk Stratification – t(4;14)
 Improved dose intensive therapy


Tandem ASCT
New regimens (“Vel-Mel,” Bu-Mel, busulfex + bortezomib)
 Post-ASCT therapy


Consolidation
Maintenance
Induction Trials before ASCT
 Many phase I-II trials of 3- and 4-drug regimens

May allow option to continue regimen without ASCT
 Phase III trials that include ASCT



3 compare novel regimen with VAD
2 compare novel regimen with thalidomide + dex
1 compares novel regimen with bortezomib + dex
Novel Induction Regimens before ASCT
VAD or Dex
THALIDOMIDE
ThalDex*
TAD*
CTD*
*Studied in phase III
transplant trials
BORTEZOMIB
(VELCADE)
Bortez+Dex*
VTD*
PAD*
VCD
Cybor-D
RVDD
Stem cell harvest
High-dose melphalan +
ASCT
LENALIDOMIDE
(REVLIMID)
RD
Rd
RVD
RD: Lenalidomide + high-dose dex
Rd: Lenalidomide + low-dose dex
Study/Author
N
Induction
regimen
MAG/Macro
204
Thal + dex
VAD
1
-
-
HOVON-50/
Lokhorst
536
TAD
VAD
1
-
Thal
Interferon
IFM 2005-02/
Harousseau
482
BD
VAD
1 or 2
+/- len
+/- len
HOVON 65/
GMMG-HD4/
Sonneveld
613
VAD
PAD
1 or 2
-
Thal 50 mg/d
B 1.3 mg/m
GIMEMA MMY3006/
Cavo
PETHEMA/
GEM05MEN0S65/
Rosinol
447
VTD
Thal + dex
2
VTD
Thal + dex
Dex
Dex
306
Thal + dex
VTD
VBMCP/VBAD/
Vel
Vel/dex
vTD
1
-
-
1 or 2
-
-
IFM 200702/Moreau
#
Consolidation Maintenance
ASCT
(q 2 weeks)
199
Study/Author
Induction
regimen
# ASCT +
Post-Rx
Post-ASCT
Response (%)
VGPRc(CR+n
CR)
Median
PFS
(mos)
Median
Overall
Survival
(mos)
MAG/Macro
TD
1
44
-
HOVON-50/
Lokhorst
TAD
1+Thal
66 (31)
34
73
BD
1 or 2
+/- Len
54 (35)
36
81%
1 or 2 +
bortez
75 (50)
2 + VTD
+ Dex
87 (55*)
IFM 2005-02/
Harousseau
HOVON
65/GMMG-HD4/
Sonneveld
GIMEMA MMY3006/Cavo
PAD
PETHEMA/
Rosinol
VTD
1
IFM 200702/Moreau
Vel/dex
vTD
1 or 2
VTD
(3 yrs)
42%
78%
(3 yrs)
(3 yrs)
85%
96%
(2 yrs)
(2 yrs)
(46*)
NYR
73 (61)
-
76% (4
yrs)
-
“CYBOR-D”: Phase II Trial
Newly Diagnosed Myeloma
28 day cycle
Schedule
Bortezomib
Cyclophosphamide
Dex
Dose
(mg/m2
)
Day
Days (300 mg/m2)
Days (40 mg)
Biweekly
1.3
1,4,8,11
1,8,15,22
1-4, 9-12, 17-20
Weekly
1.5
1,8,15,22
1,8,15,22
Same x 2 cycles, then
decreased to 1,8,15,22
•Rapid onset
•Responses after 4 cycles of weekly dosing:
•ORR 98%
•≥VGPR 68%
•CR/nCR 43%
•No issues with SC collection
Reeder C, et al. Leukemia 2009; 23: 1337-1341; Reeder CB, et al. Blood 2010; 115: 3416-3417.
Induction Therapy before ASCT - Summary
 Advantages of bortezomib-containing induction



Rapid induction of remission
Effective in renal failure
Effective in high-risk cytogenetic subgroups
 Some evidence that 3- and 4-drug regimens produce
higher remissions, and convey better PFS

Combinations of bortezomib and IMiDs very costly
 Weekly bortezomib carries much lower risk of PN
 PMH approach is to use CYBOR-D x 4 cycles
Randomized Tandem ASCT Trials
N
PostASCT
Rx
Attal,
2003
399
α IFN
42
50
25
30*
48
58*
Fermand,
2003
277
None
39
37
31
33
49
73
Goldschmidt, 268
2005
α IFN
--
--
22
NYR*
23
NYR
Sonneveld,
2004
303
α IFN
13
28
20
22*
55
50
Cavo,
2007
321
α IFN
38
48
23
35*
65
71
* p< 0.05
CR/VGPR rate
(%)
Single Tandem
Median PFS
(months)
Single Tandem
Median OS
(months)
Single Tandem
Newer Post-ASCT Strategies
 Consolidation
 VTD (GIMEMA trial)
 Lenalidomide + dexamethasone (IFM 2005 02)
 Bortezomib (Nordic Myeloma Study Group trial)
 RVD (CTN trial)
 Maintenance
 Lenalidomide (CALGB trial, IFM 2005 02)
IFM/Dana Farber 2009 Trial
VRD x 3
SC collection
CY + G-CSF
VRD x 5
Melphalan 200 mg/m2
+ ASCT
VRD x 2
Rev maintenance x 1 yr
Rev maintenance x 1 yr
HDM + ASCT
recommended at
relapse
ASCT will be considered pertinent if
EFS is prolonged by ≥ 9 months
ASCT in Myeloma
Summary and Conclusions
 Several approaches integrating novel agents with ASCT
improve outcome

Difficult to dissect contribution of induction, consolidation,
maintenance
 Improved response rates with newer strategies

≥ VGPR rates 60-75%; CR/nCR rates 30-50%
 Median PFS has improved from 2 to 3 years

3 ½ years with lenalidomide maintenance
 Overall survival results are improved in some studies
Where We Are Now
ASCT
 Preceded by novel induction





regimens
Melphalan 200 mg/m2
+/- second ASCT +/thalidomide maintenance
Overall response rate 80-90%
CR/nCR rate 35-50%
Median PFS 36 mos
2 year OS 90-93%
MPT or MPV
or Lenalidomide + Dex
 Overall response rate 65-75%
 CR/nCR 20-25%
 Median PFS 24-30 mos
 Median OS 48-50 mos
 2 year OS 70-93%
Transplant-Ineligible Patients –
Balancing the Toxicities and
Efficacy of Novel Agents
How do we choose initial therapy in
non-transplant patients?



Drug availability
Practical considerations
Patient-related features
Co-morbidities (diabetes, peripheral neuropathy)
 Marrow reserve
 Renal function


Disease-related features
Aggressive biology, such as t(4;14)
 Light chain nephropathy


Treatment related features
Rapidity of response
 Toxicity profile (VTE, peripheral neuropathy)

New Treatment Options for Newly
Diagnosed Myeloma Patients
Non-transplant Candidates
 Add novel agent to melphalan + prednisone
 Continuous suppressive therapy with IMiD +
dexamethasone (lenalidomide + weekly dex)
 Combination therapy with 3-4 drug regimens +/maintenance



1Morgan
CTD1
RVD2
CyborD3
• VDC4
• VDCR4
• Thal + dex + PLD5
• VMPT6
G, et al. Blood 2007;110: abstract 3593 2Richardson PG, et al. Blood 2008;112: abstract 92;
3Reeder CB, et al. Leukemia 2009;23: 1337-1341; Kumar S et al. Blood 2009; 114: abstract 127; 5Offandini M,
et al. Br J Haematol 2009;144: 653-659.; 6Palumbo A, et al. Blood 2009; 114: abstract 128.
Best Reported Outcomes with Newer
Non-ASCT Regimens in Phase III Trials
Author
Rx
Duration of
therapy
(wks)
Overall
response rate
(CR+nCR) (%)
Median
PFS
(mos)
Median
OS
(mos)
2 year
OS
(%)
Facon1
MPT
72
76 (18)
27.5*
51.6*
78
MPT+ T
24+
76 (28)
21.8*
45
82
Hulin3
MPT
72
61 (7)
24*
45*
70
San Miguel4
VMP
54
71 (35)
24*
NYR*
83
Palumbo5
MPR+ R
40+
77 (18)
NYR*
NYR
~70
Rajkumar6
Len+dex Until prog
70 (14 CR)
25.3
NYR
87
Palumbo2
*Significant benefit over MP alone
1Facon
T, et al. Lancet 2007:370; 1209-1218; 2Palumbo A , et al. Blood 2008;112: 3107-3114; 3 Hulin C, et al. Blood 2007; 110:
abstract 75;4San Miguel JF, et al. N Engl J Med 2008; 359: 906-917; 5 Palumbo A, et al. Blood 2009; 114: abstract 613;
6Rajkumar SV, et al. Lancet Oncol 2010; 11: 29-37.
IFM 99/06: MPT vs MP vs Mel100
65-75yo
PF
S
M
P
OS
MP
T
M
P
MP
T
M
Melphalan 0.25mg/kg and Prednisone 2mg/kg, days 1-4, for 12 cycles, q 6 weeks
P
MP
MP plus thal 200-400 mg/d (with no maintenance thalidomide phase)
T
MEL100 VADx2 + MEL100x2 + ASCTx2
Facon et al, IFM 99/06, Lancet 2007
MPT vs MP studies
Study
ORR
(%)
CR
(%)
PFS Median
(mos)
OS Median
(mos)
OS
p-value
IFM 99/06
76 v 35
13 v 2
28 v 18
52 v 33
0.0006
61 v 31
7v1
24 v 19
44 v 29
0.03
62 v 47
2v2
15 v 11
40 v 31
0.05
76 v 48
16 v 4
22 v 15
45 v 48
NS
57 v 38
13 v 4
15 v 14
29 v 33
NS
Facon1
IFM 01/01
Hulin3
HOVON
Wijermans5
GIMEMA
Palumbo2
Nordic
Waage
1Facon
4
T, et al. Lancet 2007;370:1209-18; 2Palumbo A, et al. 2008; 112: 3107-3114; 3Hulin C, et al. J Clin Oncol 2009 May 18 [Epub¸ahead of print]; 4Waage A,
et al. Blood 2007;110:abstract # 76; 5Wijermans P, et al. Blood 2008; 112: abstract #649; 6San Miguel J, et al. 2008; New Engl J Med 2008; 359: 906-917.
Select toxicities: MPT vs MP (Grade3-4)
Facon et al., IFM 99–06: 65-75yo
MP
(N=193)
MPT
(N=124)
P-value
Neutropenia
26%
48%
<0.0001
Thrombosis/embolism
4%
12%
0.0008
Peripheral neuropathy
0
6%
0.001
Solmolence/fatigue/dizziness
0
8%
<0.0001
0.5%
2%
Rate too low
0
10%
<0.0001
Cardiac (arthymia, CHF)
constipation
VISTA:
VELCADE as Initial Standard Therapy in multiple myeloma:
Assessment with melphalan and prednisone
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
Patients with newly
diagnosed MM not
transplant eligible due
to age (≥65 years) or
coexisting conditions
R
A
N
D
O
M
I
S
E
Cycles 5-9
Primary Endpoint:
Bortezomib 1.3 mg/m2 IV: days 1,8,22,29
 TTP
Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4
9 x 6-week cycles (54 weeks) in both arms
MP
Cycles 1-9
Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4
Conducted at 151 centres in 22 countries in Europe, North and South America, and Asia.
San Miguel et al. N Engl J Med 2008; 359: 906-917
Secondary
Endpoints:
 CR rate
 ORR
 TTR
 DOR
 PFS
 TNT
 OS
 QoL
VISTA: Select patient demographics and disease
characteristics
Median age
≥75yo
KPS ≤70%, (~ECOG 2+) %
ISS Stage I / II / III, %
Lytic bone lesions, %
Serum creatinine, median (mg/dL)
CrCl ≤30 / >30-60 / >60 ml/min, %
History of neurological conditions, %
History of cardiac conditions, %
VMP
MP
71
31
35
71
30
33
19 / 47 / 35
65
1.1
6 / 48 / 46
18
35
19 / 47 / 34
66
1.1
5 / 50 / 46
20
31
San Miguel et al. N Engl J Med 2008; 359: 906-917
VISTA: VMP vs MP (9 cycles)
TTP
OS
San Miguel et al. (VISTA). N Engl J Med 2008;359:906-17.
VMP: Consistent efficacy in patients with poor
prognostic characteristics
High-risk vs. standard-risk cytogenetics
TTP 1
OS 2
high
standard
standard
high
Time (months)
Time (months)
Median follow up: 25.9 months
Median follow up: 36.7 months
1. San Miguel et al. N Engl J Med 2008; 359: 906-917 (Suppl)
2. Mateos et al. J Clin Oncol 2010; 28: 2259-2266
Select Grade 3-4 Adverse events: VISTA Updated
data
VMP (N=340)
MP
(N=337)
Neutropenia
40
38
Thrombocytopenia
38
31
Anemia
19
28
Leukopenia
24
20
Lymphopenia
20
11
Pneumonia
7
5
Peripheral sensory neuropathy
14
0
Fatigue
8
2
Diarrhoea
8
1
Minimizing Neuropathy:
once- vs. twice-weekly bortezomib –
GIMEMA study
VMP
(Twice weekly)
VMP
(Once weekly)
CR
27%
23%
PFS @ 3years
32%
35%
OS @ 3 years
86%
85%
Any grade
43%
21%
Grade 3-4
14%
2%
PN discontinuation
16%
4%
Total planned dose
67.6 mg/m2
46.8 mg/m2
Total delivered dose
41 mg/m2
40 mg/m2
Sensory peripheral neuropathy
Once weekly bortezomib is new standard schedule!
Palumbo et al; ASH 2010, Abstract #620
E4A03: Phase III trial of LD vs Ld in newly
diagnosed MM
If PD within 4 mo
Newly
Lenalidomide + HighDose Dexamethasone
(LD)
[40 mg, d 1-4, 9-12, 17-20]
Salvage therapy
Thalidomide 200 mg/d po,
days 1-28
High-dose (Arm III) vs Lowdose (Arm IV)
Diagnosed
Myeloma
N = 445
Lenalidomide + LowDose Dexamethasone
(Ld)
[40 mg, d 1, 8, 15, 22]
DSMB mandated crossover
to Low-dose dex (Ld)
March 27, 2007
N = 79 patients on study at
time of crossover
Lenalidomide: 25 mg daily, days 1-21 of 28-day cycle;
D: High-dose Dex: total 480 mg/28-day cycle;
d: Low-dose Dex: total 160 mg/28-day cycle
Vesole DH et al. ASH 2010; Abstract 308.
LD vs Ld: Overall Survival by age
Age > 65

Age > 75
Len plus low-dose dex is safe and effective for both older and younger patients
Vesole et al; ASH 2010, Abstract 308
LD versus Ld: Toxicities
LD
n=223
Ld
n=220
P-value
Response at 4 cycles
79%
68%
0.008
 VGPR
42%
24%
<0.008
Blood clots
26%
12%
<0.001
Infection
16%
9%
0.043
Severe toxicity
53%
31%
<.001
Early deaths
5%
0.5%
0.003
RD in comparison to Rd is slightly more effective but significantly more toxic.
Once weekly DEX is now widely used and is generalized to the
relapsed setting and to use with other novel agents
Rajkumar et al Lancet Oncol 2010;11:29-37
Conclusions
 Not all elderly are the same. Not all myeloma is the same
 Bortezomib-based induction (e.g. VMP) is reasonably well tolerated
and associated with enhanced OS in most patients >65yo and >75yo
(and is funded in Ontario)
 Oral induction regimens (e.g. MPT, MP or len/dex) may be
appropriate in some non high-risk patients
 In patients with renal impairment or t(4;14), -17p a velcade-based
induction regimen is preferred (e.g. VMP)
 Higher intensity regimens less beneficial and may be adverse in frail
patients
 Weekly bortezomib is a new standard of administration
 Low dose dex is the standard of care in lenalidomide
Niesvizky et al. Haematologica 2011; 96 (s1): S98 (Abstract P-228); poster presentation at IMW 2011
PMH Approach to Front Line Therapy
Transplant
Eligible (<65)
Non-Transplant
Eligible (>70)
Ages 65-70
Cybor D Induction
(clinical trials)
ASCT
(Tandem if high risk)
Maintenance
Lenalidomide
VMP
MPT
MP
(Clinical trials)