Initial treatment

1
Initial treatment

• Dr Faith Davies
• Royal Marsden Hospital

2
Aims of initial Therapy

• Therapy that prolongs overall survival, ensures
  durable remission (progression-free survival),
  and preserves quality of life
• Ideally aim for high response rates with high
  complete response rates
• Treatment that targets the tumour cell and
  restores the bone marrow microenvironment

3
Factors to consider

• Since no therapy is curative, all options need to
  be considered
• Factors to consider
• disease manifestations and organ function
• age, performance status, and biological factors
• Impact of current therapy on future treatments
• response
• adverse events
• ease of administration
• patient preference
• For guidelines theoretically the full manuscript
  needs to published (cf- meeting
  reports/abstracts)

4
Older less fit patients
5
Meta-analysis of previous trials for older
patients

• Myeloma Trialists Collaborative Group JCO 1998
• Meta-analysis of CCT versus MP Overall survival

27 trials with 6633 patients
Compared melphalan and prednisolone to
combination chemo (ABCM)
6
Melphalan Prednisone Thalidomide (MPT) vs MP
Melphalan 4 mg/m2 days 1-7 Prednisone 40 mg/m2
days 1-7 4-week cycle x 6 Thalidomide 100
mg/day continuously n 129
Patients with newly diagnosed MM gt 65 years old
(n 255)
Melphalan 4 mg/m2 days 1-7 Prednisone 40 mg/m2
days 1-7 4-week cycle x 6 n 126
Thalidomide administration continued until
relapse or progressive disease Crossover to
thalidomide permitted following relapse or
progression
Palumbo et al. Lancet 2006 367 825-31
7
Melphalan Prednisone Thalidomide (MPT) vs MP
vs ASCT
Standard MP Thal (up to 400 mg/day) n 196 12
courses every six weeks
Patients with newly diagnosed MM 6575 years
old (n 436)
Standard MP n 125 12 courses every six weeks
Vincristine Doxorubicin Dex n 126 2 courses
Cyclophosphamide (3 g/m2) G-CSF
Melphalan (100 mg/m2) ASCT G-CST 2 courses
Stem cell collection
Facon et al. Lancet 2007 370 1209-18
8
Superior efficacy of MPT over MP

• Facon et al.
• Median follow-up 32 months

• Palumbo et al.
• Minimum follow-up 6 months

(Updated median FU 51m OS 51.6m, 33.2m, 38m)
Facon et al. Blood 2005106 (Abstract 780), Facon
et al. Lancet 2007 370 1209-18 Palumbo et al.
Blood 2005106 (Abstract 779), Palumbo et al.
Lancet 2006 367 825-31
at 56 months
9
MPT vs MP toxicity

• More severe adverse events with MPT than MP

Palumbo et al. Blood 2005106 (Abstract 779)
Facon et al. Blood 2005106(Abstract 780)
10
MP-T vs MP in MM Patients gt 75 Years IFM 01/01
Twelve 6-week cycles
Melphalan 0.2 mg/kg/day on Days 1-4 Prednisone
2.0 mg/kg/day on Days 1-4 Thalidomide 100
mg/day (n 113)
Patients 75 years of age or older with
untreated MM (N 229)
Melphalan 0.2 mg/kg/day on Days 1-4 Prednisone
2.0 mg/kg/day on Days 1-4 Placebo 100 mg/day
(n 116)
All patients received clodronate. Administered
continuously for 18 months.
Hulin C, et al. ASH 2007. Abstract 75.
11
IFM 01/01 Response and Survival Data
50
P .0001
MP-T
40

• Better responses with MPT
• Acceptable toxicity

MP
38
30
23
Response to Treatment ()
20
16
7
7
10
1
0
VGPR
CR
PR
Hulin C, et al. ASH 2007. Abstract 75.
12
IFM 01/01 Progression-Free Survival by Treatment
100
All 229 Patients Intent-to-Treat Basis
80
MP-T Median 24.1 mos (range 19.8-29) Y/N
64/49
60
Log-rank P .001
Percent
40
MP-Placebo Median 19 mos (range 14.1-21.3) Y/N
83/33
20
0
54
6
12
16
24
30
36
42
46
0
Time (Mos)
Hulin C, et al. ASH 2007. Abstract 75 and Blood
2008
13
IFM 01/01 Overall Survival by Treatment
100
All 229 Patients Intent-to-Treat Basis
MP-T Median OS 45.3 mos (range
33.3-unreached) Y/N 41/72
80
60
MP-Placebo Median OS 27.7 mos (range
24.6-34.9) Y/N 59/57
Percent Survival
40
20
Log-rank P .033
0
54
6
12
16
24
30
36
42
46
0
Time (Mos)
Hulin C, et al. ASH 2007. Abstract 75 and Blood
2008.
14
MPT vs MP
15
MP v MPT
16
MPT vs MP
17
Is MPT the same as CTDa?

• Previous MRC studies (MRC I-III performed in
  1970s) suggested that using cyclophosphamide was
  equivalent to using melphalan as a single agent
• ? Cyclo easier to give as weekly rather than
  monthly so can miss doses if patient drops
  neutrophils or platelets

18
Non-intensive pathway
Myeloma
IX
Randomisation
MPClodronate
MPZoledronic acid
CTDaZoledronic acid
CTDaClodronate
Maximal response
Randomisation
Thalidomide
No Thalidomide
19
Myeloma IX non intensive arm

• Preliminary data
• Response rates amazingly similar to MPT

Morgan et al ASH2007
20
Conclusions

• Efficacy
• thalidomide in combination with an alkylator and
  steroid improves the PFS and in some studies the
  OS
• It should be used as first line therapy for older
  patients not considered fit enough for an auto
  transplant
• Side effect profile needs careful management
• Thrombosis risk
• Neuropathy risk
• Consitpation
• Sedation

21
Melphalan/Prednisone Bortezomib
9 6-week cycles
RANDOMIZE
VMP Cycles 1-9 Melphalan 9 mg/m2, days 1-4
Prednisone 60 mg/m2, days
1-4 Cycles 1-4 Bortezomib 1.3 mg/m2 I.V., days
1, 4, 8, 11, 22, 25, 29, 32 Cycles 5-9
Bortezomib 1.3 mg/m2 I.V., days 1, 8, 22, 29
MP Cycles 1-9 Melphalan 9 mg/m2, days 1-4
Prednisone 60 mg/m2, days 1-4
(n 682)
Primary endpoint Time to
progression Secondary endpoints Response
rate
Time to response
Duration of response
Progression-free
survival
Overall survival
San Miguel et al, Abstract 76, ASH 2007 and NEJM
2008
22
MPV - Efficacy
San Miguel et al, Abstract 76, ASH 2007 and NEJM
2008
23
MPV - Toxicity
San Miguel et al, Abstract 76, ASH 2007 and NEJM
2008
24
Bortezomib adverse events management and
prophylaxis

• Neuropathic pain or peripheral neuropathy
• grade 1 no action
• grade 2 reduce dose to 1.0 mg/m2
• grade 3 withhold therapy until resolution, then
  restart at reduced dose of 0.7 mg/m2 once weekly
• grade 4 discontinue therapy
• Neutropenia
• G-CSF
• Thrombocytopenia
• platelet transfusions
• Herpes zoster
• antiviral prophylaxis

Richardson PG, et al. J Clin Oncol.
2006243113-20.
25
VMP vs MP Time to Progression
100
VMP
90
MP
80
70
60
Precentage of subjects w/o event ()
50
40
30
VMP 24.0 months (83 events) MP 16.6 months (146
events) HR 0.483, P lt .000001
20
10
0
0
3
6
9
12
15
18
21
24
27
Time (months)
San Miguel JF, et al. ASH 2007. Abstract 76. and
NEJM 2008
26
VMP vs MP Overall Survival
100
90
80
70
60
Precentage of subjects w/o event ()
50
VMP MP
Median follow-up 16.3 months VMP not reached (45
deaths) MP not reached (76 deaths) HR 0.607, P
.0078
40
30
20
10
0
0
3
6
9
12
15
18
21
24
27
30
Time (months)

• OS at 2 years 82.6 in VMP vs 69.5 in MP
• In pts lt 75 years, 84 in VMP vs 74 in MP
• In pts 75 years, 79 in VMP vs 60 in MP
• Treatment related deaths on each arm VMP 1 MP
  2

San Miguel JF, et al. ASH 2007. Abstract 76. and
NEJM 20008
27
Younger fitter patients
28
Characteristics of an induction regimen for
younger fitter patients

• Induce maximum numbers of responses
• Maximum depth of responses
• Maintain good harvests
• Minimise risk of MDS
• Outpatient
• Good quality of life

• Effective
• Stem cell sparing
• Few short term side effects
• Few long term side effects
• Preferably oral

29
Supporting data for thalidomide as induction pre
HDT

• Randomised phase 3 trial
• ECOG
• MM003
• Retrospective case matched analyses
• Bologna
• RMH series
• Randomised phase 3 HDT trials
• Hovon
• MRC

30
Thal/Dex vs VAD

• Retrospective matched case control analysis
• Matched age, stage and b2m
• 2 consecutive trials (1996-2004)
• VAD (Bologna 96, 1996-2000)
• Thal Dex (Bologna 2002, 2002-2004)
• 100 patients from each trial
• Comparable baseline characteristics

Cavo et al Blood 2005
31
Response to Induction Chemo
Cavo et al Blood 2005
32
Toxicities
Cavo et al Blood 2005
33
Incorporating Thal into double HDT

• Case matched comparison of 135 patients in
  Bologna 2002 with Bologna 1996
• Benefit in incorporating thalidomide into double
  HDT with respect to response and EFS

Zamagni et al ASH 2007
34
TAD vs VAD

• Prospective phase 3 Hovon-50/GMMG-HD3 trial
• Study design-
• 18-65 years
• Newly diagnosed
• 3 cycles VAD or 3 cycles TAD (Thal 200-400mg
  daily)
• Stem cells mobilised with CAD
• Single or double HDT
• IFN or Thal maintenance

Lokhorst et al Haematologica 2008
35
TAD vs VAD

• 1st interim analysis of 402 patients (201 in each
  arm)
• Median age 56 years
• Male 248 female 154
• ISS stage I 163, II 81, III 78
• Equal distribution of prognostic factors between
  arms

Lokhorst et al Haematologica 2008
36
Response rates
Plt0.001
Plt0.001
P0.55
Plt0.001
Lokhorst et al Haematologica 2008
37
Adverse Events

• CTC grade 3-4 adverse events similar between both
  arms

Lokhorst et al Haematologica 2008
38
Conclusion

• Better quality responses with TAD compared to VAD
• Similar side effect rate but different
  characteristics
• Mobilise stem cells well (TAD 9.8 x 106 VAD
  10.9 x 106)
• ? whether improved response rate translates to
  improved survival

Lokhorst et al Haematologica 2008
39
Intensive pathway
Myeloma
IX
Randomisation
CVADClodronate
CVADZoledronic acid
CTDZoledronic acid
CTDClodronate
HDM 200mg/m2
Randomisation
Thalidomide
No Thalidomide
40
Myeloma IX intensive arm
Owen, Drayson et al ASH 2007, Morgan et al ASH
2007
41
Bortezomib Younger fitter patients

• Number of studies demonstrating effective
  pre-High Dose Therapy
• PAD
• N21, response rate 95 with 24 CR
• 18 proceeded to HDT
• ITT 43 CR and 52PR
• VelDex
• N48, response rate 66 with 21 CR
• 44 proceeded to HDT
• No comment on response post HDT
• Conclusion effective and doesnt impair stem
  cell mobilisation
• Current European randomised clinical trials are
  using VelDex, PAD and VelThalDex

Oakervee et al BJH 2005 129 755-62, Harousseau
et al Haematologica 2006 91 1498-505 Harousseau
et al, Abstract 450, ASH 2007
42
Conclusions

• Randomised controlled trials confirm
  effectiveness of a number of induction
  combinations-
• For older less fit patients
• MPT, CTDa, MPV and Rd
• For younger fitter patients
• CTD, TD, TAD, VD, VTD, RD
• Trials do suggest MP or VAD are NOT the most
  effective

Yellow full manuscript published, white
abstract published
43
For All Patients

• Good supportive care
• Pain control
• Bisphosphonates
• Ensure high fluid intake and prompt management of
  infections
• Good education and support

44
Younger fitter patients

• Where ever possible patients should be entered
  into a clinical trial.
• For younger fitter patients a stem cell sparing
  induction therapy should be given followed by HDT
  (Grade A recommendation level Ib evidence).
• Initial therapy should consist of a
  thalidomide-containing regimen in combination
  with a steroid and cyclophosphamide or
  adriamycin (Grade A recommendation level Ib
  evidence).
• The results of a number of large clinical trials
  are awaited including bortezomib in combination
  with dexamethasone (/- adriamycin) or
  lenalidomide and dexamethasone.

45
Older less fit patients

• Where ever possible patients should be entered
  into a clinical trial.
• For older and/or less fit patients in whom HDT is
  not planned initial therapy should consist of a
  thalidomide-containing regimen in combination
  with an alkylating agent and steroid (Grade A
  recommendation level Ib evidence).
• Bortezomib in combination with melphalan and
  prednisolone is an alternative (Grade A
  recommendation level Ib evidence).
• For patients between 65 and 70 where HDT may be
  an option Cyclophosphamide should be the
  alkylator choice

46
Thank you!