PowerPointPrsentation

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New Developments in the Treatment of MM and WM
Patients The Role of Patient Organizations
Participation of Patient Organizations/Patients
in the Development of New Treatments and
Medication
Stefan Knop Med. Klinik und Poliklinik II der
Universität Würzburg
Maastricht, October 30th 2008
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The Mayo Clinic Experience Survival From
Diagnosis Improves over Time
Kumar et al., Blood 2008
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Titel der Präsentation
15.11.2009
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The Mayo Clinic Experience Survival From
Relapse Improves over Time
Kumar et al., Blood 2008
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Titel der Präsentation
15.11.2009
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Improvements in survival of younger patients
Period estimates of 10-yr survival by major age
groups in defined calendar periods
Brenner et al. Blood 2008
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Novel Treatment Options in Multiple Myeloma
1990s Supportive care (AB, Vaccination,
Erythropoetin)
1962 Melphalan/ Prednisone
1999Thalidomide
2002 modif. allo-SCT
2006 Lenalidomide
2000s Tandem ASCT
Since 1990s Myeloablation ASCT
2003/2004 Bortezomib
Melphalan
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Paradigm Shift Thalidomide 1999
May 1996 Hb 15.2 M-spike 3.08 IgG 2770
April 1999 Hb 12.0 M-spike 5.92 IgG 6150
Feb 2002 Hb 15.8 M-spike 1.2 IgG 1760
Harvest
Hb level
M-spike
IgG
Observation
Started Thalidomide
? Idea to use Thal came from a patient / was
promoted by patient organization
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Thalidomid versus High-dose Dexamethason in
Relapsed/Refractory MM Optimum-Study
Arm A Thalidomide 100 mg/day on d 1-28
Arm B Thalidomide 200 mg/day on d 1-28
R
Arm C Thalidomide 400 mg/day on d 1-28
Arm D High-dose dex cycles 1-4 40 mg/day on d
1-4, 9-12, 17-20
from 5th cycle 40 mg/day on Day 1-4
12 years after first administration of Thal we
still need trials for documatation of
efficacy/safety !
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Strategies to Improve Conventional Chemotherapy
Melphalan/ Prednisone

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MPT vs MP in elderly patients with MM
MPT arm (median age 72 years) Melphalan 4 mg/m2
(7 days/month) Prednisone 40 mg/m2 (7
days/month) Thalidomide 100 mg/day
(continuously) (n 129)
Newly diagnosed MM gt 65 years or younger
non-transplant eligible (n 331)
R
? ? 6 cycles
MP arm (median age 72 years) Melphalan 4 mg/m2 (7
days/month) Prednisone 40 mg/m2 (7 days/month) (n
126)
Thalidomide dose reduced to 50 if grade 2
toxicity enoxaparin prophylaxis during first 4
cycles added to protocol December 2003. Follow-up
6 months.
Palumbo A, et al. Lancet. 2006367825-31.Palumbo
A, et al. Haematologica. 200893(Suppl 1)
abstract 0916.
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MPT vs MP in elderly patients with MM Response
to treatment
Palumbo A, et al. Lancet. 2006367825-31.Palumbo
A, et al. Haematologica. 200893(Suppl 1)
abstract 0916.
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MPT vs MP in elderly patients with MM Survival
Event-free survival
Overall survival
After median follow-up of 38 mths, the 4-yrs OS
was 45.4 vs 49.3 (p 0.79). Median survival
from progression was 11.5 mths for MPT and 24.3
mths for MP (due to rescue treatment including
thalidomide or Velcade) (Palumbo EHA 2008).
Palumbo et al. Lancet 2006
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MPT is the new standard in MM pts gt 65 yrs
Overall survival
Survival after progression was /- 11 mths for
MPT and MP
Facon et al. Lancet 2007
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Maintenance after autologous stem cell
transplantation
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IFM 99-02 Maintenance treatment
n200
Arm A no maintenance
VAD 3-4 Cycles
n196
Double ASCT
Arm B Pamidronate
n201
Arm C Pamidronate and Thal
Attal et al., Blood 2006
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IFM 99-02 Response Rates
Attal et al., Blood 2006
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IFM 99 02 Thalidomid-Maintenance after Auto-SCT
Overall survival

Arm C - Thalidomide

Arm B No Thalidomide

• Inspite of 3 studies showing advantage of
  Thal-main. ? Thal not licensed for
  maintenance

P lt 0.01
Attal et al., Blood 2006
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VISTA VELCADE as Initial Standard Therapy in
multiple myeloma Assessment with melphalan and
prednisone

• Randomized phase III trial of VMP vs MP in
  previously untreated MM patients who were not
  candidates for HDT-ASCT
• Patients Symptomatic multiple myeloma/CRAB with
  measurable disease
• 65 yrs or lt65 yrs and not transplant-eligible
  KPS 60

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

• Primary Endpoint TTP
• Secondary Endpoints CR rate, ORR,

R
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
San Miguel et al., NEJM 2008
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VISTA - Response to Treatmenthigh CR with VMP
measured in serum or urine by centralized
laboratory
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VISTA - Time to progression
San Miguel et al., NEJM 2008
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VISTA Overall survival
VMP MP
Median follow-up 16.3 months VMP not reached (45
deaths) MP not reached (76 deaths) HR 0.607, p
0.0078

• OS _at_ 2-years 82.6 in VMP vs 69.5 in MP
• lt75 years OS _at_ 2-years 84 in VMP vs 74 in
  MP
• 75 years OS _at_ 2-years 79 in VMP vs 60 in
  MP
• Treatment-related deaths on each arm VMP 1 MP
  2

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Relationship between TFI and TNT
Treatment-free interval
Time on therapy
Next Therapy
Time to next therapy

• TNT not reached for VMP vs 20.8m for MP
  (p0.000009)
• Patients on VMP were 48 less likely to start
  second-line therapy
• For VMP vs MP patients, 35 vs 57 at 2-years
  started second-line therapy
• TFI not reached for VMP vs 9.4m for MP (p0.0001)

VMP MP
VMP not reached (73 events) MP 20.8 months (127
events) HR 0.522, p 0.000009
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Grade 3/4 adverse events ()Serious adverse
events were 46 for VMP vs 36 for MP
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Early outcome Then and now
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Positive Effects
Reduction of osseous complications
Direct Anti-Tumoreffects ?
Prevention of bone metastases
Induction of immune response (Stimulation of gd
T-cells)
Bisphosphonates
GI-symptoms
Osteonecrosis of the jaw
Hypocalcemia
Acute-Phase Reaction
Renal Function ?
Negative Effects
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Bisphosphonate-induced Oesteonecrosis of the Jaw
- A rare, but severe side effect
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Oesteonecrosis of the Jaw
? Osteonecrosis of the Jaw noticed as a potential
side effect of bisphosphonat use by a patient and
further promoted to the public by patient
organization
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Role of Patient Organizations

• ? Generating ideas about new treatments/side
  effects for clinicians/ research groups
• ? Support and motivate funding for research/drug
  development for Orphan diseases (MM,
  Waldenstroms macroglobulinemia)
• ? Act as a multiplier to distribute novel trials
  within the patient community
• ? Fight for broad access of new trials and
• speed up availability of novel agents for
  patients by
• - Named patient programs
• - Early access program
• - Compassionate use programm
  
  
  
  
  
  

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Partners of EMP
Myelom Kontaktgruppe Schweiz (MKgS), Switzerland
Dansk Myelomatose Forening, Denmark
Contactgroep Kahler en Waldenstrom patienten
(CKP), The Netherlands
Plasmozytom/Multiple Myelom Selbsthilfegruppe
Nordrhein-Westfalen e.V., Germany
Contactgroep Multipel Myeloom patients Vlaanderen
(CMP), Belgium
Österreich, Austria
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Partners of EMP
EMEA European Medicines Agency
European Cancer Patient Coalition
International Myeloma Foundation
Eurodis European Organisation for Rare Diseases