NOVEL THERAPIES: Frontline Approaches 2004 Brian G.M. Durie, M.D.
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Transcript of NOVEL THERAPIES: Frontline Approaches 2004 Brian G.M. Durie, M.D.
NOVEL THERAPIES:Frontline Approaches 2004
Brian G.M. Durie, M.D.
Traditional Frontline Therapy
Transplant PlannedVAD or DEX
No TransplantMP or variant
Transplant Planned
Medical EligibilityAgePersonal Choice
Consider
Novel OptionsFor Frontline
ThalidomideVELCADE
RANDOMIZATION
Dexx 4 cycles
Thal + Dexx4 cycles
A Randomized Phase III Trial of Thalidomide Plus Dexamethasone
Versus Dexamethasone in Newly Diagnosed Multiple Myeloma (E1A00)
CR/PR/Stable
Proganytime
Off Rx @ 4 months- for transplant*
Off Rx
E1A00: 207 patients
*Treatment beyond 4 cycles was permitted at physician discretion
S. V. Rajkumar et al. Proc ASCO 2004
Dose
Arm AThal 200 mg PO daily plus Dex 40 mg day 1-4, 9-12, 17-20
Arm BDex 40 mg day 1-4, 9-12, 17-20
All pts received pamidronate or zoledronic acid monthly
S. V. Rajkumar et al. Proc ASCO 2004
Results
Best Response* within 4 Cycles Thal/Dex: 67/98 pts (68%)
Dex: 46/98 pts (46%)
*allowing for using serum M protein levels in patients in whom
measurable urine M protein was unavailable at follow-up
S. V. Rajkumar et al. Proc ASCO 2004
Major Toxicities Within 4 CyclesToxicity Thal/Dex
(N=102)Dex
(N=101)
DVT (Grade >=3) 16 (16%) 3 (3%)
Rash (Grade >=3) 4 (4%) 0 (0%)
Sinus bradycardia (Grade >=3)
1 (1%) 0 (0%)
Neuropathy (Grade >=3) 6 (6%) 4 (4%)
Toxicity of Any Type (Grade >=4)
34 (33%) 16 (15%)
Total ** 45 (44%) 19 (19%)
** Rows do not add to total as patients could have more than one of these toxicity types
S. V. Rajkumar et al. Proc ASCO 2004
Conclusions
Thal/Dex is an effective induction therapy in newly diagnosed multiple myelomaResponse rates with Thal/Dex are superior to Dex alone but the risk of added toxicity is higherRisks/Benefits need to be balanced when deciding on therapy
Conclusions
Given these results there is little reason to use VAD as initial treatment for myelomaDVT prophylaxis needed while using Thal/DexFuture trials of front-line therapy using more aggressive oral/intravenous therapy need to show significant superiority over Thal/dex in randomized trialsFuture ECOG strategy: Phase III with CC-5013+Dex (E4A03)
VELCADE (bortezomib) Compared to high-dose Dexamethasone in Relapsed Multiple Myeloma:
A Phase III Randomized Study (APEX)
ASCO Press BriefingPaul Richardson, M.D. Dana Farber Cancer InstituteSaturday, June 5, 2004
Study Design
Phase III APEX trial to assess VELCADE compared to high-dose dexamethasone International, randomized, controlled study in patients with relapsed or refractory multiple myeloma
One-to-three prior lines of therapy669 patients enrolled at 94 centers
Study Design (cont’d)End points
Primary: time to progression (TTP)Secondary: survival, response rate (RR) and duration, time to skeletal events (TSE), incidence of ≥ G3 infection, safetyExploratory: quality of life (QOL), pharmacogenomics
Companion crossover study provided VELCADE to patients progressing on dexamethasone armPatients refractory to high-dose dexamethasone were excluded from the study
Time to Progression (Interim Analysis)
Bortezomib (n = 327)
Dexamethasone (n = 330)
58% improvement in median TTP with VELCADE
P < 0.0001
Median TTP: VELCADE arm – 5.7 months Dexamethasone arm – 3. 6 months
Final Survival Analysis*
Overall survival, P < 0.011-year survival, P < 0.01
244 days median follow-up in survivors -VELCADE: 48 deaths -Dexamethasone: 81 deaths
Bortezomib (n = 333)
Dexamethasone (n = 336)
1 year
*January 13, 2004
Risk of death in the first year reduced by ~30 percent in VELCADE arm
Statistical significance held even with ~50% of patients crossing over from dexamethasone arm to receive VELCADE
(Includes Crossover Patients)
First-line Therapy With Bortezomib (VELCADE®, Formerly PS-341) in Patients With Multiple Myeloma
Sundar Jagannath,1 Brian G.M. Durie,1 Jeffrey Wolf,1 Elber Camacho,1 David Irwin,1 Jose Lutzky,1 Marti McKinley,1 Eli Gabayan,1 Amitabha Mazumder,1 John Crowley,2 David Schenkein3
1Salick Health Care Research Network, Los Angeles, CA; 2Center for Research & Biostatistics, Seattle, WA; 3Millennium Pharmaceuticals, Inc., Cambridge, MA
Multi-Institutional Phase II Clinical Trial
Treatment PlanBortezomib 1.3 mg/m2 2x/week x2 q 3 weeks for a maximum of 6 cycles Dex 40 mg permitted only on the day of and after each bortezomib dose
After 2 cycles for patients who achieve less than a PR After 4 cycles for patients who achieve less than a CR (immunofixation negative)Dex dose was twice the dose used in the phase 2 bortezomib trials (SUMMIT/CREST)5,6
Premedication was allowed according to physician discretion
Current Best Overall Responses (n = 24)
Response*
n (%)
CR 2 (8)
NCR 4 (17)
PR 13 (54)
MR 4 (17)
SD 0 (0)
PD 1 (4)
Overall 79%
*Responses based on paraprotein.
• Bortezomib alone induced CR/NCR in 6 patients; 2 of these NCR patients received dexamethasone and response status remained unchanged
Addition of Dexamethasone (n = 14)Dexamethasone was added to the treatment of
8 patients at cycle 36 patients at cycle 5
Additional response after dexamethasone, 8/14Response improved by 2 levels:
SD to PR: 2Response improved by 1 level:
MR to PR: 4SD to MR: 2
Serum M Protein for First 9 Patients (≤ 4 Cycles)
Maximum toxicity grade: 1 2 3 4
Maximum grade: any AE
Constipation
Diarrhea
Fatigue
Sensory neuropathy
Neuropathic pain
Number of Patients
Treatment-Related Adverse Events* (n = 24)
0 2 4 6 8 10 12 14 16 18 20 22 24
*Adverse events graded per NCI CTC v2.
Ancillary Findings
Stem cell harvestingHas proceeded without difficultySuccessful harvest: 5/5 (100%)2 patients transplanted with complete hematologic recovery
ConclusionsBortezomib was effective and well tolerated as front-line therapy in this studyThis phase 2 study has demonstrated a 79% response rate Combination with dexamethasone provides added benefit in some patientsStem cell harvesting and engraftment was feasibleDevelopment of peripheral neuropathy and resolution requires further study; monitoring in the clinical setting is warrantedAccrual ongoing: Currently 36 patients
Multi-Institutional Phase II Clinical Trial
PAD Combination Therapy (Bortezomib/Formerly PS-341, Adriamycin and Dexamethasone) for Previously Untreated Patients With Multiple Myeloma
J. D. Cavenagh,1 N. Curry,1 J. Stec,2 C. Morris,3 M. Drake,3 S. Agrawal,1 P. Smith,1 D. Schenkein,2 D. Esseltine,2 H. Oakervee1
1St Bartholomew’s Hospital, London, UK2Millennium Pharmaceuticals, Inc., Cambridge, MA, USA; 3Belfast City Hospital, Belfast, UK
Treatment
Induction (4 cycles prior to transplantation)
Bortezomib 1.3 mg/m2 by IV bolus on days 1, 4, 8, and 11Doxorubicin administered by continuous infusion or IV push to cohorts at escalating dose levels on days 1–4Dexamethasone 40 mg PO
• Cycle 1: days 1–4, 8–11, and 15–18• All subsequent cycles: days 1–4
Day
Bortezomib 1.3 mg/m2
1 4 8 15 18Cycle 1 11 21
Dexamethasone 40 mg
Adriamycin
Day
Bortezomib 1.3 mg/m2
1 4 8 15 18Cycles 2–4 11 21
Dexamethasone 40 mg
Adriamycin
Treatment
Patient No.
Response After
4 Cycles
CD34+ cells × 106/kg (No. of harvesting
attempts)
Response 3 Mo Post-
Autograft
1 PR 4.2 (1) VGPR
2 VGPR 2.7 (2) CR
3 CR 1.6 (2) NA
Level 1: No Adriamycin
Patient No.
Response After
4 Cycles
CD34+ cells × 106/kg (No. of harvesting
attempts)
Response 3 Mo Post-
Autograft
4 PR 7.4 (1) VGPR
5 VGPR 2.3 (2) CR
6 PR 4.7 (1) PR
7 PR 3.6 (2) PR
Level 2: Adriamycin 4.5
Patient No.
Response After 4 Cycles
CD34+ cells × 106/kg (No. of
harvesting attempts)
Response 3 Mo Post-Autograft
8 PR 1.9 (1) VGPR
9 VGPR* 2.1 (1) na
10 VGPR 4.7 (4) VGPR
11 PR 0 na
12 CR 4.3 (4) na
13 SD 3.7 (2) na
14 VGPR 2.5 (3) na
15 VGPR† 2.8 (6) na
16 VGPR 10.4 (2) na
17 PR na na
18 PR na na
19 VGPR* na na
20 CR* na na
21 PR* na na
N = 142 CR, 6 VGPR, 5 PR, 1 SD
Level 3: Adriamycin 9.0
*After 1–2 cycles.†After 3 cycles.na = not available.
Outcome After PAD Induction
95% CR/PR rate (3 CR, 8 VGPR, and 9 PR) after ≥ 1 cycle of treatment (n = 21)
1 CR after PD alone2 CRs after PAD
94% CR/PR rate (2 CR, 7 VGPR, 8 PR) after 4 cycles (n = 18)
Ch
ang
e i
n M
yelo
ma
Pro
tein
(%
)
Serum/Urinary Myeloma Protein Response by PAD Cycle
• M-protein levels decreased by a mean of 70% following cycle 1 of treatment
Pre-Rx #1 #2 #3 #4
Treatment Cycle
0
10
20
30
40
50
60
70
80
90
100
110
120
IgAκ
IgAλ
IgGκ
IgGλ
κ-LCλ-LC
Isotype
Mean ± SEM
Neuropathy
More frequent after 2nd cycleNeuropathic symptoms improving in all patients after completion of therapy
N = 21
Frequency of Sensory
Neuropathy (53%)
Frequency of Painful
Neuropathy (43%)
Grade
1 9 (43) 8 (38)
3 2 (10) 1 (5)
PAD Cycle
1–2 4 (19) 2 (10)
3–4 6 (29) 5 (24)
Melphalan
1 (5) 2 (10)
Conclusions
PAD combination therapy is an effective regimen for previously untreated patients with multiple myeloma
94% CR/PR rate after 4 cycles15 of 16 patients mobilised, 11/15 transplanted thus farAll 8 evaluable patients achieved PR or better following PBSCT (2 CR, 4 VGPR, 2 PR)
Major toxicity was painful neuropathyA second cohort is being recruited to receive a reduced dose of bortezomib (1.0 mg/m2)
ORAL MELPHALAN, PREDNISONE, AND THALIDOMIDE FOR NEWLY DIAGNOSED
MYELOMA PATIENTS A. Palumbo*, A. Bertola*, P. Musto°, M. Nunzi°, V. De Stefano°, L. Catalano°, T. Caravita°, C. Cangialosi°, S. Bringhen*, M. Boccadoro*.
Divisione Universitaria di Ematologia, Azienda Ospedaliera S. Giovanni Battista, Torino–Italy*, and the Italian Multiple Myeloma Study Group°
Patient Characteristics for MPT Trial (n=42)Median age 72Range 61-80
Male 23 (55)Female 19 (45)
Stage IIA 18 (43)Stage IIIA 17 (40)Stage IIIB 7 (17)
ß2-microglobulin < 3mg/L 14 (33)ß2-microglobulin > 3mg/L 23 (55)Data missing 5 (12)
IgG 26 (62)IgA 9 (21)Bence Jones protein 7 (17)
Response After MPT (42 Patients)
CR+nCR VGPR(90%–99%)
PR(50%–89%)
%
of
R e s p o n s e
0
10
20
30
40
50 45%
12%
36%
7%
19%
26%
NR
Time to Maximum Response
0
20
40
60
80
100
0 1 2 3 4 5 6 9 12 15 16
%
months
Time to Onset of Adverse Events
0
10
20
30
40
0 2 4 6 8 10 12 14 16
%
months
Conclusions
MPT is very active in previously untreated patients with multiple myeloma.
45% of patients achieved CR and nCR93% of patients achieved a PR or better
MPT was generally well-tolerated
Conclusions (cont’d)
The most serious adverse events with this regimen were infection and DVT, suggesting the need for prophylaxis with antibiotics and anticoagulantsThe CR rate was similar to rates observed after high-dose chemotherapy followed by stem cell transplantation (42%)
Conclusions (cont’d)
MPT appears to be a promising regimen. However, a general recommendation for its adoption cannot be made until the following are determined:
Time to disease progressionOverall survival of these patientsPotential effectiveness of prophylactic antibiotics and anticoagulants
Current Status
New Trial in EuropeMPT versus MP
Plan to Register MPT As new standard of care
Frontline TherapyNew Issues
Response rate CR/PRLength of remission (TTP)/survival (EFS)Side effectsTime to harvest
WHAT’S NEXT?
Combinations
VELCADE + DOXIL (or ADRIA) + DEX
or
VELCADE + THALIDOMIDE (or REVIMID) + DEX
VELCADE + THALIDOMIDEExample of Response
PS 341 + THAL 100 mg + DEX
C y c l e s o f T r e a t m e n t (1 – 8)
11
22
44
33
M –
P r
o t
e I
n
g /
dL
0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
55
6677
88
Resistant to prior THALResistant to prior THAL
Role of Transplant
A single autotransplant is superior to standard chemotherapy aloneThe benefit in the setting of novel therapies is unknown.
Standard Dose Therapy
S9321 Survival in Context of IFM 90 & MRC VII Trials
Single Autotx
S9321
IFM90
MRC VII
S9321
IFM90
MRC VII
IFM 94 vs TT2
Overall Survival
TT1
TT2
IFM94 (2 Transplants)
IFM94 (1 Transplant)
2004 and Beyond
Conduct comparative trialsStem Cell transplant: 1 or 2?Novel Combinations
Select based on molecular data??
Response No Response
GEP Predicts Response to Velcade