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