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TKI-258 Clinical Trial After Lenalidomide/Dex. Sundar Jagannath, MD St. Vincent\'s Comprehensive Cancer Center New York, NY. Thalidomide/Dexamethasone (Thal/Dex) as Primary Induction Therapy. ECOG phase 3 clinical trial (EA100) 207 newly diagnosed MM patients Response rate: Thal/dex: 63%

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tki 258 clinical trial after lenalidomide dex

TKI-258 Clinical Trial After Lenalidomide/Dex

Sundar Jagannath, MDSt. Vincent\'s Comprehensive Cancer CenterNew York, NY

thalidomide dexamethasone thal dex as primary induction therapy
Thalidomide/Dexamethasone (Thal/Dex) as Primary Induction Therapy
  • ECOG phase 3 clinical trial (EA100)
    • 207 newly diagnosed MM patients
  • Response rate:
    • Thal/dex: 63%
    • Dex alone: 41%
    • p=0.0017

ECOG = Eastern Cooperative Oncology Group; MM = multiple myeloma;Thal = thalidomide 200 mg po qd; Dex = 40 mg po d1-4, 9-12,17-20

Rajkumar et al. J Clin Oncol. 2006;24(3):431-436.

thalidomide dexamethasone as primary induction therapy
Thalidomide/Dexamethasone as Primary Induction Therapy
  • Incidence of DVT:
    • Thal/dex: 17%
    • Dex alone: 3%
  • DVT prophylaxis not included in trial design
  • Thal/dex did not compromise successful harvest of stem cells

DVT = deep vein thrombosis

Rajkumar et al. J Clin Oncol. 2006;24(3):431-436.

thal dex as initial therapy time to progression ttp

1.0

0.8

0.6

0.4

0.2

0

6

12

18

24

30

Thal/Dex as Initial TherapyTime-to-Progression (TTP)

Thalidomide/dexamethasone Median TTP: not reached

Dexamethasone alone Median TTP: 8.1 months

Proportion of Patients

p<0.0001

Time-to-Progression (months)

Rajkumar et al. ASCO 2006, Abstract 7517.

high dose therapy with autologous stem cell transplant
High-dose Therapy WithAutologous Stem Cell Transplant
  • Treatment of choice for patients with refractory disease
  • Likelihood of long-term remission is low
patient has poor prognostic indicators
Patient Has Poor Prognostic Indicators
  • IgA isotype
  • del(13q)
  • t(4;14)

IgA = immunoglobulin A; del(13q) = deletion of the long arm of chromosome 13

treatment options for relapsed refractory disease
Treatment Options for Relapsed/Refractory Disease
  • Participation in a clinical trial
  • Allogeneic stem cell transplant
    • Morbidity/early mortality rates high
  • Combination therapy with bortezomib
    • Patient had relapsed after 8 cycles
  • Lenalidomide/dexamethasone is a viable option*

* Patients who have received at least one prior therapy

len dex vs dex alone phase 3 trial mm 009 response
Len/Dex vs Dex Alone Phase 3 Trial(MM-009): Response

59.4%*

Response Rate (%)

* p<0.001

21.1%*

Bladè Criteria

Weber et al. ASCO 2006, Abstract 7521.

mm 009 interim analysis time to progression

0

6

12

18

24

30

Time-to-Progression (months)

MM-009: Interim AnalysisTime-to-Progression

1.0

Len/Dex

Dex/Placebo

0.8

0.6

Med. 11.1 mo

Proportion of Patients

0.4

p<0.0001

0.2

Med. 4.7 mo

0.0

Weber et al. ASCO 2006, Abstract 7521.

mm 009 overall survival

0

6

12

18

24

30

Overall Survival (months)

MM-009: Overall Survival

1.0

LEN/DEX

Med OS 29.6 mo

0.8

0.6

Proportion of Patients

DEX/PLACEBO

0.4

p<0.0001

Med OS 20.2 mo

0.2

0.0

Weber et al. ASCO 2006, Abstract 7521.

len dex is more effective than dex placebo regardless of prior thalidomide
Len/Dex Is More Effective Than Dex/Placebo Regardless of Prior Thalidomide

TTP=Time-to-progression, OR=Overall Response, L=Lenalidomide, D=Dexamethasone

Wang et al. ASCO 2006, Abstract 7522.

len dex mm 009 common adverse events

Len/Dex Grade 1-2

Len/Dex Grade 3-4

Dex Gr 1-4

Len/Dex (MM-009): Common Adverse Events

Constipation

Diarrhea

Nausea

URI

Pneumonia

Neutropenia

Anemia

Thrombocytopenia

Fatigue

Hyperglycemia

DVT/PE

Per. Neuropathy

0

10

20

30

40

50

60

70

% Patients

Weber et al. ASCO 2006, Abstract 7521.

treatment recommendation
Treatment Recommendation
  • Lenalidomide/dexamethasone
  • Dosing schedule
    • Lenalidomide 25 mg, Days 1 to 21
    • High-dose dexamethasone (40 mg)*, Days 1 to 4, 9 to 12, and 17 to 20
    • Cycle repeated every 28 days

* After 4 cycles, dex schedule reduced to 40 mg on Days 1 to 4 per cycle.

treatment alternatives
Treatment Alternatives
  • Re-induction with DCEP
    • Likelihood of achieving a durable remission is low
  • Second autologous SCT
    • Meaningful remission unlikely
    • High potential morbidity
  • Enrollment in a clinical trial for FGFR3 inhibitor

DCEP = dexamethasone, cyclophosphamide, etoposide, and cisplatin SCT = stem cell transplant

phase 1 tki 258 chir 258 study
Phase 1 TKI-258 (CHIR-258) Study
  • TKI-258
    • Small-molecule inhibitor of FGFR3 and other receptor tyrosine kinases (RTKs)
  • FGFR3 is constitutively activated in patients with t(4;14)

FGFR3 = fibroblast growth factor receptor 3

Trudel et al. Blood. 2005;105(7):2941-2048; ClinicalTrials.gov, http://clinicaltrials.gov/ct/gui/show/NCT00243763?order=1?

fgfr3 in multiple myeloma
FGFR3 in Multiple Myeloma
  • Role of activated FGFR3 in myeloma:
    • Promotes proliferation and survival of myeloma cells
    • Subsequent acquisition of activating FGFR3 mutations is associated with progression to late-stage myeloma
    • Can impart chemoresistance
  • TKI-258 may be an appropriate choice

Trudel et al. Blood. 2005;105(7):2941-2048

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