Multiple Myeloma: Novel Agents Robert A. Kyle, M.D. Germany June ...

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Multiple Myeloma: Novel Agents Robert A. Kyle, M.D. Germany June ...

Multiple Myeloma: Novel Agents

Robert A. Kyle, M.D.

Germany

June 28, 2008

Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida


Multiple Myeloma Untreated

Initial Therapy

Transplant eligible


Multiple Myeloma Untreated

N = 470

Resp TTP DVT

CR/PR mos %

% (med)

Thal 50-200 mg/day +

Dex 40mg(day 1-4, 1

9-12, 9

17-20)

63 22.6 12

Placebo +

vs.

Dex 40mg (day 1-4, 1

9-12, 9

17-20)

46 6.5 2

Rajkumar et al., JCO 26:2171, 2008


Survival Rate

N

Survival Probability

One-Year

Two-Year

% %

Lenalidomide 25 mg d 1-211

+ 223 88 78

Dexamethasone 40 mg

d 1-4, 1

9-12, 9

17-20

vs.

Lenalidomide 25 mg d 1-211

+

Dexamethasone 40 mg

d 1, 8, 15, 22 222 96 88

Rajkumar, et al., ASCO 2008


Overall Survival (months)

Rd

RD

Rajkumar, et al., JCO 25:18S, 2007 (ASCO)


Multiple Myeloma

Untreated

N = 48

Response

Bortezomib 1.3 mg/M2 %

2/wk x 2 q3 wks CR/NCR 19

+

Dexamethasone 40 mg

Day of and day after Bortezomib PR 71

if no response

Total 90

Jagannath, et al., Blood 108: 238a, 2006


Multiple Myeloma Untreated

Initial therapy

Transplant ineligible

CP1123175-32


Multiple Myeloma

Untreated – age 65-75 years

IFM 99-06

N= 447

PFS

med mos

OS

med mos

MPT (400 mg) x 12 28 52

MP x 12 18 33

VAD/Mel 100x2 19 38

Facon, et al., Lancet, 2007 370:1209


Multiple Myeloma

Untreated – age > 75 years

IFM 01/01

N= 229

PFS

med mos

OS

med mos

MPT (100 mg)

d 1-4, 1

q. 6 weeks x 12 24.2 45.3

M 0.2 mg/kg + P 2 mg/kg 19 27.7

d 1-41

4 q. 6 weeks x 12

Hulin, et al., Blood 2007, 110:31a


San Miguel, et al, ASH 2007

Multiple Myeloma

Non-Transplant Candidates

Cycles 1-4

Bortezomib 1.3 mg/m2 IV d 1,4,8,11,22,25,29,32

+

Melphalan 9 mg/m2 and prednisone 60 mg/m2 d 1-4

Cycles 5-9

Bortezomib 1.3 mg/m2 IV d 1,8,22,29

+

Melphalan 9 mg/m2 and prednisone 60 mg/m2 d 1-4

vs.

Melphalan 9 mg/m2 and prednisone 60 mg/m2 d 1-4

Nine 6-week cycles of both arms


Multiple Myeloma

Response to Treatment

MPV

MP

N=336 N=331

p-value

M-protein*

M-protein* M

CR (IF-) 35% 5% (

90% ÄM-protein) 10% 5%

PR 46% 45%

*measured in serum or urine by centralized laboratory

San Miguel, et al., ASH 2007


Multiple Myeloma

Grade 3/4 adverse events (%)

VMP (n=340)

MP (n=337)

Gr 3 Gr 4 Gr 3 Gr 4

Neutropenia 30 10 23 15

Thrombocytopenia 20 17 16 14

Anemia 16 3 20 8

GI 19 1 5


Multiple Myeloma

Treatment

Relapsed, Refractory


Refractory Multiple Myeloma

Therapy

• Vcr Adria Dex (VAD)

• High-dose corticosteroids

Dexamethasone 40 mg

d 1 – 4, 9 – 12, 17 – 20 q mo

• Thalidomide

• Bortezomib (Velcade)

• Lenalidomide (Revlimid)


Single-Agent Thalidomide in

Recurrent/Refractory Multiple Myeloma

Dose

Pt

RR

Study

(mg/d)

(no.) (%)

Singhal, et al. 200-800

84 32*

Barlogie, et al. 200-800

169 30**

Grosbois 200-400

121 41

(incl minor

response)

* >25% Ä in paraprotein

** 2-yr event-free survival and overall survival rates of 20% and 48%, respectively

CP1123175-35


Refractory Multiple Myeloma

Treatment

Bortezomib (VELCADE TM ) (PS-341)

n = 193

Response (CR/PR) 35%

Duration response

12 mo

Richardson et al: NEJM 2003, 348:26.


Multiple Myeloma

Relapsed

Bortezomib, 1.3 mg/M 2

d 1, 4, 8, 11 q 3wks

vs.

N = 669

Dexamethasone, 40 mg

d 1-4; 1

9-12; 9

17-20

TTP

mos

Survival

med

mos

6.2 29.8

3.5 23.7

Richardson, et al., Blood, 2007, 110:3557


Multiple Myeloma

Relapsed/Refractory

Bortezomib, 1.3 mg/m 2 IV

d 1, 4, 8, 11

vs.

N = 646

Bortezomib, 1.3 mg/m 2 IV

d 1, 4, 8, 11

+

Doxil 30 mg/m 2 IV

d 4

Orlowski et al., JCO, 2007, 25:3892

TTP

Survival

mos

at 15 mos

med %

6.5 65

9.3 76


Lenalidomide

25 mg d1-21 +

Dexamethasone

40 mg d 1-4, 1

9-12, 9

17-20

vs.

Placebo d. 1-211

+

Dexamethasone

40 mg d 1-4, 1

9-12, 9

17-20

Multiple Myeloma

Relapsed/Refractory

009,010

N = 704

Response CR/PR

TTP

% Mos

(Med)

60.5 11.2

22 4.7

Weber, et al., NEJM, 2007, 357:2133; Dimopoulos, et al., NEJM, 2007, 2

357:2123


1.0

Multiple Myeloma 1971-1996

1996

n=2,981

Proportion surviving

0.8

0.6

0.4

0.2

0.0

Survival, med

29.9 mo

0 20 40 60 80 100 120 140

Kumar et al: Blood 111:2516, 2008

Survival, med

44.8 mo

Diagnosis during/

before 1996

Diagnosis after 1996

Time from diagnosis (months)

P


Proportion surviving

Relapse After Autologous Transplant

for Multiple Myeloma

1.0

0.8

0.6

0.4

0.2

0.0

n=161

Survival, med

30.9 mo

0 20 40 60 80 100

Kumar et al: Blood 111:2516, 2008

Exposed to new drugs

n=226

Survival, med

14.8 mo

No exposure to new drugs

n=387

P


Multiple Myeloma

Novel Agents

Histone deacetylase inhibitor

SAHA

Heat Shock protein- 90 inhibitor

KOS-953

Tanespimycin

VEGF Inhibitors

Farnesyl transferase inhibitor

Arsenic Trioxide

Proteosome inhibitor (oral)

FGFR3 inhibitor

P 38 MAPK inhibitor

PTK787/2K222584

SCH-66336

Trisenox

NPI-005

Chir-258

Scio-469

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