New Therapies For Multiple Myeloma - Abramson Cancer Center

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New Therapies For Multiple Myeloma - Abramson Cancer Center

New Therapies For Multiple Myeloma

Edward A. Stadtmauer, M.D.

Professor of Medicine

Abramson Cancer Center

University of Pennsylvania


Multiple Myeloma:

Disease Description

Etiology:

Multiple myeloma is a malignant proliferation of the plasma cells

− These cancerous cells destroy normal bone tissue causing pain and

compromising normal bone marrow function and release various cytokines

Clinical Features:

− Osteolytic lesions, bone pain, fractures, anemia, renal insufficiency,

hypercalcemia, and recurrent bacterial infections

− Characterized by a release of monoclonal immunoglobulin (M protein) from

the myeloma cells into the blood and urine

Epidemiology:

Multiple myeloma is the 2nd most common hematological malignancy (after

NHL) and is ultimately fatal (30% 5-year survival rate)

− U.S. incidence: approximately 19,000 new cases in 2007

− U.S. prevalence: approximately 50,000 patients

− Deaths: estimated 11,000 per year


Multiple Myeloma

Disease Progression

100

Asymptomatic

Symptomatic

M Protein (g/l)

50

20

MGUS* or

Smoldering

Myeloma

Active

Myeloma

Plateau

Remission

Relapse

Refractory

Relapse

Therapy

Therapy

Therapy

*Monoclonal

gammopathy

of uncertain

significance

~15,000

New cases

in U.S.

~45,000

Annual patients in the U.S. 3

~11,000

Annual

deaths in

U.S.

1. Adapted from International Myeloma Foundation; 2001. Reprinted with permission.

2. American Cancer Society. Cancer Facts & Figures; 2003. 3. Millennium Pharmaceuticals, Inc., 2003.


Upfront therapy: Current Paradigm

INDUCTION

Chemotherapy

Transplant

Non-Alkylating Agent

No Transplant

Alkylating Agent

• Induction chemotherapy choice depends on transplant status

• Transplant candidates induced with nonalkylating

agents

• Nontransplant candidates: alkylating agents

• Depth of response to induction therapy

• Not critical in transplant

• CR, PR, or SD acceptable

• Not critical for nontransplant

• Response unrelated to survival outcome


New Treatment Options

New Therapies

– Thalidomide, Lenalidomide and immune modulation

– Bortezomib and proteosome inhibition

– Immunotherapy with allogeneic stem cell

transplantation and vaccination

• Themes

– Since no therapy is curative, all options need to be

considered sequentially

– No good data on optimum sequence or regimen

– Cumulative toxicities from prior therapies may

influence decision

– All patients should be encouraged to participate in

ongoing clinical trials


Thalidomide in Multiple Myeloma:

Multiple Pathways, Multiple Targets

• Immunomodulatory

effects

– Inhibits TNFα

– Inhibits angiogenesis

(bFGP, VEGF)

– Stimulates T cells (CD8+)

– Inhibits IL-2

– Induces apoptosis

– Alters cytokines

– Affects stromal cells

Cool RM et al. Pharmacotherapy. 2002;22:1019; D’Amato RJ et al. Proc Natl Acad Sci USA.

1994;91:4082; Meierhofer C et al. BioDrugs. 2001;15:681; Thalidomide’s various effects in myeloma

[figure]. Available at: http://www.multiplemyeloma.org/treatments/3.04.asp; Weber D et al. J Clin Oncol.

2003;21:16; Bartlett JB et al. Nature Reviews/Cancer. 2004;4:314


Thalidomide/Dexamethasone vs Dexamethasone

in Newly Diagnosed MM

Phase III ECOG E1A00 Study Design

Newly

diagnosed MM

(n=207)

R

A

N

D

O

M

I

Z

A

T

I

O

N

Thalidomide, 200 mg/day orally

Dexamethasone, 40 mg/day*

days 1–4, 9–12, and 17–20

(n=103)

× 4 cycles

Dexamethasone alone,

40 mg/day*

days 1–4, 9–12, and 17–20

(n=104)

CR/PR/

stable

Any

progression

Stop therapy at mo 4 for

SCT or continue at

physician’s discretion

Stop therapy

*Administered as 4-wk cycle

All patients received monthly pamidronate or zoledronic acid

No DVT prophylaxis

Rajkumar SV et al. J Clin Oncol. 2006;24:431


Thalidomide/Dexamethasone vs Dexamethasone:

Best Response Within 4 Cycles

Endpoint

Thal/Dex

(n=99)

Dex

(n=100)

Response rate, %* 63 41

Adjusted response rate, % † 72 50

CR, % 4 0

Median time to response (range), mo 1.1 (0.7–4.1) 1.1 (0.7–2.9)

Disease progression within first 4 mo, % 2 5

P=0.0017

*Based on ITT, ≥50% reduction in serum and urine M protein, or ≥90% reduction in urine M

protein if only urinary protein was evaluable for response


Allowing for use of serum M protein when a measurable urine M protein was unavailable at

follow-up

Rajkumar SV et al. J Clin Oncol. 2006;24:431


Thal/Dex vs Dex in Newly Diagnosed MM (MM-003):

TTP and OS

Time to Progression (ITT)

Overall Survival (ITT)

Proportion of Subjects With No Progression

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

P


Thalidomide/Dexamethasone vs Dexamethasone:

Specifically Monitored AEs

AE

Thal/Dex, n (%)

(n=102)

Dex, n (%)

(n=102)

P Value

DVT ≥ grade 3 17 (17) 3 (3)


Thal/Dex vs VAD as Induction Treatment

in Newly Diagnosed MM

n=204

Untreated MM

Age


Thalidomide/Dexamethasone vs Dexamethasone:

Conclusions

• Superior response rates with Thal/Dex

compared with Dex alone in newly diagnosed

MM

• Both arms as good if not better than VAD/DVD

• Thal/Dex associated with higher toxicities than

Dex

– Need for DVT prophylaxis with Thal/Dex

• Higher response rates of Thal/Dex must be

weighed against increased toxicity for

individual patients

Rajkumar SV et al. Blood. 2004;104(part 1):63a [abstract 205]


Lenalidomide: Pharmacologic Evolution

O

N

O

H

N

O

O

N

O

H

N

O

O

Thalidomide

NH 2

Lenalidomide

• More “potent” immunomodulator than

thalidomide

Bartlett JB et al. Nat Rev Cancer. 2004;4:314

Stirling D. Semin Oncol. 2001;28:602

– Up to 50,000 times more potent inhibitor of TNFα

– Increased stimulation of T-cell T

proliferation

– Augmented stimulation of IL-2 2 and IFNγ production


© 2008 OptumHealth Education

Phase III ECOG E4A03 Trial of Lenalidomide Plus Either

High- or Low-Dose Dexamethasone

R

A

N

D

O

M

I

Z

E

RD

Lenalidomide

Dexamethasone

× 4 cycles

Rd

Lenalidomide

Low-dose

dexamethasone

× 4 cycles

CR/PR

< PR

Patients can go

off study and

have SCT

CR/PR/SD

Thalidomide

Dexamethasone

× 4 cycles

Primary analysis: response rate and safety within 4 cycles

Presented at ASH 2007 (Abstract 74)

Landmark analysis (at 4 months): Patients who received SCT

after 4 cycles vs. patients who continued Rd beyond 4 cycles

Lenalidomide 25 mg/day p.o. on days 1-21 of

a 28-day cycle

Dexamethasone 480 mg/cycle p.o. (regular

dose) or 160 mg/cycle (low dose)

Rajkumar et al, ASCO 2008, Abstract 8504


ECOG E4A03: Efficacy

• Primary endpoint: response at 4 months

RD

(n = 196)

Rd

(n = 190)

2P Value

Response Within 4 Cycles

≥ Partial response rate

80%

67%

.004

CR + VGPR rate

44%

26%

< .001

Best Overall Response

≥ Partial response rate

82%

71%

.01

CR/VGPR rate

52%

42%

.06

Survival Probability

12 month

0.88

0.96

.003

24 month

0.75

0.87

.009

Rajkumar et al, Abstract 74, ASH 2007


ECOG E4A03: Grade ≥ 3 Advers Events

RD

(n = 222)

Rd

(n = 219)

P Value

Hematologic

Neutropenia

11.7%

18.7%

.047

Thrombocytopenia

5.4%

5.5%

1.000

Anemia

8.1%

6.8%

.718

Nonhematologic

DVT/PE

Infections

Fatigue

Hyperglycemia

Cardiac Ischemia

25%

14%

13%

11%

3%

9%

7%

10%

6%

0.5%

< .001

< .030

.294

.126

.068

Early Deaths* 5% 0.5% .01

* < 4 months in all patients

Rajkumar et al, Abstract 74, ASH 2007


E4A03: Causes of Death

Median Follow up 21 mos

LD (N=46), n Ld (N=25), n

Progressive Disease 26 17

Thromboembolic 5 1

Infection 4 3

Cardiac 6 2

Stroke 1 1

Respiratory Failure 1 0

Second Cancer 1 0

Unknown 2 1

L=Lenalidomide; D=Standard-dose dexamethasone; d=Low-dose dexamethasone

Rajkumar SV et al. Presented at: 49 th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA

© 2007 i3 cme


431 patients alive after 4 cycles:

•176 off therapy at 4 cycles:

•85 to SCT

•91 no SCT

•255 had primary therapy beyond 4 cycles:

•142 Rd

•113 RD

Response to Primary Therapy Beyond 4 Cycles

Rd

(n = 142)

ORR 89%

DOR

CR (immunofixative negative) 22%

CR + VGPR 56%

25 months

2-Year OS 93%

© 2008 OptumHealth Education

ECOG E4A03 Landmark Analysis: Survival

Following Primary Therapy

Rajkumar et al, ASCO 2008, Abstract 8504


© 2008 OptumHealth Education

Phase III SWOG S0232 Trial of High-Dose Dexamethasone

± Lenalidomide in Newly Diagnosed MM

R

A

N

D

O

M

I

Z

E

(n = 198)

Induction Therapy

(3 35-day courses)

Lenalidomide 25 mg/day × 28 days

Dexamethasone 40 mg, days 1-4,

9-12, 17-20

PD

Crossover

Placebo 25 mg/day × 28 days

Dexamethasone 40 mg, days 1-4,

9-12, 17-20

Stratify by:

• PS 0/1 vs. 2/3

• ISS Stage I vs. II vs. III

Maintenance Therapy

(q 28 days until PD)

Lenalidomide 25 mg/day × 21 days

Dexamethasone 40 mg, days 1-4, 14-

18

Placebo 25 mg/day × 21 days

Dexamethasone 40 mg, days 1-

4, 14-18

Protocol closed after early interim

analysis by DSMC

Zonder et al. ASCO 2008, Abstract 8521


© 2008 OptumHealth Education

High-Dose Dexamethasone ± Lenalidomide:

Efficacy

Lenalidomide/

Dexamethason

e

(n = 73)

Dexamethasone

(n = 84)

Crossover

(n = 44)

ORR 75% 48% 69%

CR + VGPR 62% 19% 36%

CR 15% 2% 8%

VGPR 47% 17% 28%

PR 14% 29% 33%

1-Year PFS* 77% 55% 62%

1-Year OS 93% 91% 72%

* P = .002

Zonder et al, ASCO 2008, Abstract 8521


© 2008 OptumHealth Education

High-Dose Dexamethasone ± Lenalidomide:

Toxicity

Len/Dex Dex

Grade 3/4 Hematologic Adverse Events

Neutropenia* 13.8% 2.4%

Anemia 8.3% 9.8%

Thrombocytopenia 4.2% 2.4%

All-Grade Infections † 51.4% 28%

Grade 3/5 18.9% 9.8%

All-Grade Thrombosis 27.0% 14.6%

* P = .010


P = .003

Zonder et al. ASCO 2008, Abstract 8521


2 Phase III Trials of Lenalidomide/Dex in

Relapsed or Refractory MM

North American MM-009 (48 Centers USA/Canada): Weber

International MM-010 (51 Centers Europe/Australia/Israel): Dimopoulos

Inclusion criteria

≤3 3 prior therapies

No Dex resistance

Normal liver/renal

function

Lenalidomide 25 mg days 1–21

Placebo days 22–28

Dex 40 mg, days 1–4, 9–12, 17–20

× 4 COURSES

Placebo days 1–28

Dex 40 mg, days 1–4, 9–12, 17–20

Continue

until PD

Same, except

Dex days 1–4

Primary endpoint: TTP (by Bladé criteria)

Secondary endpoints: OS, RR, safety, first skeletal-related event, PS

Additional stratification by β 2 M (≤2.5(

mg/dL vs >2.5 mg/dL), prior transplant

(0 vs >1), and prior MM treatment regimens (1)

Dimopoulos MA et al. Blood. 2005;106:6a [abstract 6]

Weber DM et al. J Clin Oncol. 2006;24 (Suppl 18S):427s [abstract 7521]

© 2006 i3 dln


Phase III Trials of Lenalidomide/Dex in Relapsed

or Refractory MM: EBMT Response Data

80

PR + CR PR (>50%) CR (IF–)

80

Response Rate, %

60

40

20

0

61.2*

34.7

Len/Dex

(n=170)

22.8*

26.5 18.7

Dex

(n=171)

4.1

Response Rate, %

60

40

20

0

*P


Response Rate, %

MM-009/MM

009/MM-010: 010: EBMT Response With Prior

Thalidomide Therapy

80

Prior Thal

60 53*

40

20

0

45

8

Len/Dex

(n=124)

15*

14

Dex

(n=145)

1%

Response Rate, %

80

60

40

20

0

Prior Thal

No Prior Thal

63*

45

18

Len/Dex

(n=222)

28*

25

Dex

(n=201)

3%

PR + CR

PR (>50%)

CR (IF–)

*P


Lenalidomide/Dex is Effective in Patients

Who Progressed on Thalidomide

• Median Time from Diagnosis: 4 yrs vs. 3 yrs for Thalidomide Naive

• Median Lines of Prior Therapy: 3 lines vs. 2 lines for Thalidomide Naive

n

Overall

Response Rate

TTP

(months)

Thalomid

Exposure

Thalomid

Progression*

127 54% 8.4

54 43% 7.0

* Progressed while on thalidomide therapy

Wang M, et al. Blood. 2006;108: Abstract 3553


Bortezomib (PS 341; Velcade ® )

• Mechanism of action

– Reversible inhibitor

of chymotrypsin-like

activity of 26S

proteasome

– Inhibition of proteasome

approximately 72 hrs

prevents proteolysis of

ubiquitinated proteins

– This disrupts

homeostasis and can

lead to apoptosis

Velcade (bortezomib): prescribing information, 2004


Bortezomib/Dexamethasone Versus VAD

as Induction Therapy in MM

28-day cycle

R

A

N

D

O

M

I

Z

E

VAD × 4

VAD × 4 DCEP × 2

21-day cycle

Bz-Dex

× 4

Bz-Dex

× 4

28-day cycle

DCEP × 2

Melphalan

200 mg/m 2

+ ASCT

If < VGPR

second

ASCT/RIC

allocation

VAD: vincristine 0.4 mg/m 2 , doxorubicin 9 mg/m 2 , dexamethasone 40 mg

DCEP: dexamethasone 40 mg, days 1-4; cyclophosphamide 15 mg/m 2 ; etoposide 400 mg/m 2 ,

cisplatin 10 mg/m 2

Bz-Dex: bortezomib 1.3 mg/m 2 , dexamethasone 40 mg

Harousseau et al, Abstract 450, ASH 2007


© 2008 OptumHealth Education

IFM 2005/01 - Efficacy

Response to induction

VAD

N = 219

Bortezomib/Dex

N = 223

P-value

CR + nCR 8% 19% .0004

≥ VGPR 19% 47% < .0001

Response to first ASCT

CR + nCR 23% 35% .0063

≥ VGPR 44% 63% < .0001

Overall survival (OS)* .45

1-year 92% 95% _

Progression-free survival (PFS) .38

1-year 87.5% 91%

* Median Follow-up – 18 months

•β2 µglobulin level and presence of chr 13 abnormalities had significantly higher impact on

treatment outcomes with bortezomib/dex compared to VAD

•DCEP consolidation did not significantly improve outcomes among evaluable patients

Harosseau et al, Abstract 8505, ASCO 2008


© 2008 OptumHealth Education

IFM 2005/01 – Adverse Events

Any adverse event during induction,

%*

Hematologic adverse events

VAD

N = 239

Bortezomib/Dex

N = 239

91% 97%

Grade 3/4 Anemia 9% 4%

Grade 3/4 Neutropenia 10% 5%

Grades 1-4 Herpes zoster 2% 9%

Grade 3/4 Infection 12% 9%

Non-hematologic adverse events

Grade 2 peripheral neuropathy 8% 18%

Grade 3 peripheral neuropathy 2% 7%

* P = .01

Harosseau et al, Abstract 8505, ASCO 2008


© 2008 OptumHealth Education

Bortezomib/Thal/Dex vs Thal/Dex as Induction

Therapy in Newly Diagnosed MM

Randomized, multicenter phase III GIMENA trial

Bortezomib 1.3 mg/m 2 d1, 4, 8, 11

Newly

diagnosed,

untreated MM

(N=256)

Thalidomide 200 mg/d

Dexamethasone 40 mg/d d1–2, 4– 4

5, 8–9, 8

11–12

12

(n=129)

Three 21-day cycles

Thalidomide 200 mg/d

PBSC harvest

ASCT X2 with

MEL200

Bortezomib/Thalidomide

/Dexamethasone

Dexamethasone 40 mg/d d1–4,

8–12

each cycle

Thalidomide

/Dexamethasone

(n=127)

Patients randomized to LMWH (40 mg/d), ASA (100 mg/d) or warfarin (1.25 mg/d)

1 o Endpoint: CR/nCR rate after induction; 2 o Endpoints: CR/nCR rate after

consolidation; safety; TTP; EFS; OS; CD34+ cell yield

Cavo M et al. Presented at: 49 th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA


© 2008 OptumHealth Education

Bortezomib/Thal/Dex vs Thal/Dex as Induction

Therapy MM: Efficacy/Safety

Characteristic

Bortezomib/ThallDex

(n =129)

Thal/Dex

(n=127)

P Value

CR+nCR, % 36 9


Phase I/II Trial of Frontline Bortezomib/

Lenalidomide/Dexamethasone in MM

© 2008 OptumHealth Education

Study design:

•Bortezomib 1.0-1.3 mg/m 2 days 1, 4, 8, 11

•Lenalidomide 15-25 mg/day days 1-14

•Dexamethasone 40 mg/day (days 1, 2, 4, 5, 8, 9, 11, 12); 20 mg/day (cycles 5-8)

•Amended to 20 mg/10 mg cycles 1-4/5-8 based on safety data

•Up to 8 21-day cycles

Grade 3/4 Adverse

Events

Bortezomib/Lenalidomide/

Dexamethasone

Lymphopenia 12

Neutropenia 5

Thrombocytopenia 4

Hypophosphatemia

(Grade 3)

Neuropathic Pain

(Grade 3)

5

3

•No Grade ≥ 4 peripheral

neuropathy reported

•Grade 1/2 DVT/PE

reported in 5% of the

patients

Richardson et al, ASCO 2008, Abstract 8520


Phase I/II Trial of Frontline Bortezomib/

Lenalidomide/Dexamethasone in MM

© 2008 OptumHealth Education

Best Response

Bortezomib/Lenalidomide/Dexameth

asone

(n = 66)

ORR 98%

CR 17 (26%)

nCR 7 (11%)

VGPR 23 (35%)

PR 18 (27%)

CR/nCR + VGPR 71%

CR/nCR 36%

Median TTP, PFS, OS

Median Stem Cell Collection

Not reached

5.67 x 10 6 CD34+ cells

Richardson et al, ASCO 2008, Abstract 8520


© 2008 OptumHealth Education

IFM 01-01: MP vs MPT in Newly Diagnosed

MM Patients Aged >75 Years

IFM 01-01 Trial Design

Newly diagnosed MM

patients aged >75 yr*

(N=229)

Melphalan (M) 0.2 mg/kg/day, d1-4

Prednisone (P) 2 mg/kg/day, d1–4

Thalidomide (T) 100 mg/day †

(n=113)

Twelve 6-wk cycles

MP + Placebo

(n=116)

*All patients received clondronate


Administered continuously for 18 mo

Primary endpoint:

overall survival

Hulin C et al. Presented at: 49 th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA


MP vs MPT in Newly Diagnosed

MM Patients Aged >75 Years: PFS and OS

© 2008 OptumHealth Education

Survival Distribution Function

1.00

0.75

0.50

0.25

0.00

Median PFS

P=0.001*

MPT (n=113)

Median 24.1 mo

MP (n=116)

Median 19 mo

Survival Distribution Function

1.00

0.75

0.50

0.25

0.00

P=0.033*

Median OS

MPT (n=113)

Median 45.3 mo

MP (n=116)

Median 27.7 mo

0 10 20 30 40 50 60

Time From Randomization (mo)

0 10 20 30 40 50 60

Time From Randomization (mo)

*Log-rank test

Response MPT (n = 113) MP (n = 116)

CR, % 7 1

≥PR, % 61 31

Hulin C et al. Presented at: 49th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA


MP vs MPT in Newly Diagnosed

MM Patients Aged >75 Years: AEs

© 2008 OptumHealth Education

Adverse Event MPT (n = 113) MP (n = 116)

Any peripheral neuropathy 39 22

Grade 3 PN 2 2

Neutropenia (Grade 3/4) 23 9

• Toxicity more common with MPT vs MP: peripheral neuropathy (P =

.003), neutropenia (P=0.003)

• Significantly fewer deaths with MPT vs MP (41 vs 59; P=0.01)

– Proportion of deaths from myeloma progression: 61% vs 69%

– Proportion of deaths from toxicity: 36% vs 29%

Hulin C et al. Presented at: 49th ASH Annual Meeting; December 8–11, 2007; Atlanta, GA


Multiple Myeloma

VMP vs MP in Newly Diagnosed MM

(MMY-3002; VISTA)

54 weeks

Patients 65

years of age or

older or not

transplant

eligible with

untreated MM

(N = 682)

Bortezomib IV 1.3 mg/m 2

on Days 1, 4, 8, 11, 22,

25, 29, 32 for four 6-week

cycles +

Melphalan and

Prednisone*

(n = 344)

Bortezomib IV 1.3 mg/m 2 on

Days 1, 8, 22, 29 for

five 6-week cycles +

Melphalan and Prednisone*

(n = 344)

Melphalan and Prednisone*

for nine 6-wk cycles

(n = 338)

*Melphalan PO 9 mg/m 2 once daily and prednisone 60 mg/m 2

on Days 1-4 each cycle.

San Miguel JF, et al. ASH 2007. Abstract 76.

clinicaloptions.com/oncology


© 2008 OptumHealth Education

Bortezomib/Melphalan/Prednisone

in Newly Diagnosed MM – Adverse Events

Grade 3/4

VMP, %

(n=340)

MP, %

(n=337)

Neutropenia 40 38

Thrombocytopenia 37 30

Anemia 19 28

Gastrointestinal events 20 5-6

Peripheral neuropathy 13-14

14 0

Fatigue 8 2

Asthenia 6-7 3

Pneumonia 7 5

Herpes Zoster 3 2

San Miguel, JF et al. Presented at: 49th ASH Annual Meeting; December 8-11, 2007; Atlanta, GA


Multiple Myeloma

VMP vs MP in Newly Diagnosed MM (MMY-

3002; VISTA): Response to Treatment

• Responses with VMP

rapid and durable

– Time to response,

all responders:

1.4 vs 4.2 mos

(P < 10 -10 )

– Response duration in

patients with CR:

24.0 vs 12.8 mos

Response to Treatment (%)

100

80

60

40

20

0

P < .000001

82

50

ORR

(CR + PR)

P < .000001

46 45

35

5

CR (IF-)

PR

VMP (n = 336)

MP (n = 331)

10

5

VGPR

San Miguel JF, et al. ASH 2007. Abstract 76.

clinicaloptions.com/oncology


Multiple Myeloma

VMP vs MP (MMY-3002; VISTA):

Time to Progression

Precentage of subjects

w/o event (%)

100

90

80

70

60

50

40

30

20

10

0

VMP: 24.0 months (83 events)

MP: 16.6 months (146 events)

HR = 0.483, P < .000001

0 3 6 9 12 15 18 21 24 27

Time (months)

VMP

MP

San Miguel JF, et al. ASH 2007. Abstract 76.

clinicaloptions.com/oncology


Multiple Myeloma

VMP vs MP (MMY-3002; VISTA):

Overall Survival

Precentage of subjects

w/o event (%)

100

90

80

70

60

50

40

30

20

10

0

Median follow-up 16.3 months

VMP: not reached (45 deaths)

MP: not reached (76 deaths)

HR = 0.607, P = .0078

• OS at 2 years: 82.6% in VMP vs 69.5% in MP

– In pts < 75 years, 84% in VMP vs 74% in MP

– In pts ≥75 years, 79% in VMP vs 60% in MP

0 3 6 9 12 15 18 21 24 27

Time (months)

• Treatment related deaths on each arm: VMP 1%; MP 2%

VMP

MP

30

San Miguel JF, et al. ASH 2007. Abstract 76.

clinicaloptions.com/oncology


Multiple Myeloma

VMP vs MP (MMY-3002; VISTA):

Time to Next Treatment

Time on therapy

Treatment-free interval

Next Therapy

Precentage of subjects

w/o event (%)

100

90

80

70

60

50

40

30

20

10

0

VMP: not reached (73 events)

MP: 20.8 months (127 events)

HR = 0.522, P = .000009

Time to next therapy

VMP

MP

0 3 6 9 12 15 18 21 24 27

Time (months)

• TNT not reached for VMP vs

20.8m for MP (P =.000009)

– Patients on VMP 48% less likely

to start second-line therapy

For VMP vs MP patients, 35% vs

57% at 2-years started secondline

therapy

• TFI not reached for VMP, vs

9.4m for MP (P = .0001)

San Miguel JF, et al. ASH 2007. Abstract 76.

clinicaloptions.com/oncology


Multiple Myeloma

VMP vs MP in Newly Diagnosed MM

(MMY-3002; VISTA): More Results

• ~ 52% reduction in risk of progression

• ~ 40% reduction in risk of death

– At 16.3-week median follow-up, median OS not reached

– VMP: 45 deaths; MP: 76 deaths; HR: 0.607; P = .0078

• No impact on efficacy: age, creatinine clearance,

cytogenetics (FISH)

• VMP patients 48% less likely to start a second-line therapy

• Serious AEs: 46% for VMP; 36% for MP

– 1% DVT in both arms

San Miguel JF, et al. ASH 2007. Abstract 76.

clinicaloptions.com/oncology


Summary Of Initial Therapy for Myeloma

• Vel/Dex/ Thal/Dex superior to VAD/DVD

• Lenalidomide/Dex may be more active than

Thal/Dex

– Less toxic

– Need DVT prophylaxis

• VMP/ MPT superior to MP in older

– MP-R R under investigation

• Velcade combinations promising

– VTD, VRD, PAD, CBD

– Doxil/Velcade

• Continue to participate in comparative trials

– E1A05 MPT vs MPR, E1A06 VRD vs VD


Alternative mechanism for

the destruction of

ubiquitinated proteins

(bortezomib resistance)

Hydroxychloroquine

Hydroxychloroquine

(alters acid/base of

lysosomes)

Histone deacetylace inhibition

Figure : Relationship between the proteasome and aggresome/autophagy

pathways for disposal of ubiquitinated proteins. Adapted from Hideshima,

Clin Cancer Res 2005;11:8530-3.


Indications for Hematopoietic Stem Cell

Transplantation in the U.S.

5,500

5,000

4,500

Allogeneic (Total N~8,150)

Autologous (Total N~11,500)

4,000

Transplants

3,500

3,000

2,500

2,000

1,500

1,000

500

0

Multiple

My eloma

NHL AML Hodgkin

Disease

ALL MDS/MPD CML Aplastic

Anemia

Other Leuk

Other

Cancer

Non-Malig

Disease


Comparison of Conventional vs. High Dose

Therapy

For newly diagnosed myeloma

Patients

(n)

CR

(%)

EFS

(median, mo)

OS

(median, mo)

Attal, 1996

Barlogie, 2006

Conv

HDT

Conv

HDT

100

100

255

261

5

22

--

--

18

27

14% at 7 yrs

17% at 7 yrs

37

52

38% at 7 yrs

38% at 7 yrs

Fermand, 1998

Conv

HDT

91

94

--

--

13

39

24

64.6

Bladé, 2005

Child, 2003

Conv

HDT

Conv

HDT

83

81

200

201

11

30

8.5

44

33

42

19.6

31.6

66

61

42.3

54.1

Attal M et al. N Engl J Med. 1996;33

Barlogie, et al. J. Clin Oncol 2006, 24(6), 929-936

Fermand J et al. Blood. 1998;92:3131

Bladé J Blood. 2005;106:3755-3759

Child JA et al. N Engl J Med. 2003;348:1875


Transplant versus Conventional Chemotherapy

54

42

Attal M. N Engl J Med 1996; 335:97; Child J. N Engl J Med 2003; 348:1875


Tandem transplant Improves Response in

Patients with


Allogeneic Bone Marrow Transplantation

• High dose chemotherapy + XRT :

–Anti-tumor effects, immunosuppression, myeloablation

• Replace with normal donor hematopoietic cells.

• Get a graft versus tumor immune beneficial effect

• Get a graft vs host (skin, gut, liver) detrimental effect

Cond

Rx

Allo

BMT

T

T

T

Recipient Blood

And Leukemia

Donor

Blood Cells


Historical Results with Myeloablative

Transplantation

Patients

TRM

CR

OS

EFS

(n)

(%)

(%)

(actuarial, mos)

(acturial, mos)

Gahrton, et al 162 41 44 28% at 84 45% at 60

Bensinger et al 80 44 36 20% at 54 24% at 54

Because of high TRM, not used much in MM Rx

Gahrton G. Brit J Hematol 2001;113:209, Bensinger W. Sem Hematol 2001;38:243


Non-myeloablative (Mini) Allogeneic

Transplantation following Autologous Stem

Cell Transplantation

Conditioning

N

TRM at

one year

Response

(%)

Acute

grade

II-IV

GVHD

Chronic

extensive

GVHD

PFS/EFS/

DFS

OS

Lee

et al

Mel or

Mel/TBI/Flu

45

36%

CR 64

36%

36%

3 year EFS

13%

Median

14 mos

Kroger

et al

PBSCT +

Mel/Flu/ATG

17

18%

CR 73

PR 20

38%

7%

2 year DFS

56%

2 year

74%

Maloney

et al

PBSCT +

TBI/MMF/cyc

54

7%

CR 57

PR 26

39%

46%

2 year PFS

55%

78%

at 18 mos

Giralt

et al

Mel/Flu

13

38%

CR 54

38%

15%

Lee Exp Hematol 2003;31:73, Kroger N. Blood 2002;100:755

Maloney D. Blood 2003; 102:3447-3454 Giralt S. Proc Am Soc Clin Onc 1999;18:6a


BMT CTN #0102

MM Meeting Eligiblity

Mel 200 Autograft

Recovered at least

60 days post autograft

HLA-matched Sibling

200cGy TBI Allograft

CSA + MMF

No HLA-matched Sibling

Mel 200 Autograft

Observation Thalidomide +

Decadron for 1 yr


Estimates of Cumulative Incidence Rates

Bruno B et al. N Engl J Med 2007;356:1110-1120


Kaplan-Meier Estimates of Overall and Event-free Survival from Time of Diagnosis

Bruno B et al. N Engl J Med 2007;356:1110-1120


Activated Autologous T-cell Infusion as Post

Transplant Immunotherapy in Myeloma

• Hypothesis

– T-Cells are the anti-myeloma cells of our immune

system

– T-cell have defective function in myeloma

patients

– Activation of T-cells will lead to an anti-myeloma

effect and restore anti-infectious immunity

– Activation of autologous T-cells will be

associated less toxicity than donor T-cells


Anti-CD3/CD28 Culture System

Artificial DC: Bead

Anti-CD3

Anti-CD28

TcR/CD4

Signal 1

CD28 CTLA4

+

Science 1996; 272:1939

Growth


Results: 54 patients with MM treated

• Combination immunotherapy

consisting of a single early posttransplant

infusion of in vivo

vaccine primed and ex vivo

costimulated autologous T cells

followed by post-transplant booster

immunizations improved the severe

immunodeficiency associated with

high-dose chemotherapy and led to

the induction of clinically relevant

immunity (pneumococcal IgG) in

adults within a month after

transplantation.

• Accelerated restoration of CD4 T-

cell numbers and function,

significantly improved T-cell

proliferation.


Follow-on on Study to assess influenza immunity as

well as anti-myeloma vaccination (hTERT(

hTERT)

Patients (A2+) will receive infused T-cells that are primed not only with the pneumoccocal and

influenza vaccines, but with a myeloma vaccine consisting of peptides from telomerase and survivin

(hTERT vaccine). At days +14, +42, and +90,patients will receive the appropriate set of booster

immunizations. The hypothesis is that autologous T cell therapy can augment the potency of the

hTERT vaccine, and lead to a myeloma-directed T-cell mediated “graft vs. myeloma” effect in patients

with advance myeloma. The hope is that this combination therapy approach will result in a more rapid

recovery of acquired immunity and consequently increased cure rates and better clinical outcomes.


Multiple Myeloma

Disease Progression

100

Asymptomatic

Symptomatic

M Protein (g/l)

50

20

MGUS* or

Smoldering

Myeloma

Active

Myeloma

Plateau

Remission

Relapse

Refractory

Relapse

Therapy

Therapy

Therapy

*Monoclonal

gammopathy

of uncertain

significance

~15,000

New cases

in U.S.

~45,000

Annual patients in the U.S. 3

~11,000

Annual

deaths in

U.S.

1. Adapted from International Myeloma Foundation; 2001. Reprinted with permission.

2. American Cancer Society. Cancer Facts & Figures; 2003. 3. Millennium Pharmaceuticals, Inc., 2003.


Novel Therapies Targeting the Myeloma Cell

In Its Bone Marrow Microenvironment

(Active Trials, Not Ready for Prime Time)

Targeting MM cell

Telomestatin,17AAG

(heat shock protein), Statin,

IGF1R inhibitor, prolixin

Epothilone B, Farnesyltransferase

Inhibitor, Genasense, TRAIL,

Rituximab, CD40 MoAb, CD74 MoAb

Targeting MM cell and BM

microenvironment

Thalidomide/Lenalidomide

Carfilozomib (PR171), HDACs

PS341, PTK787,Velcade/

plaquenil, SAHA/LAQ824

2ME, LPAAT inhibitor

Atiprimod, VEGF inhibitors

Targeting BM

microenvironment

PS-1145/242 IKK inhibitor,

VX-745, P38MAPK inhibitor

MM cells

Stromal cells


The Future

• Continue to improve initial therapy

– Rev/Dex vs Bortezomib/Dex vs multi-agent regimens

– Continue to consider need for SCT

– MPT vs MPV vs other agents for older patients

• Continue to improve SCT

– Improve stem cell collection

– Need for double transplant

– Improve high-dose regimen

– Non-myeloablative Allogeneic SCT

• Continue to improve maintenance/consolidation

therapy

– Thal vs Rev vs Bortezomib vs immunotherapy

• Continue to improve salvage therapy

– Bortezomib vs Rev/Dex vs new agents vs combinations


Clinical Faculty and Staff of

Penn’s Heme Malignancy and Bone Marrow and Stem

Cell Transplant Program

BMT and Hematologic-Malignancy

Physicians

Edward Stadtmauer, MD

Selina Luger, MD

David Porter, MD

Stephen Schuster, MD

Donald Tsai, MD, PhD

Sunita Nasta, MD

Alexander Perl, MD

Alison Wakoff Loren, MD

Rebecca Elstrom, MD

Steven Goldstein, MD

Hematology-Oncology Physicians

Stephen Emerson, MD, PhD

Alan Gewirtz, MD

James Hoxie, MD

Martin Carroll, MD

Mary Ellen Martin, MD

Lynn Schuchter, MD

Radiation Oncology

Eli Glatstein, MD

Heather Jones, MD

Penn Tower 15 Clinic Staff

Chemo nurses

Nursing assistants

office staff

Laboratory staff

Blood Bank/HPC Collection Center

(Apheresis)

Donald Siegel, MD, PhD

Una O’Doherty, MD, PhD

Bruce Sachais, MD, PhD

Deborah Magee, MT (ASCP), SBB

Robert Sachs, MT

Mark Wall, MT

Gene Deleo, MT

Apheresis nurses

Advanced Practice Nurses

Patricia Mangan, MSN, CRNP

Lisa Downs, MSN, CRNP

Tammie Ball, RN, MSN

Julie Phillips, MSN, CRNP

Jacqueline Smith, MSN, CRNP

Nicole Stout, MSN, CRNP

Victoria Sherry, MSN, CRNP

Brenda Shelly, MSN, CRNP

Susan Stonehouse Lee, MSN,

CRNP

Lynn Reilly, MSN, CRNP

Heather DiFilippo, MSN, CRNP

Rahat Sayed, MSN, CRNP

Quan Thai, MSN, CRNP

Susan Rabatin, MSN, CRNP

BMT Outpatient Nurse

Patient and Family Services

Michele Renz, RN, BSN

Mindy Weismer, MFT

NMDP Coordinator

Jill Harrington-LaMorie,

Anita McAlee, RN, BSN MSW, CSW

IBMTR/ABMTR Coordinator BMT Secretary

Kim Hummel

Andrea Matthews

Administrator

BMT Administrative Assistants

Elda Ford, RN, MS

Barbette Jackson

Quality Management Coordinator Marie DiSanto

Iris Maldonado

Kathleen Cunningham, RN,

BSN

Toby Laiken

Inpatient Nurses

Dorothea Smith

Amy Avellino, RN, BSN Mary Kay Hamberger

Staff of Rhoads 7

Schante Frazier

Mauri Sullivan, RN, MSN Clinical Research Staff

Staff of Rhoads 6

Joanne Hinkle, RN, BSN

Social Work

Cheryl Sickles, CCRC

Carolyn Cristofalo, MSW Joan Waterbury, RN, BSN

Gregory Garber, MSW, LSW Maria Raguza-Lopez

Physical Therapy

Allison Kemner, RN, BSN

Dianne Tamewite

Maureen O’Connell, RN,

BSN

Nutrition

Marcy Traum

Ellen Sweeney Cordes, RD

Ambika Sohal

Carolyn Spencer, RD, CNSD

Kathleen Hinkle RN

Amanda Wasylik, RD

Pharmacy

Donna Capozzi, PharmD

Kamakshi Rao, PharmD

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