Multiple Myeloma Update from the American Society of Clinical Oncology (ASCO) 43 rd Annual Meeting Welcome and Introduction Nikhil Munshi, MD Dana-Farber

Multiple Myeloma Update from the American Society of Clinical Oncology (ASCO) 43rd Annual Meeting


Welcome and IntroductionWelcome and IntroductionWelcome and IntroductionWelcome and Introduction

Nikhil Munshi, MDNikhil Munshi, MDDana-Farber Cancer InstituteDana-Farber Cancer Institute

Boston, MABoston, MA

S. Vincent Rajkumar, MDS. Vincent Rajkumar, MDMayo ClinicMayo ClinicRochester, MNRochester, MN

Featuring:Featuring:

Moderator:Moderator:

Richard Lutes, MDRichard Lutes, MD



Upfront TherapyUpfront TherapyUpfront TherapyUpfront Therapy





Lenalidomide/high-dose dexamethasone vs lenalidomide/low-dose dexamethasone (ECOG trial E4A03)


Rajkumar SV, et al, ASCO 2007, Abstract LBA8025.

25201510500

0.2

0.6

1

Overall survival (mo)

Pro

bab

ility 0.8

0.4

Log-rank P=0.0001

Rd

RD

AB

Subjects, n Events, n (%) Censored, n (%)

Median survival (95% CI)

A Len/High-dose Dex (RD) 223 41 (18) 182 (82) NA (23.56, NA)

B Len/Low-dose Dex (Rd) 222 13 (6) 209 (94) NA (NA, NA)


1-year survival rate N Events

Survival Probability

(95% CI)

Len-High Dex (RD) 223 26 0.87 (0.82, 0.92)

Len-Low Dex (Rd) 222 8 0.96 (0.94, 0.99)



Toxicity, %

Len/High-dose Dex

n=217

Len/Low-dose Dex

n=216 P value

Any non-Hem toxicity (Grade ≥3)

52.1 34.3 <0.001

Toxicity of any type (Grade ≥4)

28.6 18.1 0.003

Early Deaths (<4 months)

4.5 1.4 0.034




Melphalan-prednisone-thalidomide (MPT) vs melphalan-prednisone (MP) in patients aged ≥75 years (IFM 01-01 trial)


Best response at 12 months, %

MPn=100

MPTn=100

At least PR (50%) 31 61

At least VGPR (90%) 8 23

Complete remission 1 7

P<0.0001

hulin c, et al, ASCO 2007, Abstract 8001.



hulin c, et al, ASCO 2007, Abstract 8001.

0

0.25

0.75

1

0.50

Time from randomization (mo)50403020100 60

Log-rank P=0.05Median follow-up time = 24 months

MPTMedian OS = 45.3 mo[33.3 – Unreached] Y/N=39/100

MP PlaceboMedian OS = 27.7 mo[24.6 – 34.9] Y/N=54/100

Pro

po

rtio

n

Overall survival by treatment (n=200)



Upfront TherapyUpfront Therapy

DiscussionDiscussion

Upfront TherapyUpfront Therapy










TransplantationTransplantationTransplantationTransplantation





TTIII plus bortezomibTTIII plus bortezomib

Barlogie B, et al, ASCO 2007, Abstract 8020.

36241200

20

60

100

Months from Start of Induction

80

40

PR

nCR

CR

Pe

rce

nt

of

pa

tien

ts (

%)

TTIII plus bortezomibTTIII plus bortezomib

Barlogie B, et al, ASCO 2007, Abstract 8020.

Endpoint at 24 months %

Overall survival 87

Event-free survival 84

CR 91

nCR 80

PR 60

Treatment-related mortality 5

Post-relapse survival 34

Alternating bortezomib and dexamethasone as induction regimen in younger MM patientsAlternating bortezomib and dexamethasone as induction regimen in younger MM patients

Rosinol L, et al, ASCO 2007, Abstract 8024.

End of Induction Treatment (n=40)

Best Response Ever Achieved(n=40)

ORR: 77.5%ORR: 82.5%

17%

42%10%

12%

3%

8%

8%17%

42%10%

12%

3%

8%

8%

MR PR VGPR CR Non-evaluable Progression Stable

17%

39%8%

13%

3%

17%

3%17%

39%8%

13%

3%

17%

3%

Alternating bortezomib and dexamethasone as induction regimen in younger MM patientsAlternating bortezomib and dexamethasone as induction regimen in younger MM patients

Rosinol L, et al, ASCO 2007, Abstract 8024.

Liver

Gastrointestinal

Peripheral Neuropathy

Thrombocytopenia

Percent

Neutropenia

SkinGrade 1

Grade 2

Grade 3

0 604020 10080

Fatigue

Characteristics of patients relapsing after autologous stem cell transplantCharacteristics of patients relapsing after autologous stem cell transplant

Characteristics, %Early relapse

n=94Late relapse

n=338 P value

Male 61.7 57.7 NS

PCLI ≥1% 41.9 15.5 <0.001

β2-microglobulin >3.5 mg/dL 28.7 23.1 NS

Bone disease 12.8 15.4 NS

Refractory at transplant 41.5 29.3 0.03

Durie-Salmon: Stage II 27.6 36.2 NS

Stage III 72.4 63.8 NS

>1 induction regimen 18 8 0.007

Abnormal karyotype 34 14.8 <0.0001

Circulating PC at collection 51.1 36.4 0.01

Mahmood ST, et al, ASCO 2007, Abstract 8022.

Mel-based autotransplants for MMMel-based autotransplants for MM

• Retrospective analysis of 2836 transplant patients identified 5 factors that could influence outcomes

– Type of treatment (tandem transplant or not)– Presence of cytogenetic abnormality

– High β2-microglobulin

– Low albumin– Low platelet counts

• Retrospective analysis of 2836 transplant patients identified 5 factors that could influence outcomes

– Type of treatment (tandem transplant or not)– Presence of cytogenetic abnormality

– High β2-microglobulin

– Low albumin– Low platelet counts

Pineda-Roman M, et al, ASCO 2007, Abstract 8043.

Reduced intensity conditioningReduced intensity conditioning

• 32 patients with relapsed/refractory MM– 19 patients with HLA-identical sibling donor

• 5 patients had disease progression• 4 patients in complete remission• 5 patients in PR or VGPR

– 13 patients with no HLA-identical donor• 11 patients had disease progression

– Overall, 6 patients died from treatment-related mortality (incidence, 33%)

• 32 patients with relapsed/refractory MM– 19 patients with HLA-identical sibling donor

• 5 patients had disease progression• 4 patients in complete remission• 5 patients in PR or VGPR

– 13 patients with no HLA-identical donor• 11 patients had disease progression

– Overall, 6 patients died from treatment-related mortality (incidence, 33%)

Mohty M, et al, ASCO 2007, Abstract 8045.



TransplantationTransplantation


TransplantationTransplantation










Treating Relapsed/Refractory DiseaseTreating Relapsed/Refractory DiseaseTreating Relapsed/Refractory DiseaseTreating Relapsed/Refractory Disease





Pegylated doxorubicin (PLD) and bortezomib vs bortezomib alonePegylated doxorubicin (PLD) and bortezomib vs bortezomib alone

Response rates, %

Bortezomibn=310

PLD + bortezomib

n=303 P value

Total (CR + nCR + PR)

44 52 0.05

CR + nCR 13 17

PR 31 35

CR + VGPR* 20 30 0.007

*According to IMWG 2006 criteria.Harousseau JL, et al, ASCO 2007, Abstract 8002.

Pegylated doxorubicin (PLD) and bortezomib vs bortezomib alonePegylated doxorubicin (PLD) and bortezomib vs bortezomib alone

Harousseau JL, et al, ASCO 2007, Abstract 8002.

PLD +Bortezomib Bortezomib

CensoredDied

82%18%

75%25%

HR (95% CI) 1.41 (1.002, 1.97)P<0.05

50040030020010000

20

60

100

Time (d)

Pe

rce

nt

of

Su

bje

cts

Aliv

e (

%)

80

40

700600

PLD + Bortezomib

Bortezomib

Overall survivalMedian follow-up time: 14 mo

Effect of prior thalidomide treatment on efficacy of pegylated doxorubicin (PLD) and bortezomib


Time to progression

PLD + bortezomib (vs bortezomib)IMiD exposed

PLD + bortezomib (vs bortezomib)

IMiD naiveHeterogeneity

test*

Median, d 270 (vs 205) 295 (vs 189)

Hazard ratio (95% CI)

Log-rank P value)

1.62 (1.08, 2.41)P=0.018

2.01 (1.42, 2.84)P<0.0001

P=0.446

*Treatment by subgroup (IMiD exposed, IMiD naïve) interaction test from the Cox model.Sonneveld P, et al, ASCO 2007, Abstract 8023.



*According to IMWG criteria.Sonneveld P, et al, ASCO 2007, Abstract 8023.

PLD + Bortezomib IMiD exposed

n=123

PLD + BortezomibIMiD naïve

n=180

Time to progression, %

OR (CR + PR) 48 47

CR 4 5

PR 44 42

nCR 9 9

CR + VGPR* 31 27

Duration of response (CR + PR), days

319 310

Factors predictive of outcome in patients treated with bortezomib, melphalan, prednisone, and thalidomide (VMPT)


Palumbo AP, et al, ASCO 2007, Abstract 8048.

1

Months

0

0.75

0.50

P=0.02

≥ PR

< PR

Age: 65 yearsResponse: PR rate

0.25

7.55.02.50 17.515.012.510.0

Pro

po

rtio

n o

f P

atie

nts

1

Months

0

0.75

0.50

P=0.19

<65 years

≥65 years

0.25

7.55.02.50 17.515.012.510.0

Pro

po

rtio

n o

f P

atie

nts



Palumbo AP, et al, ASCO 2007, Abstract 8048.

1

Months

0

0.75

0.50

P=0.98

Del (13)

No Deletion

2-microglobulinDeletion (13)

0.25

7.55.02.50 17.515.012.510.0

Pro

po

rtio

n o

f P

atie

nts

1

Months

0

0.75

0.50

P=0.06

2m <3.5 mg/dL

2m >3.5 mg/dL0.25

7.55.02.50 17.515.012.510.0

Pro

po

rtio

n o

f P

atie

nts



Novel AgentsNovel AgentsNovel AgentsNovel Agents





Tanespimycin + bortezomib in relapsed/refractory MMTanespimycin + bortezomib in relapsed/refractory MM

• Tanespimycin (17-AAG/KOS 953) disrupts heat shock protein 90 (hsp90), a molecular chaperone that transports proteins critical for MM growth, survival, and drug resistance

– Phase I dose escalation study in 49 patients• 7th dose level reached so far

– Combination treatment was well tolerated– Combination treatment resulted in inhibition of

hsp90 and proteasome activity

• Tanespimycin (17-AAG/KOS 953) disrupts heat shock protein 90 (hsp90), a molecular chaperone that transports proteins critical for MM growth, survival, and drug resistance

– Phase I dose escalation study in 49 patients• 7th dose level reached so far

– Combination treatment was well tolerated– Combination treatment resulted in inhibition of

hsp90 and proteasome activity

Richardson PG, et al, ASCO 2007, Abstract 3532.

Phase I evaluation of carfilzomib (PR-171) in hematologic malignanciesPhase I evaluation of carfilzomib (PR-171) in hematologic malignancies

• Carfilzomib is a novel irreversible proteasome inhibitor– Promotes >80% proteasome inhibition in the blood

• Dose-limiting toxicities– Myelosuppression: cyclic reversible thrombocytopenia and

neutropenia– A “first dose effect” has occurred at doses ≥20 mg/m2 and

heralds rapid decline in M-protein

• Objective responses have been observed at doses of carfilzomib ranging from 11 mg/m2 to 27 mg/m2

– Rapid onset of response (<1 month)– Responses are durable (4 to >9.5 months)– Responses noted in bortezomib and IMiD failures– Stable disease for >1 year

• Carfilzomib is a novel irreversible proteasome inhibitor– Promotes >80% proteasome inhibition in the blood

• Dose-limiting toxicities– Myelosuppression: cyclic reversible thrombocytopenia and

neutropenia– A “first dose effect” has occurred at doses ≥20 mg/m2 and

heralds rapid decline in M-protein

• Objective responses have been observed at doses of carfilzomib ranging from 11 mg/m2 to 27 mg/m2

– Rapid onset of response (<1 month)– Responses are durable (4 to >9.5 months)– Responses noted in bortezomib and IMiD failures– Stable disease for >1 year

Stewart KA, et al, ASCO 2007, Abstract 8003.



Novel AgentsNovel Agents


Novel AgentsNovel Agents










Final ThoughtsFinal ThoughtsFinal ThoughtsFinal Thoughts







Documents

Multiple Myeloma Update from the American Society of Clinical Oncology (ASCO) 43 rd Annual Meeting Welcome and Introduction Nikhil Munshi, MD Dana-Farber