Update in Myeloma Kenneth Anderson, MD Jerome Lipper Multiple Myeloma Center Dana-Farber Cancer...

Update in Myeloma

Kenneth Anderson, MD

Jerome Lipper Multiple Myeloma CenterDana-Farber Cancer Institute,

Harvard Medical SchoolBoston, MA

Integration of Novel Therapy Into Myeloma Management

Bortezomib, Lenalidomide, Thalidomide, Doxil

Target MM in the BM microenvironment to overcome conventional drug resistance in vitro and in vivo

Effective in Relapsed/Refractory MM

Effective as Induction/First-line Therapy

Effective in Consolidation/ Maintenance

Integration of Novel Therapy Into Myeloma Management

Six FDA/EMEA Drug Approvals in Last Five Years

Median survival prolonged from 3-7 years (especially in younger patients)

Three phase III trials of novel agents ongoing for FDA approval

Newly Diagnosed

Stem Cell Transplant Eligible

S-D Stage 1-3, < 70 years> 2 cycles of induction Attained SD or better 1 yr from start of therapy> 2 x 106 CD34 cells/kg

Placebo

Lenalidomide*10 mg/d with ↑↓ (5–15 mg)

Lenalidomide*10 mg/d with ↑↓ (5–15 mg)

RestagingRestagingDays 90Days 90––100100

RegistrationRegistration

A Phase III Randomized, Double-Blind Study of Maintenance Therapy With Lenalidomide (CC 5013) or Placebo Following Autologous Stem

Cell Transplantation for Multiple Myeloma

CRPRSD

Patient stratification based on diagnostic -2M and thalidomide and lenalidomide therapy during induction

Mel 200Mel 200

ASCTASCT

*provided by Celgene Corp, Summit, NJ

Randomization

McCarthy et al, ASH 2010 abstr 37

ResultsResults

• TTP was defined as disease progression or death due to any cause

• TTP was calculated from day 0 of ASCT• Of 231 lenalidomide patients, 46 have experienced an

event (progression or death)• Of 229 placebo patients, 95 have experienced an event

(p < 0.0001)• Estimated hazard ratio of 0.40, thus a 60% reduction in

the risk of disease progression with lenalidomide


ITT Analysis with a Median Follow-up from transplant of 17.5 months (p < 0.0001)

CALGB 100104,

follow up to 12/17/2009

Median TTP: 21.8mo

Median TTP: 42.3

Results• Maintenance therapy with lenalidomide when compared to

placebo will significantly prolong time to disease progression

• Currently, there is no difference in OS at a median follow-up of 1.5 years post-ASCT

• Lenalidomide prolonged TTP within patient stratification by high and low β2M, and prior thalidomide or lenalidomide induction therapy

• Lenalidomide maintenance produced some hematologic toxicity, but this was not severe with dropouts due to all AEs at 12%


ResultsResults• 86 of ~ 110 eligible placebo patients started lenalidomide therapy• As of November 2010, 122 lenalidomide patients and 86 placebo

patients remain on lenalidomide • 25 new malignancies reported so far

– 4 before randomization– 15 of 231 on lenalidomide arm– 6 of 229 on the placebo arm

• Of the 25 new malignancies, there are 5 cases of AML/MDS– 2 MDS cases did not receive lenalidomide– Of 3 MDS/AML lenalidomide pts, 1 received breast cancer therapy in the past


IFM 2005-02: Study design

Arm A=

Placebo

(N=307)

until relapse

Arm A=

Placebo

(N=307)

until relapse

Patients < 65 years, with non-progressive disease, 6 months after ASCT in first line

Arm B=

Lenalidomide

(N=307)

10-15 mg/d until relapse

Arm B=

Lenalidomide

(N=307)

10-15 mg/d until relapsePrimary end-point: PFS.

Secondary end-points: CR rate, TTP, OS, feasibility of long-term lenalidomide….

Phase III randomized, placebo-controlled trial

N= 614 patients, from 78 centers, enrolled between 7/2006 and 8/2008

ASCT = autologous stem cell transplant. IFM = Intergroupe Francophone du Myelome.

Consolidation:

Lenalidomide alone 25 mg/day p.o.

days 1-21 of every 28 days for 2 months

Consolidation:

Lenalidomide alone 25 mg/day p.o.

days 1-21 of every 28 days for 2 months

Randomization: stratified according to Beta-2m, del13, VGPRRandomization: stratified according to Beta-2m, del13, VGPR

Attal et al ASH 2010, abstr 310

PRE POST p value b

CR (IF -) 14% 20% <0.0001

≥ VGPR 58% 67% <0.0001

a IMW Criteriab Mc Nemar test

a IMW Criteriab Mc Nemar test

IFM 2005 02 : Responsea After Consolidation(n= 572)

IFM 2005 02 : Responsea After Consolidation(n= 572)Attal et al ASH 2010, abstr 310

IFM 2005-02 : PFS

. Arm A

N = 307

Arm B

N = 307P

Progression or Death 185 117

Median PFS post rando (m)

24 42

4-year post diag PFS

(or 3-year post rando)33% 60%

Hazard Ratio 1 0.5 < 10-8


IFM 2005-02 : PFS from randomization

P < 10-8

0.0

00

.25

0.5

00

.75

1.0

0

0 6 12 18 24 30 36 42

Placebo Revlimid

P < 10 -8

Rev (n =307)

Placebo (n = 307)

Median follow up: 34 m post rando, 44 m post diagMedian follow up: 34 m post rando, 44 m post diag


Grade 3-4 Adverse Events during treatment

AE (grade 4) Arm A Arm B Anemia 2% (1%) 4% (2%)

Thrombocytopenia 6% (2%) 12% (5%)

Neutropenia 14% (3%) 43% (11%)

Febrile Neutropenia 0% 2% (1%)

Infections 5% (1%) 10% (1%)

DVT 0% 2% (0.3%)

Skin disorders 4% 6%

Fatigue 0% 1%

Peripheral Neuropathy 0.3% 0.7%

Hematologic malignancies (n)

2 10

Non hematologic malignancies (n)

1 6

Definitive Discontinuation for AE: placebo = 15% vs lenalidomide = 21%

Randomization

MM Stage II or III, Age 18–65

CAD + GCSF

3 x VAD

CAD + GCSF

3 x PAD

MEL 200 + PBSCT

In GMMG 2nd

MEL 200 + PBSCT

MEL 200 + PBSCT

In GMMG 2nd

MEL 200 + PBSCT

Thalidomide

maintenance 50 mg/day for

2 years

Allogeneic Tx

Bortezomib Maintenance

1.3 mg/m2 / 2 weeks for 2 years

Hovon Trial

Bortezomib 1.3 mg/m2i.v.

Doxorubicin 9 mg/m2

Dexameth 40 mg

Sonneveld et al ASH 2010 abstr 40

PAD vs VAD response

VAD arm % PAD arm % P-value

After induction

CR/nCR 5 11 0.002

≥VGPR 15 42 <0.001

≥PR 55 78 < 0.001

After HDM 1

CR/nCR 15 30 < 0.001

≥VGPR 36 61 <0.001

≥PR 77 88 < 0.001

On protocol

CR/nCR 34 49 <0.001

≥VGPR 55 76 0.001

≥PR 83 91 0.003

ResponseSonneveld et al ASH 2010 abstr 40

Response During Maintenance

VAD armThalidomide

%

PAD armBortezomib

%Response after HDM

≥ PR≥ VGPR≥ nCR

773615

886133

Change of Response during Maintenance

< PR → PR 4 1

< VGPR → VGPR 13 11

< nCR → nCR 12 13

< CR → CR 10 12

Sonneveld et al ASH 2010 abstr 40

Conclusions

Bortezomib based treatment improves PFS (median 36 m vs 27 m) and OS (median not reached) in patients with newly diagnosed transplant candidates

Bortezomib maintenance is well tolerated and induces additional responses in patients including nCR/CR

Bortezomib treatment overcomes poor risk caused by creatinin > 2 mg/dL and del13/13q-

Bortezomib partly overcomes poor risk caused by t(4;14) and 17p-

After VAD/HSM/ASCT also additional responses are achieved with Thalidomide maintenance

BTD versus TDRANDOMIZATION

INDUCTION (three 21-d cycles)

VEL-THAL-DEX

• Vel 1.3mg/m2 twice weekly

• Thal 100200mg/day

• Dex 320mg/cycle

TRANSPLANTATION

• MEL 200

• Thal 100md/day

• Dex 160mg/cycle

• MEL 200

MAINTENANCE

• DEX

PBSC COLLECTION

• CTX

INDUCTION (three 21-d cycles)

THAL-DEX

• Thal 100200mg/day

• Dex 320mg/cycle

CONSOLIDATION (two 35-d cycles)

VEL-THAL-DEX

• Vel 1.3mg/m2 once weekly

• Thal 100mg/day

• Dex 320mg/cycle

CONSOLIDATION (two 35-d cycles)

THAL-DEX

• Thal 100mg/day

• Dex 320mg/cycle

Cavo et al, ASH 2010 abstr 42

INCREASED CR-nCR RATES WITH VTD COMPARED TO TD

31%

11%

52%

31%

55%

41%

62%

45%

P<0.0001 P<0.0001 P=0.0024 P=0.0002

EBMT criteria (with added nCR and VGPR categories) Cavo et al, ASH 2010 abstr 42

Results

• By comparison with TD, VTD as induction and consolidation therapy incorporated into double ASCT

significantly increased the rates of CR, CR-nCR and VGPR after induction, autotransplants and consolidation

significantly improved the probability to achieve a molecular remission

completely overcame the high risk of progression or death related to t(4;14)

significantly extended TTP and PFS

Cavo et al, ASH 2010 abstr 42

Upfront Revlimid Velcade Dexamethasone

• Response improvement seen in 42/56 pts (75%) from C4–8 and 20/38 pts (53%) beyond C8

• Median (range time to best overall response) was 2.1(0.6,20) mos

Best Resp, n (%) All pts (N=66) Phase II (N=35)

CR 19 (29) 13 (37)

nCR 7 (11) 7 (20)

VGPR 18 (27) 6 (17)

PR 22 (33) 9 (26)

CR+nCR 26 (39) 20 (57) (90% CI) (29, 50) (42, 71)

CR+nCR+VGPR 44 (67) 26 (74) (90% CI) (56, 76) (59, 86)

At least PR 66 (100) 35 (100) (90% CI) (96, 100) (92, 100)

Richardson et al, Blood 2010Richardson et al, Blood 2010

Conclusions

• RVD highly effective for previously untreated MM 100% response rate (≥PR) without ASCT CR/nCR (52%) and ≥VGPR (74%)

• Estimated 24-mo PFS of 68% and OS of 95% with RVD ± ASCT

• Very good tolerability Manageable toxicities Only 2% G3 sensory PN, 6% DVT; no treatment-related

mortality

Richardson et al, Blood 2010

IFM/DFCI 2009 Phase 3 StudyNewly Diagnosed MM (SCT candidates)

RVDx3

RVD x 2

RVD x 5

Lenalidomide

Melphalan 200mg/m2* +

ASCT

Induction

Consolidation

Maintenance

CY (3g/m2) MOBILIZATIONGoal: 5 x106 cells/kg

RVDx3

CY (3g/m2)MOBILIZATIONGoal: 5 x106 cells/kg

Randomize

Collection

LenalidomideSCT at relapse

*Thromboprophylaxis randomization: aspirin vs low molecular weight heparin

R, lenalidomide; M, melphalan; d, dexamethasone; P, prednisone

MPRsix 28-day coursesM: 0,18 mg/Kg/d, days 1-4P: 2 mg/Kg/d, days 1-4R: 10 mg/d, days 1-21

MEL 200Two coursesM: 200 mg/m2 day -2Stem cell support day 0

1°RANDOMIZATION

2°RANDOMIZATION

MAINTENANCE28-day courses until relapseR: 10 mg/day, days 1-21

NO MAINTENANCE

Rd*four 28-day coursesR: 25 mg/d, days 1-21d: 40 mg/d, days 1,8,15,22

402 patients (younger than 65 years) randomized from 62 centers

Patients: Symptomatic disease, organ damage, measurable disease

MPR versus Mel 200mg/m2 x 2

Palumbo et al ASCO, 2010

MPR MEL200 P value

CR 13% 16% 0.82

> VGPR 55% 53% 0.63

PFS @ 14 months 86% 86% 0.49

OS @ 14 months 96% 98% 0.13

Results

Palumbo et al ASCO, 2010

EVOLUTION STUDY: MRD negativity across arms

Response by algorithm (overall population), n (%)

VDCR (n = 42)

VDR (n = 42)

VDC (n = 32)

VDC-mod (n = 17)

TOTAL

CR 10 (24) 10 (24) 7 (22) 8 (47) 35

MRD sampling

Patients ≥CR providing MRD sample, n (%)

10 of 10 (100)

7 of 10 (70)

4 of 7 (57)

7 of 8 (88) 28

Patients ≥CR MRD –ve, n (%)

5 of 10

(50)6 of 7 (85)

0 of 4 (0) 2 of 7 (29) 13 of 28 (46)

Kumar et al, ASH 2010 abstr 621Kumar et al, ASH 2010 abstr 621

EVOLTION: Conclusions

• VDC (mod) and VDR active with reasonable toxicity profile

• VDCR and VDC (initial) do not appear to have any advantages over VDR and VDC (mod) in efficacy or toxicity

• Phase III studies should compare RVD and VDC (mod) to assess VGPR, MRD-negative CR and PFS

Kumar et al, ASH 2010 abstr 621Kumar et al, ASH 2010 abstr 621

Combinations in the Upfront Treatment of MM

Stewart AK, Richardson PG, San Miguel JF Blood 2009

Best Resp, % (N=27)

sCR/CR/nCR 55

sCR 22

CR/nCR 33

≥VGPR 70

≥PR 96

Upfront Carfilzomib Rd

*As of data cutoff date: 12 November 2010,

4 patients not evaluable for response

(2 did not complete 1 cycle, 2 response not yet confirmed)

Jakubowiak et al, ASH 2010 abstr 862

Multiple Myelomameeting

eligibility criteria

High-dose melphalan (200 mg/m2) + autologous PBSC transplant

60 to 120 days

No eligible HLA-matched sibling donor

Non-myeloablative conditioningTBI 200 cGY

allogeneic PBSC transplant

High-dose melphalan (200 mg/m2) + autologous PBSC transplant

ObservationThalidomide

Dexamethasone x12 months.

Biologic assignment*

Eligible HLA-matched sibling donor

Randomization†

PRIMARY ENDPOINT : 3yr Progression Free Survival

BMT CTN 0102 Study SchemaBMT CTN 0102 Study Schema

HLA typing of all patients with siblings

*Biologic assignment occurred when HLA-typing results were available. The time range from prior to first transplant to at most 30 days after first transplant.

† Randomization occurred once pts were assigned to auto-auto

Re

gis

te

rR

eg

ist

er

Krishan et al ASH 2010 abstr 41

Compliance with Interventions: Compliance with Interventions: Second Transplant and MaintenanceSecond Transplant and Maintenance

16 % 16 %Drop out

Rate

Auto-AutoN=436

Auto-AlloN=189

Received Second Transplant

N=156

Received Second Transplant

N=366

Thal-Dex Discontinuation at Day 365: 84%


ResultsResults

• No difference in 3-year PFS and OS between auto-auto or auto-allo for the standard risk group (vs high risk).

• Potential benefits of graft-versus-myeloma were offset by increased TRM.

• Thal-Dex maintenance did not improve PFS or OS,

due to poor tolerability or compliance.


Newly Diagnosed

Stem Cell Transplant Ineligible

VMPCycles 1-9Bortezomib 1.3 mg/m2 IV: days 1,8,15,22*Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4

VMPTCycles 1-9Bortezomib 1.3 mg/m2 IV: days 1,8,15,22*Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4Thalidomide 50 mg/day continuously

RANDOMIZE

9 x 5-week cycles in both arms

511 patients (older than 65 years) randomized from 58 Italian centers

Patients: Symptomatic multiple myeloma/end organ damage with measurable disease

≥65 yrs or <65 yrs and not transplant-eligible; creatinine ≤ 2.5 mg/dL

Treatment schedule

MAINTENANCEBortezomib 1.3 mg/m2 IV: days 1,15Thalidomide 50 mg/day continuously

NO MAINTENANCE

Until relapse

* 66 VMP patients and 73 VMPT patients were treated with twice weekly infusions of BortezomibPalumbo et al ASH 2010 abstr 620

Best response rateBest response rate

% o

f p

atie

nts

% o

f p

atie

nts

CRCR VGPRVGPR PRPR

% o

f p

atie

nts

% o

f p

atie

nts

SDSD PDPD

90%

64%

42%

VMPT-VT (N=250)

0.007

0.001

<0.0001

P value

81%> PR

50%> VGPR

24%CR

VMP (N=253)

90%

64%

42%

VMPT-VT (N=250)

0.007

0.001

<0.0001

P value

81%> PR

50%> VGPR

24%CR

VMP (N=253)

VMPT VTVMP

2 42 6

3 1

1 7

1

0

5

1 0

1 5

2 0

2 5

3 0

3 5

4 0 42

2226

6

10

5

10

15

20

25

30

35

40

45

CRCR VGPRVGPR PRPR SDSD PDPDPalumbo et al ASH 2010 abstr 620

Progression-free survival / Time t next therapyMedian follow-up 32 months

3-years PFS Median PFS

VMP

VMPT

32% 27.4 months

51% 37.2 months

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40 50 60

Time (months)

Pat

ien

ts(%

)

HR 0.59

P < 0.0001


VMP

VMPT

32% 27.4 months

51% 37.2 months


VMP

VMPT

32% 27.4 months

51% 37.2 months

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40 50 60

Time (months)

Pat

ien

ts(%

)

HR 0.59

P < 0.0001

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40 50 60

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40 50 60

Time (months)

Pat

ien

ts(%

)

HR 0.59

P < 0.0001

Time to next therapy48% Reduced Risk of Progression

3-years TNT Median TTNT

VMP

VMPT

51% 37.6 months

70% Not reached

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40 50 60

Time (months)

Pat

ien

ts(%

)HR 0.52

P < 0.0001


VMP

VMPT

51% 37.6 months

70% Not reached


VMP

VMPT

51% 37.6 months

70% Not reached

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40 50 60

Time (months)

Pat

ien

ts(%

)HR 0.52

P < 0.0001

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40 50 60

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40 50 60

Time (months)

Pat

ien

ts(%

)HR 0.52

P < 0.0001

Progression-Free survival41% Reduced Risk of Progression

Palumbo et al ASH 2010 abstr 620

Efficacy and Toxicity by Bortezomibschedule

46.8 mg/m267.6 mg/m267.6Total planned dose

4%16%NAPN discontinuation

35%32%NAPFS @ 3 years

2%14%13%Grade 3-4

NA

44%

30%

VMP*(VISTA)

40 mg/m2

21%

23%

VMP once weekly N=190

Sensory PN

43%Any grade

41 mg/m2Total delivered dose

27%CR

VMP twice weekly N=63

**MateosMateos et al. J et al. J ClinClin OncolOncol 2010; 2010; PN: peripheral neuropathyPalumbo et al ASH 2010 abstr 620

Treatment discontinuationVMPT VT VMP

Discontinuation ratea, %

65 - 75 years of age 27 16

> 75 years of age 37 18

Median cumulative doseb-mg/m2

65 - 75 years of age 61 42


VMPT VT VMP

Discontinuation ratea, %

65 - 75 years of age 27 16


Median cumulative doseb-mg/m2

65 - 75 years of age 61 42


a Discontinuation due to AEsb Cumulative dose of bortezomib Palumbo et al ASH 2010 abstr 620

Weekly Bortezomib Maintenance Therapy After Bortezomib-Based Induction Regimens in Elderly Newly Diagnosed Multiple Myeloma Patients

Induction: 21-day cyclesMaintenance: 35-day cycles

Cycles 1–4 Cycles 5–8

Vc: 1.6 mg/m2, days 1,8,15,22

Rest period:days 23–35

VcDVc: 1.3 mg/m2, days 1,4,8,11D: 20 mg, days 1,2,4,5,8,9,11,12

VcTDVc: 1.3 mg/m2, days 1,4,8,11T: 100 mg, days 1–21 D: 20 mg, days 1,2,4,5,8,9,11,12

VcMPVc: 1.3 mg/m2, days 1,4,8,11M: 9 mg/m2, days 1,2,3,4 of every other cycle P: 60 mg/m2, days 1,2,3,4 of every other cycle

RA

ND

OM

IZE

1:1

:1

Vc: 1.3 mg/m2, days 1,4,8,11D: 20 mg, days 1,2,4,5

Vc: 1.3 mg/m2, days 1,4,8,11T: 100 mg, days 1–21 D: 20 mg, days 1,2,4,5

Cycles 9–13

Interim analysis (IDMC)[ASH 2009]

Interim analysis (IDMC)[EHA 2010]

Niesvizky et al ASH 2010 abstr 619

Niesvizky et al ASH 2010 abstr 619

Summary

• All three regimens (VcD, VcTD, VcMP) were active in elderly patients with newly diagnosed MM

Grade ≥3 AEs, serious AEs, PN and study discontinuations due to AEs were highest in the VcTD arm

• Maintenance with single-agent Vc post induction was well tolerated Compared with post-induction rates, the rates of all-grade and grade ≥3

PN did not increase substantially in all three treatment arms

• Vc maintenance resulted in increased ≥VGPR rates in all three arms

• PFS appeared similar between the treatment arms in the ITT population Median follow up 13.4 months (ITT population) Patients continue to be followed for progression and survival status

1

MP

M: 0.18 mg/kg, days 1-4

P: 2 mg/kg, days 1-4

PBO: days 1-21

MPR

M: 0.18 mg/kg, days 1-4


R: 10 mg/day po, days 1-21Placebo

Placebo

Phase III Study Schema

MPR-R

M: 0.18 mg/kg, days 1-4


R: 10 mg/day po, days 1-21

RA

ND

OM

ISA

TIO

N

Double-Blind Treatment Phase

DiseaseProgression

Continuous LenalidomideTreatment

Lenalidomide

(25 mg/day) +/-

Dexamethasone

Open-Label Extension Phase

N = 459, 82 centers in Europe, Australia, and Israel

Stratified by age (≤ 75 vs > 75 years) and stage (ISS I/II vs III)

10 mg/daydays 1-21

Cycles (28-day) 1-9 Cycles 10+

M, melphalan; P, prednisone; R, lenalidomide; PBO, placebo; po, orally; ISS, International Staging System.

1

Progression-Free Survival*All Patients

60% Reduced Risk of Progression

Time (months)

Pat

ien

ts (

%)

HR 0.398 P < .0000001

Median PFS

MPR-R 31 months

MPR 14 months

MP 13 months

Median PFS

MPR-R 31 months

MPR 14 months

MP 13 months

Median follow-up 25 months

0 5 10 15 20 25 30 35 400

25

50

75

100

0 5 10 15 20 25 30 35 400

25

50

75

100

0 5 10 15 20 25 30 35 400

25

50

75

100

*Analysis based on data up to May 2010

HR 0.804P = .153

1

0 5 10 15 20 25 300

25

50

75

100

Time (months)

Pat

ient

s (%

)

0 5 10 15 20 25 300

25

50

75

100

0 5 10 15 20 25 300

25

50

75

100

Time (months)

Pat

ient

s (%

)

Landmark Analysis69% Reduced Risk of Progression

HR 0.314 P < .001

MPR-R

MPR

MPR-R

MPR

Lenalidomide Continuous TherapyMPR

Cycle 10

1

Adverse EventsDuring Induction & Maintenance

MPR-R(N = 150)

%

MPR(N = 152)

%

MP(N = 153)

%

Hematological (Grade 4)

Anemia 5 3 1

Febrile neutropenia 2 1 0

Neutropenia 36 32 8

Thrombocytopenia 13 14 4

Non-hematological (Grade 3/4)

Infections 11 15 9

Pulmonary embolism 2 2 0

DVT 3 5 <1

Fatigue 6 2 3

Peripheral neuropathy 0 0 1

Rash 5 5 <1

Cardiac disorder <1 1 3

Solid tumors <1 3 1

AML 2 1 0

MDS <1 1 0

MPR-R(N = 150)

%

MPR(N = 152)

%

MP(N = 153)

%

Hematological (Grade 4)

Anemia 5 3 1

Febrile neutropenia 2 1 0

Neutropenia 36 32 8

Thrombocytopenia 13 14 4

Non-hematological (Grade 3/4)

Infections 11 15 9

Pulmonary embolism 2 2 0

DVT 3 5 <1

Fatigue 6 2 3

Peripheral neuropathy 0 0 1

Rash 5 5 <1

Cardiac disorder <1 1 3

Solid tumors <1 3 1

AML 2 1 0

MDS <1 1 0

DVT, deep vein thrombosis; Cardiac disorder includes atrial fibrillation, myocardial ischemia, bradycardia; AML, acute myelogenous leukemia; MDS, myelodysplastic syndrome

*Based on updated data

Supportive Therapy

MRC Myeloma IX—

Trial Design

Intensive

ClodronateCVAD

Zoledronic acidCVAD

ClodronateC-TD

Zoledronic acidC-TD

MEL-200ASCT

–Thal +Thal

Non-intensive

ClodronateMP

Zoledronic acidMP

ClodronateC-TDa

Zoledronic acidC-TDa

MaxResponse

–Thal +Thal

Primary endpoints: PFS, OS, ORRSecondary endpoints: Time to first SRE, SRE incidence, Safety, and QoLZoledronic acid (4 mg IV q 3-4 wk); Clodronate (1,600 mg/d PO)

CVAD, cyclophosphamide (500 mg PO days 1, 5, and 15), vincristine (0.4 mg/d IV days 1-4), doxorubicin (9 mg/m 2/d days 1-4), dexamethasone (40 mg/d PO days 1-4, 13-15 q 3 wk); C-TD, cyclophosphamide (500 mg PO days 1, 9, and 15), thalidomide (100-200 mg/d), dexamethasone (40 mg/d PO days 1-4, 12-15 q 3 wk); C-TDa is C-TD except thalidomide 50-200 mg/d, dexamethasone 20 mg/d days 1-4, 15-18 q 4 wk; MP, melphalan (7 mg/m 2), prednisolone (40 mg) PO for 4 days; Thal, thalidomide (50 mg/d); PFS, progression-free survival; ORR, overall response rate; OS, overall survival, SRE, skeletal-related event; QoL, quality of life.

ISRCTN68454111

N = 1,960

RANDOMISATION RANDOMISATION

RANDOMISATION RANDOMISATION

Treatment continued until disease progression

47

Morgan et al ASH 2010 abstr 311

MRC Myeloma IX—

ZOLODRONIC vs CLODRONIC ACID

Endpoints (ZOL vs CLO)Primary: PFS, OS, and ORRSecondary: Time to first SRE, SRE incidence, and Safety

N = 1,960Patients with newly

diagnosed MM

(stage I, II, III)Clodronate (1,600 mg/d PO) +

intensive or non-intensive chemotherapy (n = 979)

Zoledronic acid (4 mga IV q 3-4 wk) + intensive or non-intensive chemotherapy

(n = 981)

Treatment continued at least until disease progression

Abbreviations: CLO, clodronate; IV, intravenous; MM, multiple myeloma; ORR, overall response rate; OS, overall survival, PFS, progression-free survival; PO, oral; SRE, skeletal-related event; ZOL, zoledronic acid.a Dose-adjusted for patients with impaired renal function, per the prescribing information.

48

Morgan et al ASH 2010 abstr 311

MRC Myeloma IX— ZOLODRONIC ACID Improved OS

and PFS vs CLODRONIC ACID

Abbreviations: CI, confidence interval; CLO, clodronate; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; ZOL, zoledronic acid.

a Cox model adjusted for chemotherapy, and minimization factors.

Riskreduction

Hazard ratio (ZOL versus CLO)0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2

P value

.01180.842

16%

In favor of ZOL In favor of CLO

OS

.017912%0.883

PFS

• ZOL significantly reduced relative risk of death by 16% vs CLO (HR = 0.842; 95% CI = 0.736, 0.963; P = .0118)

• ZOL prolonged OS by 5-5 mos (p=0.04)

Morgan et al, ASH 2010 abstr 311Morgan et al, ASH 2010 abstr 311

Relapsed and Relapsed/Refractory Myeloma

51

Intravenous versus Subcutaneous Bortezomib

SC:Bortezomib 1.3 mg/m2, days 1, 4, 8, 11

If ≤PR after 4 cycles:Add 20 mg Dex, days 1, 2, 4, 5, 8, 9, 11, 12

SC:Bortezomib 1.3 mg/m2, days 1, 4, 8, 11


IV:Bortezomib 1.3 mg/m2, days 1, 4, 8, 11


IV:Bortezomib 1.3 mg/m2, days 1, 4, 8, 11


1

Eight 21-day cycles (plus 2 cycles if unconfirmed or delayed PR)

RANDOMIZE

2

• Non-inferiority design 60% retention of the IV treatment effect by ORR after 4 cycles of

treatment 2:1 randomization SC vs IV (N=222) Stratification : ISS stage, number of prior lines of therapy (1 vs >1)

• 53 centers in 10 countries (Europe, Asia, and South America)

Moreau et al, ASH 2010 abstr 312

52

Primary Endpoint: Response After 4 Cycles (Single-Agent Bortezomib)

Response rate, %Bortezomib IV

(N=73)Bortezomib SC

(N=145)Relative risk

(95% CI)

ORR (CR + PR) 42 42 0.99 (0.71, 1.37)

CR 8 6

CR + nCR 14 12

PR 34 36

nCR 5 6

VGPR 3 4

≥VGPR (CR + nCR + VGPR) 16 17

Data shown for the response-evaluable population

Primary hypothesis of non-inferiority of ORR after 4 cycles clearly demonstrated


Hematology Laboratory Data

Grade 3/4, %Bortezomib IV

(N=74)Bortezomib SC

(N=147)

Hemoglobin 12 14

WBC 18 8

ANC 28 22

Platelets 23 18


Peripheral Neuropathy (PN)

Bortezomib IV

(N=74)

Bortezomib SC (N=148)

P-value*

Any PN event, % 53 38 0.04

Grade 2, % 41 24 0.01

Grade 3, % 16 6 0.03

Risk factors for PN, %

Grade 1 PN at baseline 28 23

Diabetes at baseline 11 13

Exposure to prior neurotoxic agents 85 86

*P-values are based on 2-sided Fisher’s exact test



Conclusions

• The efficacy of bortezomib was similar by SC and IV administration in patients with relapsed MM

similar PK (systemic exposure) and PD (proteasome inhibition) profiles

• SC administration has an improved safety profile significantly fewer all-grade, grade 2, and grade 3 PN

events

• SC administration had acceptable local tolerability

59

Phase 1 (MTD)

Dose

2 mg

3 mg

4 mg

5 mg

Progressive disease (PD)

or no response aftercompletion of 4 cycles

POM therapy(QD on days 1-21 of

a 28 day cycle)

Option to add low-dose dex

(40 mg/wk)

Discontinue and follow-up for survival

and subsequent treatment

PD

Phase 2 (Open Label)

RA

ND

OM

IZA

TIO

N Arm A

POM (4 mg)+ low-dose dex

Arm B

POM (4 mg)

Option to add low-dose dex

(40 mg/wk)

Discontinue and follow-up for survival

and subsequent treatment

PD

PD

MM-002 Study SchemaPOM ± Low-Dose Dex in Relapsed and Refractory MM

Concomitant Medications: anti-coagulants, G-CSF use after Cycle 1, erythroid growth factors, bisphosphonates, transfusions with platelet, RBCs as clinically indicated .

Richardson et al, ASH 2010 abstr 864

MM-002: Phase 1 POM ± Low-Dose Dex in Relapsed and Refractory MM

Best Response & Clinical Outcome (Evaluable Ptsa [n=28])

60

• Best response (≥ PR) to POM alone: 18%

• Median time to best responsec: 16.1 wks

• Median DOR: 20.1 wks (assessed for responders only)

• Median PFS: 20.1 wks (95% CI: 12.0, 36.0)

• Median OS: 79.6 wks (95% CI: 61.9, NE)

14

33 27 29 2114

27

43

25

40

10

20

30

40

50

60

70

80

2 mg (n = 3) 3 mg (n = 7) 4 mg (n = 11) 5 mg (n = 7) Total (N = 28)

Ev

alu

ab

le P

ts (

%)

CR PR MR

≥ PR: 33%≥ MR: 33% ≥ PR: 14%

≥ MR: 29%b

≥ PR: 27%≥ MR: 55%b

≥ PR: 29%≥ MR: 71%b

≥ PR: 25%≥ MR: 50%

a. Includes eligible, treated and evaluable for efficacy assessment; b. Discrepancies in totals due to roundingc. Response rates based on EBMT criteria; includes pts on POM alone (n=9), pts who had dex added for SD (n=7), and pts who had dex added for PD (n=12)


61

MM-002: Conclusions POM ± Low-Dose Dex in Relapsed and Refractory MM

• Manageable toxicity profile in heavily pretreated pts MTD: 4 mg days 1-21 of 28-day cycle Most common hematologic G 3/4 AE: myelosuppression

• Low incidence of G 3/4 PN and DVT

• Responses in heavily pretreated relapsed and refractory pts Median lines of prior therapy: 6 in Phase 1; 5 in Phase 2 Phase 1:

• ≥PR: 25%; ≥MR: 50% • Median DOR: 20.1 wks• Median PFS: 20.1 wks• Median OS: 79.6 wks

Phase 2: • ≥PR 25%; ≥MR 38%• Median DOR not reached


Pomalidomide/Dexamethasone Therapy for Relapsed/Refractory MM

Pomalidomide 2 or 4 mg daily continuous, days 1-28

Dexamethasone 40 mg days 1, 8, 15, 22

Aspirin 325 mg daily

After 2 cycles, if NR or if progression, pomalidomide dose could be increased to 4 mg/day in the 2 mg cohort

28 day cycle

Lacy et al ASH 2010, abstr 987

Response Rates

2 mgN=35

4 mg N=35

Confirmed Response Rate (>PR)

9 (26%) 9 (26%)

CR 0 1

VGPR 5 3

PR 4 5

MR 8 5

SD 13 12

PD 2 8

NE 3 1

49% 40%

Lacy et al ASH 2010 abstr 987

2mg (n=35) 4mg (n=35)

Median time to response 1 mo (range: 1-4) 1.7mo (range: 1-6)

Duration of response* 12 mo (95%CI: 11-NA) NA

Survival at 6 Months 78% (95%CI: 65-94) 69% (95%CI: 53-89)

CI: confidence interval; mo: month; NA: not attained* Kaplan Meier

Patient Outcomes Lacy et al ASH 2010 abstr 987

Conclusions

• Pom/Dex in MM refractory to lenalidomide and bortezomib

- 40-49% >MR, DOR 12 months

- 69-78% OS at 6 months

• Median time to response 1 - 2 month

• Toxicity is manageable at both dose levels and primarily neutropenia

• ORR similar at both dose levels

• Effective in high risk patients

• Ongoing study of 4 mg for 21 of 28 days

Lacy et al ASH 2010 abstr 987

• Elotuzumab (HuLuc63) is a humanized monoclonal IgG1 antibody targeting human CS1, a cell surface glycoprotein1,2

• CS1 is highly and uniformly expressed on MM cells1–3

Restricted expression on NK cells Little to no expression on normal tissues Clinical trial of Elotuzumab in MM achieved SD

• In a MM xenograft mouse model, the antitumor activity of elotuzumab was enhanced by the addition of lenalidomide4

66

MM, multiple myeloma; NK, natural killer.

1. Hsi ED et al. Clin Cancer Res. 2008;14:2775-2784. 2. Tai YT et al. Blood. 2008;112:1329-1337. 3. van Rhee F et al. Mol Cancer Ther. 2009;8:2616-2624. 4. Lonial S et al. Blood. 2009;114:432.

Elotuzumab: BackgroundRichardson et al, ASH 2010 abstr 864

67

Randomized Phase 2 Study Schema

• Pts randomized to receive elotuzumab 10 or 20 mg/kg IV, in combination with lenalidomide 25 mg PO and low-dose dexamethasone 40 mg PO wkly (28-day cycles)

• Treatment continued until PD or unacceptable toxicity

• Premedication regimen (30–60 mins prior to elotuzumab infusion) Methylprednisone 50 mg IV Diphenhydramine 25–50 mg PO or IV (or equivalent) Ranitidine 50 mg IV (or equivalent) Acetaminophen 650–1000 mg PO

Response Assessments

CYCLE 1 CYCLE 2 CYCLE 3

1 8 15 221 8 15 22 1 8 15 221 8 15 22

CYCLE 5

1 8 15 22

CYCLE 6

1 8 15 22 28

Dexamethasone

Lenalidomide

Elotuzumab

Dosing

Cycle day: 1 8 15 221 8 15 22 1 8 15 221 8 15 22 1 8 15 22 1 8 15 22 28

CYCLE 1 CYCLE 2 CYCLE 3 CYCLE N-1 CYCLE NCYCLE 4

daily dosedaily dose daily dose daily dosedaily dose daily dose


Cycle

1 D

ay 2

2

Basel

ine

Cycle

1 D

ay 2

2

Basel

ine

Cycle

1 D

ay 2

20

20

40

60

80

100

% O

ccu

pan

cy o

f C

S1

by

Elo

tuzu

mab

on

CD

45d

im/C

D13

8+ B

M c

ells

CD138+, 10 mg/kg, n=24

CD138+, 20 mg/kg, n=18

Basel

ine

Cycle

1 D

ay 2

2

Basel

ine

0

20

40

60

80

100

% O

ccu

pan

cy o

f C

S1

by

Elo

tuzu

mab

on

CD

45d

im/C

D38

+ B

M c

ells

CD38+, 10 mg/kg, n=24

CD38+, 20 mg/kg, n=18

68

CS1 Saturation on CD38+ and CD138+ in Patient BM MM Cells


69

Elotuzumab/Len/Dex

• Well tolerated Gr 3/4 AEs >10%: neutropenia (14%), lymphopenia (14%),

thrombocytopenia (13%) Premedication mitigates infusion reactions

• ORR Phase 1: 82%1,2

Phase 2: 81% ORR, 37% VGPR/CR• 10 mg/kg elotuzumab is recommended Phase 3 dose

Activity (90% ORR, 42% VGPR/CR), safety, and CS1 saturation similar to 20 mg/kg

High ORR in β2M ≥3.5 mg/L, prior thalidomide and median ≥2 prior therapies

• Phase 3: Randomized Trial of Lenalidomide/Dexamethasone With or Without Elotuzumab in Relapsed or Refractory MM in 2011

1. Lonial S et al. ASCO 2010; Abstract 8020 (Oral). 2. Lonial S et al. ASH 2010; Abstract 1936.


0 4 8hp-Akt

Akt

Bortezomib

Bortezomib

caspase ↑ Akt ↑

anti-apoptosis

Perifosine

apoptosis

C PB P+B

p-JNK1/2

caspase-8

CFPARP

CF

C: controlB: Bortezomib (10 nM)P: Perifosine (5 μM)

8h

Akt Inhibitor Perifosine Enhances Bortezomib-Induced Cytotoxicity in MM Cells

0

20

40

60

80

100

120

0 5 7.5Bortezomib (nM)

% c

on

tro

l

24hPerifosine (μM)

057.5

Hideshima et al. Blood 2006; 107: 4053-52

Perifosine/Bortezomib ± Dexamethasone in Relapsed/Refractory Myeloma: Phase I/II

• Long-term follow-up results of phase I/II study (N = 73)

• Grade 3/4 AEs in ≥ 5%: thrombocytopenia, neutropenia, anemia

Clinical trial of Bortezomib and perifosine versus Bortezomib in relapsed MM ongoing for FDA approval

Patients ORR, % Median TTP, mo (range) Median OS, mo

All 38 6.4 (5.3-7.1) > 22.5

•Bort relapsed 55 8.8 (6.3-11.2) > 25

•Bort refractory 32 5.7 (4.3-6.4) 16

Richardson P, et al. ASH 2009

Protein

protein aggregates(toxic)

UbUb

UbUb

26S proteasome

UbUb

Ub Ub

Ub

Aggresome

Panibinostat,vorinostat

dynein

UbUb

dynein

MicrotubuleAutophagy

Bortezomib

Ub Ub

Ub

Lysosome

HDAC6

HDAC6

HDAC6

Ub

Ub

Blockade of Ubiquinated Protein Catabolism

Hideshima et al, Clin Cancer Res;2005; 11: 8530Catley et al, Blood 2006; 108: 3441-9.

Panobinostat + Bortezomib EfficacySan Miguel et al, ASCO 2010

Res

pons

e R

ate

(%)

0

10

20

30

40

50

60

70

80

90

100

All (N = 47) BTZ refractory (n = 15)

MR

PR

VGPR

CR

70%70%

60%60%

HDAC6 Inhibitors Enhances Cytotoxicity Induced by Proteasome Inhibitors

0

20

40

60

80

100

120

0 nM 2.5 nM 5 nM Carflizomib 5 nM

Bortezomib

% c

on

tro

l

Tub 0 uM

Tub 0.3 uM

Tub 1 uM

Tub 3 uM

WT161 0 uM

WT161 0.3 uM

WT161 1 uM

WT161 3 uM

Luc+

Myeloma cells

Luc-

Stromal cells

Myeloma +

Stromal cells

Biolum signal No signal Biolum signal

High-Throughput Screening of MM with High-Throughput Screening of MM with BMSCs to Define Optimal CombinationsBMSCs to Define Optimal Combinations

McMillin et al. Nat Med 2010; 16: 483.

%

Su

rviv

al%

S

urv

ival

% S

urv

ival

% S

urv

ival

% S

urv

ival

% S

urv

ival

0.00.0 0.50.5 1.01.0 1.51.5 2.02.000

2525

5050

7575

100100

No BMSCsNo BMSCs

+HS-5 stroma+HS-5 stroma

Dex (uM)Dex (uM)

DexDex

00 1010 2020 3030 4040 5050 606000

2525

5050

7575

100100

Doxo (ng/mL)Doxo (ng/mL)

No BMSCsNo BMSCs

+HS-5 stroma+HS-5 stroma DoxoDoxo

No BMSCsNo BMSCs

+HS-5 stroma+HS-5 stroma

00 1010 2020 3030 404000

2525

5050

7575

100100

PS-341 (nM)PS-341 (nM)

BortezomibBortezomib

Conclusions and Future Directions

1. Combination novel therapy represents a new treatment paradigm in MM targeting the tumor cell in its microenvironment which has markedly improved OR, CR, EFS and OS.

2. Ongoing oncogenomic and proteomic studies are informing clinical protocol design and identifying novel therapeutic targets.

3. Rationally-designed combination therapies (IMiDs, proteasome inhibitors, HDAC inhibitors, and MoAbs) will achieve durable CR in the majority of pts

4. Genomics will allow for improved patient classification and personalized medicine in MM.

Update in Myeloma Kenneth Anderson, MD Jerome Lipper Multiple Myeloma Center Dana-Farber Cancer...

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Transcript of Update in Myeloma Kenneth Anderson, MD Jerome Lipper Multiple Myeloma Center Dana-Farber Cancer...