Relapsed and Refractory Myeloma PowerPoint Presentation

Relapsed and Refractory Myeloma PowerPoint Presentation

2016-12-10 74K 74 0 0

Description

Ruben Niesvizky. Myeloma Center. Myelomacenter.org. run9001@med.cornell.edu. Multiple Myeloma: Natural History of Disease. Durie B; International Myeloma Foundation. . Concise review of the disease and treatment options: multiple myeloma. 2011/2012 edition;. ID: 499729

Embed code:

Download this presentation



DownloadNote - The PPT/PDF document "Relapsed and Refractory Myeloma" is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.

Presentations text content in Relapsed and Refractory Myeloma

Slide1

Relapsed and Refractory Myeloma

Ruben Niesvizky

Myeloma CenterMyelomacenter.orgrun9001@med.cornell.edu

Slide2

Multiple Myeloma: Natural History of Disease

Durie B; International Myeloma Foundation.

Concise review of the disease and treatment options: multiple myeloma. 2011/2012 edition; Kumar SK, et al. Mayo Clin Proc. 2004;79:867-74.

M-Protein Level

MGUS or Indolent

Myeloma

Active

Myeloma

Remission

Relapse

Frontline

Therapy

Second- or Third-Line Therapy

Remission duration decreases with each line of therapy

//

//

Asymptomatic

Symptomatic

Relapsing

Refractory

Slide3

Outline

Approach to the patient with RRMM:

Evidence based

Factors to be considered in selecting therapy

Proteasome inhibitors

Inmunomodulatory

Agents

HDAC inhibitors

Alkylating agents

Slide4

Clinical Considerations for Relapsed/Refractory Disease

Disease characteristics/prior therapy

Line of therapy

Plateau phase=quiescent period

Aggressiveness

of relapse

Relapsed or relapsed and refractory disease

High risk disease

Prior therapies (

eg

SCT, prior

IMiD

,

bortezomib

-based therapy

)

Slide5

Clinical Considerations for Relapsed/Refractory Disease

Disease characteristics/prior therapy

Line of therapy

Plateau phase=quiescent period

Aggressiveness

of relapse

Relapsed or relapsed and refractory disease

High risk disease

Prior therapies (

eg

SCT, prior

IMiD

,

bortezomib

-based therapy

)

Slide6

Response Duration Decreases With Successive Therapies

578 patients; median age 65 years (follow up 55 months)Overall survivalOne year 72%Two years 55%Three years 22%84% died within five years

Kumar SK, et al.

Mayo Clin Proc

. 2004;79:867-874.

Slide7

APEX: Bortezomib Early or Late Relapse

Bortezomib1 prior therapyn = 132> 1 prior therapyn = 200 Median TTP (months)7.04.9 CR (%) 10%*7%† CR + PR (%) 51%*37%† Median Duration of Response (months)8.17.8 1-year Survival89%73%

* Evaluable patients, response to bortezomib after 1 prior therapy: n = 128† Evaluable patients, response to bortezomib after >1 prior therapy: n = 187

Sonneveld

P, et al.

Haematologica

. 2005;90:146-147. Abstract P140.721.; Data on file; Millennium Pharmaceuticals, Inc.

Slide8

Time to Progression Overall Survival

2

nd Line (LenDex)Median 17.1 months≥ 3th line(LenDex)Median 10.6 months

2nd Line (LenDex)Median 42 months ≥ 3th line(LenDex)Median 35.8 month

Improved Outcomes with the Early Use of LenDex : TTP and OS

Stadmauer EA et al. Eur J Haematol 2009; 82:426-32

Slide9

Clinical Considerations for Relapsed/Refractory Disease

Disease characteristics/prior therapy

Line of therapy

Plateau phase=quiescent period

Aggressiveness

of relapse

Relapsed or relapsed and refractory disease

High risk disease

Prior therapies (

eg

SCT, prior

IMiD

,

bortezomib

-based therapy

)

Slide10

Kumar SK, et al. Bone Marrow Transplant. 2008;42:413-420.

Time to Progression After SCT Correlates With OS After Initial Relapse

Slide11

Clinical Considerations for Relapsed/Refractory Disease

Disease characteristics/prior therapy

Line of therapy

Plateau phase=quiescent period

Aggressiveness

of relapse

Relapsed or relapsed and refractory disease

High risk disease

Prior therapies (

eg

SCT, prior

IMiD

,

bortezomib

-based therapy

)

Slide12

Frontline vs Relapsed Refractory

Response to Therapy Survival Outcomes

Toxicities and Co-morbidities

Toxicities and Co-morbidities

Response to Therapy Survival Outcomes

Treatment Naive

Relapsed and Refractory

High risk features Genomic instability

Slide13

Relapsed /Refractory

Outcomes in Relapsed and Refractory Multiple Myeloma

Adapted from: Durie BGM. Multiple Myeloma. International Myeloma Foundation. 2011/2012 edition.Jagannath S. Clin Lymphoma Myeloma. 2008;8 Suppl 4:S149-S156.

Relapsed

FrontlineTreatment

Expectedsurvival (months)20-50Sensitivity totherapySensitiveTreatment limitations/comorbiditiesPeripheral neuropathy (~15% at diagnosis)

14-16Less Sensitive/Resistant>80% incidence of peripheral neuropathyCompromised marrow reserveCytopenia

6-10ResistantIntolerant to or ineligible for available therapy

Elderly population

(

risk for heart, lung, renal, liver dysfunction, diabetes)

Slide14

Nature of Relapse

How did the patient present?

80% share clinical features with presentation

Has been a shift on presentation?

Intact immunoglobulin to light chain only

Non-secretory relapse

Extra medullar disease

Slide15

Slide16

Nature of Relapse

How did the patient present?

80% share clinical features with presentation

35% relapse both light chain and intact

Ig

49.6% intact

Ig

10% free light chain only

Slide17

Survival according to paraprotein and FLC secretion at first relapse.

Brioli A et al. Blood 2014;123:3414-3419

©2014 by American Society of Hematology

Slide18

Survival from relapse according to paraprotein and FLC secretion at relapse for patients with IgG and IgA paraproteins.

Brioli A et al. Blood 2014;123:3414-3419

©2014 by American Society of Hematology

Slide19

Nature of Relapse

How did the patient present?

80% share clinical features with presentation

35% relapse both light chain and intact

Ig

49.6% intact

Ig

10% free light chain only

Has been a shift on presentation?

Intact immunoglobulin to light chain only

Non-secretory relapse

Extra medullar disease

Slide20

Slide21

Progression-free survival according to the presence of extramedullary (EM) involvement at diagnosis.

Varettoni M et al. Ann Oncol 2009;21:325-330

© The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Slide22

Outcome according to baseline PET/CT.

Zamagni E et al. Blood 2011;118:5989-5995

©2011 by American Society of Hematology

Slide23

Patient Heterogeneity

Slide24

Clinical Considerations for Relapsed/Refractory Disease

Toxicity

considerations

Peripheral neuropathy

Thrombotic risk

Myelosuppression

Impact of prior therapies (

eg

, SCT, other cumulative toxicity)

Slide25

ANY PROGRESS?

Kumar et al. Blood. 2008 Brenner et al. Blood. 2008

Overall survival in 6-year intervals from time of diagnosis

Time (months)

Proportion of patients

0

0.2

0.4

0.6

0.8

1.0

0

20

40

60

80

100

120

140

2001

2006

1995

2000

2001

2006

1989

1994

1983

1988

1977

1982

1971

1976

Slide26

Slide27

Kumar et al: Leukemia Nov 2013

> 65 años

< 65 años

Slide28

Bortezomib

Carflizomib

Ixazomib

Oprozomib

Proteosome

Inhibitors

Slide29

Proteasome Inhibitors

Outcomes Correlate with Depth of Response

Slide30

Quality of Response: Survival

Niesvizky et al.,

Br J Haematol. 2008 Oct;143(1):46-53

Slide31

Proteasome Inhibitors

Benefits of Retreatment

Slide32

Bortezomib Retreatment– A Retrospective Multicenter Survey

Retrospectively collected data- multicenter non-interventional survey of pts who received bortezomib for a second time (retreatment) Patients: 65 pts,19 centers; median age 65 yrs

Hrusovsky I, et al. ASH 2007, abstract #2720

Results: 49 evaluable (modified ITT)

Bortezomib mg/m2InitialRe-treatment1.394%86%1.02%12%other8%4%+ Dex39%61%

Median 4 prior therapies

Retreatment

Initial

bortezomib

Diagnosis

52 mos

Mean of 5 cycles

Mean of 4 cycles

6 pts received additional therapy

Best Response

months

Patients (n)

Treatment Outcomes

Safety:

AE occurring in > 2 patients

Retreatment

Median

% Patients

Treatment received

Slide33

Petrucci

et al, Br J

Haem

2013,160,649-659

Slide34

Petrucci

et al, Br J

Haem

2013,160,649-659

Slide35

Proteasome Inhibitors

Carflilzomib

Slide36

Carfilzomib IV on days 1, 2, 8, 9, 15 and 16 every 28 days

20 mg/m2 in Cycle 1 and 27 mg/m2 from Cycle 2 and beyond (maximum 12 cycles)

Study 003-A1: Open-Label Phase 2b Study of Single-Agent Carfilzomib in Relapsed and Refractory Multiple Myeloma (R/R MM)

Primary endpoint: ORR IMWG response criteria (IRC assessed)Secondary endpointsCBR (ORR+ MR), DOR, OS, PFS, TTP, safety

Siegel D, et al. Blood. 2012;120:2817-25.

Study Population (N=266)Relapsed from ≥2 prior lines of therapyMust include bortezomibMust include thalidomide or lenalidomideRefractory to last regimen

CBR = clinical benefit rate; DOR = duration of response; IMWG = International Myeloma Working Group; IRC = Independent Review Committee; MR = minimal response; ORR = overall response rate; OS = overall survival; PFS = progression-free survival

Slide37

Single-Agent Carfilzomib: Response Rates

*IRC-determined; 11 patients had unconfirmed response

Percentage of Patients

ORR =

24%

CBR =

37%

DCR =

69%

TTR: 1.9

mo (≥PR) and 1.0 mo (≥MR)DOR: 7.8 mo (≥PR) and 8.3 mo (≥MR)

Subset analyses of higher risk populations showed similar response rates(e.g., unfavorable cytogenetics, baseline peripheral neuropathy)

Siegel D, et al. Blood. 2012;120:2817-25.

N = 257 response-evaluable population

CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease; TTR = time to response; VGPR = very good partial response

Slide38

Single-Agent Carfilzomib: PFS, OS

Siegel D, et al. Blood. 2012;120:2817-25.

Proportion alive and without progression

Months

Median PFS = 3.7 mo (95% CI 2.8–4.6)

1.0

0.8

0.6

0.4

0.2

0.0

0

3

9

12

18

6

15

Proportion surviving

Months

Median OS = 15.6

mo

(95% CI 13.0

19.2)

0

3

12

21

27

1.0

0.8

0.6

0.4

0.2

0.0

15

6

9

18

24

N = 257 response-evaluable population

Slide39

39

Slide40

Phase II Trial of Carfilzomib Plus Len/Dex in R/R MM (1-3 prior lines of therapy)

Response (N = 52 pts receiving maximal planned dose)n (%)ORRStringent CRCRVGPRPRSD40 (77)2 (4)1 (2)19 (37)18 (35)3 (6)Median duration of response, mos (range)22.1 (9.5-38.0)

Wang M, et al. Blood. 2013;122:3122-3128.

Week 1

Week 2

Week 3

Week 4: rest

Carfilzomib

20/27 mg/m

2

IV*

Dexamethasone

40 mg/d PO

Lenalidomide d1-d21

25 mg/d PO

D1/D2

D8/D9

D15/D16

D1

D8

D15

D22

*20 mg/m

2

cycle 1 days 1 and 2 only,

27 mg/m

2

thereafter

Slide41

Phase III ASPIRE Trial: Carfilzomib + Len/Dex vs Len/Dex in R/R MM (ongoing)

Study Population (N=780)Measurable disease1-3 prior regimensRelapse or PDResponse to ≥1 prior regimenExclusion factors:Bortezomib-refractoryLen/dex-refractoryPrior carfilzomib

CRdCarfilzomib27 mg/m2 IV day 1, 2, 8, 9, 15, and 16 (20 mg/m2 on days 1, 2 of cycle 1 only)Lenalidomide25 mg Days 1-21Dexamethasone40 mg once weekly

R

dLenalidomide25 mg Days 1-21Dexamethasone40 mg once weekly

Stratify: Prior bortezomib, prior lenalidomide, β2 microglobulin levelPrimary endpoint: PFS

Available at: http://clinicaltrials.gov/ct2/show/NCT01080391. Accessed April 29, 2014.

28-day cycles

Press release-

PFS 26.3

vs

17.6 HR 0.69:

Slide42

Phase 1b Study of High-Dose Carfilzomib + Dexamethasone in R/R MM

Badros A, et al. ASH 2012. Abstract 4036.

Study population: N=22 (expanded 007 cohort)Median prior regimens: 4Regimen: (28-day cycles)Carfilzomib 20/45 or 20/56 mg/m2 30-min IV D1,2,8,9,15,16Dexamethasone 20 mgD1,2,8,9,15,16 then 40 mg D22

EndpointCFZ20/45CFZ20/56TotalORR, %575055CR, %000VGPR, %145025PR, %43030DORNRNRPFS, months5.46.0

Treatment-emergent Grade ≥3 AE, %CFZ20/45CFZ20/56TotalHematologicThrombocytopeniaAnemiaLymphopenia292914502525362718NonhematologicHypertensionHypophosphatemiaPneumonia141470013999

Safety

Efficacy

CFZ =

carfilzomib

Slide43

Phase III ENDEAVOR: Carfilzomib + Dex vs Bortezomib/Dex in R/R MM1

ClinicalTrials.gov. Available at: http://clinicaltrials.gov/ct2/show/NCT01568866. Accessed March 26, 2014.Vij R, et al. Blood. 2012;119:5661-5670.

Study Population (N=888)Measurable diseaseResponsive to at least 1 prior therapyRelapsed following 1-3 prior treatment regimensECOG PS 0-2

CdCarfilzomib20/56 mg/m2 IV D1,2, 8, 9, 15, 16Dexamethasone20 mg PO or IV D1, 2, 8, 9, 15, 16, 22, 2328-day cycle

Vd

Bortezomib1.3 mg/m2 IV or SC D1, 4, 8, & 11Dexamethasone20 mg PO or IV D1, 2, 4, 5, 8, 9, 11, 1221-day cycle

Treat until PD or unacceptable toxicity

Stratify: Prior PI, prior lines of therapy, ISS, bortezomib IV vs. SCPrimary endpoint: PFS

Note use of higher

carfilzomib

dose—based on results from 004 trial, which suggested dose-response relationship of carfilzomib

2

Slide44

Novel PIs Under Investigation in R/R MM

AgentStatusIxazomibTwo phase I studies showed activity of single-agent ixazomib[2,3]OprozomibPhase 1 dose-escalation study showed some activity in patients with heavily pretreated hematologic malignancies, including MM[4]

Richardson PG, et al. ASH 2011. Abstract 302.

Lonial

S, et al. ASCO 2012. Abstract 8017.

Kumar S, et al. ASCO 2013. Abstract 8514.

Savona MR, et al. ASH 2012. Abstract 203.

Slide45

Ixazomib: Oral Proteasome Inhibitor

Slide46

Ixazomib treatment duration and response.

Kumar S K et al. Blood 2014;124:1047-1055

©2014 by American Society of Hematology

Slide47

Proteasome Inhibitors

Oprozomib

Slide48

Slide49

Slide50

Slide51

Slide52

OPomDex Study Design (Phase 1b)

Slide53

Bortezomib

Carflizomib

Ixazomib

Oprozomib

Ub

Ub

Ub

Ub

Ub

Substrates

+

Thalidomide

Lenalidomide

Pomalidomide

Proteosome

Inhibitors

Immunomodulating

Agents

Slide54

Immunomodulating Agents

Slide55

Pomalidomide in Relapsed/Refractory Multiple Myeloma

POM + LoDEX achieved responses in pts with prior LEN and/or BORT treatment, including those who are refractory1-4

StudyPhaseNTreatmentPopulationMedian Prior Tx (Range)≥ PRLacy4260POM: 2 mg(28/28-day cycle)Dex: 40 mg/week1-3 prior Tx, relapsed/refractory2 (1-3)65%234POM: 2 mg(28/28-day cycle)Dex: 40 mg/weekLEN-refractory4 (1-14)32%235POM: 2 mg (28/28-day cycle)DEX: 40 mg/weekLEN- and BORT- refractory6 (3-9)26%260POM: 4 mg(28/28-day cycle)Dex: 40 mg/week1-3 prior Tx, LEN-refractory2 (1-3)37%235POM: 4 mg(28/28-day cycle)DEX: 40 mg/weekLEN- and BORT- refractory6 (2-11)29%

55

3. Lacy MQ et al. Blood. 2011;118:2970.4. Lacy MQ et al. Blood. 2011;118: Abstract 3963.

1. Lacy MQ et al.

J Clin Oncol.

2009;27:5008.

2. Lacy MQ et al.

Leukemia.

2010;24:1934.

Slide56

Pomalidomide

Pts, nMedian No. Prior RegimensRefractory to Recent Therapy (%)ORR (%)Pomalidomide ± dex119151002534Pomalidomide, dex2706NR2629Pomalidomide, dex3845853435Pomalidomide, cyclophosphamide, prednisone432NR (1 to 3) 44*59Pomalidomide, dex, clarithromycin5 46NR (at least 3)NR60

*Len specifically

4. Palumbo A et al.

Blood. 2011;118. Abstract 632.Mark TM et al. Blood. 2011;118. Abstract 635.

1. Vij R et al.

J Clin Oncol

. 2012;30. Abstract 8016.

2. Lacy MQ et al.

Blood

. 2011;118:2970.

3. Leleu X et al.

Blood

. 2011;118. Abstract 812.

Slide57

ClaPd: Study Design

A single-center, phase 2 study of Clarithromycin combined with Pomalidomide + Low Dose Dexamethasone in RRMM

p.o., orally; b.i.d., twice a day; RRMM, relapsed, refractory MM.

1 2 8 9 15 16 21 22 28

Day

Dex

40mg PO

Dex 40mg PO

Dex 40mg PO

Dex 40mg PO

Pomalidomide

4 mg PO

Clarithromycin 500mg PO BID

Slide58

Clarithromycin???

Slide59

Results

98 patients completed at least 1 cycle of ClaPD.median number of cycles received was 6 (range 1–25)median study follow-up was 9.6 months (range 1.0–25.6)In responding patients, median time to PR was 1 cycle (range 1–7).Median time to best response was 2 cycles (range 1-14).

Best Response (IMWG Criteria)n (%)Overall(N = 98)ORR (≥ PR)56 (57)CBR (≥ MR)65 (66)sCR6 (6) VGPR 17 (17)PR33 (34)MR9 (9)SD 23 (23)PD 10 (10)

IMWG, International Myeloma Working Group; CBR, clinical benefit rate; MR, minimal response; PD, progressive disease;

sCR

, stringent complete response; SD, stable disease.

Slide60

Treatment History With Len/Bort Did Not Influence Response to ClaPD

Best Response (IMWG Criteria)n (%)Overall(N = 98)Lenalidomiderefractory(N = 83)BortezomibRefractory (N = 82)Lenalidomide and bortezomib refractory(N = 72)ORR (≥ PR)56 (57)47 (63)46 (56)39 (54)CBR (≥ MR)65 (66)56 (67)54 (65)(65)sCR6 (6) 6 (7)5 (6)5 (7)VGPR 17 (17)13 (16)13 (16)9 (13)PR33 (34)28 (34)28 (34)25 (35) MR9 (9)8 (10)8 (10)8 (11)SD 23 (23) 18 (22)19 (23)16 (22)PD 10 (10) 8 (12)9 (11)9 (13)

IMWG, International Myeloma Working Group; MR, minimal response; PD, progressive disease; sCR, stringent complete response; SD, stable disease.

Slide61

Results

OS by cytogenetic risk

OS by double-refractory state

0 200 400 600 800

Time (days)

Number of patients at risk Relapsed 41 26 16 10 0Refractory 54 33 18 9 0

1.00

Survival (%)

0.75

0.50

0.25

0

0 200 400 600 800

Time (days)

1.00

Survival (%)

0.75

0.50

0.25

0

Number of patients at risk Relapsed 26 18 13 6 0Refractory 74 44 23 14 0

Not double-refractoryDouble-refractory

Standard risk

High risk

Adverse

cytogenetics

did not appear to influence risk of death

as of last study follow-up.

HR 1.05, 95%CI (0.49,2.26),

P

= 0.888

A history of being double-refractory, however, approached a significant effect on survival time.

HR 2.67, 95%CI (0.93,7.69),

P

= 0.068

Slide62

IFM 2010-02: Study design

N = 50RRMMExposed to Lendel 17p and/or t(4;14)Measurable diseaseECOG 0–2PNn > 1 x109/LPlat ≥ 75 x109/LHb ≥ 8 g/dLCrCl ≥30 mL/min

Pomalidomide4 mg/day, po, days 1–21 (of 28 d cycle)Dexamethasone40 mg, po, days 1, 8, 15, 22 Aspirin/LMWHonce daily, continuously

Until progression

Safety analysis by DMC after 15 patients recruited

End-points

Primary: TTPSecondary: Safety, Response rate (CBR), DoR, OS, PFS, EFS, cytogenetic groupsMedian follow-up: 8.2 months

n (%)n (%)Progression25 (69)Death other cause1 (3)Toxicity9 (25)Sponsor decision1 (3)

At data cut-off, 36 patients (72%) had discontinued trial

Slide63

O/NMedian95% CIITT population33 / 502.9[2.7;5.0]8-month TTP, %22del17p12 / 22*7.3[2.7;14.7]8-month TTP, %41t(4;14)24 / 32*2.8[1.9;4.0]8-month TTP, %12.4

del17p

t(4;14)

ITT

IFM 2010-02: Time To Progression (ITT)

Slide64

O/NMedian95% CIITT population26 / 5012[4.9;15.5]8-month OS, %55del17p12 / 22*12[2.4;-]8-month OS, %58t(4;14)16 / 32*9.2[4.6;-]8-month OS, %50

IFM 2010-02: Overall Survival

Slide65

Shah JJ, et al. Blood. 2013;122:690.

Phase I/II: Carfilzomib/Pomalidomide/LoDEX (Car-Pom-d) in R/R MM

Carfilzomib*20/27 mg/m2 (D1-2, 8-9, 15-16) Pomalidomide*4 mg (D1-21)Dexamethasone*40 mg weekly (20 mg after cycle 4)

*Dosing based on MTD established in phase 1Primary endpoint: ORR Secondary endpoints:DOR, TTP, PFS, time to next therapy, OS

Study Population (N=79)Relapsed and/or refractory measurable MMLenalidomide-refractory

28-day cycles

(cycles 1-6)

CarfilzomibD1-2, 15-16 PomalidomideunchangedDexamethasoneunchanged

Maintenance(cycles 7+)

Treatment continued until PD or unacceptable toxicity

All patients received antiviral treatment and aspirin 81 mg or low molecular weight heparin

Slide66

Car-POM-d in R/R MM: Efficacy

Cytogenetic Risk (by mSMART)Response, % High (n = 18)Intermediate (n = 19)Standard (n = 38)All Pts(N = 79)ORR78537470VGPR22263227PR56264243

Median PFS: 9.7 mos; median DOR: 17.7 months; median OS not reachedNo significant difference in PFS or OS based on cytogenetics80% of pts with del(17p) were alive at 12 mos; 58% were progression-free

Shah JJ, et al.

Blood

. 2013;122:690.

Slide67

Bortezomib

Carflizomib

Ixazomib

Oprozomib

Ub

Ub

Ub

Ub

Ub

Substrates

+

Thalidomide

Lenalidomide

Pomalidomide

Romidepsin

Vorinostat

Panobinostat

Proteosome

Inhibitors

Immunomodulating

Agents

HDAC inhibitors

Slide68

Slide69

Phase 2 trial of the histone deacetylase inhibitor romidepsin for the treatment of refractory multiple myeloma

Niesvizky et al, Cancer

Volume 117, Issue 2,

pages 336-342, 22 SEP

2010

Slide70

DescriptionRegimenNORR (> PR), %HDAC InhibitorsRomidepsin + bortezomib + dex[4]2560Vorinostat + bortezomib[5]14317Bortezomib + panobinostat + dex[6]5534.5

HDAC

Inhibitors in RRMM

Slide71

Vorinostat

Bortezomib vs Placebo Bortezomib

Dimopoulos et al, Lancet Oncol. 2013 Oct;14(11):1129-40

Vorinostat

: Median PFS: 7

·63 months (95% CI 6·87-8·40)

Placebo: Median 6

·83 months (5·67-7·73

)

(

hazard ratio [HR] 0·77, 95% CI 0·64-0·94

;p

=0·0100).

Slide72

PANORAMA 1: Phase III Trial of Panobinostat + Bortezomib + Dex

Study Population (N=768)Relapse or relapsed/refractory MMBortezomib-refractory excluded1-3 prior lines of therapy

Panobinostat BortezomibDexamethasone

Placebo

BortezomibDexamethasone

Primary endpoint: PFS

Stratification based on prior lines of therapy, prior bortezomib

Richardson PG, et al. ASCO 2014. Abstract 8510.

Slide73

PANORAMA 1: Primary Endpoint Met (PFS)

Slide74

Bortezomib

Carflizomib

Ixazomib

Oprozomib

Ub

Ub

Ub

Ub

Ub

Substrates

+

Thalidomide

Lenalidomide

Pomalidomide

Melphalan

Cyclophosphamide

Bendamustin

Romidepsin

Vorinostat

Panobinostat

Slide75

Autotransplant for Refractory MM

PFS

OS

N = 66

Median = 11 mo

N

= 66Median = 19 mo

SWOG Trial 8993

Vesole DH, et al.

J Clin Oncol

. 1999;17:2173-2179.

Slide76

PBSCT in Relapsed MM

Cook G et

al,The Lancet Oncology, Volume 15, Issue 8, Pages 874 - 885, July 2014

TTP median

HD Mel

19 months [95% CI 16—25]

Cyclophosphamide 11

months [9—12];

hazard

ratio 0·36 [95% CI 0·25—0·53]

;

p<0·0001).

Slide77

A Phase 1 Study of Bendamustine and Melphalan Conditioning for Autologous Stem Cell Transplant with Multiple Myeloma.

Slide78

Dose Levels for Bendamustine

Dose Level

On Day 1 Melphalan (100mg/m

2

)

On Day 2 Melphalan (100mg/m

2

)

1

30 mg/m

2

2

60 mg/m

2

3

90 mg/m

2

4

60 mg/m

2

60 mg/m

2

5

90

mg/m

2

60

mg/m

2

6

125 mg/m

2

100 mg/m

2

Slide79

Bortezomib

Carflizomib

Ixazomib

Oprozomib

Ub

Ub

Ub

Ub

Ub

Substrates

+

Thalidomide

Lenalidomide

Pomalidomide

Filanesib

Palbociclib

Melphalan

Cyclophosphamide

Bendamustine

Romidepsin

Vorinostat

Panobinostat

Elotuzumab

Daratumumab

SAR650984

Slide80

Slide81

The Team and Collaborators

Tomer Mark MDMorton Coleman, MDRoger Pearse, MDAdriana Rossi, MDDavid JayabalanKaren Pekle RNPArthur Perry PASusan Matthew, PhD Scott Ely, MD/MPHSelina Chen-Kiang, PhDMonica Guzman, PhDGiorgio Inghirami, MDLinda Tegnestam RNKathleen Pogonowski RNStanley Goldsmith MDMaureen Lane PhDPaul Christos

Myelomacenter.org

Slide82

Slide83

Slide84

Slide85


About DocSlides
DocSlides allows users to easily upload and share presentations, PDF documents, and images.Share your documents with the world , watch,share and upload any time you want. How can you benefit from using DocSlides? DocSlides consists documents from individuals and organizations on topics ranging from technology and business to travel, health, and education. Find and search for what interests you, and learn from people and more. You can also download DocSlides to read or reference later.