Relapsed and Refractory Myeloma - PowerPoint Presentation

Slide1

Relapsed and Refractory Myeloma

Ruben Niesvizky

Myeloma CenterMyelomacenter.orgrun9001@med.cornell.eduSlide2

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

RefractorySlide3

OutlineApproach to the patient with RRMM:Evidence based Factors to be considered in selecting therapyProteasome inhibitorsInmunomodulatory

AgentsHDAC inhibitorsAlkylating agentsSlide4

Clinical Considerations for Relapsed/Refractory DiseaseDisease characteristics/prior therapyLine of therapyPlateau phase=quiescent period

Aggressiveness of relapseRelapsed or relapsed and refractory disease“High risk disease”Prior therapies (eg SCT, prior

IMiD, bortezomib-based therapy)Slide5

Clinical Considerations for Relapsed/Refractory DiseaseDisease characteristics/prior therapyLine of therapyPlateau phase=quiescent period

Aggressiveness of relapseRelapsed or relapsed and refractory disease“

High risk disease”Prior therapies (eg SCT, prior IMiD, bortezomib-based therapy)Slide6

Response Duration Decreases With Successive Therapies578 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 therapy

n = 132

> 1 prior therapy

n = 200 Median TTP (months)7.04.9 CR (%) 10%*7%† CR + PR (%) 51%*37%† Median Duration of Response (months)8.17.8 1-year Survival

89%

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

2

nd Line (LenDex)Median 42 months ≥ 3th line(LenDex)Median 35.8 monthImproved Outcomes with the Early Use of LenDex : TTP and OSStadmauer EA et al. Eur J Haematol 2009; 82:426-32Slide9

Clinical Considerations for Relapsed/Refractory DiseaseDisease characteristics/prior therapyLine of therapyPlateau phase=quiescent period

Aggressiveness of relapseRelapsed 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 RelapseSlide11

Clinical Considerations for Relapsed/Refractory DiseaseDisease characteristics/prior therapyLine of therapy

Plateau phase=quiescent period Aggressiveness of relapseRelapsed 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-morbiditiesToxicities and Co-morbiditiesResponse to Therapy Survival OutcomesTreatment Naive

Relapsed and Refractory

High risk features Genomic instabilitySlide13

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 FrontlineTreatmentExpectedsurvival (months)20-50Sensitivity totherapySensitiveTreatment limitations/comorbiditiesPeripheral neuropathy (~15% at diagnosis)14-16Less Sensitive/Resistant>80% incidence of peripheral neuropathyCompromised marrow reserveCytopenia

6-10

Resistant

Intolerant to or

ineligible for available therapy

Elderly population

(

 risk for heart, lung, renal, liver dysfunction, diabetes)Slide14

Nature of RelapseHow did the patient present?80% share clinical features with presentationHas been a shift on presentation?Intact immunoglobulin to light chain onlyNon-secretory relapse

Extra medullar diseaseSlide15
Slide16

Nature of RelapseHow did the patient present?80% share clinical features with presentation35% relapse both light chain and intact Ig

49.6% intact Ig10% free light chain onlySlide17

Survival according to paraprotein and FLC secretion at first relapse.

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

©2014 by American Society of HematologySlide18

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 HematologySlide19

Nature of RelapseHow did the patient present?80% share clinical features with presentation

35% relapse both light chain and intact Ig49.6% intact Ig

10% free light chain onlyHas been a shift on presentation?Intact immunoglobulin to light chain onlyNon-secretory relapseExtra medullar diseaseSlide20
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.orgSlide22

Outcome according to baseline PET/CT.

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

©2011 by American Society of HematologySlide23

Patient Heterogeneity Slide24

Clinical Considerations for Relapsed/Refractory DiseaseToxicity considerationsPeripheral neuropathyThrombotic risk

MyelosuppressionImpact 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

–

1976Slide26
Slide27

Kumar et al: Leukemia Nov 2013

> 65 años

< 65 añosSlide28

Bortezomib

Carflizomib

Ixazomib

Oprozomib

Proteosome

InhibitorsSlide29

Proteasome InhibitorsOutcomes Correlate with Depth of ResponseSlide30

Quality of Response: Survival

Niesvizky et al.,

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

Slide31

Proteasome InhibitorsBenefits of RetreatmentSlide32

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 yrsHrusovsky I, et al. ASH 2007, abstract #2720Results:

49 evaluable (modified ITT)

Bortezomib mg/m

2InitialRe-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 receivedSlide33

Petrucci

et al, Br J Haem

2013,160,649-659Slide34

Petrucci

et al, Br J Haem

2013,160,649-659Slide35

Proteasome InhibitorsCarflilzomibSlide36

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

20 mg/m

2 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 endpoints

CBR (ORR+ MR), DOR, OS, PFS, TTP, safetySiegel 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 regimenCBR = 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 survivalSlide37

Single-Agent Carfilzomib: Response Rates

*IRC-determined; 11 patients had unconfirmed response

Percentage of PatientsORR = 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 populationCR = complete response; PD = progressive disease; PR = partial response; SD = stable disease; TTR = time to response; VGPR = very good partial responseSlide38

Single-Agent Carfilzomib: PFS, OSSiegel D, et al. Blood

. 2012;120:2817-25.

Proportion alive and without progression MonthsMedian PFS = 3.7 mo (95% CI 2.8–4.6)

1.0

0.8

0.60.40.20.00391218

6

15

Proportion surviving

Months

Median OS = 15.6

mo

(95% CI 13.0–19.2)0

312

21271.0

0.80.60.40.2

0.015

6

9

18

24

N = 257 response-evaluable populationSlide39

39Slide40

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 (%)

ORR

Stringent CR

CRVGPRPRSD40 (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 1Week 2Week 3Week 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

thereafterSlide41

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-refractory

Len/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 weeklyRdLenalidomide25 mg Days 1-21Dexamethasone40 mg once weeklyStratify: Prior bortezomib, prior lenalidomide, β2 microglobulin levelPrimary endpoint: PFSAvailable at: http://clinicaltrials.gov/ct2/show/NCT01080391. Accessed April 29, 2014.28-day cyclesPress release-PFS 26.3 vs 17.6 HR 0.69: Slide42

Phase 1b Study of High-Dose Carfilzomib + Dexamethasone in R/R MMBadros 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 D22Endpoint

CFZ20/45CFZ20/56Total

ORR, %

575055CR, %000VGPR, %145025PR, %43030DORNRNRPFS, months5.46.0Treatment-emergent Grade ≥3 AE, %CFZ20/45CFZ20/56TotalHematologicThrombocytopeniaAnemiaLymphopenia292914502525362718NonhematologicHypertensionHypophosphatemiaPneumonia141470013999SafetyEfficacyCFZ = carfilzomibSlide43

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 therapy

Relapsed

following 1-3 prior treatment regimensECOG PS 0-2CdCarfilzomib20/56 mg/m2 IV D1,2, 8, 9, 15, 16Dexamethasone20 mg PO or IV D1, 2, 8, 9, 15, 16, 22, 2328-day cycleVdBortezomib1.3 mg/m2 IV or SC D1, 4, 8, & 11Dexamethasone20 mg PO or IV D1, 2, 4, 5, 8, 9, 11, 1221-day cycleTreat until PD or unacceptable toxicityStratify: Prior PI, prior lines of therapy, ISS, bortezomib IV vs. SCPrimary endpoint: PFSNote use of higher carfilzomib dose—based on results from 004 trial, which suggested dose-response relationship of carfilzomib2Slide44

Novel PIs Under Investigation in R/R MM

Agent

StatusIxazomibTwo phase I studies showed activity of single-agent

ixazomib[2,3]

Oprozomib

Phase 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 InhibitorSlide46

Ixazomib treatment duration and response.

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

©2014 by American Society of HematologySlide47

Proteasome InhibitorsOprozomibSlide48
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

AgentsSlide54

Immunomodulating AgentsSlide55

Pomalidomide in Relapsed/Refractory Multiple Myeloma

POM + LoDEX

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

Phase

N

TreatmentPopulationMedian Prior Tx (Range)≥ PRLacy4260POM: 2 mg(28/28-day cycle)Dex: 40 mg/week1-3 prior Tx, relapsed/refractory2 (1-3)65%

2

34

POM:

2 mg

(28/28-day cycle)

Dex

: 40 mg/week

LEN-refractory4 (1-14)

32%

2

35POM: 2 mg (28/28-day cycle)DEX:

40 mg/weekLEN- and BORT- refractory

6 (3-9)26%

2

60

POM:

4 mg

(28/28-day cycle)

Dex

:

40 mg/week

1-3 prior

Tx

, LEN-refractory

2 (1-3)

37%

2

35

POM:

4 mg

(28/28-day cycle)

DEX:

40 mg/week

LEN- and BORT- refractory

6 (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

, n

Median No. Prior Regimens

Refractory

to Recent Therapy (%)ORR (%)Pomalidomide ± dex119151002534Pomalidomide, dex2706NR2629Pomalidomide, dex3845

85

34



35Pomalidomide, cyclophosphamide, prednisone

4

32

NR (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 RRMMp.o., orally; b.i.d., twice a day; RRMM, relapsed, refractory MM.

1 2 8 9 15 16 21 22 28

Day

Dex 40mg PODex 40mg PODex 40mg PODex 40mg POPomalidomide 4 mg POClarithromycin 500mg PO BIDSlide58

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

ResultsOS by cytogenetic risk

OS by double-refractory

state 0 200 400 600 800Time (days)Number of patients at risk Relapsed 41 26 16 10 0

Refractory 54 33 18 9 01.00

Survival (%)

0.750.500.250 0 200 400 600 800Time (days)1.00Survival (%)0.750.500.250Number of patients at risk Relapsed 26 18 13 6 0Refractory 74 44 23 14 0Not double-refractoryDouble-refractoryStandard riskHigh 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

= 0.068Slide62

IFM 2010-02: Study design

N = 50

RRMM

Exposed to Len

del 17p and/or t(4;14)

Measurable diseaseECOG 0–2PNn > 1 x109/LPlat ≥ 75 x109/LHb ≥ 8 g/dLCrCl ≥30 mL/minPomalidomide4 mg/day, po, days 1–21 (of 28 d cycle)Dexamethasone40 mg, po, days 1, 8, 15, 22 Aspirin/LMWHonce daily, continuouslyUntil progressionSafety analysis by DMC after 15 patients recruited End-pointsPrimary: TTPSecondary: Safety, Response rate (CBR), DoR, OS, PFS, EFS, cytogenetic groupsMedian follow-up: 8.2 monthsn (%)n (%)

Progression

25 (69)

Death other cause

1 (3)

Toxicity

9 (25)

Sponsor decision

1 (3)

At data cut-off, 36 patients (72%) had discontinued trialSlide63

O/N

Median

95% CI

ITT population

33 / 50

2.9[2.7;5.0]8-month TTP, %22del17p12 / 22*7.3[2.7;14.7]8-month TTP, %41

t

(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/N

Median

95% CI

ITT population

26 / 50

12[4.9;15.5]8-month OS, %55del17p12 / 22*12[2.4;-]8-month OS, %58

t

(4;14

)

16 / 32*

9.2

[4.6;-]

8-month

OS, %50

IFM 2010-02: Overall SurvivalSlide65

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

Phase I/II: Carfilzomib/Pomalidomide/

LoDEX (Car-Pom-d) in R/R MMCarfilzomib*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, OSStudy Population (N=79)Relapsed and/or refractory measurable MMLenalidomide-refractory28-day cycles (cycles 1-6)CarfilzomibD1-2, 15-16 PomalidomideunchangedDexamethasoneunchangedMaintenance(cycles 7+)Treatment continued until PD or unacceptable toxicityAll patients received antiviral treatment and aspirin 81 mg or low molecular weight heparinSlide66

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 reached

No 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 inhibitorsSlide68
Slide69

Phase 2 trial of the histone deacetylase inhibitor romidepsin

for the treatment of refractory multiple myeloma

Niesvizky et al, CancerVolume 117, Issue 2, pages 336-342, 22 SEP 2010Slide70

Description

Regimen

NORR (> PR), %

HDAC Inhibitors

Romidepsin

+ bortezomib + dex[4]2560Vorinostat + bortezomib[5]14317Bortezomib + panobinostat + dex[6]5534.5HDAC Inhibitors in RRMMSlide71

Vorinostat Bortezomib

vs Placebo BortezomibDimopoulos et al,

Lancet Oncol. 2013 Oct;14(11):1129-40Vorinostat: 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 therapyPanobinostat

BortezomibDexamethasone

Placebo

BortezomibDexamethasonePrimary endpoint: PFSStratification based on prior lines of therapy, prior bortezomibRichardson 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

PanobinostatSlide75

Autotransplant for Refractory MM

PFS

OS

N = 66

Median = 11 mo

N = 66Median = 19 moSWOG Trial 8993Vesole 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/m2)

On Day 2 Melphalan (100mg/m

2

)130 mg/m2260 mg/m2390 mg/m2460 mg/m260 mg/m2

5

90

mg/m

260

mg/m2

6

125 mg/m

2100 mg/m2Slide79

Bortezomib

Carflizomib

Ixazomib

Oprozomib

Ub

Ub

Ub

Ub

Ub

Substrates

+

Thalidomide

Lenalidomide

Pomalidomide

Filanesib

Palbociclib

Melphalan

Cyclophosphamide

Bendamustine

Romidepsin

Vorinostat

Panobinostat

Elotuzumab

Daratumumab

SAR650984Slide80
Slide81

The Team and Collaborators

Tomer

Mark MDMorton Coleman, MDRoger Pearse

, MDAdriana Rossi, MD

David

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