Relapse Myeloma

Optimizing treatment for relapsed myeloma

July 2004 Myeloma “101” M.L.Gray

July 2004 Myeloma “101” M.L.Gray

Current Treatment Goals Cures are possible but should not be the

overarching goal 30% of CR’s can last 10% or more

Aim for long term complete remission Preserve quality of life

Reduce fatigue Control pain Protect from infections Improve ADLs / Performance Status

Multiple Myeloma Treatment Lines in Transplant-Eligible PatientsCurrent Paradigm

Induction Consolidation

Frontline treatment

Risk Stratification?

Maintenance

Maintenance

Rescue

Relapsed

AlkylatorsSteroidsThalidomideLenalidomideBortezomibAnthacyclines

e

SCT ThalidomideSteroidsBortezomibLenalidomide

AlkylatorsSteroidsThalidomideBortezomibAnthacyclinesCarfilzomibPomolidomideBendamustine

National Comprehensive Cancer Network. The NCCN Clinical Practice Guidelines in OncologyMultiple Myeloma (Version 1.2011). http://www.nccn.org/. Accessed October 13, 2010.

Patient Case 65-year-old male presents with anemia

• Initial workup: hemoglobin = 9.5, normal CBC and platelets Patient is referred to a local hematologist, an

extensive workup finds • IgG kappa protein (3.5 g/dL) with reciprocal depression of

the other immunoglobulins, negative UPEP • 40% plasma cells in the bone marrow with normal

cytogenetics by standard chromosomal analysis and del13 by FISH

• Diffuse lytic disease• 2-microglobulin = 3.9, albumin = 3.7

UPEP, urine protein electrophoresis.

Patient Case Continued• He begins induction therapy with thalidomide / bortezomib

/ dex (VTD)• After 2 cycles he develops paresthesia not interfering with

his function• After 4 cycles he achieves a PR (75% reduction)• Stem cells are collected and he receives a single ASCT• He achieves a CR post-ASCT and declines maintenance

therapy at day 100• He continues to experience grade 1 peripheral

neuropathy 15 months after his stem cell transplant, he has a

clinical relapse including new lytic lesions

ISS, international staging system; dex, dexamethasone; PR, partial response; ASCT, autologous stem cell transplant; CR, complete response.

Natural History of Relapse

Types of Relapse

Alegre A et al. Haematologica 2002;87(6):609-614.

88

Multiple Myeloma Expectations for Survival After Relapse

Survival as a Function of Era-SCT Patients

Which of the following should NOT be considered when developing a re-treatment plan?

• Age• Prior Therapy• Type of relapse• Duration of remission• Comorbidities

Factors in Selecting Salvage Therapy

DISEASE-RELATEDDISEASE-RELATED

DOR to initial therapyDOR to initial therapy

FISH / cytogeneticsFISH / cytogenetics

REGIMEN-RELATEDREGIMEN-RELATED

Prior drug exposurePrior drug exposure

Toxicity of regimenToxicity of regimen

Mode of administrationMode of administration

Previous SCTPrevious SCT

PATIENT-RELATEDPATIENT-RELATED

Pre-existing toxicityPre-existing toxicity

Co-morbiditiesCo-morbidities

AgeAge

Performance statusPerformance status

DOR, duration of response; FISH, fluorescent in situ hybridization; SCT, stem cell transplant. Lonial S. ASH Education Book. 2010;303-309.

Stage generally does not influence salvage therapy choice.

Relapse Approaches

Lonial S, et al. Clin Cancer Res. 2011;17:1264-1277.

Bz, bortezomib; PN, peripheral neuropathy; len, lenalidomide; thal, thalidomide; CT, chemotherapy; SCT, stem cell transplant; PS, performance status.

LENALIDOMIDE-BASEDLENALIDOMIDE-BASED

Initial therapy with bzInitial therapy with bz Underlying PNUnderlying PN

BORTEZOMIB-BASEDBORTEZOMIB-BASED

Initial therapy len / thalInitial therapy len / thal Long DOR with prior bzLong DOR with prior bz

Renal dysfunctionRenal dysfunction

TRANSPLANTTRANSPLANT

No previous SCTNo previous SCT Long remission post-SCTLong remission post-SCT

CONSIDER CLINICAL TRIAL WITH A NOVEL AGENT

EARLY

CT-BASEDCT-BASED

DCEP vs DT-PACEDCEP vs DT-PACEOral vs IV CTOral vs IV CT

PS plays an important rolePS plays an important role

CT + NOVEL AGENTCT + NOVEL AGENT

Combinations of len Combinations of len and / or bz with other and / or bz with other

agentsagents

SCT-BASEDSCT-BASED

Likely to be short-lived Likely to be short-lived Quick disease control Quick disease control Reconstitute marrowReconstitute marrow

?

AGGRESSIVE, RAPID, OR MULTIPLE RELAPSE

Consider combination therapy. Don’t wait for symptomatic relapse.

Patient Case Continued 15 months after his stem cell transplant, he has a


Treat or not• Yes, symptomatic relapse

Single or Combo• Lets look at the data

Retransplant?• Lets look at the data


Clinical Considerations for Relapsed/Refractory DiseaseClinical Considerations for

Relapsed/Refractory Disease

• Disease characteristics/prior therapy– Aggressiveness of relapse– Relapsed or relapsed and refractory disease– “High risk disease”– Prior therapies (eg SCT, prior IMiD, bortezomib-based therapy)

• Toxicity considerations– Peripheral neuropathy– Thrombotic risk– Myelosuppression– Impact of prior therapies (eg, SCT, other cumulative toxicity)

How do we treat a patient in first relapse?Sequencing of therapy is important

IssuesTreat or Not to Treat

Single Agent vs Combinations

How do we treat a patient in first relapse?Sequencing of therapy is important

IssuesTreat or Not to Treat

Single Agent vs Combinations

Classes of Drugs With Anti-MM Activity

Steroids Immuno-modulatory

Agents

Proteasome Inhibitors

Cytotoxic CT

HDACinhibitors

mTORinhibitors

mAbs

Prednisone Thalidomide Bortezomib Melphalan Vorinostat Perifosine Elotuzumab

Dexa-methasone

Lenalidomide Carfilzomib Cyclophos-phamide

Panobinostat

Pomalidomide MLN9708 PLD

ONX 0912 DCEP

Marizomib BCNU

CEP-18770 Benda-mustine

Novel Agents as MonotherapyWithout Steroids

Novel Agents as MonotherapyWithout Steroids

Regimen Phase n CR + PR CR + nCR Reference

Bortezomib

(APEX)3 331 43% 16%

Richardson, et al.

Blood. 2005;106 (abstract 2547)

Thalidomide 2

712 28.2% 1.6%Prince, et al.

Leuk Lymphoma.2007;48:46

1629 29.4% 1.6%Glasmacher, et al.

Br J Haematol. 2006;132:584

Lenalidomide 2 102 17% 4%Richardson, et al.

Blood. 2006;108:3458

Proteasome inhibitor bortezomib has the best single agent activity

Thal + Dex vs. Combination ChemotherapyThal + Dex vs. Combination Chemotherapy

PFS median 17 vs.11 months OS at 3 years 60% vs.26%

First Relapse N PFS OS at 3 yearsThalidomide + Dexamethasone 62 17 months 60%Combination Chemotherapy 82 11 months 26%

Palumbo A, et al. Hematol J. 2004;5:318-324.

THAL 100 mg/day and DEX 40 mg (days 1–4 of each month)CC: MP, VAD, intermed dose Cytoxan, VMCP-VBAP

Second Relapse N PFS OS at 3 yearsThalidomide + Dexamethasone 58 11 months 19Combination Chemotherapy 38 9 months 19

Pooled Analysis of MM-009 and MM-010 Data: Response, TTP and OS According to Number of Prior Therapies

Pooled Analysis of MM-009 and MM-010 Data: Response, TTP and OS According to Number of Prior Therapies

*EBMT Criteria

PR (>50%)

CR (IF-)

PR + CR

Res

po

nse

Rat

e (%

)

0

20

40

60

65%*

Len/Dexn=124

26%

Dexn=124

20%

Dex

58%*

Len/Dex

80

n=229 n=227

1 Prior Therapy ≥ 2 Prior Therapies

4.79.64.714.5*

P<0.05

27.333.333.639.1

Median TTP (months)

Median OS (months)

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

Pooled Analysis of MM-009 and MM-010 Data: Updated OS

Pooled Analysis of MM-009 and MM-010 Data: Updated OS

0 10 20 30 40 500

20

40

60

80

100

Overall Survival (Months)

Pat

ien

ts (

%)

*P value from log-rank test (patients analyzed for extended follow-up remained in original groups despite crossover)Weber D, et al. Blood (ASH Annual Meeting Abstracts) 2007;110:412.

Survival Benefit Retained Despite 47% Crossover

P=0.015*

Plac/Dex Median, 31 months

Len/DexMedian, 35 months(58% remain alive)

Impact of Prior Thalidomide Therapy: Pooled Analysis of MM-009 and MM-010 Data

Impact of Prior Thalidomide Therapy: Pooled Analysis of MM-009 and MM-010 Data

7.15020Refractory (PD)

7.04531SD

7.04354Progressed (CR/PR)8.354127Prior Thal

13.865226Thal Naïve

Median TTP, months

ORR (≥PR), %

n

Thal Naïve vs. Thal Exposed

Median Time from Diagnosis: 2.8 years vs. 4.0 years (P<.05)

Median Lines of Prior Therapy: 2 vs. 3 (P<.05)

Weber DM, et al. Presented at 49th ASH Annual Meeting; December 8-11, 2007; Atlanta, GA.; Weber DM, et al. N Engl J Med. 2007;357:2133-2142.; Dimopoulos M, et al. N Engl J Med. 2007;357:2123-2132.

APEX: Bortezomib Early vs. Late Relapse

APEX: Bortezomib Early vs. Late Relapse

Bortezomib1 prior therapy

n = 132

> 1 prior therapy

n = 200

Median TTP (months) 7.0 4.9

CR (%) 10%* 7%†

CR + PR (%) 51%* 37%†

Median Duration of Response (months)

8.1 7.8

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.

Updated APEX Results OS

Updated APEX Results OS

Pro

po

rtio

n o

f P

atie

nts

23.7 months

0.0

0.2

0.4

0.6

0.8

1.0

• Superior survival despite >62% of HD dexamethasone patients crossing over to bortezomib – 1-year survival rate: 80% vs. 67%; P=.0002

P=.0272

Time (Days)

Dexamethasone

Bortezomib

0 180 270 360 45090 540 720 810 900 990630 1080 1170

29.8 months

Richardson PG, et al. Blood. 2007;110:3557-3560.

23

Bortezomib Combination Therapies in Relapse

Author/Year N RegimenOverall

Response Rate (%)

CR/nCRRate (%)

Median PFS

(mos)

Median OS (mos)

Pineda-Romané/2008 85 BTD 63 22 – 22

Jakubowiak/2005 20 BD + PLD 56 33 – –

Biehn/2007 22 B + PLD 63 36 9.3 (TTP) 38.3

Popat/2005 22 B + Iv Mel +/- D 43 5 6.8 (TTP) –

Palumbo/2007 30 V Mel PT 67 17 61% (1 yr) 84% (1 yr)

Reece/2008 37 B + Cy + P 95 54 >12 >12

B = bortezomib; T = thalidomide; D = dexamethasone; PLD = pegylated liposomal doxorubicin; Mel = melphalan; P = prednisone; Cy = cyclophosphamide; PFS = progression-free survival; nCR = near complete response.

Kaufman J et al. Curr Hematol Malig Rep. 2009;4:99-107.

24

Lenalidomide Combination Therapies in Relapse

Author/Year N Regimen

Overall Response Rate (%)

CR/nCRRate (%)

Median PFS

Median OS

Schey/2009 31 LCD 81 36 (VGPR) – –

Knop/2009 66 LDoD 73 15 40 weeks 88% (1 year)

Reece/2009 15 LCP 74 45 (VGPR) – –

Baz/2006 52 L PLD ViD 75 29 (nCR) 1 year 84% (1 year)

Richardson/2009 35 LBV+/- D 60 >MR 8 7.7 months 37 months

Anderson/2009 62 LBVD 69 26 12 months 29 months

L = lenalidomide; C = cyclophosphamide; D = dexamethasone; DO = doxorubicin; P = prednisone; PLD = pegylated liposomal doxorubicin; Vi = vincristine; B = bortezomib.

Schey S et al. ASH 2008 Annual Meeting. Abstract 3707; Knop S et al. Blood. 2009;113:4137-4143; Reece DE et al. ASH 2009 Annual Meeting. Abstract 1874; Baz R et al. Ann Oncol. 2006;17:1766-1771; Richardson PG et al. J Clin Oncol. 2009;27:5713-5719; Anderson KC et al. 2009 ASCO Annual Meeting. Abstract 8536.

Main Randomized Trials of Treatment Main Randomized Trials of Treatment of Relapsed/Refractory MMof Relapsed/Refractory MM

ORR = overall response rate; CR = complete response; TTP = time to progression; NR = no response.Richardson et al, 2007; Orlowski et al, 2007; Weber et al, 2007; Dimopoulos et al, 2007.

Additional Bortezomib and Lenalidomide CombinationsAdditional Bortezomib and Lenalidomide Combinations

Study Regimen N Responses Frequent G3/4 AEs

Kropff, et al1 VCD 5016% CR66% PR

TCP, leukopenia, infection, PN, HZV, fatigue, anemia, hypotension

Morgan, et al2 CVD 4731% CR

75% ORRTCP, neutropenia, PN, infection

Reece, et al3 VCP 37>50% CR95% ORR

Nausea, TCP, neutropenia

Baz4 Len + PLD 6229% CR/nCR

75% ORRMyelosuppression

1Kropff M, et al. Br J Haematol. 2007;138:330-337. Comment in: Br J Haematol. 2008;140:115-116. 2Davies FE, et al. Haematologica. 2007;92:1149-1150. 3Reece DE, et al. J Clin Oncol. 2008;26:4777-4783. 4Baz R, et al. Ann Oncol. 2006;12:1766-1771.

PUTTING IT ALL TOGETHERPUTTING IT ALL TOGETHER

28

Indolent, Slow, First Relapse

• Initial Tx with Bz

• May consider single agent w/o Dex

• Underlying PN

IMiD-Based SalvageLenalidomideThalidomide

Likely Single-Agent Therapy With Bz or Len/Thal

Bortezomib-Based Salvage

Transplant-Based Salvage

• Initial Tx with IMiD

• Previous Bz therapy but good or long response

• Renal dysfunction

• Transplant not part of initial therapy

• Long remission post transplant

PN = peripheral neuropathy.

Lonial S et al. Clin Cancer Res. 2011;17:1264-1277. Permission requested.

29

Aggressive, Rapid, Multiple Relapse

• DCEP vs DT-PACE

• Oral vs IV chemo

• PS of patient plays important role

Chemotherapy-Based Salvage

Likely Combination TherapyDo Not Wait for Symptomatic Relapse

Chemotherapy + Novel Agent

Transplant-Based Salvage

• Combinations of Len/Bz and other chemo agents

• Likely to be short lived

• Quick disease control

• Reconstitute marrow

PS = performance status.

Lonial S et al. Clin Cancer Res. 2011;17:1264-1277. Permission requested.

Comparison of the triple (bortezomib-thalidomide-dexamethasone) and dual (thalidomide-dexamethasone) treatment groups.

Garderet L et al. JCO 2012;30:2475-2482

©2012 by American Society of Clinical Oncology

Patient Case Continued• 15 months after his stem cell transplant, he has a


• Treat or not– Yes, symptomatic relapse

• Single or Combo– I would use combination

• VTD • VRD• Carfilzomib based• DTPace if LDH elevated

• Retransplant– Difficult question if transplant naïve definitively yes.


Patient Case Continued• Receives VTD x 12 months and is placed on low

dose thalidomide maintenance. Within 2 months has new lytic lesions and increasing paraprotein peak.

• Treat or not?• Single or Combo?• Retransplant?


Response Duration Decreases With Successive Therapies

Response Duration Decreases With Successive Therapies

• 578 patients; median age 65 years (follow up 55 months)

• Overall survival– One year 72%

– Two years 55%

– Three years 22%

• 84% died within five years

Figure 3. Duration of response to each treatment

0

2

4

6

8

10

12

1 2 3 4 5 6

Treatment number

Med

ian

res

po

nse

d

ura

tio

n (

mo

nth

s)

Kumar SK, et al. Mayo Clin Proc. 2004;79:867-874.

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

Time to Progression After SCT Correlates With OS After Initial Relapse

Time to Progression After SCT Correlates With OS After Initial Relapse

Overall survival from time of relapse after ASCT- Impact of New Agents as Salvage

Therapy

Overall survival from time of relapse after ASCT- Impact of New Agents as Salvage

Therapy

Kumar SK, et al. Blood. 2008;111:2516-2520.

30.9 months (95% CI; 23.6, 38.2

14.8 months (95% CI; 11.3, 18.4

Recurrent MyelomaRecurrent Myeloma

• 45-year-old woman • κ light chain multiple myeloma diagnosed

January 2001 – Durie-Salmon Stage IIIA, ISS Stage 2

• Laboratory findings– Total proteinuria 5.82 g/day– Bence Jones protein (BJP) 3.6 g/day– Hypogammaglobulinemia– Albumin 3.9 g/dL – β2-microglobulin 4.7 mg/L


• Bone marrow biopsy – Cellularity 80% with 25% plasma cells

– Cytogenetics 46, XX, inversion 9 (p11;q13)

• FISH not done

• Skeletal survey: extensive lytic bone disease with healing fractures of left 7th and the 8th ribs

• MRI of the spine: diffuse hyperintense homogenous signal on STIR sequence

• MRI of the pelvis: diffuse marrow infiltrative changes due to myeloma


• Treatment– Vincristine 0.4 mg, doxorubicin 9 mg/m2

Days 1-4; dexamethasone 40 mg Days 1-4, 9-12, 17-20; x 4 cycles

– Followed by high-dose melphalan and stem cell transplant on July 11, 2001

• Achieved complete remission

• Maintained on pamidronate and prednisone x 1 year

First Relapse Five Years LaterFirst Relapse Five Years Later

• First relapse January 11, 2006– Urine total protein 550 mg/day– Creatinine clearance 84 mL/minute– BJP 100 mg/day– Urine IFE free κ light chain– Serum free κ 750 mg/L– Free λ 15 mg/L– κ:λ ratio 50– Multiple new lytic lesions of the skull

• MRI spine and pelvis January 11, 2006– New focal lesion at L3 vertebral body

Second Relapse After Failure of IMiDsSecond Relapse After Failure of IMiDs

• Treated with thalidomide and weekly dexamethasone for 6 months → stable disease

• Switched to lenalidomide and weekly dexamethasone x 3 months → stable disease

Third Relapse 18 Months LaterThird Relapse 18 Months Later

• Treated with bortezomib and dexamethasone x 4 cycles• Achieved CR• Painful peripheral neuropathy grade 2 • Discontinued treatment December 2006• PET/CT June 2008

– 1 cm focal hypermetabolic area in the inferior aspect of the left scapula– 2.2 cm focal hypermetabolic area in the region of right posterior superior

iliac spine, with associated lytic changes• Laboratory findings

– Free κ 117 mg/L– Free λ 15.6 mg/L– κ:λ ratio 7.5– Urine total protein 182 mg/day– BJP 60 mg/day– Urine immunofixation electrophoresis: free κ

• Treated with VRD with progressive disease

CTC=common toxicity criteria

Definition of Relapsed/Refractory MMDefinition of Relapsed/Refractory MM

Relapsed

– Relapse off therapy

Relapsed/Refractory

– Relapse while on, or within 60 days of discontinuing, therapy

– Unmet medical need

• Lack of drug approval for relapse/refractory to IMiD, bortezomib, alkylators, anthracyclines, and steroids

IMiD = immunomodulatory drugs.Anderson et al, 2008.

43Kumar SK et al. Leukemia. 2012;26:149-157.

Once Treatment Fails, Trouble Begins

Kumar S. Mayo Clin Proc. 2004;79:867-874.

Overall Survival From Start of Therapyby Regimen Number

00

.20

.40

.60

.81

.0

0 2 4 6 8 10

Cu

mu

lati

ve

Pro

ba

bil

ity

(%

)

Years From Start of Regimen

Regimen 1Regimen 2Regimen 3Regimen 4Regimen 5Regimen 6

0

20

40

60

80

100

0 12 24 36 48 60

Months From Time Zero

Survival with Bz/Len Refractory Ds

Overall Survival 173/231 9 (7, 11)

Event-Free Survival 222/291 5 (4, 6)

Events/NMedian

(Months)

Su

rviv

al

(%)

Newer agents

44

45

Bortezomib (reversible)Carfilzomib (irreversible)CEP 18770 (reversible)

MLN9708 (reversible)NPI-0052 (irreversible)

Post-glutamyl Tryptic

Chymo- tryptic

NPI

NPI NPI

Post-glutamyl

Tryptic

Chymo- tryptic

Bortezomib

Comparison of Proteasome Inhibitors

46

Study 004: Phase 2 Trial of Single-Agent Carfilzomib in

Relapsed/Refractory Multiple Myeloma

• Primary endpoint: ORR (CR + IVGPR + PR [IMWG criteria])

• Secondary endpoints: CBR (ORR + MR [EBMT criteria]), DOR, PFS, TTP, OS, safety– OS, TTP, response rate (EBMT criteria), safety

*Results for bortezomib (BOR)-treated cohort have been reported previously (Vij R et al. J Clin Oncol. 2010. Abstract 8000).†Subjects who enrolled under amended protocol allowing dose increase to 27 mg/m2 or who re-consented before Cycle 4 start were grouped in Cohort 2.

Study population (N = 165)

• Measurable disease

• Responsive to 1 prior therapy

• Relapsed and/or refractory MM following 1-3 prior treatment regimens

• ECOG PS 0-2

Carfilzomib IVqd x 2 for 3 weeks (28-day cycle for up to 12 cycles)

Cohort 120 mg/m2

Cohort 2†

20 mg/m2 cycle 1Escalation to 27 mg/m2

in all subsequent cycles

BOR-treated*(n = 35)

BOR-naive(n = 59)

BOR-naive(n = 70)

Vij R et al. ASH 2011 Annual Meeting. Abstract 813.

Bortezomib-naïve

patients (Wang, et al)

N = 59

Bortezomib-treated

patients (Siegel, et al)

N = 35

Evaluable patients 54 33

Complete response 1 (2%) 1 (3%)

Very good partial response 5 (9%) 1 (3%)

PR/MR/SD 35%/15%/22% 12%/12%/39%

Duration of response (≥ PR) 8.4 months 10.6 months

Treatment-emergent peripheral neuropathy

Grade 1/2: 12%

Grade 3: 2%

Grade 1/2: n = 3 (9%)

Grade 3: n = 1 (3%)

Results of the PX-171-004 Phase II Trial – Carfilzomib in Relapsed and/or Refractory MM

Wang L, et al. Blood (ASH Annual Meeting Abstracts). 2009;114:302.Siegel D, et al. Blood (ASH Annual Meeting Abstracts). 2009;114:303.

48

Median, monthsCohort 120 mg/m2

(n = 59)

Cohort 220/27 mg/m2

(n = 67)*

Duration of response n = 25 n = 35

Median, (95% CI) 13.1 (7.2-NE) NR (NE-NE)

Duration of clinical benefit response n = 35 n = 43

Median, (95% CI) 11.5 (6.2-NE) NR (NE-NE)

Time to progression n = 59 n = 67

Median, (95% CI) 8.3 (6.0-12.3) NR (11.3-NE)

Time to response n = 25 n = 35

Median, (min, max) 1.0 (0.5, 3.7) 1.9 (0.5, 3.7)

Time to clinical benefit response n = 35 n = 43

Median, (min, max) 0.5 (0.5, 6.5) 0.5 (0.5, 5.9)

Single-Agent Anti-Tumor Activity:Bortezomib-Naive Response-Evaluable

Population by Cohorts

*3 patients were not evaluable for response as they did not have either baseline or post-baseline assessment.

NE = not estimable; NR = not reached.


49

Progression-Free Survival:Response Evaluable Population


50

Overall Survival:Response Evaluable Population


51

Pomalidomide Summary

Study N Regimen Median Prior Therapies

ORR(%)

MR(%)

Richardson et al1

38 Pom (2-5 mg daily for 21/28 days) dex 6 25 50

120 Pom (4 mg daily for 21/28 days) dex 5 25 38

Lacy et al2

35 Pom (2 mg daily) + low-dose dex 6 26 49

35 Pom (4 mg daily) + low-dose dex 6 28 43

Leleu et al3

43 Pom (4 mg 21/28 days) + low-dose dex 4 18 NR

41 Pom (4 mg 21/28 days) + low-dose dex 4 16 NR

Pom = pomalidomide; dex = low-dose dexamethasone; ORR = overall response rate; MR = marginal response.

1. Richardson P et al. ASH 2010 Annual Meeting. Abstract 864.2. Lacy MQ et al. Blood. 2011;118;2970-2975.3. Leleu X et al. ASH 2010 Annual Meeting. Abstract 859.

52

Pomalidomide: Previous Phase 2 Studies in RRMM

Study Phase N Pom. schedule Treatment Population Prior

Lines*

ORR(≥ PR)

(%)

Richardson et al1 2 221 21/28 Pom: 4 mg vsPom 4 mg + Dex

Len & Bort refractory 5 13 vs 34

Lacy et al2 2 34 28/28# Pom: 2 mgDex: 40 mg/week Len refractory 4 32

Lacy et al3 2 70 28/28* Pom: 2 and 4 mgDex: 40 mg/week

Len & Bort refractory 6 25 and 29

Len = lenalidomide; bort = bortezomib; Pom = pomalidomide; RRMM = relapsed/refractory multiple myeloma.*Median prior therapies; †continuous.

1. Richardson P et al. ASH 2011 Annual Meeting. Abstract 634.2. Lacy MQ et al. Leukemia. 2010;24:1934-1939.3. Lacy MQ et al. Blood. 2011;118:2970-2975.

53

Arm A – Cycle 21 days

• Pomalidomide 4 mg oral/d, Days 1–21

Dexamethasone 40 mg oral/Weeks 1, 8, 15, 22

• Aspirin/LMWH continue

Primary objective:

Response rate (PR and better) according to IMWG in either arm

Arm B – Cycle 28 days

• Pomalidomide 4 mg oral/d, Days 1–28

Dexamethasone 40 mg oral/Weeks 1, 8, 15, 22

• Aspirin/LMWH continue

Key inclusion criteria:

• Relapsed MM

• Resistant or refractory to both lenalidomide and bortezomib

• Measurable disease (central lab)

• ANC >1 x109/L; Platelets ≥ 75 x109/L; Hb ≥ 8 g/dL

• Creatinine clearance ≥50 mL/min

N = 84 randomized

Pomalidomide: IFM 2009-2012 Study Design

Until progression (relapse or refractory)

17 patients per arm

40 patients per arm

6 patients per arm

DMC – TOLERANCERule: no difference

DMC – EFFICACYRule: 4 ≥ PR /arm

LMWH = low molecular weight heparin; IMWG = International Myeloma Working Group.Leleu X et al. ASH 2011 Annual Meeting. Abstract 812.

54

Time to Events0

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8 15

Su

rviv

al

Dis

trib

uti

on

Fu

nc

tio

n E

sti

ma

te

Time From First Intake (months)

HR = 1.18 [0.65]Log-rank P = 0.5875KM median: A = 9.23 [5.42]KM median: B = 7.36 [4.60, 9.96]Events: A = 21, B = 23

Time to ProgressionMedian 9.1 months

(95%CI, 5.8-10.0)

121 3 5 7 1410 139 11

AB

43 32 23 20 17 0636 30 22 19 011 215 8

41 32 23 20 16 0237 27 21 18 07 214 6

No. at Risk

A

B

Overall SurvivalMedian 13.4 months

(95%CI, 9.8-)

00

.20

.40

.60

.81

.0

0 2 4 6 8

Su

rviv

al

Dis

trib

uti

on

Fu

nc

tio

n E

sti

ma

te

Time From First Intake (months)

HR = 0.90 [0.46, 1.73]Log-rank P = 0.7453KM median: A = 13.44 [8.90, 13.93]KM median: B = 15.26 [9.17]Events: A = 19, B = 18

121 3 5 7 109 11

A

B

43 40 36 31 29 942 38 32 30 2126 14

41 39 32 30 27 840 34 32 29 1926 15

No. at Risk

A

B

Leleu X et al. ASH 2011 Annual Meeting. Abstract 812.

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≥ PR21/28N = 43

28/28N = 41

Total

All patients % 35 34 34.5

Refractory to* %

Lenalidomide 36 36 36

Bortezomib 32 26.5 29

Both lenalidomide and bortezomib 34 28 31

Last prior therapy 33 31 32

Del17p and/or t(4;14) 25 31 30

Response by Prior Therapy: ITT, IRC

*Refractory to as per IMWG criteria.


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AEs, %21/28N = 43

28/28N = 41

Total

Serious AEs 33 41.5 37

Any grade 3 and 4 AEs 91 83 87

Blood and lymphatic system disorders 72 71 71

Anemia 33 32 32

Neutropenia 63 56 59.5

Thrombocytopenia 28 24 26

General disorders and administration site conditions

23 27 25

Asthenia 14 5 9.5

Discontinued due to drug-related AE, n = 2.


Adverse Events

57

Tai YT et al. Cancer Res. 2005;65:5898-5906; Hideshima T et al. Clin Cancer Res. 2005;11:8530-8533. Permission requested; Catley L et al. Blood. 2006;108:3441-3449.

Blockade of Ubiquitinated Protein Catabolism

HDAC6

HDAC6

HDAC6

Protein

Protein aggregates(toxic)

Ub

26S Proteasome

Ub Ub

Ub

Aggresome

TubacinLBH, vorinostat

Dynein

Dynein

MicrotubuleAutophagy

Bortezomib

Ub Ub

Ub

Lysosome

Ub

Ub

Ub

Ub

UbUb

Ub

Ub Ub

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VANTAGE PN088: Phase 3 Trial Design

• Primary endpoint– PFS†

• Secondary endpoints– OS, TTP, response rate† (EBMT criteria), safety

*Constitutes patients who received treatment after randomization.†Assessed by an Independent Adjudication Committee.

EBMT = European Group for Blood and Marrow Transplantation.

Dimopoulos MA et al. ASH 2011 Annual Meeting. Abstract 811.

Patients enrolled(N = 637)

• Progressive disease after the most recent treatment

• 1 to 3 prior treatment regimens

• Bortezomib-sensitive patients

Dosing schedule

Bortezomib 1.3 mg/m2 IV on Days 1, 4, 8, 11

in combination with

Vorinostat 400 mg OR placeboOnce daily on Days 1-14

(21-day treatment cycle)

Analysis populations

Intent-to-treat (ITT)PFS, TTP, OS

Bortezomib + Vorinostat (N = 317)

Bortezomib + Placebo (N = 320)

Full analysis set (FAS)*

ORR, safetyBortezomib + Vorinostat

(N = 315)Bortezomib + Placebo (N = 320)

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EBMT Response Assessment (IAC): Response-Evaluable Population

ORR = 56% vs 41%, P<0.0001

CBR = 71% vs 54%, P<0.0001

Bortezomib + vorinostat (N = 315) Bortezomib + placebo (N = 320)

IAC = Independent Adjudication Committee; SD = stable disease.


60

0 5 10 15 20 25Time (months)

0102030405060708090

100

PF

S (

%)

BTZ + Placebo

BTZ + Vorinostat

320 157 58 12 4 0317 196 75 14 3 0

BTZ + Placebo

No. at Risk:BTZ + Vorinostat

Progression-Free Survival (IAC)

Events Median PFS (95% CI) HR (95% CI) P valueBTZ + VorinostatBTZ + Placebo

201/317216/320

7.63 months (6.9-8.4)6.83 months (5.7-7.7)

0.774 (0.64-0.94) 0.01


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Overall Survival

0 5 10 15 20 25 30Time (months)

0102030405060708090

100

OS

(%

)

320 286 235 124 48 16 0317 291 238 120 43 12 1

BTZ + Placebo

No. at Risk:BTZ + Vorinostat

Events Median OS (95% CI) HR (95% CI) P valueBTZ + VorinostatBTZ + Placebo

71/31780/320

NA28.1 months (28.1 – NA)

0.86 (0.62 – 01.18) 0.35

NA = not available.


BTZ + Placebo

BTZ + Vorinostat

Second Salvage ASCT for Relapsed MyelomaPrincess Margaret Hospital (N=79)

Mikhael J, et al. Blood 2009; 114: abstract #1217

• Median 60 years (39-72)• Median TTP after 1st transplant 2.72 years (0.81-8.26)• Median interval between transplants 3.61 years (1.63-9.59)• NRM 2.5%• Response after 2nd transplant: 15% CR/nCR, 78% PR, 8% MR/SD• Results after 2nd transplant based on TTP after 1st transplant

Group N Median PFS (mos) Median OS (mos)

All 79 18.5 52.8

<24 mos 15 12.7 42.2

24-36 mos 30 17.0 52.7

>36 mos 34 32.6 NYR

Second Salvage AlloSCT for Myeloma

Study N Median FU(mo)

Response rate (CR) (%)

Median PFS (mos)

MedianOS (mos)

Gerull/20051 52 19 -- ~6 ~16

Quazilbash/20062 26 30 69 (31) 7.3 13

Majolino/20073 41 -- -- ~28 ~30

van Dorp/20074 23 -- --(4) 12 --

de Lavallade/20085 18 36 61 ~24 ~36

Kroger/20096 96 43 95 (46) 10.6 22.6

1Gerull S, et al. Bone Marrow Transplant 2005; 36: 963-939; 2Quazilbash MH, et al. Cancer 2006; 106; 1084-1089; 3MajolinoI et al. Leuk Lymphoma 2007; 48: 759-766; 4van Dorp S, et al. Neth J Med 2007; 65: 178-184; 5 de Lavallade

H, et al. Bone Marrow Transplant 2008; 41: 953-960; 6Kroger N, et al. Br J Haematol 2010; 148: 323-331.

CIBMTR Data

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Antibodies

• BT-062 (CD138 + maytansinoids) • CD40• CD200• CD56

Bortezomib combinations have activity:Bz + CNTO 328 (anti IL6 ab)1: ORR of 57% with TTP of 8.7 months (1-3 prior lines)

Bz + Elotuzumab (anti CS1 ab)2: ORR of 48% TTP of 9.4 months (median of 2 prior lines)

1. Rossi JF et al. ASH 2008 Annual Meeting. Abstract 1867.2. Jakubowiak AJ et al. 2010 ASCO Annual Meeting. Abstract 8003.

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Elotuzumab Background

ADCC = antibody-dependent cellular cytotoxicity; DMSO = dimethyl sulfoxide; mAb = monoclonal antibody; MED = maximum efficacious dose; MoA = mechanism of action; NK = natural killer.1. Hsi ED et al. Clin Cancer Res. 2008;14:2775-2784. Permission requested; 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. ASH 2009 Annual Meeting. Abstract 432.

• Elotuzumab is a humanized IgG1 mAb targeting human CS1, a cell surface glycoprotein1,2

• CS1 is highly expressed on >95% of MM cells1-3

– Lower expression on NK cells

– Little to no expression on normal tissues

Tu

mo

r V

olu

me

(m

m3 )

Study Day

600

400

300

200

100

0

500

14 28 35 4221

Lenalidomide dosing (50 mg/kg)

Elotuzumab (1 mg/kg) or control IgG1 dosing

Control IgG1 + DMSO

Elotuzumab + DMSO

Lenalidomide + control IgG1

Elotuzumab + lenalidomide

• MoA of elotuzumab is primarily through NK cell-mediated ADCC against myeloma cells1,2

• In a MM xenograft mouse model, the combination of elotuzumab + lenalidomide significantly reduced tumor volume compared with either agent alone4

Normal plasma cells Plasmacytoma

Lymphoplasmacytic lymphoma

Myeloma cells in bone marrow

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Elotuzumab + Lenalidomide + Low-Dose Dexamethasone: Phase 1 Results

• Elotuzumab tested at 5, 10, and 20 mg/kg– Elotuzumab-related AEs were primarily infusion-related– 89% experienced at least 1 infusion reaction AE, no DLTs observed

and MTD not reached

VGPR = very good partial response; DLT = dose-limiting toxicity.

Lonial S et al. ASCO 2010 Annual Meeting. Abstract 8020; Lonial S et al. ASH 2010 Annual Meeting. Abstract 1936.

• Median TTP not reached at a median 12.7 months’ follow-up• Elotuzumab saturation of CS1 binding sites in BM MM cells >80%

at both 10 (n = 1) and 20 mg/kg (n = 4)

TotalLenalidomide-

Naive Prior ThalidomideRefractory to Most

Recent Therapy

Total Patients, n 28 22 16 12

≥ PR, n (%) 23 (82) 21 (95) 15 (94) 10 (83)

CR/VGPR, n (%) 11 (39) 10 (45) 7 (44) 5 (42)

PR, n (%) 12 (43) 11 (50) 8 (50) 5 (42)

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Elotuzumab 10 mg/kg

Elotuzumab 20 mg/kg Total

Patients, n 36 37 73

ORR (≥PR), n (%) 33 (92) 27 (73) 60 (82)

CR/stringent CR, n (%) 5 (14) 4 (11) 9 (12)

VGPR, n (%) 14 (39) 12 (32) 26 (36)

PR, n (%) 14 (39) 11 (30) 25 (34)

<PR, n (%) 3 (8) 10 (27) 13 (18)

EfficacyBest Response (IMWG Criteria)

• Median time to response: 1 month (range, 0.7-5.8)

• Median time to best response: 2.2 months (range, 0.7-17.5)

Lonial S et al. ASH 2011 Annual Meeting. Abstract 303.

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Progression-Free Survival

No. at Risk:10 mg/kg20 mg/kg

36 32 30 29 2137 29 26 23 19

13 4 1 014 4 0 0

Months

100

Pro

po

rtio

n o

f P

rog

ress

ion

-Fre

e P

atie

nts

(%

)

0 1 2 3 4 5 6 7 8 9 10 11 12 13

Median Time to Progression/Death:

10 mg/kg (n = 36): NA

20 mg/kg (n = 37): NA

14 15 16 17 18 19 20 21 22

90

80

70

60

50

40

30

20

10

0

Median Follow-Up:

10 mg/kg: 14.0 mo (range 2.6-21.2 mo)

20 mg/kg: 14.3 mo (range 2.1-20.5 mo)

At a median follow-up of 14.1 months, the median PFS was not reached– PFS rate was 75% (10 mg/kg) and 65% (20 mg/kg)


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Investigator-Designated Infusion Reactions

Elotuzumab

TotalN = 73

Parameter, n (%)10 mg/kg

n = 3620 mg/kg

n = 37

Any AE 5 (14) 4 (11) 9 (12)

Grade 1 3 (8) 2 (5) 5 (7)

Grade 2 1 (3) 2 (5) 3 (4)

Grade 3* 1 (3) Rash 0 1(1)

• Investigator-designated infusion reactions are AEs identified by the investigator as a sign or symptom of an elotuzumab-related infusion reaction

• AEs that occurred in ≥ 2 subjects included nausea, pyrexia, and rash

*There were no Grade 4 infusion reaction AEs.


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Summary

• New options and combinations are active in relapsed/refractory disease

• Novel targets help to improve outcomes perhaps even better than the historical use of alkylators

• Proteasome inhibitors, IMiDs, HDACs, and antibodies will help to improve outcomes in relapse and induction

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Conclusion

• THERE IS NO EASY ALGORITHM FOR MANAGING RELAPSED/REFRACTORY MULTIPLE MYELOMA

• Patient-specific issues and prior therapy should be used to determine choice of agents

• Use of FISH and cytogenetics can guide single-agent vs combo decision and prognosis

• New targets and agents are being explored. Phase 3 trials are in progress

Relapse Myeloma

Health & Medicine

Transcript of Relapse Myeloma