Myeloma Updates ASH 2011 Annual Meeting Steve Smith OHSU Knight Cancer Institute Center for Hematologic Malignancies [email protected]

Myeloma UpdatesASH 2011 Annual Meeting

Steve Smith

OHSU Knight Cancer Institute

Center for Hematologic Malignancies

[email protected]

What was new is now old…

long-term data on novel agent + chemo combinations

2nd generation immunomodulators, proteasome inhibitors

Will chemotherapy combinations be replaced by multitargeted therapies?

Overview: Progress in MM

Overall survival rates improving• in younger patients

Almost 800 ASH abstracts in multiple myeloma• about 10x more than a decade ago

understanding of pathbiology• of the malignant plasma cell and microenvironment

ASH 2011: • nontransplant (elderly) regimens: longer follow-up• second generation novel agents• “multitargeted” strategies

MM Survival Trends

1950 – 19591960 – 19691970 – 19791980 – 19891990 – 19992000 – 2005

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12 24 36 48 60 72 84 96 108 120 132 144 156 168 1800

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12 24 36 48 60 72 84 96 108 120 132 144 156 168 180

Patients < 65 years at Diagnosis* Patients > 65 years at Diagnosis*

Turesson I, et al. J Clin Oncol. 2009;28:830-834.

*Swedish Registry data.

MPT1

N = 129VMP2

N = 337MPR3

N = 153MPR-R4

N = 152VTP5

N = 130

CR 16% 30% 11% 16% 27%

> VGPR 29% Not reported 33% 32% 37%

> PR 69% 71% 68% 77% 81%

PFS 21.8 mo TTP: 24.0 mo 14 mo 31 mo 23 mo

Median follow-up 31.8 mo 36.7 mo 25 mo 25 mo 22 mo

1Palumbo A, et al. Blood. 2008;112:3107-3114; 2Mateos MV, et al. Blood. 2009;114(22). Abstract 3859;

3,4Palumbo A, et al. Blood. 2010;116(21). Abstract 622 and Abstract 566; 5Mateos MV, et al. Blood. 2009;114(22). Abstract 3.

MPT: melphalan, prednisone, thalidomide; VMP: bortezomib, melphalan, prednisone; MPR: melphalan, prednisone, lenalidomide; MPR-R: MPR with maintenance lenalidomide; VTP: bortezomib, thalidomide, prednisone.

Newly Diagnosed, Patients SCT Ineligible

VISTA Final Analysis

(Velcade) as Initial Standard Therapy in Multiple Myeloma= VISTA

updated OS analysis of VISTA after 5 years median follow-up

randomized, international, phase III clinical trial

Newly Diagnosed/SCT ineligible




5-year OS • VMP vs MP: 46.0% vs 34.4% • 13.3-month increase in OS

OS benefit in most subgroups • sex, race, geographic region, β2-microglobulin level, and

albumin level

OS benefit not observed for high-risk cytogenetics • OS benefit initially observed in VMP arm diminished when patients received

second-line therapy (included bortezomib in 60% of MP pts)


MPRR: Italian intergroup study MM-015 ASH 2011: 41 month f/u

MM-015: MPR with or without maintenance lenalidomide, vs MP in upfront SCT ineligible pts


Italian Intergroup MM-015

PFS benefit to lenalidomide maintenance

MPR-R vs MPR

Landmark Analysis: PFS After Cycle 9

Palumbo A, et al. Blood. 2009;114(22). Abstract 613;Palumbo A, et al. European Hematology Association 15th Congress. 2010. Abstract 566.

100

75

50

25

00 5 10 20 2515

Time (months)

Pat

ient

s(%

)

30

HR 0.314Log rank P< 0.001


MM-015: Outcomes in Overall Population

Continued lenalidomide significantly improves PFS vs placebo• PFS benefit extended through patient subgroups in landmark analysis

⁻ Age (65-75 vs > 75 yrs), response (PR vs ≥ VGPR), ISS stage (I/II vs III)

• No effect on OS or TTP with maintenance lenalidomide

Palumbo A, et al. ASH 2011. Abstract 475.

Outcome MPR-R(n = 152)

MPR(n = 153)

MP(n = 154)

Median PFS, mos HR vs MP P value vs MP

310.395< .001

140.796.135

13

4-yr OS, % HR vs MP P value vs MP

590.898.579

581.089.648

58

TTP HR vs MP 0.337 0.826

MM-015: Grade 4 Toxicities during induction and maintenance

1. é J et al. Br J Haematol. 1998;102:1115-1123. Palumbo A, et al. ASH 2011 Abstract 475

Adverse Events, %*Induction Therapy Maintenance

Therapy

MPR MP MPR-R MPR

Grade 4 hematologic events

•Neutropenia 32 7 2 0

•Thrombocytopenia 7 4 4 3

•Anemia 2 2 3 1

•Febrile neutropenia 0 0 0 0


MM-015: Second Malignancies

1. é J et al. Br J Haematol. 1998;102:1115-1123. Palumbo A, et al. ASH 2011 Abstract 475

Second Malignancies, Incidence Rate/100 Patients/Yr

MPR-R(n = 150)

MPR(n = 152)

MP(n = 153)

Total invasive second primary malignancies

3.04 2.57 0.98

Hematologic malignancies 1.75 1.54 0.24

Solid tumors 1.26 1.28 0.74

Nonmelanoma skin cancer 0.50 1.29 1.50


Kumar, et al. Haematologica. 2010;95(suppl 2). Abstract 376.

Patients Relapsing and Refractory to Bortezomib and Thalidomide or Lenalidomide

Relapsed / Refractory Disease

N Events (n) Median

Overall Survival 291 173 9 months

Event-Free Survival 291 222 5 months

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100%

0 12 24 36 48 60Months

The Next Generation…

2nd generation immunomodulatory agents

2nd generation proteasome inhibitors

HDAC Inhibitors

Monoclonal antibodies

Alkylating agents

Other proteasome inhibitors

Heat shock protein inhibitors

PI3K / AKT inhibitor

mTOR inhibitors

Carfilzomib: second-generation proteasome inhibitor

Administered IV• First 2 days of each week, for 3 weeks (repeated monthly)

Active in heavily pretreated MM patients

Mild neuropathy seen but uncommon (< 20%)• Severe neuropathy (grade 3-4): <2% • Toxicity

⁻ Myelosuppression, fatigue, URI/ PNA, infusion reactions ≈ 15% grade 3-4 anemia, thrombocytopenia, and neutropenia

PX-171-003-A1: Siegel DS, et al. Blood. 2010;116(2). Abstract 985;PX-171-004 Stewart K, et al. Hematologica. 2010;95(S2). Abstract 1099;

Wang ASH 2009 Abstract 302.

Niesvizky R, et al. Blood. 2010;116(2). Abstract 619.

Carfilzomib: Phase II Rel/Ref MM

ASH 2011: Single-Agent Carfilfzomib, rel/ref MM (PX-171-004): Final results from the bortezomib-naive group

n = 129 Treated for up to 12 cycles

Data from 2 cohorts presented

1- Carfilzomib 20 mg/m2 (n=59)

2- Carfilzomib 20 mg/m2 for cycle 1, then to 27 mg/m2 for cycles 2-12 (n=70)

Vij R, Kaufman JL, Jakubowiak AJ, et al. Abstract 813 Rel/Ref MM

Carfilzomib phase II PX-171-004: Baseline characteristics

Vij R, Kaufman JL, Jakubowiak AJ, et al. Abstract 813

CharacteristicCarfilzomib

20 mg/m2

(n = 59)

Carfilzomib 20/27 mg/m2

(n = 70)

Median age, yrs (range) 65 (38-82) 65.5 (45-85)

Median yrs from diagnosis (range) 3.5 (0.7-24.4) 3.6 (0.7-12.2)

Neuropathy, % 49 55

Median previous treatments, n (range)

2 (1-4) 2 (1-4)

Refractory to most recent therapy, %

66 64

Prior Stem cell transplantation (%)

80 67

Cyto or FISH = Unfavorable (%) 15 14

Rel/Ref MM

Carfilzomib phase II PX-171-004: Response Data

Vij R, Kaufman JL, Jakubowiak AJ, et al. Abstract 813

OutcomeCarfilzomib

20 mg/m2

(n = 59)

Carfilzomib 20/27 mg/m2

(n = 67)*

ORR, % 42 52 CR 3 2

VGPR 14 27

PR 25 24

Median time to response, mos

1.0 1.9

Median PFS, mos 8.2 NR

Median duration of f/u, mos

23.2 13.8

Rel/Ref MM

Carfilzomib phase II PX-171-004: Conclusions

In bortezomib-naïve rel/ref MM pts, combined ORR 48%• Potential dose-response relationship

No increase in neuropathy risk with carfilzomib in pts with history of, or pre-existing, neuropathy• PNP is

⁻ Mostly mild to moderate severity , not dose limiting

Grade 3/4 adverse events in 80% of patients- primarily hematologic

⁻ Generally reversible

AE’s led to treatment discontinuation in 16% of patients

Vij R, Kaufman JL, Jakubowiak AJ, et al. Abstract 813 Rel/Ref MM

ASH 2011: Phase 2 results

Carfilzomib + len + dex

Upfront, SCT-eligible






MLN9708 Phase I Study: ASH 2011

MLN9708, PO proteasome inhibitor Phase I study relapsed/refractory MM (N = 56)

⁻ Dose-escalation phase (n = 26)⁻ Expansion phase (n = 36; 6 from dose-escalation cohort)⁻ 27% to 32% refractory to bortezomib on last previous therapy

MLN9708 dosing ⁻ Starting 0.24 mg/m2, increased to 2.23 mg/m2 on Days 1, 4, 8, 11 of a

21-day cycle for up to 12 cycles

• 46 patients evaluable for response

Richardson PG, et al. ASH 2011. Abstract 301.Rel/Ref MM

MLN9708 Phase I Study: Safety and Response

MTD 2.0 mg/m2

• 32% of patients required dose reductions due to adverse events⁻ Mainly thrombocytopenia, neutropenia, and rash⁻ 9% of patients discontinued treatment due to adverse events

Grade 3/4 adverse events: thrombocytopenia (34%), neutropenia (14%), fatigue (9%), rash (9%)• No grade 3 /4 neuropathy

15% (n = 7) patients achieved response• Durable disease control up to 15.9 mos• Majority (61%) of remaining patients reached SD, durable for up to 12.9

mos


MLN9708 + Len + Dex: Phase I/II Combination

Open-label, multicenter, dose-escalation phase I/II trial• Primary endpoints: safety, MTD, recommended phase II dose

⁻ Secondary endpoints: MLN2238 pharmacokinetics, treatment response

Previously untreated MM (n = 15 to date)

Treatment: 28-day cycles for up to 12 mos⁻ MLN9708: started at 1.68 mg/m2, increased in 33% increments based DLT

⁻ Dex: 40 mg/day on Days 1, 8, 15, 22

⁻ Lenalidomide: 25 mg/day on Days 1-21

Berdeja JG, et al. ASH 2011. Abstract 479.Upfront, SCT-eligible

MLN9708 + Len + Dex Phase I/II: outcomes

Responses observed in all patients (N =15), generally in cycle 1• CR (n = 4), VGPR (n = 5), and PR (n = 6)

No DLT observed up to 2.23 mg/m2 MLN9708• Recommended phase II dose: 2.23 mg/m2/wk

Well tolerated • Grade 1 peripheral neuropathy (n = 3)

• Grade 3: vomiting (n = 2), deep vein thrombosis (n = 2), anemia (n = 2),rash (n = 2)

• Grade 4: thrombocytopenia (n = 1)

Berdeja JG, et al. ASH 2011. Abstract 479.Upfront, SCT-eligible

Final topic…Relapsed/novel agents:

Multitargeted combinations

clinicaloptions.com/oncologyUpdate on Multiple Myeloma

VANTAGE 088: Study Design

International, multicenter, double-blind, randomized phase III trial[1]

– Vorinostat: HDAC inhibitor active when combined with bortezomib in phase I and II trials[2-4]

1. Dimopoulos MA, et al. ASH 2011. Abstract 811. 2. Weber D, et al. ASCO 2008. Abstract 871.3. Badros A, et al. Clin Cancer Res. 2009;15:5250-5257. 4. Siegel DS, et al. ASH 2011. Abstract 480.

Relapsed/refractory MM

patients with PD followingmost recent therapy

(N = 637)

1-3 previous therapies; bortezomib sensitive

PD or unacceptable

toxicity

Bortezomib 1.3 mg/m2

on Days 1, 4, 8, 11 +Vorinostat 400 mg/day

on Days 1-14(n = 317)

Bortezomib 1.3 mg/m2

on Days 1, 4, 8, 11 +Placebo(n = 320)

21-day cycles

Primary endpoint: PFSSecondary endpoints:OS, TTP, ORR, safety

Rel/Ref MM


VANTAGE 088: PFS, OS, and Response

PFS significantly prolonged with addition of vorinostat to bortezomib

– No difference in median OS (data not yet mature)

Dimopoulos MA, et al. ASH 2011. Abstract 811.

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ORR CR VGPR PRResponse Type

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pons

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MR SD

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

7.63 vs 6.83 mosHR: 0.774 (95% CI: 0.64-0.94; P = .01)

P < .0001

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PANORAMA-2: Study Design

Panobinostat: potent, investigational HDAC inhibitor

– Combination with bortezomib active in relapsed/refractory MM

– ORR: 80% (overall population); 50% (bortezomib-refractory subset)[1]

Current study evaluated efficacy of panobinostat with bortezomib plus dexamethasone in relapsed bortezomib-refractory MM patients (N = 55)[2]

– Single-arm phase II trial

– Primary endpoint: ORR

1. San Miguel J, et al. 2011 EHA. Abstract 0314. 2. Richardson PG, et al. ASH 2011. Abstract 814.

Phase I: 8 x 3-wk cyclesPanobinostat 20 mg on Days 1, 3, 5, 8, 10, 12 +

Bortezomib 1.3 mg/m2 on Days 1, 4, 8, 11 +Dexamethasone 20 mg on Days 1, 2, 4, 5, 8, 9, 11, 12

Phase II (for patients with clinical benefit after phase I):6-wk cycles until PD

Panobinostat 20 mg on Days 1, 3, 5, 8, 10,12, 22, 24, 26, 29, 31, 33 +

Bortezomib 1.3 mg/m2 on Days 1, 8, 22, 29 +Dexamethasone 20 mg on Days 1, 2, 8, 9, 22, 23, 29, 30

Rel/Ref MM


PANORAMA-2: Response and Safety

Responses were rapid, often within 1-2 cycles

Most frequent grade 3/4 events: thrombocytopenia (53%), anemia (16%), neutropenia (12%)

– Peripheral neuropathy (24%) was grade 3/4 in only 1 patient (2%)

– Fatigue (63%) was grade 3/4 in 16%; generally manageable with dose reduction

Response Rate, % Panobinostat + Bortezomib + Dexamethasone (n = 55)

ORR (CR + nCR + PR) 29

CR 0

nCR 4

PR 25

Clinical benefit (ORR + MR) 49

MR 20

VGPR 6



PANORAMA-2: Conclusions

Combination of investigational HDAC inhibitor panobinostat with bortezomib active[1]

– Effective even in this heavily pretreated, bortezomib-refractory MM patient set

Treatment relatively well tolerated[1]

– Grade 3/4 myelosuppression manageable with dose reduction or interruption

– Infrequent grade 3/4 peripheral neuropathy

Lower toxicity with this dose schedule (1 wk rest period between cycles) vs previously observed in phase I trial[2]

1. Richardson PG, et al. ASH 2011. Abstract 814. 2. San Miguel J, et al. 2011 EHA. Abstract 0314.Rel/Ref MM

On the horizon

Improving outcomes for lenalidomide/bortezomib- refractory patients

maximizing clinical benefit • disease control using maintenance? drug holiday? Multitargeted combinations?

Active clinical trials: • Novel agents, orally administered• MLN+rev+dex upfront • optimal ASCT regimen? CTN 0702:

⁻ tandem len maintenance ⁻ single len+bort+dex consolidation len maintenance⁻ single len maintenance

Acknowledgements

Myeloma Program at OHSU: • Emma Scott, MD ([email protected])• Anne Kratz, RN• Richard Maziarz, MD ([email protected])• All other MD, RN, PA/NP, admin staff at OHSU

Slides• Rachid Baz, MD (Moffitt Cancer Center, Tampa, FL)• Clinical Care Options (clinicaloptions.com)• educational concepts group (www.educationalconcepts.net)

(Extra slides)

(Extra slides)Consolidation after ASCT- already presented in Paris 2011…

CALGB 100104 • OS benefit to len maintenance after ASCT (90 vs 83% OS

at 28 months, p=.02)• TTP benefit 48 mo vs 31 mo• second malignancies higher (n=15 vs 6)

IFM 2005- clear PFS benefit (42 vs 22 mo), second malignancies higher, study halted

both: higher cumulative grade 3-4 PMN with maintenance, more 2nd malignancies…


QuiRedex: Study Design

Multicenter, open-label, randomized phase III trial

– Evaluated new treatment regimen for smoldering MM vs current standard of care

Mateos MV, et al. ASH 2011. Abstract 991.

Patients with high-risk

smoldering MM

(N = 126)

Lenalidomide 25 mg/day on Days 1-21 +

Dexamethasone 20 mg/day on Days 1-4, 12-15

No Treatment No Treatment

Lenalidomide10 mg/day on Days 1-21

(Low-dose dexamethasoneadded at time of

biologic progression)

Induction9 x 28-day cycles

Maintenance28-day cycles

2 yrs

Primary endpoint: TTP to symptomatic MMSecondary endpoints: response, duration of response, safety and tolerability, PFS, OS


QuiRedex: TTP to Symptomatic MM and OS Significant increase in TTP with vs without treatment

Significantly prolonged OS with vs without treatment

– Median 3-yr OS (from study inclusion): 93% vs 76%; P = .04

– Median 5-yr OS (from diagnosis): 94% vs 79%; P = .03


Median TTPLenalidomide/dexamethasone: NR

No treatment: 23 mosHR: 6.0 (95% CI: 2.9-12.6; P < .0001)

Median follow-up: 32 mos (range: 12-49)

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Lenalidomide + dexamethasoneNo treatment


QuiRedex: Safety

3 cases of second primary malignancies reported in treatment arm


Adverse Event, % Lenalidomide + Dexamethasone(n = 57)

No Treatment(n = 62)

Grade 1/2 Grade 3 Grade 1/2

Anemia 28 2 --

Neutropenia 20 5 --

Thrombocytopenia 13 2 --

Asthenia 20 7 11

Constipation 18 -- 2

Diarrhea 24 2 4

Rash 33 4 --

Paresthesias 5 -- --

Tremor 13 -- 2

Infection 46 6 26

Deep vein thrombosis 5 --

Alternative Bortezomib Regimens

Reeder CB, et al. ASH Annual Meeting Abstracts. 2009;114(22):616; Palumbo A, et al. ASH Annual Meeting Abstracts. 2010;116(21):620.

Regimen N ORR CR Grade 1/2 PN

> Grade 3 PN

CyBorD Twice weekly btz Once weekly btz

3330

88%93%

39%40%

64%56%

6%0%

VMPT-VT Twice weekly btz Once weekly btz

63190

86%85%

35%30%

29%19%

14%2%

Btz: bortezomib; PN: peripheral neuropathy; CyBorD: cytarabine, bortezomib, dexamethasone; VMPT-VT: bortezomib, melphalan, prednisone, thalidomide followed by maintenance bortezomib and thalidomide.

Bort- Alternative Modes of Administration

Moreau P, et al. Blood. 2010;116(21). Abstract 312.

IV BortezomibN = 73

SC BortezomibN = 145

P

ORR after 8 cycles CR > VGPR

52%12%25%

52%10%25%

NSNSNS

Median TTP 9.4 months 10.4 months 0.39

1-year OS 77% 73% NR

Any grade 3/4 AE 70% 57% NR

PN Any grade > grade 3

53%16%

38%6%

0.040.03

IV: intravenous; SC: subcutaneous; CR: complete response; VGPR: very good partial response; TTP: time to progression; OS: overall survival; AE: adverse event; PN: peripheral neuropathy.

Documents

Myeloma Updates ASH 2011 Annual Meeting Steve Smith OHSU Knight Cancer Institute Center for Hematologic Malignancies [email protected]