multiple myeloma highlights from the 2015 asco annual ... · slides multiple myeloma highlights...

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SLIDESMultiple Myeloma Highlights From the

2015 ASCO & EHA Annual Meetings

Multiple Myeloma Highlights From the 2015 ASCO Annual Meeting and the 20th Congress of EHA

July 13, 2015

Welcome and Introductions

Anne Quinn Young, MPHMultiple Myeloma Research Foundation

Norwalk, CT

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Shaji Kumar, MDMayo Clinic

Rochester, MN

Jeffrey Wolf, MDUniversity of California San Francisco

San Francisco, CA

Faculty

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San Francisco, CA

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Improvement in Overall Survival in the Treatment of Myeloma (By Decade)

1961-701971-801981-901991-20002001-2010

Follow up from Diagnosis (Years)

Pro

po

rtio

n S

urv

ivin

g

0 2 4 6 8 10 12 14 16 18 20

0.0

0.2

0.4

0.6

0.8

1.0

Wolf J Presentation at 2015 ASCO

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Diagnostic Criteria for MGUS, SMM, and MM

< 3 g/dL serum

AND

< 10%

AND

Absent

MGUS

Present(serum/urine)

AND

> 10%b

AND

Present

MM

3 g/dL serum

AND/OR

10-60%

AND

Absent

SMM

Monoclonal Component

Bone MarrowPlasma Cells (%)

End-organ Damage

Mateos M-V. Presentation at ASCO 2015

MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; SMM, smoldering multiple myeloma.

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New Definitions for Smoldering Multiple Myeloma and Symptomatic Multiple Myeloma

Changes to smoldering classification criteria

CRAB criteria

Calcium elevation

Renal insufficiency

Anemia

Bone disease

Plasmacytosis ≥60%

Light chains involved/uninvolved >100

≥1 focal lesion on magnetic resonance imaging (MRI)

Rajkumar et al. Lancet Oncol. 2014;15(12):e538.

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monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM)

Asymptomatic Symptomatic

ACTIVE MYELOMA

M-p

rote

in (

g/L

)

20

50

100

FIRST RELAPSE

SECOND

RELAPSEREFRACTORY RELAPSE

First-line therapy

Plateau remission

Second-line Third-line

Myeloma is always preceded by MGUS or SMM

Mateos M-V. presentation at ASCO 2015

Natural History of Multiple Myeloma

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Smoldering Multiple Myeloma

All patients with smoldering myeloma are not equal

Probability of progression to symptomatic disease increases with increased number of risk factors:

− Evolving M protein pattern

− Immunoparesis

− Bone marrow plasma cell involvement ≥20%

Time to Progression to Symptomatic Myeloma, Years

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

0.0

0.2

0.4

0.6

0.8

1.0

On

e M

inu

s C

um

ula

tive

Su

rviv

al

No risk factors

1 risk factor

3 risk factors P < 0.001

2 risk factors

Mateos M-V. Presentation at ASCO 2015; de Larrea et al. Blood. 2014;124(21):Abstract 3363

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Transplant Inelegible Patients

Update from the FIRST study

Newly diagnosed

patients

Continuous lenalidomide/dex (N = 535)

18 cycles of lenalidomide/dex (N = 541)

12 cycles of melphalan, prednisone, thalidomide (N = 547)

Median follow-up of 45.5 months

Cont. Len/dex 18 cycles Len/dex MPT

Median OS (months)

58.9 56.7 48.5

Facon T et al J Clin Oncol 33, 2015 (suppl; abs 8524)

MPT, melphalan–prednisone–thalidomide; OS, overall survival

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Transplant Versus No Transplant

Lenalidomide, dexamethasone

6 cycles: cyclophosphamide, lenalidomide, dexamethasone

(CRD)

Mel200/ASCT

N = 389 Mel200/ASCT CRD P value

4-year PFS 87% 71% 0.028

Grade 3 or 4 hematologic AEs 84% 26% 0.001

Grade 3 or 4 non-hematologic AEs 39% 22% 0.008

Gay F et al. EHA 2015 (abs S101)

AE, adverse event; ASCT, autologous stem cell transplant; PFS, progression-free survival.

Maintenance With Lenalidomide(Revlimid)

Holstein SA et al J Clin Oncol 33, 2015 (suppl; abs 8523)

Time to progression and overall survival were significantly improved

− Regardless of response

Lenalidomide may be associated with a risk of secondary primary malignancies

ASCTCRPRSD

Placebo

Lenalidomide

Time to Progression Overall Survival

Time Since ASCT (Months)

Pro

ba

bil

ity

0.0

0.2

0.4

0.6

0.8

1.0

Placebo

Time Since ASCT (Months)

Pro

ba

bil

ity

0.0

0.2

0.4

0.6

0.8

1.0

0 20 40 60 80 1000 20 40 60 80 100

LenalidomidePlaceboLenalidomide

Median: 53 vs 26 mosHazard ratio 0.54(p<0.001)

Median: NR vs 76 mosHazard ratio 0.60(p=0.001)

CR, complete response; NR, not reached; PR, partial response; SD, stable disease.

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Lenalidomide (Revlimid) Plus Dexamethasone ±ASCT


Collect Collect stem cells


(N = 29)

ASCT(n = 31)

Continue lenalidomide,

dexamethasone

Response rates, progression-free survival, and overall survival were similar in patients with and without ASCT

Lentzsch S et al J Clin Oncol 33, 2015 (suppl; abs 8530)

Overall Survival Progression-free Survival

Time from First Treatment (Months)

Pro

po

rtio

n A

live

0.0

0.2

0.4

0.6

0.8

1.0

0 6 12 24 30 36 42 48 54 66 7860 7218

Arm A (Ld+ASCT) Arm B (Ld alone)

Time to Progression or Death (Months)

Pro

po

rtio

n A

live

or

Pro

gre

ssio

n F

ree

0.0

0.2

0.4

0.6

0.8

1.0

0 6 12 24 30 36 42 48 54 66 7860 7218

HR (Arm B [Ld alone]: Arm A [Ld+ASCT] = 0.73; 95% CI, 0.26–2.01; p=0.54

Arm A (Ld+ASCT) Arm B (Ld alone)

HR (Arm B [Ld alone]: Arm A [Ld+ASCT] = 1.02; 95% CI, 0.51–2.05; p=0.96

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MMRC Phase 2 Trial; Carfilzomib in Newly Diagnosed Patients

Phase 2 trial from the MMRC Open-label, single-arm Primary endpoint: rate of sCR after 8 cycles of carfilzomib

(Kyprolis), lenalidomide (Revlimid), and dexamethasone

ASCTMaintenance

with RdMaintenance

with KRdInduction Consolidation

Cycles 1-4 Cycles 19+Cycles 9-18Cycles 5-8

Zimmerman TM et al J Clin Oncol 33, 2015 (suppl; abs 8510)

CR, complete response; KRd, Kyprolis–Revlimid–dexamethasone; nCR, near complete response; Rd, Revlimid–dexamethasone; sCR, stringent complete response; VGPR; very good partial response.

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MMRC Phase 2 Trial (cont.); MinimalResidual Disease

*MRD by 10-color flow cytometry from indicated number of patients available for MRD evaluation

Carfilzomib plus lenalidomide and dexamethasone with ASCT produced higher rates of sCR than was seen previously with this treatment without transplant

Responses improved with duration of treatment

Adverse events were as expected with this treatment

Zimmerman TM et al J Clin Oncol 33, 2015 (suppl; abs 8510)

MRD, minimum residual disease.

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ASPIRE Phase 3 Trial

Relapsed / refractory1-3 prior therapies

Carfizomib, lenalidomide and dexamethasone

Lenalidomide and dexamethasone

Dimopoulos MA et al J Clin Oncol 33, 2015 (suppl; abs 342); Dimopoulos MA et al EHA abs S427

1 prior therapy ≥2 prior therapies

No prior therapies Carf/Len/dex Len/dex Carf/Len/dex Len/dex

PFS (months) 29.6 17.6 25.8 16.7

ORR 87% 70% 87% 64%

Stringent CR 13% 3% 15% 5%

CR 21% 4% 15% 6%

VGPR 42% 36% 34% 28%

PR 11% 27% 23% 26%

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ENDEAVOR Phase 3 Trial

Relapsed / refractory

Carfilzomib plus dexamethasone

N = 464

Bortezomib plus dexamethasone

N = 465

Dimopoulos MA et al J Clin Oncol 33, 2015 (suppl;abs 8509); Dimopoulos MA et al EHA LB2071

Carfilzomib/dex Bortezomib/dex

ORR 77% 63%

CR 13% 6%

≥VGPR 54% 29%

Patients had received 1-3 prior treatments Treated until disease progression or unacceptable toxicity Median PFS with carfilzomib was 18.7 months vs 9.4 months with bortezomib

(P< .0001) Rates of grade ≥ 2 peripheral neuropathy were 6.3% vs 32.0% (P< .0001)

ORR, overall response rate.

Summary


Norwalk, CT

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Rochester, MN

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Panobinostat: Update FromPANORAMA 1

Panobinostat (Farydak) combined with bortezomib and dexamethasone was recently approved for patients with relapsed/refractory multiple myeloma

− Treated with ≥2 prior therapies including IMiDs (lenalidomide, thalidomide, or pomalidomide) and bortezomib

Subgroup analysis showed:

− Progression-free survival benefit in patients with prior treatment with:

IMiDs or bortezomib and IMiDs

Bortezomib and IMiDs and ≥ 2 prior therapies

More patients had nCR or VGPR, and these were associated with longer PFS

San-Miguel JF et al J Clin Oncol 33, 2015 (suppl; abs 8526); Hungria VTM et al J Clin Oncol 33, 2015 (suppl; abs 8575)

IMiD, immunomodulatory drug.

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Ongoing Trials With Panobinostat

Chari A et al J Clin Oncol 33, 2015 (suppl; abs 8528)

Panobinostat, lenalidomide, and dexamethasone

Patients had a median of 3 prior therapies

− 15 (74%) were refractory to lenalidomide

− 7 (35%) refractory to pomalidomide− 9 (45%) refractory to bortezomib− 6 (30%) refractory to carfilzomib

ORR was 45%− 1 CR, 3 VGPR, 5 PR

Additionally, there were 8 MR, 2 SD, and 1 PD for a clinical benefit rate of 85%

No grade 3 or 4 gastrointestinal toxicities reported

Panobinostat Plus Carfilzomib All patients had received prior

bortezomib and/or carfilzomib− 81% had received prior IMiDs− 58% previously had ASCT

Responses so far:− 1 (3%) CR, 10 (29%) VGPR, 14

(45%) PR, 4 (13%) MR, 4 (13%) SD− ORR was 77%

Most gastrointestinal toxicities were grade 1 or 2

Grade 3/4 toxicities:− Thrombocytopenia (47%) − Neutropenia (8%)− Anemia (9%)− Diarrhea (6%)

MR, minimum response.

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ELOQUENT Phase 3 trial

Relapsed/Refractory1-3 prior therapiesnot lenalidomide

refractory

Elotuzumab, lenalidomide, and dexamethasone(N = 321)

Lenalidomide and dexamethasone(N = 325)

Lonial S et al J Clin Oncol 33, 2015 (suppl; abs 8508)

Elo/Len/dex Len/dex P value

PFS (months) 19.4 14.9 0.0004

ORR 79% 66% 0.0002

Median number of prior therapies was 2 Elotuzumab added very little toxicity

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Phase 2 Trial: Daratumumab

Relapsed/refractory1-3 prior therapies

Daratumumab 16 mg/kg(N = 106)

Lonial S et al J Clin Oncol 33, 2015 (suppl; abs LBA8512)

Median of 5 prior therapies

Median time to progression: 3.7 months

ORR: 29.2%

− 3 sCR, 10 VGPR, and 18 PR

Median duration of response: 7.4 months

Estimated 1-year OS: 65%

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Novel Agents & New CombinationsFor Relapsed, Refractory Patients

Drug Class

CAR-T cells Immunotherapy

CUDC-907 Histone deacetylase inhibitor

Ixazomib Oral proteasome inhibitor

Melflufen Alkylator

MOR202 Monoclonal antibody against CD38

Oprozomib Oral proteasome inhibitor

Ricolinostat Histone deacetylase inhibitor

SAR650984 Monoclonal antibody against CD38

Venetoclax (ABT-199) BCL-2 inhibitor

Raab M EHA 2015, abs S789; Raab M ASCO abs 8574; Raje N et al EHA 2015 P279; Magarotto V et al EHA P285; Moreau P EHA P289; Kumar S EHA P658; Oki Y et al EHA P325; Vij R et al EHA P646

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Summary


Norwalk, CT

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Rochester, MN


San Francisco, CA

Question and Answer

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Closing Remarks


Norwalk, CT

To learn more about the MMRF, please visit:www.multiplemyeloma.org

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