multiple myeloma updates from the 2015 asco annual … · slides multiple myeloma update from the...

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SLIDES

Multiple Myeloma Update From the

2015 ASCO Annual Meeting and 20th Congress of EHA

Multiple Myeloma Updates From

the 2015 ASCO Annual Meeting

and 20th Congress of EHA

Welcome and Introductions

Joan Levy, PhD

Multiple Myeloma Research Foundation

Norwalk, CT

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Multiple Myeloma Updates From the 2015 ASCO

Annual Meeting and 20th Congress of EHA

Jesus Berdeja, MD

Tennessee Oncology

Nashville, TN

Saad Zafar Usmani, MD

Levine Cancer Institute

Charlotte, NC

Faculty

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Smoldering Multiple Myeloma

Jesus Berdeja, MD

Tennessee Oncology

Nashville, TN



Charlotte, NC

Faculty

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SLIDES



Mateos MV. ASCO Educational Book 2015; e484.

Differential Diagnosis for MGUS,

SMM, and Symptomatic MM

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Feature MGUS SMM MM

Serum-M Protein <3 g/dL and ≥ 3 g/dL and/or

Clonal BMPC

Infiltration

<10% 10-60% ≥ 10% biopsy-

proven

plasmacytoma

Symptomatology Absence of CRAB* Absence of MDE**

or amyloidosis

Presence of

MDE**

* CRAB Includes (1) hypercalcemia: serum calcium > 0.25 mmol/L (>1 mg/dL) higher than the upper

limit of normal or > 2.75 mmol/L (>11 mg/dL); (2) renal insufficiency: serum creatinine > 177µ mol/L

(2 mg/dL) or creatinine clearance < 40 ml/minute; (3) anemia: hemoglobin value of > 2 g/dL below the

lower normal limit or a hemoglobin value < 10 g/dL; (4) bone lesions: one or more osteolytic lesion

revealed by skeletal radiography, CT, or PET-CT.

** MDE: Myeloma-defining events include CRAB symptoms (above) or any one or more of the following

biomarkers or malignancy: clonal bone marrow plasma cell percentage ≥ 60%; involved/uninvolved

serum free light-chain ratio ≥ 100; > 1 focal lesions revealed by MRI studies.

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

myeloma; BMPC, bone marrow plasma cell

Treatment of High-Risk Smoldering

MM With Len/Dex

Mateos MV, et al. ASH 2014: abstract 3465

ITT analysis TTP to active disease (n = 119)

Len/Dex

Median TTP: NR

14 Progressions (25%)

HR: 6.1; 95% IC (3.3–11); p < 0.0001

Time from inclusion

Pro

po

rtio

n o

f p

ati

en

ts p

rog

ressio

n-f

ree

10 0 20 30 40 50 60

1,0

0,8

0,6

0,4

0,2

0,0

No treatment

Median TTP: 21m

53 Progressions (85%)

Median follow-up: 64 months (range 49-81)

Len/Dex, lenalidomide-dexamethasone; HR, hazard ratio; ITT, intention to treat; TTP, time-to-progression

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Treatment of High-Risk Smoldering

MM With Len/Dex (cont)

Mateos MV, et al. ASH 2014: abstract 3465

OS from inclusion (n=119) Median follow-up: 64 months (range 49–81)

Len/Dex

94% at 7 years

No treatment

64% at 7 years

Time from inclusion

Pro

po

rtio

n o

f p

ati

en

ts a

live

HR: 4.6; 95% IC (1.5–13.1); p=0.001

1,0

0,8

0,6

0,4

0,2

0,0

20 0 30 40 50 70 80 10 60

Median follow-up: 64 months (range 49-81)

Len/Dex, lenalidomide-dexamethasone; HR, hazard ratio; OS, overall survival

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Progression From SMM to

Active MM – Clinical Variables

• An elevated involved/uninvolved light chain ratio (>100)

• More than 60% bone marrow plasmacytosis

• More than 1 focal lesion on either an axial skeletal MRI

or a whole body MRI

Rajkumar SV et al. Lancet 2014; 15:e538-48. 8

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FDG-PET/CT Focal Lesions as a

Marker of Progression

Zamagni E, Nani C, Gay F, et al. Poster 267 presented at EHA Learning Center May 31, 2015.

• PET/CT reliably assesses early skeletal involvement

• PET/CT positivity significantly increased the risk of

progression from SMM to MM

• PET/CT could become a new risk factor to define

high-risk SMM

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Predictors of Myeloma Progression

(SWOG S0120)

Dhodapkar M, et al. Blood. 2014;123:78-85.

• A prospective observational study of 331 AMG patients

• Baseline data from clinical variables, GEP, and MRI

findings correlated with risk of progression to CMM

• An increased risk score was an independent predictor

of risk of progression

• Combination of elevated serum free light chain,

M-spike, and GEP70 risk score identified high risk of

progression to CMM

AMG, asymptomatic monoclonal gammopathy; GEP, gene expression profiles; MRI, magnetic

resonance imaging; CMM, clinical multiple myeloma.

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Upfront Therapy

Jesus Berdeja, MD

Tennessee Oncology

Nashville, TN



Charlotte, NC

Faculty

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Update From the FIRST Study

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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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Update From the FIRST Study (cont)

Median follow-up of 37 months

Cont. Len/dex 18 cycles Len/dex MPT

Age≤75 Age>75 Age≤75 Age>75 Age≤75 Age>75

3-Yr OS % 74 63 70 58 67 54

PFS* 27.4 21.2 21.3 19.4 21.8 19.2

Duration of

Response*

77 71 77 66 66 55

Hulin C. EHA20 Abstract 429. June 2015.

*Median, months

OS, overall survival; PFS, progression-free survival.

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Toxicity Related Dose Adjustment

Effects Cost Savings With LEN

Arikian S. 2015 EHA Abstract P284.

• Treatment costs of NDMM (n=2843) and second line

MM patients (n=1361) were analyzed

• Quarterly cost reduction patterns were consistent

• Over 3 years average monthly total costs were lower

for NDMM LEN patients due to extended interval prior

to 2nd line therapy initiation

NDMM, newly diagnosed multiple myeloma; LEN, lenalidomide

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FIRST Study Sub-Analysis

Dimpooulos 2015 EHA Abstract 274

Normal Renal Mild RI Moderate RI Severe RI

PFS*

Len/dex cont 37.7 26.7 18.7 17.2

Len/dex 18 cycles 24.6 21.0 18.7 12.1

MPT 24.9 21.4 17.5 11.7

OS*

Len/dex cont NR NR 43.7 33.2

Len/dex 18 cycles 53.6 NR 41.8 42.6

MPT NR NR 38.5 42.9

*Median, months

Impact of Renal Impairment on Outcomes

• Len/dex continuous was well tolerated consistently across renal

subgroups

• Renal function also improved more in patients treated with len/dex

continuous therapy vs 18 cycles or MPT

Len, lenalidomide; dex, dexamethasone; MPT, melphalan-prednisone-thalidomide; RI, renal impairment

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Quadruplet Induction in Transplant

Eligible NDMM Patients

Pawlyn C. 2015 EHA Abstract S428

• Upfront KCRD quadruplet vs sequential triplet IMiD

combinations (followed by PI triplet if response

suboptimal)

• Patients (n=257) completed mean 4.2 KCRD cycles

prior to transplant

• Dose modifications required in 63% of KCRD patients

but low incidences of toxicities reported

• Quadruplet KCRD induction presents a promising

option

IMiD, immunomodulatory drug; KCRD, carfilzomib-cyclophosphamide-lenalidomide-dexamethasone;

PI, proteasome inhibitor

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SLIDES



MMRC Phase 2 Trial for

Newly Diagnosed Patients

Open-label, single-arm

Primary endpoint: rate of sCR after 8 cycles of carfilzomib

(Kyprolis), lenalidomide (Revlimid), and dexamethasone

ASCT Maintenance

with Rd Maintenance

with KRd Induction Consolidation

Cycles 1-4 Cycles 19+ Cycles 9-18 Cycles 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.)

Minimal Residual 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)

ASCT, autologous stem cell transplant; KRd, carfilzomib-lenalidomide-dexamethasone; MRD, minimum

residual disease; sCR, stringent complete response 18

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Maintenance With Lenalidomide

Following Single ASCT

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

Time to progression and overall survival were significantly improved with

len regardless of response

Len may be associated with a risk of secondary primary malignancies

ASCT CR

PR

SD

Placebo

Lenalidomide

Time to Progression Overall Survival

Time Since ASCT (Months)

Pro

bab

ilit

y

0.0

0.2

0.4

0.6

0.8

1.0

Placebo

Time Since ASCT (Months)

Pro

bab

ilit

y

0.0

0.2

0.4

0.6

0.8

1.0

0 20 40 60 80 100 0 20 40 60 80 100

Lenalidomide

Median: 53 vs 26 mos

Hazard ratio 0.54

(p<0.001)

Median: NR vs 76 mos

Hazard ratio 0.60

(p=0.001)

ASCT, autologous stem cell transplant; CR, complete response; NR, not reached; PR, partial response;

SD, stable disease.

Placebo

Lenalidomide

Improved Response Beyond Day

+100 is Rare Without Maintenance

De Larrea 2015 EHA P278

Objective - Evaluate patients who improve response beyond day

+100 after ASCT with and without maintenance

• Patients (N=144) who had ASCT with melphalan-based

conditioning were studied

• Of the 74 who did not receive maintenance, only 1 patient

improved response from VGPR to CR at +100 days after ASCT

• The remaining patients received maintenance with either

interferon (37%), glucocorticoids (20%), thalidomide (4.9%), or

thalidomide + bortezomib (6.9%)

• Beyond day +100 after ASCT 8.3% of patients receiving

maintenance improved response

− The outcome of these patients was better than those who did not

upgrade their response in terms of PFS and OS

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SLIDES



Transplant

Jesus Berdeja, MD

Tennessee Oncology

Nashville, TN



Charlotte, NC

Faculty

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Transplant

• Dr. Usmani noted that only approximately 13% of

multiple myeloma patients in the United States receive

a stem cell transplant

• Two pivotal studies (from the French Myeloma Group,

and Medical Research Council UK) showed transplants

do improve PFS and OS

• Further clinical study from Dr. Palumbo solidified the

importance of ASCT

• Importance of ASCT timing?

− Awaiting results of the Dana-Farber/IFM trial

1. Attal M. N Engl J Med. 1996;335:91-97 2.Child JA. N Engl J Med. 2003;348:1875-1883

3. Palumbo A. N Engl J Med. 2014;371:895-905. 22

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Lenalidomide (Revlimid) Plus

Dexamethasone ±ASCT

Lenalidomide,

dexamethasone

Collect

stem

cells

Lenalidomide,

dexamethasone

(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

liv

e

0.0

0.2

0.4

0.6

0.8

1.0

0 6 12 24 30 36 42 48 54 66 78 60 72 18

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

Time to Progression or Death (Months)

Pro

po

rtio

n A

liv

e o

r P

rog

ressio

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 78 60 72 18

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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Transplant Versus No Transplant

Lenalidomide,

dexamethasone

6 cycles: cyclophosphamide,

lenalidomide, dexamethasone

(CRD)

2 cycles: Mel200/ASCT

N = 389 Mel200/ASCT CRD P value

4-year PFS 42% 28% 0.014

4-year OS 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.

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ASCT ±Consolidation vs. Tandem

ASCT With Len Maintenance

• Phase III, 3-arm study (BMT CTN 0702)

• Consolidation is RVD (lenalidomide, bortezomib, and

dexamethasone

• All 3 arms receive len maintenance

• Fully accrued, results anticipated in 2016

www.clinicaltrials.gov, trial identifier NCT01109004

Relapsed/Refractory

Multiple Myeloma

Jesus Berdeja, MD

Tennessee Oncology

Nashville, TN



Charlotte, NC

Faculty

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Several Relapsed/Refractory Studies

Presented at ASCO

Phase 3 Trials

• ELOQUENT-2

− Lenalidomide and dexamethasone with/without

elotuzumab

• ENDEAVOR

− Carfilzomib and dexamethasone vs bortezomib and

dexamethasone

• ASPIRE

− Carfilzomib, lenalidomide, and dexamethasone vs

lenalidomide and dexamethasone

Phase 2 Trial

• Daratumumab Monotherapy

− Patients with ≥ 3 lines of prior therapy

or double refractory multiple myeloma

ENDEAVOR Phase 3 Trial

Relapsed/ refractory

1-3 prior treatments

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%

• 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)

CR, complete response; ORR, overall response rate; VGPR, very good partial response

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15

SLIDES



ASPIRE Phase 3 Trial

Relapsed/refractory

1-3 prior therapies

Carfizomib, lenalidomide

and dexamethasone

Lenalidomide and

dexamethasone

Dimopoulos MA et al J Clin Oncol 33, 2015 (suppl; abs 8525); Dimopoulos MA et al EHA abs S427

1 prior therapy ≥2 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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ELOQUENT-2 Phase 3 Trial

Relapsed/Refractory

1-3 prior therapies

not 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 Monotherapy

Relapsed/refractory

≥ 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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Panobinostat Update

• Panobinostat combined with bortezomib and

dexamethasone was recently approved for patients with

relapsed/refractory MM

− Treated w/≥ 2 prior therapies including IMiDs and bortezomib

• PANORAMA 1 Phase 3 trial

− Patients w/1-3 prior therapies (IMiDs and bortezomib)

− Panobinostat or placebo in combo w/bortezomib and

dexamethasone

− Panobinostat combination was very active but with significant

GI and hematologic toxicities

1. San-Miguel JF et al J Clin Oncol 33, 2015 (suppl; abs 8526); 2. Hungria VTM et al J Clin Oncol 33, 2015 (suppl; abs

8575); San-Miguel JF, et al. Lancet Oncol. 2014;15:1195-1206. 32

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Panobinostat Plus Carfilzomib

Ongoing Phase 1/2 trial

• Evaluating the dose of the combination

• 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%)

Berdeja JG et al ASCO 2015 (abs 8513) 33

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Novel Agents For

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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SLIDES



Galetto R, et al. EHA 2015 Abstract P724.

Allogenic CAR-T Cells

Targeting CS1

• CS1 glycoprotein (SLAMF7) highly expressed on MM tumor

cells

• Immunotherapy against MM studying chimeric antigen receptor

(CAR)-redirected T-cells in the targeting of CS1

• CAR approach restricted to targeting antigens on the tumoral

cells surface but absent from T-cells

• Galetto evaluated CS1 expression on T-cells to ensure

approach enabled harnessing activated T-cells to attack MM

cells

• CS1-gene-edited CAR cells found to have significantly

increased cytotoxic activity against MM cells with percentage of

CD8+ T-cells remaining unaffected

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Novel Agents For

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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STRATUS Phase 3b Trial

1. Cavo M, et al. EHA20 June 13, 2015. 2. Weisel K, et al. J Clin Oncol. 33:2015 (suppl; abstr 8593).

• Pomalidomide plus low-dose dexamethasone in heavily

pretreated RRMM

• Most patients were refractory to both bortezomib and

lenalidomide

• The combination was active and well tolerated

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Closing Remarks

Joan Levy, PhD

Multiple Myeloma Research Foundation

Norwalk, CT

To learn more about the MMRF, please visit:

www.multiplemyeloma.org

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http://www.multiplemyeloma.org/

multiple myeloma updates from the 2015 asco annual … · slides multiple myeloma update from the...

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