Impact of POM + LoDEX on Disease Parameters and ...static9.light-kr.com/documents/IMW2013/Richardson...

Impact of POM + LoDEX on Disease Parameters and Cytogenetic Status in Relapsed and

Refractory Multiple Myeloma (RRMM)

Paul G. Richardson 1, Sagar Lonial 2, Andrzej Jakubowiak 3, Rachid Baz 4, Nizar Bahlis 5, David S.

Siegel 6, Christine Chen 7, Andrew Belch 8, Martha Lacy 9, Min Chen 10, Mohamed H. Zaki 10, Kenneth C. Anderson 1

1Dana-Farber Cancer Institute, Boston, MA, USA; 2Emory University School of Medicine, Atlanta, GA, USA; 3University of Chicago Medical Center, Chicago, IL, USA; 4H. Lee Moffitt Cancer Center and Research Institute,

Tampa, FL, USA; 5Southern Alberta Cancer Research Institute, University of Calgary, Calgary, AB, Canada; 6John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA; 7Princess Margaret

Hospital, Toronto, ON, Canada; 8University of Alberta, Edmonton, AL, Canada; 9Mayo Clinic, Rochester, MN, USA; 10Celgene Corporation, Summit, NJ, USA

Disclosures

• Consultancy: Celgene, Millennium, Novartis, Bristol-Myers Squibb, Onyx, Merck

Background

• In patients with MM, clinical parameters and certain cytogenetic abnormalities are associated with poor prognosis1,2

• The MM-002 phase 2 study showed that POM is effectiveand well tolerated in RRMM patients3

• We assessed the impact of high-risk cytogenetics on the efficacy of POM + LoDEX:

– High-risk cytogenetic profile included Del(17p13) and/or t(4p16/14q32)

– Data cutoff was March 30, 2012

LoDEX, low-dose dexamethasone; MM, multiple myeloma ; POM, pomalidomide; RRMM, relapsed and refractory m ultiple myeloma.1. Kumar SK, et al. Mayo Clin Proc. 2004;79:867-74. 2. Avet-Loiseau H, et al. J Clin Oncol. 2012;30:194 9-52. 3. Richardson PG, et al. Blood. 2011;118:abstr act 634.

Richardson PG, et al. IMW 2013;Abstract 369.

• Aspirin (80–100 mg) or equivalent was mandated for all patients• Patients aged > 75 yrs had a starting DEX dose of 2 0 mg/week

Ran

dom

izat

ion

N =

221

Option to add LoDEX

(40 mg/week) a

Discontinue and follow -up for survival

and subsequent treatment

Progressive disease

Progressive disease

POM (4 mg days 1–21 of each 28-day cycle)

+ LoDEX (40 mg/week)N = 113

POM (4 mg days 1–21 of each 28-day cycle)

N = 108

DEX, dexamethasone; DOR, duration of response; LoDEX , low-dose DEX; ORR, overall response rate; OS, overa ll survival; PFS, progression-free survival; POM, pomalidomide.1. Bladé J, et al. Br J Haematol. 1998;102:1115-23. 2. Richardson PG, et al. N Engl J Med. 2003;348:2609 -17.


Progressive disease

• Primary end point : PFS• Secondary end points : ORR1,2, DOR, OS, and safety

MM-002: Study Design

MM-002: Key Eligibility Criteria

• Aged ≥ 18 years

• Patients with RRMM:– Measurable levels of M-protein in serum or urine

– Serum creatinine ≤ 3.0 mg/dL

– ≥ 2 prior therapies

– Prior therapy must have included ≥ 2 cycles of LEN and ≥ 2 cycles of BORT separately or in combination

– Documented progression ≤ 60 days after the last treatment (refractory disease)

BORT, bortezomib; LEN, lenalidomide; RRMM, relapsed/ refractory multiple myeloma.


MM-002: Baseline Characteristics

Patient characteristicsPOM + LoDEX

(n = 113)POM

(n = 108)

Median age, years (range) 64 (34–88) 61 (37–88)

Male (%) 55 53

Durie-Salmon MM stage ≥ II (%) 93 93

ECOG performance status score (%)

0–1 88 88

2–3 12 12

Cytogenetic profile, n (%)

High-risk a 30 (27) 30 (28)

Del(17p13) 19 (17) 11 (10)

Standard-risk 57 (50) 43 (40)

a High-risk cytogenetic profile defined as those with abnormalities del(17p13) and/or t(4p16/14q32).ECOG, Eastern Cooperative Oncology Group; LoDEX, low-do se dexamethasone; MM, multiple myeloma; POM, pomalid omide.


MM-002: Prior Therapy

Type of prior therapyPOM + LoDEX

(n = 113)POM

(n = 108)

Median number of prior therapies (range) 5 (2–13) 5 ( 1–12)

LEN / BORT / steroids (%) 100 100

LEN as last prior therapy (%) 39 31

BORT as last prior therapy (%) 50 47

Alkylators (%) 93 95

Stem cell transplantation (%) 73 76

Thalidomide (%) 67 67

Anthracyclines (%) 49 50

BORT, bortezomib; LEN, lenalidomide; LoDEX, low-dose dexamethasone; POM, pomalidomide.


Discrepancies in totals are due to rounding. aResponse rate by investigator (based on best respon se assessment using EBMT criteria). bLoDEX was added in 64 patients (59%).cFor patients who achieved ≥ PR, efficacy evaluable population.CR, complete response; EBMT, European Group for Bloo d and Marrow Transplantation; ITT, intent-to-treat; LoDEX, low-dose dexamethasone; MR, minor response; ORR, overall response rate; PD, progressive disease; POM, pomalidomide; PR, partial response; SD, stable disease.


• Median number of cycles received was 5 (range 1–28)

• Disease control ( ≥ SD) was observed in 81% of patients

Response a POM + LoDEX (n = 113)

POM (n = 108)b

ORR (≥ PR) (%) 34 15≥ MR (%) 45 31

CR 3 1PR 31 14MR 12 16

SD (%) 37 48PD (%) 6 10Median time to ORR c, months 1.9 3.7

MM-002: Best Response (EBMT Criteria) ITT Population

Median PFS (mos)

POM + LoDEX (n = 113) 4.6

POM (n = 108)a 2.6

aLoDEX was added in 64 patients (59%).DOR, duration of response; HR, hazard ratio; ITT, in tent-to-treat; LoDEX, low-dose dexamethasone; PFS, progression-free survival; POM, pomalidomide.


HR = 0.67P = 0.002

0

20

40

60

80

100

0 5 10 15 20 25 30

Pat

ient

s (%

)

PFS (months) DOR (months)

0

HR = 0.89P = 0.734

20

40

60

80

100

0 5 10 15 20 25

Pat

ient

s (%

)

Median DOR (mos)

POM + LoDEX (n = 38) 8.3

POM (n = 16) 8.8

MM-002: PFS and DORITT Population

Median OS (mos)

POM + LoDEX (n = 113) 16.5

POM (n = 108)a 13.6

HR = 0.92P = 0.609

0

20

40

60

80

100

0 5 10 15 20 25 30

Pat

ient

s (%

)

OS (months)

aLoDEX was added in 64 patients (59%).DEX, dexamethasone; HR, hazard ratio; ITT, intent-t o-treat; LoDEX, low-dose DEX; OS, overall survival; POM, pomalidomide.


• The OS of the POM alone arm includes 59% of patients who added LoDEX upon disease progression

MM-002: OS ITT Population

Grade 3–4 AEs of special interest (%)POM + LoDEX

(n = 112)POM

(n = 107)

HematologicNeutropenia 41 47Anemia 22 24Thrombocytopenia 19 22Leukopenia 10 7

Non-hematologicPneumonia 22 14Fatigue 14 11Dyspnea 13 8

AE, adverse event; DVT, deep-vein thrombosis; LoDEX , low-dose dexamethasone; POM, pomalidomide.


MM-002: AEs All Patients Treated

MM-002: Baseline Characteristics by Cytogenetic Risk POM + LoDEX

a High-risk cytogenetic profile defined as those with abnormalities Del(17p13) and/or t(4p16/14q32).BORT, bortezomib; ECOG, Eastern Cooperative Oncology Gr oup ; LEN, lenalidomide; LoDEX, low-dose dexamethas one; MM, multiple myeloma; POM, pomalidomide; THAL, thalidomide.


Patient characteristicsPOM + LoDEX

High-risk a

(n = 30)

POM + LoDEX Standard-risk

(n = 57)

Median age, years (range) 64 (52–88) 64 (34–83)

Male (%) 47 58

Durie-Salmon MM stage ≥ II (%) 93 91

ECOG Performance status score (%)

0–1 90 88

2–3 10 12

Median no. of prior therapies (range) 5 (3–11) 5 (2–1 2)

Prior LEN / BORT 100 100

Prior THAL 70 67

MM-002: Efficacy by Cytogenetic Risk POM + LoDEX

a For patients who achieved ≥ PR.CI, confidence interval; DOR, duration of response; LoDEX, low-dose dexamethasone; NR, not reached; ORR , overall response rate; OS, overall survival; PFS, progression-free survival; POM, pomalidomide; PR, pa rtial response; TTR, time to response.


Efficacy outcomesPOM + LoDEX

High-risk(n = 30)


(n = 57)

ORR (≥ PR), % (n) 23 (7) 40 (23)

TTRa, months (range) 1.2 (0.9–2.8) 1.9 (0.9–14.4)

DORa, months (95% CI) 4.9 (1.9–13.1) 10.1 (7.7–NR)

Median PFS, months (95% CI) 3.1 (1.9–3.9) 5.5 (3.7–8. 7)

Median OS, months (95% CI) 13.2 (4.7–19.8) 21.7 (12.4 –NR)

• Among patients with del(17p13), ORR was 21%

AE, adverse event; LoDEX, low-dose dexamethasone; P OM, pomalidomide.


Grade 3–4 AEs of special interest (%)POM + LoDEX

High-risk (n = 29)


(n = 57)

Hematologic

Neutropenia 48 40

Thrombocytopenia 31 16

Anemia 24 25

Non-hematologic

Pneumonia 21 28

Fatigue 10 18

Dyspnea 17 11

MM-002: AEs by Cytogenetic RiskPOM + LoDEX (All Patients Treated)

a Median values at cycle 8.b Number of patients with abnormal baseline values us ed to calculate percentages. c Normal values were 150–350 × 10 3/mm3, 8.3–10.6 mg/dL, and 0.9–1.5 mg/dL respectively.LoDEX, low-dose dexamethasone; POM, pomalidomide.


Platelet count n = 50b,c

Serum calciumn = 15b,c

Serum creatininen = 36b,c

205.5 × 103/mm3,a

9 mg/dLa

1 mg/dLa

MM-002: Demonstration of Clinical BenefitPOM + LoDEX

Pat

ient

s (%

)

Pat

ient

s (%

)

Hemoglobin improvement a

≥ 1 g/dLAlbumin improvement a

≥ 0.5 g/dL

aAll the patients in the POM + LoDEX safety populatio n (n = 112) were evaluated to calculate percentages .LoDEX, low-dose dexamethasone; POM, pomalidomide.


MM-002: Demonstration of Clinical BenefitPOM + LoDEX (All Patients Treated)

ECOG, Eastern Cooperative Oncology Group; LoDEX, low-do se dexamethasone; POM, pomalidomide.


MM-002: ECOG Changes from BaselinePOM + LoDEX

• POM is currently approved by the US FDA for the treatment of RRMM patients with ≥ 2 prior therapies, including LEN and BORT, and who have demonstrated PD ≤ 60 days after their last therapy

• POM + LoDEX shows efficacy in RRMM patients with high-ri sk cytogenetics, including patients with Del(17p13)

• Overall efficacy and safety findings are associated wi th a consistent improvement in critical end-organ functional parameters

• The efficacy and safety data strongly favor future combi nation strategies, including proteasome inhibitors and other nov el agents, especially in high-risk RRMM patients

BORT, bortezomib; FDA, Food and Drug Administration; LEN, lenalidomide; LoDEX, low-dose dexamethasone; PD, progressive disease; POM, pomalidomide; RRMM, relapsed refractory multiple myeloma.


MM-002: Conclusions & Future Directions

Phase 2 Investigators Including:Ravi Vij, Craig Hofmeister, Sundar Jagannath, Kevin Song, Noopur Raje, Joseph Mikhael,

Asher Alban A. Chanan-Khan, Suzanne Lentzsch, Jeffr ey Matous, Chaim Shustik

Our Patients and Their Families

Institutions With Study Sites

• Dana-Farber Cancer Institute

• John Theurer Cancer Center – Hackensack University Medical Center

• Washington University School of Medicine

• The Ohio State University – James Cancer Hospital

• H. Lee Mofitt Cancer and Research Institute

• Mount Sinai Medical Center

• Princess Margaret Hospital – UHN

• Cross Cancer Institute

• Emory University Hospital

• Multiple Myeloma Research Consortium

• University of Michigan, Comprehensive Cancer Center

• University of Calgary – Tom Baker Cancer Center

• Vancouver General Hospital, Diamond Health Care Centre

• Massachusetts General Hospital

• Royal Victoria Hospital – McGill University of Pittsburgh Cancer Institute

• Mayo Clinic Minnesota

• Mayo Clinic Arizona

• Rocky Mountain Cancer Centers

• St. Vincent’s Comprehensive Cancer Center

Medical writing assistance: Supported by Celgene Corpo ration and provided by Anna Georgieva, PhD, and Eva Polk, PhD (Excerpta M edica)

Acknowledgments

Thank you!Arigat ō!

ありがとうありがとうありがとうありがとう

谢谢谢谢谢谢谢谢 ขอขอบคุณคุณ

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