Pomalidomide + Low-Dose Dexamethasone Following Second-Line Lenalidomide-Based Therapy in Relapsed or Refractory Multiple Myeloma: A Phase 2 Study Investigating Efficacy and Safety

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David S. Siegel,1 Gary J. Schiller,2 Kevin W. Song,3 Richy Agajanian,4 Keith Stockerl-Goldstein,5 Hakan Kaya,6 Michael Sebag,7 Frederic J. Reu,8 Ehsan Malek,9 Jorge Mouro,10 Weiyuan Chung,10 Shankar Srinivasan,10 Max Qian,10 Syed Rizvi,10

Anjan Thakurta,10 Nizar J. Bahlis11

1John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey; 2David Geffen School of Medicine at University of California, Los Angeles, California; 3Leukemia/BMT Program of BC, Vancouver, British Columbia, Canada; 4The Oncology Institute of Hope and Innovation, Downey, California; 5Washington University School of Medicine, St. Louis, Missouri; 6Cancer Care Northwest, Spokane, Washington; 7McGill University Health Centre, Montreal, Quebec, Canada; 8Cleveland Clinic, Cleveland, Ohio; 9University Hospitals Case Medical Center, Cleveland, Ohio; 10Celgene Corporation, Summit, New Jersey; 11University of Calgary, Calgary, Alberta, Canada

� Preclinical studies have demonstrated that lenalidomide (LEN) is not cross-resistant with pomalidomide (POM) and that LEN-resistant myeloma cells remain sensitive to POM1,2

� POM is a potent immunomodulatory agent with direct anti-tumor and immunoregulatory properties3

� POM + low-dose dexamethasone (POM + LoDEX) is approved for the treatment (Tx) of relapsed/refractory multiple myeloma (RRMM) in patients (pts) who had ≥ 2 prior lines of therapy, including LEN and a proteasome inhibitor4,5

� Sub-analyses of the MM-002 and MM-003 clinical trials demonstrated that POM + LoDEX had comparable efficacy in pts refractory to their last prior Tx with LEN as in the overall pt population6,7

� Here, we present an updated analysis of cohort A of the phase 2 MM-014 trial, in which pts with MM were treated with POM + LoDEX immediately after they relapsed and were refractory to LEN-based second-line therapy (Figure 1)

RESULTS (cont) CONCLUSIONS�MM-014 is the first prospective clinical trial evaluating a

POM-based doublet or triplet combination sequenced immediately after pts became refractory to LEN-based therapy in the first or second line

�This updated analysis of the MM-014 trial demonstrates the safety and efficacy of POM + LoDEX in pts who require third-line therapy following last prior Tx with LEN– Rates of hematologic AEs were lower compared with previous

studies evaluating POM + LoDEX in pts with RRMM6,7

� Immune subset analyses confirmed the persistent T-cell stimulatory activity of POM following prior exposure to LEN8,9,10

�Results support the use of POM + LoDEX immediately after LEN-based therapy to treat pts with RRMM

�POM + LoDEX was active, with 86% of pts having at least disease stabilization, suggesting that pts could benefit from the addition of a mechanistically synergistic active agent

�Future analyses will include a cohort of pts treated with POM + LoDEX + daratumumab immediately after pts become refractory to LEN-based therapy in the first or second line

REFERENCES1. Ocio EM, et al. Leukemia. 2015;29:705-714. 2. Lopez-Girona A, et al. Leukemia.2012;26:2326-2335. 3. Quach H, et al. Leukemia. 2010;24:22-32. 4. Pomalyst(pomalidomide) [package insert]. Summit, NJ: Celgene Corporation; 2016. 5. Imnovid(pomalidomide) [summary of product characteristics]. Uxbridge, UK: Celgene Europe;2016. 6. San Miguel J, et al. Lancet Oncol. 2013;14:1055-1066. 7. Richardson PG, etal. Blood. 2014;123:1826-1832. 8. Gandhi AK, et al. Br J Haematol. 2014;164(6):811-821. 9. Hayashi T, et al. Br J Haematol. 2005;128:192-203. 10. Sehgal K, et al. Blood.2015;125:4042-4051.

ACKNOWLEDGEMENTS� We thank all the patients, nurses, study personnel, and investigators who

participated in this study� The authors acknowledge the financial support for this study from Celgene

Corporation. The authors received editorial assistance from MediTech Media (Mihaela Marina, PhD, and Kerry Garza, PhD) and printing support from MediTech Media, sponsored by Celgene Corporation.

Copies of this poster obtained through the QR Code are for personal use onlyand may not be reproduced without permission from the author of this poster.

Presented at 58th ASH Annual Meeting and Exposition; December 3-6, 2016; San Diego, CA.

INTRODUCTION

� To assess the efficacy and safety of POM + LoDEX (cohort A) in pts with MM who relapsed after or were refractory to LEN-based second-line therapy

� Exploratory objective: to investigate potential molecular, immune, and cellular biomarkers for POM + LoDEX response, resistance, or mechanism of action

OBJECTIVES

Exclusion Criteria� Absolute neutrophil count < 1000/μL� Platelet count < 75,000/μL (< 30,000/μL if ≥ 50% bone marrow

nucleated cells were plasma cells)� Severe renal impairment (creatinine clearance [CrCl] < 30

mL/min) requiring dialysis

METHODS

RESULTSPatient and Disease Characteristics�A total of 51 pts have been enrolled to date (Table 1)�Median time from diagnosis was 4.2 yrs (range, 1.3-13.3 yrs)� 39 pts discontinued from Tx for various reasons (Figure 2)

Response�With a median follow-up of 13.6 months, ORR was 29.4%

(Figure 3)�Based on investigator’s assessment, median time to response

was 1.9 months (range, 0.9-12.0 months) and at 1 year, 66% of pts had an ongoing response

Safety�Anemia was the most common grade 3/4 hematologic TEAE

(Table 5)�Most common grade 3/4 non-hematologic TEAEs were

infections, including pneumonia�No secondary primary malignancies were observed

Figure 3. Response per mIMWG Criteria

CBR, clinical benefit rate; CR, complete response; ITT, intent-to-treat; mIMWG, modified International Myeloma Working Group; MR, minimal response; ORR, overall response rate; PR, partial response; SD, stable disease; VGPR, very good partial response.

DISCLOSURES

D.S.S. reports speakers bureau for Celgene, Amgen, Takeda, Merck, Novartis; G.J.S.reports research funding from Celgene; K.W.S. reports honoraria, research funding,and has served as a member on an entity’s Board of Directors or advisory committeefor Celgene Canada; R.A., M.S. report nothing to disclose; K.S.-G. has served on thespeakers bureau for Celgene and Onyx; H.K. reports honoraria and has served on thespeakers bureau for Millennium, Novartis, Celgene, Onyx, Amgen; F.J.R. reportsresearch funding from Celgene, Novartis, Takeda/Millennium; J.M., S.S., A.T. reportsemployment and equity ownership in Celgene; M. Sturniolo reports employment byCelgene; N.J.B. reports consultancy, honoraria, research funding, and speakers bureaufor Celgene, consultancy for Amgen, and speakers bureau, consultancy, and researchfunding from Johnson & Johnson.

CORRESPONDENCEDavid S. Siegel − DSiegel@HackensackUMC.org

RESULTS (cont)

Prior Therapy�All 51 pts had prior LEN-based Tx; 88.2% of pts were

refractory to LEN (Table 2)�Median duration of the most recent prior LEN-based Tx was

24.6 months

Table 1. Patient and Disease CharacteristicsITT Population (N = 51)

Median age, yrs (range) 68 (44-85)

Male, n (%) 28 (55)

Median time from diagnosis, yrs (range) 4.2 (1.3-13.3)

ECOG performance status, n (%)012

19 (37)28 (55)

4 (8)

ISS (calculated), n (%)IIIIII

30 (58.8)16 (31.4)

5 (9.8)ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System; ITT, intent-to-treat.

Table 2. Prior TherapyITT Population

(N = 51)Number of prior lines of therapy, median 2Prior therapies, n (%)LEN HDM/ASCTBORTCFZIXA

51 (100)33 (65)37 (73)

2 (4)1 (2)

Refractory to LEN, n (%) 45 (88.2)ASCT, autologous stem cell transplant; BORT, bortezomib; CFZ, carfilzomib; HDM, high-dose melphalan; ITT, intent-to-treat; IXA, ixazomib; LEN, lenalidomide; Tx, treatment.

Table 5. TEAEs (≥ 5% of patients)a

TEAEs, n (%) ITT Population (N = 51)Grade 3/4 hematologicAnemiaNeutropeniaThrombocytopenia

13 (25)6 (12)5 (10)

Grade 3/4 non-hematologicInfections and infestationsPneumoniaFatigue

10 (20)5 (10)5 (10)

Special interestDVT/PEPEDVTPeripheral sensory neuropathy

3 (6)2 (4)1 (2)2 (4)

aTEAE severity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4.03.DVT, deep vein thrombosis; ITT, intent-to-treat; PE, pulmonary embolism; TEAE, treatment-emergent adverse event.

Immune Biomarkers�The proportion of CD3+ and CD3+/CD8+ T cells increased

significantly from baseline to post baseline (Figure 4) �Pts with response vs without response had a greater mean

change in T cells from baseline; differences were significant for CD3+ and CD3+/CD4+ T-cell populations (Figure 5)

(N = 51)

Figure 2. Reasons for Tx Discontinuation

AE, adverse event; PD, progressive disease.

Progression and Survival Outcomes�Median TTP and OS were not reached� 1-year TTP and PFS were calculated based on investigator’s

assessment (Table 4)

Table 3. Dose Intensity and Treatment DiscontinuationsITT Population (N = 51)

POM LoDEX

Median relative dose intensity (range)a 0.9 (0.2-1.1)

0.9 (0.3-1.1)

Discontinuation due to TEAE, n (%) 6 (12) 7 (14)Interruption due to TEAE, n (%) 26 (51) 24 (47)Dose reduction due to TEAE, n (%) 9 (18) 6 (12)a Relative dose intensity = actual dose intensity/planned dose intensity.ITT, intent-to-treat; LoDEX, low-dose dexamethasone; POM, pomalidomide; TEAE, treatment-emergent adverse event.

Treatment Exposure�Median Tx duration was 5.1 months for POM and LoDEX �Median number of cycles was 6 (range, 1-28) for POM and 5

(range, 1-28) for LoDEX � 51% and 47% of pts reported ≥ 1 TEAE leading to interruption of

POM and LoDEX, respectively (Table 3)

Amendment� The study has been amended to include a cohort of pts treated

with POM + LoDEX + daratumumab (cohort B; Figure 1)

Figure 5. Immune Subset by Responsea

a Change was evaluated from modified baseline to post baseline. Modified baseline includes only pts who had baseline and post baseline data. Post baseline data were collected on day 1, cycles 3, 5.CD, cluster of differentiation.

*

*

Figure 4. Immune Subset (n = 14)a

a Modified baseline includes only pts who had baseline and post baseline data. Post baseline data were collected on day 1, cycles 3, 5. CD, cluster of differentiation.

CD3+ CD3+/CD4+ CD3+/CD8+

n = 39

CD3+ CD3+/CD4+ CD3+/CD8+

*P = .0396

P = .86*

P = .0015

P = .0026

P = .0432 P = .1867

Figure 1. MM-014 Trial Design

a Thromboprophylaxis with low-dose aspirin, low-molecular-weight heparin, or equivalent was required for all pts.AE, adverse event; CR, complete response; DARA, daratumumab; DEX, dexamethasone; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group Performance Status; LEN, lenalidomide; LoDEX, low-dose dexamethasone; mIMWG, modified International Myeloma Working Group; MM, multiple myeloma; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; POM, pomalidomide; PR, partial response; pt, patient; RRMM, relapsed/refractory MM; SPM, second primary malignancy; TTP, time to progression; TTR, time to response; Tx, treatment; VGPR, very good partial response.

Primary endpoint: ORR (CR + VGPR + PR) by mIMWG criteriaSecondary endpoints: PFS, OS, DOR, TTR, TTP, safety (AEs and SPM)

Cohort Aa

n ≈ 55POM: 4 mg D1-21LoDEX: 40 mg (≤ 75 yrs) or

20 mg (> 75 yrs)D1, 8, 15, 2228-day cycles Follow-up for

OS, subsequent Tx, and SPM

until 5 yrs post-enrollment

N ≈ 155 Planned

•Age ≥ 18 yrs

•RRMM

•LEN-basedregimen in theimmediate priorline

•PD during orafter last anti-MM therapy

•ECOG PS ≤ 2

2 prior lines of Tx

1 or 2 prior lines of Tx

Cohort Ba

n ≈100 POM: 4 mg D1-21LoDEX: 40 mg (≤ 75 yrs) or

20 mg (> 75 yrs)D1, 8, 15, 22

DARA: 16 mg/kg Cycles 1-2: D1, 8, 15, 22Cycles 3-6: D1, 15Cycles 7+: D1

28-day cyclesNCT01946477

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Responders (n = 7)Non-responders (n = 7)Table 4. Progression and Survival Outcomes

ITT Population (N = 51)

1-year TTP, % 60.9

1-year PFS, % 54.6

1-year OS, % 88.2ITT, intent-to-treat; OS, overall survival; PFS, progression-free survival; TTP, time to progression.