Phase I/II Trial of the Combination of Lenalidomide, Thalidomide and Dexamethasone In Relapsed/Refractory Multiple Myeloma

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Dina Hodges
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$Phase I/II Trial of the Combination of Lenalidomide, Thalidomide and Dexamethasone In Relapsed/Refractory Multiple Myeloma Jatin J Shah, MD 1, Robert Z.$

1 Phase I/II Trial of the Combination of Lenalidomide, Thalidomide and Dexamethasone In Relapsed/Refractory Multiple Myeloma Jatin J Shah, MD 1, Robert Z. Orlowski, MD, PhD 1, Raymond Alexanian, MD 1, Michael Wang, MD 1, Sheeba Thomas, MD 1, Muzaffar H. Qazilbash, MD 2, Simrit Parmar, M.D. 2, Nina Shah, MD 2, Qaiser Bashir, MD 2, Uday Popat, MD 2 and Donna Weber, MD 1 1 Lymphoma & Myeloma, U.T. M.D. Anderson Cancer Center, Houston, TX; 2 SCT/CT Unit 423, UT M.D. Anderson Cancer Ctr., Houston, TX

2 Disclosures Research Funding: Onyx, Celgene, Novartis, Array Biopharma, Millennium Speaking : None Advisory Board: Onyx, Celgene, Array

3 Background Combination of Lenalidomide (Len) and high dose dexamethasone (D) has demonstrated overall response rates (ORR) of 60% in patients with relapsed/refractory multiple myeloma (RRMM) 40% of patients have disease refractory and do not respond to Lenalidomide/dex; and those who do respond will ultimately develop disease resistance and become refractory to Lenalidomide/dex Strategies to improve outcome Develop novel, more potent Immunomodulatory drugs including Pomalidomide Understanding and Targeting mechanisms of Lenalidomide resistance

4 Lenalidomide Resistance Gene expression profiling of Lenalidomide refractory cells identify Wnt/β-catenin cascade as the most commonly dysregulated pathway Preclinical studies have demonstrated Lenalidomide resistance is mediated via the wnt-β-catenin pathway which can be modulated by Thalidomide Bjorklund C C et al. J. Biol. Chem. 2011;286:

5 Background / Rationale The minimal overlapping side effect profile Lenalidomide and Thalidomide and preclinical data provided the rationale for the combination of Lenalidomide, Thalidomide and dexamethasone We hypothesize that the combination will overcome Lenalidomide resistance and improve response rates The aim of this study was to determine the tolerability, maximum tolerated dose (MTD) of the combination and evaluate preliminary activity

6 Objective Phase 1: Primary Objective To determine the maximum tolerated dose (MTD) of the combination of lenalidomide and thalidomide and dexamethasone (Len/Thal/dex) in patients with relapsed/refractory multiple myeloma (RRMM) Phase 2: Primary objective To determine the overall (CR + VGPR+ PR) response rate of the combination Secondary Objectives To determine the Clinical Benefit Rate To determine the Time to progression (TTP) To determine the Progression free survival (PFS) To determine Overall Survival Safety of the combination of LTD in patients with RRMM

7 Study Design Phase I: Bayesian Model Dose Escalation with 4 cohorts enrolling 18 patients Level -1 Level 1 Level 2 Level 3 Dose Lenalidomide 15 mg / Thalidomide 50 mg / dexamethasone Lenalidomide 15 mg / Thalidomide 100 mg / dexamethasone Lenalidomide 25 mg / Thalidomide 100 mg / dexamethasone Lenalidomide 25 mg / Thalidomide 200 mg / dexamethasone Phase II: 36 patients enrolled at MRD + 10 additional patients with Lenalidomide refractory disease Patients treated until Progressive Disease

8 Dosing Schema Cycle 1-8: 28 day cycle Lenalidomide 1 21 Thalidomide 1 28 Dexamethasone Dexamethasone dosing for cycle 1-2: 40 mg days 1-4, 9-12, and 17-20; all subsequent cycles weekly dosing Last cohort of 10 patients with Lenalidomide refractory disease: weekly dosing started with cycle 1 Cycle 9 +: Maintenance Thalidomide decreased to 50 mg; Lenalidomide/dex unchanged All patients received full dose anticoagulation

9 Study Design: Inclusion Criteria Patients with relapsed/refractory myeloma with 1 line of therapy Adequate hematology, cardiac, pulmonary and renal function Patient were eligible regardless of prior exposure to Lenalidomide/ Thalidomide or disease sensitive/refractory Measureable Disease Able to take prophylactic anticoagulation: warfarin or equivalent agent

10 Phase I 18 patients were dosed based on Bayesian Model Dose Escalation Patients DLT Cohort 1 (len15 / thal 100) 3 0 Cohort 2 (len25 / thal 100) 6 1 Cohort 3 (len25 / thal 200) 9 2 DLT in cohort 2: Steroid induced toxicity, requiring reduction in dex dosing in cycle 1 DLT in cohort 3: G3 rash; asymptomatic G2 atrial fibrillation G3 hypertensive crisis and volume overload due to dexamethasone MRD : Lenalidomide 25 mg / Thalidomide 100 mg / Dex

11 Patient Demographics N = 64 Age (median) 65 (36-85) Male 40 (63%) Prior Lines of Therapy (median) 4 (1-12) ISS Stage Stage I 17 Stage II 15 Stage III 8 Stage n/a 24 Cytogenetics ( 4 missing) Del 13 24/60 (40%) Del 17 8/60 (13%) t(4;14) 3/60 (5%) t(11;14) 7/60 (12%) Unknown 4

12 Prior Therapies N = 64 Prior Regimens (median) 4 (1-12) Prior ASCT 49 (77%) Prior Thalidomide 36 (56%) Prior Lenalidomide 48 (75%) Refractory 44 (69%) Prior Lenalidomide exposed 4 (6%)

13 Results N = 61 Overall Response Rate ( PR) 31 (51%) Stable Disease 15 (25%) Minimal Response 8 (13%) Partial Response 19 (31%) VGPR 4 (7%) ncr/cr 8 (13%) Progressive Disease 7 (11%) Clinical Benefit Ratio ( MR) of 64% 3 patients were not evaluable for efficacy as they withdrew consent during first cycle

14 Response rates in Lenalidomide Refractory Disease N = 41* Overall Response 13 (34%) Stable Disease 12 (29%) Minimal Response 8 (20%) Partial Response 11 (27%) VGPR 1 (2%) CR / ncr 2 (5%) Progressive Disease 7 (17%) Lenalidomide Refractory: Clinical Benefit Ratio ( MR) of 51% Lenalidomide Naïve: Overall Response ( PR) of 14/16 (88%) *3 patients were not evaluable for efficacy as they withdrew consent during first cycle

15 Progression Free survival Median PFS 8.0 months

16 Overall survival Median OS 29 months

17 Survival Across Response PFS OS Stable Disease 4 months 10 month Minimal Response 7 months 21 months Partial Response 8 months 29 months

$Survival in Lenalidomide Refractory Progression Free Survival Overall Survival Len Refractory :$

18 Survival in Lenalidomide Refractory Progression Free Survival Overall Survival Len Refractory : 6 months Len sensitive/naïve: 18 months Len Refractory: 18 months Len sensitive/naïve: not reached

19 Survival in High Risk: 17p Progression Free Survival Overall Survival Not Del 17p Del 17p Not Del 17p Del 17p 17p- : 7 months Without 17 p- : 8 months

20 Hematolgoic Adverse Events N=64 Grade 1 Grade 2 Grade 3 Grade 4 Anemia Thrombocytopnia Neutropenia G 3/4 Anemia : 17% G 3/4 Plt : 22% G 3/4 ANC : 30%

21 Non-Hematologic Adverse Events Grade 1 Grade 2 Grade 3 Grade 3 ALT/AST Creatnine Dyspnea Edema PN Rash Diarhea Constipation Fatigue

22 Notable Serious Adverse Events N Atrial Fibrillation 2 Neutropenic Fever 3 Pneumonia 14 Altered Mental Status 5 Cardiac Arrest 1 Hypertensive Crisis 1 Hyperglycemia 2 Weakness/fatigue 5 Pulmonary Emboli / DVT 2 SPM 1 (Basal cell)

23 Conclusions The Maximum Recommended dose is concurrent Lenalidomide 25 mg Thalidomide 100 mg / dex The combination is very well tolerated with a manageable side effect profile; 2 pt with VTE Majority adverse event are steroid related The combination of Concurrent LTD is highly active with a ORR of 51% and CBR of 64%. Remissions are durable with a PFS of 8 months The combination is active in Lenalidomide refractory patients with a CBR of 51% and PFS of 6 months Additional studies are needed to confirm role addition of thalidomide Targeting Mechanisms of Resistance is important Imid Sequencing

24 41 pt Len refractory 25 had prior Thal CBR: 13/25 (52%)

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