A Phase II Study of IRd (Ixazomib, Lenalidomide, & - PowerPoint PPT Presentation

A Phase II Study of IRd (Ixazomib, Lenalidomide, & Dexamethasone) for Consolidation Therapy Post Autologous Stem Cell Transplantation followed by Maintenance Ixazomib or Lenalidomide for Multiple Myeloma Ravi Vij 1 , Nitya Nathwani 2 , Thomas G. Martin 3 , Mark A. Fiala 1 , Abhinav Deol 4 , Francis K. Buadi 5 , Jonathan L. Kaufman 6 , Craig C. Hofmeister 6 , Tara K. Gregory 7 , Jesus Berdeja 8 , Ajai Chari 9 , Ashley Rosko 10 1. Washington University School of Medicine, St. Louis, MO 2. Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope Comprehensive Cancer Center, Duarte, CA 3. University of California- San Francisco 4. Wayne State University/Karmanos Cancer Institute, Detroit MI 5. Mayo Clinic- Rochester 6. Emory University 7. Colorado Blood Cancer Institute 8. Sarah Cannon Research Institute, Nashville, TN 9. Mount Sinai 10. Ohio State University

Disclosures Study Takeda Oncology is providing material and funding support Adaptive Biotechnologies Corporation is providing MRD assessments Multiple Myeloma Research Consortium is providing administrative support Speaker Celgene: Honoraria, Advisory committee, and Research Funding Bristol-Myers Squibb: Honoraria, Advisory committee, and Research Funding Takeda: Honoraria, Advisory committee, and Research Funding Jazz Pharmaceuticals: Honoraria and Advisory committee Amgen: Honoraria and Advisory committee Jansson: Honoraria and Advisory committee Karyopharma: Honoraria and Advisory committee

Background • ASCT remains the standard for eligible patients with newly diagnosed MM Adapted from Cavo M. 2017 European Hematology Association conference

Consolidation • Consolidation therapy: a brief duration of more-intensive chemotherapy administered prior to maintenance Adapted from Cavo M. 2017 European Hematology Association conference

MRD-ve: A new goal for treatment? Reference Regimen MRD-Negative Method Sensitivity Rawstron C-VAMP 42% MFC 10 -4 2002 Mel ASCT San Miguel VBMCP or VBAD 36% MFC 10 -4 2002 Mel ASCT Paiva VBMCP/VBAD 42% MFC 10 -4 2008 Mel ASCT Korthals Ida/Dex 45% PCR 10 -4 2012 Mel ASCT Dal Bo Unreported Induction 60% MFC 10 -4 2013 Mel ASCT Rawstron CTD or CVAD 62% MFC 10 -4 2013 Mel ASCT Ferrero VAD 67% PCR 10 -4 2014 Mel ASCT VTD Consolidation Roussel RVD 68% MFC 10 -4 2014 Mel ASCT R Maintenance

MRD: NGS vs MFC Regimen Method Sensitivity MRD-Negative RVD MFC 10 -4 79% Mel ASCT RVD Consolidation NGS 10 -6 30% R Maintenance (VGPR/CR only) Perrot A, Lauwers-Cances V, Corre J, et al. Blood, 2018.

IRd Schema NCT0225316 Consolidation N = 240 Ixazomib: 4mg on Days 1, 8, 15 Lenalidomide: 15mg Days 1-21 Dexamethasone: 40mg Days 1, 8 ,15 Primary Objective To determine the improvement in MRD-negative rate after 4 cycles of IRD consolidation Secondary Objectives: IMWG response, PFS, Maintenance OS, and Toxicity Ixazomib: 4mg on Days 1, 8, 15 or Lenalidomide: 15mg Daily Primary Objective To compare MRD-negative rate after 12 cycles of Ixazomib or Lenalidomide Maintenance Secondary Objectives: IMWG response, PFS, OS, and Toxicity

Sample Size Calculations If the true rate of MRD-negative is 40-60% at the Day 100 post-transplant/pre- consolidation visit, 220 evaluable patients will detect a >10% improvement in MRD- negative rate with 90% power at 1-sided 0.05 alpha. Due to highly varied data of baseline MRD as well as the lack of pilot information for the association over time, we chose a rather conservative estimation and the sample size was estimated using a non-paired design. Exact - Proportion: Difference from constant (binomial test, one sample case) Tail(s) = One, Constant proportion = 0.50, α err prob = 0.05, Effect size g = 0.1 0.95 0.9 Power (1-β err prob) 0.85 0.8 0.75 0.7 0.65 100 150 200 250 300 Total sample size

Key Eligibility Criteria • Symptomatic MM • 18-70 years old at time of enrollment • 2-12 cycles of induction chemo followed by ASCT; 2-16 months following first dose • No prior progression/relapse • Must not be intolerant of Ixazomib, Lenalidomide, or Dexamethasone • ANC >1,000; PLT >75,000 • Bilirubin <1.5x ULN; AST and ALT <3x ULN • Creatinine Clearance >30ml/min

MRD Assessment https://www.adaptivebiotech.com/clonoseq/how-clonoseq-works Primary: Adaptive clonoSEQ Secondary: MFC Aug 2017 – current Mayo MRDMM (Euroflow) [CD138, CD27, CD38, CD56, CD45, CD19, CD117, CD81, cyKappa, & cyLambda] Jan 2015- Aug 2017 Mayo PCPRO [CD138, CD38, CD56, CD19, cyKappa & cyLambda]

Enrollment- IA2 T otal 191 Washington University 68 Wayne State University 8 Ohio State University 45 City of Hope 20 Emory Winship University 5 University of California- San Francisco 21 Tennessee Oncology 5 Colorado Blood Cancer Institute 4 Mount Sinai 6 Mayo Clinic- Rochester 9

Patient Disposition Consented N = 321 In Screening Screen Failure N = 34 N = 96 Started IRd N = 191 Receiving IRd Discontinued N = 22 N = 14 Restaging N = 155 Maintenance Discontinued Assigned N = 4 N = 6 Randomized N = 145* *100 by NGS; 40 by MFC (18 MRDMM; 22 PCPRO); 5 no MRD results Ixazomib Lenalidomide N = 74 N = 71

Patient Demographics N = 169 Age (Median, Range) 57 (28-70) Gender Male 67% Female 33% Race White 76% African-American/Black 10% Other Race 13% ISS Stage Stage I 41% Stage II 27% Stage III 19% Unreported 14% Isotype IgG 47% IgA 25% Light Chain 14% Other/Unreported 14%

Treatment History N = 169 Induction PI-based 15% IMID-based 1% Combination PI/IMID 83% Number of Cycles 4 (2-13) (Median, Range) Conditioning Melphalan 100% Days from diagnosis to ASCT 170 (83-428) (Median, Range) Days from ASCT to IRd 110 (80-138) (Median, Range)

Hematologic Toxicity Neutropenia Thrombocytopenia Anemia Grade 1 2 3 4 Grade 1 2 3 4 Grade 1 2 3 4 n 73 10 3 0 n 21 16 8 0 n 55 9 5 0 % 12.4% 9.5% 4.7% 0.0% % 32.5% 5.3% 3.0% 0.0% % 43.2% 5.9% 1.8% 0.0%

Non-Hematologic Toxicity Grade 1 2 3 4 5 Gastrointestinal Nausea 29.6% 1.2% 2.4% 0% 0% Vomiting 11.8% 1.2% 1.8% 0% 0% Diarrhea 28.4% 3.6% 1.2% 0% 0% Constipation 30.2% 0.6% (n = 1) 0% 0% 0% General Edema 14.8% 2.4% 0% 0% 0% Fatigue 35.5% 9.5% 0.6% 0% 0% Insomnia 16.6% 4.1% 1.2% 0% 0% Infections C. Diff/GI 0.6% (n = 1) 0.6% (n = 1) 1.2% 0% 0% Sepsis 0% 0% 0% 0.6% (n = 1) 0% Upper Respiratory/Lung 12.4% 16.6% 5.9% 0% 0.6% (n = 1) Urinary Tract 2.4% 1.8% 0% 0% 0% Investigations Hyperglycemia 26.6% 3.6% 3.0% 0% 0% Transminitis 16.0% 3.0% 1.2% 0% 0% Peripheral Neuropathy Sensory 40.8% 3.6% 0% 0% 0% Motor 5.9% 1.8% 0% 0% 0% Skin Rash 11.8% 3.0% 0% 0% 0% Pruritis 3.0% 0.6% (n = 1) 0% 0% 0%

Dose Reductions Ixazomib Lenalidomide Dexamethasone Starting Dose 4mg 15mg 40mg 84.6% 81.1% 75.7% Dose -1 3mg 10mg 20mg 6.5% 7.7% 13.0% Dose -2 2.3mg 5mg 8mg 0% 0.6% 2.4% Dose -3 Discontinue Discontinue Discontinue 0.6% 2.4% 0.6% Discontinue all Treatment 8.3% overall 4.1% due to toxicity 2.4% due to progression 1.2% due to other reasons

Response Pre-Consolidation Post-Consolidation CR/sCR 47% 16% 63% p < 0.0001 86% p = 0.0495 VGPR or better 81% 5% MRD-Negative (clonoSEQ) 30% p = 0.0389 22% 8% (N = 125)* MRD-Negative (All) 38% (N = 153) 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% *MRD-Negative among CR/sCR: Pre 33%; Post 39%

clonoSEQ Pre-Consolidation N = 125 Negative Positive 18% 11% Negative Post- (N = 23) (N = 14) Consolidation 4% 66% Positive (N = 5) (N = 83) McNemar’s x 2 = 4.26, p = 0.0389

Current Status • Median follow-up from start of IRD: 19 months • Median F/U on maintenance: 15 months • Progression 36 patients • Deaths 6 patients* * 1 Death on study and 5 in follow-up

Conclusions • IRD consolidation resulted in improvement of MRD negativity rates. • IRd consolidation following ASCT appears to be safe and effective. • The all oral regimen is convenient for patients which greatly simplifies follow-up in the peri-transplant period. • Whether improvement in MRD-ve rate translates to improved long-term outcomes is yet to be determined • An interim analysis is planned for 2019, representing the first comparison of ixazomib and lenalidomide maintenance

Acknowledgements • Patients and their families • Clinical Sites and all their staff • Takeda Oncology • Adaptive Biotechnologies Corporation • Multiple Myeloma Research Consortium