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 Vij1, Nitya Nathwani2, Thomas G. Martin3, Mark A. Fiala1, Abhinav Deol4, Francis K. Buadi5, Jonathan L. Kaufman6, Craig C. Hofmeister6, Tara K. Gregory7, Jesus Berdeja8, Ajai Chari9, Ashley Rosko10

• 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 2002 C-VAMP Mel ASCT 42% MFC 10-4 San Miguel 2002 VBMCP or VBAD Mel ASCT 36% MFC 10-4 Paiva 2008 VBMCP/VBAD Mel ASCT 42% MFC 10-4 Korthals 2012 Ida/Dex Mel ASCT 45% PCR 10-4 Dal Bo 2013 Unreported Induction Mel ASCT 60% MFC 10-4 Rawstron 2013 CTD or CVAD Mel ASCT 62% MFC 10-4 Ferrero 2014 VAD Mel ASCT VTD Consolidation 67% PCR 10-4 Roussel 2014 RVD Mel ASCT R Maintenance 68% MFC 10-4

MRD: NGS vs MFC

Perrot A, Lauwers-Cances V, Corre J, et al. Blood, 2018.

Regimen Method Sensitivity MRD-Negative RVD Mel ASCT RVD Consolidation R Maintenance MFC 10-4 79% NGS 10-6 30% (VGPR/CR only)

IRd Schema

Consolidation

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, OS, and Toxicity

Maintenance

Ixazomib: 4mg on Days 1, 8, 15

• r

Lenalidomide: 15mg Daily Primary Objective To compare MRD-negative rate after 12 cycles

• f Ixazomib or Lenalidomide Maintenance

Secondary Objectives: IMWG response, PFS, OS, and Toxicity NCT0225316

N = 240

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.

Total sample size Power (1-β err prob) 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 0.65 0.7 0.75 0.8 0.85 0.9 0.95 100 150 200 250 300

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

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]

https://www.adaptivebiotech.com/clonoseq/how-clonoseq-works

Enrollment- IA2

T

• tal

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 Randomized N = 145* Ixazomib N = 74 Lenalidomide N = 71 In Screening N = 34 Screen Failure N = 96 Receiving IRd N = 22 Discontinued N = 14 Discontinued N = 4

Maintenance Assigned

N = 6 Restaging N = 155 Started IRd N = 191 *100 by NGS; 40 by MFC (18 MRDMM; 22 PCPRO); 5 no MRD results

Patient Demographics

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

Treatment History

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

Hematologic Toxicity

Neutropenia Anemia Thrombocytopenia

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

Non-Hematologic Toxicity

Grade 1 2 3 4 5 Gastrointestinal Nausea Vomiting Diarrhea Constipation 29.6% 11.8% 28.4% 30.2% 1.2% 1.2% 3.6% 0.6% (n = 1) 2.4% 1.8% 1.2% 0% 0% 0% 0% 0% 0% 0% 0% 0% General Edema Fatigue Insomnia 14.8% 35.5% 16.6% 2.4% 9.5% 4.1% 0% 0.6% 1.2% 0% 0% 0% 0% 0% 0% Infections

• C. Diff/GI

Sepsis Upper Respiratory/Lung Urinary Tract 0.6% (n = 1) 0% 12.4% 2.4% 0.6% (n = 1) 0% 16.6% 1.8% 1.2% 0% 5.9% 0% 0% 0.6% (n = 1) 0% 0% 0% 0% 0.6% (n = 1) 0% Investigations Hyperglycemia Transminitis 26.6% 16.0% 3.6% 3.0% 3.0% 1.2% 0% 0% 0% 0% Peripheral Neuropathy Sensory Motor 40.8% 5.9% 3.6% 1.8% 0% 0% 0% 0% 0% 0% Skin Rash Pruritis 11.8% 3.0% 3.0% 0.6% (n = 1) 0% 0% 0% 0% 0% 0%

Dose Reductions

Ixazomib Lenalidomide Dexamethasone Starting Dose 4mg 84.6% 15mg 81.1% 40mg 75.7% Dose -1 3mg 6.5% 10mg 7.7% 20mg 13.0% Dose -2 2.3mg 0% 5mg 0.6% 8mg 2.4% Dose -3 Discontinue 0.6% Discontinue 2.4% Discontinue 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

22% 81% 47% 38% 8% 5% 16% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% MRD-Negative (All) MRD-Negative (clonoSEQ) VGPR or better CR/sCR Pre-Consolidation Post-Consolidation

63% 86% 30% p = 0.0389 (N = 125)* (N = 153) p < 0.0001 p = 0.0495 *MRD-Negative among CR/sCR: Pre 33%; Post 39%

clonoSEQ

N = 125 Negative Positive Negative

18% (N = 23) 11% (N = 14)

Positive

4% (N = 5) 66% (N = 83)

Pre-Consolidation Post- Consolidation

McNemar’s x2 = 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