Phase II Trial of Ixazomib and Dexamethasone Versus Ixazomib, Dexamethasone and Lenalidomide, Randomized with NFKB2 Rearrangement. (Proteasome Inhibitor NFKB2 Rearrangement Driven Trial, PINR)
Authors: Bernal-Mizrachi Leon , Nooka Ajay K. , Heffner Leonard , Cole Craig E. , Ye Jing C. , Vij Ravi , Hofmeister Craig C. , Rushton John , Chen Zhengjia , Goyal Subir , Switchenko Jeffrey M. , Lonial Sagar , Kaufman Jonathan L. 
Published: November 2021

Abstract
Introduction: Proteasome inhibitors (PI) and immunomodulatory drugs have become the backbone of therapy for multiple myeloma (MM). The oral boron-containing selective and reversible proteasome inhibitor ixazomib has shown to induce deep and durable responses (Kumar RK et la, Blood 2016. 128(20):2415-2422). Triplets containing ixazomib, has shown to be more efficacious than doublet regimens in the relapse setting (Moreau P, et al. N Engl J Med 2016. 374:1621-1634).However, to date, there is not companion diagnostics capable of predicting PI response.
We have recently discovered that MM patients resistant to PI lack of the ankyrin (ANK) and death domain (DD) present in the 3'-end of NFKB2. Loss of NFKB2 3'end frequently resulted from a structural rearrangements. We found that NFKB2-ANK and -DD are crucial at initiating bortezomib's apoptotic signal by facilitating caspase-8 activation (unpublished data). Based on this findings, we designed this study to examine the efficacy of NFKB2 break apart FISH to predict the response to ixazomib and dexamethasone (Id) vs. ixazomib, lenalidomide and dexamethasone (IRd) in early relapse MM patients.
Methods: In this phase 2 biomarker-driven open-label trial, relapsed patients with &lt;4 lines of therapy were randomized to ixazomib 4 mg weekly 3 of 4 weeks and 40 mg weekly dexamethasone vs. Id plus 25 mg of lenalidomide daily days 21/28, based on the status of NFKB2 rearrangement in plasma cells. Patients were screened for NFKB2 rearrangement detected by NFKB2 break apart FISH. Patients without NFKB2 rearrangement received Id and patients with NFKB2 rearrangement were subsequently randomized in a 1:1 fashion to receive Id or IRd. The primary endpoint is to compare the response rate (MR or better) of Id or IRd at 4 cycles according to the rearrangement status of NFKB2
Results: At the moment of the interim analysis, 60 patients have achieved 4 cycles of treatment. All treatment groups (NFKB2 FISH [-] Id, n=27, NFKB2 FISH [+] Id, n=20 and IRd, n=19) received a median of 2 prior lines of therapy. A trend to higher ORR was observed in NFKB2 FISH negative treated with Id compared with NFKB2 FISH positive (41% CI:58%-97% vs. 30% CI:8%-60%, P=0.4, target p-value goal 0.15), including significantly higher rates of ≥ very good partial response, ≥ partial response, ≥ minimal response (15%, 25%, 15% vs. 4%, 25%, 10%, respectively). ORR for IRd arm is for now 57% CI:27%-80%. Interestingly, &gt;G3 treatment related adverse events were higher in Arm A (15%) and Arm C (13%) vs Arm B (0%). The most common (≥10%) ≥ grade 3 include URI/pneumonia 16% and diarrhea 12% in Id NFKB2 FISH negative vs. neutropenia 18% and diarrhea (10%) in the IRd NFKB2 FISH positive arm. Treatment discontinuations only occurred in 3 NFKB2 FISH positive Id treated patient (13%).
Conclusion: Interim analysis demonstrates a trend higher efficacy and ≥G3 toxicity of ixazomib with dexamethasone in MM patients with negative NFKB2 break-apart FISH compared to those with a positive test. Efficacy and toxicity of the triplet regimen are comparable to what is seen in the Tourmaline 1 trial. This study is registered clinicaltrials.gov# NCT02765854

Disclosures
Bernal-Mizrachi: Kodikaz Therapeutic Solutions: Consultancy, Current holder of individual stocks in a privately-held company, Patents & Royalties; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Winship Cancer Institute of Emory University: Current Employment; Bigene: Membership on an entity's Board of Directors or advisory committees. Nooka: Takeda: Consultancy, Research Funding; Janssen Oncology: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Other: Travel expenses; Sanofi: Consultancy; Bristol-Myers Squibb: Consultancy; Amgen: Consultancy, Research Funding; Oncopeptides: Consultancy; Adaptive technologies: Consultancy; Karyopharm Therapeutics: Consultancy. Ye: Alexion, AstraZeneca Rare Disease: Other: Study investigator. Vij: BMS: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; BMS: Honoraria; GSK: Honoraria; Oncopeptides: Honoraria; Karyopharm: Honoraria; CareDx: Honoraria; Legend: Honoraria; Biegene: Honoraria; Adaptive: Honoraria; Harpoon: Honoraria. Hofmeister: Ohio State University: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: IP rights, Patents & Royalties; Medscape: Other: Non-pharma speaker for education, research, marketing; DAVA Oncology: Other: Non-pharma speaker for education, research, marketing; TRM Oncology: Other: Non-pharma speaker for education, research, marketing; Verascity: Other: Non-pharma speaker for education, research, marketing; Aptitude Health: Other: Non-pharma speaker for education, research, marketing; BlueBird Bio: Other: Non-CME speaker; Amgen: Other: Non-CME speaker; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Philips Gilmore: Other: CME speaker; Non-pharma speaker for education, research, marketing; BioAscend: Other: CME speaker; Imbrium: Membership on an entity's Board of Directors or advisory committees; Myeloma360: Membership on an entity's Board of Directors or advisory committees; Genzyme: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Local PI of CST; Oncolytics: Other: National PI for CST; PI or co-PI IST; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Local PI of CST; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Local PI of CST; Nektar Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Local PI of CST; BMS/Celgene: Other: National PI for CST; PI or co-PI IST; Local PI of CST; Sanofi: Other: National PI for CST; PI or co-PI IST. Rushton: KSL: Current Employment. Lonial: Merck: Honoraria; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Kaufman: Incyte, celgene: Consultancy; Genentech, AbbVie, Janssen: Consultancy, Research Funding; Tecnofarma SAS, AbbVie: Honoraria; Heidelberg Pharma: Research Funding; Janssen: Honoraria; Novartis: Research Funding; Incyte, TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Fortis Therapeutics: Research Funding; BMS: Consultancy, Research Funding; Amgen: Research Funding; Roche/Genetech, Tecnopharma: Consultancy, Honoraria; Sutro, Takeda: Research Funding.