Phase II Trial of Ixazomib and Dexamethasone Versus Ixazomib, Dexamethasone and Lenalidomide, Randomized with NFKB2 Rearrangement. (Proteasome Inhibitor NFKB2 Rearrangement Driven Trial, PINR)

• Published in: Blood 2018-11, Vol.132 (Supplement 1), p.2011-2011
• Main Authors: Bernal-Mizrachi, Leon, Cole, Craig E., Heffner, Leonard, Nooka, Ajay K, Vij, Ravi, Kelkar, Nyaya, Sridhar, Akshata, Cinar, Munevver, Chen, Zhengjia, Chang, Zhao, Lonial, Sagar, Kaufman, Jonathan L
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2018-99-119337

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. Activation of this caspase resulted from NFKB2 interaction with FADD/caspase-8/p62 (unpublished data). Based on this findings, we design this study to examine the efficacy of NFKB2 break apart FISH to predict the response to the duplet ixazomib and dexamethasone (Id) vs ixazomib, lenalidomide and dexamethasone (IRd) in early relapse MM patients (1-3 lines of therapy). Methods: In this phase 2 biomarker driven open label trial, relapse patients with