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

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that NFKB2-ANK and -DD are crucial at initiating bortezomib's apoptotic signal by facilitating caspase-8 activation (unpublished data).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 <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, 69 out of 71 patients have achieved 4 cycles of treatment. All treatment groups (NFKB2 FISH [-] Id, n=27, NFKB2 FISH [+] Id, n=21 and IRd, n=21) 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 (59% CI:43.6%-74.4% vs. 42% CI:17.5%-67.3%, P=0.2, target p-value goal 0.15), including significantly higher rates of ≥ very good partial response, ≥ partial response, ≥ minimal response (15%, 25%, 15% vs. 4.7%, 23.8%, 14.2%, respectively). ORR for IRd arm was higher the patients with an NFKB2 positive FISH treated with Id (65%:CI:48.5%-81.5% vs. 42% CI:17.5%-67.3%, P=0.15). Progression free survival (PFS) at 12 and 24 months was higher in patients treated with Id with negative NFKB2 FISH than those with positive FISH ( 40.7 % CI:20.3-60% and 35% CI:15.6-55% vs 21% CI 7-41%, p-value 0.012 and 35% CI:15.6-55% vs 10.7% CI: 1.8- 28.7%, p-value:0.002, respectively). Treatment with IRd in patients with positive NFKB2 FISH demonstrated higher PFS at 12 months compared to those treated with Id (46% CI: 23-67% vs 21% CI 7-41%, p-value of 0.004). However, this difference disappeared after 18 months. Interestingly, >G2 treatment related adverse events were higher in Arm A (66%) and Arm C (55%) vs Arm B (28%). The most common (≥10%) ≥ grade 3 include URI/pneumonia 15% and diarrhea 22% in Id NFKB2 FISH negative vs. URI 10% (10%) in the Id 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 significantly better PFS in 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 somewhat lower than what is seen in the Tourmaline 1 trial. This study is registered clinicaltrials.gov# NCT02765854

Bernal-Mizrachi:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kodikaz Therapeutic Solutions LLC: Other: Founder and Scientific Board; Winn Career Development Program: Other: Scientific Board. Nooka:Bristol-Myers Squibb, Janssen, Takeda, Amgen, Adaptive, GlaxoSmithKline, Sanofi, Oncopeptides, Karyophram, SecureBio, and BeyondSprings: Consultancy, Honoraria. Vij:Beigene: Honoraria; adaptive: Honoraria; Sanofi: Honoraria, Other: Grant support; BMS: Honoraria, Other: Grant support; Takeda: Honoraria, Other: Grant support; Janssen: Honoraria; oncopetideslegend: Honoraria; GSK: Honoraria. Ye:Karyopharm: Research Funding; Portola: Research Funding; MingSight: Research Funding; Nektar: Research Funding; GSK: Research Funding; Janssen: Consultancy, Research Funding; sanofi: Research Funding; Ascentage: Research Funding; BMS: Consultancy; Regeneron: Research Funding; Genmab: Research Funding. Hofmeister:Janssen: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; BlueBird Bio: Honoraria; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Membership on an entity's Board of Directors or advisory committees. Lonial:Celgene, Janssen, Takeda: Research Funding; Novartis, BMS, GSK, Amgen, Merck, Janssen: Honoraria; AbbVie, Bluebird, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Novartis Pharma, and Takeda.: Consultancy. Kaufman:AbbVie, Genentech, and Bristol Myers Squibb: Consultancy; Incyte: Other: Member of data safety monitoring committee ; AbbVie: Other: Member of steering committee.