Triplet Combo Therapy Provides Limited Toxicity in Relapsed MM

Phase 2 toxicity and response data of a biomarker-driven, open-label trial of the triplet combination of ixazomib, lenalidomide, and dexamethasone for early relapsed patients with multiple myeloma (MM) were presented at the 2021 American Society of Hematology (ASH) Annual Meeting.

“Proteasome inhibitors (PI) and immunomodulatory drugs have become the backbone of therapy for MM. The oral boron-containing selective and reversible PI ixazomib has shown to induce deep and durable responses. Triplets containing ixazomib have shown more efficacious results than doublet regimens in the relapse setting,” explained Leon Bernal-Mizrachi, MD, Winship Cancer Institute, Emory University, Georgia, and co-researchers.

Patients with MM resistant to PI were found to lack both the ankyrin (ANK) and death domain (DD) present in the 3’-end of NFKB2. This loss was associated with structural arrangements.

“We found that NFKB2-ANK and -DD are crucial at initiating bortezomib’s apoptotic signal by facilitating caspase-8 activation. Based on these findings, we designed this study to examine the efficacy of NFKB2 break-apart FISH to predict responses to ixazomib and dexamethasone versus this doublet combo with lenalidomide,” continued Dr Bernal-Mizrachi and co-authors.

The primary endpoint was to compare response rates of ixazomib plus dexamethasone versus the triplet combo at 4 cycles according to the rearrangement status of NFKB2.

Interim analysis data of 60 relapsed patients with MM were provided. Patients were randomized to either <4 lines of therapy to ixazomib 4 mg weekly (3 out of 4 weeks) with 40mg weekly dexamethasone, or ixazomib and dexamethasone plus 25mg of lenalidomide daily.

All treatment groups received a median of 2 prior lines of therapy. A trend to higher overall response rate (ORR) was shown in the NFKB2 FISH negative group treated with ixazomib plus dexamethasone compared to those who received the same treatment and were NFKB2 FISH positive (41% CI, 58%-97% versus 30% CI, 8%-60%, P=0.4).

Currently, the ORR for patients treated with the triplet combo is 57% (95% CI, 27%-80%).

Notably, grade 3 or higher treatment related adverse events (TEAEs) were highest in the NFKB2 FISH negative ixazomib plus dexamethasone (15%) and triplet therapy (13%) arms versus 0% for NFKB2 FISH positive patients treated with ixazomib plus dexamethasone.

“Interim analysis demonstrates a trend higher and grade 3 or higher toxicity of ixazomib plus dexamethasone in patients with MM and NFKB2 break-apart FISH compare to those with a positive test. Efficacy and toxicity of the triplet regimen are comparable to what is seen in the Tourmaline 1 trial,” concluded Dr Bernal-Mizrachi, et al.—Alexa Stoia

Bernal-Mizrachi L, Nooka A, Heffner L, et al. Phase II Trial of Ixazomib and Dexamethasone Versus Ixazomib, Dexamethasone, and Lenalidomide, Randomized with NFKB2 Rearrangement. Presented at: the 2021 ASH Annual Meeting; Dec. 11-14; 2021; Abstract 2758.