Added value of ixazomib to lenalidomide plus dexamethasone in transplant-ineligible newly diagnosed MM

The phase 3 TOURMALINE-MM2 trial demonstrated that in elderly, transplant-ineligible patients with newly diagnosed multiple myeloma (MM), the addition of ixazomib, the first oral proteasome inhibitor (PI), to lenalidomide and dexamethasone (Rd) leads to a clinically meaningful improvement of progression-free survival (PFS), although this did not reach statistical significance.

The transplant-ineligible newly diagnosed MM patient population is diverse, ranging from fit patients aged ≥70 to elderly and/or frail patients with poor performance status. Hence, treatment must be adapted to individual patient settings. Continuous Rd-based regimens are among the standard of care. Use of PIs has shown to improve outcomes, but long-term administration of injectable PIs may be challenging due to limitations in terms of tolerability and treatment burden [1]. In this setting, an oral PI-Rd triplet may be useful. Ixazomib is suitable for continuous dosing, with predictable and manageable toxicities [2].

The multicentre, double-blind, placebo-controlled phase 3 TOURMALINE-MM2 trial (NCT01850524) compared ixazomib-Rd (n=351) versus placebo-Rd (n=354) in transplant-ineligible newly diagnosed MM patients (median age 73 years) [3]. There was a positive, but not statistically significant trend in PFS favouring ixazomib-Rd (median PFS 35.3 vs 21.8 months; HR 0.830; 95% CI 0.676-1.018; P=0.073; see Figure). There was also a clinically meaningful benefit in time to progression (HR 0.738; 95% CI 0.589-0.925; P=0.008) and complete response rate (HR 2.10; 95% CI 1.43-3.09; P<0.001), with deeper responses in the ixazomib-Rd arm compared with the placebo-Rd arm. Overall response rates were similar between arms, but depth of response was greater with ixazomib-Rd. After a median follow-up of approximately 58 months, median overall survival was not reached in either arm. Treatment-emergent adverse events were mostly grade 1/2. Both PFS and safety results were generally consistent with results from the TOURMALINE-MM1 trial [2].

Figure: PFS in the ixazomib-Rd and placebo-Rd arms [1]



PFS, progression-free survival; Rd, lenalidomide-dexamethasone; IRd, ixazomib-Rd

According to Prof. Thierry Facon (University Hospital Lille, France), these data demonstrate that ixazomib-Rd is a feasible treatment option for transplant-ineligible patients with newly diagnosed MM who could benefit from an oral triplet combination.

1. Jimenez-Zepeda VH, et al. Ann Hematol. 2017;96:431-9.
2. Avet-Loiseau H, et al. Blood. 2017;130:2610-8.
3. Facon T, et al. The Phase 3 TOURMALINE-MM2 Trial: Oral Ixazomib, Lenalidomide, and Dexamethasone (IRd) Vs Placebo-Rd for Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma (NDMM). 62^nd ASH Annual Meeting, 5-8 December 2020. Abstract 551.

Posted on 18 February 202122 February 2021