Ixazomib (Ninlaro®) is an orally bioavailable, reversible and selective proteasome inhibitor, which binds to the beta 5 subunit of the 20S proteasome and thereby inhibit its chymotrypsin-like activity. Ixazomib has shown, in vitro, that it induces apoptosis of multiple myeloma cell lines. Currently, ixazomib is approved in the US for the treatment of patients with multiple myeloma (MM), who have received at least one prior therapy. In November 2016 ixazomib received marketing authorisation by the European Medicines Agency (EMA) for the combination therapy with lenalidomide and dexamethasone for adult MM patients who have received at least one prior therapy.

The US Food and Drug Administration (FDA) approval of ixazomib in combination with lenalidomide and dexamethasone was based on the TOURMALINE-MM1 trial, a randomised, double-blind, multicentre, placebo-controlled phase III study. It was conducted to assess the addition of ixazomib to lenalidomide and dexamethasone for the treatment of patients, who have relapsed, refractory, or relapsed and refractory MM. Two pre-specified interim analysis were performed, both results are reported in this study. A total of 722 patients were randomly assigned in a 1:1 ratio to either receive ixazomib in combination with lenalidomide and dexamethasone or lenalidomide and dexamethasone in addition to a placebo. The stratification of randomisation was based on the number of prior therapies, prior treatment with proteasome inhibitors and International Staging System disease stage. The median number of treatment cycles in the ixazomib group was 17 and 15 in the placebo group. The primary outcome of the study was progression-free survival (PFS). PFS was significantly improved (p = 0.01) in the intention-to-treat population of the ixazomib group (5.9 months gain). In contrast, at the time of the second interim analysis (23 months) median overall survival (OS), secondary outcome, had not yet been reached in any of the two study groups. In terms of safety, grade ≥ 3 adverse events (AEs) as well as serious AEs could be observed more often in the ixazomib group than in the placebo group. The most common AEs of any grade in the ixazomib group were diarrhoea (45%), rash (36%), constipation (35%), fatigue (29%) and nausea (29%).

In conclusion, the treatment with ixazomib in combination with lenalidomide and dexamethasone offers a significant improvement in PFS (median gain 5.9 months, intention-to-treat population). However, the missing data for OS and the lack of benefit of the ixazomib therapy for the actual patient population that is most affected by MM in clinical practice (> 65 years), highlight the requirement for long-term data. Furthermore, the direct comparison of ixazomib to the carfilzomib and elotuzumab triplet combination regimens is necessary to identify the best treatment option for MM patients, who received prior therapies.