Lessons learned from the clinical trial portfolio of ixazomib in multiple myeloma: A systematic review and meta-analysis Free

Introduction: Ixazomib is a next-in-class oral proteasome inhibitor approved for relapsed multiple myeloma (MM). However, it has failed to meet its primary endpoint in numerous trials and has led to worse survival in the maintenance setting (TOURMALINE-MM3 and TOURMALINE-MM4). In this systematic review and meta-analysis, we reviewed ixazomib's entire clinical trial portfolio.

Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we conducted a systematic review of all interventional clinical trials investigating ixazomib in MM through July 2025, searching ClinicalTrials.gov and PubMed databases. Two independent reviewers screened trials and extracted data on trial characteristics, endpoints, and safety. Revenue data was obtained from Takeda's Securities and Exchange Commission filings. This review was registered with PROSPERO (CRD420251080385). Trials that led to regulatory approval, or that were intended to seek regulatory approval (TOURMALINE-MM platform), were identified and analyzed in detail. Pooled risk ratios (RR) with 95% confidence intervals were calculated using fixed-effects meta-analysis for the TOURMALINE-MM trials.

Results: 87 studies were included. Trial phases included Phase 1 (14%), Phase 1/2 (11%), Phase 2 (54%), Phase 3 (10%), and Phase 4 (7%). Published results were available for 56 trials (64%). Median sample size among non-randomized trials was 35 (IQR 42.5), compared to 127 (IQR 262) among randomized controlled trials (RCTs).

In the only trial of ixazomib that led to FDA approval for a specific label, the TOURMALINE-MM1 trial, a statistically significant improvement in progression-free survival (PFS) was seen for ixazomib-lenalidomide-dexamethasone vs. placebo-lenalidomide-dexamethasone in relapsed/refractory MM, but no overall survival (OS) improvement. TOURMALINE-MM2, conducted in newly diagnosed MM failed to demonstrate a statistically significant benefit in either PFS or OS. Other studies, including TOURMALINE-MM3 (NDMM maintenance) and TOURMALINE-MM4 (NDMM maintenance, transplant-ineligible), reported PFS benefits but worse OS in ixazomib arms. No trial of ixazomib has been powered for, or has demonstrated, an OS benefit.

A meta-analysis of 2,754 patients across four TOURMALINE RCTs demonstrated a significantly increased risk of adverse events leading to treatment discontinuation in the ixazomib group (pooled RR 1.32, 95% CI 1.12-1.56, p<0.001). There were also increased risks for diarrhea (RR 1.32, 95% CI 1.20-1.45), nausea (RR 1.67, 95% CI 1.45-1.91), vomiting (RR 2.41, 95% CI 2.0-2.9), and peripheral neuropathy (RR 1.30, 95% CI 1.13-1.50).

In non-randomized trials (n=59), ixazomib was used as monotherapy in 7 studies (12%). Among non-randomized trials with posted results (n=38), none had OS as the primary endpoint; 3 (8%) used PFS (1 met, 33%; 2 were unable to ascertain, 67%), and 20 (53%) used response rate (12 met, 60%; 4 did not meet, 20%; and 4 were unable to ascertain, 20%). All 15 non-randomized trials with safety as a primary endpoint met it (100%).

Nine of 28 RCTs (32%) included ixazomib in both arms, also precluding effect isolation. Among RCTs with posted results (n=18), none used OS as the primary endpoint. 13 (72%) used PFS (5 met; 38%; 8 did not meet, 62%), and 5 (28%) used response rate (1 met; 20%; 4 did not meet, 80%). Amongst RCTs with clinical endpoints (PFS/response), only 6 of 18 (33%) met the primary endpoint. Notably, no trial directly compared ixazomib to another proteasome inhibitor.

From 2016 to 2024, worldwide sales of ixazomib totaled approximately $4.6Bn, peaking at $732Mn in 2020 before declining to $578Mn in 2024.

Conclusion: A comprehensive review of ixazomib's clinical trial portfolio reveals that across 87 unique trials over 16 years, no study has demonstrated an OS benefit, despite substantially increased toxicity. The majority of ixazomib RCTs with clinical endpoints were unsuccessful. A preponderance of single-arm trials utilizing other myeloma drugs in combination failed to isolate the clinical efficacy of this drug. Concerningly, an OS decrement was seen in RCTs in the maintenance setting. As a result, the clinical value of ixazomib remains unclear, despite $4.6 billion in revenue, highlighting the urgent need for intentional trial design with appropriate regulatory oversight to ensure meaningful clinical benefit in myeloma by novel therapeutics.