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Ixazomib maintenance significantly delays the disease progression in transplant-ineligible patients with newly diagnosed multiple myeloma

The phase III TOURMALINE-MM4 trial evaluated the efficacy and safety of ixazomib as maintenance therapy following standard-of-care induction therapy in patients with transplant-ineligible, newly diagnosed multiple myeloma (NDMM). Compared to placebo, ixazomib maintenance resulted in a statistically significant and clinically meaningful 8-months increase in the median progression-free survival (PFS). This PFS benefit was seen across all the prespecified patient subgroups, including elderly patients and patients with ISS stage III disease. Finally, ixazomib was well tolerated and did not have a negative impact on the quality of life of patients.


It is well established that maintenance therapy following initial treatment delays the disease progression in patients with NDMM who are not eligible to undergo an autologous stem cell transplant (ASCT). Currently, this maintenance therapy is mainly limited to immunomodulatory agents (i.e. lenalidomide), but other options that complement the induction regimen and have favourable toxicity profiles would be welcomed. Thus far, proteasome inhibitor (PI)-based maintenance has not been studied in a placebo-controlled trial. Ixazomib as post-transplant maintenance therapy was already shown to prolong the PFS versus placebo and has a limited cumulative toxicity or impact on quality of life. The TOURMALINE-MM4 phase III, randomised, double-blind, placebo-controlled trial evaluated the efficacy and safety of ixazomib as maintenance therapy in transplant-ineligible NDMM patients, following standard of care induction therapy.

In total, 706 non-ASCT NDMM patients who received 6–12 months of standard-of-care induction therapy and achieved at least a partial response (≥PR) were randomised (3:2) to ixazomib (N=425; 3 mg for cycles 1 to 4; then, if tolerated, 4 mg from cycle 5 onwards) or placebo (N=281) on days 1, 8, and 15 of 28-day cycles for up to 2 years (26 cycles). Patients were stratified by prior PI exposure, pre-induction International Staging System (ISS) disease stage (I/II versus III), age (<75 versus ≥75 years), and post-induction best response (complete or very good partial response [CR/VGPR] versus PR). Baseline characteristics were well balanced in the ixazomib versus placebo arms.


After a median follow-up of 21.1 months, ixazomib resulted in a significant 34.1% reduction in the risk of disease progression or death, as compared to placebo (HR [95% CI]: 0.659 [0.542-0.801], p<0.001). Patients treated with ixazomib maintenance had a median PFS of 17.4 months, which was 8 months longer than the 9.4 months median PFS seen in the placebo arm. The median total PFS time from the start of the induction therapy was 26.3 versus 20.3 months for ixazomib and placebo, respectively (HR [95% CI]: 0.65 [0.534-0.791], p<0.001). The most pronounced PFS benefit with ixazomib was seen in patients who obtained a CR or a VGPR to the initial therapy (median 25.6 versus 12.9 months, HR [95% CI]: 0.576 [0.499-0.765], p<0.001). In addition, also patients with ISS stage III disease (median 16.6 versus 7.8 months, HR [95% CI]: 0.695 [0.499-0.967], p=0.030) and in patients aged 75 years or older (median 16.7 versus 10.6 months, HR [95% CI]: 0.738 [0.537-1.014], p=0.060) seemed to derive a particularly high PFS benefit with ixazomib. Time to treatment progression was significantly prolonged with ixazomib versus placebo (median 17.8 versus 9.6 months, HR [95% CI]: 0.655 [0.537-0.799], p<0.001). Time to second disease progression (PFS2, 22.4% of events) and overall survival (OS, 19.1% of events) data are not yet mature and therefore the study remains blinded and follow-up for PFS2 and OS continues.

Overall rates of treatment-emergent adverse events (TEAEs) were similar between both treatment arms. The rate of serious TEAEs (22% versus 17%) and the incidence of treatment discontinuation due to TEAEs (13% versus 8%) was slightly higher with ixazomib than with placebo. The most common TEAEs were nausea (27% versus 8%), vomiting (24% versus 4%) and diarrhoea (23% versus 12%). In total, 5.2% and 6.2% of patients in the ixazomib and placebo groups had new primary malignancies. Finally, the mean EORTC QLQ-C30 Global Health Status/ Quality of life scores were similar in both treatment arms at study entry and this was maintained throughout the treatment, indicating that ixazomib maintenance did not have a detrimental effect on the quality of life of patients.


Ixazomib maintenance following standard-of-care induction in transplant-ineligible NDMM patients resulted in a statistically significant and clinically meaningful 8-month increase in median PFS. This corresponds with a 34.1% reduction in the risk of progression or death versus. placebo. In addition, the benefits of ixazomib maintenance were realised in the context of a well-tolerated safety profile without an adverse impact on the quality of life. As such, ixazomib represents the first oral PI maintenance option for non-ASCT NDMM patients and may provide a valuable maintenance option in combination with other agents such as immunomodulatory drugs and monoclonal antibodies.


Dimopoulos MA, Spicka I, Quach H, et al. Ixazomib vs placebo as post-induction maintenance therapy in newly diagnosed multiple myeloma (NDMM) patients (pts) not undergoing autologous stem cell transplant (ASCT): phase 3 TOURMALINE-MM4 trial. Presented at EHA 2020; Abstract S200.

Speaker M. Dimopoulos


M. Dimopoulos, MD, PhD, National and Kapodistrian University of Athens, Athens, Greece


See: Keyslides


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