Maintenance therapy with ixazomib: An in-depth analysis of TOURMALINE-MM4 results

This article summarizes the discussion on the results of the TOURMALINE-MM4 trial, held between Mohamad Mohty, María-Victoria Mateos, and Karthik Ramasamy at a live virtual journal club organized by the International Academy for Clinical Hematology (IACH).¹

The TOURMALINE-MM4 trial was reported during this year’s European Hematology Association (EHA) Annual Congress and the American Society of Clinical Oncology (ASCO) Annual Meeting, indicating the clear survival benefit of ixazomib for transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). These results were recently published in the Journal of Clinical Oncology by Meletios Dimopoulos and colleagues² and reported on the Multiple Myeloma Hub here.

The trial met its primary endpoint: a superior median progression-free survival (PFS)

• TOURMALINE-MM4 is a phase III, randomized, placebo-controlled, double-blind study in adult patients with NDMM ineligible for autologous stem cell transplantation.
  • Patients had received 6–12 months of induction therapy and must have achieved a partial response or better.
  • A total of 706 patients were enrolled and randomized to single-agent ixazomib or placebo.
  • Ixazomib (3 mg, or placebo capsule) was orally administered on Days 1, 8, and 15 of each 28-day cycle for up to 26 cycles.
• The primary endpoint of the trial was PFS from randomization (i.e., after completion of induction therapy), as determined by an independent review committee.
• With a median follow-up of 21.1 months, median PFS from randomization was significantly higher in the ixazomib arm than the placebo arm: 17.4 vs 9.4 months, respectively; HR, 0.659; 95% CI, 0.542–0.801; p < 0.001.

Highlights of the panel discussion

• The panelists considered the median PFS in the placebo arm as nonoptimal and inferior to what clinicians would expect today in patients who responded to the induction regimen. This result might be explained by the different induction regimens received, which at the same time, might be more representative of real-world practice.
• The panel expects that the advantage in PFS seen with ixazomib will also translate into an improved overall survival at a longer follow-up.
• They speculated that the ixazomib results might have been improved if maintenance therapy had been extended beyond 2 years, although the possibility of having a treatment-free interval between lines of therapy is attractive from a patient’s point of view.
• The experts agreed that the discussion is not about the benefit of continuous therapy vs fixed-duration therapy, but about identifying the patient that will benefit most from maintenance and tolerate the treatment without significant negative impact on their quality of life.

Will all induction regimens benefit from ixazomib maintenance?

• When PFS was landmarked to the date of initiation of induction therapy, ixazomib still led to a significantly longer median PFS when compared to placebo: 26.3 vs 20.3 months, respectively; HR, 0.650; 95% CI, 0.534–0.791; p < 0.001.
• This trial started in 2015; hence, some induction regimens administered to patients at that time are no longer considered a standard of care. Nevertheless, the panel highlighted the following:
  • More than 80% of patients received a proteasome inhibitor (PI) therapy as part of their induction, and this trial demonstrates that it is possible to extend proteasome inhibition safely.
  • Patients who received a lenalidomide-based regimen may benefit the most from maintenance therapy with a PI such as ixazomib.
• However, when these results were put in context with some of the latest approved induction regimens (i.e., daratumumab-based triplets and quadruplets), the panel made the following conclusions:
  • Ixazomib might have a role in patients being treated with bortezomib, allowing switching to an oral PI for maintenance (± daratumumab), thereby helping with treatment compliance.
  • Ixazomib could be an effective alternative for patients who do not tolerate lenalidomide and cannot continue with lenalidomide as a maintenance therapy without dose reductions and treatment suspension.

Putting the results into context: was placebo the best control arm?

• Lenalidomide maintenance treatment in elderly patients had already demonstrated positive results in 2015 when the TOURMALINE-MM4 trial was designed.
  • The FIRST phase III trial reported a median PFS of 26 months with continuous therapy of lenalidomide plus dexamethasone in patients ineligible for transplant.
• The panel speculated that lenalidomide could have potentially been a better control arm than placebo, alone or as an add-on therapy to ixazomib, if the objective were to improve the current standard of care.
• Of note, this trial started recruiting only those who had an excellent response to induction therapy, which can be considered a selection bias in this elderly population because early deaths or drop-offs usually seen in frontline trials have been excluded.
• The Myeloma-XI study also explored maintenance with lenalidomide and reported a median PFS of 26 months for transplant-ineligible patients in a similar context compared to the TOURMALINE-MM4 study randomizing patients to maintenance therapy only if they were in remission.
• The experts agreed that if this trial were redesigned today, the control arm, and probably the experimental arm, would incorporate daratumumab as the current standard of care in this setting.

PI maintenance in high-risk MM

• TOURMALINE-MM4 investigators analyzed PFS in different subgroups and did not report a statistically significant benefit in patients with high-risk cytogenetics, although there was a positive trend favoring ixazomib when patients with amp1q21 were added to the high-risk group analysis.
• Extended proteasome inhibition has been recommended for patients with high-risk cytogenetics, mainly with bortezomib. However, the median PFS of 10 months in this subgroup in the TOURMALINE-MM4 trial might indicate the need for a combination maintenance therapy to overcome the poorer prognosis of these patients.

Final considerations

• The panel concludes that the TOURMALINE-MM4 trial is a well-designed phase III placebo-controlled trial conducted in elderly patients with MM, including fit and unfit patients, where safety and tolerability are critical.
• Ixazomib is the first oral PI to exhibit a significant benefit for PFS as maintenance therapy in transplant-ineligible patients, with a good safety profile. Its benefit extended to every prespecified subgroup of patients included in the trial.