Ixazomib Maintenance Prolongs Progression-Free Survival in Newly Diagnosed Multiple Myeloma

For the substantial portion of patients with multiple myeloma (MM) who relapse following autologous hematopoietic cell transplantation (AHCT), maintenance therapy with ixazomib could offer a new treatment option to delay disease progression and extend survival, according to results from the TOURMALINE-MM3 trial.

The drug also was associated with deeper responses, while still maintaining a “favorable” safety profile, Meletios A. Dimopoulos, MD, from the National and Kapodistrian University of Athens School of Medicine in Greece, said during his presentation of results from the phase III, double-blind, placebo-controlled, multicenter study at the 2018 ASH Annual Meeting.

While lenalidomide is a commonly used post-AHCT maintenance therapy, Dr. Dimopoulos noted that nearly one-third of patients discontinue the drug due to toxicity. The oral proteasome inhibitor (PI) ixazomib, however, has a less-frequent administration and has been shown to have manageable toxicity. “We think that these findings show ixazomib to have a very good therapeutic value,” he added.

The TOURMALINE-MM3 trial enrolled 656 adult patients with newly diagnosed MM who had achieved at least a partial response (PR) to induction therapy with a PI or immunomodulatory agent (IMiD) prior to undergoing a single AHCT. Patients were excluded from the analysis if their disease relapsed or was unresponsive to frontline therapy, if they had undergone a tandem AHCT, or had received post-AHCT consolidation therapy.

Patients were stratified based on induction protocol, pre-induction International Staging System (ISS) stage disease, and response following AHCT, then randomized 3:1 to receive either weekly ixazomib (n=395) or matched placebo (n=261). Ixazomib 3 mg was administered on days 1, 8, and 15 of 28-day cycles for 2 years or until disease progression or unacceptable toxicity, up to 26 cycles. If patients tolerated ixazomib 3 mg during the first four cycles, dose was increased to 4 mg (n=317 in the ixazomib group and n=222 in the placebo group).

Participants’ median age was 58 years, “however, 15 percent of patients were older than 65 years,” Dr. Dimopoulos noted. Other baseline characteristics were similar between the treatment groups: Most patients in each group (59%) had induction therapy with a PI, while 11 percent in each group received an IMiD and 30 percent in each group received both agents.

In the ixazomib group, 34 percent, 45 percent, and 21 percent of patients had achieved a complete response, very good PR, or PR with induction and AHCT. Also, a similar portion of patients in each group had achieved minimal residual disease (MRD)–negative status (33%).

Also, approximately one-fifth of patients in each group had high-risk cytogenetics.

As of April 16, 2018 (data cutoff), the median duration of treatment at 4 mg was 15.2 months on the ixazomib arm and 16.2 months in the placebo group.

Ixazomib demonstrated a 28 percent lower risk of disease progression/death compared with placebo (primary endpoint; median progression-free survival = 26.5 months vs. 21.3 months, respectively; hazard ratio [HR] = 0.72; 95% CI 0.58-0.89; p=0.002).

Patients who received maintenance therapy with ixazomib also had deeper responses, Dr. Dimopoulos noted, with a higher rate of conversion from MRD-positive to MRD-negative status, compared with placebo (12% vs. 7%; p value not provided).

The benefit in PFS was observed across subgroups, including patients with:

  • ISS stage III disease: HR=0.0661 for ixazomib vs. placebo
  • prior exposure to PI during induction: HR=0.750
  • no exposure to PI: HR=0.497
  • high-risk cytogenetics: HR=0.625

When the researchers looked at safety of the two arms, all-grade treatment-related adverse events (AEs) occurred in 78 percent of ixazomib-treated patients and 58 percent of placebo-treated patients. A greater proportion of patients in the ixazomib experienced grade ≥3 AEs (42% vs. 26%), the most common of which were infections (15% with ixazomib vs. 8% with placebo), pneumonia (6% vs. 4%), gastrointestinal disorders (6% vs. 1%), neutropenia (5% vs. 3%), and thrombocytopenia (5% vs. <1%).

Serious AEs also appeared to be more frequent in the ixazomib arm (27% vs 20%), and one patient in the ixazomib group and none in the placebo group died during follow-up. However, Dr. Dimopoulos said that discontinuation related to AEs “was relatively low across both arms,” at 7 percent and 5 percent, respectively

As a limitation of the study, Dr. Dimopoulos noted that overall survival data (a secondary endpoint of the study) were not mature and could not be presented. Researchers are continuing to study ixazomib combinations in different MM settings to further improve patient outcomes, he said.

The authors report financial relationships with Takeda, which sponsored the trial.

Reference

Dimopoulos MA, Gay F, Schjesvold FH, et al. Maintenance therapy with the oral proteasome inhibitor (PI) ixazomib significantly prolongs progression-free survival (PFS) following autologous stem cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma (NDMM): phase 3 Tourmaline-MM3 trial. Abstract #301. Presented at the 2018 ASH Annual Meeting, December 2, 2018; San Diego, CA.

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