Philippe Moreau, MD

Photo courtesy of ASH

In the phase 3 TOURMALINE-MM1 trial, adding the oral proteasome inhibitor ixazomib to treatment with lenalidomide and dexamethasone significantly extended progression-free survival (PFS), with limited additional toxicity, in patients with relapsed/refractory multiple myeloma (MM).

The median PFS was about 21 months for patients who received ixazomib, lenalidomide, and dexamethasone (IRd) and about 15 months for those who received placebo, lenalidomide, and dexamethasone (Rd).

Gastrointestinal adverse events (AEs), rash, and grade 3/4 thrombocytopenia were more common in the IRd arm than the Rd arm.

These results were published in NEJM. The study was sponsored by Millennium Pharmaceuticals, Inc. Results from this trial were previously presented at ASH 2015, but the data in NEJM differ slightly from that presentation.

“NEJM has published the results of the first phase 3 study supporting an all-oral triplet regimen containing a proteasome inhibitor in multiple myeloma,” said study author Philippe Moreau, MD, of University of Nantes in France.

“The TOURMALINE-MM1 results demonstrated that ixazomib in combination with lenalidomide and dexamethasone is an effective and tolerable oral regimen with a manageable safety profile for patients with relapsed and/or refractory multiple myeloma.”

TOURMALINE-MM1 enrolled 722 patients with relapsed (77%), refractory (11%), relapsed and refractory (12%), or primary refractory (6%) MM.

The patients were randomized to receive IRd (n=360) or Rd (n=362). Baseline patient characteristics were similar between the treatment arms. The median age was 66 in both arms (overall range, 30-91), and nearly 60% of patients were male.

About 60% of patients in both arms had received 1 prior therapy, roughly 30% had received 2, and about 10% had received 3. Seventy percent of patients in both arms had received prior treatment with a proteasome inhibitor, and about 55% had received an immunomodulatory drug.

Efficacy

The study’s primary endpoint was PFS. And the researchers saw a significant improvement in PFS for the IRd arm compared to the Rd arm. The median PFS was 20.6 months and 14.7 months, respectively. The hazard ratio was 0.74 (P=0.01).

There was a benefit in PFS in the IRd arm across pre-specified patient subgroups, including patients with poor prognosis, such as elderly patients, those who had received 2 or 3 prior therapies, those with advanced stage disease, and those with high-risk cytogenetic abnormalities.

At a median follow-up of about 23 months, the median overall survival had not been reached in either treatment arm.

The overall response rates were 78% in the IRd arm and 72% in the Rd arm. The complete response rates were 12% and 7%, respectively, and the stringent complete response rates were 2% and <1%, respectively.

The median time to response was 1.1 months in the IRd arm and 1.9 months in the Rd arm. The median duration of response was 20.5 months and 15.0 months, respectively.

Safety

AEs occurred in 98% of patients in the IRd arm and 99% in the Rd arm. Grade 3 or higher AEs occurred in 74% and 69% of patients, respectively, serious AEs occurred in 47% and 49%, respectively, and on-study deaths occurred in 4% and 6%, respectively.

Grade 3 and 4 thrombocytopenia was more frequent in the IRd arm (12% and 7%, respectively) than in the Rd arm (5% and 4%, respectively). Rash also occurred more frequently in the IRd arm than in the Rd arm (36% and 23%, respectively).

Gastrointestinal AEs were more frequent in the IRd arm than the Rd arm, including diarrhea (45% vs 39%), constipation (35% vs 26%), nausea (29% vs 22%), and vomiting (23% vs 12%).

The incidence of peripheral neuropathy was 27% in the IRd arm and 22% in the Rd arm. Grade 3 events occurred in 2% of patients in each arm, and no grade 4 events were reported.

Roughly the same percentage of patients developed new primary malignant tumors—5% in the IRd arm and 4% in the Rd arm.

All-oral combo extends PFS in rel/ref MM