Ixazomib Maintenance Delays Progression in Non-Transplanted Patients With Newly Diagnosed Myeloma

Postinduction maintenance therapy with the oral proteasome inhibitor ixazomib prolonged progression-free survival (PFS) in patients with newly diagnosed multiple myeloma (MM) who were not undergoing autologous hematopoietic cell transplantation (AHCT), according to results from the placebo-controlled phase III TOURMALINE-MM4 trial. The PFS benefit was greatest in patients who achieved a complete response (CR) or very good partial response (VGPR) following induction, the authors, led by Meletios Dimopoulos, MD, noted.

According to Dr. Dimopoulos, from the National and Kapodistrian University of Athens in Greece, lenalidomide is currently the only approved drug for continuous treatment of patients with newly diagnosed MM who are ineligible for AHCT. “However, lenalidomide may have some long-term side effects and may be less active in subsets of patients, such as those with International Staging System (ISS) stage III disease or with abnormal cytogenetics,” he said. “Thus, new agents are needed for these patients.”

In the TOURMALINE-MM4 trial, researchers randomized patients with newly diagnosed MM who did not undergo an AHCT and who had achieved at least a partial response after 6 to 12 months of induction therapy to receive maintenance with either:

  • ixazomib 3 mg on days 1, 8, and 15 of 28-day cycles for up to 24 months (n=425)
  • placebo (n=281)

At baseline, the median ages for patients in the ixazomib and placebo arms were 72 and 73 years, respectively. Approximately 17% of patients in each group had high-risk cytogenetic features and the most prevalent stage in each group was ISS stage II disease (38.8% and 40.6%).

Most of the induction regimens used prior to enrollment included a proteasome inhibitor (82.6% in the ixazomib arm and 81.9% in the placebo arm), and about 16% of patients in each group received a regimen containing a proteasome inhibitor and an immunomodulatory drug.

“Ixazomib may provide a valuable maintenance option in combination with other agents.”

—Meletios Dimopoulos, MD

At study entry, 62% of the overall population were in CR or VGPR.

Over a median follow-up period of 21.1 months, treatment with ixazomib was associated with a 34.1% reduction in combined risk of disease progression or death, compared with placebo (hazard ratio [HR] = 0.659; p<0.001). Ixazomib-treated patients also had significantly longer PFS: 17.4 months versus 9.4 months.

The PFS benefit was significant among patients who achieved a CR or VGPR following induction as demonstrated by a longer median PFS with ixazomib relative to placebo (25.6 vs. 12.9 months, respectively; HR=0.586; p<0.001).

The investigators also found a significant benefit with ixazomib across prespecified subgroups, including patients with ISS stage III disease, those with high-risk cytogenetic abnormalities, and patients ≥75 years of age (TABLE).

The proportions of patients who experienced grade ≥3 treatment-emergent adverse events (TEAEs) were 36.6% for the ixazomib arm versus 23.2% for the placebo arm. A higher percentage of patients in the ixazomib group discontinued treatment because of TEAEs (12.9% vs. 8.0%). The most frequently reported any-grade TEAEs were nausea (26.8% vs. 8.0%), vomiting (24.2% vs. 4.3%), and diarrhea (23.2% vs. 12.3%).

The investigators observed no increase in new primary malignancies in the ixazomib group (5.2%) versus the placebo arm (6.2%). The rates of on-study deaths were 2.6% in the ixazomib arm compared with 2.2% in the placebo group.

“These results indicate that ixazomib is well tolerated and provides a PFS benefit in this setting, thereby representing a valuable treatment option for patients,” Dr. Dimopoulos and coauthors concluded. “Furthermore, ixazomib may provide a valuable maintenance option in combination with other agents, such as immunomodulatory drugs and monoclonal antibodies.”

A limitation of this study was the comparison of ixazomib with placebo rather than an active therapy control such as lenalidomide; however, no approved or standard-of-care maintenance therapy was available for non-transplantation newly diagnosed MM at the time of the TOURMALINE-MM4 trial, the authors noted.

Dr. Dimopoulos added that the benefit associated with ixazomib maintenance is modest, indicating the need for additional investigation into ixazomib as part of a combination therapy as a maintenance strategy for newly diagnosed MM.

Study authors report relationships with Millennium Pharmaceuticals, which sponsored this trial.


Dimopoulos MA, Špička I, Quach H, et al. Ixazomib as Postinduction Maintenance for Patients With Newly Diagnosed Multiple Myeloma Not Undergoing Autologous Stem Cell Transplantation: The Phase III TOURMALINE-MM4 Trial. J Clin Oncol. 2020 October 6. [Epub ahead of print]