Ixazomib Shows PFS Benefit Across Age and Frailty Subgroups in Multiple Myeloma

In an in-depth subgroup analysis of the phase 3 TOURMALINE-MM4 trial (NCT02312258), postinduction maintenance therapy with ixazomib demonstrated a progression-free survival (PFS) benefit vs placebo regardless of age or frailty status in patients with multiple myeloma.

Ixazomib, an oral proteasome inhibitor, showed a favorable safety profile and efficacy across subgroups in the original TOURMALINE-MM4 analysis. The new study, published in Clinical Lymphoma, Myeloma, and Leukemia, adds additional safety, efficacy, and quality-of-life (QOL) data to those findings.

Multiple myeloma typically affects elderly patients—more than 30% of whom are 75 years or older, the authors noted—who are more likely to have impaired QOL and experience reduced survival compared with younger patients. Comorbidities, early discontinuation of treatment, and toxicity concerns are often the causes of these outcomes.

“Elderly MM patients are a heterogenous population with greatly varying levels of physical and psycho-social functioning,” the authors wrote. “Assessment tools incorporating patients’ functionality that can predict outcomes and help determine the most suitable treatment are important for stratifying this population.” The validated International Myeloma Working Group (IMWG) frailty score is the current standard for classification.

Patients with nontransplant newly diagnosed multiple myeloma who experienced at least a partial response to 6 to 12 months of standard-of-care induction therapy were enrolled in the study. Patients were randomly assigned to receive either ixazomib or a placebo within 60 days of their last dose of induction therapy. Of 706 patients, 425 received ixazomib and 281 received a placebo.

In the overall cohort, 10% of patients were younger than 65 years, 52% were aged 65 to 74 years, and 38% were 75 years or older. A total of 699 patients had data available on IMWG classification: 41% were classified as fit, 35% intermediate-fit, and 24% frail. Across subgroups, the rates of treatment discontinuation were similar.

In the age subgroups, the percentages of patients considered intermediate-fit and frail increased with age; and in the frailty subgroups, the proportion of elderly patients was higher as fitness decreased.

PFS benefit was demonstrated across age groups with ixazomib treatment vs the placebo. The HRs were 0.576, 0.615, and 0.740 in patients aged 65 or younger, 65 to 75 years, and 75 years or older, respectively.

Regarding frailty subgroups, PFS benefit was seen regardless of status. The group considered fit showed an HR of 0.530, intermediate-fit patients had an HR of 0.746, and frail patients had an HR of 0.733.

The rates of grade 3 or higher treatment-emergent adverse events (TEAEs) and serious TEAEs were higher with ixazomib treatment vs placebo, and both arms showed increased grade 3 or higher and serious TEAEs with age. Rates of discontinuation were similar in patients younger than 65 years or 65 to 75 years of age but higher in patients 75 years or older. Patient-reported QOL scores were similar across age groups and frailty cohorts.

“This subgroup analysis of TOURMALINE-MM4 demonstrated the tolerability of ixazomib maintenance regardless of age and frailty status, although with some differences in TEAE rates and treatment exposure across subgroups,” the authors wrote.

The findings are in line with data from other phase 3 trials of continuous or continuous vs fixed-term therapy in patients with nontransplant newly diagnosed multiple myeloma, although differences in treatment regimens, durations of therapy, and study populations are potential confounding factors for comparisons between studies, the authors noted.

Still, the authors conclude that ixazomib as postinduction therapy in patients with multiple myeloma not undergoing transplant is a well-tolerated and effective treatment option.

“Our data indicate that ixazomib could provide a valuable single-agent maintenance option for elderly/frail patients and may also have utility in the non-transplant post-induction setting in combination with other agents, such as immunomodulatory drugs and monoclonal antibodies,” the authors concluded.

Reference

Bringhen S, Pour L, Benjamin R, et al. Ixazomib versus placebo as post-induction maintenance therapy in newly diagnosed multiple myeloma patients: an analysis by age and frailty status of the TOURMALINE-MM4 study. Clin Lymphoma Myeloma Leuk. Published online March 28, 2023. doi:10.1016/j.clml.2023.03.007