Overall Survival With Ixazomib Combo Trended Toward Benefit in Relapsed Myeloma With Adverse Prognostics

Final overall survival results from TOURMALINE-MM1 failed to show statistical significance of an ixazomib combination for relapsed/refractory multiple myeloma overall.

Despite showing the longest overall survival (OS) results for lenalidomide/dexamethasone (Rd)–based triplets in a phase 3 trial of relapsed or refractory multiple myeloma (RRMM), ixazomib (Ninlaro) plus Rd failed to induce statistically significant benefit over placebo/Rd in the final read-out from the phase 3 TOURMALINE-MM1 study (NCT01564537) reported in the Journal of Clinical Oncology.

The investigators on the trial indicated that imbalances in subsequent therapies, such as the CD38-targeting agent daratumumab (Darzalex) and proteasome inhibitors, may have confounded the OS results in this population.

“Although the slight favorable trend in OS seen with ixazomib-Rd versus placebo-Rd at this final analysis of TOURMALINE-MM1 was not significant, these results were obtained in the context of the longest median OS reported to date in phase III studies of Rd-based therapy in RRMM,” reported investigators of the study.

The double-blind, placebo-controlled study randomized patients with relapsed or refractory disease in a 1:1 fashion to ixazomib-Rd (n = 360) or placebo-Rd (n = 362). On days 1, 8, and 15 of each 28-day cycle, patients received 4 mg of ixazomib or placebo. On days 1 through 21 in both arms, patients received lenalidomide at 25 mg; 40 mg of dexamethasone was administered on days 1, 8, 15, and 22.

OS was a secondary end point and assigned in the intent-to-treat (ITT) population as well as in those with del(17p) or high-risk and expanded high-risk cytogenetics. The primary end point was progression-free survival (PFS).

Median follow-up for OS was 85.0 and 85.1 months in the ixazomib-Rd and placebo-Rd arms. In the ITT population, 484 patients (67%) had died, of whom 240 (66.7%) and 244 (67.4%) were treated in the ixazomib-Rd and placebo-Rd arms, respectively. At the last point of contact, 113 (31.4%) and 116 (32%) were still alive.

In the ixazombi-Rd arm, median OS was 53.6 months (95% CI, 49.25-62.95) and in the placebo-Rd arm versus 51.6 months (95% CI, 44.78-59.14) in the placebo group (HR, 0.939; 95% CI, 0.784-1.125; P = .495).

Patients with del(17p) on ixazomib-Rd showed an OS benefit (HR 0.916; 95% CI, 0.516-1.626), as did those with high-risk cytogenetics (HR 0.870; 95% CI, 0.580-1.305), or expanded-risk cytogenetics (HR 0.862; 95% CI, 0.660-1.124).

For patients who did receive subsequent therapy in the ixazomib-Rd arm, the median OS was 54.3 months (95% CI, 49.84-62.95) versus the placebo-Rd arm at 58.1 months (95% CI 50.30-60.94; HR 0.985; 95% CI, 0.800-1.213). In patients who did not receive subsequent therapy, OS was 50.4 months (95% CI, .800 to 1.213) compared with 31.5 months (95% CI, 22.70 to 50.17), respectively (HR 0.877; 95% CI, 0.603 to 1.275).

Grade 3 or higher adverse effects occurring in less than 5% of patients included thrombocytopenia (21.3% with ixazomib-Rd vs 10.3% with placebo) and diarrhea (10% vs 3.1%, respectively).

“Although the slight trend in favor of ixazomib-Rd in the ITT population was not statistically significant, greater magnitudes of OS benefit (lower HRs) were observed in predefined patient subgroups with adverse-risk characteristics, including more heavily pretreated patients, patient’s refractory to prior treatment, patients with stage III [myeloma], and those with high-risk or expanded high-risk cytogenetics,” the investigators of the study wrote.

Given its convenience as an all-oral treatment regimen that confers PFS benefit in this group of patients, the investigators concluded that ixazomib-Rd will continue to represent an important therapy option for these patients.

Reference:

Richardson PG, Kumar SK, Masszi T, et al. Final Overall Survival Analysis of the TOURMALINE-MM1 Phase III Trial of Ixazomib, Lenalidomide, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma [published online ahead of print, 2021 Jun 11]. J Clin Oncol. 2021;JCO2100972. doi:10.1200/JCO.21.00972