Impact of prior therapy on the efficacy and safety of oral ixazomib-lenalidomide-dexamethasone vs. placebo-lenalidomide-dexamethasone in patients with relapsed/refractory multiple myeloma in TOURMALINE-MM1

Abstract

Prior treatment exposure in patients with relapsed/refractory multiple myeloma may affect outcomes with subsequent therapies. We analyzed efficacy and safety according to prior treatment in the phase 3 TOURMALINE-MM1 study of ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) versus placebo-Rd. Patients with relapsed/refractory multiple myeloma received ixazomib-Rd or placebo-Rd. Efficacy and safety were evaluated in subgroups defined according to type (proteasome inhibitor [PI] and immunomodulatory drug) and number (1 vs. 2 or 3) of prior therapies received. Of 722 patients, 503 (70%) had received a prior PI, and 397 (55%) prior lenalidomide/thalidomide; 425 patients had received 1 prior therapy, and 297 received 2 or 3 prior therapies. At a median follow up of ~15 months, PFS was prolonged with ixazomib-Rd vs. placebo-Rd regardless of type of prior therapy received; HR 0.739 and 0.749 in PI-exposed and -naïve patients, HR 0.744 and 0.700 in immunomodulatory-drug-exposed and -naïve patients, respectively. PFS benefit with ixazomib-Rd vs. placebo-Rd appeared greater in patients with 2 or 3 prior therapies (HR 0.58) and in those with 1 prior therapy without prior transplant (HR 0.60) versus those with 1 prior therapy and transplant (HR 1.23). Across all subgroups, toxicity was consistent with that seen in the intent-to-treat population. In patients with relapsed/refractory multiple myeloma, ixazomib-Rd was associated with a consistent clinical benefit vs. placebo-Rd regardless of prior treatment with bortezomib or immunomodulatory drugs. Patients with 2 or 3 prior therapies, or 1 prior therapy without transplant seemed to have greater benefit than patients with 1 prior therapy and transplant. TOURMALINE-MM1 registered at clinicaltrials.gov identifier: 01564537.

Trial registration: ClinicalTrials.gov NCT01564537.

Figure 1.

Forest plot of progression-free survival (PFS) according to number and type of prior therapies (A), and forest plot of PFS according to type of prior therapy in patients who have received 1 versus 2 or 3 prior therapies (B). CI: confidence interval; HR: hazard ratio; PI: proteasome inhibitor; Rd: lenalidomide-dexamethasone.

Figure 2.

Kaplan-Meier analysis of progression-free survival (PFS) with ixazomib-Rd vs. placebo-Rd according to prior therapy. (A) PI-exposed patients; B) PI-naïve patients; C) immunomodulatory drug-exposed patients; D) immunomodulatory drug-naïve patients; E) patients with 1 prior therapy; F) patients with 2/3 prior therapies. CI: confidence interval; Rd: lenalidomide-dexamethasone.

Figure 3.

Forest plot of time to progression (TTP) according to number and type of prior therapies. CI: confidence interval; PI: proteasome inhibitor; Rd: lenalidomide-dexamethasone.