The Phase 3 TOURMALINE-MM2 Trial: Oral Ixazomib, Lenalidomide, and Dexamethasone (IRd) Vs Placebo-Rd for Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma (NDMM)

Background

Continuous Rd-based regimens are among the standards of care in transplant-ineligible NDMM patients. These patients are diverse, ranging from fit 70-plus-year-olds to elderly and/or frail patients with poor performance status, requiring treatment to be adapted to individual patient settings. The use of proteasome inhibitors (PIs) in a continuous fashion or to higher cumulative doses leads to improved long-term outcomes; however, long-term administration of injectable PIs may present challenges associated with treatment burden and tolerability. An all-oral PI-Rd triplet may be useful for patients who do not want to or cannot travel to the clinic frequently. The oral PI ixazomib is suitable for continuous dosing, with predictable, manageable toxicities. The multicenter, double-blind, placebo-controlled TOURMALINE-MM2 trial compared IRd vs placebo-Rd in transplant-ineligible NDMM patients.

Methods

Transplant-ineligible NDMM adult patients were randomized (1:1) to ixazomib 4 mg (n=351) or matching placebo (n=354) on days 1, 8, and 15 of 28-day cycles, plus lenalidomide 25 mg on days 1–21 (10 mg for patients with renal impairment), and dexamethasone 40 mg on days 1, 8, 15, and 22 (20 mg for patients aged >75 years). After 18 cycles, dexamethasone was discontinued and treatment continued using ixazomib 3 mg and lenalidomide 10 mg until progression or toxicity. Randomization was stratified by age (<75 vs ≥75 years), International Staging System (ISS) stage (I or II vs III), and Brief Pain Inventory-Short Form (BPI-SF) worst pain score (<4 vs ≥4) at screening. The primary endpoint was progression-free survival (PFS) assessed by an Independent Review Committee (IRC); key secondary endpoints included overall survival (OS), complete response (CR) rate, and pain response rate. Other secondary endpoints included overall response rate (ORR), time to response (TTR), time to progression (TTP), and safety. Sample size was determined to provide 80% power for OS and 92% power for PFS. PFS was tested in the intent-to-treat (ITT) population (alpha=0.04) and 3 prespecified subgroups in parallel (total alpha=0.01), including patients with expanded high-risk cytogenetics [t(4;14), t(14;16), del(17p), amp(1q21)], patients aged <75 years, and patients with a creatinine clearance (CrCl) >60 mL/min. We report data from the final analysis for PFS.

Results

At data cutoff (Dec 2, 2019), in the IRd vs placebo-Rd arms, median age was 73 vs 74 years (43% vs 44% ≥75 years), 16% vs 17% had ISS stage III MM, and 54% of patients in each arm had a BPI-SF worst pain score of ≥4. At a median follow-up of 53.3 vs 55.8 months, there was an obvious positive trend in PFS favoring IRd; with 169 vs 209 patients having progressed or died in the IRd vs placebo-Rd arms, median PFS was 35.3 vs 21.8 months (hazard ratio [HR] 0.830; p=0.073; Figure). Median PFS in the 3 prespecified subgroups of patients with expanded high-risk cytogenetics, patients aged <75 years, and patients with CrCl >60 mL/min are shown in the Table. ORRs were similar between arms, but depth of response was greater with IRd vs placebo-Rd (Table). Median TTR and TTP for IRd and placebo-Rd are shown in the Table. Median OS was not reached in either arm (HR 0.998) after a median follow-up of ~58 months and with 136 and 148 patients having died in the IRd and placebo-Rd arms, respectively. Treatment-emergent adverse events (TEAEs) were mostly grade 1/2. With IRd vs placebo-Rd, 88% vs 81% of patients had grade ≥3 TEAEs; the most common grade ≥3 events (≥5% difference) included neutropenia (17% vs 27%), rash (17% vs 7%), thrombocytopenia (13% vs 5%), and diarrhea (10% vs 2%); 66% vs 62% had serious TEAEs, 35% vs 27% had TEAEs resulting in discontinuation of the full regimen, and 8% vs 6% of patients died on study.

Conclusions

Addition of ixazomib to Rd led to a clinically meaningful, obvious positive trend in PFS, with a 13.5-month improvement in the median in transplant-ineligible NDMM patients. Improvements in TTP and CR rate were also observed. In line with TOURMALINE-MM1 (Avet-Loiseau Blood 2017), IRd improved the poor PFS associated with expanded high-risk cytogenetics vs placebo-Rd. Safety findings were generally consistent with the well-characterized, tolerable, and manageable toxicity profile of ixazomib/IRd. IRd is a feasible treatment option for certain patients who could benefit from an all-oral triplet combination.