Thierry Facon, MD from the Centre Hospitalier Universitaire (CHU) Lille, Service des Maladies du Sang, University of Lille discusses the ASH 2020 abstract – 551 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).
Context
In transplant-ineligible NDMM patients, continuous Rd-based regimens are among the standards of care. These patients are diverse, ranging from fit 70-plus-year-olds to elderly and/or frail patients with poor performance status, requiring individual patient settings to be adapted to treatment. The continuous or higher cumulative dose use of proteasome inhibitors (PIs) leads to improved long-term outcomes; however, long-term administration of injectable PIs may present difficulties associated with the burden of treatment and tolerability. For patients who do not want to or can not travel to the clinic frequently, an all-oral PI-Rd triplet may be useful. With predictable, manageable toxicities, the oral PI ixazomib is suitable for continuous dosing. In transplant-ineligible NDMM patients, the multicenter, double-blind, placebo-controlled TOURMALINE-MM2 study compared IRd versus placebo-Rd.
Methodology
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). Dexamethasone was discontinued after 18 cycles and treatment with ixazomib 3 mg and lenalidomide 10 mg continued until progression or toxicity occurred. Randomization was stratified at screening by age (<75 vs 75 years), stage of the International Staging System (ISS) (I or II vs III), and Brief Pain Inventory-Short Form (BPI-SF) worst pain score (<4 vs ⇠4). An Independent Review Committee (IRC) assessed progression-free survival (PFS) was the primary endpoint; key secondary endpoints included overall survival (OS), complete response (CR) rate, and pain response rate. Total response rate (ORR), time to response (TTR), time to progression (TTP), and safety were additional secondary endpoints. The sample size was determined to provide an OS power of 80 per cent and PFS power of 92 per cent. Intention-to-treat (ITT) populations (alpha=0.04) and 3 prespecified parallel subgroups (total alpha=0.01) were tested for PFS, including patients with expanded high-risk cytogenetics [t(4;14), t(14;16), del(17p), amp(1q21)], patients <75 years of age, and patients with creatinine clearance (CrCl) >60 mL/min. For PFS, we report data from the final analysis.
Outcomes
In the IRd vs placebo-Rd arms, the median age at the data cutoff (Dec 2, 2019) was 73 vs 74 years (43 percent vs 44 percent ⇠75 years), 16 percent vs 17 percent had ISS stage III MM, and 54 percent of patients in each arm had the worst BPI-SF pain score of ⇠4. There was a clear positive trend in PFS favoring IRd at a median follow-up of 53.3 vs 55.8 months; with 169 vs 209 patients having progressed or died in the IRd vs placebo-Rd arms, the median PFS was 35.3 vs 21.8 months (hazard ratio [HR] 0.830; p=0.073; Figure). The median PFS is shown in the table in the three prespecified subgroups of patients with expanded high-risk cytogenetics, patients <75 years of age, and patients with CrCl >60 mL/min. ORRs were similar between arms, but with IRd vs placebo-Rd, the response depth was greater (Table). In the table, the median TTR and TTP are shown for IRd and placebo-Rd. Median OS was not achieved in either arm (HR 0.998) after a median follow-up of ~58 months, and in the IRd and placebo-Rd arms, respectively, 136 and 148 patients died. For the most part, treatment-emergent adverse events (TEAEs) were grade 1/2. With IRd vs placebo-Rd, 88% vs. 81% of patients had grade 3 TEAEs; neutropenia (17% vs. 27%), rash (17% vs. 7%), thrombocytopenia (13% vs. 5%), and diarrhea (10% vs. 2%) were the most common grade 3 events (about 5% difference); 66% vs. 62% had severe TEAEs, 35% vs. 27% had TEAEs resuscitated
Findings
The addition of ixazomib to Rd led to a clinically significant, obvious positive trend in PFS, with a median improvement of 13.5 months in patients with transplant-ineligible NDMM. Improvements were also observed in the TTP and CR rates. IRd improved the poor PFS associated with expanded high-risk cytogenetics vs. placebo-Rd in line with TOURMALINE-MM1 (Avet-Loiseau Blood 2017). Safety results were generally consistent with ixazomib/well-characterized, IRd’s tolerable, and manageable toxicity profile. For certain patients who could benefit from an all-oral triplet combination, IRd is a feasible treatment choice.
