Robert M. Rifkin, MD of the Rocky Mountain Cancer Center speaks about 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).
In transplant-ineligible NDMM patients, continuous Rd-based regimens are among the standards of treatment. These patients are diverse, ranging from healthy 70-plus-year-olds to elderly and/or vulnerable patients with low-performance status, requiring individual patient environments to be tailored to care. The continuous or higher cumulative dose use of proteasome inhibitors (PIs) contributes to improved long-term outcomes; however, long-term administration of injectable PIs can present difficulties associated with the burden of treatment and tolerability. For patients who do not want to or can not drive to the clinic regularly, an all-oral PI-Rd triplet can be useful. With predictable, manageable toxicities, the oral PI ixazomib is ideal for continuous dosing. In transplant-ineligible NDMM patients, the multicenter, double-blind, placebo-controlled TOURMALINE-MM2 analysis compared IRd versus placebo-Rd.
Adult transplant-unqualified NDMM patients were randomized (1:1) to ixazomib 4 mg (n=351) or placebo-matched (n=354) on days 1, 8, and 15 of the 28-day periods, plus 25 mg of lenalidomide on days 1-21 (10 mg for patients with renal impairment), and 40 mg of dexamethasone on days 1, 8, 15, and 22 (20 mg for patients >75 years). Dexamethasone was discontinued after 18 cycles and treatment with ixazomib 3 mg and lenalidomide 10 mg continued until development or toxicity occurred. Randomization was stratified at the 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) determined progression-free survival (PFS) was the primary endpoint; main secondary endpoints included overall survival (OS), complete response (CR) rate, and pain response rate. Complete response rate (ORR), time to response (TTR), time to progression (TTP), and protection were additional secondary endpoints. The sample size was calculated to provide OS power of 80 percent and PFS power of 92 percent. Intention-to-treat (ITT) populations (alpha=0.04) and 3 prespecified parallel subgroups (total alpha=0.01) were tested for PFS, including patients with extended 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 record data from the final study.
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 strong positive trend in PFS favoring IRd at a median follow-up of 53.3 vs 55.8 months; with 169 vs 209 patients having advanced 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 extended high-risk cytogenetics, patients <75 years of age, and patients with CrCl >60 mL/min. ORRs were comparable between weapons, 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 obtained 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 effects (TEAEs) is 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 incidents (about 5% difference); 66% vs. 62% had extreme TEAEs, 35% vs. 27% had TEAEs resuscitated
The addition of ixazomib to Rd led to a clinically important, obvious positive trend in PFS, with a median increase of 13.5 months in patients with transplant-ineligible NDMM. Improvements were also observed in the TTP and CR rates. IRd increased the low PFS associated with extended high-risk cytogenetics vs. placebo-Rd in line with TOURMALINE-MM1 (Avet-Loiseau Blood 2017). Protection results were generally consistent with ixazomib/well-characterized, IRd's tolerable, and manageable toxicity profile. For those patients who could benefit from an all-oral triplet combination, IRd is a viable treatment option.