Oral ixazomib, lenalidomide, and dexamethasone for transplant-ineligible patients with newly diagnosed multiple myeloma

Abstract

Continuous lenalidomide-dexamethasone (Rd)-based regimens are among the standards of care in transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients. The oral proteasome inhibitor ixazomib is suitable for continuous dosing, with predictable, manageable toxicities. In the double-blind, placebo-controlled TOURMALINE-MM2 trial transplant-ineligible NDMM patients were randomized to ixazomib 4 mg (n = 351) or placebo (n = 354) plus Rd. After 18 cycles, dexamethasone was discontinued; treatment continued using reduced-dose ixazomib (3 mg) and lenalidomide (10 mg) until progression/toxicity. The primary endpoint was progression-free survival (PFS). Median PFS (mPFS) was 35.3 vs 21.8 months with ixazomib-Rd vs placebo-Rd, respectively (hazard ratio [HR], 0.830; 95% confidence interval, 0.676-1.018; P = .073; median follow-up, 53.3 and 55.8 months). Complete (26% vs 14%; odds ratio [OR], 2.10; P < .001) and ≥ very good partial response (63% vs 48%; OR, 1.87; P < .001) rates were higher with ixazomib-Rd vs placebo-Rd. In a prespecified high-risk cytogenetics subgroup, mPFS was 23.8 vs 18.0 months (HR, 0.690; P = .019). Overall, treatment-emergent adverse events (TEAEs) were mostly grade 1/2. With ixazomib-Rd vs placebo-Rd, 88% vs 81% of patients experienced grade ≥3 TEAEs, 66% vs 62% serious TEAEs, and 35% vs 27% TEAEs resulting in regimen discontinuation; 8% vs 6% died on study. Ixazomib-Rd is a feasible option for certain patients who can benefit from an all-oral triplet combination. This trial was registered at www.clinicaltrials.gov (#NCT01850524).

Newly Diagnosed Multiple Myeloma: How Many Drugs Are Enough?

“…The TOURMALINE-MM2 trial of lenalidomide 1 dexamethasone in combination with ixazomib or a placebo failed to meet the prespecified threshold for improved PFS. 17 However, the median PFS duration was found to be similar to that of the standard and less-intense lenalidomide/bortezomib/dexamethasone regimens.…”

Cardiovascular Complications of Modern Multiple Myeloma Therapy: Analysis of FDA Adverse Event Reporting System

“…Unspecified cardiac adverse events were reported among 7 patients with one death from heart failure with no concerning effects on QT prolongation (Dimopoulos et al, 2018;Passey, Darbenzio, Jou, Lynch, & Gupta, 2016). The TOURMALINE trials that demonstrated the efficacy of Ixazomib on multiple myeloma reported similar adverse cardiac events (heart failure, myocardial infarction and arrhythmia) between the Ixazomib and the placebo group (Dimopoulos et al, 2020;Facon et al, 2021;Moreau et al, 2016). Three cases of myocardial infarction reported with panobinostat compared to placebo group (San-Miguel et al, 2014).…”

Current approaches to management of newly diagnosed multiple myeloma

“…In the TOURMALINE‐MM2 trial, transplant ineligible NDMM patients were randomized to receive IRd versus placebo‐Rd as induction followed by IR versus R maintenance, respectively. Complete response (26% vs. 14%, p < .01) and ≥VGPR (63% vs. 48%, p < .01) rates were higher with IRd than with placebo‐Rd 25 . Median PFS was 35.3 months with the IRd group versus 21.8 months with placebo‐Rd, but the difference was not statistically significant (HR = 0.83, 95% CI: 0.67–1.01).…”

“…A clinically meaningful improvement in PFS was seen in the TOURMALINE‐MM2 trial with ixazomib and lenalidomide versus lenalidomide maintenance. Improvement in PFS was also seen in patients with del(17p), t(4;14), t(14;16), and amp(1q21) (23.8 months vs. 18 months in placebo‐Rd, HR = 0.69, 95% CI: 0.50–0.94) 25 . Both above trials do not have conclusive OS data.…”

“…High‐risk patients therefore need more intensive treatment approaches that maximize the depth of response 21–23 . Similarly, they benefit with more intensive maintenance therapies 24,25 . Thus, risk stratification helps in formulating a treatment plan for the patient.…”