Analysis Finds Value in Safety-Driven Personalized Dosing of Ixazomib

New results of the TOURMALINE-MM4 study highlight the value of safety-driven personalized dosing of ixazomib in patients with multiple myeloma to maximize benefit and risk.

Findings were published in Clinical Pharmacology and Therapeutics.

The treatment has been approved in several countries as a single-agent maintenance therapy for patients with newly diagnosed multiple myeloma in the posttransplant and transplant-ineligible settings. These approvals were based on findings from 2 phase 3 studies where patients were initially administered 3 mg of ixazomib and then escalated to 4 mg if the initial dose level was well tolerated through cycles 1 through 4.

In the current analysis, researchers reported results of exposure response in TOURMALINE-MM4 participants.

Ixazomib is a small molecule inhibitor of the 20S proteasome. It was first approved in the United States in 2015 for patients with relapsed/refractory multiple myeloma (RRMM).

“In a maintenance setting, patients have previously demonstrated a clinical response to initial treatment; thus, there is a particular emphasis on maintaining or improving that response, in addition to progression-free and/or overall survival, without significantly risking treatment-emergent adverse events that would negatively impact patients' quality of life,” the authors explained. To achieve this, patients completed a long-duration, low-intensity therapy that emphasizes tolerability while maintaining clinical efficacy, they added.

Researchers assessed progression-free survival (PFS) and clinical response and safety end points like anemia, neutropenia, thrombocytopenia, and diarrhea, among others. They also evaluated the relationship between the treatment exposure and end points reflective of the therapeutic setting, including maintenance of complete response and maintenance of minimal residual disease.

Participants were randomized to the ixazomib or placebo control arms and received doses on days 1, 8, and 15 of the first four 28-day treatment cycles.

“Only patients who had no grade ≥ 2 nonhematologic [adverse events] or study drug-related toxicity-driven dose delays > 1 week during cycles 3-4 and who did not undergo any dose reductions, were eligible for dose escalation,” the authors noted.

The escalation framework is of particular importance in the maintenance setting where patients have already responded to prior treatment and are mostly asymptomatic.

Data showed:

• Similar PFS benefits were observed across the range of ixazomib exposures achieved in the study
• Increased ixazomib exposures corresponded to a higher probability of maintaining complete response
• Exposure was not a significant predictor (P > .05) of hematological adverse events (anemia, neutropenia, thrombocytopenia) and peripheral neuropathy
• Higher exposures did correlate to increased probabilities of experiencing diarrhea, vomiting, nausea, rash, and fatigue
• Although ixazomib exposure was not predictive of dose reductions, lower apparent clearance values (corresponding to higher systemic exposures) correlated with a reduced likelihood of escalating to the 4-mg dose

Overall, “the dose titration approach balanced patient benefit and risk; it ensured that only patients for whom the 3-mg dose was safe/tolerable escalated to the higher dose, while maximizing the fraction of patients (85%) who were able to derive additional clinical benefit at 4 mg,” the authors wrote.

Results also showed gender was a significant covariate of PFS, as women were predicted to survive without progression longer than men, a result that is consistent with previous meta-analyses. The underlying reasons for this difference remain unclear; however, the researchers hypothesize it’s possible differences in innate and adaptive immunity may play a role.

“Collectively, the results of the exposure–efficacy and exposure–safety analyses, combined with the consistency of the PFS benefit observed across the ixazomib exposures achieved in the analysis population, confirm a favorable benefit–risk profile of the approved dosing regimen as maintenance therapy for patients with newly diagnosed multiple myeloma not treated with stem cell transplantation,” the authors said.

“Critically, dose titration represents an individualized way to maximize patient benefit while ensuring safety: patients with lower CL/F [oral clearance] values require lower doses, while the tolerability-driven escalation at cycle 5 allows patients to derive the full benefit of higher ixazomib exposures. In this way, dose titration may maximize drug tolerability, particularly for treatments associated with early-onset safety risks or dose modifications,” they concluded.

Reference

Srimani JK, Diderichsen PM, Hanley MJ, Labotka R, Gupta N. Dose titration of ixazomib maintenance therapy in transplant-ineligible multiple myeloma: exposure-response analysis of the TOURMALINE-MM4 Study. Clin Pharmacol Ther. Published online April 25, 2023. doi:10.1002/cpt.2917