Dose Titration of Ixazomib Maintenance Therapy in Transplant-Ineligible Multiple Myeloma: Exposure-Response Analysis of the TOURMALINE-MM4 Study

Ixazomib has been approved in several countries as single-agent maintenance therapy in newly diagnosed multiple myeloma, in both posttransplant and transplant-ineligible settings, based on two phase III studies. In these maintenance studies, patients were initially administered 3 mg ixazomib, escalating to 4 mg if the initial dose level was well tolerated through Cycles 1-4. Here, we report the results of exposure-response analyses of TOURMALINE-MM4, wherein relationships between exposure and clinical response, dose adjustments, and selected adverse events were evaluated. Similar progression-free survival benefits were observed across the range of ixazomib exposures achieved in the study. Moreover, increased ixazomib exposures corresponded to a higher probability of maintaining complete response. Exposure was not a significant predictor (P > 0.05) of hematological adverse events (anemia, neutropenia, thrombocytopenia) and peripheral neuropathy; however, higher exposures did correlate to increased probabilities of experiencing diarrhea, vomiting, nausea, rash, and fatigue. While ixazomib exposure was not predictive of dose reductions, lower apparent clearance values (corresponding to higher systemic exposures) were correlated with a reduced likelihood of escalating to the 4 mg dose. Thus, 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. Collectively, these results highlight the value of safety-driven personalized dosing to maximize patient benefit/risk.

Automated summary

Ixazomib has been approved for maintenance therapy in multiple myeloma patients, with similar progression-free survival benefits seen across different exposure levels. Higher exposures were associated with increased probabilities of maintaining complete response and experiencing certain adverse events, while exposure did not predict hematological adverse events and peripheral neuropathy. Lower apparent clearance values were correlated with a reduced likelihood of escalating the dose to 4 mg. The dose titration approach balanced patient benefit and risk, maximizing the fraction of patients who benefited from the higher dose.