Ixazomib is an investigational proteasome inhibitor that is orally administered, thus facilitating better convenience for patients and enhancing quality of life. Based on previous studies demonstrating the feasibility of combining a protease inhibitor with cyclophosphamide and dexamethasone, a phase 2 study was conducted to evaluate the all-oral triplet combination of Ixazomib plus cyclophosphamide and low-dose dexamethasone (ICd), with 2 different doses of cyclophosphamide, as a 12-month induction therapy in previously untreated, transplant-ineligible patients with multiple myeloma (MM).1,2 Dimopoulos and colleagues reported on the results of the preliminary analysis of postinduction data.3 Patients were randomized to receive induction therapy with Ixazomib (4.0 mg orally on days 1, 8, and 15), plus either 300 mg/m2 (ICd-300 arm) or 400 mg/m2 (Cd-400 arm) of cyclophosphamide (orally on days 1, 8, and 15), plus dexamethasone (40 mg orally on days 1, 8, 15, and 22); patients may receive up to 13 cycles of 28-day induction therapy. Responding patients (? stable disease [SD]) went on to receive maintenance therapy with ixazomib at end-of-induction dose on days 1, 8, and 15 in 28-day cycles until progressive disease, death, or unacceptable toxicity. After cycle 1, a safety lead-in evaluation of dose-limiting toxicities (DLTs) was performed in 6 evaluable patients. The primary end point was the combined rate of complete response (CR) plus very good partial response (VGPR); secondary end points included overall response rate (ORR) and safety. Seventy patients were randomized on the trial; 36 patients received ICd-300 and 34 received ICd-400. At a mean follow-up of 7.0 months, ORRs were 78% for the ICd-300 cohort and 65% for the ICd-400 cohort; best unconfirmed CR+VGPR rates were 28% and 21%, respectively. At a median follow-up of 9.2 months, the 12-month progression-free survival (PFS) was 68% and 91% in the ICd-300 and ICd-400 treatment arms, respectively. No DLTs were observed in either arm; mean ixazomib relative dose intensity was about 90% in both arms. The incidence of grade 3/4 adverse events (AEs) were 64% in the ICd-300 cohort and 68% in the ICd-400 cohort; serious AEs were 39% and 50%, respectively; and treatment discontinuations due to AEs were 14% and 18%, respectively. Most common grade 3/4 hematologic AEs were neutropenia (14% and 35%) and anemia (11% and 15%). Other AEs of interest included all-grade peripheral neuropathy (19% and 26%), fatigue (14% and 18%), pneumonia (8% and 9%), rash (25% and 21%), and cardiac SOC (11% and 21%). Overall, the AE rates were higher in the ICd-400 cohort, suggesting that ICd-300 may be a more preferable regimen in this patient population. Three deaths were reported in the study (cardiac arrest, upper gastrointestinal hemorrhage, pneumonia), which were ruled as not treatment-related. Higher rates of antiemetic use (8% and 18%) and granulocyte colony-stimulating factor use (11% and 53%) for AEs was reported in the ICd-400 cohort than in the ICd-300 cohort. Based on these results, the authors concluded that the all-oral triplet combination of ICd is tolerable, with a manageable toxicity profile, and represents a novel treatment option for transplant-ineligible patients with newly diagnosed MM.
