An open-label, randomized, phase 2 study evaluated the all-oral triplet combination of ixazomib (an orally administered proteasome inhibitor) plus cyclophosphamide (at 2 different doses) and low-dose dexamethasone (ICd) as a 12-month induction therapy in previously untreated, transplant-ineligible patients with multiple myeloma (MM). Meletios A. Dimopoulos, Professor, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece, and colleagues presented preliminary analysis results of the postinduction data from this trial at the 57th American Society of Hematology (ASH) Annual Meeting and Exposition.1
Seventy patients were randomized to receive 2 induction therapies: ixazomib (4.0 mg orally [PO] on days 1, 8, and 15) plus cyclophosphamide (PO on days 1, 8, and 15) dosed at 300 mg/m2 (ICd-300 arm; n = 36) or 400 mg/m2 (ICd-400 arm), and dexamethasone (40 mg PO on days 1, 8, 15, and 22); patients may receive up to 13 cycles of 28-day induction therapy. After cycle 1, a safety lead-in evaluation of dose-limiting toxicities (DLTs) was performed in 6 evaluable patients from each arm; no DLTs were observed in either arm.
Following induction, all patients received maintenance therapy with single-agent ixazomib 4.0 mg PO on days 1, 8, and 15 of each 28-day cycle; this therapy was repeated every 28 days until progressive disease, death, or unacceptable toxicity. At a mean follow-up of 9 cycles, the primary end point of complete response plus very good partial response rates was 28% for the ICd-300 cohort and 21% for the ICd-400 cohort; overall response rates were 78% and 65%, respectively. Grade ≥3 adverse events (68% vs 64%), mainly neutropenia (35% vs 14%) and anemia (15% vs 11%), were higher in the ICd-400 arm in comparison to the ICd-300 arm, as were rates of serious adverse events (50% vs 39%) and dose reductions (21% vs 19%); treatment discontinuations were similar between the 2 arms.
Higher rates of antiemetic use for adverse events (50% and 39%) and granulocyte colony-stimulating factor use for adverse events (53% and 11%) were also reported in the ICd-400 versus ICd-300 cohort. Four deaths were reported in the study (cardiac arrest, upper gastrointestinal hemorrhage, pneumonia). Based on these results, the authors concluded that the all-oral triplet combination of ICd-300 showed a tolerable and manageable toxicity profile, and represents a novel frontline treatment option for elderly, transplant-ineligible patients with newly diagnosed MM.
1. Dimopoulos MA, Grosicki S, Jedrzejczak WW, et al. Randomized phase 2 study of the all-oral combination of investigational proteasome inhibitor (PI) ixazomib plus cyclophosphamide and low-dose dexamethasone (ICd) in patients (Pts) with newly diagnosed multiple myeloma (NDMM) who are transplant-ineligible (NCT02046070). Blood. 2015;126