Liviu Niculescu

Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma

BACKGROUND Ixazomib is an oral proteasome inhibitor that is currently being studied for the treatment of multiple myeloma. METHODS In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 722 patients who had relapsed, refractory, or relapsed and refractory multiple myeloma to receive ixazomib plus lenalidomide-dexamethasone (ixazomib group) or placebo plus lenalidomide-dexamethasone (placebo group). The primary end point was progression-free survival. RESULTS Progression-free survival was significantly longer in the ixazomib group than in the placebo group at a median follow-up of 14.7 months (median progression-free survival, 20.6 months vs. 14.7 months; hazard ratio for disease progression or death in the ixazomib group, 0.74; P=0.01); a benefit with respect to progression-free survival was observed with the ixazomib regimen, as compared with the placebo regimen, in all prespecified patient subgroups, including in patients with high-risk cytogenetic abnormalities. The overall rates of response were 78% in the ixazomib group and 72% in the placebo group, and the corresponding rates of complete response plus very good partial response were 48% and 39%. The median time to response was 1.1 months in the ixazomib group and 1.9 months in the placebo group, and the corresponding median duration of response was 20.5 months and 15.0 months. At a median follow-up of approximately 23 months, the median overall survival has not been reached in either study group, and follow-up is ongoing. The rates of serious adverse events were similar in the two study groups (47% in the ixazomib group and 49% in the placebo group), as were the rates of death during the study period (4% and 6%, respectively); adverse events of at least grade 3 severity occurred in 74% and 69% of the patients, respectively. Thrombocytopenia of grade 3 and grade 4 severity occurred more frequently in the ixazomib group (12% and 7% of the patients, respectively) than in the placebo group (5% and 4% of the patients, respectively). Rash occurred more frequently in the ixazomib group than in the placebo group (36% vs. 23% of the patients), as did gastrointestinal adverse events, which were predominantly low grade. The incidence of peripheral neuropathy was 27% in the ixazomib group and 22% in the placebo group (grade 3 events occurred in 2% of the patients in each study group). Patient-reported quality of life was similar in the two study groups. CONCLUSIONS The addition of ixazomib to a regimen of lenalidomide and dexamethasone was associated with significantly longer progression-free survival; the additional toxic effects with this all-oral regimen were limited. (Funded by Millennium Pharmaceuticals; TOURMALINE-MM1 ClinicalTrials.gov number, NCT01564537.).

Effect of cumulative bortezomib dose on survival in multiple myeloma patients receiving bortezomib-melphalan-prednisone in the phase III VISTA study.

This analysis, using data from the bortezomib‐melphalan‐prednisone (VMP) arm of the Phase III VISTA study, investigated whether increased cumulative bortezomib dose could improve overall survival (OS) in transplant‐ineligible patients with previously untreated multiple myeloma. Median cumulative bortezomib dose received by the 340 patients was 39 mg/m2; this was selected as the cut‐off for defining the dose groups to be compared for OS. Patient characteristics were well balanced between dose groups except for age. OS was significantly longer in the higher (≥39 mg/m2) versus lower (<39 mg/m2) cumulative bortezomib dose group (median 66.3 vs. 46.2 months; hazard ratio (HR) 0.533, P < 0.0001; age‐adjusted HR 0.561, P = 0.0002). To overcome confounding effects of early discontinuations/deaths, which were more common in the lower cumulative dose group (27 vs. 4% of patients discontinued due to adverse events (AEs) in the lower and higher cumulative dose groups, respectively), a landmark analysis was conducted at 180 days, eliminating patients who died or discontinued before this time from the analysis. OS from this landmark remained significantly longer in the higher dose group (median 60.4 vs. 50.3 months; HR 0.709, P = 0.0372). Thus, higher cumulative bortezomib dose, reflecting prolonged treatment duration and/or dose intensity, appears associated with improved OS. Approaches to achieve higher cumulative doses could include subcutaneous bortezomib administration, dose/schedule modifications, continuing therapy in responding patients, and proactive AE management. Am. J. Hematol. 90:314–319, 2015.

A retrospective analysis of 3954 patients in phase 2/3 trials of bortezomib for the treatment of multiple myeloma: towards providing a benchmark for the cardiac safety profile of proteasome inhibition in multiple myeloma

This retrospective analysis aimed to establish the overall cardiac safety profile of bortezomib using patient‐level data from one phase 2 and seven phase 3 studies in previously untreated and relapsed/refractory multiple myeloma (MM). Seven clinically relevant primary [congestive heart failure (CHF), arrhythmias, ischaemic heart disease (IHD), cardiac death] and secondary (hypertension, dyspnoea, oedema) cardiac endpoints were defined based on MedDRA v16.0 preferred terms. 2509 bortezomib‐treated patients and 1445 patients in non‐bortezomib‐based control arms were included. The incidence of grade ≥3 CHF was 1·3–4·0% in studies in relapsed/refractory MM and 1·2–4·7% in previously untreated MM (2·0–7·6% all grades), with no significant differences between bortezomib‐ and non‐bortezomib‐based arms in comparative studies. Incidences of arrhythmias (1·3–5·9% grade ≥2; 0·6–4·1% grade ≥3), IHD (1·2–2·9% all grades; 0·4–2·7% grade ≥3) and cardiac death (0–1·4%) were low, with no differences between bortezomib‐based and non‐bortezomib‐based arms. Higher rates of oedema (mostly grade 1/2) were seen in bortezomib‐based versus non‐bortezomib‐based arms in one study and a pooled transplant study analysis. Logistic regression analyses of comparative studies showed no impact on cardiac risk with bortezomib‐based versus non‐bortezomib‐based treatment. Bortezomib‐based treatment was associated with low incidences of cardiac events.

The challenge of cross-trial comparisons using limited data

The manuscript by Dr David Siegel and colleagues,[1][1] “Integrated safety profile of single-agent carfilzomib: experience from 526 patients enrolled in 4 phase 2 clinical studies”, provides a comprehensive assessment of the available safety data associated with the new proteasome inhibitor

Treatment patterns and outcomes with subcutaneous bortezomib in patients with relapsed mantle cell lymphoma: a retrospective, observational study of patient medical records from US community oncology practices.

Alan P. Skarbnik, Esprit Ma, Marie-H el ene Lafeuille, Jonathan Fortier, Tatyana Feldman, Mei Sheng Duh, Helgi van de Velde, Liviu Niculescu, Vijayveer Bonthapally and Andr e Goy Lymphoma Division, Blood and Marrow Transplantation Program, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA; Millennium Pharmaceuticals Inc, Cambridge, MA, USA; Groupe d’analyse, Lt ee, Montreal, QC, Canada; Analysis Group, Inc, Boston, MA, USA