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

Abstract

Summary 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.

Bortezomib‐based therapy for relapsed/refractory multiple myeloma in real‐world medical practice

“…The rate of cardiac events in eVOBs (including cardiac failure, atrial fibrillation, tachycardia NOS, and cardiac failure NOS) was 6%. This is consistent with a retrospective analysis that examined data from almost 4000 patients with RRMM in phase 2 and phase 3 studies and found that bortezomib‐based treatment appeared to have low incidences of cardiac events . Nevertheless, the bortezomib summary of product characteristics section on warnings and precautions mention heart failure and ECG QT‐interval prolongation…”

“…This is consistent with a retrospective analysis that examined data from almost 4000 patients with RRMM in phase 2 and phase 3 studies and found that bortezomib-based treatment appeared to have low incidences of cardiac events. 36 Nevertheless, the bortezomib summary of product characteristics section on warnings and precautions mention heart failure and ECG QT-interval prolongation. 37 Interpretation of data regarding resource utilization is limited due to differences in clinical practice and healthcare systems between the different countries participating in eVOBS.…”

Recurrent cardiotoxicity potentiated by the interaction of proteasome inhibitor and immunomodulatory therapy for the treatment of multiple myeloma

“…In the ENDEAVOR (Randomiz e d, ope n label, phase 3 study of carfilzomib plus de xameth a sone v s bortezomib plus dexamethas o ne in patients with r elapsed multiple myeloma) trial, hypertension was reported in 25% of patients receiving combination carfilzomib and dexamethasone with grade 3 or higher CV events occurring in 9% (compared to 3% in the bortezomib treated arm) (Dimopoulos et al , ). Although the specific cardiotoxicities are unclear, these probably do not represent a class‐related effect as recent data suggest low cardiotoxicity associated with bortezomib (Laubach et al , ).…”

Breakthroughs in modern cancer therapy and elusive cardiotoxicity: Critical research‐practice gaps, challenges, and insights

“…Several proteasome‐targeting inhibitors (e.g., bortezomib, carfilzomib) have been introduced in the clinic. A retrospective analysis of 3954 patients in phase 2/3 trials of bortezomib for the treatment of multiple myeloma reported that bortezomib‐based treatment was associated with a low incidence of cardiac events . Epigenetic cancer therapy using histone deacetylase inhibitors is also emerging, as epigenetic gene silencing is a hallmark of cancer cells.…”