Ibrutinib alone or with dexamethasone for relapsed or relapsed and refractory multiple myeloma: phase 2 trial results

Abstract

SummaryNovel therapies with unique new targets are needed for patients who are relapsed/refractory to current treatments for multiple myeloma. Ibrutinib is a first‐in‐class, once‐daily, oral covalent inhibitor of Bruton tyrosine kinase, which is overexpressed in the myeloma stem cell population. This study examined various doses of ibrutinib ± low‐dose dexamethasone in patients who received ≥2 prior lines of therapy, including an immunomodulatory agent. Daily ibrutinib ± weekly dexamethasone 40 mg was assessed in 4 cohorts using a Simon 2‐stage design. The primary objective was clinical benefit rate (CBR; ≥minimal response); secondary objectives included safety. Patients (n = 92) received a median of 4 prior regimens. Ibrutinib + dexamethasone produced the highest CBR (28%) in Cohort 4 (840 mg + dexamethasone; n = 43), with median duration of 9·2 months (range, 3·0–14·7). Progression‐free survival was 4·6 months (range, 0·4–17·3). Grade 3–4 haematological adverse events included anaemia (16%), thrombocytopenia (11%), and neutropenia (2%); grade 3–4 non‐haematological adverse events included pneumonia (7%), syncope (3%) and urinary tract infection (3%). Ibrutinib + dexamethasone produced notable responses in this heavily pre‐treated population. The encouraging efficacy, coupled with the favourable safety and tolerability profile of ibrutinib, supports its further evaluation as part of combination treatment.

A phase 2 study of ibrutinib in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma

“…However, it should be noted that a higher dose of ibrutinib (840 mg once daily) was used in the current study compared with other haematological malignancies (420 mg or 560 mg once daily). The ibrutinib dose used in the current study was chosen based on clinical activity and a favourable safety profile observed at the 840 mg dose level of ibrutinib in combination with carfilzomib with or without dexamethasone and in combination with dexamethasone in two early phase studies in MM . Plasma exposures to ibrutinib and bortezomib were consistent with those previously reported, suggesting that drug‐drug interactions may not be contributing factors to the safety observations.…”

“…This phase 2 study evaluated the efficacy and safety of ibrutinib in combination with bortezomib plus dexamethasone in patients with R/R MM who had received one to three previous lines of therapy. After 74 patients had received at least one dose of study treatment, study enrolment was suspended as a risk‐minimisation measure to address concerns over an increased incidence of serious and fatal infections compared with other studies of ibrutinib in R/R MM . While the incidence of infection of any grade in this study (80%) was similar to rates reported with ibrutinib in other haematological malignancies (68%‐78%) over median follow‐up durations of 9.4 to 33.4 months, the incidence of grade ≥3 infections (43%) was higher than rates previously reported with ibrutinib (7%‐29%) .…”

Drug targets and resistance mechanisms in multiple myeloma

“…The drug regimen was either ibrutinib alone or in combination with dexamethasone. Response was observed in 51% of the patients treated with this combination regimen [234] . A large number of novel substances have been recently developed to target critical components in several epigenetic processes, particularly DNA methylation, histone acetylation and methylation.…”

High-Risk Multiple Myeloma: Integrated Clinical and Omics Approach Dissects the Neoplastic Clone and the Tumor Microenvironment

“…The most important toxicity concerns infusion reactions, which are limited to the first administrations and adequately prevented by premedication with steroids and anti-H1 Also mentioned above, MM is running in the field of the new T cell immunotherapies as wells with chimeric antigen receptor T cells program, already targeting BCMA [149], and with new bi-specific antibodies still in clinical trials (Figure 4a). [184][185][186][187][188][189][190], for details).…”