Phase I/II trial of bendamustine, ixazomib, and dexamethasone in relapsed/refractory multiple myeloma

Abstract

In this phase I/II trial, BID, bendamustine (70, 80, or 90 mg/m 2 ), ixazomib (4 mg), and dexamethasone (40 mg), was administered to 28 patients with relapsed and/or refractory multiple myeloma (RRMM) exposed to bortezomib and lenalidomide and refractory to at least one. A 3 + 3 dose escalation based on dose-limiting toxicities (DLTs) was employed in phase I (total 15); 2/6 patients developed DLTs (neutropenia and thrombocytopenia) at dose level 3 establishing the recommended phase II dose as bendamustine 80 mg/m 2 , ixazomib 4 mg, and dexamethasone 40 mg. The median age was 67 years (range, 42–72), and 43% were females. Patients received a median of 4 (range, 4–9) prior lines of therapy, of which ~50% were double refractory. In phase II, total 19 patients were treated. With a median follow-up of 17 months, 11% achieved very good partial response, 50% achieved partial response, and 27% achieved stable disease. Median progression free (PFS) and overall (OS) survival were 5.2 months (95% CI, 1.96–8.3) and 23.2 months (95% CI 16.3–30.07). The most frequent adverse events were anemia, thrombocytopenia, leukopenia, nausea, diarrhea, and infections. Peripheral neuropathy was infrequent. BID is a well-tolerated and effective combination therapy for patients with RRMM.

Phase Ib Study of the Oral Proteasome Inhibitor Ixazomib (MLN9708) and Fulvestrant in Advanced ER+ Breast Cancer Progressing on Fulvestrant

“…This study fulfilled its primary objective of establishing a safety profile for ixazomib and identifying a maximum tolerated dose of 4 mg PO on Days 1, 4, 8, and 11 in a 21-day cycle when combined with fulvestrant in patients with fulvestrant-resistant metastatic breast cancer. The most common Grade 3/4 treatment-related adverse event was thrombocytopenia, which occurred in four subjects (lasting one cycle each) in a dose-dependent manner and is consistent with reports of ixazomib use [26,28,29]. Other observed Grade 2-4 adverse events included anemia (n=3 subjects), nausea (n=2), hypertension (n=6 subjects), dyspnea (n=3), cough (n=2), pulmonary hypertension (n=1), and pneumonia (n=1).…”

The role of ubiquitination in tumorigenesis and targeted drug discovery

“…In the clinic, ixazomib citrate is also recommended for the treatment of relapsed and refractory MM with a positive safety profile. 357,366,367 Moreover, in a phase 3 trial (NCT02181413), ixazomib maintenance can prolong progression-free survival (PFS) and is regarded as an additional option for posttransplant maintenance therapy in patients with newly diagnosed MM. 368 Delanzomib (CEP-18770) is also a reversible and orally bioavailable structural analog of bortezomib ( Fig.…”

Emerging agents and regimens for multiple myeloma

“…The triplet of bendamustine, ixazomib, and DEX (BID) was used in a phase I/II trial in patients with RRMM who previously had received a median of 4 (range 4–9) lines of therapy. With a median follow-up of 17 months, 11% achieved VGPR and 50% achieved partial response, with median PFS of 5.2 months (95% CI 1.96–8.3) and OS of 23.2 months (95% CI 16.3–30.07) [ 129 ]. Another phase II study evaluated the bendamustine, BTZ and DEX regimen (BBD) as a front line therapy for patients who were not candidates for high dose chemotherapy [ 130 ].…”