Dose‐escalation study of tabalumab with bortezomib and dexamethasone in Japanese patients with multiple myeloma

Abstract

B‐cell activating factor (BAFF) promotes the survival and adhesion of multiple myeloma (MM) cells. Tabalumab (LY2127399) is an anti‐BAFF monoclonal antibody. This phase 1, multicenter, open‐label, nonrandomized, dose‐escalation study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of tabalumab in combination with bortezomib and dexamethasone in Japanese patients with relapsed or refractory MM (RRMM). Sixteen patients received intravenous i.v. tabalumab 100 mg (Cohort 1, n = 4) or i.v. tabalumab 300 mg (Cohort 2, n = 12) in combination with oral dexamethasone 20 mg/day and i.v. or s.c. bortezomib 1.3 mg/m2. All patients had treatment‐emergent adverse events (TEAE) possibly related to study treatment; the most common TEAE were thrombocytopenia (81.3%), lymphopenia (43.8%) and increased alanine aminotransferase (43.8%). Two (20.0%) dose‐limiting toxicities were observed, both in Cohort 2 (tabalumab 300 mg), which was below the predefined cutoff for tolerability (<33%). The pharmacokinetics of tabalumab were similar when bortezomib was coadministered i.v. versus s.c. The overall response rate was 56.3%, suggesting that the combined treatment was effective. In conclusion, combined treatment with these three agents was well tolerated in this population of Japanese patients with RRMM. The study was registered at www.clinicaltrials.gov (NCT01556438).

Investigational Monoclonal Antibodies in the Treatment of Multiple Myeloma: A Systematic Review of Agents under Clinical Development

“…Rossi et al evaluated atacicept as monotherapy in 12 patients who had failed 5 prior lines of therapy and no OR was achieved [65]. Shinsuki et al studied tabalumab in doses of 100-200 mg in combination with Vd in RRMM patients with 1-5 prior lines of therapy and reported a combined OR of 56.3% and tabalumab was well tolerated [66]. Raje et al studied tabalumab 100mg, 300mg and placebo + Vd each and found no statistically significant difference between OR and PFS.…”

Immune-based therapies in the management of multiple myeloma

“…Tabalumab, an mAb against B-cell activating factor (BAFF), has been tested in a dose-escalation phase I study in combination Vd in RRMM. The combination was well tolerated with an ORR of 56% 54 . However, a phase II study of tabalumab 100 or 300 mg in combination with Vd failed to show an improvement in the PFS of patients with tabalumab and Vd compared to the placebo-Vd arm 55 .…”

Pathogenesis and Treatment of Myeloma-Related Bone Disease

“…Treatment of mice with tabalumab resulted in a significant reduction in tumor burden, prolonged survival, decreased osteoclast recruitment and activation, which caused fewer lytic lesions in the bone by a reduction in NF-κB signaling [ 154 ]. In Phase I studies, tabalumab in combination with bortezomib was well tolerated for patients with relapsed/refractory MM [ 147 , 148 ]. In a Phase II trial, patients with relapsed/refractory multiple myeloma were randomly assigned 1:1:1 to receive placebo, tabalumab 100 mg, or tabalumab 300 mg, each in combination with dexamethasone and bortezomib.…”