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/m(2) . 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).

Keywords: Anti-B-cell activating factor monoclonal antibody; LY2127399; multiple myeloma; phase 1 study; tabalumab.

Figure 1

Patient disposition. BTZ, bortezomib 1.3 mg/m²; DEX, dexamethasone 20 mg/day; IV, intravenous; LY, LY2127399 (tabalumab); SC, subcutaneous.

Figure 2

Mean ± SD serum LY2127399 (tabalumab) concentration–time profiles (linear) following intravenous infusion of LY2127399 (tabalumab) 100 or 300 mg in combination with i.v. or s.c. bortezomib 1.3 mg/m² and oral dexamethasone 20 mg during Day 1 of Cycle 1 and Cycle 7. BTZ, bortezomib 1.3 mg/m²; DEX, dexamethasone 20 mg; IV, intravenous; LY, LY2127399 (tabalumab); SC, subcutaneous.

Figure 3

Mean plasma bortezomib concentration–time profiles (semi‐logarithmic) following intravenous infusion of LY2127399 (tabalumab) 100 or 300 mg in combination with i.v. or s.c. bortezomib 1.3 mg/m² and oral dexamethasone 20 mg during Day 1 of Cycle 1. BTZ, bortezomib 1.3 mg/m²; DEX, dexamethasone 20 mg; IV, intravenous; LY, LY2127399 (tabalumab); SC, subcutaneous.

Figure 4

Relationship between baseline B‐cell activating factor (BAFF) levels and tumor response. Each data point represents an individual patient for responders (partial response or better: ●) and nonresponders (stable or progressive disease: Δ). For two patients, the response status was unknown.

Figure 5

Change in the immunoglobulins (Ig) A, G and M, and CD19+, IgD−, CD27+ (mature naïve B‐cell subset) over time for each patient in Cohort 1 (^……..) and Cohort 2 (^____). BTZ, bortezomib 1.3 mg/m²; DEX, dexamethasone 20 mg; IV, intravenous; LY, LY2127399 (tabalumab); SC, subcutaneous.