Preliminary Results of CNTO 328, An Anti-Interleukin-6 Monoclonal Antibody, in Combination with Bortezomib in the Treatment of Relapsed or Refractory Multiple Myeloma
Authors: Rossi Jean-Francois , Manges Robert F. , Sutherland Heather J. , Jagannath Sundar , Voorhees Peter , Sonneveld Pieter , Delforge Michel , Pegourie Brigitte , Alegre Adrian , de la Rubia Javier , La Police David , Bandekar Rajesh , Xie Hong , Orlowski Robert Z. 
Published: October 2019

Abstract
Background: CNTO 328 is an anti-interleukin (IL)-6 chimeric monoclonal antibody demonstrated to have anti-myeloma activities in vitro. Because IL-6 signaling augments the anti-apoptotic heat shock protein response, a potential resistance mechanism for bortezomib, downregulation of IL-6 signaling may enhance bortezomib’s anti-myeloma activity. Pre-clinical studies have shown that this combination had an additive to synergistic effect in inducing apoptosis in IL-6-dependent and independent multiple myeloma cell lines.
Methods: In this open-label, safety lead-in cohort of a pivotal phase II trial, bortezomib naïve patients with relapsed/refractory multiple myeloma received CNTO 328 at 6mg/kg IV every 2 weeks in combination with 1.3 mg/m2 bortezomib IV on days 1, 4, 8, and 11 every 3 weeks. Patients received a maximum of 4, 6-week treatment cycles, after which bortezomib was reduced to 4, once weekly doses in a 5-week maintenance cycle. Dexamethasone was added to the regimen at disease progression.
Results: Twenty-one patients (median age 66, range 39–85) were treated with bortezomib + CNTO 328. The median number of prior lines of therapy was 2 (range 1–3); the median duration since diagnosis was 3.5 years (range 1–10). Eleven patients had received prior autologous stem cell transplantation; 8 patients had received prior IMiDs. Baseline β2M levels of >3.5mg/L were reported in 13 patients; median CRP was 2.21 mg/L (range 0.4 – 86.1). Utilizing EBMT criteria, 12 patients (57%) achieved either a complete response (CR) or partial response (PR): 3 CR, 9 PR (including 2 very good partial response [>90% reduction] and 1 unconfirmed due to discontinuation for renal insufficiency). Thirteen of twenty-one patients discontinued treatment: 5 due to disease progression, 7 adverse events (AEs), and 1 withdrawal of consent. The other 8 remain on treatment. The median number of CNTO 328 administrations was 11 (range 2–38). Median time to disease progression/death was 280 days (range 36–540+). Grade 3 and higher hematologic toxicity was common: neutropenia (15/21); thrombocytopenia (8/21); lymphopenia (6/21); leukopenia (5/21). Grade 3 and higher hematologic AEs considered to be possibly related to CNTO 328 included neutropenia (10/21), leukopenia (3/21), lymphopenia (2/21) and thrombocytopenia (1/21). Grade 3 and higher infections were reported in 5 patients (urinary tract, bacterial, and campylobacter infection, pneumococcal sepsis, and pneumonia, 1 case each, among which the urinary tract and campylobacter infections were considered to be possibly CNTO 328-related). Other common CNTO 328-related AEs (>15%) of any grade included diarrhea (5/21), fatigue (5/21), and hypercholesterolemia (4/21). No patients died during treatment. Dexamethasone was added to the treatment regimen for only 4/21 patients, and no conclusions regarding this treatment modification can be drawn at present.
Conclusion: Treatment with CNTO 328 combined with bortezomib is a promising new regimen for the treatment of relapsed/refractory multiple myeloma. Enrollment in a larger phase 2 randomized trial with bortezomib and either CNTO 328 or placebo is now ongoing to explore its full potential.