Preliminary Results of CNTO 328, An Anti-Interleukin-6 Monoclonal Antibody, in Combination with Bortezomib in the Treatment of Relapsed or Refractory Multiple Myeloma

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.

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.