A phase 2, randomized, double‐blind, placebo‐controlled study of siltuximab (anti‐IL‐6 mAb) and bortezomib versus bortezomib alone in patients with relapsed or refractory multiple myeloma

Abstract

We compared the safety and efficacy of siltuximab (S), an anti-interleukin-6 chimeric monoclonal antibody, plus bortezomib (B) with placebo (plc)+B in patients with relapsed/refractory multiple myeloma in a randomized phase II study. Siltuximab was given by 6 mg/kg IV every 2 weeks. On progression, B was discontinued and high-dose dexamethasone could be added to S/plc. Response and progression-free survival (PFS) were analyzed pre-dexamethasone by EBMT criteria. For the 281 randomized patients, median PFS for S+B and plc+B was 8.0 and 7.6 months (HR 0.869, p=0.345), overall response rate was 55% vs. 47% (p=0.213), complete response rate was 11% vs. 7%, and median overall survival (OS) was 30.8 vs. 36.8 months (HR 1.353, p=0.103). Sustained suppression of C-reactive protein, a marker reflective of inhibition of interleukin-6 activity, was seen with S+B. Siltuximab did not affect B pharmacokinetics. S/plc discontinuation (75% vs. 66%), grade ≥3 neutropenia (49% vs. 29%), thrombocytopenia (48% vs. 34%), and all-grade infections (62% vs. 49%) occurred more frequently with S+B. The addition of siltuximab to bortezomib did not appear to improve PFS or OS despite a numerical increase in response rate in patients with relapsed or refractory multiple myeloma.

Bortezomib in Multiple Myeloma: Systematic Review and Clinical Considerations

“…Bortezomib monotherapy improved os significantly more than did dexamethasone (hr: 0.77, p = 0.003; and hr: 0.67, p = 0.47) 23,33 . No significant difference was seen with the administration of bortezomib before or after melphalan 17 or in combination with thalidomide, dexamethasone, or siltuximab 25,30,83 .…”

“…Seven abstract publications of interim analyses of ongoing trials were also identified [79][80][81][82][83][84][85] . They are presented in Table i, but are not further discussed here.…”

“…All studies but one were fully published reports. Three included only bortezomib-naïve patients 20,23,25 ; the remaining four 17,22,30,83 included patients who had previously received treatment for mm, including bortezomib. 22 reported on pharmacodynamic and pharmacokinetic parameters, response, and the toxicity of bortezomib.…”

Phase 2 randomized study of bortezomib-melphalan-prednisone with or without siltuximab (anti–IL-6) in multiple myeloma

“…19 In a large, randomized, phase 2 study of siltuximab in combination with bortezomib vs bortezomib alone in relapsed MM, an overall response rate ($PR) of 55% was seen with the combination as compared with 47% with single-agent bortezomib, but there was no improvement in progressionfree survival (PFS) with the addition of siltuximab (median PFS, 8.0 months vs 7.6 months). 20 This moderate additional activity of siltuximab in relapsed MM could be interpreted as advanced MM having become increasingly independent of the bone marrow microenvironment in general, and of IL-6 in particular, and left open the question of whether IL-6 blockade would be more relevant in newly diagnosed MM.…”

The immunotherapy era of myeloma: monoclonal antibodies, vaccines, and adoptive T-cell therapies

“…However, the results of a randomized control trial in combination with bortezomib failed to report statistically significant differences in response rate, PFS, or OS, whereas it did increase the frequency of adverse events including cytopenias. [46][47][48] Currently it is being tested in patients with high-risk smoldering myeloma.…”