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

Abstract

• Adding siltuximab to VMP did not improve CR, progressionfree survival, or overall survival but improved very good partial response in MM.• This suggests that the association of less than CR with long-term outcomes and the role of IL-6 in MM should be reassessed.Because interleukin-6 (IL-6) is considered important in the proliferation of early multiple myeloma (MM), we hypothesized that the addition of the anti-IL-6 monoclonal antibody siltuximab to the bortezomib-melphalan-prednisone (VMP) regimen would improve outcomes in transplant-ineligible patients with newly diagnosed MM. One hundred and six patients were randomized to receive 9 cycles of VMP or VMP plus siltuximab (11 mg/kg every 3 weeks) followed by siltuximab maintenance. Baseline characteristics were well balanced except for immunoglobulin A subtype and 17p deletions. With a complete response (CR) rate of 27% on siltuximab plus VMP (S1VMP) and 22% on VMP, the study did not confirm its hypothesis that the addition of siltuximab would increase the CR rate by at least 10%. Overall response rate was 88% on S1VMP and 80% on VMP, and at least very good partial response rates were 71% and 51% (P 5 .0382), respectively. Median progression-free survival (17 months) and 1-year overall survival (88%) were identical in the 2 arms. Grade ‡3 adverse-event incidence was 92% on S1VMP and 81% on VMP (P 5 .09), with trends toward more hematologic events and infections on S1VMP. Maintenance therapy with siltuximab was well tolerated. In conclusion, the addition of siltuximab to VMP did not improve the CR rate or long-term outcomes. This study was registered at http://clinicaltrials.gov as #NCT00911859. (Blood. 2014;123(26):4136-4142)

Interleukin-6 as a Therapeutic Target

“…The CNTO328 chimeric anti-IL6 mAb (siltuximab) was used in clinical trials for multiple myeloma (20,21), MRCC (22), and prostate cancer (23) and was recently registered for treating patients with Castleman disease (24). Sirukumab, a humanized anti-IL6 mAb, has been assayed in healthy subjects to determine PK/PD and safety.…”

“…Two randomized trials were recently published showing a lack of effect of anti-IL6 therapy. In one trial, the anti-IL6 mAb silxutimab was given to transplant-ineligible patients in association with a regimen of bortezomib-melphalan-prednisone compared with bortezomib-melphalan-prednisone and then as a maintenance therapy for 18 months or until relapse (20). In another trial, siltuximab was given in relapsed/refractory multiple myeloma in association with bortezomib compared with bortezomib alone and then as maintenance therapy until progression (21).…”

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.…”

A Phase I Dose-Escalation Study of Antibody BI-505 in Relapsed/Refractory Multiple Myeloma

“…and commercially available therapeutic antibody for multiple myeloma; however, a broad range of monoclonal antibodies with different targets is being tested in clinical trials (9)(10)(11)(12), such as CD20 (13), CD56 (14), CD38 (15), CD138 (16,17), CS-1 (18,19), 21), and RANKL (22). This fact suggests that antibody-therapy will become as important in multiple myeloma as in other cancer treatments.…”