A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Siltuximab (Anti IL-6 Monoclonal Antibody) in Patients with High-Risk Smoldering Multiple Myeloma

Introduction: Siltuximab is a chimeric (murine-human) IgG1κ monoclonal antibody (mAb) that binds and neutralizes human IL-6, a proinflammatory cytokine involved in the growth and proliferation of myeloma cells, with high affinity. This study was to evaluate if blocking IL-6 with siltuximab would delay pts transitioning from a smoldering multiple myeloma (SMM) to multiple myeloma (MM).

Methods: This was a randomized, double-blind, placebo-controlled, multicenter study to evaluate the safety and efficacy of siltuximab compared with placebo in pts with high-risk SMM (bone marrow plasma cells [BMPC] ≥10% and serum M-protein ≥3 g/dL). With a planned sample size of 74, pts were randomized in a 1:1 ratio to 15 mg/kg of siltuximab or placebo administered as a 1 hour IV infusion every 4 weeks until disease progression to MM, unacceptable toxicity, withdrawal of consent, or the end of the study. The primary endpoint was the delay in progression of high-risk SMM as measured by the 1-year PFS rate. Secondary endpoints included PFS, safety, antibodies to siltuximab, and progressive disease indicator rate (PDIR)-defined as proportion of pts with any of the following: progression events, increase in serum M-protein by 25%, unequivocal increase in focal bone lesions, immunoparesis including decrease by 25% compared with baseline of 2 nonaffected immunoglobulins, or decrease in hemoglobin by 1.5 g/dL-at 6 months.

Results: From March 2012-May 2015, 85 pts (43, siltuximab; 42, placebo) were randomized at 33 centers in 9 countries. The 2 groups were generally well balanced in demography and baseline disease characteristics, except for cytogenetic abnormality and ultra-high risk (BMPC ≥60% or free light chain [FLC] ratio ≤0.01 or ≥100). The numbers of pts who met high-risk SMM criteria were similar between the 2 treatment groups. The median age for both groups was 62 years (range: 21-84 years); 57% were men and 85% White. The majority of pts (87%) had a baseline ECOG score of 0 (range: 0-2). After a median follow-up of 29.2 months, there were 32.6% PFS events (14/43 pts) in the siltuximab group and 42.9% (18/42 pts) in the placebo group. The 1-year PFS rate was 84.5% (95%CI: 68.6-92.8) in the siltuximab group and 74.4% (95%CI: 57.3-85.5) in the placebo group. The median PFS was not reached in the siltuximab group but was 715.0 days (95%CI: 490-1232) in the placebo group. In a subgroup analysis of PFS for pts with ultra-high risk SMM, the median PFS was 526 days (95%CI: 117-774) in the siltuximab group and 450 days (95%CI: 89-777) in the placebo group. Of the response-evaluable pts, 13 (30.2%) pts in the siltuximab group and 18 (42.9%) pts in the placebo group met the PDIR criteria. The majority of adverse events (AEs) were of Grade 2 or 3 toxicity, and 1 patient in the siltuximab group and 2 pts in the placebo group reported a grade 5 AE. The most common SAEs were infections and infestations (5 pts in the siltuximab group and 6 pts in the placebo group) and renal and urinary disorders (1 patient in the siltuximab group and 3 pts in the placebo group). Seven pts died during the study: 3 pts in the siltuximab group and 4 pts in the placebo group. In the placebo group, causes of death were ischemia; progression to MM; cardiac arrest; and septic shock (n=1 each). In the siltuximab group, causes of death were pneumonia (n=1) and unknown (n=2).

Conclusion: The results of this study should be interpreted with caution due to the imbalance in the number of pts with cytogenetic abnormalities and ultra-high risk pts in the placebo group at baseline. Although this study did not meet the pre-specified hypothesis that siltuximab would increase the 1-year PFS rate by at least 14%, it does suggest that siltuximab may delay the progression of high-risk SMM.