Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Siltuximab in High-Risk Smoldering Multiple Myeloma.

PURPOSE: IL6 is important for the growth and survival of myeloma cells. This study evaluated blocking IL6 with siltuximab to delay the transition from high-risk smoldering multiple myeloma (SMM) to multiple myeloma. PATIENTS AND METHODS: In a randomized, double-blind, placebo-controlled, multicenter study, 85 patients with high-risk SMM were randomized to 15 mg/kg siltuximab (43 patients) or placebo (42 patients). The primary endpoint was 1-year progression-free survival (PFS) rate, based on IMWG CRAB criteria. Secondary endpoints included progressive disease indicator rate, PFS, and safety. RESULTS: Median age was 62 years (range: 21-84); 57% were male and 87% had a baseline Eastern Cooperative Oncology Group score of 0. The 1-year PFS rate was 84.5% (siltuximab) and 74.4% (placebo). After a median follow-up of 29.2 months, 32.6% of PFS events occurred with siltuximab and 42.9% with placebo. Median PFS was not reached with siltuximab but was 23.5 months with placebo [HR 0.50 (95% confidence interval, 0.24-1.04); P = 0.0597]. The safety profile of siltuximab was comparable with placebo. Most adverse events in the siltuximab group were grade 2/3; the most common serious adverse events were infections/infestations, and renal/urinary disorders. Mortality was low in both groups (3 deaths in the siltuximab group and 4 in the placebo group). CONCLUSIONS: Although this study did not meet the prespecified protocol hypothesis criteria, data suggest that siltuximab may delay the progression of high-risk SMM.

Economic burden of relapsed or refractory multiple myeloma: Results from an international trial.

OBJECTIVE: The direct cost of relapsed or refractory multiple myeloma (RRMM) is documented; indirect costs are being explored. Healthcare payers seek cost-offsets from therapies that improve clinical outcomes but challenge budgets; employers seek lower absenteeism and better productivity. Study goals were to: (i) identify direct and indirect economic factors of RRMM, and (ii) explore longitudinal relationships between clinical, economic, and health-related quality of life (HRQoL) assessments. METHODS: Economic questionnaire, clinical, and HRQoL data from a multisite, international, randomized, controlled study in RRMM were analyzed. RESULTS: Patients (n=263) were 53.6% male, 91.6% Caucasian; mean age of 62.9 years, median Eastern Cooperative Oncology Group status of 1 (56.3%). Moderate to severe pain or fatigue was reported by 30.4% and 70.6%, respectively. At baseline, ≥1 hospitalization was reported by 107 (41.8%); 182 (71.1%) and 86 (33.6%) reported specialist and family physician visits, respectively. A total of 28 (10.8%) were working: 10 (37.0%) of which reported RRMM-driven absenteeism ≥1 day. Of those who were not working, 110 (48.2%) indicated that it was due to RRMM. Multivariate modeling showed lower hospitalization with a major tumor response (ß=-1.44, CI: -2.89 to 0.01, P=.05). CONCLUSIONS: Substantial RRMM indirect, social costs were observed. Better major tumor response may reduce hospital visits.

A phase 2, randomized, double-blind, multicenter study comparing siltuximab plus best supportive care (BSC) with placebo plus BSC in anemic patients with International Prognostic Scoring System low- or intermediate-1-risk myelodysplastic syndrome.

Interleukin-6 (IL-6) may play an important role in the pathophysiology of anemia of inflammation associated with myelodysplastic syndrome (MDS). This double-blind, placebo-controlled, phase 2 study assessed the efficacy and safety of siltuximab, a chimeric anti-IL-6 monoclonal antibody, in patients with low- and intermediate-1-risk MDS who require transfusions for MDS anemia. Patients were randomized in a 2:1 ratio to siltuximab 15 mg kg(-1) every 4 weeks + best supportive care (BSC) or placebo + BSC for 12 weeks. The primary endpoint was reduction in red blood cell (RBC) transfusions to treat MDS anemia, defined as ≥50% relative decrease and ≥2-unit absolute decrease in RBC transfusions. Fifty and 26 patients were randomized to the siltuximab and placebo groups, respectively. The study did not meet its prespecified hypothesis, with six (12%) patients in the siltuximab group and one (3.8%) in the placebo group having reductions in RBC transfusions (P = 0.271). At the time of the planned futility analysis, the prespecified cutoff criteria were not met, and the study was terminated early due to lack of efficacy. No unexpected safety findings were observed. In conclusion, compared to placebo, treatment with siltuximab did not reduce RBC transfusions in transfusion-dependent patients with low- and intermediate-1-risk MDS. Future studies might explore siltuximab in patients with less iron overload and with elevated IL-6 levels and/or using higher doses for MDS.

A phase 2 multicentre study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with relapsed or refractory multiple myeloma.

Interleukin-6 (IL6) plays a central role in multiple myeloma pathogenesis and confers resistance to corticosteroid-induced apoptosis. We therefore evaluated the efficacy and safety of siltuximab, an anti-IL6 monoclonal antibody, alone and in combination with dexamethasone, for patients with relapsed or refractory multiple myeloma who had ≥ 2 prior lines of therapy, one of which had to be bortezomib-based. Fourteen initial patients received siltuximab alone, 10 of whom had dexamethasone added for suboptimal response; 39 subsequent patients were treated with concurrent siltuximab and dexamethasone. Patients received a median of four prior lines of therapy, 83% were relapsed and refractory, and 70% refractory to their last dexamethasone-containing regimen. Suppression of serum C-reactive protein levels, a surrogate marker of IL6 inhibition, was demonstrated. There were no responses to siltuximab but combination therapy yielded a partial (17%) + minimal (6%) response rate of 23%, with responses seen in dexamethasone-refractory disease. The median time to progression, progression-free survival and overall survival for combination therapy was 4.4, 3.7 and 20.4 months respectively. Haematological toxicity was common but manageable. Infections occurred in 57% of combination-treated patients, including ≥ grade 3 infections in 18%. Further study of siltuximab in modern corticosteroid-containing myeloma regimens is warranted, with special attention to infection-related toxicity.