QT Interval Effects and M-Protein Response in a Phase 1 Study of Siltuximab (Anti-IL-6 Monoclonal Antibody) in Patients with Monoclonal Gammopathy of Undetermined Significance, Smoldering Multiple Myeloma, or Indolent Multiple Myeloma.

Siltuximab is a chimeric monoclonal antibody that binds human interleukin (IL)-6 with high affinity. Formal assessments of siltuximab's effects on cardiac repolarization using triplicate electrocardiograms (ECGs) have not yet been performed in clinical studies. A phase 1 study was conducted to evaluate the effect of siltuximab, administered at the highest dose level used in clinical studies, on the QT interval in patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or indolent multiple myeloma (IMM, i.e., asymptomatic MM with ≤3 lytic bone lesions but no other end organ damage).

Thirty patients with MGUS, SMM, or IMM who met the following criteria on ECG at screening: pulse 45−90 bpm, QTcF and QTcB ≤500 ms, QRS <100 ms, and PR <200 ms received siltuximab 15 mg/kg q3w as a 60 min IV infusion for 4 cycles. Patients were excluded for significant cardiac disease. ECGs and pharmacokinetics assessment were performed at Cycle 1 (pre-infusion [baseline]; end of infusion; and 1, 3, and 24 hrs post-infusion) and at Cycle 4 (pre-infusion, end of infusion, and 1 hr post-infusion). At all timepoints, triplicate 12-lead ECGs were conducted and evaluated by a central cardiology laboratory. No effect on QTc interval was concluded if the upper limit of the least square (LS) mean 90% confidence interval (CI) for the change from baseline QTc at each time point was <20 ms. Safety data were also collected. Preliminary assessment of clinical activity was performed using M-protein measurements from local laboratories. Patients achieving a 50% reduction from baseline in M-protein after 4 cycles were eligible for extended siltuximab therapy (15 mg/kg q4w).

Thirty patients (14 MGUS, 15 SMM, 1 IMM) with median age 59.5 (range 24, 79) yrs were enrolled. Median serum protein electrophoresis was 1.21 (range 0, 5.4) g/dL, and median urine protein electrophoresis was 0 (range 0, 267) mg/24 hrs.

Twenty-eight patients completed all 4 treatment cycles, among whom 27 were evaluable for the primary endpoint of QT interval assessment. The maximum mean increase in QTc from baseline occurred 3 hrs after the Cycle 1 infusion (QTcF = 3.2 ms [LS mean 90% CI −0.01, 6.45]; QTcB = 2.7 ms [LS mean 90% CI −0.69, 6.14]). At all other time points for both QTcF and QTcB, the mean increase from baseline was ≤1.5 ms and the upper limit of LS mean 90% CI was ≤5.07 ms. An effect of siltuximab on QTc interval was therefore ruled out. Furthermore, no patient had a QTcF or QTcB increase from baseline >30 ms, and no correlation was observed between siltuximab serum concentrations and change from baseline in QTcB or QTcF.

Twenty (67%) of 30 treated patients had ≥1 adverse events (AEs). AEs reported by ≥10% of patients were nausea, fatigue (20% each); thrombocytopenia, headache (each 13%); dyspnea, leukopenia, neutropenia, paraesthesia, and upper respiratory tract infection (each 10%). The majority of AEs were grade ≤2. However, 8 (27%) patients had ≥1 AE grade ≥3: neutropenia (n=3); hypertriglyceridemia, hypertension, hypotension, leukopenia, and myalgia (each n=1); and 1 patient had grade 3 ascites, cellulitis, peripheral edema, portal hypertension, and hepatic cirrhosis (diagnosis made during hospitalization). This patient discontinued treatment due to cellulitis (possibly related to siltuximab) with peripheral edema and ascites (not related to siltuximab). A second patient discontinued treatment due to grade 2 atrial fibrillation that was not related to siltuximab. No severe infusion reactions or deaths were reported.

After the first 4 cycles (3 mos), 3 MGUS patients achieved an M-protein response (≥50% reduction from baseline), and 9 patients (3 MGUS, 5 SMM, 1 IMM) had minor responses (≥25% and <50% reduction from baseline). Two patients who qualified for extended treatment with siltuximab continued to receive therapy (17 and 6 cycles, respectively) at the time of database lock.

Siltuximab, given at the highest dose level used in clinical studies, did not affect the QTc interval. Overall safety was similar to what has been previously reported for other single-agent siltuximab studies. M-protein responses were seen by local laboratory assessment within the first 4 cycles. A randomized phase 2 study is ongoing to further evaluate the efficacy and safety of single-agent siltuximab in high-risk SMM.

Thomas:Millenium: Research Funding; Novartis: Research Funding; Immunomedics: Research Funding; Johnson & Johnson: Research Funding; Celgene: Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees. van de Velde:Johnson & Johnson: Employment, Equity Ownership. Bandekar:Johnson & Johnson: Employment, Equity Ownership. Puchalski:Johnson & Johnson: Employment, Equity Ownership. Qi:Johnson & Johnson: Employment, Equity Ownership. Uhlar:Johnson & Johnson: Employment, Equity Ownership.