Clinical development of siltuximab.

Siltuximab is a chimeric monoclonal antibody targeting interleukin-6 (IL-6), which in the fall of 2014 became the first FDA-approved treatment of the rare disease idiopathic multicentric Castleman's disease (MCD). MCD is a non-clonal lymphoproliferative disorder in which common symptoms include fever, night sweats, weight loss, and fatigue. Symptoms are driven by an overall hypercytokinemia, predominantly IL-6. While under clinical development, siltuximab was studied in several other disease states including multiple myeloma, non-Hodgkin lymphomas, and several solid tumors in which it did not demonstrate significant benefit. The efficacy of siltuximab in MCD is mainly confined to systemic symptomatic response and quality of life benefits with minimal complete responses and approximately 30 % partial responses, by radiographic criteria. Siltuximab treatment therefore is important in the overall treatment of this rare disease state. This review focuses on the clinical development and pharmaceutical approval of siltuximab.

Safety of proteasome inhibitors for treatment of multiple myeloma.

INTRODUCTION: Proteasome inhibitors (PIs) have revolutionized the treatment of multiple myeloma and are a backbone of therapy. Bortezomib, the first PI approved, has shown efficacy in both front-line and relapsed/refractory settings however the development of resistance and side effects such as peripheral neuropathy can limit its use. The second generation PIs carfilzomib and ixazomib, both approved in relapsed/refractory cases, may help to overcome resistance mechanisms and increase tolerability. While bortezomib is approved to be administered intravenously (IV) or subcutaneously (SC) and carfilzomib IV, ixazomib is the first and only approved PI that is orally bioavailable. Areas covered: This review focuses on the safety data from clinical trials for the three approved PIs and how to manage adverse effects. A summary of efficacy data from select clinical trials is also included. Expert commentary: Targeting the proteasome/ubiquitin system is a validated and important part of current anti-myeloma therapy. The availability of an oral proteasome inhibitor without significant neuropathy as a side effect offers patients an important step forward over their treatment.

Efficacy and tolerability of anthracycline-based therapy in elderly patients with diffuse large B-cell lymphoma.

INTRODUCTION: Although diffuse large B-cell lymphoma (DLBCL) can be cured with rituximab and anthracycline-based therapy, within the elderly population there are additional factors to consider in selecting a treatment regimen including comorbid conditions, decreased drug metabolism, decreased hematologic reserve, reduced performance status, and regimen-related toxicity. PATIENTS AND METHODS: We performed a retrospective cohort analysis of patients with DLBCL aged ≥ 65 years at time of diagnosis treated with either an anthracycline-containing regimen (ACR; n = 59) or a non-ACR (n = 13) to assess factors that led to treatment selection, tolerability, and outcomes. RESULTS: The mean age was 73 years in the ACR and 77 years in the non-ACR group (P = .009), and median left ventricular ejection fraction (LVEF) at diagnosis was 60% in the ACR group and 45% in the non-ACR group (P < .001). With an ACR, elderly DLBCL patients had a median overall survival of 28 months and a 2-year progression-free survival (PFS) of 64%. After an ACR, 14 patients [24%] (out of 59 total patients) had a decrease in LVEF, 7 patients [15%] (% is based off of those who we had the data collected, so this is out of 45 with this specific data) required a dose reduction of the anthracycline, and 15 patients [33%] (% is based off of those who we had the data collected, so this is out of 45 with this specific data) could not complete the regimen as planned. Hospitalization due to toxicity occurred in 20 patients [44%] (% is based off of those who we had the data collected, so this is out of 45 with data) of patients in the ACR group and 3 patients [75%] (% is based off of those who we had the data collected, so this is out of 4 with this specific data) in the non-ACR group, and was the only predictor of overall survival. CONCLUSION: Results of this study suggest that elderly patients with DLBCL experience meaningful PFS with ACRs, but a third experience toxicity requiring therapy modification. Future studies should examine larger patient populations and define treatments with outcomes similar to ACR that also decrease toxicity and hospitalization in the elderly DLBCL population.