Angiogenic cytokines profile in smoldering multiple myeloma: No difference compared to MGUS but altered compared to symptomatic myeloma

Background: Symptomatic multiple myeloma (MM) evolves from an asymptomatic precursor state termed monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM). Angiogenesis plays a key role in the pathogenesis of MM but there are very limited data for angiogenesis in SMM. Material/Methods We measured the circulating levels of angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), vascular endothelial growth factor (VEGF), and angiogenin in 54 patients with SMM. The results were compared with those of 27 MGUS patients, 55 MM patients, and 22 healthy controls. The expression of VEGF-A gene was also evaluated in 10 patients with SMM, 10 with symptomatic MM, and 10 with MGUS. Results: The ratio of circulating Ang-1/Ang-2 was reduced in MM patients with symptomatic disease due to a dramatic increase of Ang-2 (p<0.001), but not in patients with SMM or MGUS, in whom it did not differ compared to controls. VEGF and angiogenin were increased in all patients compared to controls. However, circulating VEGF was higher in symptomatic MM compared to SMM and MGUS, while angiogenin was reduced. There were no differences in the expression of VEGF-A among the 3 patients categories. Conclusions: SMM has a circulating angiogenic cytokine profile similar to that of MGUS, but has altered profile compared to symptomatic MM. Thus, in the progression of MGUS to SMM, circulating angiogenic cytokines seem to be the same. On the contrary, in symptomatic myeloma, the alterations of angiopoietins along with VEGF contribute to myeloma cell growth, supporting the target of these molecules for the development of novel anti-myeloma agents

An overview of treatment options for patients with relapsed/refractory multiple myeloma and renal impairment

Renal impairment (RI) is a relatively common complication of multiple myeloma, which increases in frequency as disease becomes more advanced and recovery of renal function becomes less likely as patients progress through lines of therapy. Clinical trials in the relapsed/refractory multiple myeloma (RRMM) setting have not uniformly included patients with RI or robustly reported their outcomes. Here, we review existing data among patients with RI and RRMM across drug classes (including immunomodulatory agents, proteasome inhibitors, monoclonal antibodies, antibody-drug conjugates, chimeric antigen receptor T-cell therapies, and exportin-1 inhibitor) to provide an improved understanding of available treatment options for this important population. We highlight data from pivotal clinical trials, including data relating to renal response (as defined by the International Myeloma Working Group) and discuss real-world experiences in patients with RI, where applicable. Despite substantial advances in RRMM treatment, the presence of RI remains associated with reduced overall survival. Consistent inclusion of patients with RI, and uniform reporting of their outcomes, should be encouraged in future prospective trials of treatments for RRMM

A cost-effectiveness analysis of denosumab for the prevention of skeletal-related events in patients with multiple myeloma in the United States of America

Objective: A large, pivotal, phase 3 trial in patients with newly diagnosed multiple myeloma (MM) demonstrated that denosumab, compared with zoledronic acid, was non-inferior for the prevention of skeletal-related events (SREs), extended the observed median progression-free survival (PFS) by 10.7 months, and showed significantly less renal toxicity. The cost-effectiveness of denosumab vs zoledronic acid in MM in the US was assessed from societal and payer perspectives. Methods: The XGEVA Global Economic Model was developed by integrating data from the phase 3 trial comparing the efficacy of denosumab with zoledronic acid for the prevention of SREs in MM. SRE rates were adjusted to reflect the real-world incidence. The model included utility decrements for SREs, administration, serious adverse events (SAEs), and disease progression. Drug, administration, SRE management, SAEs, and anti-MM treatment costs were based on data from published studies. For the societal perspective, the model additionally included SRE-related direct non-medical costs and indirect costs. The net monetary benefit (NMB) was calculated using a willingness-to-pay threshold of US$150,000. One-way deterministic and probabilistic sensitivity analyses were conducted. Results: From a societal perspective, compared with zoledronic acid, the use of denosumab resulted in an incremental cost of US$26,329 and an incremental quality-adjusted life-year (QALY) of 0.2439, translating into a cost per QALY gained of US$107,939 and a NMB of US$10,259 in favor of denosumab. Results were sensitive to SRE rates and PFS parameters. Limitations: Costs were estimated from multiple sources, which varied by tumor type, patient population, country, and other parameters. PFS and overall survival were extrapolated beyond the follow-up of the primary analysis using fitted parametric curves. Conclusion: Denosumab’s efficacy in delaying or preventing SREs, potential to improve PFS, and lack of renal toxicity make it a cost-effective option for the prevention of SREs in MM compared with zoledronic acid

Autophagy activation can partially rescue proteasome dysfunction-mediated cardiac toxicity.

The ubiquitin-proteasome pathway and its functional interplay with other proteostatic and/or mitostatic modules are crucial for cell viability, especially in post-mitotic cells like cardiomyocytes, which are constantly exposed to proteotoxic, metabolic, and mechanical stress. Consistently, treatment of multiple myeloma patients with therapeutic proteasome inhibitors may induce cardiac failure; yet the effects promoted by heart-targeted proteasome dysfunction are not completely understood. We report here that heart-targeted proteasome knockdown in the fly experimental model results in increased proteome instability and defective mitostasis, leading to disrupted cardiac activity, systemic toxicity, and reduced longevity. These phenotypes were partially rescued by either heart targeted- or by dietary restriction-mediated activation of autophagy. Supportively, activation of autophagy by Rapamycin or Metformin administration in flies treated with proteasome inhibitors reduced proteome instability, partially restored mitochondrial function, mitigated cardiotoxicity, and improved flies' longevity. These findings suggest that autophagic inducers represent a novel promising intervention against proteasome inhibitor-induced cardiovascular complications