Discussion
active rheumatoid arthritis, MM, toxicity, cancer, lung infection, toxicities, infections, psychiatric, bone marrow lesions, chronic disease
MULTIPLE MYELOMA, CANCER, LUNG INFECTION, DISEASE, INFECTIONS, RECRUITMENT, ADVERSE EFFECTS, INFLUENZA, CHRONIC DISEASE
We conducted a combined phase I/IIa open label interventional trial designed to evaluate the safety and efficacy of a pegylated liposome formulation of dexamethasone (Dex-PL). We found that a single intravenous infusion of liposomal dexamethasone was well tolerated, both during the infusion and the follow-up study period. Regarding pharmacokinetics, while the type of patients treated IV with Dex-PL was clearly different from the patients in the referenced study on free dexamethasone, the multifold lower Cl and Vd with liposomal dexamethasone are hard to miss, as is the more than tenfold longer half-life (Table The increasing number of treatment options developed during the past decade have turned MM from a cancer with a poor survival outcome into a more chronic disease mostly treated in an outpatient setting in which clinically quieter stages (e.g., under oral maintenance treatment) alternate with relapses that require changes in the (now mostly targeted) treatment strategy. Almost all conventional drug therapies in MM are combinations in which dexamethasone represents an important backbone. Also, in the new targeted combination treatment approaches that involve proteasome inhibitors, immunomodulatory drugs, and/or monoclonal antibodies, dexamethasone retains its place as standard-of-care [Outside the field of cancer, several lines of investigation have been pursued to improve the therapeutic index of systemically administered GC [The most advanced GC nanodrug is pegylated liposomal prednisolone, which was recently shown to improve efficacy over GC standard-of-care in a large cohort of patients with active rheumatoid arthritis [Although the current dataset is limited, we believe the results presented here support the hypothesis that long-circulating liposomes are safe and (pending confirmation in follow up trials) may provide for a favorable tolerability of dexamethasone therapy in MM. Among the most interesting findings are the changes in pharmacokinetic behavior of the GC conferred by liposomal encapsulation. Interestingly, the enormously increased area under the curve (AUC) does not seem translate in high systemic activity, suggested by the limited number of adverse effects observed. Possible steroid-related psychiatric and nervous system-related side effects were seen in one patient. These side effects mostly resolved in the weeks after treatment. With regard to infections, it is noteworthy that although a moderate lung infection and a mild influenza were reported, these resolved and were judged as not related by the investigator.The observation that a multifold larger AUC does not lead to marked and substantial systemic dexamethasone effects corroborates the assumption that dexamethasone largely remains in its inactive phosphate prodrug form, safely encapsulated in the liposomes, limiting systemic exposure. At the same time, the high plasma concentrations may result in high drug concentrations at target sites, because MM bone marrow lesions are characterized by increased micro-vessel density, permeability, and by ongoing angiogenesis, which could render the target tissue directly accessible to the liposomes [An obvious limitation of this study is the small number of patients due to the premature closing of the trial. The study protocol intended a higher number of patients with higher and also repeated doses of dexamethasone. Unfortunately, recruitment into the study became increasingly difficult. When the study was planned, only lenalidomide and bortezomib were widely available. Finally, when the study was running, several more and well-tolerated drugs had been approved for the treatment of multiple myeloma, making inclusion into a study with dexamethasone monotherapy difficult.The administration of liposomal dexamethasone up to a single dose of 40 mg seems safe and led to extended circulating drug levels, and no dose-limiting toxicities were observed yet. The levels of circulating free active drug were low. There appeared to be a dose-dependent pharmacological effect, as 40 mg of Dex-PL lead to disease stabilization in 4 out of 4 patients at week 4, while 10 mg of Dex-PL resulted in progressive disease in 3 out of 3 patients. Further studies are needed to investigate higher doses, to characterize side effects as well as to identify of the dose-limiting toxicity, and above all to obtain evidence for improved efficacy. Possibly, liposomal dexamethasone can serve as a combination formulation in many drugs regimens in the future, with higher drug concentrations in the bone marrow and fewer side effects due to lower systemic exposure. All in all, this first-in-man MM patient study may provide a stepping stone to future studies in which this potentially safer form of dexamethasone is explored alongside other and newer MM drug combinations.