A safety review of recently approved and emerging drugs for patients with relapsed or refractory multiple myeloma.

INTRODUCTION: Multiple new drugs have been approved over the past 5 years for the treatment of relapsed/refractory multiple myeloma (RRMM), and these are being increasingly widely used. Clinicians need to familiarize themselves with common toxicities associated with these drugs and with novel toxicities requiring specific management and supportive care. AREAS COVERED: We review common toxicities associated with agents approved for RRMM in the past 5 years, including the anti-CD38 monoclonal antibody isatuximab, the antibody-drug conjugate belantamab mafodotin, the bispecific antibody teclistamab, the chimeric antigen receptor (CAR) T cell products idecabtagene vicleucel and ciltacabtagene autoleucel, the selective inhibitor of nuclear export compound selinexor, and the drug-peptide conjugate melflufen, as well as toxicities associated with emerging agents for RRMM including additional bispecific antibodies, the BCL-2 inhibitor venetoclax, and the cereblon E3 ligase modulators iberdomide and mezigdomide. We searched the published literature using PubMed, plus congress abstracts, for the above list of drug names or classes and 'myeloma.' EXPERT OPINION: Optimal management of toxicities associated with these recently approved and emerging therapies will be critical in maximizing clinical benefit and aiding widespread adoption in routine clinical practice. We summarize current recommendations and guidelines and provide expert insights into supportive care requirements.

Mutations in the alternative complement pathway in multiple myeloma patients with carfilzomib-induced thrombotic microangiopathy.

Thrombotic microangiopathy (TMA) has been reported to occur in multiple myeloma (MM) patients in association with treatment with carfilzomib, an irreversible proteasome inhibitor (PI). The hallmark of TMA is vascular endothelial damage leading to microangiopathic hemolytic anemia, platelet consumption, fibrin deposition and small-vessel thrombosis with resultant tissue ischemia. The molecular mechanisms underlying carfilzomib-associated TMA are not known. Germline mutations in the complement alternative pathway have been recently shown to portend increased risk for the development of atypical hemolytic uremic syndrome (aHUS) and TMA in the setting of allogeneic stem cell transplant in pediatric patients. We hypothesized that germline mutations in the complement alternative pathway may similarly predispose MM patients to carfilzomib-associated TMA. We identified 10 MM patients with a clinical diagnosis of TMA in the context of carfilzomib treatment and assessed for the presence of germline mutations in the complement alternative pathway. Ten, matched MM patients exposed to carfilzomib but without clinical TMA were used as negative controls. We identified a frequency of deletions in the complement Factor H genes 3 and 1 (delCFHR3-CFHR1) and genes 1 and 4 (delCFHR1-CFHR4) in MM patients with carfilzomib-associated TMA that was higher as compared to the general population and matched controls. Our data suggest that complement alternative pathway dysregulation may confer susceptibility to vascular endothelial injury in MM patients and predispose to development of carfilzomib-associated TMA. Larger, retrospective studies are needed to evaluate whether screening for complement mutations may be indicated to properly counsel patients about TMA risk with carfilzomib use.

A retrospective observational study of a low fixed-dose rasburicase protocol for the treatment of tumor lysis syndrome in adults.

INTRODUCTION: Tumor lysis syndrome is an oncologic emergency characterized by hyperuricemia. Previous studies have demonstrated that a fixed-dose strategy of rasburicase is as effective as the FDA approved weight-based dose. Albany Medical Center employs rasburicase 1.5 mg in patients with a uric acid (UA) between 8 and 12 mg/dL and 3 mg for UA above12 mg/dL.We aimed to evaluate the UA lowering effectiveness and provider adherence to the institutional protocol, as well as the cost-efficiency of this dosing strategy. METHODS: This is a single center, retrospective, cohort study. The electronic medical record was used to identify patients receiving rasburicase and to collect baseline demographic and laboratory data. The fixed-dose strategies of rasburicase 1.5 mg and 3 mg were compared in their degree of UA reduction and clinical outcomes. Cost-savings of fixed-dosing was compared to the FDA-approved weight-based dose. RESULTS: Mean UA reduction in the 1.5 mg group (n = 49) from baseline to 24 hours was 2.88 ± 0.88 mg/dL (p < 0.0001) and 4.83 ± 1.39 mg/dL (p < 0.0001) in the 3 mg group (n = 105). A subgroup analysis of patients who received per protocol initial doses of rasburicase showed a mean reduction in UA from baseline to 24 hours of 2.83 ± 0.62 mg/dL in the 1.5 mg group (n = 42) and 6.12 ± 1.87 mg/dL in the 3 mg group (n = 42). Using a low fixed-dose approach resulted in a cost-savings of $138,077.30 annually. CONCLUSION: Low fixed-dose rasburicase was an effective treatment, with a dose of 1.5 mg being sufficient to reach a goal UA of less than 8 mg/dL for serum UA levels below 12 mg/dL, while a 3 mg dose is appropriate for levels above 12 mg/dL. Cost analysis indicates this strategy is more cost-efficient than the FDA-approved weight-based dose.

Impact of COVID-19 pandemic on training of pharmacy residents and fellows: Results from a national survey of postgraduate pharmacy trainees.

PURPOSE: The coronavirus disease 2019 (COVID-19) pandemic has impacted the activities of healthcare workers, including postgraduate pharmacy trainees. Quality training experiences must be maintained to produce competent pharmacy practitioners and maintain program standards. METHODS: A cross-sectional survey of postgraduate pharmacy trainees in the United States was conducted to evaluate training experience changes and assess perceived impacts on residents and fellows following the COVID-19 pandemic's onset. RESULTS: From June 4 through June 22, 2020, 511 pharmacy trainees in 46 states completed the survey. Participants' median age was 26 (interquartile range [IQR], 25-28) years, with included responses from postgraduate year 1 residents (54% of sample), postgraduate year 2 residents (40%), and postgraduate fellows (6%). Compared to experiences prior to the onset of the COVID-19 pandemic, fewer trainees conducted direct patient care (38.5% vs 91.4%, P < 0.001), more worked from home (31.7% vs 1.6%, P < 0.001), and less time was spent with preceptors per day (2 [IQR, 2-6] hours vs 4 [IQR, 1-4] hours, P < 0.001). Sixty-five percent of respondents reported experiencing changes in their training program, 39% reported being asked to work in areas outside of their routine training experience, and 89% stated their training shifted to focus on COVID-19 to some degree. Most respondents perceived either major (9.6%) or minor (52.0%) worsening in quality of experience, with major and minor improvement in quality of experience reported by 5.5% and 8.4% of respondents, respectively. CONCLUSION: Pharmacy resident/fellow experiences were perceived to have been extensively impacted by the COVID-19 pandemic in varying ways. Our findings describe shifts in postgraduate training and may aid in the development of best practices for optimizing trainee experiences in future crises.

Ultrafast Structural Dynamics of BlsA, a Photoreceptor from the Pathogenic Bacterium Acinetobacter baumannii.

Acinetobacter baumannii is an important human pathogen that can form biofilms and persist under harsh environmental conditions. Biofilm formation and virulence are modulated by blue light, which is thought to be regulated by a BLUF protein, BlsA. To understand the molecular mechanism of light sensing, we have used steady-state and ultrafast vibrational spectroscopy to compare the photoactivation mechanism of BlsA to the BLUF photosensor AppA from Rhodobacter sphaeroides. Although similar photocycles are observed, vibrational data together with homology modeling identify significant differences in the ß5 strand in BlsA caused by photoactivation, which are proposed to be directly linked to downstream signaling.