Toxicity Profile of Chimeric Antigen Receptor T-Cell and Bispecific Antibody Therapies in Multiple Myeloma: Pathogenesis, Prevention and Management.

Multiple myeloma is the second-most common hematologic malignancy in adults worldwide. Despite ongoing advancement in therapeutic modalities, it remains an incurable disease with a 5-year survival rate of approximately 50%. The recent development and introduction of anti-BCMA immunotherapies into clinical practice, including chimeric antigen receptor T-cell (CAR-T) therapies and bispecific antibodies, has radically shifted the treatment paradigm. However, despite the promising potential of these therapies for broader application, frequent and significant adverse effects have been reported, both in short- and in long-term settings, requiring increasing awareness and vigilance in the treating team, close monitoring, and prompt interventions with a multidisciplinary approach. In this review, we will discuss the toxicities associated with CAR-T cell and bispecific antibody therapies, focusing on results from major clinical studies and real-world observations. In addition, we will emphasize on effective strategies for prevention, monitoring and management, and provide expert recommendations.

'Fast but not so Furious': Short observation time after subcutaneous Daratumumab administration is both a safe and cost-effective strategy.

BACKGROUND: Daratumumab, an anti-CD38 monoclonal antibody, is a key component in the treatment paradigms of multiple myeloma and AL amyloidosis in both the newly diagnosed and relapsed and/or refractory setting. Intravenous (IV) daratumumab administration requires extended infusion times and is associated with higher rates of infusion related reactions (IRRs) when compared to the subcutaneous (SC) formulation. We report real world safety outcomes and infusion chair time savings associated with SC administration in daratumumab naïve patients. METHODS: We retrospectively analyzed medical records at our institution for the incidence and severity of IRRs following differing observation periods post SC daratumumab administration. Infusion chair time was calculated to quantify chair time savings with SC administration. RESULTS: Sixty-six daratumumab naïve patients were included. Nine percent of patients developed IRRs with SC daratumumab with all reactions occurring within six hours of the first dose. All reactions were grade ≤ 2 in severity and were reversible with supportive care. Over the 18 month study period, a total of 904 SC doses were administered, amounting to a potential 1785 hours of infusion chair time savings when compared to IV administration. CONCLUSION: SC daratumumab may be given safely with a short initial observation period and without observation for subsequent doses, resulting in reduced infusion chair time as well as administration related cost and resources.

Vascular endothelial growth factor inhibitor induced hypertension: Retrospective analysis of the impact of blood pressure elevations on outcomes.

BACKGROUND: Vascular endothelial growth factor (VEGF) inhibitors are known to cause hypertension. The purpose of this study was to assess the impact of blood pressure (BP) elevations on outcomes in patients receiving VEGF inhibitors. METHODS: This retrospective chart review analyzed patients receiving treatment with VEGF inhibitors. The primary endpoint was time to progression (TTP) in those with or without significant increase in BP (increase in systolic BP greater than 20 mm Hg or greater than 10 mm Hg increase in diastolic BP). Secondary endpoints included treatment interruption, therapy discontinuation due to documented adverse effect, and time to BP elevation. Subgroup analyses were completed in those receiving bevacizumab and oral tyrosine kinase inhibitors. RESULTS: A total of 155 patients were included and 93 patients (60%) experienced a significant increase in BP. Median time to development of an elevated BP was 47 days. Patients with significant increases in BP had a longer median TTP compared to patients without (8.1 months vs 4.4 months, p = 0.002). No differences were present between groups in treatment interruption or discontinuation due to a documented adverse effect and outcomes were similar in those receiving bevacizumab and oral tyrosine kinase inhibitors. In the analysis of the impact of severity of BP elevations, those with severe BP elevations were more likely to have treatment interrupted but discontinuation rates were similar across groups. CONCLUSION: Development of significant BP elevations may be a marker of therapeutic response to VEGF inhibitors and does not limit treatment duration, even in those with severe elevations.

Embolia Cutis Medicamentosa (Nicolau Syndrome) Secondary to Intramuscular Fulvestrant Injection: A Case Report.

PURPOSE: A case of embolia cutis medicamentosa (Nicolau syndrome) in a patient receiving monthly intramuscular fulvestrant injections is presented. SUMMARY: An 85-year-old woman receiving monthly fulvestrant injections in the outpatient setting developed a necrotic lesion at the fulvestrant injection site on her right buttock. Her medical history is notable for metastatic breast cancer with bone metastases. Prior to developing the necrotic lesion, the patient was receiving monthly fulvestrant injections for 6 years. Other potential causes such as infection and pressure necrosis were ruled out clinically. After 185 days of wound care involving multiple surgical debridements, topical therapy, and frequent follow-up appointments, the patient's wound resolved with 100% epithelialization. Nicolau syndrome has been reported with other non-vesicant, injectable medications such as antibiotics and corticosteroids; however, it has not been previously reported with fulvestrant. CONCLUSION: Nicolau syndrome developed in the right buttock of a patient with metastatic breast cancer following an intramuscular fulvestrant injection. Healthcare practitioners need to be cognizant of this adverse effect with intramuscular injections in order to recognize and refer patients for wound care evaluation early in the evolution of this syndrome. Proper injection technique is recommended to reduce the risk of this idiopathic adverse effect.

Tolerability of Highly Protein Bound Targeted Oral Oncolytic Drugs in Patients With Hypoalbuminemia: A Retrospective Analysis.

BACKGROUND: Hypoalbuminemia is commonly observed in cancer patients. Given the pharmacokinetic interactions between serum proteins and protein bound medications, administration of highly protein bound targeted oral oncolytic drugs may result in elevated unbound drug levels and decreased tolerability in those with hypoalbuminemia. OBJECTIVE: To describe the impact of hypoalbuminemia on oral oncolytic drug tolerability. METHODS: A retrospective study was conducted of adult patients receiving treatment with targeted oral oncolytic drugs with ≥95% protein binding. The primary end point of this study was to compare time to discontinuation resulting from documented toxicity in those with and without hypoalbuminemia. RESULTS: The study included 143 patients receiving 16 targeted oral oncolytic drugs (42% with hypoalbuminemia, 58% without hypoalbuminemia). Adverse events were common, with similar incidence among patients with and without hypoalbuminemia (73% vs 76%, respectively; P = 0.727). Median time to therapy discontinuation resulting from documented toxicity was significantly shorter in those with hypoalbuminemia (22 months vs not reached; P = 0.003). Cox regression demonstrated that hypoalbuminemia was the only significant risk factor for shorter time to discontinuation resulting from documented adverse effects (hazard ratio = 3.0; 95% CI = 1.15-8.0; P = 0.025). CONCLUSION AND RELEVANCE: This represents the first report of the impact of hypoalbuminemia on tolerability of highly protein bound oral oncolytic drugs, demonstrating that patients with hypoalbuminemia may be at increased risk for early discontinuation resulting from toxicity. Given the importance of maintaining dose intensity in patients receiving oncolytic therapy, albumin levels should be monitored throughout treatment and supportive care maximized in those developing hypoalbuminemia.

Trastuzumab/Hyaluronidase-oysk: A New Option for Patients With HER2-Positive Breast Cancer.

OBJECTIVE: To assess the use of subcutaneous trastuzumab/hyaluronidase-oysk (SQ trastuzumab) in comparison to intravenous (IV) trastuzumab. DATA SOURCES: A comprehensive PubMed literature search was performed from August 2012 to August 2019 using search terms Herceptin Hylecta, trastuzumab, hyaluronidase, subcutaneous, preference, safety, efficacy, and cost. STUDY SELECTION & DATA EXTRACTION: English-language clinical trials focusing on SQ trastuzumab were evaluated. DATA SYNTHESIS: In phase III trials, adverse event (AE) rates ranged from 64% to 97.6% of patients receiving SQ trastuzumab in 3 studies compared to 94.6% of patients receiving IV trastuzumab. In the phase III trial comparing SQ trastuzumab to IV trastuzumab, six-year overall survival (OS) was 84% in both groups. In pharmacokinetic analyses, trough concentrations and AUC0-21 were slightly higher in patients receiving SQ trastuzumab and differences were larger at the extremes of body weight. Two pharmacoeconomic analyses reported cost-savings associated with a 52-week treatment cycle of trastuzumab of $2,090 USD and $4,600 USD. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Food and Drug Administration (FDA)-approved in February 2019, SQ trastuzumab, a monoclonal antibody that binds to human epidermal growth factor receptor 2 (HER2) protein in combination with hyaluronidase, offers an alternative dosage form for patients with breast tumors overexpressing HER2. CONCLUSIONS: SQ trastuzumab has a similar safety profile to IV trastuzumab. Although it may be slightly more cost-effective, its role in the treatment of HER2-overexpressing tumors requires further study in those at the extremes of body weight due to differences in drug exposure compared to IV trastuzumab.