Challenges in the management of patients with systemic light chain (AL) amyloidosis during the COVID-19 pandemic

Summary: The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)‐associated coronavirus disease 2019 (COVID‐19) is primarily manifested as a respiratory tract infection, but may affect and cause complications in multiple organ systems (cardiovascular, gastrointestinal, kidneys, haematopoietic and immune systems), while no proven specific therapy exists. The challenges associated with COVID‐19 are even greater for patients with light chain (AL) amyloidosis, a rare multisystemic disease affecting the heart, kidneys, liver, gastrointestinal and nervous system. Patients with AL amyloidosis may need to receive chemotherapy, which probably increases infection risk. Management of COVID‐19 may be particularly challenging in patients with AL amyloidosis, who often present with cardiac dysfunction, nephrotic syndrome, neuropathy, low blood pressure and gastrointestinal symptoms. In addition, patients with AL amyloidosis may be more susceptible to toxicities of drugs used to manage COVID‐19. Access to health care may be difficult or limited, diagnosis of AL amyloidosis may be delayed with detrimental consequences and treatment administration may need modification. Both patients and treating physicians need to adapt in a new realit

Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis

PURPOSE: Oral melphalan and dexamethasone (MDex) were considered a standard of care in light-chain (AL) amyloidosis. In the past decade, bortezomib has been increasingly used in combination with alkylating agents and dexamethasone. We prospectively compared the efficacy and safety of MDex and MDex with the addition of bortezomib (BMDex). METHODS: This was a phase III, multicenter, randomized, open-label trial. Patients were stratified according to cardiac stage. Patients with advanced cardiac stage (stage IIIb) amyloidosis were not eligible. The primary end point was hematologic response rate at 3 months. This trial is registered with ClinicalTrials.gov identifier NCT01277016. RESULTS: A total of 109 patients, 53 in the BMDex and 56 in the MDex group, received ≥ 1 dose of therapy (from January 2011 to February 2016). Hematologic response rate at 3 months was higher in the BMDex arm (79% v 52%; P = .002). Higher rates of very good partial or complete response rates (64% v 39%; hazard ratio [HR], 2.47; 95% CI, 1.30 to 4.71) and improved overall survival, with a 2-fold decrease in mortality rate (HR, 0.50; 95% CI, 0.27 to 0.90), were observed in the BMDex arm. Grade 3 and 4 adverse events (the most common being cytopenia, peripheral neuropathy, and heart failure) were more common in the BMDex arm, occurring in 20% versus 10% of cycles performed. CONCLUSION: BMDex improved hematologic response rate and overall survival. To our knowledge, this is the first time a controlled study has demonstrated a survival advantage in AL amyloidosis. BMDex should be considered a new standard of care for AL amyloidosis

Outcome of Patients With Newly Diagnosed Systemic Light-Chain Amyloidosis Associated With Deletion of 17p

We analyzed 44 patients with newly diagnosed systemic light-chain amyloidosis (AL) and del 17p, a rare finding in AL. Predictors of overall and progression-free survival were cardiac involvement at diagnosis and hematologic response to therapy, respectively. Median survivals of patients with > 50% and ≤ 50% del 17p plasma cells were 28 and 52 months (P =.08). Introduction: Deletion 17p (del 17p) portends a poor prognosis in myeloma, but its significance in light-chain amyloidosis is unknown. Patients and Methods: We identified patients with light-chain amyloidosis and del 17p at diagnosis, and analyzed presenting characteristics, treatments, and clinical outcomes. All had baseline biopsy results showing amyloid and serologic and marrow studies, including standard fluorescence in-situ hybridization determinations of del 17p using commercial probes. Consensus criteria for hematologic and organ involvement, progression, and response were used. Kaplan-Meier (log rank) analyses and Cox regression analysis of baseline variables were used to identify predictors of overall and progression-free survival (PFS). Six-month landmark analyses were performed to assess the impact of treatment-related variables. Results: We identified 44 patients from 7 countries with median marrow and del 17p plasma cells of 22% (range, 3%-100%) and 30% (2%-93%). Ninety-five percent had cardiac involvement, including 44% stage III. Two-thirds of the patients initially received bortezomib-based therapy. Forty-nine percent of patients experienced complete response or very good partial response, with median time to best response of 4 months (range, 1-28 months). Median overall survival and PFS were 49 and 32 months. Cardiac stage and hematologic response were the key predictors of outcomes. Patients with > 50% and ≤ 50% del 17p in clonal plasma cells had median survivals of 28 and 52 months, respectively (P =.08). In landmark analyses, only hematologic response predicted both overall survival and PFS. Conclusion: Cardiac stage, hematologic response, and del 17p percentage impact outcomes in these cases. Emphasis should be placed on optimizing supportive care and achieving a deep hematologic response

Thalidomide, dexamethasone and lovastatin with autologous stem cell transplantation as a salvage immunomodulatory therapy in patients with relapsed and refractory multiple myeloma

The treatment of patients with multiple myeloma usually includes many drugs including thalidomide, lenalidomide and bortezomib. Lovastatin and other inhibitors of HMG-CoA reductase demonstrated to exhibit antineoplasmatic and proapoptotic properties in numerous in vitro studies involving myeloma cell lines. We treated 91 patients with relapsed or refractory multiple myeloma with thalidomide, dexamethasone and lovastatin (TDL group, 49 patients) or thalidomide and dexamethasone (TD group, 42 patients). A clinical response defined of at least 50% reduction of monoclonal band has been observed in 32% of TD patients and 44% of TDL patients. Prolongation of overall survival and progression-free survival in the TDL group as compared with the TD group has been documented. The TDL regimen was safe and well tolerated. The incidence of side effects was comparable in both groups. Plasma cells have been cultured in vitro with thalidomide and lovastatin to assess the impact of both drugs on the apoptosis rate of plasma cells. In vitro experiments revealed that the combination of thalidomide and lovastatin induced higher apoptosis rate than apoptosis induced by each drug alone. Our results suggest that the addition of lovastatin to the TD regimen may improve the response rate in patients with relapsed or refractory myeloma

Pegylated Liposomal Doxorubicin plus Bortezomib in Relapsed or Refractory Multiple Myeloma: Efficacy and Safety in Patients with Renal Function Impairment

A retrospective analysis was undertaken of patients (n = 193) with renal insufficiency (creatinine clearance [CrCl] < 60 mL/min) from a phase III trial comparing bortezomib +/- pegylated liposomal doxorubicin (PLD) in relapsed/refractory myeloma (n = 646). The response rate (49% vs. 42%) and median time to disease progression (331 days vs. 199 days) were comparable or slightly better for patients with renal insufficiency treated with PLD/bortezomib compared with patients treated with bortezomib alone. There was a steady, clinically meaningful improvement in renal function for patients with renal insufficiency in both treatment arms. However, patients with impaired renal function were at a slightly increased risk of a drug-related serious adverse event (28% vs. 19% for CrCl < 60 and ! 60 mL/min, respectively)

Challenges in the management of patients with systemic light chain (AL) amyloidosis during the COVID‐19 pandemic

Summary: The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)‐associated coronavirus disease 2019 (COVID‐19) is primarily manifested as a respiratory tract infection, but may affect and cause complications in multiple organ systems (cardiovascular, gastrointestinal, kidneys, haematopoietic and immune systems), while no proven specific therapy exists. The challenges associated with COVID‐19 are even greater for patients with light chain (AL) amyloidosis, a rare multisystemic disease affecting the heart, kidneys, liver, gastrointestinal and nervous system. Patients with AL amyloidosis may need to receive chemotherapy, which probably increases infection risk. Management of COVID‐19 may be particularly challenging in patients with AL amyloidosis, who often present with cardiac dysfunction, nephrotic syndrome, neuropathy, low blood pressure and gastrointestinal symptoms. In addition, patients with AL amyloidosis may be more susceptible to toxicities of drugs used to manage COVID‐19. Access to health care may be difficult or limited, diagnosis of AL amyloidosis may be delayed with detrimental consequences and treatment administration may need modification. Both patients and treating physicians need to adapt in a new realit