Department of Hematology-Oncology, Myeloma and Amyloidosis Program, Maroone Cancer Center, Cleveland Clinic Florida, Weston, FL 33331, USA.
Medical University of the Americas, Devens, MA 01434, USA.
Discov Med. 2024 Sep;36(188):1761-1771. doi: 10.24976/Discov.Med.202436188.162.
Systemic light-chain (AL) amyloidosis is a rare and complex clonal plasma cell neoplasm characterized by the production of misfolded and unstable immunoglobulin light-chains leading to multisystem amyloid deposition, which progresses to organ dysfunction and eventual failure. The importance and urgency of AL amyloidosis depends on its potential to induce significant organ impairment, progressive course, risk of life-threatening complications, and the limited treatment options available. Treatment options and prognosis depend on the number and severity of organ involvement at the time of diagnosis with cardiac involvement carrying the worst outcomes. The treatments aim to target eliminating the underlying clonal plasma cell neoplasm and prevent the production and deposition of amyloid precursor immunoglobulin light-chain protein in the affected vital organs. Strategies for treating systemic AL amyloidosis have incorporated anti-plasma cell therapies approved in the management of multiple myeloma due to their shared cellular derivation. Quadruplet therapy of cyclophosphamide, bortezomib, dexamethasone and daratumumab (DaraCyborD) is the currently approved first-line induction therapy for systemic AL amyloidosis. Some patients need upfront autologous hematopoietic stem cell transplantation (HSCT) after high-dose melphalan conditioning particularly if DaraCyborD is not able to achieve complete hematologic response (CHR). Additionally, a promising treatment option involves disassembling amyloid deposits from the vital organs using monoclonal antibodies such as CAEL 101 or Birtamimab with the expectation of restoring damaged tissues of the vital organs affected thereby improving or reversing patients' symptoms. Both CAEL 101 and Birtamimab are currently being tested in phase 3 clinical trials for systemic AL amyloidosis patients with advanced cardiac involvement. This comprehensive review provides an up-to-date overview of AL amyloidosis therapy, with a particular focus on recent advances and future directions of immunotherapeutic strategies.
系统性轻链（AL）淀粉样变性是一种罕见且复杂的克隆性浆细胞肿瘤，其特征是产生错误折叠和不稳定的免疫球蛋白轻链，导致多系统淀粉样沉积，进而导致器官功能障碍和最终衰竭。AL 淀粉样变性的重要性和紧迫性取决于其诱导显著器官损害、进行性病程、发生危及生命并发症的风险以及可用治疗选择有限的能力。治疗选择和预后取决于诊断时器官受累的数量和严重程度，心脏受累的预后最差。治疗旨在靶向消除潜在的克隆性浆细胞肿瘤，并防止受影响重要器官中淀粉样前体免疫球蛋白轻链蛋白的产生和沉积。由于其具有共同的细胞来源，用于多发性骨髓瘤治疗的抗浆细胞疗法已被纳入治疗系统性 AL 淀粉样变性的策略中。环磷酰胺、硼替佐米、地塞米松和达雷木单抗（DaraCyborD）的四联疗法是目前批准的系统性 AL 淀粉样变性一线诱导治疗。一些患者在接受大剂量美法仑预处理后需要进行 upfront 自体造血干细胞移植（HSCT），特别是如果 DaraCyborD 不能达到完全血液学缓解（CHR）的情况下。此外，一种有前途的治疗选择涉及使用单克隆抗体（如 CAEL 101 或 Birtamimab）从重要器官中分解淀粉样沉积物，期望恢复受影响重要器官的受损组织，从而改善或逆转患者的症状。CAEL 101 和 Birtamimab 目前都在进行 3 期临床试验，用于治疗有晚期心脏受累的系统性 AL 淀粉样变性患者。本综述全面介绍了 AL 淀粉样变性的治疗方法，特别关注了免疫治疗策略的最新进展和未来方向。
