Upfront treatment algorithm for AL amyloidosis. At our center, the first step in the design of the therapeutic strategy is assessing eligibility for ASCT. However, the role of ASCT in AL amyloidosis is not supported by controlled trials and is challenged by the availability of very effective treatments like Dara-CyBorD. Yet, large long-term outcome studies, which are lacking for newer combinations, show that ASCT grants long-lasting responses with a prolonged improvement in survival.⁴⁰ At our center, eligibility for stem cell transplant with full dose (200 mg/m²) melphalan requires the following: age <70 years, Eastern Cooperative Oncology Group performance status <2, NT-proBNP <5000 ng/L, troponin T <60 ng/L, left ventricular ejection fraction > 45%, New York Heart Association class <III, systolic blood pressure ≥100 mm Hg, glomerular filtration rate >50 mL/min unless on dialysis, bilirubin <2 mg/dL, and diffusing capacity of the lungs for carbon monoxide >50%. At some referral centers, including ours, transplant is performed only in patients who are eligible for full-dose melphalan.⁴² Eligibility can be extended with a risk-adapted conditioning dose of melphalan (100-140 mg/m²).¹⁰⁴ However, there is no evidence that reduced-dose melphalan is better than bortezomib-based chemotherapy, and this approach is even more challenged by newer powerful nontransplant regimens.^44,105 Induction should be performed with Dara-CyBorD. If daratumumab is not yet available, CyBorD can be used. In subjects who have contraindications to bortezomib (eg, peripheral neuropathy), daratumumab-based induction without bortezomib may be considered, or ASCT can be performed upfront. In some cases, a satisfactory response (CR or VGPR, accompanied by organ response) can be achieved after induction alone. In these cases, treatment can be discontinued, and close monitoring initiated to detect hematologic relapse before this causes progression of organ involvement. This sequential approach reduces treatment-related mortality to less than 1% and allows fully exploiting modern powerful regimens in transplant-eligible patients.^45-47 This approach is adopted at some referral centers, but it is not supported by controlled studies. If patients achieve less than a satisfactory response after ASCT, consolidation with bortezomib may improve the outcome.¹⁰⁶ Dara-CyBorD is a new standard of care for patients who do not undergo ASCT. In patients who are potentially eligible for transplantation, melphalan should be avoided. In elderly individuals, BMDex may be considered. Patients with contraindications to bortezomib can be treated with MDex. Patients with advanced cardiac involvement (stage IIIb) should start bortezomib based treatment immediately, with attenuated dosages and under close medical control. Cardiac transplant may be considered. Dara-CyBorD, daratumumab, cyclophosphamide, bortezomib, and dexamethasone; OR, organ response.