Therapeutic approach to systemic AL amyloidosis. Indications on the therapeutic approach to AL amyloidosis mostly derive from uncontrolled studies. Treatment should be risk adapted. At our center, 14% of patients are low risk and transplant eligible, 42% are intermediate risk, and 44% are high risk. Of the potential ASCT candidates, 80% receive frontline CyBorD. Patients with more than 10% bone marrow plasma cell infiltrate benefit most from induction before ASCT. Post-transplant treatment with bortezomib increases the rate of CR. Characteristics of the amyloidogenic plasma cell clone can guide the choice of chemotherapy: Patients with t(11;14) have a poorer outcome with bortezomib-based therapy, whereas MDex had a worse performance in subjects with gain of 1q21, and BMDex seems superior to MDex and CyBorD in subjects with elevated (>180 mg/L) dFLC. High-risk patients do not tolerate full-dose therapy. These patients should receive low-dose combinations. Low-dose weekly (0.7-1.0 mg/m²) bortezomib is preferred in this setting because of its rapid action. Young patients with isolated advanced cardiac involvement can be considered for heart transplant followed by ASCT. BDex, bortezomib dexamethasone; BMPC, bone marrow plasma cell; DLCO, lung diffusion of CO; EF, ejection fraction; MEL, melphalan; NYHA, New York Heart Association; PS, performance status by Eastern Cooperative Oncology Group; sBP, systolic blood pressure. Stage is standard Mayo Clinic cardiac stage. Stage IIIb is defined as stage III with NT-proBNP level higher than 8500 ng/L.