Background: In light-chain amyloidosis (AL), amyloid deposits cause disruption of organ function. High-dose chemotherapy with melphalan (HD) followed by autologous stem cell transplantation (ASCT) is considered the most effective therapy for AL, if tolerable. Recently, the Andromeda study demonstrated high response rates and long PFS without ASCT in AL. In AL, the biology of AL plasma cell dyscrasia varies widely. Both MM and MGUS, which can be biologically and genetically distinct, can be the cause of symptomatic AL and may warrant different therapeutic strategies. Only half of AL cases classify as myeloma with bone marrow plasma cells (BMPC) >10% and (SLiM-)CRAB criteria. Although high BMPC infiltration is associated with inferior therapy outcomes, clinical information are lacking whether patients with less than 10% BMPC equally benefit from ASCT or if less toxic approaches can be performed without decreasing efficacy. Methods: We retrospectively analyzed 150 patients from our institution with biopsy-proven systemic MGUS/MM derived AL amyloidosis diagnosed and treated between January 1, 2006 and June 30, 2023. 62 patients had BMPC >10% and 17 patients were excluded due to unknown bone marrow infiltration. Overall, we identified 71 patients with <10% BMPC and/or negative (SLiM-)CRAB criteria. To correlate therapy with clinical outcome, we divided this cohort based on treatment into two groups of patients that had received ASCT vs. patients treated without ASCT. All patients treated with ASCT had a cumulative melphalan dose of at least 140 mg/m². Non-HD therapies consisted of combinations with alkylators, CD38 moAbs, IMiDs, proteasome inhibitors and steroids. High-risk cytogenetics were assessed according to current IMWG criteria. Results: 21 (29.6 %) out of the 71 patients with <10% BMPCs received ASCT and 50 (70.4 %) were treated without ever receiving HD. 18 out of those received at least three cycles of Daratumumab containing regimen. Both groups were comparable with a medium BMPC infiltration of 5.4 and 4.7% and mainly exhibited lambda phenotype (81 and 70%, respectively). FISH analysis was available in 34 of them (47.9%) with t(11;14) in 80% of all cases and del13q14 in 40% as most common alterations. We identified a high-risk phenotype (del17p and gain1q) in 30% in patients receiving ASCT and in 19% of patients without. ECOG status at diagnosis was significantly lower (0.71 vs. 1.1) in the ASCT population compared to no ASCT and patients receiving HD were younger (mean age 57 vs. 66 years). Median PFS was 68 months for patients that received HD vs. 61 months for patients without HD and did not differ significantly between the two groups (p = 0.67) at a median follow- up of 33.5 months. Interestingly, the 18 patients treated with DaraVCd had a PFS of 100%, but at a comparably low median follow-up of 12.5 months, significantly surpassing ASCT in this population. However, the number of Daratumumab-based therapies in the ASCT population was low (n = 5). Conclusion: In a low risk population defined by <10% BMPC, patients treated with HD melphalan did not show a statistical PFS difference when compared to patients treated without ASCT. Acknowledging the fact that only a minor subset of our ASCT-treated patients received Dara, our data still provide evidence that less aggressive therapy omitting ASCT may be a resonable strategy for biologically low-risk AL.