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AL amyloidosis (AL) and monoclonal gammopathy of renal significance (MGRS) are both paraprotein-associated diseases. Both entities are based on a monoclonal paraprotein produced by a clonal plasma-cell population like in monoclonal gammopathy of undetermined significance (MGUS) or by a B-cell population like in low grade lymphoma. Per definition MGUS and low-grade lymphoma do not require treatment. But in rare cases the monoclonal M‑gradient acts as a “toxic” protein inducing severe multimodal organ damage as in AL and MGRS. Urgent treatment is indicated in AL and in MGRS to avoid irreparable loss of organ function or death. No treatment is currently approved in Europe for AL or MGRS. On January 15, 2021 the US Food and Drug Administration approved the monoclonal anti-CD38 antibody for treatment of AL. To minimize the serum M‑gradient concentration, a clone directed therapy as in multiple myeloma or B‑cell malignancies treatment regimens can be applied. In AL, an additional treatment option is under investigation. These special drugs are directed against the typical amyloid-fibrils responsible for deposition formation. An additional and important consideration in this special field of rare diseases is the option of organ transplantation in particular kidney transplantation in MGRS. All these treatment modalities are addressed in this article.