Intermediate Dose Intravenous Melphalan and Dexamethasone Treatment in 144 Patients with Systemic AL Amyloidosis.

The optimal intensity of chemotherapy in AL amyloidosis remains contentious. Traditional low dose oral melphalan and prednisolone therapy is ineffective in most patients, whereas high dose therapy with autologous stem cell rescue carries substantial procedure related mortality. We report here the outcome of intermediate dose intravenous melphalan (IDM) (25mg/m² d1 + dexamethasone 20mg po d1-4, repeated every 21-28d) among 144 patients with amyloidosis (83M:61F, median age 62yrs, range 30–79). The median number of organs involved by amyloid was 2, including kidneys in 74% of patients, heart in 56%, neuropathy in 25% and liver in 20%. Median follow-up was 13mo (0.5–53). Patients received a median of 3 cycles of treatment (range 1–8). Dexamethasone was omitted in 51 cases, principally due to concern about fluid retention associated with nephrotic syndrome or cardiac amyloidosis. There were 52 deaths of which 3 (2%) were considered treatment-related (1 neutropenic sepsis, 2 dexamethasone-induced pulmonary oedema). Serum free light chain (sFLC) measurements were available before and after at least one cycle of IDM in 140 patients; 23% achieved complete response (CR, sustained normalization of sFLC ratio), 31% a partial response (PR, sustained >50% reduction in pre-treatment clonal isotype) and 46% did not respond (NR). Rates of sFLC CR+PR were higher among patients who also received dexamethasone at 64% vs 37% (p<0.0004). Paraproteins were detectable by electrophoresis and immunofixation of serum and/or urine in 115pts (80%); 85 of these pts had post-treatment data, showing CR (complete resolution of serum and urine paraprotein) in 17 (20%), PR (50% reduction) in 24 (28%) and NR in 44 (52%). Cycle by cycle assays of sFLC allowed rapid assessment of early clonal response, which was evident within 2 cycles in almost all responders. Maximal response was usually achieved by the fourth cycle. Median survival was 44 months among patients with CR or PR, and 18 months among non-responders (p<0.003). Amyloidotic organ dysfunction improved in 14%, remained stable in 51%, and deteriorated in 19% of evaluable cases. The findings support the use of IDM coupled with cycle by cycle sFLC measurements as a valid treatment strategy in patients with AL amyloidosis. Although clonal response rates in this series may be lower than selected patients treated with high dose therapy and autologous stem cell rescue, IDM can be delivered to a wider range of patients, in whom the rapidity of its action, relative simplicity of the regimen, and much lower treatment related mortality favor its continued use and further investigation.