Clinical Profile and Treatment Outcome in 92 Patients with AL Amyloidosis Associated with IgM Paraproteinaemia.
Authors: Wechalekar Ashutosh D. , Goodman Hugh J.B. , Gillmore Julian D. , Lachmann Helen J. , Offer Mark , Bradwell Arthur R. , Hawkins Philip N. 
Published: April 2020

Most patients with AL amyloidosis (AL) have a subtle underlying plasma cell dyscrasia but IgM paraproteinaemia is rare. IgM paraproteinaemia is usually associated with low grade non-Hodgkins lymphoma (NHL) or lymphoplasmacytic lymphoma (LPL)/Waldenstroms macroglobulinaemia(WM) and only rarely with a plasma cell dyscrasia. The profile of AL amyloidosis associated with IgM paraproteinaemia remains poorly studied and the treatment outcome is not well known. We report the clinical profile and outcome of 92 patients with IgM associated AL amyloidosis seen at the National Amyloidosis Centre, UK. Patients were selected by the presence of an IgM paraprotein and absence of any other monoclonal protein in the serum or urine by electrophoresis or immunofixation. There were 68 males and 34 females with a median age 69 yrs (range 50–89). The underlying diseases were WM/LPL in 25 (28%), non specified low grade NHL in 17 (18%), myeloma, non-specified MGUS and CLL in 2 (2.1%) each and uncharacterized in the rest. The median number of organs involved was 2, including renal 56%, heart 32%, liver 41%, lymph nodes 16%. Amyloid was localized only to lymph nodes in 5 (5.5%) patients. The median IgM level was 9g/l (range immunofixation positive to 60g/l). The median follow-up was 19mo (2.4–186).

A total of 83 patients received chemotherapy. All patients were evaluable for survival but only 60% were evaluable for haematological response. Responses were defined as complete response (CR) - sustained normalisation of sFLC (serum free light chains) ratio, partial response (PR) - sustained ≥50% reduction in pre-treatment clonal isotype and no response - &lt;50% sFLC reduction or rise in sFLC. The treatments were: oral chlorambucil 18 (19.5%), intermediate dose melphalan (IDM) or VAD 9 (9.7%) each, oral cyclophosphamide 5 (5.4%), oral melphalan or a thalidomide based combination in 3 (3.2%) each, CHOP or single agent fludarabine in 2 (2.1%) each, CVP, fludarabine plus cyclophosphamide (FC), FC plus rituximab (FCR), idarubicin plus dexamethasone or CCNU plus dexamethasone in 1 (1%) each. Due to the small numbers in each group, all patients were analyzed as a single cohort. Only 1 (1%) patient achieved a complete response (CR), 14 (30%) had a partial response (PR), 31 (67%) had no response. The median overall survival was 4.1 years. The responders (CR+PR) had a significantly better overall survival (median not reached; p&lt;0.017) compared to the non-responders (median 3.1 years). The median survival with chlorambucil, VAD or IDM was 8 yrs, 1.4 yrs and 5.1 yrs respectively. Significant factors affecting overall survival were response to treatment, cardiac, renal, liver involvement and IgM level. In summary, the presenting features of IgM associated AL are similar to AL with non-IgM paraproteins, though lymph node involvement is more common. The response to treatment is very poor. There is no consensus about the best chemotherapy regime. The only patient who had a CR was treated with FCR. There is a significant improvement in survival for patients responding to treatment. Antibody based combination chemotherapy may help to improve the haematological response to treatment and improve survival.