AL amyloidosis and progression to multiple myeloma with gain(1q) (2008)

In their recent comprehensive review of systemic light-chain (AL) amyloidosis, Wechalekar et al (2008) noted that ‘progression to overt myeloma is rare’ and that ‘more studies are required to determine the significance of cytogenetic abnormalities in AL amyloidosis’. The International Myeloma Working Group (IMWG) definition of multiple myeloma (IMWG 2003) does include amyloidosis as an ‘end organ damage’ criterion- but practically most experts approach the plasma cell disease in AL as more ‘pre-malignant’ in nature, as implied by Wechalekar et al (2008). Recently investigators at Mayo Clinic have characterized two sister cell lines derived pre- and post-stem cell transplant (SCT) from a patient with AL amyloidosis (Arendt et al, 2008). Post-SCT the patient developed frank multiple myeloma (MM) associated with gain(1q). Patients with MM can have coexistent AL but the progression from AL to symptomatic MM has not been frequently observed (Rajkumar et al, 1998). In the era of improved therapies and survival for AL, however, the frequency of cases of progression may increase. We report on two patients with AL who progressed to MM 30 and 9 months post-SCT with complex cytogenetics and gain(1q) identified at progression. These observations suggest that the clonal plasma cell disease in AL amyloidosis may be viewed more properly as a smouldering form of MM (SMM) rather than as a monoclonal gammopathy of undetermined significance (MGUS). Patient 1 was 59 years old when she presented with AL, 3% lambda-restricted plasma cells (PC), 0·14 g/l lambda free light chains (FLC), 5·0 g/l IgG-lambda M-spike and renal involvement only (3978 mg/d proteinuria). Renal and marrow biopsies showed amyloid. She underwent MEL 200 (melphalan 200 mg/m2) autologous SCT and adjuvant thalidomide and dexamethasone (TD) therapy, achieving a complete haematological and an organ response (Gertz et al, 2005; Cohen et al, 2007). Thirty months post-SCT, lambda FLC rose abruptly to 0·763 g/l with pancytopenia and 18% marrow PC with morphologic atypia compared to baseline, possessing gain(1q), del(13q) and del(17p). Proteinuria increased to 12 367 mg/d and brain natriuretic peptide from normal to 394 pg/ml. MM progressed despite bortezomib and two cycles of DT-PACE (cisplatin 10 mg/m2, doxorubicin 10 mg/m2, cyclophosphamide 400 mg/m2, and etoposide 40 mg/m2 per day by intravenous continuous infusion on days 1–4, plus oral dexamethasone 40 mg on days 1–4 and thalidomide 100–200 mg on days 1–4). She died of refractory MM 42 months after diagnosis with AL. Patient 2 was 49 years old when he presented with AL, 55% lambda-restricted PC, 1·46 g/l lambda FLC, and renal involvement (13 725 mg/d). Renal and gastric biopsies showed amyloid; spinal magnetic resonance imaging and skeletal survey were negative. He received MEL 200 autologous SCT, adjuvant TD and had a complete haematological and an organ response. Nine months post-SCT, lambda FLC rose abruptly to 0·65 g/l with pancytopenia and 98% marrow PC with morphologic atypia compared to baseline, possessing gain(1q), add(3)(q27), add(17)(p11·1), −6, del(13q) and t(2;3). MM progressed despite bortezomib therapy but responded to two cycles of DT-PACE. He then underwent a non-ablative allogeneic stem cell transplant with a graft from his human leucocyte antigen-identical sister but died 6 months later from complications of gastrointestinal amyloidosis and late acute graft-versus-host disease, 23 months after diagnosis with AL. These two cases highlight a relatively new phenomenon: AL progressing to frank MM that is bortezomib-resistant. Given the efficacy of bortezomib in AL and in MM, this observation raises several issues (Wechalekar et al, 2008). In these two cases and in the case from Mayo Clinic, abnormalities of chromosomes 1, 3 and 17 were identified and gain(1q) was present at progression to MM (Sawyer et al, 2005). Although the possibility exists that the amyloid-forming light chains block neoplastic proliferation in some manner, thus limiting progression from AL to MM, it may be the case that in the era of novel agents for PC diseases, survival is improved and, therefore, we may see more AL patients evolving to MM. Indeed, for the same reason, we may also see MM patients with prolonged exposure to pathological FLC developing AL. Historically, AL patients did not live long enough to progress to MM and AL was considered similar to MGUS, as noted by Wechalekar et al (2008) (Kyle et al, 1997). With new knowledge of cytogenetic abnormalities in AL, the underlying PC disease may more reasonably be viewed as similar to SMM, that is, as a malignant not a pre-malignant clonal disease (Bochtler et al, 2008). The incidence of and basis for progression from AL to MM is dependent on unknown risk factors but in these three cases progression is characterized by clonal cytogenetic abnormalities including gain(1q). Historically it has been reasonable not to pursue sophisticated cytogenetic studies of bone marrow aspirates in AL amyloidosis because of the low number of clonal plasma cells present (Merlini & Stone, 2006). However, with current techniques, such as interphase fluorescent in situ hybridization performed on CD138-selected plasma cells, one could reasonably argue that such marrow studies be performed routinely in AL patients with a concern about risk of clonal progression in mind (Bochtler et al, 2008).