AL amyloidosis or multiple myeloma? An important distinction

Abstract

I read with interest the paper by Dinner et al (2013), which concluded that multiple myeloma coexists with AL amyloidosis in 57–80% of cases. I believe that the conclusions of this paper are erroneous and are based upon a misunderstanding and misreading of standard criteria for the definition of smoldering (asymptomatic) multiple myeloma. AL amyloidosis is a well-recognized plasma cell dyscrasia, with distinct clinical features, generally considered a separate disease from multiple myeloma. In their evaluation of 46 consecutive patients with AL amyloidosis, the authors argue for a high overlap between these diseases based on the 2003 International Myeloma Working Group (IMWG) report (The International Myeloma Working Group, 2003). This consensus document describes smoldering myeloma as a plasma cell dyscrasia with an M-protein in the serum greater than 30 g/l, and/or bone marrow clonal plasma cells ≥ 10%, and it is on this definition that Dinner et al (2013) rely. However, there is a critical additional part of this definition, namely that there should be ‘no related organ or tissue impairment (no end organ damage, including bone lesions) or symptoms.’ Surprisingly, while Dinner et al (2013) acknowledge that the IMWG ‘does recognize amyloidosis is a form of end organ damage’, they then ignore this critical part of the definition and proceed to define any AL amyloidosis patient found to have a bone marrow plasmacytosis ≥10% as having coexistent multiple myeloma and AL amyloidosis. Utilizing their new definition of myeloma, which runs contrary to the IMWG definition, they defined 57% of their AL cases as also having multiple myeloma. Not satisfied with this remarkably high prevalence of overlapping diseases, they then opted to re-evaluate the numbers, by adding CD138 immunohistochemistry as recommended by ‘The International Myeloma Workshop Consensus 3’ (Dimopoulos et al, 2011), and conclude that the figure for amyloidosis and coexistent myeloma is now 80%. However, once again, they selectively choose from the recommendations of a quoted consensus document. The International Myeloma Workshop Consensus 3, while supporting the use of CD138 immunohistochemistry for more precisely defining the number of clonal plasma cells in the marrow, also precisely defines asymptomatic myeloma. A requirement for this definition is ‘absence of end-organ damage…which can be attributed to a plasma cell proliferative disorder.’ As AL amyloidosis is a plasma cell disorder and, by definition, has end organ damage of at least one (and often many) organs due to amyloid deposition, the diagnosis of asymptomatic multiple myeloma can never coexist with AL amyloidosis. Publications from experts in the field of amyloidosis and myeloma (many of whom are members of the IMWG) have never defined coexistent multiple myeloma and AL amyloidosis in the manner defined by Dinner et al (2013). When addressed, the definition of the overlap has been described as AL amyloidosis with a minimum of 30% plasmacytosis in the marrow, or the presence of bony lesions and other manifestations of overt myeloma (Rajkumar et al, 1998; Pardanani et al, 2003). If that well-recognized definition is used in the current series, the AL/myeloma overlap falls to 20%, which is within the realm of well-recognized and currently accepted percentages. The authors' attempt to redefine the criteria of overlapping AL amyloidosis and multiple myeloma has neither precedent from previous definitions, nor has prognostic value, as demonstrated by their results. Indeed, the only near-significant prognostic definition of this overlapping disease (as shown in their Figure 1C) was the previously well-used definition of myeloma as lytic bone lesions and/or greater than 30% plasma cells in the bone marrow. It is therefore disturbing to see an attempted redefinition of AL amyloidosis coexisting with multiple myeloma which is neither based on previously well-considered expert consensus nor which has any prognostic value. AL amyloidosis and multiple myeloma are similar diseases but with different outcomes and they possibly benefit from different treatment approaches once a remission has been achieved. By blurring the distinction between these diseases, Dinner et al (2013) have sown unnecessary confusion and done a disservice to the multispecialty community of physicians who specialize in the treatment of AL amyloidosis and related disorders.