High dose melphalan in primary systemic amyloidosis: status quo?

Primary systemic light chain (AL) amyloidosis is clonal plasma cell disorder characterized by the deposition of amyloid fibrils in various tissues which are derived from the polymerization of fragments of light chains and result in organ dysfunction. The bone marrow plasmacytosis is usually mild or moderate and the clinical presentation and the outcome of these patients are affected mainly by the extent and the severity of organ involvement by amyloid, particularly of the heart [1]. Patients with AL amyloidosis are characterized by significant heterogeneity in terms of clinical presentation and prognosis. In a rare disease and with such differences in the characteristics and the prognosis of patients, the definition of a treatment as a ‘standard’ is not easy. The randomized trials that have been conducted in patients with AL amyloidosis are limited and of small size. Alkylating agents and standard dose steroids were the mainstay of therapy for several years, however with modest effectiveness: a hematologic response was seen in fewer than 50% and was slow, and complete responses were rare and only a few patients showed significant improvement in organ dysfunction [2]. High dose melphalan (HDM) with autologous stem cell transplant (ASCT) was introduced as a treatment option for patients with AL amyloidosis in the mid 1990s, and although this procedure was associated with significant treatment related mortality (TRM), it induced high rates of complete hematologic responses and organ responses [3]. Pulsed high dose dexamethasone was also associated with improved responses, which occurred rapidly, but is poorly tolerated in patients with AL, especially those with multisystem involvement. Oral melphalan combined with dexamethasone (MDex), in a regimen in which dexamethasone was used for 4 days every month, resulted in hematologic responses in 67%, with almost 30% of patients achieving a complete hematologic response and 48% an organ response [4]. This regimen is effective and relatively non-toxic; however, in patients with cardiac involvement the results are poor [5,6]. A multicenter randomized trial conducted in France compared MDex to HDM in patients with AL amyloidosis [7]. In this study MDex was superior, or at least not inferior, to HDM, but this study was conducted in unselected patients in centers with limited experience, and the TRM in patients treated with HDM was high. Thus, the ‘optimal’ treatment for patients eligible for HDM remained unresolved. In this issue of Leukemia and Lymphoma, Gertz et al. [8] analyze the outcome of 434 patients with AL treated with HDM in a tertiary, specialized center. This is the largest published series of patients with AL treated with HDM, with a long follow-up; furthermore, the data set includes cardiobiomarkers [9]. A hematologic response was recorded in 76%, including hematologic complete response (CR) in 39% and organ responses in 47%. After a median follow-up for the survivors of about 4 years, the median survival for patients who achieved a CR has not been reached, and for those with a partial response (PR) is about 9 years but just 2.5 years for those who did not respond. Elevated cardiobiomarkers remain a major unfavorable prognostic feature, as well as high levels of free light chains (FLCs). The TRM associated with the procedure was 10%, although 25% of patients were stage III according to cardiobiomarker staging [9]; this relatively low