2 therapy since the fundamental underlying problem in both these conditions is the same. Early studies established melphalan as an eﬀective agent. In randomized controlled trials comparing melphalan plus prednisone to colchicine in patients with AL amyloidosis, the melphalan and prednisone combination was associated with objective responses and prolonged survival compared to colchicine [6, 7]. Melphalan has continued to be a key agent in the treatment of amyloidosis. Melphalan combined with dexamethasone is considered a “standard” ﬁrst line therapy. Palladini et al. showed that this combination results in high response rates, 67% hematologic response including 33% complete response, and 48% of patients had objective organ function response. Responses were durable, and CR was maintained in 9 of 15 patients after a median of 4.8 years. Six- year progression-free survival was 40%, and median overall survival was 5.1 years [8, 9]. Other studies with oral or intravenous melphalan combined with dexamethasone have shown less robust responses with complete response rates of 11 and 13%, likely because of diﬀerent patient characteristics especially cardiac involvement [10, 11]. The development of free immunoglobulin light chain (FLC) assay allowed quantitation of circulating amyloidogenic light chains. Reduction in FLC with treatment was subsequently shown to be associated with decrease in amyloid load, clinical improvement, and survival beneﬁt [12]. The introduction of new agents (IMiDs and bortezomib) in the last 10 years has revolutionized the treatment of multiple myeloma and improved survival [13]. Since the underlying problem in amyloidosis is also plasma cell dyscrasia, it is logical to expect that these agents will also be eﬀective in the treatment of primary amyloidosis. Studies with thalidomide, lenalidomide, and bortezomib indeed demonstrate activity of these agents. Bortezomib appears to be highly eﬀective with hematologic response rates of 50%– 94% and CR rates of 20–44% in diﬀerent studies [14–16]. 3. Autologous Stem Cell Transplant (ASCT) High-dose chemotherapy followed by ASCT reliably pro- duces hematologic complete remissions in a sizable pro- portion of patients with multiple myeloma. Because plasma cell dyscrasia is the underlying cause of AL amyloidosis, ASCT has also been adopted for the treatment of AL amyloidosis. Early studies of ASCT reported signiﬁcant toxicity including mortality rate of over 40% in one small study [17]. Subsequent studies showed better results and showed that with careful patient selection transplant can be performed with acceptable toxicity [18, 19]. Autologous stem cell transplant has remained an important treatment option for systemic AL amyloidosis. 3.1. Selection of Patients. Although mortality from autolo- gous stem cell transplant has continued to decrease over time, [20, 21] the procedure remains high risk, and careful selection of patients is critical for good outcomes. Best results were obtained in patients with nephrotic syndrome as the predominant manifestation of amyloidosis. Patients with Bone Marrow Research multiple organ involvement, particularly those with cardiac dysfunction, fare poorly with high risk of morbidity and mortality [22]. Many patients with primary amyloidosis are too sick to undergo autologous stem cell transplant. Predictors of poor prognosis in patients with amyloidosis include the number of organs involved, cardiac involvement evidenced by clinical cardiac dysfunction or elevation of cardiac biomarkers (troponin-T and N-terminal brain natri- uretic peptide (NT-pro-BNP)), pretransplant free light chain ratio, and elevated serum uric acid [23–26]. The number of organs involved and the extent of cardiac dysfunction are by far the dominant predictors of prognosis with or without transplant [22, 26]. Excessive ﬂuid retention during stem cell mobilization and harvest may be a reﬂection of limited cardiac and/or renal reserve and is associated with poor outcomes during transplant [27]. Although older individuals are more likely to have comorbidities, age per se is not a contraindication, and older individuals can successfully undergo autologous HSCT [28]. A risk-adapted approach to transplant has been suggested wherein the melphalan dose in the conditioning regimen is lowered for individuals considered at high risk for transplant toxicity. However, the risk-adjusted lowering of conditioning chemotherapy is associated with reduced response rates [29]. The risks and beneﬁts of transplant have to be carefully evaluated for each individual patient to ensure optimal balance between eﬃcacy and toxicity. 3.2. Outcomes. Autologous stem cell transplant is associated with substantial likelihood of hematologic response includ- ing organ function improvement. Long-term posttransplant follow-up studies show the durability of responses and better survival of responders. Cibeira et al. reported longterm outcomes of 421 AL patients transplanted between 1994 and 2008. Hematologic CR rate was 43%, and 78% of complete responders had improvement in organ function. For patients achieving a CR the median event free survival (EFS) and overall survival (OS) were 8.3 and 13.2 years compared to organ response rate of 52%, EFS of 2 years, and OS of 5.9 years in those who did not achieve hematologic CR [20]. Investigators from Mayo Clinic reported their experience with 434 transplants since 1996. Hematologic response rate of 76% (CR rate 38.7%) and organ response rate of 46.8% were described. Median OS was not reached for patients achieving hematologic CR and was 107 months and 32 months, respectively, for those with partial response and no response [30]. Outcomes of 107 recipients of ASCT performed at 48 centers between 1995 and 2001 were reported by Center for International Blood & Marrow Transplant Research (CIBMTR) investigators. A relatively high transplant-related mortality of 18% at 30 days was noted. One-year and 3-year survival rates were 66% and 56%, respectively. The outcomes were better in patients transplanted in later years possibly related to better patient selection, improved supportive care and/or physician expe- rience [31]. These and other studies show that hematologic response, particularly CR is associated with better survival and improvement in organ function, including renal and