Bone Marrow Research cardiac functions in substantial proportion of patients [32– 34]. Histologic regression of amyloid has been shown but seems to occur only in patients who achieve normalization of free light chains [35]. 4. Hematopoietic Stem Cell Transplant versus Other Therapies The exact role of autologous stem cell transplant in the treatment of primary AL amyloidosis and the beneﬁt relative to other available therapies continues to be debated. It has been argued that apparent superior outcomes of patients undergoing transplant are a function of selection bias since only healthier patients, who are destined to do better, are selected to undergo transplant. A retrospective study looked at outcomes of patients who were transplant eligible but did not undergo transplant. Transplant eligibility itself identiﬁed a good risk group who did better than transplant ineligible patients even with nontransplant therapy [36]. A case control study compared the overall survival of 63 ASCT recipients with matched controls not undergoing transplant. The groups were matched for age, gender, time to pre- sentation, left ventricular function, serum creatinine, inter- ventricular septal thickness, nerve involvement, and 24-hour proteinuria). One-, 2-, and 4-year overall survival rates for the transplant versus non-transplant groups were 89% versus 71%, 81% versus 55%, and 77% versus 41%, respectively [37]. These data showing better overall survival as well as studies demonstrating improved quality of life [38] provide strong arguments in support of the role of autologous HSCT for AL amyloidosis. However, randomized trials have not substantiated the beneﬁt of autologous transplant. In a randomized control trial 100 patients with AL amyloidosis aged 18–70 years were randomized between HSCT and conventional therapy. The overall survival was similar in the two arms [39]. High transplant-related mortality of 24% in this study is a notable concern. The publication generated many letters to the journal highlighting concerns about patient selection, inclusion of high-risk patients which necessitated reduction in melphalan dose in 10 of 37 patients, lack of information about cardiac biomarkers, and whether transplants performed at low volume centers in this multicenter study may have biased the results against ASCT [40–42]. A systematic review and meta-analysis of 1 randomized control trial, 2 other control studies, and 9 single arm studies also did not provide a conclusive answer. The study did not ﬁnd a survival beneﬁt with transplant but the authors commented that the quality of evidence was low, indicating a need for well-designed and adequately powered trials to better address the role of AHCT in AL amyloidosis [43]. Therapeutic options for AL amyloidosis are constantly changing. As newer, more eﬀective therapies become avail- able, and the role of transplant will need to be reevaluated. Modern, bortezomib-based therapies are associated with response rates approaching those obtained by transplant. Bortezomib as monotherapy or with other agents is active in AL amyloidosis, and produces rapid responses and high rates 3 of hematologic and organ response [44–46]. The durability of these responses is unclear at present since only relatively short followup is available. A phase III, multicenter study evaluating melphalan and dexamethasone with or without bortezomib in patients with previously untreated systemic AL amyloidosis is currently ongoing (NCT01078454). Borte- zomib has also been used for amyloidosis relapsing after transplant. It is eﬀective in that setting and can lead to normalization of free light chains and potentially render patients previously not candidates for transplant safe to undergo high-dose therapy [47]. The availability of multiple very active treatment options for patients is clearly welcome news for patients with this devastating disorder. Conventional therapy with bortezomib or other agents and ASCT should not be seen as competitive but rather additive or complementary in nature. Achieving a CR is a key predictor of overall survival. ASCT after a bortezomib-based induction regimen may improve the pro- portion of patients achieving complete remission. However, that remains to be shown in clinical trials. Amyloidosis is a heterogeneous disease with a large variation in the range and severity of clinical presentations, tempo of disease progres- sion, and comorbidities. The challenge for the physicians is to individualize treatment by selecting the optimal combination or sequence of the various therapies to achieve best possible results for the patient. Clearly, optimal approach will be diﬀerent for each patient depending on their disease status (number of organs involved, organ function), overall health status and co-morbidities, and their personal choice and goals. 5. Conclusions ASCT is an eﬀective therapy for primary amyloidosis. It is associated with consistently high hematologic response rates, which lead to improvement in organ function, quality of life, and survival. Best results are obtained in patients with 1- 2 organ involvement and no cardiac dysfunction. Patients with multiple (more than 2) organ involvement, particularly advanced cardiac involvement and renal insuﬃciency, are not suitable candidates for this therapy. The question whether ASCT should be the preferred therapy for patients who are healthy enough to tolerate it has not been answered deﬁnitely. In the consensus opinion of physicians at the Mayo Clinic experienced in the treatment of amyloidosis the answer to this question is yes [48]. The importance of patient selection to ensure safety and optimal outcomes cannot be overemphasized. The role of HSCT in the overall treatment of AL amyloidosis is likely to evolve as new, more eﬀective therapies become available and will need to be continually assessed in future prospective trials. References [1] R. H. Falk, R. L. Comenzo, and M. Skinner, “The systemic amyloidoses,” New England Journal of Medicine, vol. 337, no. 13, pp. 898–909, 1997. [2] J. D. Sipe, M. D. Benson, J. N. Buxbaum et al., “Amyloid ﬁbril protein nomenclature: 2010 recommendations from