High-dose melphalan and stem cell transplantation in systemic AL amyloidosis in the era of novel anti-plasma cell therapy: a comprehensive review


The application of high-dose melphalan and autologous stem cell transplant (SCT) to systemic AL amyloidosis (AL) has evolved over the past two decades and remains an important component of therapy for patients with AL. The era of novel agents created the opportunity to provide well -tolerated induction and post-SCT consolidation to AL patients eligible for SCT and the current availability of new monoclonal antibody therapies will likely provide additional opportunities to enhance the outcomes with SCT. In this review, we touch on the history of SCT for AL and examine the data on eligibility, mobilization, induction, risk-adapted melphalan dosing, engraftment, consolidation and maintenance, and long-term outcomes with SCT. We note that induction therapy may deprive some patients of the opportunity to proceed to SCT but is likely needed if the marrow plasmacytosis is > 10%, that risk-adapted melphalan dosing continues to be relevant, and that post-SCT consolidation improves the complete response rate as well as long-term overall survival. The importance of baseline cytogenetics is also highlighted, particularly for patients whose clonal plasma cells are ≤ 10% but harbor the t(11;14), because they may have improved survival with SCT.


Immunoglobulin light-chain amyloidosis (AL) is a rare clonal plasma cell disorder characterized by the production of toxic free light chains (FLCs) and their systemic deposition as fibrils in and around tissues resulting in the disruption of organ function. AL and multiple myeloma (MM) are similar diseases in that they both involve clonal plasma cells in the bone marrow that produce monoclonal proteins in the serum and/or urine. Unlike MM, the mechanism of disease is not cell mass in AL and therefore, the concentration of the monoclonal protein as a correlate of myeloma cell burden is less relevant (Table 1). In AL, the physicochemical properties of the FLC can be more significant than the FLC concentration, although both are important. The availability of the FLC assay and of specific typing of amyloid by mass spectrometry have enhanced diagnosis and patient care, and have contributed to the emergence and testing of new therapies [1,2,3]. The incidence of AL is one-tenth that of MM, ~6 to 10 cases per million in the United States [4]. Patients present with visceral organ damage manifested as proteinuria, restrictive cardiomyopathy, hepatomegaly, and autonomic or peripheral neuropathy [5]. Herein, the key aspects of stem cell transplantation (SCT) in the treatment of AL will be reviewed.

Table 1 Characteristics of the clonal plasma cell diseases MM and systemic AL

The beginning

The backbone of MM treatment was revolutionized with the use of high-dose melphalan in the early 1980’s [6, 7]. Autologous SCT with high-dose melphalan and mobilized peripheral blood stem cell support was first introduced to AL patients in the mid-1990’s at a time when its use in MM was also being developed [8,9,10]. A pivotal study enrolled 25 patients with AL to receive melphalan 200 mg/m2, the majority of whom (64%) had never received prior therapy [10]. At a median follow-up of 24 months, 17 of 25 were still alive and over 60% had achieved strictly defined complete hematologic responses (CR); in contrast, at that time the use of oral melphalan and prednisone (MP) for AL resulted in a median survival of 18 months with a 5% CR rate [11]. SCT was a promising novel approach to a hitherto fatal disorder.


By 2007, the role of SCT for AL remained controversial because of the potential toxicity. The French myeloma study group reported the results of a multicenter randomized trial comparing SCT with oral melphalan and dexamethasone (MDex). After a median follow-up of 3 years, the median overall survival (OS) in the SCT arm was only 22.2 months vs. 56.9 months in the MDex arm [12]. Critics noted that the high treatment-related mortality (TRM) in the SCT arm (24%) indicated that many patients were likely not fit to undergo SCT [13]. The use of SCT continues with success in the United States and in Germany with attention to patient selection [14, 15]. Selection criteria from institutions in the United States and from the Heidelberg University Hospital program are listed in Table 2 [14,15,16]. There are only a few studies comparing SCT with chemotherapy and none in the era of novel agents (Table 3). Nevertheless, there are data indicating that currently, patients who fail to respond to bortezomib-based initial therapy can be successfully mobilized, collected, and treated with SCT with high rates of hematologic response [17].

Table 2 Eligibility criteria for SCT
Table 3 Autologous SCT vs. chemotherapy (chemo) alone

Hematologic response

The importance of achieving a hematologic response post-SCT has been illustrated in many series (Table 4) [18]. In a series of 629 consecutive AL patients treated with SCT over a span of 20 years, median survival was 7.6 years for all but not reached for those with a CR, although until about 2005 the FLC assay had not yet been incorporated into the definition of CR [19, 20]. Patients who were able to achieve a CR (immunofixation negative) also had superior rates of organ responses (79% vs. 39%) (Table 5).

Table 4 Autologous SCT for AL 1994–2014 and CR rates
Table 5 Retrospective studies of risk-adapted melphalan dose without post-SCT consolidation

A retrospective study looked at the impact of achievement of a partial response (PR) on long-term outcomes. Of 282 patients, 108 (38%) and 93 (33%) achieved PR and CR, and those achieving CR lived longer (Fig. 1a) [21]. In a multivariate analysis, the only significant predictors of survival were hematologic response and Troponin T levels. The current definitions of hematologic response have been validated as shown in Fig. 1b; a FLC CR in AL is called an aCR and requires both serum and urine immunofixation studies to be negative and the FLC ratio to be normal [22].

Fig. 1

In a, we see the impact on OS of hematologic response in a series of patients undergoing SCT before 2007, with survival assessed from the time of SCT [20]. In b, the 6-month landmark analysis is shown that validated hematologic response criteria based on FLC and immunofixation results and emerged from the 2010 International Amyloidosis Symposium; an amyloid CR (aCR) requires negative serum and urine immunofixation tests and a normal FLC ratio [21]. In c, long-term outcomes in patients undergoing SCT from 2000 through 2011 (n = 143), many of whom received post-SCT consolidation, are shown as a function of baseline clonal plasmacytosis; patients with > 10% clonal plasma cells at diagnosis had poorer long-term survival and therefore are currently treated with pre-SCT induction [24]. In d, the OS of all 143 SCT patients is shown highlighting the improved OS of those achieving aCR

Pre-SCT induction

Induction therapy was initially thought to be unnecessary in AL patients given the small percent of plasma cells in the bone marrow at diagnosis (Table 1). In a turn-of-the-century prospective trial, 100 newly diagnosed patients were randomized to receive either SCT as initial therapy or two cycles of oral MP followed by SCT. After a median follow-up of 45 months, OS and hematologic/organ responses were not significantly different. Of note, fewer patients who were assigned to MP actually received SCT due to disease progression while on MP, making them ineligible for SCT. This was true particularly among patients with cardiac involvement [23].

Similar findings were noted in a 2015 prospective study in which 30 patients received 2 cycles of induction with bortezomib (twice weekly) and dexamethasone followed by conditioning with bortezomib and high-dose melphalan before stem cell infusion [24]. The overall response rate (ORR) was 100% (63% CR and 37% very good partial response (VGPR)) and the median OS and progression-free survival (PFS) were not reached after a median follow-up of 36 months. Despite the high ORR in this study, 5 of the 35 transplant-eligible patients (14%) could not proceed to SCT due to bortezomib-related complications in induction causing deterioration in clinical status. Currently, the use of cytoreduction prior to SCT should be reserved for the following patients: (i) those with concurrent MM or those who have plasmacytosis > 10% in the bone marrow at diagnosis, because the presence of clonal cells above this level influences long-term OS (Fig. 1c) [25], and ii) those with advanced/progressive disease and an anticipated delay to SCT beyond 2 months; induction can slow amyloid production and limit further organ damage,


Successful mobilization of stem cells is critical for timely engraftment in patients undergoing autologous SCT. Although stem cell collection is generally safe, patients with AL can incur significant toxicities such as fluid retention, weight gain, low blood pressure, cardiac arrhythmias, and heart failure [26,27,28]. Risk factors for serious adverse events during mobilization include low albumin levels, increased interventricular septal thickness, and elevated N-terminal pro-B-type natriuretic peptide cardiac biomarker levels (NT-pro BNP, see below) [29]. Risk factors for poor stem cell yield include increased age and prior exposure to alkylating agents [30]. Failure rates using granulocyte macrophage-stimulating factor (G-CSF) alone for stem cell collection are as high as 5%–10% [31]. In Germany, many patients are mobilized with chemotherapy and G-CSF, except patients with advanced cardiac involvement or those who are post-heart transplant [15].

Plerixafor is a reversible antagonist to the alpha chemokine receptor CXCR4 implicated in the homing of hematopoietic stem cells to the bone marrow [32]. In a retrospective study comparing collection with G-CSF alone (G) vs. G-CSF + plerixafor (GP) in patients with AL, GP resulted in a higher yield of CD34 + cells/kg (12.8 × 106 vs. 6.3 × 106). Furthermore, no patients failed collection in the GP cohort vs. a 16% failure rate in the G alone cohort. There was no significant difference in number of apheresis sessions, days in the hospital, infections, cardiac arrhythmia events, time to engraftment or transplant outcomes. Overall, the addition of plerixafor was well tolerated and resulted in better stem cell yield and significantly less weight gain than G-CSF alone [26].

Risk-adapted melphalan dosing

The use of various dose reductions of melphalan has been explored [33] and remains controversial among experts Table 5. Some believe that if a dose reduction of melphalan is being considered, with the exception of renal function impairment, then he or she is not a candidate for SCT. Others believe that lower doses of melphalan still provide a greater benefit to patients over chemotherapy alone. In a 2004 retrospective comparison of outcomes in patients who received intermediate doses (100 mg/m2 or 140 mg/m2) vs. 200 mg/m2, TRM was similar but the ORR was superior in the high-dose group (75% vs. 53%) [34]. To our knowledge, this was the only study to report no significant difference in survival among responders based on the melphalan dose received. It is important to note that the numbers in this study were small (only 40 patients received Melphalan 140 mg/m2) and the follow-up period was too short to calculate the median survival or the risk of relapse. Patient selection may have also played a role in the observations reported. Overall, this series suggested that lower doses of melphalan increased eligibility at the expense of response, although a prospective study would be required to better address this controversial topic. Interestingly, summary data from the ABMTR indicated that in the period 2007–2012, doses of melphalan lower than 180 mg/m2 were extensively used (64% of patients received < 180 mg/m2, and 34% of patients received < 140 mg/m2) with better hematologic response rates in this cohort compared to the 2001 to 2006 cohort [14, 34], although higher doses were associated with a lowered risk of relapse.

Post-SCT Consolidation and Maintenance

The use of consolidation chemotherapy has been implemented to improve hematologic response if an aCR is not achieved in the post-SCT setting. In several phase II trials, patients with treatment-naive AL were assigned to SCT with risk-adapted dosing of melphalan at 100, 140, or 200 mg/m2 based on age, renal compromise, and cardiac Mayo stage. Consolidation therapy in the form of thalidomide and dexamethasone (Td) in one trial, and bortezomib and dexamethasone (Bd) in the other, was administered if an aCR was not reached by day + 90. At that time point, almost half of patients had a PR or better and one-quarter had an aCR. With Td almost 40%, and with Bd over 85%, benefited with an improvement in hematologic response, and with Bd consolidation, organ responses were noted in 55% and 70% of patients at 12 and 24 months post-SCT, respectively [35]. In 2017, the long-term outcomes of patients treated in this way (n = 143) were reported [25]. The median OS for all patients was 10.4 years and for those achieving aCR was not reached (Fig. 1d). The notable absence of treatment-related deaths in the melphalan 200 mg/m2 group reflected the favorable host factors in this cohort. Overall, risk-adapted SCT with bortezomib-based consolidation resulted in an aCR rate of 62% [25].

Post-SCT maintenance therapy in MM with the immunomodulatory drug lenalidomide has been shown to be beneficial with respect to PFS and OS [36]. Bortezomib has also been used in maintenance post-SCT in MM [37]. Lenalidomide, however, although active in relapsed AL, has been found to have both renal and cardiac side effects that limit its use in AL patients [38,39,40,41]. Bortezomib, although used in consolidation, has not been studied in maintenance in AL; moreover, the clonal plasma cell disease in AL differs from MM (Table 1) and therefore the benefit from maintenance remains to be determined in randomized trials. As we mentioned earlier, even with consolidation, patients whose baseline marrows contain > 10% clonal plasma cells have poorer OS post-SCT. To what degree pre-SCT induction, post-SCT consolidation, and the addition of maintenance may improve outcomes in these patients remains to be learned.


Amyloid deposits can be detected within the bone marrow in over half of AL patients, raising a concern about whether the deposits can negatively impact stem cell yield and/or peri-transplant engraftment. An early trial suggested no impact of marrow deposits on mobilization or engraftment [10], and a retrospective look at over 350 patients undergoing SCT, 65% of whom had marrow deposits, showed that the presence of marrow amyloid, even if extensive, did not negatively impact stem cell yield or engraftment [42]. Whether other features of the marrow environment or immune system may be affected is not known.

Cardiac AL

SCT is an important treatment modality for patients with AL but requires adequate cardiac reserve given poor outcomes in this patient population [43,44,45]. More than 60% of AL patients present with cardiac involvement and because of that, cardiac biomarkers have been shown to be valid predictors of survival and useful in cardiac staging of AL patients. Risk-based staging employs the NT-pro BNP (cutoff 332 ng/L) and cardiac Troponin T (cutoff 0.035 ng/mL) [46]. In AL patients undergoing SCT between 1996 and 2003, median survival was not reached for patients with NT-pro BNP and TnT values below those thresholds at diagnosis. Only in the stage III cardiac cohort was median survival reached, at 8.4 months [47]. In a large retrospective study (n = 499) by the same group, outcomes based on cardiac biomarkers were examined in patients who underwent SCT between 1996 and 2011. Forty-one of the 43 patients who died early had NT-pro BNP values > 5000 in this series and that level is used by some as a threshold for eligibility for SCT (Table 2) [48]. However, investigators at a major center reported on the outcomes of 53 patients with cardiac AL who underwent SCT, most of whom had advanced cardiac involvement (stage III) and multi-organ AL. Forty-five percent of patients received melphalan 200 mg/m2, while the remainder received 140 mg/m2. After a median follow-up of 36 months, the TRM for the entire cohort was 4% but was 8% among the stage III patients. At 3 years, OS was 89% with a trend towards longer survival among patients with stage I and II cardiac disease. There was no difference in response rates between doses of melphalan. At 12 months, the cardiac response rate, based on reductions in cardiac biomarkers and reduced left ventricular wall thickness on echocardiogram, was 53%, mostly among patients who achieved at least a VGPR. The authors emphasized the importance of careful patient selection and risk-adapted strategies to optimize the outcomes of patients with cardiac disease undergoing SCT [28]. SCT outcomes in patients with advanced cardiac involvement are best attained in specialized centers and under the supervision of experienced transplant teams who understand the disease. With the hematologic response criteria, the staging system incorporating cardiac biomarkers, and the validated biomarker response criterion, both clinical trial design and comparison of single-center case series in AL have become more straightforward [3, 22].

Renal AL

AL of the kidneys occurs in almost 70% of newly diagnosed patients. Deposits can be appreciated with Congo red staining and electron microscopy (Fig. 2a, b). These patients are eight-fold more likely to require dialysis at any point after diagnosis and have a median survival of less than a year if they require dialysis during SCT [49]. With stricter inclusion criteria for SCT limiting the participation of patients with advanced cardiac disease, most patients now undergoing SCT have renal involvement. SCT can be performed safely in patients on dialysis by employing a melphalan dose of 140 mg/m2, while patients with an estimated glomerular filtration rate (eGFR) < 30 not on dialysis are likely best served by foregoing SCT [50, 51].

Fig. 2

In a, we see an example of renal amyloid deposits with a Congo red stained renal biopsy (left) that shows the apple-green birefringence in polarized light (right) indicative of amyloidosis and in b we see characteristic amyloid fibrils 7 to 10 nm in diameter extracted post-mortem from the spleen of a patient with rapidly progressive AL (reprinted from reference [72]). In c, we see the impact of SCT on patients with and without t(11;14), highlighting the importance of high-dose melphalan for these patients all of whom underwent SCT [58]. In d, we see OS of 148 AL patients with < 10% clonal marrow plasma cells (about a third of whom underwent SCT) as a function of presence or absence of t(11;14), the only negative prognostic factor in this group of patients [59]

Predisposing factors for the development of acute kidney injury during SCT include lower creatinine clearance, higher urinary protein, cardiac AL, age, and active urinary sediment at baseline [52]. In a retrospective series of patients undergoing SCT between 1994 and 2000, approximately 21% developed acute renal failure (ARF), 5% of whom needed dialysis during the peri-SCT period [36]. Overall, 46% of patients with ARF had complete recovery of renal function. There was no significant difference in baseline characteristics among patients with ARF, who did and who did not require dialysis. Risk factors for ARF included higher urinary protein excretion, lower creatinine clearance at baseline, cardiac involvement, higher melphalan dose, and development of bacteremia in the peri-transplant period. At a median follow- up of 2.9 years, there was no significant difference in survival between the ARF and non-ARF groups. In another series of 428 patients undergoing SCT between 1996 and 2010, median survival was just over 8 years with the shortest OS, only 7 months, belonging to patients who were started on dialysis within 30 days of SCT [53]. Dialysis independence was associated with better survival, whereas the median survival for those who remained on dialysis was 30 months. Independent risk factors for dialysis within 30 days of SCT were an eGFR < 40 mL/min/1.73 m2 and a serum albumin < 2.5 g/dL before treatment, suggesting that patients who met both of these thresholds should be ineligible for SCT.

Baseline plasma cell cytogenetics

In MM, cytogenetics at baseline have an important role in risk stratification and in outcomes following therapy [54,55,56]. Translocation (11;14) is seen in 50%–60% of AL patients [57,58,59] and has been associated with bortezomib-resistance [60, 61]. Other common cytogenetic abnormalities include deletion 13q and gain 1q21. Hyperdiploidy and deletion 17p are less prevalent. Patients with t(11;14) had a significantly higher aCR rate in response to SCT than patients without it (41.2% vs. 20%) and also had a trend for a longer OS, whereas other cytogenetic abnormalities had no significant impact on aCR. In a multivariate analysis, t(11;14) was associated with a longer event-free survival  with SCT, and overall, despite t(11;14) having been associated with reduced responses to bortezomib-based therapy, it conferred a better OS on AL patients undergoing SCT (Fig. 2d) [61]. In contrast, in a series of 148 AL patients with ≤ 10% clonal marrow plasma cells only a third of whom underwent SCT, those with t(11;14) had poorer OS (Fig. 2e) [62].


At present, newly diagnosed AL patients who do not enroll on clinical trials have a choice of two effective therapies: high-dose melphalan with SCT or bortezomib-based chemotherapy [63, 64]. Currently, there are no randomized trials reporting the superiority of one modality over the other in eligible patients. From the data presented in this review, it is clear that the best prospect for survival is the achievement of an aCR and organ response(s); the latter require a profound suppression of clonal plasma cells and do not always occur [65]. We believe that the risk-benefit ratio for SCT has improved in recent years due to better patient selection, more specialized centers performing these procedures and the adoption of risk-adapted approaches. For eligible patients, SCT rather than chemotherapy alone remains the treatment of choice for upfront therapy in our opinion. SCT can result in high rates of aCR and organ improvement as well as OS that can exceed 10 years.

The use of novel agents such as Ixazomib to treat relapsed AL is gaining momentum given the low toxicity profile of such drugs [66]. Future directions include the use of immunotherapy, in particular anti-CD38 monoclonal antibodies such as Daratumumab [67]. Daratumumab is currently being evaluated in newly diagnosed AL patients in a phase III trial in which patients receive bortezomib-based therapy with or without it (NCT03201965). By combining such agents with SCT, the hope is that we will witness a sea-change in the therapeutic algorithm for this disease in coming years.


  1. 1.

    Dispenzieri A, Kyle R, Merlini G, Miguel JS, Ludwig H, Hajek R, et al. International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders. Leukemia. 2008;23:215–24.

    Article  Google Scholar 

  2. 2.

    Vrana JA, Gamez JD, Madden BJ, Theis JD, Bergen HR 3rd, Dogan A. Classification of amyloidosis by laser microdissection and mass spectrometry-based proteomic analysis in clinical biopsy specimens. Blood. 2009;114:4957–9.

    CAS  Article  Google Scholar 

  3. 3.

    Comenzo RL, Reece D, Palladini G, Seldin D, Sanchorawala V, Landau H, et al. Consensus guidelines for the conduct and reporting of clinical trials in systemic light-chain amyloidosis. Leukemia. 2012;26:2317–25.

    CAS  Article  Google Scholar 

  4. 4.

    Kyle RA, Linos A, Beard CM, Linke RP, Gertz MA, O’Fallon WM, et al. Incidence and natural history of primary systemic amyloidosis in Olmsted County, Minnesota, 1950 through 1989. Blood . 1992;79:1817–22.

    CAS  PubMed  Google Scholar 

  5. 5.

    Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses. N Engl J Med. 1997;337:898–909.

    CAS  Article  Google Scholar 

  6. 6.

    Alexanian R, Haut A, Khan AU, Lane M, McKelvey EM, Migliore PJ, et al. Treatment for multiple myeloma. Combination chemotherapy with different melphalan dose regimens. JAMA. 1969;208:1680–5.

    CAS  Article  Google Scholar 

  7. 7.

    McElwain TJ, Powles RL. High-dose intravenous melphalan for plasma-cell leukaemia and myeloma. Lancet. 1983;2:822–4.

    CAS  Article  Google Scholar 

  8. 8.

    Barlogie B, Hall R, Zander A, Dicke K, Alexanian R. High-dose melphalan with autologous bone marrow transplantation for multiple myeloma. Blood. 1986;67:1298–301.

    CAS  PubMed  Google Scholar 

  9. 9.

    Merlini G. Treatment of primary amyloidosis. Semin Hematol. 1995;32:60–79.

    CAS  PubMed  Google Scholar 

  10. 10.

    Comenzo RL, Vosburgh E, Falk RH, Sanchorawala V, Reisinger J, Dubrey S, et al. Dose-intensive melphalan with blood stem-cell support for the treatment of AL (amyloid light-chain) amyloidosis: survival and responses in 25 patients. Blood. 1998;91:3662–70.

    CAS  PubMed  Google Scholar 

  11. 11.

    Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, et al. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997;336:1202–7.

    CAS  Article  Google Scholar 

  12. 12.

    Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, et al. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007;357:1083–93.

    CAS  Article  Google Scholar 

  13. 13.

    Sanchorawala V, Skinner M, Quillen K, Finn KT, Doros G, Seldin DC. Long-term outcome of patients with AL amyloidosis treated with high-dose melphalan and stem-cell transplantation. Blood. 2007;110:3561–3.

    CAS  Article  Google Scholar 

  14. 14.

    D’Souza A, Dispenzieri A, Wirk B, Zhang MJ, Huang J, Gertz MA, et al. Improved outcomes after autologous hematopoietic cell transplantation for light chain amyloidosis: a center for International Blood and Marrow Transplant Research Study. J Clin Oncol. 2015;33:3741–9.

    Article  Google Scholar 

  15. 15.

    Schonland SO, Dreger P, de Witte T, Hegenbart U. Current status of hematopoietic cell transplantation in the treatment of systemic amyloid light-chain amyloidosis. Bone Marrow Transplant. 2012;47:895–905.

    CAS  Article  Google Scholar 

  16. 16.

    Landau HJ, Gertz MA, Comenzo RL. Autologous hematopoietic cell transplantation for systemic light chain (AL-) amyloidosis. Thomas’ Hematopoietic Cell Transplantation. Eds. Stephen J. Forman MD, Robert S. Negrin MD, Joseph H. Antin MD, Frederick R. Appelbaum MD. John Wiley & Sons, Ltd; Singapore, USA. 2016. p. 724–41.

  17. 17.

    Wong SW, Larivee D, Warner M, Sprague KA, Fogaren T, Comenzo RL. Stem cell transplantation in patients with systemic AL amyloidosis referred for transplant after suboptimal responses to bortezomib-based initial therapy. Bone Marrow Transplant. 2017;52:936–7.

    CAS  Article  Google Scholar 

  18. 18.

    Cibeira MT, Sanchorawala V, Seldin DC, Quillen K, Berk JL, Dember LM, et al. Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation: long-term results in a series of 421 patients. Blood. 2011;118:4346–52.

    CAS  Article  Google Scholar 

  19. 19.

    Sanchorawala V, Sun F, Quillen K, Sloan JM, Berk JL, Seldin DC. Long-term outcome of patients with AL amyloidosis treated with high-dose melphalan and stem cell transplantation: 20-year experience. Blood. 2015;126:2345–7.

    Article  Google Scholar 

  20. 20.

    Gertz MA, Comenzo R, Falk RH, Fermand JP, Hazenberg BP, Hawkins PN, et al. Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, 18-22 April 2004. Am J Hematol. 2005;79:319–28.

    Article  Google Scholar 

  21. 21.

    Gertz MA, Lacy MQ, Dispenzieri A, Hayman SR, Kumar SK, Leung N, et al. Effect of hematologic response on outcome of patients undergoing transplantation for primary amyloidosis: importance of achieving a complete response. Haematologica. 2007;92:1415–8.

    Article  Google Scholar 

  22. 22.

    Palladini G, Dispenzieri A, Gertz MA, Kumar S, Wechalekar A, Hawkins PN, et al. New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes. J Clin Oncol. 2012;30:4541–9.

    CAS  Article  Google Scholar 

  23. 23.

    Sanchorawala V, Wright DG, Seldin DC, Falk RH, Finn KT, Dember LM, et al. High-dose intravenous melphalan and autologous stem cell transplantation as initial therapy or following two cycles of oral chemotherapy for the treatment of AL amyloidosis: results of a prospective randomized trial. Bone Marrow Transplant. 2004;33:381–8.

    CAS  Article  Google Scholar 

  24. 24.

    Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, et al. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015;21:1445–51.

    CAS  Article  Google Scholar 

  25. 25.

    Landau H, Smith M, Landry C, Chou JF, Devlin SM, Hassoun H, et al. Long-term event-free and overall survival after risk-adapted melphalan and SCT for systemic light chain amyloidosis. Leukemia. 2017;31:136–42.

    CAS  Article  Google Scholar 

  26. 26.

    Dhakal B, Strouse C, D’Souza A, Arce-Lara C, Esselman J, Eastwood D, et al. Plerixafor and abbreviated-course granulocyte colony-stimulating factor for mobilizing hematopoietic progenitor cells in light chain amyloidosis. Biol Blood Marrow Transplant. 2014;20:1926–31.

    CAS  Article  Google Scholar 

  27. 27.

    Bashir Q, Langford LA, Parmar S, Champlin RE, Qazilbash MH. Primary systemic amyloid light chain amyloidosis decompensating after filgrastim-induced mobilization and stem-cell collection. J Clin Oncol. 2011;29:e79–80.

    Article  Google Scholar 

  28. 28.

    Girnius S, Seldin DC, Meier-Ewert HK, Sloan JM, Quillen K, Ruberg FL, et al. Safety and efficacy of high-dose melphalan and auto-SCT in patients with AL amyloidosis and cardiac involvement. Bone Marrow Transplant. 2014;49:434–9.

    CAS  Article  Google Scholar 

  29. 29.

    Yeh JC, Shank BR, Milton DR, Qazilbash MH. Adverse prognostic factors for morbidity and mortality during peripheral blood stem cell mobilization in patients with light chain amyloidosis. Biol Blood Marrow Transplant. 2017;24:815–9.

    Article  Google Scholar 

  30. 30.

    Lisenko K, Wuchter P, Hansberg M, Mangatter A, Benner A, Ho AD, et al. Comparison of different stem cell mobilization regimens in AL amyloidosis patients. Biol Blood Marrow Transplant. 2017;23:1870–8.

    Article  Google Scholar 

  31. 31.

    Perotti C, Del Fante C, Viarengo G, Perlini S, Vezzoli M, Rodi G, et al. Peripheral blood progenitor cell mobilization and collection in 42 patients with primary systemic amyloidosis. Transfusion. 2005;45:1729–34.

    CAS  Article  Google Scholar 

  32. 32.

    Fricker SP. Physiology and pharmacology of plerixafor. Transfus Med Hemother. 2013;40:237–45.

    Article  Google Scholar 

  33. 33.

    Comenzo RL, Sanchorawala V, Fisher C, Akpek G, Farhat M, Cerda S, et al. Intermediate-dose intravenous melphalan and blood stem cells mobilized with sequential GM + G-CSF or G-CSF alone to treat AL (amyloid light chain) amyloidosis. Br J Haematol. 1999;104:553–9.

    CAS  Article  Google Scholar 

  34. 34.

    Gertz MA, Lacy MQ, Dispenzieri A, Ansell SM, Elliott MA, Gastineau DA, et al. Risk-adjusted manipulation of melphalan dose before stem cell transplantation in patients with amyloidosis is associated with a lower response rate. Bone Marrow Transplant. 2004;34:1025–31.

    CAS  Article  Google Scholar 

  35. 35.

    Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, et al. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013;27:823–8.

    CAS  Article  Google Scholar 

  36. 36.

    McCarthy PL, Holstein SA, Petrucci MT, Richardson PG, Hulin C, Tosi P, et al. Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: a meta-analysis. J Clin Oncol. 2017;35:3279–89.

    CAS  Article  Google Scholar 

  37. 37.

    Scheid C, Sonneveld P, Schmidt-Wolf IG, van der Holt B, el Jarari L, Bertsch U, et al. Bortezomib before and after autologous stem cell transplantation overcomes the negative prognostic impact of renal impairment in newly diagnosed multiple myeloma: a subgroup analysis from the HOVON-65/GMMG-HD4 trial. Haematologica. 2014;99:148–54.

    CAS  Article  Google Scholar 

  38. 38.

    Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, et al. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007;109:465–70.

    CAS  Article  Google Scholar 

  39. 39.

    Sanchorawala VFK, Fennessey S, Shelton A, Dember LM, Zeldis JB, Skinner M, et al. Durable haematologic complete responses can be achieved with lenalidomide in AL amyloidosis. Amyloid. 2010;17:84a.

    Google Scholar 

  40. 40.

    Specter R, Sanchorawala V, Seldin DC, Shelton A, Fennessey S, Finn KT, et al. Kidney dysfunction during lenalidomide treatment for AL amyloidosis. Nephrol Dial Transplant. 2010;26:881–6.

    Article  Google Scholar 

  41. 41.

    Tapan U, Seldin DC, Finn KT, Fennessey S, Shelton A, Zeldis JB, et al. Increases in B-type natriuretic peptide (BNP) during treatment with lenalidomide in AL amyloidosis. Blood. 2010;116:5071–2.

    CAS  Article  Google Scholar 

  42. 42.

    Cowan AJ, Seldin DC, Skinner M, Quillen K, Doros G, Tan J, et al. Amyloid deposits in the bone marrow of patients with immunoglobulin light chain amyloidosis do not impact stem cell mobilization or engraftment. Biol Blood Marrow Transplant. 2012;18:1935–8.

    CAS  Article  Google Scholar 

  43. 43.

    Saba N, Sutton D, Ross H, Siu S, Crump R, Keating A, et al. High treatment-related mortality in cardiac amyloid patients undergoing autologous stem cell transplant. Bone Marrow Transplant. 1999;24:853–5.

    CAS  Article  Google Scholar 

  44. 44.

    Falk RH. Diagnosis and management of the cardiac amyloidoses. Circulation. 2005;112:2047–60.

    Article  Google Scholar 

  45. 45.

    Comenzo RL, Gertz MA. Autologous stem cell transplantation for primary systemic amyloidosis. Blood. 2002;99:4276–82.

    CAS  Article  Google Scholar 

  46. 46.

    Dispenzieri A, Gertz MA, Kyle RA, Lacy MQ, Burritt MF, Therneau TM, et al. Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis. J Clin Oncol. 2004;22:3751–7.

    CAS  Article  Google Scholar 

  47. 47.

    Dispenzieri A, Gertz MA, Kyle RA, Lacy MQ, Burritt MF, Therneau TM, et al. Prognostication of survival using cardiac troponins and N-terminal pro-brain natriuretic peptide in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation. Blood. 2004;104:1881–7.

    CAS  Article  Google Scholar 

  48. 48.

    Gertz MA, Lacy MQ, Dispenzieri A, Kumar SK, Dingli D, Leung N, et al. Refinement in patient selection to reduce treatment-related mortality from autologous stem cell transplantation in amyloidosis. Bone Marrow Transplant. 2013;48:557–61.

    CAS  Article  Google Scholar 

  49. 49.

    Gertz MA, Leung N, Lacy MQ, Dispenzieri A, Zeldenrust SR, Hayman SR, et al. Clinical outcome of immunoglobulin light chain amyloidosis affecting the kidney. Nephrol Dial Transplant. 2009;24:3132–7.

    CAS  Article  Google Scholar 

  50. 50.

    Palladini G, Hegenbart U, Milani P, Kimmich C, Foli A, Ho AD, et al. A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis. Blood. 2014;124:2325–32.

    CAS  Article  Google Scholar 

  51. 51.

    Wong SW, Toskic D, Warner M, Varga C, Moreno-Koehler A, Fein D, et al. Primary amyloidosis with renal involvement: outcomes in 77 consecutive patients at a single center. Clin Lymphoma Myeloma Leuk. 2017;17:759–66.

    Article  Google Scholar 

  52. 52.

    Leung N, Slezak JM, Bergstralh EJ, Dispenzieri A, Lacy MQ, Wolf RC, et al. Acute renal insufficiency after high-dose melphalan in patients with primary systemic amyloidosis during stem cell transplantation. Am J Kidney Dis. 2005;45:102–11.

    CAS  Article  Google Scholar 

  53. 53.

    Leung N, Kumar SK, Glavey SV, Dispenzieri A, Lacy MQ, Buadi FK, et al. The impact of dialysis on the survival of patients with immunoglobulin light chain (AL) amyloidosis undergoing autologous stem cell transplantation. Nephrol Dial Transplant. 2016;31:1284–9.

    CAS  Article  Google Scholar 

  54. 54.

    Munshi NC, Anderson KC, Bergsagel PL, Shaughnessy J, Palumbo A, Durie B, et al. Consensus recommendations for risk stratification in multiple myeloma: report of the International Myeloma Workshop Consensus Panel 2. Blood. 2011;117:4696–700.

    CAS  Article  Google Scholar 

  55. 55.

    Neben K, Lokhorst HM, Jauch A, Bertsch U, Hielscher T, van der Holt B, et al. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012;119:940–8.

    CAS  Article  Google Scholar 

  56. 56.

    Neben K, Jauch A, Hielscher T, Hillengass J, Lehners N, Seckinger A, et al. Progression in smoldering myeloma is independently determined by the chromosomal abnormalities del(17p), t(4;14), gain 1q, hyperdiploidy, and tumor load. J Clin Oncol. 2013;31:4325–32.

    Article  Google Scholar 

  57. 57.

    Bochtler T, Hegenbart U, Cremer FW, Heiss C, Benner A, Hose D, et al. Evaluation of the cytogenetic aberration pattern in amyloid light chain amyloidosis as compared with monoclonal gammopathy of undetermined significance reveals common pathways of karyotypic instability. Blood. 2008;111:4700–5.

    CAS  Article  Google Scholar 

  58. 58.

    Bryce AH, Ketterling RP, Gertz MA, Lacy M, Knudson RA, Zeldenrust S, et al. Translocation t(11;14) and survival of patients with light chain (AL) amyloidosis. Haematologica. 2009;94:380–6.

    CAS  Article  Google Scholar 

  59. 59.

    Hayman SR, Bailey RJ, Jalal SM, Ahmann GJ, Dispenzieri A, Gertz MA, et al. Translocations involving the immunoglobulin heavy-chain locus are possible early genetic events in patients with primary systemic amyloidosis. Blood. 2001;98:2266–8.

    CAS  Article  Google Scholar 

  60. 60.

    Bochtler T, Hegenbart U, Kunz C, Granzow M, Benner A, Seckinger A, et al. Translocation t(11;14) is associated with adverse outcome in patients with newly diagnosed AL amyloidosis when treated with bortezomib-based regimens. J Clin Oncol. 2015;33:1371–8.

    CAS  Article  Google Scholar 

  61. 61.

    Bochtler T, Hegenbart U, Kunz C, Benner A, Kimmich C, Seckinger A, et al. Prognostic impact of cytogenetic aberrations in AL amyloidosis patients after high-dose melphalan: a long-term follow-up study. Blood. 2016;128:594–602.

    CAS  Article  Google Scholar 

  62. 62.

    Warsame R, Kumar SK, Gertz MA, Lacy MQ, Buadi FK, Hayman SR, et al. Abnormal FISH in patients with immunoglobulin light chain amyloidosis is a risk factor for cardiac involvement and for death. Blood Cancer J. 2015;5:e310.

    CAS  Article  Google Scholar 

  63. 63.

    Jaccard A, Comenzo RL, Hari P, Hawkins PN, Roussel M, Morel P, et al. Efficacy of bortezomib, cyclophosphamide and dexamethasone in treatment-naive patients with high-risk cardiac AL amyloidosis (Mayo Clinic stage III). Haematologica. 2014;99:1479–85.

    CAS  Article  Google Scholar 

  64. 64.

    Wechalekar AD, Schonland SO, Kastritis E, Gillmore JD, Dimopoulos MA, Lane T, et al. A European collaborative study of treatment outcomes in 346 patients with cardiac stage III AL amyloidosis. Blood. 2013;121:3420–7.

    CAS  Article  Google Scholar 

  65. 65.

    Weiss BM, Wong SW, Comenzo RL. Beyond the plasma cell: emerging therapies for immunoglobulin light chain amyloidosis. Blood 2016;127:2275–80. https://doi.org/10.1182/blood-2015-11-681650

    CAS  Article  Google Scholar 

  66. 66.

    Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, et al. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017;130:597–605.

    CAS  Article  Google Scholar 

  67. 67.

    Kaufman GP, Schrier SL, Lafayette RA, Arai S, Witteles RM, Liedtke M. Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis. Blood. 2017;130:900–2.

    CAS  Article  Google Scholar 

  68. 68.

    Gertz et al. Stem Cell Transplantation Compared With Melphalan Plus Dexamethasone in the Treatment of Immunoglobulin Light Chain Amyloidosis. Cancer. 2016.

  69. 69.

    M.A. Gertz, E. Blood, D.H. Vesole, et al. A multicenter phase 2 trial of stem cell transplantation for immunoglobulin light-chain amyloidosis (E4A97): an Eastern Cooperative Oncology Group Study Bone Marrow Transplant, 34 (2004), pp. 149–54.

  70. 70.

    Skinner et al. High-Dose Melphalan and Autologous Stem-Cell Transplantation in Patients with AL Amyloidosis: An 8-Year Study. Ann Int Med 2004;140:85–93.

    CAS  Article  Google Scholar 

  71. 71.

    Dispenzieri et al. Patients with immunoglobulin light chain amyloidosis undergoing autologous stem cell transplantation have superior outcomes compared with patients with multiple myeloma: a retrospective review from a tertiary referral center. Bone Marrow Transplantation volume 48, 1302–07 (2013).

    CAS  Article  Google Scholar 

  72. 72.

    Comenzo RL. How I treate amyloidosis. Blood. 2009.

  73. 73.

    Perfetti et al. Long term results of a risk-adapted approach to melphalan conditioning in ASCT for primary AL amyloidosis Haematologica, 2006.

Download references


We thank the Division of Hematology-Oncology and Departments of Medicine and Pathology and Laboratory Medicine at Tufts for their continued support, and also acknowledge the support by the Amyloidosis and Myeloma Research Fund at Tufts, the Cam Neely and John Davis Myeloma Research Fund, the John C Davis Program for Myeloma and Amyloid at Tufts, the Sidewater Family Fund, the Lavonne Horowitz Trust, the Werner and Elaine Dannheiser Fund for Research on the Biology of Aging of the Lymphoma Foundation, David and Barbara Levine (in memoriam), and the Demarest Lloyd Jr Foundation.

Author information



Corresponding author

Correspondence to Cindy Varga.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Varga, C., Comenzo, R.L. High-dose melphalan and stem cell transplantation in systemic AL amyloidosis in the era of novel anti-plasma cell therapy: a comprehensive review. Bone Marrow Transplant 54, 508–518 (2019). https://doi.org/10.1038/s41409-018-0284-4

Download citation