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 . Patients present with visceral organ damage manifested as proteinuria, restrictive cardiomyopathy, hepatomegaly, and autonomic or peripheral neuropathy . Herein, the key aspects of stem cell transplantation (SCT) in the treatment of AL will be reviewed.
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 . 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 . 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 . 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 . 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 .
The importance of achieving a hematologic response post-SCT has been illustrated in many series (Table 4) . 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).
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) . 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 .
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 .
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 . 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) , 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) . Risk factors for poor stem cell yield include increased age and prior exposure to alkylating agents . Failure rates using granulocyte macrophage-stimulating factor (G-CSF) alone for stem cell collection are as high as 5%–10% . In Germany, many patients are mobilized with chemotherapy and G-CSF, except patients with advanced cardiac involvement or those who are post-heart transplant .
Plerixafor is a reversible antagonist to the alpha chemokine receptor CXCR4 implicated in the homing of hematopoietic stem cells to the bone marrow . 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 .
Risk-adapted melphalan dosing
The use of various dose reductions of melphalan has been explored  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%) . 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 . In 2017, the long-term outcomes of patients treated in this way (n = 143) were reported . 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% .
Post-SCT maintenance therapy in MM with the immunomodulatory drug lenalidomide has been shown to be beneficial with respect to PFS and OS . Bortezomib has also been used in maintenance post-SCT in MM . 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 , 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 . Whether other features of the marrow environment or immune system may be affected is not known.
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) . 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 . 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) . 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 . 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].
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 . 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].
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 . 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 . 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 . 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) . 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) .
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 . 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 . Future directions include the use of immunotherapy, in particular anti-CD38 monoclonal antibodies such as Daratumumab . 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.
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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.
Conflict of interest
The authors declare that they have no conflict of interest.
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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
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