DOI: https://doi.org/https://doi.org/10.57187/s.4219
Treatment strategies for systemic light-chain amyloidosis (AL) have evolved since the publication of the first consensus recommendations by the experts of the Swiss Amyloidosis Network (SAN) in 2020 [1]. To address and discuss the new aspects, the SAN held its third joint meeting in April 2024 in Zurich, Switzerland. Participants were clinical specialists from all fields of medicine involved in the care of amyloidosis patients. The discussion resulted in an update of the SAN recommendations on light-chain amyloidosis with a particular focus on treatment and supportive care. The following update reflects the available published evidence, including the results of clinical trials and recently published abstracts, as well as existing guidelines from international societies and expert consensus.
The SAN recommendations are tailored to address the structures of the Swiss healthcare system and aim to provide guidance for clinical practitioners in Switzerland. To this end, the manuscript avoids in-depth discussions of the literature and diagnostic considerations, instead concentrating on practical “therapeutic recommendations”. This version is not intended to be exclusive, particularly given the anticipation of continued rapid therapeutic advancements.
Prior to discussion within the SAN, we performed a PubMed search, focusing on studies published since the release of the first guidelines in 2020. This search included clinical trial publications, treatment recommendations by other societies, review articles as well as published meeting abstracts with high relevance to the field. Relevant publications on light-chain amyloidosis in English were first reviewed and summarised by the first and last author and later discussed, point by point, with experts of the SAN. To increase transparency, the panel used the GRADE approach to assess the underlying level of evidence [2] (table 1).
Table 1GRADE levels of evidence.
| Grade | Level | Origin of evidence |
| A | I | (Meta)-analysis of ≥1 randomised controlled trial (RCT) |
| B | IIA | ≥1 non-randomised trial (incl. phase II and case-control) |
| IIB | ≥1 other prospective non-experimental study (incl. observational studies) | |
| III | ≥1 descriptive study or abstract of meta-analysis and/or randomised controlled trial | |
| C | IV | Expert consensus or opinion statement and/or experience of respected authorities |
Where published evidence was limited or insufficient, consensual expert opinions were included in the recommendations. Evaluation of the resulting recommendations was performed by all authors in a stepwise approach. The strength of a recommendation was graded as either strong (Grade A or B; “The SAN recommends…”) or conditional (Grade C; “The SAN suggests…”). To strengthen methodological transparency and quality, the final update followed best practice for guideline development according to the principles of AGREE II [3] (Appraisal of Guidelines for Research and Evaluation). The manuscript was finally approved by all active members of the SAN as listed in the author section.
In anticipation of an evolving treatment landscape and more therapeutic advances, the recommendations will be considered current for the following three years or until the publication of an earlier update by the SAN, as future progress may require earlier revisions.
The revised Mayo 2004 criteria and its European modification are the two best established staging systems, both including cardiac biomarkers (NT-proBNP, Troponin-T), given that the degree of cardiac involvement has been shown to be the most relevant prognostic factor [4, 5]. For assessment of renal involvement, a separate renal staging system has been developed predicting renal involvement and outcome [6]. Baseline assessment generally also includes evaluation of “fitness” for high-dose (HD) melphalan treatment and autologous stem cell transplantation (ASCT). This initial evaluation is crucial as it affects intensity and sequence of treatment upfront and downstream. Criteria for assessing fitness are subject to ongoing debate. In Switzerland, the criteria proposed by the EHA-ISA working group are the best established [7, 8].
The SAN suggests the use of evaluation criteria for high-dose therapy / autologous stem cell transplantation as proposed by the EHA-ISA working group [7, 8]. (Grade C, Level III)
Importantly, although clonal plasma cells are the amyloid-producing cell of origin in most cases, the predominance of lymphoplasmacytic cells should always be excluded in patients with IgM-related amyloidosis, as it modifies the proposed treatment algorithm [9] (see section “IgM-directed treatment”). Organ response remains the ultimate goal of treatment and usually occurs within months after the start of treatment, depending on the speed and depth of the haematological response [10, 11]. Criteria of haematological and organ response have continuously been improved in recent years (table 2). Haematological and organ response should be validated at least at 3 and 6 months after initiation of therapy [12]. However, in routine care, assessments every 1–2 months are an established practice. As the clinical outcome has been shown to be directly related to the depth of response [10], obtaining at least a very good partial response (VGPR) is considered standard. While achievement of a haematological complete response is desirable, assessment of bone marrow minimal residual disease (MRD) is the subject of clinical trials and not yet established as a routine response parameter [13].
The SAN recommends assessment of haematological and organ response at least at the beginning of every cycle and at the end of treatment (every month under treatment, every 3–6 months under surveillance, respectively). (Grade B, Level IIB)
Insufficient response: The SAN suggests change of treatment if no haematological very good partial response is reached within 3–4 months from initiation. (Grade C, Level IV)
Table 2Response criteria.
| Haematological* [12, 14] | ||
| Complete response (CR) | 1. Negative serum and urine immunofixation AND | |
| 2. Free light-chain ratio within reference range OR uninvolved free light chain > involved free light chain | ||
| Very good partial response (VGPR) | dFLC <40 mg/l | |
| Partial response (PR) | Decrease of dFLC ≥50% | |
| No response (NR) | All other | |
| Organ response [6, 10, 15] | ||
| Complete response (CR) | Heart | NTproBNP: nadir ≤350 ng/l |
| Kidney | Proteinuria: nadir ≤200 mg / 24 h | |
| Liver | Alkaline phosphatase: nadir ≤2 × ULN | |
| Very good partial response (VGPR) | Heart | NTproBNP: decrease >60%, not meeting complete response |
| Kidney | Proteinuria: decrease >60% not meeting complete response | |
| Liver | Alkaline phosphatase: decrease >60% not meeting complete response | |
| Partial response (PR) | Heart | NTproBNP: decrease of 30% to 60%, not meeting complete response |
| Kidney | Proteinuria: decrease of 30% to 60% of baseline OR <0.5 g/24 h if >0.5 g/24 h/d at baseline AND no worsening of eGFR >25% of baseline | |
| Liver | Alkaline phosphatase: decrease ≥50% OR decrease of liver size ≥2 cm | |
| Peripheral nervous system | Electromyoneurography: any improvement | |
| No response (NR) | None of the response criteria is met | |
dFLC: difference involved minus uninvolved free light chain; eGFR: estimated glomerular filtration rate; NTproBNP: N-terminal pro-B-type natriuretic peptide; ULN: upper limit normal.
* Adapted criteria for patients with low baseline free light-chain burden (<50 mg/l) [16].
For patients with rMayo Stage I–IIIa, as represented in the ANDROMEDA trial [17], first-line treatment generally includes induction with Dara-CyBorD (Daratumumab, Cyclophosphamide, Bortezomib and Dexamethasone). The potential benefit of upfront high-dose therapy / autologous stem cell transplantation has not been clearly established yet. The only RCT on this particular matter did not show a survival benefit but was criticised for its unrepresentative inclusion criteria [18]. The ongoing uncertainty has led to country-specific differences in the indication for performing high-dose therapy / autologous stem cell transplantation. In general, given the rarity of the disease and the many unknown variables, if available, treatment in clinical trials should be considered. In Switzerland, treatment with Dara-CyBorD requires prior health insurance approval, which is generally granted. The SAN has agreed on the following recommendations regarding first-line therapy (figure 1):
The SAN recommends induction with Dara-CyBorD. (Grade A, Level I)
For patients fit for high-dose therapy / autologous stem cell transplantation, the SAN suggests early stem cell collection after 2–4 cycles of induction. (Grade C, Level IV)
The SAN recommends upfront treatment with high-dose therapy / autologous stem cell transplantation after insufficient haematological response (no very good partial response after 4 months) to induction or in patients with concomitant symptomatic myeloma [8, 19–21]. (Grade B, Level IIB)
The SAN recommends deferral of high-dose therapy / autologous stem cell transplantation in fit patients who achieve at least very good partial response after 4 induction cycles [24]. (Grade B, Level IIB)
If high-dose therapy / autologous stem cell transplantation is not performed or is deferred, the SAN recommends continuation of induction with Dara-CyBorD for a total of 6 cycles followed by 18 cycles of maintenance with daratumumab [17]. (Grade B, Level IIA)
In Stage I–IIIa unfit for high-dose therapy; the SAN recommends induction with 6 cycles of Dara SC-CyBorD followed by 18 cycles of daratumumab maintenance [17]. (Grade A, Level I)
In Stage IIIb/IV with advanced cardiac involvement; the SAN recommends a daratumumab-based induction treatment, i.e. as monotherapy, in combination with dexamethasone [25], or as a modified, dose-reduced Dara-CyBorD protocol [26]. (Grade B, Level III–IV)
In IgM-type amyloidosis, non-Hodgkin’s lymphoma (NHL) clonal B cells (less commonly plasma cells) are usually at the origin of the disease. When clonal B cells are identified, rituximab-based treatment regimens are established first-line therapies [9, 27, 28], combinations with Bruton’s tyrosine kinase (BTK) inhibitors [29], bendamustin, cyclophosphamide, chlorambucil, bortezomib and systemic corticosteroids may be appropriate depending on the biology of the underlying clone [27, 29, 30]. Plasma cell-directed treatment may also be appropriate if plasma cells are (part of) the identified clonal population.
The SAN recommends rituximab-based induction therapy in the treatment of IgM-associated amyloidosis. (Grade B, Level IIB)
Figure 1First-line treatment algorithm as proposed by the Swiss Amyloidosis Network (SAN). ASCT: autologous stem cell transplantation; BSC: best supportive care; CyBorD: cyclophosphamide-bortezomib-dexamethasone; Dara: daratumumab; Dex: dexmethasone; HD: high-dose therapy; PBSC: peripheral blood stem cells; rMayo: revised Mayo stage; VGPR: haematological very good partial remission.
Although the pathological plasma cell clone is generally responsive to multiple treatment options, many therapeutic agents are poorly tolerated and disease- and treatment-related morbidity and mortality may be significant, especially at the beginning of treatment. Multidisciplinary evaluation and frequent adjustment of the therapeutic regimen are common, and individualised symptom management is an integral part of therapy (figure 2).
Figure 2Treatment algorithm for r/r light-chain amyloidosis (AL) as proposed by the SAN (SAN). ASCT: autologous stem cell transplantation; BSC: best supportive care; Dara: daratumumab; Dexa: dexamethasone; HD: high-dose therapy; IMIDs: immunomodulatory agents; PBSC: peripheral blood stem cells; PI: proteasome inhibitor; r/r: relapsed/refractory; t(11;14): translocation 11;14; 1L: first-line treatment.
The optimal timing of second-line treatment initiation is a matter of debate [31], weighing the apparent benefits (prevention of organ deterioration ) against potential therapy-associated side effects. Palladini et al. suggested treatment restart at high risk for progression, defined as a dFLC of >20 mg/l, a level >20% of baseline and a >50% increase from the lowest value reached [32].
The SAN recommends initiation of rescue therapy in haematological relapse as proposed by Palladini et al. [32]. (Grade B, Level IIB)
The SAN recommends earlier initiation (at biochemical loss of response) of rescue therapy in patients with cardiac involvement to prevent cardiac deterioration [32]. (Grade B, Level III)
In the relapsed/refractory setting, a variety of possible treatment options are available, most of which are derived from myeloma treatment [31]. The optimal type and intensity of treatment depends on previous exposure and response, time to relapse and current disease stage/comorbidities. Access to treatment can be challenging however, as there is no guaranteed reimbursement beyond first-line treatment in the absence of plasma cell myeloma in Switzerland. Requests for cost coverage must be justified in accordance with Article 71 of the Health Insurance Act [33].
The SAN recommends r/r treatment with an anti-CD38-Ab and/or a proteasome inhibitor, if not already included in previous therapy [34, 35]. (Grade B, Level IIB)
The SAN suggests retreatment with the initial regimen in patients with good initial response and tolerance of first-line and after at least 24 months of treatment-free remission. (Grade C, Level IV)
If relapse occurs after the current standard-of-care, Dara-CyBorD or similar protocols including an anti-CD38-Ab and proteasome inhibitor, there is no universal standard for further-line therapy and the available evidence is often limited to registry data and small case series. Therefore, the following options are Grade B or C recommendations and are based on expert consensus within the SAN.
Venetoclax is a B-cell lymphoma-2 (BCL-2) inhibitor active in plasma cell neoplasia such as myeloma (PCM), particularly those harbouring t(11;14), which is associated with high BCL-2 expression [36–38]. Approximately 50% of patients with light-chain amyloidosis show t(11;14) [39, 40], making venetoclax a valuable option. Growing evidence in a heavily pretreated patient population demonstrates efficacy as a single agent or in combination with an acceptable safety profile, with tumour lysis syndrome (TLS) being rare [36, 37]. If not already performed at diagnosis, an iFiSH and/or BCL-2 expression analysis is a prerequisite for treatment with venetoclax.
The SAN recommends second-line treatment with venetoclax in patients with t(11;14) and previous exposure to an anti-CD38-Ab. (Grade B, Level IIB)
The SAN suggests venetoclax in patients with t(11;14), as monotherapy or in combination with an anti-CD38-Ab and/or a proteasome inhibitor in case of no pre-exposure. (Grade C, Level IV)
Various case series and phase II trials report the efficacy of immunomodulatory agents (IMIDs) in pretreated patients. However, unlike plasma cell myeloma, the tolerability of immunomodulatory agents in light-chain amyloidosis is poor, the discontinuation rate is high (>40%) and reduced cardiac and renal function as well as possible cytopenia are major limiting factors [41]. Published evidence favours pomalidomide over lenalidomide due to better tolerability [41, 42]. Potential effects on volume homeostasis, cardiac function (biomarkers/rhythm) and renal function should be closely monitored.
In patients with progression to standard treatment, adequate organ function and without t(11;14), the SAN recommends treatment with immunomodulatory agents ± dexamethasone as second-line treatment [43, 44]. (Grade B, Level IIB)
Melphalan alone or in combination with dexamethasone (MelDex) has been studied quite extensively in the field of light-chain amyloidosis. In selected patients, without significant comorbidities or advanced cardiac involvement, it has been shown to be effective but is associated with relevant toxicity [46, 47].
The SAN recommends treatment with melphalan/dexamethasone (MEL 0.22 mg/kg/d and Dex 20–40 mg/d , d1–4 every 28 days [46]) in patients without significant cardiac involvement (<revised Mayo Stage III) and not qualifying for the other therapeutic options. (Grade A, Level I)
If not already performed upfront, in patients considered medically fit according to the proposed criteria (see above, “Considerations before and during treatment”) and when autologous stem cells are available, high-dose therapy and autologous stem cell transplantation may be considered at relapse [24].
The SAN recommends early consideration of high-dose therapy / autologous stem cell transplantation as part of relapse treatment for eligible patients. (Grade B, Level III)
Prior reinduction is optional. (Grade C, Level IV)
Ixazomib-dexamethasone was evaluated in a phase III study [48] (Tourmaline) where it showed no advantage in haematological response over physician’s choice. As the proteasome-inhibitor bortezomib is often part of first- or second-line treatment, an additional benefit of ixazomib at later time points is expected only in very specific scenarios, i.e. if tolerability is of higher priority [49] (see below, “Supportive care and treatment in advanced organ involvement”).
The SAN recommends treatment with ixazomib only in selected scenarios and if bortezomib is not feasible. (Grade A, Level 1)
If patients progress after the proposed second-line options and do not qualify for retreatment, the optimal treatment will again depend on prior exposure, comorbidities and potential access to novel therapies, which is often limited to patients with associated symptomatic myeloma.
Early retrospective studies have been published demonstrating efficacy and good tolerability of BCMA-directed bispecific antibodies [50, 51]. Given the often low plasma cell burden in light-chain amyloidosis and the therefore high “effector to target” ratio, they potentially reflect a very effective, well-tolerated and promising treatment option.
The SAN suggests treatment with BCMA-BiTe in eligible patients, relapsed/refractory or not qualifying to all other established 2nd line treatment options. (Grade C, Level III)
Preliminary data on successful CAR-T cell treatment has recently been published in a very selected patient population [52–54]. Given its potential side effects in patients with severe organ involvement and its financial burden, CAR-T cells are not yet established outside of clinical trials and rather reflect a potential future option.
So far, the SAN does not recommend treatment with CAR-T cells outside clinical trials. (Grade B, Level IIB)
Carfilzomib has been shown to be associated with a high rate of severe adverse events in patients with light-chain amyloidosis, especially resulting from its potential cardiac toxicity [55].
If other options are available, the SAN does not recommend carfilzomib-based treatment. (Grade B, Level IIA)
Various light-chain amyloid-targeting agents have been developed. To date, none of them has been translated into clinical practice. A phase III study with birtamimab, a humanised IgG1 binding circulating and deposited light-chain fibrils, is currently recruiting (AFFIRM-AL). Prior phase I/II studies have shown somewhat inconsistent results [56–59].
Localised amyloidosis, if not involving a critical site, generally does not impair survival of affected patients and almost never progresses to a systemic disease [60]. The treatment of “amyloidoma” is therefore reserved for symptomatic disease and usually involves surgical excision whenever possible (although evidence is sparse) [61, 62]. In selected cases where surgery is not feasible, radiotherapy or laser treatment can be an alternative local treatment options [63].
The SAN recommends local treatment (such as surgical resection) of localised light-chain amyloidosis in symptomatic patients. (Grade B, Level III)
If local treatment is not feasible and need for therapy is high, an individualised approach with systemic treatment may be considered. (Grade C, Level IV)
The SAN recommends annual follow-up to screen for local recurrence [64]. (Grade B, Level III)
During follow-up, the SAN generally suggests not to perform repetitive extensive evaluation for systemic involvement, but to perform a regular basic screening with NT-proBNP and albuminuria measurements. (Grade B, Level III)
Supportive care requires a multidisciplinary approach. Monitoring of organ function includes repetitive assessment of involved organs and screening of new potential end-organ disease [65]. The SAN suggests the following approach [66–68]:
The SAN suggests a comprehensive cardiac assessment every 6–12 months (cardiac biomarkers, ECG, Holter ECG, echocardiography, MRI if image quality is poor).
The SAN suggests routine renal assessment at least every 3 months with standard measurements (eGFR, proteinuria in spot urine) and a more comprehensive assessment every 6–12 months in case of significant renal involvement or treatment toxicity.
The SAN suggests assessment of liver enzymes at least every 3 months and a more comprehensive assessment every 12 months (sonography, liver stiffness) in case of involvement or associated toxicity.
The SAN suggests clinical screening for polyneuropathy at least every 3 months and a comprehensive assessment (clinical examination, autonomic testing and ENMG) every 12 months in case of organ involvement or significant treatment-related neuropathy. Additional skin biopsy for assessment of small-fibre neuropathy can be considered [69, 70].
Supportive care includes symptom management; anti-infective strategies; management of cardiac and renal involvement, neuropathy and GI dysfunction; and treatment of potential therapy-induced toxicities [65, 71]. Optimal supportive care is achieved through multidisciplinary care, preferably within the SAN. Due to the rarity of the disease and the heterogeneity of the clinical picture, studies focusing on supportive measures are rare. Therefore, many of the following recommendations are extrapolated from similar scenarios in other diseases. The few supportive care drugs that have been studied specifically in light-chain amyloidosis include doxycycline and Epigallo-Catechin-Gallat (EGCG). However, after promising early-phase study results, doxycycline failed to show significant benefit in a phase III trial and should therefore no longer be part of supportive care in light-chain amyloidosis [72]. Similarly, although often associated with much patient hope, there is only insufficient evidence to support the use of Epigallo-Catechin-Gallat or other green tea extracts [73, 74]. Patients should be advised not to co-administer Epigallo-Catechin-Gallat with immunochemotherapy agents due to potential interactions.
The SAN recommends against the use of doxycycline as a supportive agent in light-chain amyloidosis. (Grade A, Level I)
The SAN suggests not to use Epigallo-Catechin-Gallat in light-chain amyloidosis during chemo-immunotherapy. (Grade C, Level IV)
The most common early clinical manifestations of cardiac involvement in light-chain amyloidosis are heart failure with preserved ejection fraction (HFpEF), with predominant diastolic dysfunction and its consequences. Fluid retention with elevated filling pressures together with structural alterations in the atria increase the likelihood for atrial fibrillation and thromboembolic stroke. Amyloid deposition can also lead to heart block and arrhythmia such as ventricular tachycardia.
As early mortality is high in patients with advanced cardiac involvement (revised Mayo Stage IV / European modification Stage IIIb), immediate initiation of plasma cell-directed therapy is crucial. Treatment requires close collaboration with heart failure specialists and may even require in-hospital monitoring during the first days of treatment. Daratumumab alone or in combination with dexamethasone has been shown to be safe and effective as initial treatment [25] (see section “First-line treatment of light-chain amyloidosis”).
In advanced cardiac involvement (rMayo IV), the SAN suggests in-hospital monitoring during initiation of treatment. (Grade C, Level IV)
Administration of diuretics is often required (furosemide or torasemide ± spironolactone). However, careful dose titration is advised to avoid symptomatic hypotension and significant reduction of preload, which may further deteriorate cardiac function. Potential potassium supplementation and restriction of salt and volume intake may be advisable [67].
Standard heart failure therapy including beta-blockers, RAAS inhibitors and calcium-channel blockers should be used with great caution as they are often not well tolerated and may worsen clinical symptoms (orthostatic hypotension, volume overload) [75].
The SAN suggests initiation of loop diuretics in patients with volume overload (low starting dose, e.g. torasemide 5–10 mg). (Grade C, Level IV)
The SAN suggests that calcium-channel blockers should generally be avoided. RAAS inhibitors and beta-blockers should only be used in selected cases and with great caution [76, 77]. (Grade C, Level IV)
The SAN cannot recommend for or against treatment with SGLT2 inhibitors due to insufficient evidence. (Grade C, Level IV)
Heart transplant is an option for eligible patients in the absence of severe other organ involvement [78, 79]. It should always be followed by very close monitoring of haematological response and a low threshold for light-chain amyloidosis directed treatment.
The SAN recommends evaluation of heart transplantation in young patients. (Grade B, Level IIb)
Due to its frequency, arrhythmia should be actively screened for (see section “Monitoring during follow-up” above). Antiarrhythmic therapy should generally be limited to amiodarone. Rate control with a beta-blocker is also an option, but heart rate should not be lowered too much as cardiac output depends on heart rate with stroke volume fixed due to amyloid deposition [80].
If required, the SAN suggests pharmacological antiarrhythmic therapy preferably with amiodarone [80, 81]. (Grade C, Level IV)
With cardiac involvement, all patients with atrial fibrillation (Afib) are at very high risk of thromboembolic events [82]. Oral anticoagulation, irrespective of the CHA2DS2-VA score, is therefore generally advisable in the absence of overt bleeding or amyloidosis-associated coagulopathies. Particular attention should also be given to ventricular arrhythmias with the risk for sudden cardiac death [83]. Although an implanted cardiac defibrillator (ICD) may potentially be life-saving, its long-term benefit on mortality has not yet been proven in cardiac light-chain amyloidosis [84].
The SAN suggests oral anticoagulation irrespective of CHA2DS-VA in patients with cardiac involvement and Afib (unless there is significant coagulopathy). (Grade C, Level IV)
In selected patients with atrial mechanical dysfunction and restrictive filling pattern (severe diastolic dysfunction), anticoagulation can be evaluated in the absence of Afib. (Grade C, Level IV)
The SAN suggest the use of ICD in cardiac amyloidosis only in selected cases and after interdisciplinary discussion [85–87]. (Grade B, Level IIa)
The SAN cannot recommend for or against catheter ablation or LAA-occlusion in patients with cardiac light-chain amyloidosis. (Grade C, Level IV)
Fluid management and diuretic therapy (preferably loop diuretics, may be combined with thiazides and/or spironolactone in diuretic resistance) are among the mainstays of treatment. To date, evidence to support albumin infusions is insufficient. In patients with progressive hypoalbuminaemia, management of haemostasis can be particularly challenging (see section “Management of gastrointestinal involvement and haemostasis”).
The SAN does not generally suggest prophylactic anticoagulation in severe nephrotic syndrome with serum albumin <25 g/l due to the potentially increased risk of bleeding. (Grade C, Level IV)
In patients with renal light-chain amyloidosis and proteinuria, the SAN does not recommend anti-proteinuric treatment with RAAS-blocking agents, as their potential harm in co-existing autonomic dysfunction and cardiac amyloidosis may outweigh the potential benefits [88–90]. (Grade B, Level IIb)
The SAN suggests salt and fluid restriction in resistant oedema. (Grade C, Level IV)
RAAS-blocking agents may be introduced, but caution is advised concerning hypotension and autonomic dysfunction (see above). Optimal control of independent cardiovascular risk factors is recommended. Dialysis has been shown to improve survival particularly in patients without end-stage heart disease [91–94]. Peritoneal dialysis may be preferable over haemodialysis in end-stage renal disease and heart failure, given its superior haemodynamic tolerance [95]. Standard first-line Dara SC-CyBorD can be safely administered to patients with end-stage renal disease with or without dialysis. However, many other light-chain amyloidosis treatment options should be dose-reduced or omitted in patients with end-stage renal disease.
The SAN recommends evaluation of dialysis in end-stage renal disease. (Grade B, Level IIB)
Kidney transplantation has been shown to have similar outcomes in renal light-chain amyloidosis compared to other causes of end-stage renal disease [92, 96]. An adequate haematological response (very good partial response or better) to light-chain amyloidosis treatment and/or promising further therapies are prerequisites, as local recurrence is otherwise foreseeable.
The SAN recommends evaluation of kidney transplantation in selected patients. (Grade B, Level IIB)
Management of gastrointestinal complaints is challenging and often focuses on symptomatic treatment [97]. Malnutrition may require nutritional counselling; evidence on parenteral nutrition is very sparse. Patients with high bilirubin represent a particular challenge because liver-specific dose modification for many established amyloidosis-directed treatment options remains poorly studied.
In advanced amyloidosis, bleeding potentially complicates severe hepatic failure or may be associated with amyloid vasculopathy, factor X deficiency, hypofibrinogenaemia or other clotting factor deficiency [98]. However, risk of thrombosis may also be relevant due to the disease-associated immobility, therapy (e.g. immunomodulatory agents) or possible nephrotic syndrome. The optimal strategy for managing haemostasis therefore requires an individualised, multidisciplinary consensus.
Supportive care measures focus on symptom management and prevention of further treatment-related damage. In patients with neuropathic pain associated with peripheral neuropathy, symptomatic treatment is essential. First-line treatments include serotonin-noradrenaline reuptake inhibitors and gabapentinoids. Second-line treatments include tramadol, tricyclic antidepressants (beware of hypotension), combinations and adjunctive psychotherapy. Autonomic neuropathy presents a particular challenge (postural hypotension) and may also require symptomatic treatment [99].
Amyloidosis-directed treatment in patients with significant neuropathy should not include bortezomib. Daratumumab, alone or in combination with cyclophosphamide and/or dexamethasone, as well as immunomodulatory agents are feasible. In this specific patient population, the SAN also considers ixazomib a reasonable alternative when bortezomib is not feasible [48].
The SAN recommends initial treatment with single-agent daratumumab in patients with severe polyneuropathy (CTCAE grade III). (Grade C, Level IV)
The SAN suggests symptomatic treatment of peripheral nervous system involvement with gabapentin (start dose 100 mg 3 ×/d, ramp up to max. 1200 mg 3 ×/d) and/or duloxetine (start dose 30 mg/d, ramp up to max. 120 mg/d) under close blood pressure monitoring [81]. (Grade C, Level IV)
In symptomatic hypotension, pressure stockings, abdominal binders and midodrine are valuable options [100] (starting dose 3 × 2.5 mg/d and escalation to a max. of 10 mg 3 ×/d). (Grade C, Level IV)
Many forms of amyloid- and/or plasma cell-directed treatment, particularly daratumumab, often cause profound hypogammaglobulinaemia, increasing the risk of infections. Immunoglobulin substitution may be beneficial; it is reimbursed in Switzerland in cases of total IgG <4 g/l and repetitive infections or inadequate antibody response to vaccination [101].
The SAN suggests immunoglobulin substitution in patients with total serum IgG <4 g/l and infectious complications. (Grade C, Level IV)
The SAN recommends seasonal vaccination against influenza and COVID infections during treatment and pre-therapeutic invasive pneumococcal disease vaccination. (Grade B, Level III)
The SAN suggests Varicella zoster virus-reactivation prophylaxis in light-chain amyloidosis patients undergoing plasma cell-directed treatment; PJP prophylaxis may be considered. (Grade C, Level IV)
Fortunately, the evidence for upfront management of patients with light-chain amyloidosis has improved significantly in recent years. However, management in the relapsing/remitting setting, in patients with more significant comorbidities or in those with very advanced disease, still requires expert consensus, as the available evidence is limited to small prospective phase II or observational studies. Supportive care should always involve a multidisciplinary team, as patterns of organ involvement and clinical presentation are very heterogeneous. In particular, management of the most advanced and morbid patients requires a comprehensive care approach. Whenever possible, patients should be considered for clinical trials.
Conceptualisation: Rahel Schwotzer, Max Rieger, Bernhard Gerber. Data curation, investigation and methodology: Rahel Schwotzer, Max Rieger. Funding acquisition: Rahel Schwotzer. Drafting of the original manuscript, project administration: Max Rieger, Rahel Schwotzer. Revision and Editing: All authors. Visualisation: Max Rieger, Rahel Schwotzer. Administrative, technical and material support: Max Rieger, Rahel Schwotzer. Supervision and validation: Rahel Schwotzer, Bernhard Gerber.
The third meeting of the Swiss Amyloidosis Network was supported by Alnylam, AstraZeneca and Pfizer. The funders did not participate in the meeting and had no role in the decision to publish or in the preparation of the manuscript.
All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. – Rieger: fees from Sobi and Amgen unrelated to this article. – Flammer: fees from Alnylam and Pfizer relevant for this article, as well as fees from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Fresenius, Imedos Systems, Mundipharma, Novartis, Orion Pharma, Roche, Schwabe Pharma, Vifor, and Zoll, unrelated to this article. – Gerull: Advisory board role for Sanofi, Janssen and GlaxoSmithKline, unrelated to this article. – Pabst: fees from Amgen, AstraZeneca, Beigene, BMS-Celgene; Daiichi; Kite/Gilead, Janssen, Jazz, Novartis, Roche; Sanofi, unrelated to this article. – Auner: institutional fees from Johnson&Johnson, Amgen, Takeda and BMS, unrelated to this article. – Samii: institutional fees from Sobi, GSK, BeGene, Orpha and Sanofi, unrelated to this article. – Hitz: Advisory board role for Amgen, Bristol-Myers Squibb, Janssen-Cilag, Takeda, Abbvie, Roche, unrelated to this article. – Mey: travel support from Amgen, Bristol-Myers Squibb/Celgene, Gilead, Janssen-Cilag, and Roche; advisory board role for Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Gilead, Incyte, Janssen-Cilag, Novartis, Pfizer, Roche, Sanofi, and Takeda, unrelated to this article. – Ballova: travel support from Sanofi, BeiGene and Johnson&Johnson, unrelated to this article. – Battegay: travel support from Amgen and Sanofi, unrelated to this article. – Melli: consulting fees from AstraZeneca and speaker services to Anylam, unrelated to this article. – Benz: fees from Pfizer relevant for this article, as well as fees from AstraZeneca and Philips Research, unrelated to this article. – Yakupoglu: nothing to declare. – Gräni: funding from the Swiss National Science Foundation, InnoSuisse, Center for Artificial Intelligence in Medicine University Bern, GAMBIT foundation, Novartis Foundation for Medical-Biological Research, Swiss Heart Foundation, outside of the submitted work. – Schläger: honorarium for presentation from Alnylam and Advisory board role for Alnylam, AstraSeneca and Sobi, unrelated to this article and paid to institution. – Hugelshofer: Fees from Pfizer, Alnylam, unrelated to this article and paid to institution. – Studer: nothing to declare. – Oechslin: nothing to declare. – Bakula: speaker fees from Pfizer and travel support from Pfizer and Alnylam, unrelated to this article. – Suter: nothing to declare. – Leo-Stickelberger: nothing to declare. – Averiamo: nothing to declare. – Fehr: nothing to declare. – Jung: fees from Alnylam related to this article as well as Biogen, Sanofi-Aventis, Ipsen, Alexion, Mitsubishi, Allergan and CSL Behring, unrelated to this article. – Laptseva: fees from Alnylam and Pfizer, relevant for this article. – Manka: speakers fees and travel grants from Bayer AG, speakers fees from Siemens, Philips and Bristol Myers Squibb, unrelated to this article. – Rüfer: nothing to declare. – Schmidt: fees from Takeda, Janssen, Celgene, Sobi, Roche, Sanofi, Amgen, Beigene, Novartis, Incyte and Bayer, unrelated to this article. – Seeger: fees from AstraZeneca, Alexion, Alnylam, Boehringer-Ingelheim, and travel grants from Alexion, unrelated to this article. – Müllhaupt: consulting fees from Abbvie, and lecture honoraria and travel support from Gilead, unrelated to this article. – Stämpfli: travel grants, speaker fees, consulting fees, or proctoring fees from Abbott Structural Heart, Alnylam, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, Edwards, Fumedica, Novartis, Novo Nordisk, Polares Medical, Pfizer, and Takeda as well as research grants from Pfizer and GAMBIT Foundation, unrelated to this article. – de Ramon Ortiz: institutional fees from Pfizer, Janssen, Sanofi and Amgen, unrelated to this article. – Théaudin: fees from Alnylam relevant for this article, research grant from Pfizer not related to this article, fees from Biogenldec, Sanofi, Merck, Roche, unrelated to this article. – Gerber: fees from Alnylam, Pfizer, Janssen and an unrestricted research grant from Pfizer relevant for this article, funding for accredited continuing medical education from Alnylam, Axonlab, Bayer, Bristol Myers Squibb, Celgene, Daiichi-Sankyo, Janssen, Mitsubishi Tanabe Pharma, NovoNordisk, Octapharma, Takeda, Sanofi, Sobi; and non-financial support from Axonlab and ThermoFisher not related to this article. – Schwotzer: fees from Alnylam, AstraZeneca, Sobi and Pfizer and fincancial support for the Center of Excellence for Amyloidosis from Alnylam, AstraZeneca, Sobi, as well as an unrestricted research grant from Pfizer relevant for this article as well as a travel grant from Johnson and Johnson, unrelated to this article.
1. Schwotzer R, Flammer AJ, Gerull S, Pabst T, Arosio P, Averaimo M, et al. Expert recommendation from the Swiss Amyloidosis Network (SAN) for systemic AL-amyloidosis. Swiss Med Wkly. 2020 Dec;150(4950):w20364. doi: https://doi.org/10.4414/smw.2020.20364
2. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al.; GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008 Apr;336(7650):924–6. doi: https://doi.org/10.1136/bmj.39489.470347.AD
3. Cluzeau F, et al.; AGREE Collaboration. Development and validation of an international appraisal instrument for assessing the quality of clinical practice guidelines: the AGREE project. Qual Saf Health Care. 2003 Feb;12(1):18–23. doi: https://doi.org/10.1136/qhc.12.1.18
4. 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 Sep;22(18):3751–7. doi: https://doi.org/10.1200/JCO.2004.03.029
5. 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 Apr;121(17):3420–7. doi: https://doi.org/10.1182/blood-2012-12-473066
6. 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 Oct;124(15):2325–32. doi: https://doi.org/10.1182/blood-2014-04-570010
7. Schönland 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 Transplantat. 2012;47(7:895–905. doi: https://doi.org/10.1038/bmt.2011.152
8. Sanchorawala V. Summary of the EHA-ISA Working Group Guidelines for High-dose Chemotherapy and Stem Cell Transplantation for Systemic AL Amyloidosis. HemaSphere. 2022 Jan;6(2):e681.
9. Sidana S, Larson DP, Greipp PT, He R, McPhail ED, Dispenzieri A, et al. IgM AL amyloidosis: delineating disease biology and outcomes with clinical, genomic and bone marrow morphological features. Leukemia. 2020 May;34(5):1373–82. doi: https://doi.org/10.1038/s41375-019-0667-6
10. Muchtar E, Dispenzieri A, Leung N, Lacy MQ, Buadi FK, Dingli D, et al. Depth of organ response in AL amyloidosis is associated with improved survival: grading the organ response criteria. Leukemia. 2018 Oct;32(10):2240–9. doi: https://doi.org/10.1038/s41375-018-0060-x
11. Palladini G, Merlini G. How I treat AL amyloidosis. Blood. 2022 May;139(19):2918–30. doi: https://doi.org/10.1182/blood.2020008737
12. 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 Dec;30(36):4541–9. doi: https://doi.org/10.1200/JCO.2011.37.7614
13. Palladini G, Paiva B, Wechalekar A, Massa M, Milani P, Lasa M, et al. Minimal residual disease negativity by next-generation flow cytometry is associated with improved organ response in AL amyloidosis. Blood Cancer J. 2021 Feb;11(2):34. doi: https://doi.org/10.1038/s41408-021-00428-0
14. Palladini G, Schönland SO, Sanchorawala V, Kumar S, Wechalekar A, Hegenbart U, et al. Clarification on the definition of complete haematologic response in light-chain (AL) amyloidosis. Amyloid. 2021 Mar;28(1):1–2. doi: https://doi.org/10.1080/13506129.2020.1868810
15. Muchtar E, Dispenzieri A, Wisniowski B, Palladini G, Milani P, Merlini G, et al. Graded Cardiac Response Criteria for Patients With Systemic Light Chain Amyloidosis. J Clin Oncol. 2023 Mar;41(7):1393–403. doi: https://doi.org/10.1200/JCO.22.00643
16. Milani P, Basset M, Russo F, Foli A, Merlini G, Palladini G. Patients with light-chain amyloidosis and low free light-chain burden have distinct clinical features and outcome. Blood. 2017 Aug;130(5):625–31. doi: https://doi.org/10.1182/blood-2017-02-767467
17. Kastritis E, Palladini G, Minnema MC, Wechalekar AD, Jaccard A, Lee HC, et al.; ANDROMEDA Trial Investigators. Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis. N Engl J Med. 2021 Jul;385(1):46–58. doi: https://doi.org/10.1056/NEJMoa2028631
18. Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, et al.; Myélome Autogreffe (MAG) and Intergroupe Francophone du Myélome (IFM) Intergroup. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep;357(11):1083–93. doi: https://doi.org/10.1056/NEJMoa070484
19. Gertz MA. Immunoglobulin light chain amyloidosis: 2022 update on diagnosis, prognosis, and treatment. Am J Hematol. 2022 Jun;97(6):818–29. doi: https://doi.org/10.1002/ajh.26569
20. Sanchorawala V, Quillen K, Sloan JM, Andrea NT, Seldin DC. Bortezomib and high-dose melphalan conditioning for stem cell transplantation for AL amyloidosis: a pilot study. Haematologica. 2011 Dec;96(12):1890–2. doi: https://doi.org/10.3324/haematol.2011.049858
21. Basset M, Milani P, Nuvolone M, Benigna F, Rodigari L, Foli A, et al. Sequential response-driven bortezomib-based therapy followed by autologous stem cell transplant in AL amyloidosis. Blood Adv. 2020 Sep;4(17):4175–9. doi: https://doi.org/10.1182/bloodadvances.2020002219
22. Nguyen VP, Landau H, Quillen K, Brauneis D, Shelton AC, Mendelson L, et al. Modified High-Dose Melphalan and Autologous Stem Cell Transplantation for Immunoglobulin Light Chain Amyloidosis. Biol Blood Marrow Transplant. 2018 Sep;24(9):1823–7. doi: https://doi.org/10.1016/j.bbmt.2018.06.018
23. Sanchorawala V, Wright DG, Quillen K, Finn KT, Dember LM, Berk JL, et al. Tandem cycles of high-dose melphalan and autologous stem cell transplantation increases the response rate in AL amyloidosis. Bone Marrow Transplant. 2007 Sep;40(6):557–62. doi: https://doi.org/10.1038/sj.bmt.1705746
24. Manwani R, Hegenbart U, Mahmood S, Sachchithanantham S, Kyriakou C, Yong K, et al. Deferred autologous stem cell transplantation in systemic AL amyloidosis. Blood Cancer J. 2018 Nov;8(11):101. doi: https://doi.org/10.1038/s41408-018-0137-9
25. Oubari S, Hegenbart U, Schoder R, Steinhardt M, Papathanasiou M, Rassaf T, et al. Daratumumab in first-line treatment of patients with light chain amyloidosis and Mayo stage IIIb improves treatment response and overall survival. Haematologica. 2024 Jan;109(1):220–30.
26. Wechalekar AD, Sanchorawala V. Daratumumab in AL amyloidosis. Blood. 2022 Dec;140(22):2317–22. doi: https://doi.org/10.1182/blood.2021014613
27. Palladini G, Foli A, Russo P, Milani P, Obici L, Lavatelli F, et al. Treatment of IgM-associated AL amyloidosis with the combination of rituximab, bortezomib, and dexamethasone. Clin Lymphoma Myeloma Leuk. 2011 Feb;11(1):143–5. doi: https://doi.org/10.3816/CLML.2011.n.033
28. Milani P, Schönland S, Merlini G, Kimmich C, Foli A, Dittrich T, et al. Treatment of AL amyloidosis with bendamustine: a study of 122 patients. Blood. 2018 Nov;132(18):1988–91. doi: https://doi.org/10.1182/blood-2018-04-845396
29. Buske C, Tedeschi A, Trotman J, García-Sanz R, MacDonald D, Leblond V, et al. Ibrutinib Plus Rituximab Versus Placebo Plus Rituximab for Waldenström’s Macroglobulinemia: Final Analysis From the Randomized Phase III iNNOVATE Study. J Clin Oncol. 2022 Jan;40(1):52–62. doi: https://doi.org/10.1200/JCO.21.00838
30. Manwani R, Sachchithanantham S, Mahmood S, Foard D, Sharpley F, Rezk T, et al. Treatment of IgM-associated immunoglobulin light-chain amyloidosis with rituximab-bendamustine. Blood. 2018 Aug;132(7):761–4. doi: https://doi.org/10.1182/blood-2018-04-846493
31. Dima D, Mazzoni S, Anwer F, Khouri J, Samaras C, Valent J, et al. Diagnostic and Treatment Strategies for AL Amyloidosis in an Era of Therapeutic Innovation. JCO Oncol Pract. 2023 May;19(5):265–75. doi: https://doi.org/10.1200/OP.22.00396
32. Palladini G, Milani P, Foli A, Basset M, Russo F, Perlini S, et al. Presentation and outcome with second-line treatment in AL amyloidosis previously sensitive to nontransplant therapies. Blood. 2018 Feb;131(5):525–32. doi: https://doi.org/10.1182/blood-2017-04-780544
33. Revision Art. 71 a/b KVV. Schweiz Arzteztg. 2017 Jan;98(4):122–5. doi: https://doi.org/10.4414/saez.2017.05084
34. Theodorakakou F, Fotiou D, Spiliopoulou V, Roussou M, Malandrakis P, Ntanasis-Stathopoulos I, et al. Outcomes of patients with light chain (AL) amyloidosis after failure of daratumumab-based therapy. Br J Haematol. 2023 Nov;203(3):411–5. doi: https://doi.org/10.1111/bjh.19042
35. Shragai T, Gatt M, Lavie N, Vaxman I, Tadmor T, Rouvio O, et al. Daratumumab for relapsed AL amyloidosis-When cumulative real-world data precedes clinical trials: A multisite study and systematic literature review. Eur J Haematol. 2021 Feb;106(2):184–95. doi: https://doi.org/10.1111/ejh.13535
36. Rieger MJ, Pabst T, Jeker B, Paul P, Bergamini F, Bühler MM, et al. Three years follow-up of Venetoclax in advanced-stage, relapsed or refractory AL amyloidosis with cardiac involvement and t(11;14) with BCL2 expression. Ann Hematol. 2024 Oct;103(10):4163–70. doi: https://doi.org/10.1007/s00277-024-05901-x
37. Lebel E, Kastritis E, Palladini G, Milani P, Theodorakakou F, Aumann S, et al. Venetoclax in Relapse/Refractory AL Amyloidosis-A Multicenter International Retrospective Real-World Study. Cancers (Basel). 2023 Mar;15(6):1710. doi: https://doi.org/10.3390/cancers15061710
38. Le Bras F, et al. Venetoclax induces sustained complete responses in refractory/relapsed patients with cardiac AL amyloidosis. J. Clin. Oncol. 2019;37_suppl.15.e19538. doi.org/
39. Bochtler T, Hegenbart U, Heiss C, Benner A, Moos M, Seckinger A, et al. Hyperdiploidy is less frequent in AL amyloidosis compared with monoclonal gammopathy of undetermined significance and inversely associated with translocation t(11;14). Blood. 2011 Apr;117(14):3809–15. doi: https://doi.org/10.1182/blood-2010-02-268987
40. 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 Jul;128(4):594–602. doi: https://doi.org/10.1182/blood-2015-10-676361
41. Warsame R, LaPlant B, Kumar SK, Laumann K, Perez Burbano G, Buadi FK, et al. Long-term outcomes of IMiD-based trials in patients with immunoglobulin light-chain amyloidosis: a pooled analysis. Blood Cancer J. 2020 Jan;10(1):4. doi: https://doi.org/10.1038/s41408-019-0266-9
42. Wechalekar AD, Cibeira MT, Gibbs SD, Jaccard A, Kumar S, Merlini G, et al. Guidelines for non-transplant chemotherapy for treatment of systemic AL amyloidosis: EHA-ISA working group. Amyloid. 2023 Mar;30(1):3–17. doi: https://doi.org/10.1080/13506129.2022.2093635
43. Milani P, Sharpley F, Schönland SO, Basset M, Mahmood S, Nuvolone M, et al. Pomalidomide and dexamethasone grant rapid haematologic responses in patients with relapsed and refractory AL amyloidosis: a European retrospective series of 153 patients. Amyloid. 2020 Dec;27(4):231–6. doi: https://doi.org/10.1080/13506129.2020.1767566
44. Sanchorawala V, Shelton AC, Lo S, Varga C, Sloan JM, Seldin DC. Pomalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 1 and 2 trial. Blood. 2016 Aug;128(8):1059–62. doi: https://doi.org/10.1182/blood-2016-04-710822
45. Wechalekar AD, Gillmore JD, Bird J, Cavenagh J, Hawkins S, Kazmi M, et al.; BCSH Committee. Guidelines on the management of AL amyloidosis. Br J Haematol. 2015 Jan;168(2):186–206. doi: https://doi.org/10.1111/bjh.13155
46. Palladini G, Milani P, Foli A, Obici L, Lavatelli F, Nuvolone M, et al. Oral melphalan and dexamethasone grants extended survival with minimal toxicity in AL amyloidosis: long-term results of a risk-adapted approach. Haematologica. 2014 Apr;99(4):743–50. doi: https://doi.org/10.3324/haematol.2013.095463
47. Gibbs SD, Gillmore JD, Sattianayagam PT, Offer M, Lachmann HJ, Hawkins PN, et al. In AL Amyloidosis, Both Oral Melphalan and Dexamethasone (Mel-Dex) and Risk-Adapted Cyclophosphamide, Thalidomide and Dexamethasone (CTD) Have Similar Efficacy as Upfront Treatment. Blood. 2009 Nov;114(22):745. doi: https://doi.org/10.1182/blood.V114.22.745.745
48. Dispenzieri A, Kastritis E, Wechalekar AD, Schönland SO, Kim K, Sanchorawala V, et al. A randomized phase 3 study of ixazomib-dexamethasone versus physician’s choice in relapsed or refractory AL amyloidosis. Leukemia. 2022 Jan;36(1):225–35. doi: https://doi.org/10.1038/s41375-021-01317-y
49. Sanchorawala V, Wechalekar AD, Kim K, Schönland SO, Landau HJ, Kwok F, et al. Quality of life and symptoms among patients with relapsed/refractory AL amyloidosis treated with ixazomib-dexamethasone versus physician’s choice. Am J Hematol. 2023 May;98(5):720–9. doi: https://doi.org/10.1002/ajh.26866
50. Chakraborty R, Bhutani D, Maurer MS, Mohan M, Lentzsch S, D’Souza A. Safety and efficacy of teclistamab in systemic immunoglobulin light chain amyloidosis. Blood Cancer J. 2023 Nov;13(1):172. doi: https://doi.org/10.1038/s41408-023-00950-3
51. Forgeard N, Elessa D, Carpinteiro A, Belhadj K, Minnema M, Roussel M, et al. Teclistamab in relapsed or refractory AL amyloidosis: a multinational retrospective case series. Blood. 2024 Feb;143(8):734–7. doi: https://doi.org/10.1182/blood.2023022937
52. Das S, Ailawadhi S, Sher T, Roy V, Fernandez A, Parrondo RD. Anti-B Cell Maturation Antigen Chimeric Antigen Receptor T Cell Therapy for the Treatment of AL Amyloidosis and Concurrent Relapsed/Refractory Multiple Myeloma: Preliminary Efficacy and Safety. Curr Oncol. 2023 Oct;30(11):9627–33. doi: https://doi.org/10.3390/curroncol30110697
53. Oliver-Caldes A, Jiménez R, Español-Rego M, Cibeira MT, Ortiz-Maldonado V, Quintana LF, et al. First report of CART treatment in AL amyloidosis and relapsed/refractory multiple myeloma. J Immunother Cancer. 2021 Dec;9(12):3783. doi: https://doi.org/10.1136/jitc-2021-003783
54. Lebel E, Asherie N, Kfir-Erenfeld S, Grisariu S, Avni B, Elias S, et al. Efficacy and Safety of Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor T-Cell for the Treatment of Relapsed and Refractory AL Amyloidosis. J Clin Oncol. 2024 Dec;JCO2402252. doi: https://doi.org/10.1200/JCO-24-02252
55. Cohen AD, Landau H, Scott EC, Liedtke M, Kaufman JL, Rosenzweig M, et al. Safety and Efficacy of Carfilzomib (CFZ) in Previously-Treated Systemic Light-Chain (AL) Amyloidosis. Blood. 2016 Dec;128(22):645. doi: https://doi.org/10.1182/blood.V128.22.645.645
56. Gertz MA, Landau H, Comenzo RL, Seldin D, Weiss B, Zonder J, et al. First-in-human phase I/II study of NEOD001 in patients with light chain amyloidosis and persistent organ dysfunction. J Clin Oncol. 2016 Apr;34(10):1097–103. doi: https://doi.org/10.1200/JCO.2015.63.6530
57. Richards DB, Cookson LM, Berges AC, Barton SV, Lane T, Ritter JM, et al. Therapeutic Clearance of Amyloid by Antibodies to Serum Amyloid P Component. N Engl J Med. 2015 Sep;373(12):1106–14. doi: https://doi.org/10.1056/NEJMoa1504942
58. Merlini G, Liedtke M, Landau HJ, Comenzo RL, Sanchorawala V, Weiss BM, et al. The PRONTO amyloidosis study: A randomized, double-blind, placebo-controlled, global, phase 2b study of NEOD001 in previously treated subjects with light chain amyloidosis and persistent cardiac dysfunction. J Clin Oncol. 2016 May;34(15) _suppl):TPS8073–8073. doi: https://doi.org/10.1200/JCO.2016.34.15_suppl.TPS8073
59. Gertz MA, Cohen AD, Comenzo RL, Kastritis E, Landau HJ, Libby EN, et al. Birtamimab plus standard of care in light-chain amyloidosis: the phase 3 randomized placebo-controlled VITAL trial. Blood. 2023 Oct;142(14):1208–18. doi: https://doi.org/10.1182/blood.2022019406
60. Mahmood S, Sachchithanantham S, Bridoux F, Lane T, Rannigan L, Foard D, et al. Risk Of Progression Of Localised Amyloidosis To Systemic Disease In 606 Patients Over 30 Years. Blood. 2013 Nov;122(21):3143. doi: https://doi.org/10.1182/blood.V122.21.3143.3143
61. Tahara S, Kohyama M, Nakamitsu A, Sugiyama Y, Tazaki T, Taogoshi H, et al. Surgical strategies for localized colorectal amyloidosis. Surg Case Rep. 2023 Apr;9(1):66. doi: https://doi.org/10.1186/s40792-023-01649-0
62. Kennedy TL, Patel NM. Surgical management of localized amyloidosis. Laryngoscope. 2000 Jun;110(6):918–23. doi: https://doi.org/10.1097/00005537-200006000-00005
63. Hall J, Rubinstein S, Lilly A, Blumberg JM, Chera B. Treatment of Localized Amyloid Light Chain Amyloidosis With External Beam Radiation Therapy. Pract Radiat Oncol. 2022;12(6):504–10. doi: https://doi.org/10.1016/j.prro.2022.03.011
64. Benson MD, Buxbaum JN, Eisenberg DS, Merlini G, Saraiva MJ, Sekijima Y, et al. Amyloid nomenclature 2018: recommendations by the International Society of Amyloidosis (ISA) nomenclature committee. Amyloid. 2018 Dec;25(4):215–9. doi: https://doi.org/10.1080/13506129.2018.1549825
65. Gertz MA, Lacy MQ, Dispenzieri A. Therapy for immunoglobulin light chain amyloidosis: the new and the old. Blood Rev. 2004 Mar;18(1):17–37. doi: https://doi.org/10.1016/S0268-960X(03)00027-4
66. Maroun BZ, Allam S, Chaulagain CP. Multidisciplinary supportive care in systemic light chain amyloidosis. Blood Res. 2022 Jun;57(2):106–16. doi: https://doi.org/10.5045/br.2022.2021227
67. Wong SW, Fogaren T. Supportive Care for Patients with Systemic Light Chain Amyloidosis. Hematology/Oncology Clinics of North America. 2020;34(6:1177–1191. doi: https://doi.org/10.1016/j.hoc.2020.08.007
68. Jensen CE, Byku M, Hladik GA, Jain K, Traub RE, Tuchman SA. Supportive Care and Symptom Management for Patients With Immunoglobulin Light Chain (AL) Amyloidosis. Front Oncol. 2022;12:907584. doi: https://doi.org/10.3389/fonc.2022.907584
69. Cheshire WP et al. Electrodiagnostic assessment of the autonomic nervous system: A consensus statement endorsed by the American Autonomic Society, American Academy of Neurology, and the International Federation of Clinical Neurophysiology. Clinical Neurophysiology. 2021;132(2):666–682. doi: https://doi.org/10.1016/j.clinph.2020.11.024
70. Devigili G, Tugnoli V, Penza P, Camozzi F, Lombardi R, Melli G, et al. The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain. 2008 Jul;131(Pt 7):1912–25. doi: https://doi.org/10.1093/brain/awn093
71. Cibeira MT, Ortiz-Pérez JT, Quintana LF, Fernádez De Larrea C, Tovar N, Bladé J. Supportive care in AL amyloidosis. Acta Haematologica. 2020;143(4):335–342. doi: https://doi.org/10.1159/000506760
72. Shen KN, Fu WJ, Wu Y, Dong YJ, Huang ZX, Wei YQ, et al. Doxycycline Combined With Bortezomib-Cyclophosphamide-Dexamethasone Chemotherapy for Newly Diagnosed Cardiac Light-Chain Amyloidosis: A Multicenter Randomized Controlled Trial. Circulation. 2022 Jan;145(1):8–17. doi: https://doi.org/10.1161/CIRCULATIONAHA.121.055953
73. Hora M, Carballo-Pacheco M, Weber B, Morris VK, Wittkopf A, Buchner J, et al. Epigallocatechin-3-gallate preferentially induces aggregation of amyloidogenic immunoglobulin light chains. Sci Rep. 2017 Jan;7(1):41515. doi: https://doi.org/10.1038/srep41515
74. Fernandes L, Cardim-Pires TR, Foguel D, Palhano FL. Green Tea Polyphenol Epigallocatechin-Gallate in Amyloid Aggregation and Neurodegenerative Diseases. Frontiers in Neuroscience. 2021;15. doi: https://doi.org/10.3389/fnins.2021.718188
75. Gertz MA, Dispenzieri A, Sher T. Pathophysiology and treatment of cardiac amyloidosis. Nature Reviews Cardiology. 2015;12(2):91–102. doi: https://doi.org/10.1038/nrcardio.2014.165
76. Shams P, Ahmed I. Cardiac Amyloidosis. StatPearls Publishing; 2024.
77. Gertz MA, Falk RH, Skinner M, Cohen AS, Kyle RA. Worsening of congestive heart failure in amyloid heart disease treated by calcium channel-blocking agents. Am J Cardiol. 1985 Jun;55(13 Pt 1):1645. doi: https://doi.org/10.1016/0002-9149(85)90995-6
78. Dubrey SW, Burke MM, Khaghani A, Hawkins PN, Yacoub MH, Banner NR. Long term results of heart transplantation in patients with amyloid heart disease. Heart. 2001 Feb;85(2):202–7. doi: https://doi.org/10.1136/heart.85.2.202
79. Kumar S, Li D, Joseph D, Trachtenberg B. State-of-the-art review on management of end-stage heart failure in amyloidosis: transplant and beyond. Heart Fail Rev. 2022;27(5):1567–1578. doi: https://doi.org/10.1007/s10741-021-10209-3
80. Ashraf I, Peck MM, Maram R, Mohamed A, Ochoa Crespo D, Kaur G, et al. Association of Arrhythmias in Cardiac Amyloidosis and Cardiac Sarcoidosis. Cureus. 2020 Aug;12(8):e9842. doi: https://doi.org/10.7759/cureus.9842
81. Weber N, et al. Management of systemic AL amyloidosis: Recommendations of the Myeloma Foundation of Australia Medical and Scientific Advisory Group. Intern Med J. 2015;45(4):371–382. doi: https://doi.org/10.1111/imj.12566
82. Feng D, Edwards WD, Oh JK, Chandrasekaran K, Grogan M, Martinez MW, et al. Intracardiac thrombosis and embolism in patients with cardiac amyloidosis. Circulation. 2007 Nov;116(21):2420–6. doi: https://doi.org/10.1161/CIRCULATIONAHA.107.697763
83. Palladini G, Malamani G, Cò F, Pistorio A, Recusani F, Anesi E, et al. Holter monitoring in AL amyloidosis: prognostic implications. Pacing Clin Electrophysiol. 2001 Aug;24(8 Pt 1):1228–33. doi: https://doi.org/10.1046/j.1460-9592.2001.01228.x
84. Dhoble A, Khasnis A, Olomu A, Thakur R. Cardiac amyloidosis treated with an implantable cardioverter defibrillator and subcutaneous array lead system: report of a case and literature review. Clin Cardiol. 2009 Aug;32(8):E63–5. doi: https://doi.org/10.1002/clc.20389
85. Kristen AV, Dengler TJ, Hegenbart U, Schonland SO, Goldschmidt H, Sack FU, et al. Prophylactic implantation of cardioverter-defibrillator in patients with severe cardiac amyloidosis and high risk for sudden cardiac death. Heart Rhythm. 2008 Feb;5(2):235–40. doi: https://doi.org/10.1016/j.hrthm.2007.10.016
86. Varr BC, Zarafshar S, Coakley T, Liedtke M, Lafayette RA, Arai S, et al. Implantable cardioverter-defibrillator placement in patients with cardiac amyloidosis. Heart Rhythm. 2014 Jan;11(1):158–62. doi: https://doi.org/10.1016/j.hrthm.2013.10.026
87. ZeppenfeldK, et al. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J. 2022;43(40):3997–4126. doi: https://doi.org/10.1093/eurheartj/ehac262
88. Mayr M, Dickenmann MJ. [Further evidence for the renoprotective effect of ACE inhibitors: ramipril protects against the progression of chronic renal insufficiency in non-diabetic nephropathy with nephrotic proteinuria]. Schweiz Med Wochenschr. 2000 Apr 1;130(13):491. doi:https://pubmed.ncbi.nlm.nih.gov/10812646/
89. Paydas S. Report on 59 patients with renal amyloidosis. Int Urol Nephrol. 1999;31(5):619–31. doi: https://doi.org/10.1023/A:1007152320216
90. Gentile G, Remuzzi G, Ruggenenti P. Dual renin-angiotensin system blockade for nephroprotection: still under scrutiny. Nephron J. 2015;129(1):39–41. doi: https://doi.org/10.1159/000368331
91. Gertz MA, Kyle RA, O’Fallon WM. Dialysis support of patients with primary systemic amyloidosis. A study of 211 patients. Arch Intern Med. 1992 Nov;152(11):2245–50. doi: https://doi.org/10.1001/archinte.1992.00400230061010
92. Pinney JH, Lachmann HJ, Bansi L, Wechalekar AD, Gilbertson JA, Rowczenio D, et al. Outcome in renal Al amyloidosis after chemotherapy. J Clin Oncol. 2011 Feb;29(6):674–81. doi: https://doi.org/10.1200/JCO.2010.30.5235
93. Herrmann SM, Gertz MA, Stegall MD, Dispenzieri A, Cosio FC, Kumar S, et al. Long-term outcomes of patients with light chain amyloidosis (AL) after renal transplantation with or without stem cell transplantation. Nephrol Dial Transplant. 2011 Jun;26(6):2032–6. doi: https://doi.org/10.1093/ndt/gfr067
94. Angel-Korman A, Stern L, Sarosiek S, Sloan JM, Doros G, Sanchorawala V, et al. Long-term outcome of kidney transplantation in AL amyloidosis. Kidney Int. 2019 Feb;95(2):405–11. doi: https://doi.org/10.1016/j.kint.2018.09.021
95. Kunin M, Klempfner R, Beckerman P, Rott D, Dinour D. Congestive heart failure treated with peritoneal dialysis or hemodialysis: typical patient profile and outcomes in real-world setting. Int J Clin Pract. 2021 Mar;75(3):e13727. doi: https://doi.org/10.1111/ijcp.13727
96. Sattianayagam PT, Gibbs SD, Pinney JH, Wechalekar AD, Lachmann HJ, Whelan CJ, et al. Solid organ transplantation in AL amyloidosis. Am J Transplant. 2010 Sep;10(9):2124–31. doi: https://doi.org/10.1111/j.1600-6143.2010.03227.x
97. Fritz CD, Blaney E. Evaluation and Management Strategies for GI Involvement with Amyloidosis. Am J Med. 2022 Apr;135 Suppl 1:S20–3. doi: https://doi.org/10.1016/j.amjmed.2022.01.008
98. Mumford AD, O’Donnell J, Gillmore JD, Manning RA, Hawkins PN, Laffan M. Bleeding symptoms and coagulation abnormalities in 337 patients with AL-amyloidosis. Br J Haematol. 2000 Aug;110(2):454–60. doi: https://doi.org/10.1046/j.1365-2141.2000.02183.x
99. Merlini G, Dispenzieri A, Sanchorawala V, Schönland SO, Palladini G, Hawkins PN, et al. Systemic immunoglobulin light chain amyloidosis. Nat Rev Dis Primers. 2018 Oct;4(1):38.
100. Cruz DN. Midodrine: a selective alpha-adrenergic agonist for orthostatic hypotension and dialysis hypotension. Expert Opin Pharmacother. 2000 May;1(4):835–40. doi: https://doi.org/10.1517/14656566.1.4.835
101. Bundesamt für Gesundheit (BAG). Spezialitätenliste (SL) - Präparate. Available from: https://spezialitaetenliste.ch/ShowPreparations.aspx?searchType=SUBSTANCE