Systemic amyloid light-chain amyloidosis beyond ANDROMEDA: Diagnostic challenges and therapeutic updates.

INTRODUCTION TO SYSTEMIC AMYLOIDOSIS

Systemic amyloidosis is a group of diseases caused by misfolded proteins that form amyloid fibrils and deposit in various organs, leading to pathologic tissue remodeling, fibrosis and progressive organ and systemic damage. Unlike localized amyloidosis, in which fibrils form and deposit within the same tissue, systemic amyloidosis involves circulating amyloidogenic proteins that deposit at sites distant from their production. To date, 42 human proteins have been identified that can form amyloid fibrils, of which 19 are associated with systemic deposition and disease. 1 The most common precursors in systemic amyloidosis are immunoglobulin light chains, produced by monoclonal plasma cells, which form light‐chain fibrils in amyloid light‐chain (AL) amyloidosis, and amyloid transthyretin (ATTR), including both wild‐type (ATTRwt) and variant (ATTRv) forms, which cause ATTR amyloidosis.

Although systemic amyloidosis has traditionally been considered a rare disease, increasing recognition and improved diagnostic methods have led to a more nuanced understanding of its true incidence and prevalence. AL amyloidosis is considered uncommon, with reported incidence ranging from 9.7 to 14.0 per million in the United States. 2 , 3 In contrast, ATTR amyloidosis, particularly the wild‐type form, is now recognized as underdiagnosed rather than truly rare. The reported incidence of ATTR cardiac amyloidosis increased from approximately six per million person‐years in 2011 to 36 per million person‐years in 2019 worldwide. 4 , 5

In addition to varying incidence, the clinical heterogeneity of systemic amyloidosis is determined by features of the precursor protein and involved organs. AL amyloidosis is characterized by a propensity for multiorgan involvement, commonly affecting the heart, kidneys, liver, gastrointestinal tract, and peripheral nerves, while sparing the central nervous system. ATTRwt primarily involves the heart and may also affect ligaments and tenosynovial structures. ATTRv commonly involves both the heart and the peripheral nervous system, with organ predominance varying by transthyretin variant. 6 Apart from the overlapping organ involvement, AL amyloidosis often demonstrates a more aggressive clinical course, likely related to the direct proteotoxic effects of circulating amyloidogenic light‐chain oligomers. 7 , 8

The rarity of the diseases and the overlapping, nonspecific clinical manifestations but divergent disease courses make early and accurate diagnosis particularly difficult, yet critical. This review focuses on systemic AL amyloidosis, summarizing the diagnostic challenges, the recommended diagnostic workflows, and the progress and remaining gaps in management.

CLINICAL MANIFESTATIONS OF AL AMYLOIDOSIS

The clinical manifestations of systemic amyloidoses depend on the type of precursor protein. Although all amyloidogenic proteins form fibrils with similar ultrastructure, they exhibit distinct organ tropisms, the mechanisms of which remain incompletely understood. In AL amyloidosis, circulating monoclonal light chains misfold and aggregate into oligomers and fibrils, ultimately causing progressive organ damage. Symptoms are typically insidious, nonspecific, and often recognized late. Yet, once organ dysfunction develops, rapid progression and early mortality may occur. 9 , 10 , 11 , 12 AL amyloid fibrils can deposit in virtually any organ or tissue, with the exception of the central nervous system, in which involvement is exceedingly rare and usually presents as a localized amyloidoma rather than systemic disease. 13 , 14 , 15 Common constitutional symptoms include fatigue (12%–45%), weight loss (22%–50%), and edema (approximately 35%). 16 , 17 , 18 Other nonspecific but suggestive signs include periorbital ecchymosis, macroglossia, easy bruising, and submandibular swelling. The most frequently involved organs are the heart (60%–80%), kidneys (50%–70%), peripheral nerves (40%–50%), autonomic nervous system (10%–25%), liver (10%–30%), and gastrointestinal tract (10%–15%). 19 , 20 , 21 , 22 , 23 , 24 , 25

Cardiac involvement is the principal determinant of prognosis and the leading cause of death in AL amyloidosis. It typically manifests as a restrictive cardiomyopathy, resulting in exertional dyspnea, peripheral edema, and arrhythmias, such as atrial fibrillation or ventricular tachyarrhythmias. Laboratory evaluation commonly reveals elevated cardiac troponins and N‐terminal pro–B‐type natriuretic peptide (NT‐proBNP) levels, reflecting myocardial injury and wall stress. These clinical and laboratory abnormalities are accompanied by characteristic cardiac imaging findings, as detailed below (see Diagnosis of AL Amyloidosis).

Renal involvement typically presents with nephrotic‐range proteinuria, predominantly albuminuria, reflecting glomerular basement membrane damage from amyloid deposition. Many patients also show renal impairment, with a reduced estimated glomerular filtration rate (eGFR) at diagnosis, and 30%–40% progress to end‐stage kidney disease throughout the course. 26 , 27 , 28 Approximately 5% of patients exhibit minimal proteinuria, corresponding to vascular, tubular, and interstitial patterns of amyloid deposition rather than glomerular involvement. 29 , 30 When AL amyloidosis involves the kidney, it is considered a type of monoclonal gammopathy of renal significance (MGRS) when the underlying clone does not meet criteria for multiple myeloma or lymphoma, and it is the most common MGRS condition. Other MGRS subtypes are less common, and their treatment strategies are less well established. 31 , 32

Peripheral nervous system involvement typically presents as a length‐dependent, symmetrical polyneuropathy, although polyradiculoneuropathy and small‐fiber neuropathy may also occur. 23 , 33 Autonomic dysfunction is identified in approximately 10%–40% of patients, manifesting as orthostatic hypotension (approximately 25%), erectile dysfunction, and gastrointestinal symptoms, such as diarrhea, bloating, or constipation. 23 , 34 Orthostatic hypotension and bowel dysfunction may also reflect cardiac or gastrointestinal involvement, respectively, which may coexist and are difficult to distinguish clinically. It is important to note that several studies suggest autonomic dysfunction is an independent marker of a poor prognosis in AL amyloidosis. 35 , 36

Involvement of the gastrointestinal tract, lungs, or tracheobronchial tree can lead to malabsorption, diarrhea, gastrointestinal bleeding, or airway obstruction. Articular involvement can manifest as amyloid arthropathy, often mimicking rheumatoid arthritis. Ligamentous and soft tissue deposition may cause carpal tunnel syndrome because of amyloid infiltration of the transverse carpal ligament and tenosynovium. Acquired factor X deficiency caused by the adsorption of clotting factors onto amyloid fibrils can result in a coagulopathy and bleeding diathesis. 37 , 38 However, nephrotic range proteinuria caused by kidney involvement may confer an increased risk of thrombosis. 39

In rare cases, AL amyloid deposition has been reported in the ligamentum flavum and may present with spinal stenosis, chronic back pain, or radiculopathy, although amyloid in this location is most commonly ATTR, particularly ATTRwt (Figure 1 ). Such localized involvement can precede systemic diagnosis by months to years, contributing to delayed recognition. 40 , 41 , 42

DIAGNOSIS OF AL AMYLOIDOSIS

Diagnostic criteria

The diagnosis of AL amyloidosis requires four key elements: (1) evidence of clonal plasma cell–producing monoclonal immunoglobulin light chain, demonstrated by serum or urine monoclonal protein studies and bone marrow findings; (2) demonstration of amyloid fibrils in tissue by Congo red staining or equivalent methods; (3) confirmation that the amyloid fibrils are composed of immunoglobulin light chains, most reliably by mass spectrometry; and (4) evidence of systemic organ involvement attributable to amyloid deposition. 24 , 43 , 44 Thus a definitive diagnosis requires a complete chain of evidence linking monoclonal plasma cells that produce amyloidogenic light chains, the resulting amyloid fibrils, and the associated systemic organ involvement.

Identify monoclonal plasma cells

Evaluation for plasma cell clones relies on serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP), serum immunofixation electrophoresis (SIFE) and urine immunofixation electrophoresis (UIFE), and serum‐free light chain (FLC) assays. Although SIFE is sometimes performed only as a reflex test after an abnormal SPEP result, in patients with suspected AL amyloidosis, all five studies should be obtained (or, at minimum SIFE, UIFE, and the serum FLC assay). Monoclonal proteins in AL amyloidosis are often small and may not produce a visible spike on SPEP or UPEP alone, and using SPEP together with SIFE and serum FLC increases the diagnostic sensitivity from approximately 82% to > 98%. 45 , 46 A 24‐hour urine for UPEP, UIFE, and protein quantification is preferred when available. If not feasible, a urine protein–creatinine ratio can be used to estimate total 24‐hour protein excretion, although it does not accurately quantify Bence–Jones proteins, which can distinguish AL amyloidosis from multiple myeloma. 47 In patients with suspected amyloidosis and evidence of monoclonal light chains, a bone marrow biopsy is recommended to document the plasma cell clone and to assess for concurrent multiple myeloma, which occurs in approximately 10% of patients and may influence treatment selection. 48

Distinguishing fibrils formed from light chains

A tissue biopsy is required to confirm the diagnosis of AL amyloidosis and can be accomplished by sampling a surrogate site, which spares an invasive procedure. 49 Subcutaneous abdominal fat pad aspiration is simple and safe, with a sensitivity of approximately 80% on routine assessment and >90% when multiple smears are carefully examined. 50 , 51 Amyloid may also be present in the bone marrow of patients with AL and has a reported sensitivity of 56%–70%. 24 When abdominal fat aspiration and bone marrow biopsy are combined, diagnostic sensitivity can reach 85%–90%, which reduces the need for higher risk organ biopsies. 24 , 43 , 51 , 52 Sampling of the gastrointestinal tract and oral tissues, such as salivary glands, buccal mucosa, and tongue, could also be surrogate sites given the high sensitivity, especially in the presence of clinical symptoms like diarrhea, gastrointestinal bleeding, abdominal pain, macroglossia, submandibular enlargement, etc. 53 , 54 However, a tongue biopsy in a patient with macroglossia is not a benign procedure and may induce swelling, pain, and heal slowly. Previously obtained tissue specimens, when available, may be revisited for Congo red staining or amyloid typing. Occasionally, amyloid deposits are confined to bone marrow or to another single site without systemic organ involvement; such cases are classified as localized AL, and progression to systemic AL amyloidosis is exceedingly rare if the diagnosis is accurate. 55 , 56 In contrast, in patients with a very high clinical suspicion of systemic AL amyloidosis and negative fat, bone marrow, or other soft tissue biopsies, which account for roughly 10%–15% of patients in some series, biopsy of an involved organ is recommended. 24

After tissue acquisition, Congo red staining with apple‐green birefringence under polarized light confirms the presence of amyloid. The amyloid type should then be defined, most reliably by laser microdissection followed by liquid chromatography–tandem mass spectrometry, which is considered the most reliable method for amyloid typing and has become the gold standard in clinical practice. 57 Emerging techniques, such as matrix‐assisted laser desorption/ionization mass spectrometry imaging, have shown promising accuracy for direct in‐tissue peptide mapping of amyloid deposits and subtyping but are not widely available. 58 Alternative approaches include immunohistochemistry, immunofluorescence, and immunoelectron microscopy, although these methods are less reliable. 57 , 59 Once AL‐type amyloid is identified in the presence of an amyloidogenic plasma cell clone and associated organ involvement, a diagnosis of systemic AL amyloidosis is established.

Cardiac amyloidosis: Diagnostic challenges and when to biopsy

If cardiac amyloidosis is suspected, a major diagnostic challenge is to accurately distinguish AL from ATTR amyloidosis because prognosis and treatment strategies fundamentally differ. Although tissue biopsy remains the gold standard, advances in noninvasive imaging and laboratory testing now permit reliable diagnoses in many patients. 60 Referral to an amyloidosis center should be considered because specialized centers can facilitate expedited workup, multidisciplinary care, clinical trial evaluation, and may be associated with improved outcomes. This section summarizes the contemporary diagnostic pathways for AL and ATTR cardiac amyloidosis and outlines scenarios in which myocardial biopsy is still required.

Role of cardiac imaging

Echocardiography is typically the first‐line imaging modality in the evaluation of suspected cardiac amyloidosis. Common findings include increased left and right ventricular wall thickness, bi‐atrial enlargement, interatrial septal and diffuse valvular thickening, preserved or mildly reduced left ventricular ejection fraction with low stroke volume, and a restrictive diastolic filling pattern. It is important to note that electrocardiographic features, such as low QRS voltage and pseudoinfarct patterns, are frequently present and may appear discordant with the degree of myocardial thickening seen on echocardiography. 16 Strain imaging provides an important diagnostic clue, with global longitudinal strain often demonstrating relative apical sparing; an increased left ventricular ejection fraction‐to‐global longitudinal strain ratio >4 in particular should raise suspicion for cardiac amyloidosis. In some patients, a granular or sparkling myocardial texture may also be appreciated. 61

Cardiac magnetic resonance imaging (CMR) serves as a valuable adjunct in the assessment of cardiac amyloidosis by providing complementary tissue characterization. It is highly sensitive for identifying infiltrative cardiomyopathy, with reported sensitivity approaching 95%, although performance varies by disease subtype and imaging criteria. 62 For cardiac amyloidosis, CMR demonstrates high specificity, which is reported to be as high as 98%. 63 In addition, CMR helps define disease distribution and burden. Characteristic CMR findings include diffuse subendocardial or transmural late gadolinium enhancement, abnormal myocardial nulling behavior, and increased native T1 values with elevated extracellular volume, all of which are indicative of diffuse amyloid infiltration 64 , 65 , 66 (Figure 2 ).

Radionuclide imaging, including single‐photon emission computed tomography with bone‐avid, technetium‐labeled tracers and positron emission tomography with amyloid‐binding radiotracers, has an emerging role in the evaluation of cardiac amyloidosis. Bone‐avid tracer scintigraphy has transformed the diagnosis of ATTR cardiac amyloidosis by enabling a nonbiopsy diagnosis in selected patients. 60 Amyloid‐binding positron emission tomography tracers are being investigated for the direct detection of myocardial amyloid. 67 Iodine‐124 evuzamitide positron emission tomography/computed tomography has demonstrated high sensitivity for both ATTR and AL cardiac amyloidosis and may enable quantitative assessment of cardiac amyloid burden, although it remains investigational. 68 , 69

Diagnostic workflow

Given the urgency of therapy in AL amyloidosis, exclusion or confirmation of a monoclonal light‐chain process represents the first and most critical step in the diagnostic evaluation. If any monoclonal protein is identified, further evaluation with tissue biopsy is recommended to establish amyloid deposition and enable definitive typing, preferably by mass spectrometry. When extracardiac biopsies are negative but clinical suspicion remains high, biopsy of an involved organ, including the myocardium, should be considered. In contrast, if serum FLC assays, SIFE, and UIFE are entirely normal, AL amyloidosis is highly unlikely. A diagnostic workflow for patients with suspected amyloidosis is illustrated in Figure 3 .

After AL amyloidosis has been excluded, bone‐avid tracer scintigraphy using technetium‐labeled tracers, such as technetium 99m using pyrophosphate, 3‐diphosphono‐1,2‐propanodicarboxylic acid, or hydroxymethylene diphosphonate, can be used to evaluate for ATTR cardiac amyloidosis (Figure 2 ). In the absence of any detectable monoclonal protein, Perugini grade 2 or 3 myocardial tracer uptake has a very high positive predictive value for ATTR amyloidosis and is sufficient to establish a noninvasive diagnosis without tissue biopsy. 60 In such patients, subsequent transthyretin gene sequencing is required to distinguish ATTRwt from ATTRv amyloidosis, which has implications for prognosis, family screening, and therapy selection.

Despite these advances, myocardial biopsy remains important for selected clinical scenarios in which noninvasive testing is discordant or insufficient to establish the amyloid subtype with confidence. Biopsy is suggested when bone scintigraphy suggests ATTR amyloidosis but a monoclonal protein is present, creating uncertainty between ATTR and AL amyloidosis. Similarly, when cardiac imaging strongly suggests the presence of amyloid infiltration but light‐chain studies, extracardiac biopsies, and scintigraphy are inconclusive, tissue confirmation is required. Myocardial biopsy is also appropriate when there is a mismatch between minimal extracardiac disease and disproportionately severe cardiac involvement, raising concern that a detected monoclonal gammopathy may be incidental rather than causative. Additional indications include atypical clinical or imaging presentations that raise concern for alternative diagnoses, such as other infiltrative or hypertrophic cardiomyopathies, and rare situations in which dual pathology is suspected.

Although it is uncommon, concurrent AL and ATTR cardiac amyloidosis has been reported; and, in such patients, biopsy may be necessary to guide appropriate management. 70 Therefore, decisions regarding myocardial biopsy should be individualized, balancing pre‐test probability, diagnostic uncertainty, and the clinical consequences of delayed or incorrect classification.

STAGING AND RISK STRATIFICATION

The prognosis in AL amyloidosis is largely determined by the extent of cardiac involvement; accordingly, contemporary staging systems are fundamentally anchored in cardiac biomarkers. Currently, five prognostic staging models are in use (Table 1 ). 71 , 72 , 73 , 74 , 75 , 76 The earliest, the Mayo 2004 staging system, incorporates two cardiac biomarkers, NT‐proBNP ≥332 pg/mL and troponin T ≥0.035 ng/mL (or troponin I ≥0.1 ng/mL), to stratify patients into stages I–III. 71 The European modification (2015) refined this model by subdividing stage III into stages IIIa and IIIb using an NT‐proBNP threshold of 8500 pg/mL, thereby improving the identification of very‐high‐risk patients. This modification remains the most widely applied in both clinical practice and trials, with consistent prognostic performance across treatment eras. 72 , 73

The Mayo 2012 staging system introduced the difference between involved and uninvolved FLCs (FLC difference [dFLC] ≥180 mg/L, the median value for their data set) as a third variable and initially outperformed the European modification in predicting long‐term survival. 77 However, with therapeutic advances and markedly improved outcomes, its utility has diminished, likely related to substantial interassay variability in FLC quantification across platforms and waning relevance of the dFLC being used. 78 , 79 Rather, a lower baseline dFLC of <50 mg/L, which differentiates a highly favorable subgroup or dynamic measures like rapid dFLC reduction and early treatment response, provides more accurate prognostic discrimination in the setting of effective therapy. 73 , 80 , 81

In 2019, the Boston University staging system was developed as an alternative for centers lacking NT‐proBNP, paralleling the Mayo 2004 system with European modification model but substituting B‐type natriuretic peptide ≥81 pg/mL and troponin I ≥0.1 ng/mL as cutoff levels, with B‐type natriuretic peptide ≥700 pg/mL distinguishing stages IIIa and IIIb; both internal and external validations have confirmed its predictive value. 10 , 75 , 82 The AL International Staging System incorporated left ventricular longitudinal strain (less than −9%) to identify an ultrahigh‐risk stage IIIc, refining risk stratification among patients with advanced cardiac involvement beyond stage IIIb of the European‐modified Mayo 2004 staging system. 76

Although overall survival is primarily associated with cardiac involvement, renal staging provides important prognostic information for progression to end‐stage renal disease. 83 Three renal staging systems have been proposed (Table 2 ). 28 , 84 , 85 The most widely used is the Palladini et al. 2014 renal staging system, which applies cutoffs of eGFR 50 mL per minute/1.73 m 2 and 24‐hour urine protein 5 g, and has demonstrated robust predictive value for renal outcomes. 84 Subsequently, Kastritis et al. developed a staging system based on the 24‐hour urine protein–to–eGFR ratio; compared with the model by Palladini et al., this approach demonstrated inferior performance for predicting early progression at 3 months but performed better in assessing renal response at 3 months after treatment. 28 , 86 Given the limitations of 24‐hour urine collection and the imprecision of creatinine‐based estimates, Basset et al. proposed a simplified model using a urine albumin‐to‐creatinine ratio cutoff of 3600 mg/g as a surrogate marker of renal progression, which also demonstrated good prognostic performance. 85

Cytogenetic abnormalities are detectable in approximately 75%–90% of patients with AL amyloidosis, and their prognostic impact has varied across treatment eras. 87 , 88 Among these, t(11;14) is the most prevalent (38%–55%), followed by deletion 13q (22%–30%), gain 1q (22%–28%), hyperdiploidy (10%), deletion 17p (5%), and myeloma high‐risk translocations (6%–7%), such as t(4;14) or t(14;16). 89 , 90 , 91 , 92 , 93 The t(11;14) subgroup is typically characterized by a lower plasma cell burden and was associated with inferior survival with bortezomib‐based therapy before daratumumab was available. 88 , 94 However, this adverse association is no longer observed in the daratumumab era. 92 Gain 1q is associated with less favorable outcomes when patients are treated with oral melphalan or with daratumumab‐based regimens. 92 Hyperdiploidy and deletion 17p have also been linked to inopportune outcomes, although data remain limited and are less consistent across studies. 88 , 94 , 95

TREATMENT RESPONSE ASSESSMENT

Hematologic response

Response assessment in systemic AL amyloidosis is based on both hematologic and organ‐specific parameters. Hematologic response criteria are well established, validated, and correlate with increased frequency of organ responses and extended overall survival (Table 3 ). 11 , 96 , 97 , 98 The goal is to achieve at least a hematologic very good partial response (VGPR) or, ideally, a complete response (CR) within 2–3 months of initiating therapy. Measurable clonal disease has traditionally been defined by a baseline dFLC ≥50 mg/L so that hematologic responses can be assessed and designated. 99 , 100 At lower levels, dFLC fluctuations are prone to analytical and biologic variability, limiting the reliability of conventional percentage‐based response determination. As an alternative a low dFLC response criterion, based on achieving a posttreatment dFLC <10 mg/L, has been studied and independently predicts superior overall survival in patients who present with baseline dFLC between 20 and 50 mg/L. 98 , 101 For those with baseline dFLC <20 mg/L, only a CR is considered a meaningful hematologic end point. Although these refinements have not yet been incorporated into formal International Society of Amyloidosis consensus, they are widely adopted in clinical practice.

More potent therapies can lead to profound reductions in amyloidogenic light chains. Achieving deeper FLC suppression, such as dFLC <10 mg/L, involved FLC <20 or <10 mg/L, or normalization of involved FLC, has been associated with improved survival across multiple cohorts. 102 , 103 , 104 , 105 However, comparative analyses demonstrated that a CR, as defined by the International Society of Amyloidosis (ISA) consensus, remains the most robust predictor of outcome, with no additional survival advantage observed among patients with a CR who had further reductions in FLC levels with available therapies in the era before daratumumab. 106 , 107

Hematologic progression

Historically, hematologic progression in AL amyloidosis has lacked a fully validated and universally accepted definition, reflecting a persistent gap in guiding the timing of initiation of next‐line therapy at relapse. 100 Although the 2005 ISA consensus criteria proposed definitions for progression, these were largely expert‐derived and were not validated in prospective cohorts. 97 In 2018, Palladini et al. introduced a data‐driven refinement, proposing a high‐risk dFLC progression metric, defined as dFLC >20 mg/L, representing ≥20% of the baseline measure and a ≥50% increase from best response; it identified a subset of patients with biochemical relapse who were at increased risk of adverse outcomes and supported consideration of second‐line therapy before overt organ progression. 108 Their findings suggested that waiting for clear evidence of organ progression may represent a late intervention point. Nonetheless, a uniformly validated definition for hematologic progression has not been established, and the optimal threshold for initiating retreatment remains guided by FLC kinetics, organ biomarkers, and overall clinical context.

Measurable residual disease

Emerging evidence suggests that measurable residual disease (MRD) may provide additional prognostic information in AL amyloidosis. 11 MRD is assessed in bone marrow aspirates using next‐generation flow cytometry or next‐generation sequencing, both of which are capable of detecting residual clonal plasma cells at a sensitivity of ≤10 −5 . Mass spectrometry–based assays for serum or urine light chains also offer a promising approach for detecting peripheral residual disease. 109 Several retrospective studies have demonstrated that negative MRD status is associated with improved cardiac and renal responses as well as longer progression‐free survival. 110 , 111 , 112 , 113 , 114

However, unlike multiple myeloma, in which both bone marrow and serologic MRD negativity have been correlated with superior overall survival, no clear association with overall survival has yet been demonstrated in AL amyloidosis. 111 , 115 This likely reflects the selection of patients who have a VGPR or better for MRD assessment, because they represent a biologically favorable subgroup with prolonged survival under contemporary regimens, thereby limiting the ability to detect incremental survival benefit within available follow‐up. Technical limitations also exist: next‐generation sequencing requires the identification of a clonotypic sequence before treatment, which is feasible in approximately 95% of patients with myeloma but in only about 85% in those with AL amyloidosis. 116 Looking forward, whether MRD can serve as an exploratory biomarker of treatment efficacy, a therapeutic target, or an early indicator of relapse remains an important area for future investigation.

Organ response

Organ response criteria were initially proposed at the 2005 ISA consensus forum and included cardiac, renal, hepatic, and peripheral nerve involvement, although nerve criteria have been used infrequently in subsequent studies. 97 Subsequent data have led to refined and validated, graded cardiac and renal response systems, which demonstrate superior prognostic discrimination for renal‐replacement therapy and long‐term survival compared with binary definitions (Table 4 ). 97 , 117 , 118 , 119 Hepatic response remains binary, and patients who had hepatic response within the first 6 months of treatment initiation had longer survival. 120 , 121 Organ responses typically occur later than hematologic responses, and the time to response varies across cohorts. The median time from treatment initiation to organ response is about 6–10 months. Organ responses may continue to improve for up to 3 years, and the time to best organ response ranges from 16 to 36 months. 117 , 118 , 120 , 122

In the context of treatment, accumulating evidence indicates that early and deep cardiac and renal responses are strongly associated with improved survival outcomes. 117 , 118 , 123 , 124 Predictors of organ response include the depth of hematologic response, baseline organ staging, and amyloid burden, which underscore the importance of early diagnosis. 125 , 126 A large, multicenter, retrospective study also suggested practical renal goals, including a renal partial response (PR) at 6 months and a renal VGPR at 12 and 24 months. 118 Achieving profound clonal suppression and durable organ responses together remains the long‐term goal of therapy.

TREATMENT LANDSCAPE

The overarching therapeutic goals in AL amyloidosis are to preserve organ function and prolong survival. To achieve these objectives, the first step is rapid reduction of circulating amyloidogenic light chains and, ideally, attaining a hematologic CR using plasma cell–directed therapy. Because the time to response can be critical for patient outcomes, treatment modification should be considered when patients achieve less than a PR by cycle two or a VGPR by cycle three, especially in the absence of organ improvement. 126 Although prompt and deep suppression of amyloidogenic light‐chain production is necessary to halt further amyloid deposition and enable organ recovery over time, it does not address the resident amyloid that has already been deposited in tissues. Therapies directed against amyloid fibrils, including monoclonal antibodies designed to promote fibril clearance, remain under active clinical investigation. Finally, organ‐specific management and supportive care are essential to mitigate end‐organ dysfunction and optimize quality of life and should be considered as soon as the diagnosis is made.

Frontline therapy: Daratumumab plus cyclophosphamide, bortezomib, and dexamethasone

Daratumumab is a highly effective anti‐CD38 monoclonal antibody and was the first agent approved by the US Food and Drug Administration for the treatment of AL amyloidosis. The phase 3 ANDROMEDA trial (ClinicalTrials.gov identifier NCT03201965 ) established daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (Dara‐CyBorD) as the standard frontline regimen, demonstrating a three‐fold higher likelihood of achieving a hematologic CR (53%) compared with CyBorD alone (18%), with VGPR or better rates of 78% and organ response rates of approximately 50%–55% at 18 months. 127

Notably, the ANDROMEDA trial excluded patients with advanced cardiac disease (Mayo stage IIIb or NY Heart Association class IV), advanced renal dysfunction (eGFR <20 mL per minute/1.73 m 2 ), poor performance status (Eastern Cooperative Oncology 3–4), concurrent multiple myeloma, or other significant comorbidities. Several real‐world studies have subsequently explored the applicability of either Dara‐CyBorD or daratumumab plus bortezomib and dexamethasone in these high‐risk populations, reporting comparable hematologic responses and encouraging outcomes and suggesting broader utility beyond the trial population. 128 , 129 Nevertheless, given the largely off‐label use and limited prospective data, these approaches should be applied with caution at experienced centers, with treatment individualized to the extent of organ involvement and anticipated toxicity. For example, in frail patients who are unlikely to tolerate cyclophosphamide, daratumumab with bortezomib and dose‐reduced dexamethasone has been associated with favorable response rates and represents a reasonable alternative strategy. 130 Similarly, dexamethasone should be reduced or even omitted after the initial two doses of daratumumab in patients who are prone to volume retention or other steroid‐associated side effects.

When daratumumab is unavailable, CyBorD remains the preferred alternative frontline regimen, followed by combined bortezomib, melphalan, and dexamethasone, which is generally reserved for patients who are ineligible for autologous stem cell transplantation (ASCT) given the stem cell toxicity of melphalan. Bortezomib serves as the backbone of frontline therapy because proteasome inhibition is particularly effective against clonal plasma cells by disrupting proteostasis, impairing degradation of misfolded light chains, and rapidly inducing apoptosis. 131 However, CyBorD alone is associated with modest depth of response, with a CR rate of approximately 18% and a rate of VGPR or better of approximately 50%, underscoring the added benefit of incorporating daratumumab into frontline regimens.

Autologous stem cell transplantation

The 2022 European Hematology Association‐ISA guidelines emphasize that a key early step in AL amyloidosis management is an assessment of eligibility for ASCT, based on established ISA criteria. 126 , 132 For transplantation‐eligible patients, the recommended approach includes induction with Dara‐CyBorD to achieve a rapid hematologic response before stem‐cell collection, followed by high‐dose melphalan conditioning and ASCT. For transplantation‐ineligible patients, first‐line therapy is also Dara‐CyBorD if the patient can achieve at least a partial hematologic response by 2 months, a VGPR by 4 months, complete six cycles and, consider Dara maintenance for up to 18 cycles. 46

High‐dose melphalan with ASCT has historically been one of the few strategies capable of delivering deep, durable hematologic responses and long‐term survival in AL amyloidosis, including in carefully selected patients with cardiac involvement. 133 , 134 However, cardiac amyloidosis remains the dominant determinant of risk: multiple cohorts indicate that advanced Mayo stage, high NT‐proBNP levels, and overt cardiomyopathy are strongly associated with early transplantation‐related mortality and shorter progression‐free and overall survival. Improvements in patient selection, risk‐adapted melphalan dosing, and peritransplantation supportive care have progressively reduced early treatment‐related mortality among patients with cardiac AL. 132 , 135

In contemporary clinical practice, however, the role of ASCT—particularly after daratumumab‐based induction—is less certain and is now the subject of prospective evaluation. SWOG S2213 (ClinicalTrials.gov identifier NCT06022939 /Blood and Marrow Transplant Clinical Trials Network trial 2205) is a pivotal phase 3 trial directly testing whether consolidative high‐dose melphalan/ASCT after Dara‐VCD induction improves outcomes compared with Dara‐VCD consolidation plus daratumumab maintenance in patients who have newly diagnosed AL amyloidosis, an effort that should help define the incremental value of transplantation in this new therapeutic landscape. At the same time, B‐cell maturation antigen (BCMA)‐directed therapies, including bispecific antibodies (BsAbs) like teclistimab, elranatamab (ClinicalTrials.gov identifier NCT06569147 ), and etentamig (ClinicalTrials.gov identifier NCT06158854 ), and emerging chimeric antigen receptor (CAR) T‐cell approaches (ClinicalTrials.gov identifiers NCT06097832 and NCT07081646 ), are being studied and are producing unprecedented response depths and rapid organ improvement in relapsed/refractory (RR) AL with favorable safety profiles, even in patients who have cardiac involvement. 136 , 137 Yet the total number of treated patients with cardiac AL remains small, and follow‐up is short, limiting definitive conclusions. Taken together, high‐dose melphalan/ASCT is best viewed as a historically validated, potentially high‐impact option, the contemporary value of which must now be balanced against, and rigorously compared with, potent, daratumumab‐based combinations and next‐generation, BCMA‐directed therapies.

Refractory/relapsed AL amyloidosis treatment

The treatment choice for patients with RR disease is a complex decision. Major determinant factors include the class of medications not used during prior lines of therapy, the depth and duration of the initial responses, and the patient’s functional status, organ damage, and cytogenetics, etc. For patients who are daratumumab‐naive, daratumumab‐based regimens should be considered; if they are transplantation‐eligible, ASCT may be considered. If patients are not bortezomib‐refractory, they also can consider CyBorD, melphalan plus dexamethasone, or ixazomib plus dexamethasone if they have significant neuropathy. For patients who are refractory to bortezomib, although pomalidomide‐based or lenalidomide‐based combinations can be considered, their utility is often limited by tolerability and NT‐proBNP surges, complicating response assessment; furthermore, although regimens involving carfilzomib, bendamustine, or repeat ASCT are available, treatment‐related toxicities are considerable, and the probability of achieving a CR with conventional remains suboptimal, ranging from 10% to 40%. 138 , 139

Venetoclax is a selective BCL‐2 inhibitor that targets the antiapoptotic protein BCL‐2, promoting apoptosis in BCL‐2–dependent cells. Studies have demonstrated that, in multiple myeloma, t(11;14) is strongly associated with a BCL‐2–primed phenotype, making venetoclax an effective, targeted therapeutic option for this specific patient subgroup. 140 , 141 Several retrospective studies have explored the use of venetoclax in RR AL amyloidosis with t(11;14), demonstrating CR rates of 35–53% and VGPR or better rates of 68%–88%. Although these results highlight venetoclax as a potentially effective targeted therapy for this subgroup, confirmation in larger prospective trials is required. 142 , 143

Immune‐directed and cell therapy

BCMA is a promising new target for AL amyloidosis. 144 There are several types of novel therapies targeting BCMA that were approved by the US Food and Drug Administration for RR myeloma and are now under exploration for RR AL, including BsAbs, antibody–drug conjugates, and CAR T cells.

Several BsAbs targeting BCMA are currently under investigation in RR AL amyloidosis in ongoing phase 1 and 2 clinical trials, including teclistamab (ClinicalTrials.gov identifier NCT06649695 ), etentamig (ABBV‐383; ClinicalTrials.gov identifier NCT06158854 ), linvoseltamab (ClinicalTrials.gov identifier NCT06292780 ), and elranatamab (ClinicalTrials.gov identifier NCT06569147 ). In addition, a trispecific antibody, ramantamig (JNJ‐79635322), which targets BCMA, GPRC5D (G‐protein–coupled receptor family C group 5 member D), and CD3, is being evaluated in a phase 1 study (ClinicalTrials.gov identifier NCT05652335 ). Although these studies are ongoing, early efficacy signals are highly encouraging. Phase 1 dose‐level 1 results of etentamig presented at the 2025 American Society of Hematology annual meeting demonstrated a 100% overall VGPR rate among 34 patients, with 82% achieving a hematologic CR and a median time to CR of 0.9 months (range, 0.3–9.3 months). 137 Consistent with these findings, small retrospective series have reported similarly striking activity with other BCMA‐directed BsAbs, including a 100% overall response rate (ORR) with a 67% hematologic CR for elranatamab and ORRs of 83%–100% with high rates of hematologic CR for teclistamab. 145 , 146 , 147 , 148 Together, these exceptionally high and rapid response rates provide early but promising evidence supporting the transformative potential of BCMA‐targeted BsAbs in the treatment of AL amyloidosis.

Belantamab mafodotin is an antibody–drug conjugate linking monomethyl auristatin‐F to an anti‐BCMA monoclonal antibody. It received US Food and Drug Administration approval in October 2025 in combination with bortezomib and dexamethasone for RR multiple myeloma. A phase 2 study evaluating belantamab mafodotin in RR AL amyloidosis (ClinicalTrials.gov identifier NCT04617925 ) has completed enrollment, with preliminary results demonstrating a 75% ORR, including a 42% hematologic CR rate and an approximately 30% organ response rate. 149

CAR T‐cell therapy is another novel therapeutic approach actively being explored in early phase clinical trials for AL amyloidosis. Single‐target, anti‐BCMA CAR T‐cell products include NXC‐201 (formerly HBI0101; ClinicalTrials.gov identifiers NCT04720313 and NCT06097832 ) for RR AL amyloidosis as well as equecabtagene autoleucel (ClinicalTrials.gov identifier NCT07055724 ), which is being evaluated in newly diagnosed, severe AL amyloidosis. In addition, AZD0120 is a dual‐target, CAR T‐cell construct directed against BCMA and CD19 that is currently under investigation in R/R AL amyloidosis (ALACRITY; ClinicalTrials.gov identifier NCT07081646 ). Other CAR T‐cell products, such as idecabtagene vicleucel and ciltacabtagene autoleucel, have been reported primarily in small retrospective series or case reports. Despite limited case numbers, studies have consistently demonstrated highly promising hematologic responses, with an ORR near 100% in RR AL amyloidosis. 150 , 151 , 152 The largest cohort to date, reported by Landau et al. (ClinicalTrials.gov identifier NCT06097832 ) at the 2025 American Society of Hematology meeting, included 20 patients and demonstrated rapid reductions in disease markers, with 95% of patients achieving normalization at a median of 7 days after CAR T‐cell infusion. A hematologic CR was observed in 75% of patients, with 16 of 18 evaluable patients achieving negative MRD status, and no significant toxicity was reported. 151 In the published experience, CAR T‐cell therapy appears to be feasible in carefully selected patients with AL amyloidosis, and durable remissions after a single CAR T‐cell infusion have been reported. 151

Fibril‐directed therapy

Despite major advances in plasma cell–directed therapy, organ responses in patients with AL amyloidosis often lag hematologic responses, reflecting the slow clearance of preexisting amyloid fibrils from affected tissues. This limitation has driven sustained interest in fibril‐directed therapies, which aim to directly remove deposited amyloid and thereby enhance organ recovery. Currently, those therapies are assessed in clinical trials and have not been incorporated into clinical practice.

Birtamimab (NEOD001) is a humanized immunoglobulin G1 monoclonal antibody designed to bind misfolded light‐chain aggregates, facilitating macrophage‐mediated clearance. 153 Although early studies suggested biologic activity, the phase 3 VITAL trial (ClinicalTrials.gov identifier NCT02312206 ) in patients with newly diagnosed AL amyloidosis failed to meet its primary end point and was terminated after futility analysis. Subsequent post‐hoc observations in very‐high‐risk patients prompted the AFFIRM‐AL study (ClinicalTrials.gov identifier NCT04973137 ), which evaluated birtamimab versus placebo in Mayo stage IV AL amyloidosis; however, the trial did not meet its primary end point (hazard ratio for all‐cause mortality, 0.915; p = .77), after which further development of birtamimab in AL amyloidosis was not pursued.

Anselamimab (CAEL‐101) is a chimeric immunoglobulin G1κ antibody derived from the murine precursor 11‐1F4 that targets a conformational epitope on misfolded light chains. By binding to the light chains and deposited fibrils, CAEL‐101 is intended to promote macrophages/neutrophil–mediated phagocytosis and subsequent amyloid fibril clearance. 154 Phase 1 studies demonstrated an acceptable safety profile and provided early signals of organ improvement, supporting advancement into two phase 3 CARES (Cardiac Amyloid Reaching for Extended Survival) trials in advanced cardiac AL amyloidosis (stage IIIa [ClinicalTrials.gov identifier NCT04512235 ] and stage IIIb [ClinicalTrials.gov identifier NCT04504825 ]). Based on sponsor disclosures, the primary end point in the overall patient population was not met in the CARES trials, but there is reference to a subgroup that benefited; the full data are awaited.

AT‐02 is a recombinant pan‐amyloid fusion protein that binds to amyloid fibrils and hypersulfated glycoaminoglycans through P5R and triggers amyloid fibril clearance through opsonization. 155 Early phase trials enrolling patients with systemic amyloidosis, including AL, are ongoing (ClinicalTrials.gov identifiers NCT05951049 and NCT05521022 ), with preliminary data reporting dose‐dependent renal function improvement in patients with AL amyloidosis who had achieved sustained hematologic responses. 156

With negative results from all of the clinical trials studying antifibrillar antibodies to date, the question arises whether or not we understand the components of organ damage and the variability of tissue responses to both proteotoxic light chains and fibrillar deposits. Recent cardiac amyloid imaging studies using labelled fibroblast activation protein indicate a high level of fibroblast activation protein activity in the amyloid heart. 157 Indeed, the role of AL light chain in triggering cardiac fibroblast activation and subsequent generation of reactive oxygen species and matrix production, resulting in pathologic remodeling and fibrosis, may represent an important component of cardiac injury in AL. How the immune‐mediated phagocytosis of amyloid fibrils interacts with this remodeling process is unknown but may contribute to the failure of these trials.

Organ transplantation

Solid organ transplantation has become an increasingly viable and effective strategy for select patients with AL amyloidosis who develop irreversible end‐organ dysfunction, particularly of the heart and/or kidneys, in the setting of well controlled or controllable plasma cell disease. 158 For cardiac involvement, orthotopic heart transplantation can be lifesaving in carefully chosen individuals with advanced, otherwise fatal, restrictive cardiomyopathy. The quoted 1‐year and 5‐year survival after heart transplantation for cardiac amyloidosis has approached that of nonamyloid transplantation recipients, reflecting better patient selection, optimization of systemic therapy, and comprehensive multidisciplinary care. Overall survival and early event rates are similar between amyloid and nonamyloid indications in the late transplantation era, supporting heart transplantation as a life‐saving option for patients with advanced cardiac amyloid when extracardiac disease is controlled. 158 , 159

Similarly, kidney transplantation offers significant survival and quality‐of‐life benefits for patients with AL amyloidosis–associated end‐stage renal disease, particularly for those who have achieved deep and durable hematologic responses. A large, multicenter, observational study demonstrated that renal transplantation recipients with AL amyloidosis experienced extended overall and graft survival, with a median overall survival exceeding 8 years and death‐censored graft survival often surpassing 5 years; outcomes were significantly better among patients who had complete or very good partial hematologic responses at the time of transplantation. 160 Even among patients who experienced hematologic progression, allograft failure was rare. These outcomes published in 2022 do not reflect the increased depth of response that occurs in patients treated with daratumumab, which will improve outcomes. 127

Multidisciplinary consensus of hematologists, nephrologists, and transplantation nephrologists have published management recommendations for kidney transplantation in plasma cell disorders, including AL amyloidosis, offering eligibility criteria and emphasizing that transplantation should not be unnecessarily delayed in patients who have adequate disease control, particularly those with living donors. 161 For patients with combined cardiac and renal failure, combined heart–kidney transplantation has been successfully performed in highly selected patients with favorable functional outcomes, illustrating that dual‐organ transplantation can be a viable rescue strategy when systemic amyloid is quiescent and hematologic remission is established. 162

FUTURE DIRECTIONS

Despite substantial advances in AL amyloidosis over recent decades, important gaps persist, and continued research efforts are needed to further improve quality of life, achieve durable disease control, and extend survival. Earlier and more accurate diagnosis remains an unmet need. Beyond increasing education and awareness, future work could explore whether risk‐adapted screening strategies among patients with monoclonal gammopathy of undetermined significance or smoldering myeloma could identify those at highest risk of progression to AL amyloidosis. 163 Meanwhile, more sensitive diagnostic approaches, such as emerging blood‐based assays targeting amyloidogenic light chain‐associated epitopes, and imaging tools capable of detecting early organ deposition before irreversible dysfunction warrant investigation. 164

In treatment response assessment, standardized criteria to define progression and guide the timing of subsequent therapy are lacking in AL amyloidosis, particularly in the setting of discordant hematologic and organ responses, and will require prospective validation and expert consensus. Similarly, the role of MRD and the clinical relevance of deep and sustained hematologic responses in predicting durable organ response require further investigation.

Therapeutically, ongoing development in clone‐directed therapies continue to improve hematologic response, whereas fibril‐directed approaches remain and may offer a strategy to address persistent amyloid deposition and delayed organ recovery. At the same time, more inclusive and clinically representative trial designs are needed because current eligibility criteria frequently exclude patients with advanced organ dysfunction, limiting trial access for many real‐world patients. 165

Conclusion

AL amyloidosis is a treatable and increasingly controllable disease when an early and accurate diagnosis is achieved. In patients who have cardiac involvement and evidence of monoclonal protein, tissue biopsy with typing is essential to distinguish AL from other types of amyloidosis. After diagnosis, Dara‐CyBorD has become the standard frontline therapy, whereas ASCT may be considered as consolidation or in subsequent lines for selected patients, although the clinical development of safer and more effective treatment strategies may change this paradigm. The management of relapsed disease remains heterogeneous; however, emerging modalities, such as BsAbs and CAR T‐cell therapies, show considerable promise and will likely further expand treatment options.

CONFLICT OF INTEREST STATEMENT

Heather Landau reports grants/contracts from AbbVie Inc., CAELUM (SK2020‐1205 and SK2020‐1206), Janssen Research and Development LLC, Nexcella, Protego Biopharma Inc., Prothena, and Partnership for Health Analytic Research; personal/consulting fees from Karyopharm Therapeutics and Pfizer; and support for other professional activities from AbbVie Inc., Alexion Pharmaceuticals, Arcellx, Bristol Myers Squibb Company, Johnson & Johnson, and Nexcella outside the submitted work. Jennifer E. Liu reports personal/consulting fees from Nexcella; and support for other professional activities from Axios Biosciences, GE Healthcare, and Philips outside the submitted work. Raymond L. Comenzo (12091466, Granted September 16, 2024) reports personal/computing fees from Janssen Biotech and has a patent with Jannsen Biotech outside the submitted work. The remaining authors disclosed no conflicts of interest.

ACKNOWLEDGMENTS

This research was funded in part through National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30 CA008748, R01‐CA279808. This review is the result of funding in whole or in part by the National Institutes of Health (NIH). It is subject to the NIH Public Access Policy. Through acceptance of this federal funding, the NIH has been given the right to make this article publicly available in PubMed Central upon the Official Date of Publication, as defined by the NIH.

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