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Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis

Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis
Literature review current through: Sep 2023.
This topic last updated: Mar 13, 2023.

INTRODUCTION — Immunoglobulin light chain (AL) amyloidosis (previously referred to as primary amyloidosis), is a monoclonal plasma cell proliferative disorder characterized by tissue deposits of fibrils composed of monoclonal light chain fragments, leading to organ dysfunction.

The incidence of AL amyloidosis is approximately one-fifth that of multiple myeloma (MM). At the time of diagnosis, approximately 10 percent of patients with AL amyloidosis will meet diagnostic criteria for MM as defined by CRAB (hypercalcemia, renal insufficiency, anemia, or bone disease) criteria; nearly another 40 percent of patients with AL do not meet criteria for MM but have 10 percent or more bone marrow plasmacytosis at diagnosis. The clinical course and treatment of these patients is dependent on which of the two diseases is dominant in terms of end-organ damage and symptoms. Less than 1 percent of patients with isolated AL amyloidosis at diagnosis develop MM at a future time point.

The treatment and prognosis of AL amyloidosis will be reviewed in detail here. The pathogenesis, clinical features, and diagnosis of these disorders and the diagnosis and management of amyloid cardiomyopathy and renal amyloid are discussed in detail separately.

(See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis".)

(See "Monoclonal immunoglobulin deposition disease".)

(See "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis".)

(See "Cardiac amyloidosis: Treatment and prognosis".)

(See "Renal amyloidosis".)

PRETREATMENT EVALUATION

Assessment — To best treat patients with AL amyloidosis, the initial evaluation must confirm the diagnosis, establish the extent and sites of disease, and evaluate for comorbidities that are likely to have an impact on treatment options. The diagnosis of AL amyloidosis is presented separately. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis".)

In addition to a history and physical examination, it is our practice to perform the following pretreatment studies in patients with AL amyloidosis some of which will have already been performed as part of the diagnostic evaluation:

Laboratory studies include a complete blood count with differential, chemistries with liver and renal function and electrolytes, electrophoresis of the serum and urine, immunofixation of the serum and urine, serum free light chain assay, 24-hour urinary protein and creatinine clearance, troponin T, N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and thyroid stimulating hormone (TSH). We measure factor X levels for all patients; alternatively, clinicians may choose to check prothrombin time (PT) and partial thromboplastin time (PTT) with plans to check factor X levels in patients with abnormal bleeding or abnormal PT/PTT testing.

Unilateral bone marrow aspirate and biopsy with immunohistochemical staining for kappa and lambda and Congo red staining for amyloid. The prognostic value of fluorescence in situ hybridization (FISH) studies is not well established. We perform FISH to identify t(11;14), t(4;14), t(6;14), t(14;16), t(14;20), trisomies, 1q+, and del17p. While there are data that patients with t(11;14) are less likely to respond to bortezomib-based therapy [1,2], this poor prognosis may be abrogated partially by the use of transplant, daratumumab, or low dose alkylator, but these data need further confirmation [3,4]. (See "Multiple myeloma: Staging and prognostic studies".)

Bone imaging should be performed in patients with ≥10 percent bone marrow plasma cells. As with other patients with suspected multiple myeloma, cross sectional imaging is preferred over plain radiographs. This is discussed in more detail separately. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Choice of modality'.)

Electrocardiogram, echocardiogram, and chest radiograph. A cardiac magnetic resonance imaging (MRI) study may be valuable in certain circumstances. Late gadolinium enhancement can diagnose cardiac involvement, but it is not independently prognostic of other cardiac measures [5]. Equilibrium contrast cardiovascular magnetic resonance can be used to quantify the cardiac interstitial compartment, measured as myocardial extracellular volume (ECV) fraction [6].

Blood pressure should be measured while the patient is seated and standing to assess for orthostatic (postural) hypotension due to autonomic neuropathy. Patients with neurologic symptoms should be evaluated with electromyography (EMG) and nerve conduction studies (NCS). Since the neuropathy is most typically a small fiber neuropathy, EMG/NCS are often normal despite symptoms of paresthesia or dysesthesia. (See "Musculoskeletal manifestations of amyloidosis" and "Myopathies of systemic disease", section on 'Amyloid myopathy'.)

Craniocaudal liver span should be documented with an ultrasound or computed tomography. Patients with symptoms of gastroparesis should undergo a study of gastric emptying. (See "Gastroparesis: Etiology, clinical manifestations, and diagnosis", section on 'Scintigraphic gastric emptying'.)

Men and women with child-bearing potential should receive counseling about the potential effect of treatment on their fertility and options for fertility-preserving measures. Given the urgent need for treatment, options for women are limited, but men can often participate in sperm banking. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)

Organ involvement defined — For treatment purposes, organ involvement by amyloidosis is defined by consensus criteria created in 2005 at the 10th International Symposium on Amyloid and Amyloidosis and revised in 2011 [7,8]:

Kidney – Direct biopsy verification with clinical or laboratory evidence of organ dysfunction or, if amyloid deposits have been confirmed at another site, 24-hour urine protein >0.5 g/day, predominantly albumin. Other causes of proteinuria (eg, poorly controlled diabetes mellitus or uncontrolled hypertension) should be excluded. (See "Renal amyloidosis".)

The likelihood of requiring dialysis can be predicted using two risk factors: 24-hour urinary protein excretion ≥5 g/24 hours and estimated glomerular filtration rate (eGFR) <50 mL/min/1.73 m2 [9]. In one study, among patients with previously untreated AL amyloidosis, dialysis was required within two years in 0 to 3, 11 to 25, and 60 to 75 percent of those with none, one, or both risk factors, respectively.

Heart – Direct biopsy verification with clinical or laboratory evidence of organ dysfunction or, if amyloid deposits have been confirmed at another site, echocardiogram with mean wall thickness (interventricular septum and posterior wall) >12 mm with no other cardiac cause or an elevated NT-proBNP (>332 ng/L) in the absence of renal failure or atrial fibrillation. NT-proBNP is highly sensitive for cardiac involvement in patients with AL amyloidosis and a normal NT-proBNP rules out the possibility of clinically meaningful cardiac involvement [10]. (See "Cardiac amyloidosis: Treatment and prognosis" and "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis".)

Liver – Direct biopsy verification with laboratory evidence of organ dysfunction or, if amyloid deposits have been confirmed at another site, total liver span >15 cm in the absence of heart failure or alkaline phosphatase >1.5 times institutional upper limit of normal. (See "Gastrointestinal amyloidosis: Clinical manifestations, diagnosis, and management", section on 'Hepatic amyloidosis'.)

Nerve – Clinical symmetric lower extremity sensorimotor peripheral neuropathy or gastric-emptying disorder, intestinal pseudo-obstruction, voiding dysfunction not related to direct organ infiltration.

Gastrointestinal tract – Direct biopsy verification with symptoms (eg, diarrhea, motility disturbances, and weight loss). Identification of vascular-only amyloid deposits without symptoms should not be considered intestinal organ involvement. (See "Gastrointestinal amyloidosis: Clinical manifestations, diagnosis, and management", section on 'Gastrointestinal tract amyloidosis'.)

Lung – Direct biopsy verification with symptoms and an interstitial radiographic pattern is included in the consensus criteria; however, we do not consider direct biopsies to be necessary in most of these patients.

Soft tissue – Clinical tongue enlargement, arthropathy, claudication (presumed vascular amyloid), skin involvement, myopathy by biopsy or muscle pseudohypertrophy, lymph node involvement (may be localized), carpal tunnel syndrome.

Staging — While multiple prognostic models have been proposed for patients with amyloidosis, simple staging models that incorporate N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and cardiac troponin are easily applied in clinical practice (table 1). The systems below can used to assess prognosis at diagnosis, and to compare clinical trials. The Mayo 2004 and revised Mayo system can also be used for restaging at three and six months from treatment initiation and at the time of second-line therapy [11,12].

NT-proBNP plus cardiac troponin T (Mayo 2004 Stage with European Modification) – The Mayo 2004 staging system uses cardiac troponin and NT-proBNP to determine stage as follows (table 1) [13]:

Stage I – Cardiac troponin <0.035 mcg/L and NT-proBNP <332 ng/L

Stage II – Cardiac troponin ≥0.035 mcg/L or NT-proBNP ≥332 ng/L (not both)

Stage III – Cardiac troponin ≥0.035 mcg/L and NT-proBNP ≥332 ng/L

In 2015, the Europeans proposed splitting the stage III patients into IIIa and IIIb based on the absence or presence of NT-proBNP >8500 ng/L, respectively [14]:

Stage IIIA – Cardiac troponin ≥0.035 mcg/L and NT-proBNP 332 to <8500 ng/L

Stage IIIB – Cardiac troponin ≥0.035 mcg/L and NT-proBNP ≥8500 ng/L

Of note, some laboratories measure cardiac troponin I instead of T. If cardiac troponin I is used instead of T, a value of ≥0.10 mcg/L is considered a risk factor in this model [15].

The Mayo 2004 staging system was originally derived using clinical information from 242 patients with newly diagnosed AL amyloidosis seen at a single institution [13]. Median survivals for those not undergoing hematopoietic cell transplantation (HCT) with stage I, II, and III AL amyloidosis were 26, 11, and 4 months, respectively. Another study reported that this model predicted prognosis in patients with AL amyloidosis undergoing HCT, with stage III patients having a median survival of less than one year despite HCT [16].

BNP plus cardiac troponin I (Boston University Staging System) – The Boston University staging system uses cardiac troponin I and brain natriuretic peptide (BNP) as risk factors (table 1) [17]:

Stage I – Cardiac troponin I ≤0.10 ng/mL and BNP ≤81 pg/mL

Stage II – Cardiac troponin I >0.10 ng/mL or BNP >81 pg/mL (not both)

Stage IIIA – Cardiac troponin I >0.10 ng/mL and BNP >81 to 700 pg/mL

Stage IIIB – Cardiac troponin I >0.10 ng/mL and BNP >700 pg/mL

When applied to a cohort of 250 consecutive patients referred to their center in 2016, corresponding estimated median overall survival times were not reached, 9.4 years, 4.3 years, and 1 year [17]. This system has not yet been validated by other groups. Importantly, a variety of clinical immunoassays are available for plasma BNP and they are not completely interchangeable.

NT-proBNP, cardiac troponin T, and serum free light chains (Mayo 2012 Stage) – The Mayo 2012 staging system uses NT-proBNP ≥1800 ng/L, cardiac troponin T ≥0.025 mcg/L, and the difference between involved and uninvolved serum free light chains (dFLC) ≥18 mg/dL as risk factors (table 1) [18]:

Stage I – None elevated

Stage II – One elevated

Stage III – Two elevated

Stage IV – Three elevated

If cardiac troponin T is measured using a high sensitivity assay, a cutoff of 40 pg/mL should be used [15,19].

The Mayo 2012 staging system was developed using data from 810 patients with newly diagnosed AL amyloidosis seen at a single institution and validated in another 303 patients undergoing HCT and 103 patients enrolled onto different clinical trials [18]. For patients classified as having stage I, II, III, or IV disease, median overall survival from diagnosis was 94, 40, 14, and 6 months, respectively. For patients undergoing HCT, the four-year estimated overall survival rates were 87, 72, 56, and 46 percent, respectively, with median overall survivals of not reached, 97, 58, and 22 months.  

GENERAL CONCEPTS

Goals of therapy — Patients with systemic AL amyloidosis are not cured with conventional treatment. However, early mortality rates have decreased and survival has improved as there has been a shift toward earlier diagnosis and therapy aimed at achieving deep remissions [20]. (See 'Prognosis' below.)

While remissions can be attained, relapses are common. Treatment directed at the plasma cells aims to decrease amyloid production, limit further organ damage, and allow for regression of tissue amyloid deposits. With this approach, regression of tissue amyloid deposits is uncommon; as such, symptoms due to these deposits are likely not reversible. Management is multidisciplinary, often involving the collaboration of experts in hematology, cardiology, nephrology, gastroenterology, and neurology.

Indications for systemic therapy — Virtually all patients with systemic AL amyloidosis require treatment at the time of diagnosis. An important exception is patients with AL amyloid in the bone marrow discovered incidentally as part of the evaluation of monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma in whom initial therapy can be postponed until the first sign of organ involvement. Such patients are seen in clinic every three months. At these visits we perform a focused review of systems and examination along with laboratory studies to detect progression (serum immunoglobulin, free light chains, alkaline phosphatase, troponin, NT-proBNP, creatinine, and spot urine for albumin).

Systemic therapy is also not necessary for patients with localized forms of AL amyloidosis (eg, tracheobronchial, genitourinary, isolated carpal tunnel and non-purpuric cutaneous lesions). These deposits are not due to an underlying systemic clonal plasma cell disorder and do not progress to systemic disease [21]. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'Localized amyloidosis'.)

Amyloid cardiomyopathy — Patients with amyloid cardiomyopathy due to AL amyloidosis need careful management of cardiac complications including heart failure (HF), atrial fibrillation, and conduction disease. In particular, treatment of HF in patients with cardiac amyloidosis differs from the therapy generally recommended in patients with diastolic or systolic HF. This is described in more detail separately. (See "Cardiac amyloidosis: Treatment and prognosis".)

INITIAL TREATMENT

Determining transplant eligibility — All patients with newly diagnosed AL amyloidosis need to be assessed to determine eligibility for autologous hematopoietic cell transplantation (HCT). Eligibility for autologous HCT in AL amyloidosis varies across countries and institutions. Autologous HCT is offered primarily to patients less than 70 years of age. However, a strict age-limit is not used and retrospective analyses suggest that carefully selected patients over age 70 years may have good outcomes with HCT [22]. As such, decisions are made on a case-by-case basis based on "physiologic age" and vary across institutions. Over 80 percent of newly diagnosed patients will be ineligible for transplant due to advanced age, renal insufficiency, advanced heart failure, or multiorgan involvement [23]. (See "Determining eligibility for autologous hematopoietic cell transplantation".)

In general, patients should meet all of the following criteria in order to be eligible for autologous HCT in AL amyloidosis [24,25]:

Physiologic age ≤70 years

Troponin T <0.06 ng/mL (or hs-Troponin T <75 ng/mL)

Systolic blood pressure ≥90 mmHg

Creatinine clearance ≥30 mL/min (unless on chronic stable dialysis)

Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (table 2)

New York Heart Association (NYHA) functional status class I or II (table 3)

No more than two organs significantly involved (liver, heart, kidney, or autonomic nerve)

No large pleural effusions

No dependency on oxygen therapy

These are guidelines; the decision on transplant eligibility should be made based on a risk-benefit assessment and the needs and wishes of the patient. Of importance, patients with severe (<25 percent) factor X deficiency have a transplant-related mortality (TRM) rate that approaches 50 percent [26]. Splenectomy may be performed in such patients in an effort to increase factor X levels prior to HCT [27].

Cardiac and renal transplantation followed by HCT has been used in selected patients with cardiac and renal amyloidosis, respectively, and is discussed separately. (See "Renal amyloidosis", section on 'Dialysis and kidney transplantation' and "Cardiac amyloidosis: Treatment and prognosis".)

Support for the use of these transplant eligibility criteria comes from retrospective analyses and small prospective series that have demonstrated the adverse prognostic importance of organ involvement in patients with AL amyloidosis undergoing HCT [28-33]. As an example, in a series of 21 transplanted patients, the most striking finding was the prognostic value of the number of clinical manifestations of amyloidosis at the time of transplantation [28]. The criteria used included creatinine clearance <30 mL/min, nephrotic syndrome, heart failure, neuropathy, or hepatomegaly associated with an alkaline phosphatase concentration >200 international units (IU)/L. Patients with less than two of these manifestations had a much higher overall (92 versus 11 percent) and event-free (46 versus 11 percent) survival than those with two or more manifestations. The poor outcomes in the latter group were primarily due to a greater than 75 percent incidence of toxic death with intensive therapy.

Patients eligible for transplant

Choice of therapy — There is uncertainty regarding the preferred management of patients who are eligible for HCT, and participation in clinical trials should be encouraged. Outside of a clinical trial, we suggest the use of induction therapy followed by high dose melphalan and autologous HCT for patients who are fit enough, rather than HCT or chemotherapy alone (algorithm 1). HCT should be performed at a center with specific expertise in AL amyloidosis. Other experts offer induction therapy and defer HCT in those with a satisfactory response [25].

Our preference for HCT is based on low quality data that suggest HCT can result in longer remissions, though data using daratumumab-based inductions may eventually challenge that paradigm [34]. As with any therapy that results in deep hematologic response, HCT stops amyloid production, amyloid deposits are slowly resorbed, and organ function, performance status, and quality of life improve. However, careful selection of patients is critical since there is an increased risk of TRM from compromised organ reserve due to amyloid deposition. (See 'HCT efficacy and toxicity' below.)

Emerging data suggest better outcomes for patients who receive two to four cycles of bortezomib-based induction therapy prior to stem cell mobilization and transplantation. Our preferred induction therapy is subcutaneous daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (CyBorD). If daratumumab is not available, we offer induction with CyBorD alone. (See 'Bortezomib-based regimens' below.)

Treatment regimens that include immunomodulatory derivatives (eg, lenalidomide, thalidomide) are generally avoided as these drugs are typically less well-tolerated in patients with AL amyloidosis [35-39]. Following HCT, we consider further therapy based on the degree of response achieved. This is discussed in more detail below. (See 'Monitoring response' below.)

Maintenance therapy is offered after HCT to all patients with overt multiple myeloma (MM), and to selected patients without overt MM but with at least 20 percent bone marrow plasma cells and/or high-risk findings on fluorescence in situ hybridization (FISH; ie, del17p, t(4;14), t(14;16), and t(14;20)). (See "Multiple myeloma: Use of hematopoietic cell transplantation", section on 'Maintenance'.)

Although one study has suggested that there might be a component of graft-versus-tumor effect in patients receiving myeloablative or nonmyeloablative allogeneic HCT, allogeneic HCT is not considered a treatment option given an extremely high incidence of TRM [40].

HCT efficacy and toxicity — Autologous HCT allows for the delivery of myeloablative doses of melphalan aimed at the underlying plasma cell dyscrasia. Delivery of higher melphalan doses is associated with deeper responses and better clinical outcomes [28,29,41-45]. When successful, HCT stops amyloid production, amyloid deposits are slowly resorbed, and organ function, performance status, and quality of life improve [46]. However, careful selection of patients is critical since there is an increased risk of TRM from compromised organ reserve due to amyloid deposition.

Patients with AL amyloidosis are at increased risk for early TRM due to cardiac arrhythmias, sepsis, intractable hypotension, gastrointestinal bleeding, and multiorgan failure. Experienced referral centers have multidisciplinary teams that are well equipped to manage these complicated patients. At these centers, early TRM is <5 percent [47-50].

Studies that have compared HCT with conventional chemotherapy have had mixed results [42,51-58].

While the results of a small randomized trial suggested no benefit from HCT, a number of flaws in study design question the applicability of these results to this patient population [59]. Retrospective studies have suggested improved overall survival (OS) and improved quality of life among patients with AL amyloidosis undergoing HCT when compared with similar patients undergoing chemotherapy alone [51,60]. Results may be even better with careful patient selection and implementation of a risk-adapted approach [42,51,52,54-56,61].

The following studies illustrate outcomes seen with HCT:

A retrospective analysis of the International Blood and Marrow Transplant Research database identified 1536 patients with AL amyloidosis who underwent autologous HCT between 1995 and 2012 [47]. Over the study time-period there was a decline in early mortality and improvement in OS. Among the 800 patients transplanted from 2007 to 2012, the mortality rate at 100 days was 5 percent; the estimated OS rate at five years was 77 percent. Outcomes were better at centers that performed more transplants. Factors associated with worse outcomes included cardiac involvement, poor performance status, and increased creatinine. It is unknown whether the improved outcomes over time were a result of improved patient selection, changes in the transplant protocols, better supportive care, or a combination of these factors.

A series of 629 patients treated with high dose melphalan (100 to 200 mg/m2) followed by autologous HCT at Boston University School of Medicine reported the following [48,62,63]:

The 100-day TRM was 7.5 percent. The TRM in patients transplanted after 2005 was lower at 3.4 percent, probably reflecting better patient selection and improvements in supportive care. Median survival was 7.6 years.

Complete response (CR) was obtained in 40 percent. Patients who attained a CR had superior median OS (not reached at 8 years follow-up versus 6.3 years) and estimated rates of survival at 1 (100 versus 94 percent), 5 (88 versus 60 percent), 10 (72 versus 34 percent), and 15 (57 versus 18 percent) years. The median survival following hematologic relapse was 4.3 years.

TRM, rates of CR, and median survivals were similar in older (65 to 79 years) and younger (<65 years) patients eligible for, and receiving, HCT [64].

A higher dose of melphalan (200 mg/m2) was associated with a higher CR rate and improved OS.

Improvement in the function of at least one organ system (eg, hepatic, renal, cardiac, neurologic) occurred in 79 percent of those achieving a CR, and in 39 percent of those who did not achieve CR status.

In a series of 672 patients undergoing autologous HCT at the Mayo Clinic, the 100-day TRM declined over time (14.5 percent from 1996 to 2002; 8.6 percent from 2003 to 2009; 2.4 percent from 2010 to 2016) [49]. CR was obtained in 40 percent and a partial response (PR) or better was seen in 80 percent. Median OS was 122 months. For the most recent cohort, over 85 percent were alive at one year and the estimated rate of survival at five years exceeded 80 percent. Earlier disease stage and deeper responses were associated with superior survival.

Other experts offer bortezomib-based therapy (eg, daratumumab plus CyBorD, cyclophosphamide, bortezomib, dexamethasone) to all patients with deferral of HCT in those who achieve a satisfactory response (eg, CR or organ response plus an at least partial response) [25]. This approach places a higher value on the avoidance of HCT-related toxicity, while recognizing the risk that some patients may become ineligible for HCT. While most studies evaluated this approach with CyBorD alone, daratumumab plus CyBorD is the preferred induction regimen, if available, based on the Andromeda study [4].

In a report from one center that used this approach, 63 of 139 patients (45 percent) achieved a satisfactory response and were treated with CyBorD alone; of the 76 patients with unsatisfactory response, 55 patients proceeded with HCT, 16 patients lost eligibility for HCT, and 5 patients refused HCT [58]. The estimated five-year OS was similar among the patients treated with HCT or CyBorD alone (86 versus 84 percent); however, five-year OS was 51 percent among the patients with unsatisfactory response who did not undergo HCT.

A retrospective analysis of >650 patients who underwent stem cell collection at a large referral center reported similar OS among patients who underwent HCT within 90 days of collection and those who had not undergone HCT by 90 days [65]. Median OS was similar among patients who achieved an at least very good partial response at the time of collection and underwent early HCT or deferred HCT (14.2 versus 13.4 years). However, when the analysis was limited to patients who received induction therapy prior to stem cell collection, there was a trend for better OS among those who underwent early HCT, although this difference did not reach statistical significance.  

Melphalan dosing — The standard preparative (conditioning) regimen used for HCT in AL amyloidosis is melphalan at a dose of 200 mg/m2. Even in transplant-eligible patients, the TRM is higher in AL amyloidosis than in myeloma [66]. Although a risk-adapted dosing strategy using lower conditioning doses of melphalan has been evaluated in an attempt to reduce TRM, this has been associated with lower efficacy [42,44,62,67]. Patients who are considered to be ineligible to receive a melphalan dose of 200 mg/m2 are probably best treated with nontransplant approaches. One exception is patients who are on chronic stable dialysis and are being considered for transplantation in whom a reduced melphalan dose of 140 mg/m2 is used. (See "Multiple myeloma: Use of hematopoietic cell transplantation", section on 'Preparative chemotherapy'.)

Patients not eligible for transplant

Choice of therapy — The preferred management of patients who are not eligible for HCT is unclear, and participation in clinical trials should be encouraged. Outside of a clinical trial, we offer combination therapy with daratumumab, bortezomib, cyclophosphamide, dexamethasone (dara-CyBorD), or a triplet like CyBorD or bortezomib, melphalan, and dexamethasone (BMD) (algorithm 1). This preference is based on clinical trials and large case series with these regimens demonstrating encouraging response rates and tolerability. If the patient is not a candidate for bortezomib, we offer daratumumab as a single agent or in combination with cyclophosphamide and dexamethasone. This includes patients with sensory neuropathy that is painful or limiting self-care.

Support for the use of bortezomib-based regimens comes from a randomized trial that showed an OS benefit for the addition of bortezomib to melphalan plus dexamethasone [68]. BMD has not been directly compared with CyBorD in randomized trials; retrospective analyses suggest equipoise [69]. In another randomized trial, the addition of daratumumab to CyBorD deepened responses and delayed major organ deterioration [70]. Our approach for patients who are not candidates for transplantation is to initiate therapy with one of these regimens, assess response each cycle, and modify therapy if an optimal response is not achieved. Better treatments are needed and patients, especially those with advanced cardiac involvement, should be encouraged to participate in clinical trials. (See 'Clinical trials' below.)

We offer alternative systemic therapy if the initial therapy fails to achieve >50 percent reduction in the difference between involved free light chain (FLC) levels and uninvolved FLC levels (dFLC) after two cycles; or dFLC ≥40 mg/L after four to six cycles; or if there is disease progression at any time. (See 'Response assessment' below.)

Although for many years melphalan and prednisone was the standard treatment of patients with AL amyloidosis who were not candidates for HCT [53,71-76], this has been replaced by regimens described below as front-line therapy in these patients.

Bortezomib-based regimens — For most patients who are not candidates for HCT, we recommend a bortezomib-based regimen. If available, we prefer the combination of daratumumab, cyclophosphamide, bortezomib, and dexamethasone (dara-CyBorD) based on the Andromeda trial which demonstrated that the addition of daratumumab to CyBorD resulted in deeper responses and delayed major organ deterioration [4]. If daratumumab is not available, we prefer cyclophosphamide, bortezomib, and dexamethasone (CyBorD) or bortezomib, melphalan, and dexamethasone (BMD), rather than melphalan plus dexamethasone. Rapid responses are seen in a majority of patients and the most common toxicities are vomiting, diarrhea, and cytopenias [14,69,77-81]. Neuropathy can be dose limiting, but is abrogated by subcutaneous administration.

CyBorD with or without daratumumab — For AL amyloidosis, CyBorD is usually administered on a 28-day cycle as follows:

Bortezomib 1.3 to 1.5 mg/m2 subcutaneous administration once a week

Cyclophosphamide 500 mg (total dose) by mouth once a week

Dexamethasone 20 to 40 mg by mouth once a week

If available, daratumumab-hyaluronidase (1800 mg daratumumab with 30,000 units hyaluronidase) is administered subcutaneously once a week for cycles 1 and 2, then every two weeks for cycles 3 through 6, then every four weeks until disease progression or for a maximum of two years. Given concerns about cardiac toxicity, approval of daratumumab-hyaluronidase by the US Food and Drug Administration does not include patients with NYHA class IIIB or class IV cardiac disease or Mayo 2004 stage IIIB.

Depending on the degree of cytopenias and other side effects, an alternative CyBorD schedule is to administer bortezomib, cyclophosphamide, and dexamethasone for three consecutive weeks followed by a one-week break before proceeding with subsequent cycles. Note that the doses used are different than those used in multiple myeloma. Dose modifications may be needed for patients with renal and/or hepatic dysfunction. This regimen has a low or very low risk of emesis and antiemetic prophylaxis is not necessary. Patients should be encouraged to maintain adequate oral hydration to void every two to three hours to reduce the risk of hemorrhagic cystitis. Bortezomib therapy may be associated with an increased risk of herpes zoster and infections not related to neutropenia. Antiviral prophylaxis (eg, acyclovir 400 mg orally twice a day) should be administered to all patients receiving CyBorD. Some clinicians also administer trimethoprim-sulfamethoxazole double strength once daily on Mondays, Wednesdays, and Fridays during treatment.

In a phase 3 trial (ANDROMEDA), 388 patients with newly diagnosed AL amyloidosis were randomly assigned to receive six cycles of CyBorD with or without subcutaneous daratumumab [4]. Those assigned to daratumumab also received maintenance with single-agent daratumumab monthly for up to two years. After a median follow-up of 11.4 months, the addition of daratumumab to CyBorD resulted in higher rates of hematologic complete response at any time (53 versus 18 percent); higher rates of cardiac response (42 versus 22 percent) and renal response (53 versus 24 percent) at six months; and delayed a composite endpoint of major organ deterioration, hematologic progression, or death (hazard ratio 0.58; 95% CI 0.36-0.93).

Toxicity was also increased with higher rates of grade 3 or 4 adverse events (17 versus 10 percent) but a similar percentage of patients discontinuing therapy due to adverse events (4.1 versus 4.3 percent). Daratumumab increased the rates of lymphopenia (19 versus 15 percent), upper respiratory tract infections (26 versus 11 percent), and peripheral sensory neuropathy (31 versus 20 percent). A minority of patients have died in the two arms (27 and 29 patients, respectively); those assigned to daratumumab had a numerically higher percentage of deaths attributed to adverse events (11.9 versus 7.4 percent) and lower percentage of deaths attributed to disease progression (1 versus 4.8 percent) or other reasons (1 versus 2.7 percent). Most deaths, including those attributed to adverse events, occurred in patients with cardiac involvement at baseline. Longer follow-up is needed to assess impact on overall survival.

These results led to accelerated approval by the US Food and Drug Administration of subcutaneous daratumumab-hyaluronidase in combination with CyBorD for newly diagnosed AL amyloidosis [82]. In patients with AL amyloidosis, the prescribing information describes cardiac failure and/or cardiac arrest in 16 percent and fatal cardiac disorders in 10 percent. Patients with baseline cardiac involvement may be at higher risk and should be monitored closely for cardiac adverse reactions; daratumumab-hyaluronidase should not be used for patients with AL amyloidosis who have NYHA class IIIB or class IV cardiac disease or Mayo stage IIIB. Additional administration considerations are described separately. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Anti-CD38 monoclonal antibodies'.)

The strongest data regarding the efficacy of CyBorD as initial treatment for AL amyloidosis comes from two large series, which included over 1000 patients [14,69]. Hematologic responses were seen in 60 to 65 percent (approximately 25 percent complete). Cardiac (17 to 33 percent), renal (15 to 25 percent), and liver (30 percent) responses were also reported. Survival correlated with Mayo Stage and degree of response. For the larger study, estimated median OS was 72 months for the entire population and not reached, 80, 36, and 4 months for patients with Mayo Stage I, II, IIIa (stage III with NT-proBNP ≤8500 ng/L), and IIIb (stage III with NT-proBNP >8500 ng/L), respectively. Stringent dFLC response (<10 mg/L) correlated with superior survival. Most toxicities were grade 1 to 2 with the most common being lethargy (56 percent), constipation (26 percent), fluid overload (24 percent), and sensory neuropathy (21 percent).

Bortezomib, melphalan, and dexamethasone — For AL amyloidosis, BMD is can be administered as follows [68]:

Bortezomib 1.3 mg/m2 subcutaneous administration on days 1, 4, 8, and 11 of cycles 1 and 2 (cycle length = 28 days), and on days 1, 8, 15, and 22 of subsequent cycles (cycle length = 35 days)

Melphalan 0.22 mg/kg by mouth for four consecutive days each cycle

Dexamethasone 40 mg by mouth for four consecutive days each cycle

Dose modifications may be needed for patients with renal and/or hepatic dysfunction. This regimen has a low or very low risk of emesis and antiemetic prophylaxis is not necessary. Bortezomib therapy may be associated with an increased risk of herpes zoster and infections not related to neutropenia. Antiviral prophylaxis (eg, acyclovir 400 mg orally twice a day) should be administered to all patients receiving BMD. Some clinicians also administer trimethoprim-sulfamethoxazole double strength once daily on Mondays, Wednesdays, and Fridays during treatment. Primary prophylaxis with granulocyte-stimulating factor is not indicated. While the above schedule was used for the trial described below, prior studies have demonstrated better tolerability and higher effective doses of bortezomib delivered when using weekly bortezomib [77].

Data supporting the use of BMD comes from a phase III international, open-label trial in which 109 transplant-ineligible patients with previously untreated AL amyloidosis were randomly assigned to receive BMD versus melphalan plus dexamethasone alone [68]. The trial excluded patients with advanced cardiac stage (stage IIIb) amyloidosis. After a median follow-up of 50 months, BMD resulted in improved response rates (hematologic response at three months 79 versus 52 percent; very good partial response [VGPR] plus CR rate 64 versus 39 percent) and superior OS (median OS not reached versus 34 months; HR 0.50, 95% CI 0.27-0.90). BMD also increased the percentage of treatment cycles with grade 3 or 4 adverse events (20 versus 10 percent), although patient-reported quality of life after three cycles was similar between the two arms. The most common nonhematologic adverse events with BMD were peripheral sensory neuropathy (52 percent); gastrointestinal disorders (40 percent); and fluid retention, fatigue, and fever (approximately 20 percent each). Approximately 20 percent of patients in this trial received intravenous bortezomib; rates of peripheral neuropathy are lower with subcutaneous bortezomib administration. As this was a highly selected cohort, toxicities are likely to be more common in a broader population.

Melphalan and dexamethasone — Melphalan and dexamethasone is an option for patients with AL amyloidosis who are not candidates for HCT, cannot receive bortezomib, and do not have access to daratumumab. This regimen is well tolerated with cytopenias being the most common dose-limiting toxicity. Approximately 60 percent of patients will demonstrate an at least partial hematologic response, although response rates are much lower in patients with advanced cardiac involvement [83-85]. A hematologic response is required for functional improvement of involved organs (organ response).

Melphalan plus dexamethasone is administered in 28-day cycles as follows:

Melphalan 0.22 mg/kg by mouth daily on days 1 through 4

Dexamethasone 40 mg by mouth daily on days 1 through 4

This regimen has low or very low risks of emesis and infection and does not require prophylaxis for either. The melphalan dose can be reduced by 25 to 30 percent for patients with renal failure.

Support for the use of melphalan plus dexamethasone in this population comes from case series of patients treated at amyloid referral centers. Differences in response rates and survival have been largely attributed to the different proportions of high-risk patients.

In an early study, 46 patients with AL amyloidosis who did not meet criteria for HCT because of severe organ damage were treated with this regimen [86]. Prophylactic omeprazole (20 mg/day by mouth), ciprofloxacin (250 mg by mouth twice per day), and itraconazole (100 mg/day by mouth), were also given for the first 10 days of each cycle. Treatment was continued for up to nine courses. The following findings were noted [86]:

CRs and overall response rates were noted in 33 and 67 percent of the patients, respectively, following a median of four treatment courses (4.5 months).

Seventy-one percent of the 31 responding patients (ie, monoclonal protein decreased by at least 50 percent), achieved significant functional improvement of involved organs. No functional improvement was noted in the 15 patients not responding to treatment.

At a median follow-up of five years, median progression-free survival (PFS) and OS were 3.8 and 5.1 years, respectively [87].

CRs were durable, being maintained for at least three years in 70 percent of patients. In relapsing patients, the amyloid-producing clone remained sensitive to this regimen, and CR could be restored by repeat treatment [87].

In a subsequent report of 119 HCT-ineligible patients treated with this regimen at this center, hematologic and CR rates were 76 and 31 percent with a median survival of 7.4 years [85]. The same center used a lower dexamethasone dose (20 mg) in combination with standard melphalan to treat 140 patients with AL amyloidosis and advanced cardiac disease (eg, those with repetitive ventricular arrhythmias or fluid retention >3 percent of body weight). This higher risk population had hematologic and CR rates of 51 and 12 percent, respectively, and a median survival of 20 months. It is not clear whether these inferior outcomes were related to the increased baseline risk of the population, the lower dexamethasone dose, or a combination of the two.

Comparable results have been demonstrated by the French [59], but other studies have demonstrated inferior results, which are thought to be at least partially explained by a higher incidence of cardiac involvement in the patient populations [88,89].

RESPONSE ASSESSMENT

Monitoring response — Patients are monitored to determine whether the disease is responding appropriately to therapy and whether a change in management is needed (algorithm 1). In general, we offer alternative systemic therapy in the following scenarios [90] (see 'Relapsed or refractory disease' below):

Hematologic or organ progression at any time

<50 percent reduction in the difference between involved free light chain (FLC) levels and uninvolved FLC levels (dFLC) after two cycles of chemotherapy

dFLC ≥40 mg/L after four to six cycles of chemotherapy or on day 100 after transplant [90] (see 'Relapsed or refractory disease' below)

We follow patients monthly for the first year and while on active therapy. At these monthly visits, we routinely perform serum protein electrophoresis and serum FLC assay.

For organ response, we select among the following tests depending on the type of existing organ involvement and any new suspected organ involvement based on clinical features: serum troponin, N-terminal prohormone of brain natriuretic peptide (NT-proBNP), creatinine, 24-hour urine protein electrophoresis, liver function tests, electrocardiography, and echocardiography. The frequency of the tests used to assess organ response varies according to the clinical condition, but is usually every three months.

Response criteria — Hematologic (table 4) and organ (table 5) response is determined by the criteria validated by the Roundtable on Clinical Research in Immunoglobulin Light Chain Amyloidosis [7,91,92]. Response to treatment correlates with overall survival (OS) (figure 1 and figure 2) [23,90-93].

The dFLC values used in these response criteria do not apply to the approximately 20 percent of patients with a pretreatment dFLC <50 mg/L. In patients with a pretreatment dFLC between 20 and 50 mg/L, two studies demonstrated superior OS among those achieving a post-treatment dFLC <10 mg/L [94,95].

There is uncertainty regarding the best definition for progressive disease. Interpretation of FLC values for identifying progression should consider the FLC value at diagnosis (baseline FLC), the lowest FLC achieved (nadir FLC), and limitations of the FLC assay [96]. A nadir FLC <20 mg/L is associated with higher organ response rates and superior progression-free and overall survival [97]. Outcomes are also better if treatment is reinstated before cardiac progression [98].

While initial retrospective studies suggest that the addition of multiparametric flow cytometry of the bone marrow to the hematologic response assessment may improve the distinction of prognostic groups, further study is needed to validate these findings and determine how to incorporate them into practice [99-101].

RELAPSED OR REFRACTORY DISEASE — For patients who relapse after or are refractory to initial therapy (bortezomib-based regimen, melphalan plus dexamethasone, or hematopoietic cell transplantation [HCT]), treatment options include daratumumab, proteasome inhibitor-based regimens, and immunomodulatory-based regimens [78,102-104].

There are no good data to determine which of these regimens will be of most benefit; the choice will be dictated by prior therapy, patient and physician preferences, expected toxicity, drug availability, and insurance coverage. As an example, daratumumab may be preferred for patients with severe cardiac involvement, while a lenalidomide-based regimen may be preferred for patients with peripheral neuropathy. Lenalidomide-based regimens are also preferred for patients who received bortezomib as part of their original therapy. We typically reserve bendamustine-based regimens for patients who have received multiple prior regimens, or for those with toxicities that limit the use of other agents.

Our experience and other case series suggest that venetoclax is very effective in patients with t(11;14) [105-112]. Clinical trials are in progress to fully evaluate the safety and efficacy of this drug as a single agent or in combination.

Daratumumab-based regimens — The anti-CD38 monoclonal antibody daratumumab and daratumumab-based combination regimens are treatment options that have demonstrated activity in AL amyloidosis. While off-label for this population, these regimens may be particularly attractive for patients with severe cardiac involvement. Use in newly diagnosed AL amyloidosis is discussed separately. (See 'CyBorD with or without daratumumab' above.)

Daratumumab can be administered subcutaneously (daratumumab 1800 mg with hyaluronidase 30,000 units) or intravenously (daratumumab 16 mg/kg) depending on formulation availability. Subcutaneous administration has fewer infusion-related reactions and a faster administration time. Either formulation is administered weekly for eight weeks, then every two weeks for 16 weeks, and then every four weeks for up to a maximum of two years [113,114]. Administration requires premedication to minimize infusion-related reactions, and antimicrobial prophylaxis to reduce viral reactivation. Daratumumab can interfere with cross-matching and red blood cell antibody screening. These and other administration considerations are discussed separately and in the prescribing information. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Anti-CD38 monoclonal antibodies'.)

Retrospective studies and small phase 2 trials have described the safety and efficacy of daratumumab in patients with relapsed or refractory AL amyloidosis [113-122]. In the retrospective studies, single-agent daratumumab was associated with high rates of hematologic response (76 to 78 percent), with median times to first response less than three months. Toxicity was similar to that seen in patients with multiple myeloma, although infection may be more common in the AL amyloidosis population [121].

Further data come from two prospective trials that evaluated single-agent daratumumab in patients with previously treated AL amyloidosis [113,114]. In a single-center phase 2 trial that enrolled 22 patients with a median of two prior therapies, hematologic very good partial response (VGPR) or better was seen in 86 percent of patients with a median time to first response of four weeks and a median progression-free survival (PFS) of 28 months [114]. In a multicenter phase 2 trial that enrolled 40 patients with a median of three prior therapies, hematologic VGPR or better was seen in 48 percent with a median time to first response of one week, and median PFS of 25 months [113]. Both studies reported renal and cardiac responses. Further response was unlikely in those without response after four doses. Adverse events were mostly low grade and similar to those reported in other populations; the most common were infections (55 percent), infusion reactions (53 percent), and gastrointestinal disorders (43 percent).

Retrospective analyses suggest that response rates may be even higher when daratumumab is used in combination with dexamethasone and other therapies such as lenalidomide, pomalidomide, or bortezomib [117,119,123].

Proteasome inhibitor-based regimens — The proteasome inhibitor bortezomib is frequently used as part of an initial treatment regimen for patients with AL amyloidosis based on prospective trials that have demonstrated efficacy. Ixazomib is an oral proteasome inhibitor with demonstrated efficacy in relapsed disease [124,125]; we consider its off-label use in this setting. Cardiovascular toxicities with carfilzomib are expected to limit its use in this population. (See 'Bortezomib-based regimens' above.)

Data regarding the use of ixazomib come from a phase 3 trial (TOURMALINE-AL1) of 168 patients with relapsed or refractory AL amyloidosis following one to two prior lines of therapy who were randomly assigned to ixazomib plus dexamethasone or to physician's choice of a non-proteasome inhibitor containing regimen from a prespecified list [126]. The most common physician's choice regimens were lenalidomide plus dexamethasone (47 patients), melphalan plus dexamethasone (24 patients), and cyclophosphamide plus dexamethasone (10 patients). The following results were reported:

Approximately half of patients in each treatment arm had a hematologic response to treatment.

Patients assigned to ixazomib plus dexamethasone had a longer treatment duration (median 11.7 versus 5.0 months) and median time to vital organ deterioration or mortality (35 versus 26 months; HR 0.53, 95% CI 0.32-0.87).

Adverse effects included diarrhea (34 versus 30 percent), rash (33 versus 20 percent), cardiac arrhythmias (26 versus 15 percent), and nausea (24 versus 14 percent).

These results suggest that ixazomib plus dexamethasone provides more durable responses than non-proteasome inhibitor based therapies despite similar response rates.

Bortezomib has been studied in the relapsed setting. In retrospective studies and small prospective single-arm trials of bortezomib in relapsed AL amyloidosis, overall response rates (ORRs) were 70 to 80 percent with complete responses (CRs) in 25 to 40 percent [77,127]. Expected toxicities include cytopenias, gastrointestinal distress, and peripheral neuropathy. When used to treat relapsed disease, once-weekly bortezomib is better tolerated and has similar efficacy to twice-weekly bortezomib.

Once-weekly bortezomib is usually preferred over twice-weekly bortezomib. While the response time appears slower with once-weekly administration, the toxicities are markedly less and may reduce the risk of neuropathy and neuropathic pain. Bortezomib has also been administered in combination with cyclophosphamide and dexamethasone (CyBorD) with rapid responses in patients with and without cardiac involvement. (See 'Bortezomib-based regimens' above.)

The incorporation of bortezomib-based consolidation was investigated in a phase II trial of 40 patients with AL amyloidosis who underwent initial treatment with high dose melphalan and autologous HCT [128]. Consolidation with six cycles of bortezomib plus dexamethasone was offered to patients with less than a complete hematologic response at three months. At a median follow-up of 45 months, the estimated PFS and overall survival (OS) rates at two years were 69 and 82 percent, respectively. The most common severe (grade 3/4) toxicities during consolidation were thrombocytopenia (40 percent), cardiac toxicity (17 percent), and anemia (13 percent). The majority (57 percent) experienced grade 2 or greater neuropathy.

Immunomodulatory derivatives — The immunomodulatory derivatives (IMiDs), lenalidomide, pomalidomide, and thalidomide, have demonstrated efficacy among patients with relapsed AL amyloidosis but have not been compared with other regimens in this setting. Of importance, the dosing used is lower than that used in patients with multiple myeloma. In general, pomalidomide- and lenalidomide-based regimens are preferred to thalidomide-based regimens. IMiDs have been associated with a rise in cardiac biomarkers. This is sometimes asymptomatic, but other times associated with worsening symptoms.

Lenalidomide-based regimens — The combination of lenalidomide plus low dose dexamethasone with or without cyclophosphamide is a reasonable option for patients with relapsed AL amyloidosis.

Lenalidomide plus dexamethasone is administered in a 28-day cycle as follows:

Lenalidomide 15 mg by mouth daily for 21 days

Dexamethasone 40 mg by mouth once per week

Of importance, the initial dose of lenalidomide as used in multiple myeloma (ie, 25 mg/day) is poorly tolerated in those with AL amyloidosis [35,36,129]. A lower dose, in the range of 5 to 15 mg/day, has been better tolerated [129]. Cardiac and renal toxicity have been reported, so the use of this drug should be reassessed in the setting of worsening clinical status [37,130,131]. This regimen has low or very low risks of emesis and infection and does not require prophylaxis for either. The combination of lenalidomide plus dexamethasone is associated with an increased risk of thrombosis and therefore requires thromboprophylaxis. (See "Multiple myeloma: Prevention of venous thromboembolism".)

Two studies evaluated the efficacy of lenalidomide (initial dose 25 mg/day by mouth for 21 days of a 28-day cycle) with or without dexamethasone in patients with AL amyloid [35,36]. ORRs for subjects taking both medications were 67 to 75 percent, with CRs in 16 percent [129]. In one of the studies, organ responses were seen in 42 percent of patients who received at least three cycles of therapy [35].

A phase I/II dose-escalation study in 26 patients with de novo AL amyloidosis reported complete hematologic responses in 42 percent of patients when lenalidomide 15 mg per day was combined with melphalan and dexamethasone [132]. At a median follow-up of 19 months, the estimated rates of OS and event-free survival (EFS) at two years were 81 and 54 percent, respectively. It is notable that only patients with a performance status (PS) of 0 or 1 were eligible for this trial. Two other trials that allowed patients with PS 2 or better have had nearly comparable results with hematologic responses in 44 to 68 percent of patients, hematologic CR in fewer than 20 percent of patients and approximate two-year OS and EFS of 7 and 50 percent, respectively [133,134]. One study that allowed patients with advanced cardiac disease had far inferior results [135].

In phase II trials of lenalidomide, cyclophosphamide, and dexamethasone administered at different doses, hematologic responses were seen in 46 to 77 percent [38,136,137]. Estimated two-year survival rates were 41 to 59 percent. The most common toxicities were cytopenias, fatigue, edema, gastrointestinal, and rash.

Together, these studies suggest that lenalidomide-based regimens are active in patients with relapsed AL amyloidosis and associated with acceptable toxicity. The low levels of neurotoxicity make them particularly attractive for patients with baseline neuropathy.

Pomalidomide-based regimens — Small prospective trials have evaluated the use of pomalidomide plus dexamethasone (Pd) in patients with previously treated AL amyloidosis [138-140]. Pomalidomide appears to be well tolerated, and hematologic responses are seen in approximately half of patients. When used for AL amyloidosis, the starting dose is pomalidomide 2 mg daily for 28-day cycles with dose adjustments made based on toxicity and efficacy. If the drug is tolerated and there is no response after a two-month trial, we increase the dose to 4 mg daily.

In a phase 2 trial of pomalidomide (2 mg daily for 28-day cycles) and low dose dexamethasone in 33 patients with previously treated AL amyloidosis, hematologic responses were seen in 48 percent with a median time to response of 1.9 months [138]. Five patients had improvement in organ involvement. The median OS and PFS times were 28 and 14 months, respectively. Estimated OS and PFS at one year were 76 and 59 percent, respectively. The most common severe toxicities were neutropenia and fatigue. Two additional trials of Pd in previously treated AL amyloidosis reported hematologic response rates of 50 and 68 percent [139,140].

Thalidomide-based regimens — The combination of thalidomide plus low dose dexamethasone with or without cyclophosphamide is an option for patients with relapsed AL amyloidosis that has demonstrated efficacy [141,142]. However, pomalidomide- and lenalidomide-based regimens are generally preferred to thalidomide-based regimens due to the toxicity of the latter.

Cyclophosphamide, thalidomide, and dexamethasone is administered as follows:

Cyclophosphamide 500 mg once weekly

Thalidomide 50 mg by mouth daily starting dose, and increased to a maximum dose of 200 mg/day over the course of four weeks

Dexamethasone 20 to 40 mg by mouth once weekly

Of importance, higher doses of thalidomide such as those used in multiple myeloma are poorly tolerated in patients with AL amyloid [143,144]. Starting at a lower dose (50 mg daily) and slowly titrating minimizes toxicities. The combination of thalidomide plus dexamethasone is associated with an increased risk of thrombosis and therefore requires thromboprophylaxis. Treatment may be complicated by bradycardia, worsening heart failure, and neuropathy. (See "Multiple myeloma: Prevention of venous thromboembolism", section on 'Thalidomide'.)

Bendamustine-based regimens — Bendamustine plus dexamethasone is moderately effective in AL amyloidosis without significant cardiac, renal, or pulmonary toxicities. We typically reserve bendamustine-based regimens for patients who have received multiple prior regimens, or for those with toxicities that limit the use of other agents.

A multicenter phase 2 trial evaluated bendamustine (100 mg/m2 on days 1 and 2) and dexamethasone (40 mg weekly) administered in 28-day cycles in 31 patients with persistent or progressive AL amyloidosis after at least one prior therapy [145]. Hematologic responses were seen in 57 percent with a median time to first response of 1.9 months. Seven patients had improvement in organ involvement. The median PFS and OS were 11 months and 18 months, respectively. OS was better among those with a hematologic response. Grade ≥3 adverse events were reported in 65 percent of patients. The most common adverse events were myelosuppression, fatigue, nausea, and vomiting.

In contrast, in a retrospective study of 122 patients with AL amyloidosis treated with bendamustine and prednisone with or without rituximab, the hematologic response rate was only 32 percent, and the median PFS among previously treated patients was eight months [146]. Response rates appeared to be higher among patients with AL amyloidosis and IgM monoclonal proteins. However, interpretation is limited by the inclusion of newly diagnosed and relapsed/refractory patients and the retrospective nature of the analysis. Prospective studies are needed to better evaluate the role of this combination.

PROGNOSIS

Impact of organ involvement — The prognosis of AL amyloidosis varies considerably depending on the nature, number, and extent of organ involvement (table 1). As such, prognosis is intimately tied to:

Assessment of organ involvement (see 'Organ involvement defined' above)

Staging with cardiac biomarkers (see 'Staging' above)

AL amyloidosis has a poor long-term prognosis when detected at an advanced stage [53,71,73,84,147,148]. Median survival may be as short as four to six months, with cardiac or hepatic failure and infection being the major causes of death. In one series, heart failure accounted for 51 percent of deaths, with renal failure and infection accounting for 15 percent each [53].

On the other hand, patients with limited organ involvement can expect a median survival in excess of five years with current therapy [60,149]. In approximately 15 to 20 percent of patients, the difference between the involved and uninvolved free light chains (dFLC) is <50 mg/L [94,95]. Such patients have superior survival rates and a different pattern of organ damage with less severe heart involvement and more frequent kidney involvement.

Since the early 2000s, we have observed a shift toward earlier diagnosis, with a reduction in early mortality and improvement in survival [20].

Coexisting myeloma — AL amyloidosis can occur in patients with other plasma cell dyscrasias, including multiple myeloma (MM) and Waldenström macroglobulinemia. When MM and AL amyloidosis are diagnosed in the same patient, the MM is typically diagnosed before or around the time of the amyloid diagnosis. Less commonly, MM develops more than six months after the diagnosis of amyloid. Patients that have a coexisting MM have a worse prognosis than patients who do not. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'Relation to other plasma cell disorders'.)

A single-center retrospective analysis evaluated the prognostic impact of bone marrow plasma cells and MM-related end-organ damage (ie, CRAB) in 1255 patients diagnosed with AL amyloidosis between 2000 and 2010 [150]. The majority (679 patients) had AL amyloidosis without signs or symptoms of MM at the time of diagnosis and had a median overall survival of 46 months. MM-related end-organ damage was present in 100 patients, while 476 patients had bone marrow plasma cells >10 percent (without evidence of end-organ damage). Both of these latter findings were associated with advanced stage disease, increased cardiac biomarkers, and inferior median overall survival (10.6 and 16 months, respectively). The negative prognostic value of plasma cells >10 percent and of end-organ damage was independent of other prognostic factors.

In a retrospective analysis of 147 patients with biopsy-proven AL amyloidosis who also had specialized testing for determination of circulating plasma cells, 20 patients had concurrent MM [151]. Of the subset of patients with ≥2 percent circulating plasma cells, 50 percent had clinical MM, a rate significantly higher than the 12 percent incidence seen in those with fewer circulating plasma cells. Patients with both AL amyloidosis and MM had a significantly worse prognosis than those with AL amyloidosis alone (14 versus 32 months). (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Peripheral smear'.)

IgM-related amyloidosis — Approximately 5 percent of AL amyloidosis is associated with an IgM monoclonal protein produced by a lymphoproliferative disorder such as lymphoplasmacytic lymphoma [152]. IgM-related AL amyloidosis appears to be a distinct clinical entity with less cardiac involvement and a higher incidence of lymph node and soft tissue involvement (eg, liver damage, peripheral and autonomic neuropathy). A relatively lower light chain clonal burden makes the application of standard response assessment criteria and prognostic tools challenging. Serial IgM measurements can be followed to help monitor response. In addition, a novel prognostic score has been proposed that incorporates liver and nerve involvement in addition to age and cardiac stage [152]. Overall, patients with IgM-related AL amyloidosis have had worse outcomes than non-IgM-related AL amyloidosis since they are less likely to respond to plasma cell-directed treatments. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'IgM-associated AL amyloidosis'.)

CLINICAL TRIALS — Often there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov).

Areas of interest include the use of hematopoietic cell transplantation, new combinations of available agents, the use of novel agents studied in related diseases, and experimental agents designed to degrade or interfere with the formation of amyloid fibrils [153,154]. (See "Treatment of AA (secondary) amyloidosis", section on 'Investigational approaches'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Immunoglobulin light chain (AL) amyloidosis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

Basics topics (see "Patient education: AL amyloidosis (The Basics)")

SUMMARY AND RECOMMENDATIONS

Definitions – Immunoglobulin light chain (AL) amyloidosis is a monoclonal plasma cell proliferative disorder characterized by tissue deposits of fibrils composed of monoclonal light chain fragments, leading to organ dysfunction. This disorder has a poor long-term prognosis, with cardiac or hepatic failure, and infection being the major causes of death. (See "Renal amyloidosis" and "Gastrointestinal amyloidosis: Clinical manifestations, diagnosis, and management", section on 'Hepatic amyloidosis' and "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis".)

Pretreatment evaluation – To best treat patients with AL amyloidosis, the initial evaluation must confirm the diagnosis, establish the extent and sites of disease, and evaluate for comorbidities that are likely to have an impact on prognosis and treatment options. Simple staging systems that incorporate NT-proBNP and cardiac troponin are easily applied at the point of care (table 1). (See 'Pretreatment evaluation' above.)

Initial therapy – Our approach to the initial management of patients with AL amyloidosis varies depending on whether patients are eligible to pursue high dose melphalan followed by autologous hematopoietic cell transplantation (HCT) (algorithm 1). Eligibility for autologous HCT in AL amyloidosis varies across countries and institutions. In general, patients with poor performance status, major comorbidities, involvement of three or more organs, and advanced cardiac amyloidosis are not considered transplant candidates. Participation in a well-conducted research trial is always a reasonable alternative. (See 'Determining transplant eligibility' above.)

HCT-eligible patients – For patients eligible for HCT, we suggest induction therapy followed by high dose melphalan and autologous HCT rather than chemotherapy alone, provided that HCT can be performed in referral centers with adequate expertise in the procedure for this group of patients (Grade 2C). With better patient selection, and by using a risk-adapted approach, results with HCT may be superior to those obtained following chemotherapy. (See 'Choice of therapy' above.)

As induction therapy, we offer two to four cycles of a bortezomib-based regimen. Our preferred regimen is daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (CyBorD). If daratumumab is not available, we offer induction with CyBorD alone. (See 'Bortezomib-based regimens' above.)

Not eligible for HCT – For patients not eligible for HCT, we recommend a bortezomib-based regimen rather than melphalan plus dexamethasone (Grade 1B). Daratumumab plus CyBorD is our preferred regimen. If daratumumab is not available, acceptable alternatives are CyBorD alone or bortezomib, melphalan, and dexamethasone. Daratumumab is offered as a single agent or in combination with cyclophosphamide and dexamethasone to patients who are not candidates for bortezomib. (See 'Choice of therapy' above.)

Monitoring response – Patients are monitored to determine whether the disease is responding appropriately to therapy and whether a change in management is needed (algorithm 1). In general, we offer alternative systemic therapy if there is hematologic or organ progression at any time; if there is <50 percent reduction in the difference between the involved and uninvolved free light chain levels (dFLC) after two cycles of chemotherapy; or if dFLC is ≥40 mg/L after four to six cycles of chemotherapy or on day 100 after transplant. (See 'Monitoring response' above.)

Relapsed or refractory disease – For patients with relapsed or refractory disease, reasonable approaches include treatment with proteasome inhibitor-based regimens, immunomodulatory derivative-based regimens, daratumumab, or enrollment on a clinical trial. There are no good data to determine which of these regimens will be of most benefit; the choice will be dictated by prior therapy, patient and physician preferences, expected toxicity, drug availability, and insurance coverage. As an example, daratumumab may be preferred for patients with severe cardiac involvement while a lenalidomide-based regimen may be preferred for patients with peripheral neuropathy. We typically reserve bendamustine-based regimens for patients who have received multiple prior regimens, or for those with toxicities that limit the use of other agents. (See 'Relapsed or refractory disease' above.)

Prognosis – The prognosis of AL amyloidosis varies considerably depending on the nature, number, and extent of organ involvement. AL amyloidosis has a poor long-term prognosis when detected at an advanced stage. Earlier diagnosis is associated with lower early mortality and improved survival. (See 'Prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert A Kyle, MD, who contributed as a Section Editor to earlier versions of this topic review.

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Topic 6666 Version 90.0

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