Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis

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 are 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".)

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 [1,2]. (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, symptoms and signs due to these deposits are 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, N-terminal prohormone of brain natriuretic peptide (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 nonpurpuric cutaneous lesions). These deposits are not due to an underlying systemic clonal plasma cell disorder in the bone marrow but rather adjacent to where the amyloid is being deposited; therefore, these localized forms do not typically progress to systemic disease [3]. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'Localized amyloidosis'.)

Supportive therapy

Cardiac amyloidosis — 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, the treatment of HF in patients with cardiac amyloidosis differs from the therapy generally recommended in patients with systolic HF. This is described in more detail separately. (See "Cardiac amyloidosis: Treatment and prognosis".)

Renal amyloidosis — In addition to therapy directed at the AL amyloidosis, patients with kidney involvement require general supportive measures (eg, dietary sodium restriction) and may require dialysis and/or kidney transplantation. Although nephrologists are accustomed to maximizing angiotensin-converting enzyme (ACE) inhibition or angiotensin II receptor blockers (ARBs) in patients with diabetic kidney disease, there are no data to suggest that this is of value in AL-associated nephrotic syndrome, and if these patients have coexisting AL cardiomyopathy or autonomic dysfunction, the afterload reduction can be catastrophic. Renal amyloidosis is described in more detail separately. (See "Renal amyloidosis".)

Other complications — Other complications of AL amyloidosis that may require specific supportive therapy include autonomic neuropathy, peripheral neuropathy, diarrhea, fluid retention, and bleeding complications (eg, acquired factor X deficiency). Because AL amyloidosis is typically a multisystem disease, supportive care for one organ cannot be considered in isolation. For example, although midodrine, salt tablets, and fludrocortisone are typically used for individuals with hypotension due to autonomic neuropathy, using fludrocortisone and/or salt tablets is impractical with patients with either cardiomyopathy or nephrotic syndrome due to fluid retention properties of these interventions.

PRETREATMENT EVALUATION

Assessment — To best treat patients with AL amyloidosis, the initial evaluation must confirm the diagnosis, establish the extent and sites of involvement, 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 electrophoresis of the serum and urine, serum free light chain assay, 24-hour urinary protein and creatinine clearance, troponin T and/or troponin I, N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and/or BNP, 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 or flow cytometry 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, gain 1q, and del17p. While there are data that patients with t(11;14) are less likely to respond to bortezomib-based therapy [4-10], this poor prognosis may be abrogated partially by the use of high-dose chemotherapy with hematopoietic cell transplantation, daratumumab, low-dose alkylator, and/or venetoclax [11-13]. (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, although it cannot differentiate between AL amyloidosis and ATTR amyloidosis [14,15]. Late gadolinium enhancement can diagnose cardiac involvement, but it is not independently prognostic of other cardiac measures [16]. T1 mapping and extracellular volume measurements can be useful prognostic measures among patients with AL cardiomyopathy. (See "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis", section on 'Cardiovascular magnetic resonance'.)

●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'.)

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

●Individuals 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 females are limited, but males 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 [17,18]. Direct organ biopsy is not required if there is clinical evidence of organ involvement and a tissue diagnosis of AL amyloid has been confirmed at another site, including surrogate sites like fat or bone marrow.

●Kidney – Direct biopsy verification with clinical or laboratory evidence of organ dysfunction or 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/day and estimated glomerular filtration rate (eGFR) <50 mL/min/1.73 m² [19]. 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 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 to cardiac involvement in patients with AL amyloidosis, and a normal NT-proBNP rules out the possibility of clinically meaningful cardiac involvement [20]. (See "Cardiac amyloidosis: Treatment and prognosis" and "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis".)

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

●Peripheral nerve – Clinical symmetric lower extremity sensorimotor peripheral neuropathy (most often small fiber).

●Autonomic nerve – 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 manifestations'.)

●Lung – Direct biopsy verification with symptoms and an interstitial radiographic pattern is included in the consensus criteria; however, we do not consider direct biopsies 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 NT-proBNP and cardiac troponin are easily applied in clinical practice (table 1). These systems have weathered the test of time. As therapies improve, so do the expected overall survival rates by stage, but the separation of the curves persists, both at the time of diagnosis and even at the time of reinstituting another line of therapy [21,22].

●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 the stage as follows (table 1) [23]:

•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 [24]:

•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 [25]. Also, high-sensitivity troponin T can replace troponin T using a threshold of 50 pg/mL [25].

●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) [26].

•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 [25,27].

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 hematopoietic cell transplantation (HCT) and 103 patients enrolled onto different clinical trials [26]. 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.

●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) [28]:

•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 [28]. This system has not yet been validated by other groups. Importantly, a variety of clinical immunoassays are available for plasma BNP and troponin I, and they are not completely interchangeable.

Assess transplant eligibility — All patients with newly diagnosed AL amyloidosis should be assessed to determine eligibility for autologous HCT. Clinicians should have a low threshold to refer patients to a center with specific expertise in AL amyloidosis and HCT to discuss candidacy, the role of HCT, and preferred timing. The role of HCT in AL amyloidosis is evolving, and not all patients who are eligible for HCT will undergo HCT as part of their initial treatment. (See 'Timing of HCT' below.)

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 the age of 70 years may have good outcomes with HCT [29]. 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, kidney impairment, advanced heart failure, or multiorgan involvement [30]. (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 [31,32]:

●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)

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 treatment-related mortality (TRM) rate that approaches 50 percent [33]. Splenectomy may be performed in such patients in an effort to increase factor X levels prior to HCT [34].

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

Although one study 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 [35].

INITIAL TREATMENT

Induction therapy

Planning an approach — The treatment of AL amyloidosis is complicated and evolving rapidly (algorithm 1). Clinicians should have a low threshold to refer patients to a center with specific expertise in AL amyloidosis and hematopoietic cell transplantation (HCT) to discuss treatment options, including HCT candidacy, the role of HCT, and preferred timing. (See 'Assess transplant eligibility' above.)

For patients with stage I to IIIA AL amyloidosis, we recommend daratumumab, cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) rather than CyBorD alone. If the patient is not a candidate for bortezomib (eg, sensory neuropathy that is painful or limiting self-care), we offer daratumumab as a single agent or in combination with cyclophosphamide and dexamethasone. Patients with stage IIIB AL amyloidosis (ie, elevated cardiac troponin and N-terminal prohormone of brain natriuretic peptide [NT-proBNP] >8500 ng/L) were excluded from trials of Dara-CyBorD; the management of such patients is individualized. (See 'Dara-CyBorD (preferred)' below.)

Further management depends on whether patients are eligible to pursue high-dose melphalan followed by autologous HCT and the response to therapy (algorithm 1). For patients ineligible for HCT, Dara-CyBorD is administered for six cycles (months) followed by 18 months of single-agent daratumumab.

There is uncertainty regarding the preferred management of patients who are eligible for HCT, and participation in clinical trials is encouraged. Outside of a trial, we offer Dara-CyBorD for four cycles (months). Then a decision is made regarding whether to proceed with autologous HCT (early HCT strategy) or to continue treatment with chemotherapy, reserving HCT for first relapse (delayed HCT strategy). Those following a delayed HCT strategy receive an additional two cycles of Dara-CyBorD (to complete six total cycles) followed by 18 months of single-agent daratumumab. (See 'Timing of HCT' below.)

Following HCT, observation until progression is appropriate for most patients who achieve a hematologic complete response (CR) and some patients who achieve a very good partial response (VGPR). Consultation with an Amyloid Center of Excellence is advised.

Although data are limited, we offer post-transplant maintenance with lenalidomide or daratumumab to all patients with overt multiple myeloma (MM) and to selected patients without overt MM but with ≥20 percent bone marrow plasma cells and/or with myeloma-like features, including bone lesions, high plasmacytosis, or high-risk cytogenetics on fluorescence in situ hybridization (FISH; ie, del17p, t(4;14), t(14;16), and t(14;20)). (See 'Coexisting myeloma' below and "Multiple myeloma: Use of hematopoietic cell transplantation", section on 'Maintenance'.)

In all patients, response to therapy is monitored closely. We consider the following to be markers of refractory disease requiring a change in systemic therapy: failure to achieve a hematologic partial response (PR) after two cycles; or failure to achieve a hematologic VGPR after four to six cycles or on day 100 after HCT; or if there is disease progression at any time. (See 'Response assessment' below and 'Choice of therapy' below.)

Dara-CyBorD (preferred)

Mayo stage I to IIIA disease — For patients with stage I to IIIA AL amyloidosis, we recommend induction with Dara-CyBorD followed by daratumumab maintenance (the "ANDROMEDA regimen") rather than CyBorD alone or other regimens (algorithm 1). The addition of daratumumab to CyBorD deepens responses and improves organ function and overall survival.

For AL amyloidosis, Dara-CyBorD is administered in 28-day cycles as follows [12]:

●Bortezomib 1.3 mg/m² subcutaneous administration once a week

●Cyclophosphamide 300 mg/m² (maximum weekly dose of 500 mg) by mouth once a week

●Dexamethasone 20 to 40 mg by mouth once a week

●Daratumumab-hyaluronidase (1800 mg daratumumab with 30,000 units hyaluronidase subcutaneously) weekly for 8 weeks (cycles 1 and 2) and every other week for 16 weeks (cycles 3 to 6)

After six cycles of Dara-CyBorD, single-agent daratumumab is continued every four weeks for an additional 18 months.

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. Patients receiving Dara-CyBorD are at high risk for bacterial infections and reactivation of herpes zoster, herpes simplex virus, and hepatitis B virus. Antiviral prophylaxis (eg, acyclovir 400 mg orally twice a day) should be administered to all patients receiving Dara-CyBorD. Prophylaxis for Pneumocystis pneumonia is strongly encouraged (eg, trimethoprim-sulfamethoxazole double strength once daily on Mondays, Wednesdays, and Fridays during treatment). Patients may also develop hypogammaglobulinemia, although primary prophylaxis with intravenous immunoglobulin is not standard.

Daratumumab can also interfere with cross-matching and red blood cell antibody screening and can be detected on serum protein electrophoresis (SPEP) and immunofixation assays as an immunoglobulin G (IgG) kappa monoclonal protein. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Anti-CD38 monoclonal antibodies'.)

The ANDROMEDA regimen is derived from years of experience using combinations of alkylators, bortezomib, and corticosteroids. (See 'Other bortezomib-based regimens' below.)

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 [12,36-38]. Those assigned to daratumumab also received maintenance with single-agent daratumumab monthly for an additional 18 months. After a median follow-up of 11.4 months, the addition of daratumumab to CyBorD resulted in higher rates of hematologic CR 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 [HR] 0.58; 95% CI 0.36-0.93). Longer follow-up after a median of 61 months, available in abstract form only, reported improved major organ deterioration (MOD), progression-free survival (median not reached versus 30.2 months; HR 0.44, 95% CI 0.31-0.63), and overall survival (five-year overall survival 76 versus 65 percent; HR 0.62, 95% CI 0.42-0.90) [39].

Toxicity was also increased with higher rates of grade 3 or 4 adverse events (17 versus 10 percent), but a similar percentage of patients discontinued therapy due to adverse events (4.1 versus 4.3 percent) and similar patient-reported quality of life. 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 a 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.

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 [40]. Administration considerations are described separately. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Anti-CD38 monoclonal antibodies'.)

Mayo stage IIIB disease — Patients with Mayo stage IIIB AL amyloidosis (ie, elevated cardiac troponin and NT-ProBNP >8500 ng/L) and those with New York Heart Association (NYHA) class IIIB or class IV cardiac disease were excluded from trials of Dara-CyBorD, and there are concerns about potential cardiac toxicity with this regimen. Management of such patients is highly individualized. Many experts, including ourselves, have successfully used daratumumab-based regimens in this population.

In patients with AL amyloidosis, the prescribing information for daratumumab-hyaluronidase describes cardiac failure and/or cardiac arrest in 16 percent and fatal cardiac disorders in 10 percent [40]. Patients with baseline cardiac involvement may be at higher risk and should be monitored closely for cardiac adverse reactions. The prescribing information for daratumumab-hyaluronidase includes a warning that it should not be used for patients with AL amyloidosis who have NYHA class IIIB or class IV cardiac disease or Mayo stage IIIB [40]. However, many experts, including ourselves, have successfully used daratumumab-hyaluronidase or intravenous daratumumab in this population [41-43].

Small phase 2 trials have evaluated modifications to Dara-CyBorD in this population. It is not known how much the cyclophosphamide is contributing to the Dara-CyBorD regimen. While it has not been directly compared with Dara-CyBorD, a small phase 2 trial reported favorable tolerability and comparable efficacy following the combination of daratumumab, bortezomib, and dexamethasone (without cyclophosphamide) in patients with Mayo stage IIIA or IIIB amyloidosis [41]. Others have tried a staged approach of gradually adding agents for those who do not respond to less intensive therapy. Preliminary results from a phase 2 trial (EMN22) reported high response rates and an improvement over historical outcomes in patients with stage IIIB AL amyloidosis treated with a staged approach to daratumumab-based therapy [44]. In this trial, patients initially received three cycles of single-agent daratumumab. Those with greater than or equal to a VGPR or a PR with improved organ function continued single-agent daratumumab. All others underwent treatment escalation with the addition of bortezomib and low-dose dexamethasone.

Other bortezomib-based regimens

CyBorD — If daratumumab is not available (ie, in resource-limited settings), we offer treatment with a bortezomib-based regimen rather than melphalan plus dexamethasone. Adding bortezomib to an alkylator-based regimen improves responses and likely overall survival. We prefer cyclophosphamide, bortezomib, and dexamethasone (CyBorD) rather than bortezomib, melphalan, and dexamethasone (BMD), although BMD is an acceptable alternative for HCT-ineligible patients. These two regimens have not been directly compared in randomized trials; retrospective analyses suggest equipoise [45]. Other experts may prefer BMD because it was used in the randomized trial that demonstrated an overall survival benefit when compared with melphalan plus dexamethasone [46].

The CyBorD regimen used is the same as in the Andromeda regimen described separately. Note that the dose and schedule used are different than those used in MM. Most patients will have a rapid response, and the most common toxicities are vomiting, diarrhea, and cytopenias [24,45,47-51]. Neuropathy can be dose-limiting but is abrogated by subcutaneous bortezomib administration. (See 'Dara-CyBorD (preferred)' above.)

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. Dose modifications may be needed for patients with kidney and/or liver dysfunction. Antiviral and anti-Pneumocystis pneumonia prophylaxis is typically used whenever bortezomib and dexamethasone are administered. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Proteasome inhibitors'.)

The strongest data regarding the efficacy of CyBorD as an initial treatment for AL amyloidosis come from the Andromeda study evaluating the addition of daratumumab, and from two large series, which included over 1000 patients [12,24,39,45]. Hematologic responses were seen in 60 to 65 percent (approximately 25 percent complete). Cardiac (17 to 33 percent), kidney (15 to 25 percent), and liver (30 percent) responses were also reported. Survival correlated with Mayo Stage and degree of response. In Andromeda, five-year overall survival was 65 percent with CyBorD [39]. For the larger series, the estimated median overall survival 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 III- (stage III with NT-proBNP >8500 ng/L), respectively [45]. The stringent difference between involved and uninvolved serum free light chains (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 — If daratumumab is not available (ie, resource-limited settings), BMD is an option for HCT-ineligible patients, although we prefer CyBorD in this setting. BMD results in deeper responses and improved overall survival when compared with melphalan plus dexamethasone [46].

For AL amyloidosis, BMD can be administered as follows [46]:

●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

Data supporting the use of BMD come from a phase 3 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 [46]. 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 (three-month hematologic VGPR plus CR rate 64 versus 39 percent) and superior overall survival (median overall survival 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 the 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.

Bortezomib-free regimens — Bortezomib-free regimens are reserved for those who are not candidates for bortezomib. This includes patients with sensory neuropathy that is painful or limiting self-care. For such patients, we offer daratumumab as a single agent or in combination with cyclophosphamide and dexamethasone (ie, Dara-CyBorD without bortezomib). While used in the past, melphalan plus dexamethasone has a limited role in the treatment of AL amyloidosis, and other regimens are preferred whenever possible.

Data for single-agent daratumumab are extrapolated from studies in patients with relapsed or refractory disease that demonstrate rapid, deep responses and good tolerability. (See 'Daratumumab-based regimens' below.)

There are limited data regarding the use of daratumumab, cyclophosphamide, and dexamethasone (without bortezomib). However, many experts, including ourselves, have successfully used this regimen in this setting.

Melphalan plus dexamethasone has a limited role in the treatment of AL amyloidosis, and other regimens are preferred whenever possible. It 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 [52-59]. 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 kidney failure.

Autologous hematopoietic cell transplant

HCT efficacy and toxicity — Autologous HCT allows for the delivery of myeloablative doses of melphalan aimed at the underlying plasma cell dyscrasia. Careful patient selection is critical since there is an increased risk of treatment-related mortality (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 [60-63].

Studies that have compared HCT versus conventional chemotherapy have had mixed results [64-73]. While the results of a small randomized trial suggested no benefit from HCT, a number of flaws in the study design question the applicability of these results to this patient population [52]. Retrospective studies have suggested improved overall survival and improved quality of life among patients with AL amyloidosis undergoing HCT when compared with similar patients undergoing chemotherapy alone [65,74]. Results may be even better with careful patient selection and implementation of a risk-adapted approach [64-66,68-70,75].

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 [60]. Over the study time period, there was a decline in early mortality and improvement in overall survival. Among the 800 patients transplanted from 2007 to 2012, the mortality rate at 100 days was 5 percent; the estimated overall survival 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.

Similarly, a series of 648 patients treated with high-dose melphalan (100 to 200 mg/m²) followed by autologous HCT at Boston University School of Medicine reported the following [61,76,77]:

●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.

●CR was obtained in 40 percent. Patients who attained a CR had superior median overall survival (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 [78].

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

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

In another 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) [62]. 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.

In another report of >600 patients who underwent stem cell collection at the Mayo Clinic, overall survival was no different for the 124 patients who did not undergo HCT within 90 days (13.0 versus 11.4 years, p = NS) even though 94 of the 124 never went on to have an HCT at a later time [73]. On multivariate analysis, however, only advanced amyloid stage and treatment response were significant predictors of overall survival.

Timing of HCT — Autologous HCT is a standard part of the initial treatment of most eligible patients (algorithm 1). Select patients with deep responses may be candidates for a delayed HCT strategy in which HCT is deferred until the time of first relapse; such patients receive further chemotherapy akin to what is done for those who are not eligible for HCT. Clinicians should have a low threshold to refer patients to a center with specific expertise in AL amyloidosis and HCT to discuss candidacy, the role of HCT, and preferred timing.

We discuss the option of a delayed HCT strategy if a patient has achieved a complete hematologic response after four cycles of induction therapy and does not have high-risk plasma cell features or myeloma-like features [32]. If HCT is deferred, the stem cells can be collected and stored for later use or collected at the time of progression (which usually requires plerixafor).

Our historical preference for early HCT was based on low-quality data that suggested HCT can result in longer remissions, though data using daratumumab-based inductions have challenged that paradigm [79]. As with any therapy that results in a 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' above.)

A delayed HCT strategy 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, Dara-CyBorD is the preferred induction regimen, if available, based on the ANDROMEDA study [12]. (See 'Dara-CyBorD (preferred)' above.)

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 an unsatisfactory response, 55 patients proceeded with HCT, 16 patients lost eligibility for HCT, and 5 patients refused HCT [72]. The estimated five-year overall survival was similar among the patients treated with HCT or CyBorD alone (86 versus 84 percent); however, five-year overall survival was 51 percent among the patients with unsatisfactory responses who did not undergo HCT.

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 [80]. 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 [64,76,81,82]. 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'.)

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 [83] (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 is not yet <40 mg/L after four to six cycles of chemotherapy or on day 100 after transplant.

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. Upon completion of therapy, we monitor patients every one to three months using FLC and immunofixation (if hematologic complete response [CR]) or FLC alone (if less than a hematologic CR).

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 — Response assessment includes an evaluation of both hematologic and organ response (table 4). Response to treatment correlates with overall survival (figure 1 and figure 2) [30,83-89]. A nadir FLC <20 mg/L (<2 mg/dL) is associated with higher organ response rates and superior progression-free and overall survival [87].

A hematologic CR requires both the absence of amyloidogenic light chain (free and/or part of a complete immunoglobulin) defined by negative serum and urine immunofixation plus either an FLC ratio within the reference range or an inversion of the FLC ratio, such that the uninvolved FLC concentration is greater than the involved FLC concentration with or without an abnormal FLC ratio (as can be seen with severe immunoparesis from effective therapy) [84,85,90]. Hematologic partial response (PR) and very good partial response (VGPR) are defined by the dFLC, which is the difference between the involved FLC and uninvolved FLC. 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 overall survival among those achieving a post-treatment dFLC <10 mg/L [91,92].

There is uncertainty regarding the best definition for hematologic 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 the limitations of the FLC assay [93]. Outcomes are also better if treatment is reinstated before cardiac progression [94].

Although 2012 consensus guidelines provide a definition of hematologic progression for the purpose of clinical trials [84], in general practice, most experts use a different approach. For those who have achieved a hematologic CR, the guidelines define progression as any detectable monoclonal protein or abnormal FLC ratio (light chain must double). However, most experts will wait to resume therapy until the dFLC is closer to 30 to 50 mg/L. For those progressing from a prior VGPR, many experts may resume therapy before a dFLC of 100 mg/L.

Deeper organ response is associated with improved overall survival, and graded organ response (ie, CR, VGPR, PR) provides greater insight into prognosis than dichotomous assessments used in the 2012 consensus guidelines [84,88]. Heart involvement is strongly correlated with clinical outcomes and is the basis for staging criteria [23]. Graded cardiac response criteria are based on NT-proBNP or BNP [86]. A cardiac CR is defined as a nadir NT-proBNP ≤350 pg/mL (≤41.39 pmol/L) or BNP ≤80 pg/mL (≤9.46 pmol/L). Limited data suggest that patients who achieve a cardiac CR may have survival rates similar to those of a matched population without AL amyloidosis [2].

While initial studies suggest a potential prognostic role for the addition of more sensitive studies (eg, multiparametric flow cytometry, next-generation sequencing, mass spectrometry), further study is needed to validate these findings and determine how to incorporate them into practice [95-102].

RELAPSED OR REFRACTORY DISEASE

Choice of therapy — Our choice of subsequent therapy for patients with relapsed or refractory disease is individualized. While we offer guidance, experts differ in their preferred approach, and there is no agreed-upon standard. We always encourage patients to enroll in a well-conducted clinical trial.

In addition to the options discussed below, autologous hematopoietic cell transplantation (HCT) should be considered in first relapse for HCT-eligible patients who elected to delay autologous HCT until relapse. (See 'Autologous hematopoietic cell transplant' above.)

For patients who relapse after or are refractory to initial therapy, treatment may include the following (as long as there is no evidence of cross-resistance with prior therapy):

●Daratumumab

●A proteasome inhibitor (eg, ixazomib, bortezomib)

●An immunomodulatory derivative (eg, lenalidomide, pomalidomide, thalidomide)

●The BCL2 inhibitor venetoclax (only for patients with t(11;14))

There are emerging data on the use of belantamab (an anti-B cell maturation antigen [BCMA] drug antibody conjugate) bispecific T cell engagers, and chimeric antigen receptor (CAR)-T cell therapy. Clinical trials are in progress to fully evaluate the safety and efficacy of these novel agents.

There are no good data to determine which of these regimens will be of most benefit; the choice is dictated by prior therapy, patient and physician preferences, expected toxicity, drug availability, and insurance coverage. As an example:

●Daratumumab-based regimens may be preferred in patients with severe cardiac involvement, those who are daratumumab-naïve, and those with prior exposure who relapse off daratumumab therapy.

●Lenalidomide-based or pomalidomide-based regimens may be preferred for patients with relapsed or refractory AL amyloidosis who received bortezomib as part of their original therapy, and for those with peripheral neuropathy and no significant cardiomyopathy.

●We consider off-label use of venetoclax alone or in combination as a late line of treatment for patients with t(11;14) who have limited treatment options or as an earlier line of treatment in patients with t(11;14) who have highly aggressive disease refractory to initial treatment.

●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.

Daratumumab-based regimens — The anti-CD38 monoclonal antibody daratumumab is highly active in AL amyloidosis, and the combination of daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (CyBorD) is our preferred initial treatment for most patients with AL amyloidosis. Daratumumab-based regimens are also active in relapsed or refractory AL amyloidosis and may be preferred in patients with severe cardiac involvement, those who are daratumumab-naïve, and those with prior exposure who relapse off daratumumab therapy. Those with disease progression within 60 days of treatment with daratumumab are considered daratumumab-refractory. Use as initial therapy is discussed separately. (See 'Dara-CyBorD (preferred)' 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 [103,104]. Administration requires premedication to minimize infusion-related reactions and antimicrobial prophylaxis to reduce viral reactivation. (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 [103-112]. 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 (MM), although infection may be more common in the AL amyloidosis population [111].

Further data come from two prospective trials that evaluated single-agent daratumumab in patients with previously treated AL amyloidosis [103,104]. 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 [104]. 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 progression-free survival of 25 months [103]. 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).

Response rates may be even higher when daratumumab is used in combination with dexamethasone and other therapies such as lenalidomide, pomalidomide, or bortezomib [41,107,109,113].

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 [114,115]; we consider its off-label use in this setting. Cardiovascular toxicities with carfilzomib are expected to limit its use in this population. (See 'Dara-CyBorD (preferred)' above and 'Other 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 the physician's choice of a nonproteasome inhibitor-containing regimen from a prespecified list [116]. 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 one-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 months) and median time to vital organ deterioration or mortality (35 versus 26 months; hazard ratio [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 nonproteasome inhibitor-based therapies despite similar response rates.

Bortezomib has been studied in the relapsed setting [117,118]. 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 [47,119]. Expected toxicities include cytopenias, gastrointestinal distress, and peripheral neuropathy. Further data for its use come from extrapolation of data showing deep responses in the front-line setting when bortezomib is combined with CyBorD, with daratumumab and CyBorD, and with melphalan and dexamethasone (BMD). (See 'Dara-CyBorD (preferred)' above and 'Other bortezomib-based regimens' above.)

Once-weekly bortezomib is better tolerated and has similar efficacy to 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.

The incorporation of bortezomib-based consolidation for those with a suboptimal response was investigated in a phase 2 trial of 40 patients with AL amyloidosis who underwent initial treatment with high-dose melphalan and autologous HCT [120]. 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 progression-free survival and overall survival 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. Pomalidomide- and lenalidomide-based regimens are generally preferred to thalidomide-based regimens due to the toxicity of the latter [121-124].

Lenalidomide-based regimens — Lenalidomide-based regimens may be preferred for patients with relapsed or refractory AL amyloidosis who received bortezomib as part of their original therapy and for those with peripheral neuropathy and no significant cardiomyopathy. Lenalidomide is not appropriate for patients with significant cardiac involvement given the significant toxicity in this patient population [125]. It has been associated with a rise in cardiac biomarkers. This is sometimes asymptomatic but other times associated with worsening symptoms.

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

●Lenalidomide 15 mg by mouth daily for 21 days

●Dexamethasone 20 to 40 mg by mouth once per week

Of importance, the initial dose of lenalidomide as used in MM (ie, 25 mg/day) is poorly tolerated in those with AL amyloidosis [126-131]. A lower dose, in the range of 5 to 15 mg/day, has been better tolerated [131]. Cardiac and kidney toxicity has been reported, so the use of this drug should be reassessed in the setting of worsening clinical status [128,132,133]. 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", section on 'Immunomodulatory drugs'.)

A phase 1/2 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 [134]. At a median follow-up of 19 months, the estimated rates of overall survival and event-free survival 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 overall survival and event-free survival of 7 and 50 percent, respectively [135,136]. One study that allowed patients with advanced cardiac disease had far inferior results [125].

In phase 2 trials of lenalidomide, cyclophosphamide, and dexamethasone administered at different doses, hematologic responses were seen in 46 to 77 percent [129,137,138]. 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 plus dexamethasone — Small prospective trials have evaluated the use of pomalidomide plus dexamethasone (Pd) in patients with previously treated AL amyloidosis [139-141]. Pomalidomide appears to be well-tolerated, and hematologic responses are seen in approximately one-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 [139]. Five patients had improvement in organ involvement. The median overall survival and progression-free survival times were 28 and 14 months, respectively. Estimated overall survival and progression-free survival 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 [140,141].

Bendamustine-based regimens — Bendamustine plus dexamethasone is moderately effective in AL amyloidosis without significant cardiac, kidney, 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 [142]. 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 progression-free survival and overall survival were 11 months and 18 months, respectively. Overall survival 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.

By 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 progression-free survival among previously treated patients was eight months [143]. Response rates appeared to be higher among patients with AL amyloidosis and immunoglobulin M (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.

Venetoclax for those with t(11;14) — Although it is not approved for this indication, the BCL2 inhibitor venetoclax has demonstrated substantial activity in AL amyloidosis with t(11;14) [6-9,144-148]. We consider off-label use of venetoclax alone or in combination as a late line of treatment for patients with t(11;14) who have limited treatment options or as an earlier line of treatment in patients with t(11;14) who have highly aggressive disease refractory to initial treatment, ideally within the context of a clinical trial. We do not offer venetoclax to other patients with AL amyloidosis, regardless of BCL-2 expression. We do not use BCL-2 expression to guide therapy as it is difficult to measure, and testing is not standardized. Results from ongoing trials will be important to exclude unrecognized toxicities specific to patients with AL amyloidosis.

Venetoclax can be administered as a single agent, but it is most often given in combination with dexamethasone without or without other agents (eg, daratumumab, bortezomib).

Support for the use of venetoclax in patients with t(11;14) positive disease comes from a retrospective study, which reported outcomes for 31 patients with t(11;14)-positive relapsed or refractory AL amyloidosis treated with venetoclax-based therapy [9]. All patients had received prior bortezomib, cyclophosphamide, and daratumumab, and 16 percent had prior autologous HCT. Regimens received included venetoclax plus dexamethasone (10 patients); combinations of venetoclax plus daratumumab (14 patients); and combinations of venetoclax, a proteasome inhibitor, and dexamethasone (7 patients). The following results were noted:

●The hematologic ORR was 97 percent with 91 percent achieving VGPR or better. Evaluable patients demonstrated high rates of cardiac response (74 percent) and renal response (46 percent).

●With a median follow-up of 22 months, most patients did not require further treatment at the 12-month (74 percent) and 24-month (56 percent) timepoints. The overall survival rates at 12 and 24 months were 89 and 85 percent, respectively. Four patients died, all from complications related to AL organ damage.

●Grade 3 or greater toxicity was seen in 5 of 31 patients (16 percent). Two patients discontinued treatment due to toxicity. The most common nonhematologic toxicities were fatigue, gastrointestinal toxicity, and infection.

We do not offer venetoclax to patients without t(11;14). In a retrospective study of 43 patients with relapsed or refractory AL amyloidosis treated with a venetoclax-containing regimen, those with t(11;14) were more likely to achieve a VGPR/CR (78 versus 30 percent) and had a reduced risk for progression or death (HR 0.29, 95% CI 0.05-1.86) when compared with those without t(11;14) [7].

BCMA-directed therapies — There are limited data regarding the use of BCMA-directed therapies in AL amyloidosis, although initial reports have demonstrated responses to the antibody-drug-conjugate belantamab mafodotin, the BCMA/CD3 bispecific antibody teclistamab, and BCMA-directed CAR-T cell therapy.

Although belantamab mafodotin has been pulled from the United States and European markets, promising data in patients with MM suggest that it will likely become available once again. High response rates have been reported in small case series [149-151]. In a retrospective study of 31 patients with relapsed or refractory AL amyloidosis (median of three prior therapies) treated with belantamab mafodotin, the hematologic overall response rate was 71 percent, and the CR or VGPR rate was 58 percent [152]. After a median follow-up of 12 months, the estimated median treatment-free survival was 27 months, and the one-year treatment-free survival was 70 percent. Keratopathy was the most common toxicity, occurring in 68 percent; ocular toxicity improved with treatment delay, and only one patient required treatment discontinuation due to ocular toxicity.

Teclistamab does not have regulatory approval for the treatment of AL amyloidosis, but small retrospective case series have reported rapid and deep responses in patients with heavily pretreated AL amyloidosis with or without concurrent MM. In one report, responses were seen in all seven patients treated with teclistamab; six achieved a stringent difference between involved and uninvolved serum free light chains (dFLC) response, and three of four evaluable patients achieved a cardiac response [153]. There were no reports of disease progression after a median follow-up of 3.2 months. In a second report, 15 of 17 patients (88 percent) achieved a hematologic response (seven complete), one patient died from organ progression, and one patient died from infection [154]. After a median follow-up of three months, none had a hematologic relapse, and five had achieved an organ response (four cardiac, one kidney). In both reports, toxicities were similar to those seen in patients with MM. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Bispecific antibodies'.)

Studies are evaluating the use of BCMA-directed CAR-T cell therapy in AL amyloidosis. In a phase 1 trial, four patients with relapsed AL amyloidosis achieved a complete hematologic response following a novel BCMA-directed CAR-T cell therapy, and all remained without progression after a median follow-up of 5.2 months (range 2.5 to 9.5 months) [155]. Another report described hematologic stringent CR and organ responses maintained 12 months after infusion of a novel BCMA-directed CAR-T cell therapy [156].

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, the prognosis is intimately tied to:

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

●Staging with cardiac biomarkers (see 'Staging' above)

Historically, AL amyloidosis has a poor long-term prognosis when detected at an advanced stage [54,67,157-160]. Median survival has been 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 kidney failure and infection accounting for 15 percent each [67]. However, initial studies suggest that early mortality is lower with treatment regimens that incorporate daratumumab. (See 'Dara-CyBorD (preferred)' above.)

On the other hand, patients with limited organ involvement have better outcomes with 60 to 70 percent of patients alive five years after initial treatment with daratumumab, cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) [39,74,161]. In approximately 15 to 20 percent of patients, the difference between the involved and uninvolved free light chains (dFLC) is <50 mg/L [91,92]. 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 [1,162].

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 who have a coexisting MM have a worse prognosis than patients who do not. Although data are limited, we offer early hematopoietic cell transplantation (HCT; if eligible) and post-transplant maintenance to all patients with overt MM and to selected patients without overt MM but with ≥20 percent bone marrow plasma cells (BMPCs) and/or with myeloma-like features including bone lesions, high plasmacytosis, or high-risk cytogenetics on fluorescence in situ hybridization (FISH; ie, del17p, t(4;14), t(14;16), and t(14;20)). (See 'Planning an approach' above.)

A single-center retrospective analysis evaluated the prognostic impact of BMPCs and MM-related end-organ damage (ie, CRAB [hypercalcemia, renal insufficiency, anemia, or bone disease]) in 1255 patients diagnosed with AL amyloidosis between 2000 and 2010 [163]. 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 BMPCs >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 BMPCs >10 percent and of end-organ damage was independent of other prognostic factors. In a subsequent study, median overall survival was inversely associated with BMPCs being 81, 33, and 12 months for those with <5 percent, 5 to 19 percent, and ≥20 percent, respectively [164].

IgM-related amyloidosis — Approximately 5 to 6 percent of AL amyloidosis is associated with an IgM monoclonal protein produced by a lymphoproliferative disorder such as lymphoplasmacytic lymphoma (LPL) [165-167]. IgM-related AL amyloidosis appears to be a distinct clinical entity with different clinical, genomic, and bone marrow features. There is less cardiac involvement and a higher incidence of peripheral nerve and soft tissue involvement.

In one study, bone marrow evaluation revealed an associated lymphoplasmacytic neoplasm in 63 percent of patients and a pure plasma cell neoplasm in 23 percent [167]. Of the former, approximately one-half were LPL, and a smaller percentage were low-grade B cell lymphoma with plasmacytic differentiation or another lymphoplasmacytic neoplasm. MYD88 mutation was present in 58 percent of patients, all of whom had LPL morphology. When compared with non-IgM AL amyloidosis, IgM-related AL amyloidosis was less likely to have t(11;14) (27 versus 50 percent).

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 [165].

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. In one series, patients with IgM AL amyloidosis were less likely to achieve a hematologic response (39 versus 59 months at six months) and had inferior overall survival when stratified by Mayo 2012 stage (stage 1 or 2: median overall survival 59 versus 126 months; stage 3 or 4: median overall survival 6.5 versus 12.9 months) [167]. (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. (See "AA amyloidosis: Treatment", 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 5^th to 6^th 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 10^th to 12^th 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

●Goals of therapy – Patients with systemic AL amyloidosis are not cured with conventional treatment. However, early diagnosis and modern therapy have improved survival. (See 'Goals of therapy' above.)

Virtually all patients require treatment at the time of diagnosis. Important exceptions are those with localized forms of AL amyloidosis and patients with incidentally detected AL amyloid in the bone marrow. (See 'Indications for systemic therapy' above.)

AL amyloidosis is a multisystem disease that requires multidisciplinary management of end-organ involvement. (See 'Supportive therapy' above.)

●Pretreatment evaluation – The pretreatment evaluation must confirm the diagnosis, establish the extent and sites of disease, and evaluate for comorbidities that are likely to impact prognosis and treatment options. Simple staging systems that incorporate N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and cardiac troponin are easily applied at the point of care (table 1). (See 'Pretreatment evaluation' above.)

Clinicians should have a low threshold to refer patients to a center with specific expertise in AL amyloidosis and autologous hematopoietic cell transplantation (HCT) to discuss candidacy, the role of HCT, and preferred timing. The role of HCT in AL amyloidosis is evolving, and not all patients who are eligible for HCT will undergo HCT as part of their initial treatment. (See 'Assess transplant eligibility' above.)

●Initial therapy – For patients with stage I to IIIA AL amyloidosis, we recommend daratumumab, cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) rather CyBorD alone or other regimens (algorithm 1) (Grade 1B). The addition of daratumumab deepens responses and improves organ function and overall survival. If the patient is not a candidate for bortezomib (eg, sensory neuropathy that is painful or limiting self-care), we offer daratumumab as a single agent or in combination with cyclophosphamide and dexamethasone. Patients with stage IIIB AL amyloidosis (ie, elevated cardiac troponin and NT-ProBNP >8500 ng/L) were excluded from trials of Dara-CyBorD; management of such patients is individualized. (See 'Dara-CyBorD (preferred)' above.)

The number of cycles and further management depends on whether patients are eligible to pursue high-dose melphalan followed by autologous HCT and the response to therapy (algorithm 1). For patients ineligible for HCT, Dara-CyBorD is administered for 6 cycles (months) followed by 18 months of single-agent daratumumab.

The management of HCT-eligible patients is evolving, and we encourage enrollment in a clinical trial. Outside of a trial, for patients eligible for transplant, we offer Dara-CyBorD for four cycles. We then discuss the option of a delayed HCT strategy if a patient has achieved a complete hematologic response after four cycles of induction and does not have high-risk plasma cell features or myeloma-like features. Those who select delayed HCT receive further chemotherapy akin to what is done for those who are not eligible for HCT. For patients with an incomplete response or high-risk plasma cell or myeloma-like features, we suggest proceeding with HCT rather than a delayed HCT strategy (Grade 2C). (See 'Timing of HCT' above.)

Although data are limited, we offer post-transplant maintenance with lenalidomide or daratumumab to all patients with overt multiple myeloma (MM) and to selected patients without overt MM but with ≥20 percent bone marrow plasma cells and/or with myeloma-like features, including bone lesions, high plasmacytosis, or high-risk cytogenetics 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'.)

●Monitoring response – Patients are monitored to determine whether the disease is responding appropriately to therapy and if a change in management is needed (algorithm 1 and table 4). In general, we consider the following to be markers of refractory disease requiring a change in systemic therapy: failure to achieve a hematologic partial response after two cycles of induction therapy; failure to achieve a hematologic very good partial response after four to six cycles of induction therapy or on day 100 after HCT; or if there is disease progression at any time. (See 'Monitoring response' above.)

●Relapsed or refractory disease – Our choice of subsequent therapy for patients with relapsed or refractory disease is individualized. Autologous HCT should be considered in first relapse for HCT-eligible patients who elected to delay autologous HCT until relapse. The choice of therapy will be dictated by prior therapy, patient and physician preferences, expected toxicity, drug availability, and insurance coverage. (See 'Choice of therapy' 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.