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Immunoglobulin light chain (AL) amyloidosis is a clonal plasma cell disorder leading to progressive and life-threatening organ failure. The heart and the kidneys are the most commonly involved organs, but almost any organ can be involved. Because of the nonspecific presentation, diagnosis delay is common, and many patients are diagnosed with advanced organ failure. In the era of effective therapies and improved outcomes for patients with AL amyloidosis, the importance of early recognition is further enhanced as the ability to reverse organ dysfunction is limited in those with a profound organ failure. As AL amyloidosis is an uncommon disorder and given patients’ frailty and high early death rate, management of this complex condition is challenging. The treatment of AL amyloidosis is based on various anti–plasma cell therapies. These therapies are borrowed and customized from the treatment of multiple myeloma, a more common disorder. However, a growing number of phase 2/3 studies dedicated to the AL amyloidosis population are being performed, making treatment decisions more evidence-based. Supportive care is an integral part of management of AL amyloidosis because of the inherent organ dysfunction, limiting the delivery of effective therapy. This extensive review brings an updated summary on the management of AL amyloidosis, sectioned into the 3 pillars for survival improvement: early disease recognition, anti–plasma cell therapy, and supportive care.
Immunoglobulin light chain amyloidosis (AL amyloidosis) and immunoglobulin heavy chain amyloidosis (AH amyloidosis) are plasma cell disorders characterized by deposition of insoluble amyloid fibrils composed of immunoglobulin chains. Most of the literature to date refers to AL amyloidosis, the more common immunoglobulin-related type. As there is no evidence for a clear difference in clinical presentation, treatment, or prognosis between AL and AH amyloidosis, both types are referred to as AL amyloidosis.
AL amyloidosis is the most commonly diagnosed form of systemic amyloidosis,
In the case of systemic AL amyloidosis, the precursor protein is bone marrow plasma cell–derived immunoglobulin light chains, and targeting the plasma cell clone is the mainstay of therapy.
Table 1Classification of the Most Common Amyloidoses
AL/AH amyloidosis is the only form of amyloidosis that is secondary to a clonal plasma cell disorder. AL amyloidosis can be associated with multiple myeloma or more rarely with other B-cell–secreting disorders.
AA (previously referred to as secondary amyloidosis)
Serum amyloid A
Renal presentation most common; associated with chronic inflammatory conditions; underlying disease is typically acquired, but hereditary in case of familial periodic fever syndromes
ALECT2
Leukocyte chemotactic factor 2
Acquired; renal or liver presentation
Αβ2M
β2-microglobulin
Acquired in patients on long-term dialysis; carpal tunnel syndrome, large joint arthropathy
AApoA-IV
Apolipoprotein A-IV
Acquired; renal or cardiac amyloidosis
Rare hereditary amyloidosis types
AGel; also known as familial amyloidosis, Finnish type
Gelsolin
Triad of corneal lattice dystrophy, facial nerve paralysis, and cutis laxa
AFib
Fibrinogen α-chain
Usually renal presentation
ALys
Lysozyme
Sicca syndrome, renal dysfunction, liver or spleen rupture, gastrointestinal ulcers
AApoA-I
Apolipoprotein A-I
Mutation-dependent, can affect various organs
AApoA-II
Apolipoprotein A-II
Renal amyloidosis
AApoC-II
Apolipoprotein C-II
Renal amyloidosis
AApoC-III
Apolipoprotein C-III
Renal amyloidosis, sicca syndrome
a AL/AH amyloidosis is the only form of amyloidosis that is secondary to a clonal plasma cell disorder. AL amyloidosis can be associated with multiple myeloma or more rarely with other B-cell–secreting disorders.
b TTR refers to transthyretin, previously known as prealbumin.
In this article, we discuss the 3 fundamental pillars to improve survival in AL amyloidosis, namely, early disease recognition, anti–plasma cell therapy, and supportive care (Figure 1). These 3 pillars, when combined, enhance the likelihood of overcoming this life-threatening disorder and improving long-term survival.
Whereas the management of anti–plasma cell therapy is within the scope of hematology, both disease recognition and supportive care domains expand beyond the hematologist’s reach. Therefore, efforts should be invested in improving disease recognition among the medical specialists who often encounter AL patients at symptom onset, including primary care physicians, cardiologists, nephrologists, neurologists, and gastroenterologists.
We present an extensive review of the literature with the aim of making recommendations within the context of the best evidence and expert opinion as we have done in the past for patients with AL amyloidosis,
Utilization of hematopoietic stem cell transplantation for the treatment of multiple myeloma: a Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus statement.
Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines 2013 [erratum appears in Mayo Clin Proc. 2013;88(7):777].
Recognizing amyloidosis is challenging, given the nonspecific symptoms and heterogeneity in presentation. The median time from symptom onset to diagnosis is approximately 6 to 12 months.
Once the patient seeks medical attention, the barrier to diagnosis becomes within the health care system, with an average of 3 or 4 different physicians visited before the diagnosis is established. During the journey to diagnosis, misdiagnosis is not uncommon and further contributes to diagnosis delay.
Notably, patients with renal involvement usually have a more straightforward pathway to diagnosis, and many are diagnosed within 6 months from symptom onset.
Other common symptoms include exertional dyspnea, peripheral edema, paresthesias, weight loss, purpura, dysgeusia, xerostomia, and macroglossia. The 2 most commonly involved organs are the heart and the kidneys; each exists in 60% to 80% of patients. Heart involvement is defined on the basis of typical echocardiographic findings, including thickened heart walls, restrictive filling pattern, sparkling appearance of the myocardium, and abnormal strain pattern with a base-to-apex gradient. Cardiac magnetic resonance can assist in clarifying heart involvement when echocardiographic findings are equivocal. The hallmark feature of cardiac amyloidosis on cardiac magnetic resonance is late gadolinium enhancement. Elevated soluble cardiac biomarkers, cardiac troponins and natriuretic peptides, are sensitive but not specific. Endomyocardial biopsy is rarely required to confirm heart involvement and should be mainly used when heart involvement is highly suspected but tissue diagnosis of amyloidosis from more accessible tissues is not successful. Renal involvement is defined as the presence of more than 0.5 g/24-hour nonselective proteinuria,
Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, 18-22 April 2004.
A modern primer on light chain amyloidosis in 592 patients with mass spectrometry–verified typing [erratum appears in Mayo Clin Proc. 2019;94(6):1121].
Kidney involvement can be manifested with or without renal failure. Rarely, renal failure without proteinuria is seen in vascular-limited renal involvement.
Other organ involvement is notable for peripheral neuropathy (symmetric painful neuropathy, numbness, imbalance), autonomic neuropathy (orthostatic hypotension, alteration in bowel movement, early satiety, erectile dysfunction, and urinary retention), liver (hepatomegaly or elevated serum alkaline phosphatase, jaundice, weight loss), gastrointestinal tract (diarrhea, constipation, malabsorption, weight loss, gastrointestinal bleeding), muscle (muscle weakness, myalgia, pseudohypertrophy, atrophy), joints (polyarthropathy), spleen (hyposplenism), lungs (dyspnea, cough, diffuse interstitial infiltrates on imaging), bleeding diathesis (deficiencies of clotting factors, such as factor X), and skin (alopecia, purpura). Vascular involvement can result in exercise-induced limb claudication or angina pectoris as well as in jaw claudication on chewing.
Given the wide organ involvement, review of systems at initial encounter is paramount to assess disease extent and to guide the diagnostic evaluation. As the most commonly involved organs are heart, kidneys, liver, and nerves, the minimal evaluation should include measurement of seated and standing blood pressure, N-terminal brain natriuretic peptide (NT-proBNP) or brain natriuretic peptide, troponin T or troponin I, alkaline phosphatase, creatinine, and 24-hour urine protein.
Prognostication of survival using cardiac troponins and N-terminal pro-brain natriuretic peptide in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation.
The combination of high-sensitivity cardiac troponin T (hs-cTnT) at presentation and changes in N-terminal natriuretic peptide type B (NT-proBNP) after chemotherapy best predicts survival in AL amyloidosis.
Abnormal N-terminal fragment of brain natriuretic peptide in patients with light chain amyloidosis without cardiac involvement at presentation is a risk factor for development of cardiac amyloidosis.
Nerve conduction studies and electromyography aid in assessment of large-fiber peripheral neuropathy. Autonomic testing is appropriate on the basis of symptoms and should include evaluation of sweating and cardiovagal and adrenergic function as well as of gastric motility and bladder emptying.
Diagnosis of AL Amyloidosis
The diagnosis of amyloidosis relies on demonstration of amyloid deposits on a tissue sample. The tissue source can be the affected organ. However, a more accessible tissue, such as subcutaneous fat, should initially be pursued when suspicion for amyloidosis is raised. Fat aspiration combined with bone marrow biopsy (performed for assessment of the underlying plasma cell disorder) will yield the diagnosis in approximately 90% of patients.
For amyloid to be recognized, special staining is required. Congo red is the “gold standard” staining, but thioflavin T or sulfated alcian blue can also be used. Congo red staining under polarized light demonstrates apple-green birefringence, illustrating the highly organized ultrastructure of the amyloid fibrils.
Once a tissue diagnosis is established, the next step is to type the amyloid (ie, determine the precursor protein) as clinical manifestation, treatment, and prognosis are driven by the precursor protein. Several methods of typing are available. The gold standard technique is laser microdissection, followed by mass spectrometry–based proteomic analysis, which has high sensitivity and specificity.
However, antigen-antibody–based analyses have several limitations, including suboptimal specificity (due in part to cross-reactivity with deposited immunoglobulins), suboptimal sensitivity (due to bias toward common or suspected amyloid types), and potential for specimen depletion because a different tissue section is needed for each antibody tested. Mass spectrometry–based proteomics, in contrast, has high sensitivity and specificity, requires very little tissue, and unambiguously identifies all amyloid types in a single assay. A study reported that mass spectrometry–based proteomics is able to identify the amyloid type in 80% of amyloid specimens that could not be typed by immunohistochemistry.
Finally, the distinction between localized and systemic AL amyloidosis is required. The designation localized applies to AL amyloidosis in which the precursor protein is produced at the site of amyloid deposition and is typically not associated with a detectable circulating monoclonal protein in the serum or urine. The common sites of localized amyloidosis are the tracheobronchial tree, lungs, urinary tract, skin and soft tissue, oropharynx, gastrointestinal tract, and eyes.
Screening for a monoclonal protein (M-protein) is done by serum and urine electrophoresis/immunofixation studies and serum free light chain (FLC) assay.
The Mass-Fix assay has the ability to detect M-proteins with light chain glycosylation, which has been reported to be a risk factor for progression of AL amyloidosis and other plasma cell disorders.
A modern primer on light chain amyloidosis in 592 patients with mass spectrometry–verified typing [erratum appears in Mayo Clin Proc. 2019;94(6):1121].
In addition, bone marrow aspiration and biopsy and fluorescence in-situ hybridization (FISH) testing are indicated and can affect treatment decisions during the disease course. Rarely, other B-cell secretory diseases including Waldenström macroglobulinemia, chronic lymphocytic leukemia, and other non-Hodgkin lymphomas can be the underlying cause of AL amyloidosis.
The prognosis of AL amyloidosis is dependent on the 2 compartments of the disease—organ involvement and the underlying plasma cell clone. The degree of heart involvement is the single most important predictor for short-term
A modern primer on light chain amyloidosis in 592 patients with mass spectrometry–verified typing [erratum appears in Mayo Clin Proc. 2019;94(6):1121].
the proportion of patients dying within 6 to 12 months of diagnosis remains fixed at approximately 30% to 45%, with the least improvement in survival noted for these sickest patients.
However, in recent years with the advent of effective therapies, the rate of early death has declined, marking an important step in improving outcome in this disease. In our institution, the 6-month death rate among newly diagnosed patients declined from 37% before 2005 to 25% from 2005 onward.
Soluble cardiac biomarkers are the basis for cardiac staging. Given the profound impact of heart involvement on survival, the use of cardiac biomarkers for staging not only informs on the degree of heart involvement but also is prognostic. The advantage of blood tests for assessing cardiac status includes assay reproducibility, ease of testing, and relatively low cost. Disadvantages of the cardiac biomarkers include the number of assays available and the impact of renal failure on interpretation of the results.
The first cardiac model was the 2004 Mayo model, which incorporated troponin T and NT-proBNP into a 3-stage model (Table 2).
We have provided a conversion tool between troponin T and high-sensitivity troponin T following the adoption of this assay by the Food and Drug Administration in 2017, making it widely available in the United States.
For each stage, stage 1 is absence of any risk factors; stage 2 is presence of 1 risk factor; stage 3 is presence of 2 risk factors; and where applicable, stage 4 is all risk factors present. The exception is the European 2015 modification of the Mayo 2004 model, in which stage 3 (2 risk factors) is further divided by whether NT-proBNP is >8500 ng/L.
Prognostication of survival using cardiac troponins and N-terminal pro-brain natriuretic peptide in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation.
A matched comparison of cyclophosphamide, bortezomib and dexamethasone (CVD) versus risk-adapted cyclophosphamide, thalidomide and dexamethasone (CTD) in AL amyloidosis.
Bortezomib-based chemotherapy reduces early mortality and improves outcomes in patients with ultra-high-risk light-chain amyloidosis: a retrospective case control study.
For each stage, stage 1 is absence of any risk factors; stage 2 is presence of 1 risk factor; stage 3 is presence of 2 risk factors; and where applicable, stage 4 is all risk factors present. The exception is the European 2015 modification of the Mayo 2004 model, in which stage 3 (2 risk factors) is further divided by whether NT-proBNP is >8500 ng/L.
a dFLC, difference between involved and uninvolved immunoglobulin free light chains; NT-proBNP, N-terminal brain natriuretic peptide.
b For each stage, stage 1 is absence of any risk factors; stage 2 is presence of 1 risk factor; stage 3 is presence of 2 risk factors; and where applicable, stage 4 is all risk factors present. The exception is the European 2015 modification of the Mayo 2004 model, in which stage 3 (2 risk factors) is further divided by whether NT-proBNP is >8500 ng/L.
c Data are derived from Supplemental Table 2 of reference number 54.
Independent predictors of survival in primary systemic (AL) amyloidosis, including cardiac biomarkers and left ventricular strain imaging: an observational cohort study.
introduced a model for prediction of the risk of progression to dialysis. The rationale for this staging system is driven by the fact that renal involvement does not markedly increase the risk of death, but advanced renal involvement increases the risk of dialysis dependence. This 3-stage model is based on an eGFR of less than 50 mL/min per 1.73 m2 and 24-hour proteinuria of more than 5 g. When both were present at diagnosis, the risk for dialysis at 3 years was 60% and 85% in 2 separate cohorts, whereas not having any of these parameters yielded very low 3-year risk of progression to dialysis (0% and 4%, respectively).
Prognostic Impact of Serum Immunoglobulin FLCs
As mentioned before, serum immunoglobulin FLCs are prognostic. Immunoglobulin FLCs are also the main tool for assessing the hematologic response (HR),
New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes.
Coexistent multiple myeloma or increased bone marrow plasma cells define equally high-risk populations in patients with immunoglobulin light chain amyloidosis.
Bone marrow plasma cells 20% or greater discriminate presentation, response, and survival in AL amyloidosis [erratum appears in Leukemia. 2020;34(10):2819].
These patients are more likely to have concomitant myeloma phenotype and high-risk FISH abnormalities, explaining in part the worse outcome in this group of patients. In contrast, the Boston University (BU) group did not find that more than 10% plasmacytosis had an impact on survival, but their analysis was restricted to patients undergoing autologous stem cell transplant (ASCT) with up to 30% plasmacytosis.
The effect of bone marrow plasma cell burden on survival in patients with light chain amyloidosis undergoing high-dose melphalan and autologous stem cell transplantation.
Other plasma cell characteristics, like proliferative rate and FISH abnormalities, have also been reported to be prognostic. Translocation t(11;14) is associated with inferior survival of patients treated with bortezomib,
Interphase fluorescence in situ hybridization in untreated AL amyloidosis has an independent prognostic impact by abnormality type and treatment category.
Interphase fluorescence in situ hybridization in untreated AL amyloidosis has an independent prognostic impact by abnormality type and treatment category.
At present, the mainstay of treatment is targeting the underlying plasma cell clone. The amyloid fibrils in the tissue and intermediate soluble fibrils are the source of tissue injury and dysfunction,
and by their elimination, organ recovery can take place. Another approach for therapy by targeting the amyloid deposits using monoclonal antibodies has been investigated in the past decade with several antibodies, but none has yet reached a regulatory approval stage.
Any recommendation for the treatment of AL is confounded by disease heterogeneity, its rarity, and the paucity of randomized clinical trials. Despite these challenges, we believe that the combination of the literature and the experience of the authors, who are experts in the field, makes these recommendations sound. Table 4 contains current HR and organ response (OR) criteria.
Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, 18-22 April 2004.
New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes.
Clinical trials should always be considered the first choice when available. In the absence of clinical trials, recommendations are as discussed here. For each recommendation we assigned the level of evidence and its grade to indicate the quality of evidence the recommendations are based upon [for details see Box].
Table 4AL Amyloidosis Hematologic and Organ Response Criteria
New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes.
Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, 18-22 April 2004.
New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes.
Decrease of NT-proBNP by >30% and 300 ng/L (if baseline NT-proBNP >650 ng/L)
Renal response
At least 30% decrease in proteinuria or drop below 0.5 g/24 h, in the absence of renal progression, defined as a >25% decrease in eGFR
Hepatic response
50% decrease in abnormal alkaline phosphatase value or decrease in radiographic liver size by at least 2 cm
dFLC, difference between involved and uninvolved serum immunoglobulin free light chains (a value adequate to measure response is deemed to be 50 mg/L); eGFR, estimated glomerular filtration rate; FLC, free light chain; NT-proBNP, N-terminal brain natriuretic peptide.
Guideline: The goal of treatment should be hematologic very good partial response (VGPR) or better.
Level of Evidence: II
Grade of Recommendation: A
Guideline: The ideal goal is hematologic complete response (CR), but this has to be weighed against toxicity of therapy and lack of specificity and sensitivity of assays.
Level of Evidence: III
Grade of Recommendation: B
Guideline: Patients who do not achieve at least partial response (PR) within 2 cycles or VGPR within 4 cycles of therapy or after ASCT should be offered an alternative therapy.
Level of Evidence: III
Grade of Recommendation: B
Guideline: Improvement in organ function, preferably to near-normal value, is the preferred organ response goal.
Level of Evidence: III
Grade of Recommendation: B
Hematologic Response Goal
Our consensus recommendation is to aim for at least hematologic VGPR (difference between involved and uninvolved light chains [dFLC] <40 mg/L). Achievement of hematologic CR (negative serum and urine immunofixation and normal serum FLC ratio) is the optimal response category, but it can be safely achieved only in a subset of patients. As the survival difference between VGPR and CR is smaller compared with the survival difference between VGPR and PR (>50% reduction in dFLC),
New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes.
Nonetheless, we recommend referral of patients who achieved a VGPR but not a CR to an amyloidosis center to further assess the need for and feasibility of CR.
The importance of deep HR in AL can also be viewed from the perspective of light chain burden. Patients who achieved VGPR or CR and in whom the involved FLC (iFLC) serum level was 20 mg/L or less had superior OR, progression-free survival (PFS), and overall survival (OS) compared with those with CR or VGPR but with iFLC level of more than 20 mg/L. Similarly, the UK group reported that the achievement of dFLC below 10 mg/L at 6 months, irrespective of baseline dFLC, was associated with the best cardiac response rate, time to next therapy, and OS and was independent of CR or VGPR state.
We recently proposed a new definition for hematologic CR to include serum and urine immunofixation negativity plus iFLC level of 20 mg/L or less or dFLC of 10 mg/L or less, both of which were superior to the current CR definition.
This definition, however, has not been validated. Both the BU and the Pavia groups reported that the addition of iFLC level below 20 mg/L to the conventional definition of CR carries a survival advantage compared with CR alone.
Whether long-term outcomes will differ according to the means of arriving at a hematologic CR is still a matter of debate. This is most notable in the context of ASCT vs standard-intensity therapies. For patients achieving hematologic CR after standard-intensity therapies, the 5-year OS is about 70%. For patients undergoing ASCT and who achieve a CR, 5-year survival rates approach 90%.
However, this survival gap is confounded by the fact that patients undergoing ASCT are selected and fit at baseline and thus more likely to survive long term.
New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes.
These criteria were assessed at 3 months and 6 months from therapy initiation, and it was found that CR or VGPR achievement as early as 3 months from therapy initiation translated into survival advantage over those who achieved less than VGPR. Because AL amyloidosis is typically diagnosed late when organ function is profoundly affected, early HR is critical to maximize organ recovery and survival. This is the basis for our recommendation to switch therapy if PR is not achieved after 2 cycles. Similarly, if VGPR is not achieved within 4 cycles, change to alternative therapy or therapy intensification (if feasible) is recommended.
The Role of Bone Marrow Minimal Residual Disease in Response Assessment
Assessment of marrow residual disease using immunohistochemistry is challenging, especially in low-burden disease such as AL amyloidosis. Multiparametric flow cytometry (MFC) has increasingly been used to assess minimal residual disease (MRD) in various hematologic malignant neoplasms. In AL amyloidosis, the use of MFC to assess MRD has been investigated in several studies, most of them from our group. The first study with 82 patients reported that low residual disease by MFC (<0.1%) is prognostic for PFS and OS.
Subsequent analysis of this study with a longer follow-up reported that lack of clonal marrow plasma cells by MFC is associated with improved PFS compared with patients with residual clonal plasma cells, particularly among patients who achieved a CR. We recently reported the results of MFC with a higher sensitivity of 1 × 10−5 or more among 44 patients.
MRD negativity was more likely to be achieved among those who received ASCT and in those who achieved a CR. The achievement of MRD negativity was associated with a longer PFS and higher likelihood of cardiac response. The Greek group reported on the clinical outcomes of 51 patients based on MRD status using next-generation flow cytometry.
Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, 18-22 April 2004.
New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes.
New OR criteria, which are based on graded organ function improvement, are the focus of an international collaboration study. Preliminary results from that study confirm that deeper OR correlates with a longer survival.
The OR lags behind the HR. Organ response kinetics has been investigated among 414 patients who achieved OR to first-line therapy.
The median time from treatment initiation to heart, kidney, and liver response was 9, 6, and 6 months, respectively, whereas the median time to best organ function was 24, 29, and 35 months, respectively. These figures highlight the slow process of organ recovery, which requires regular organ function monitoring and provision of long-term supportive care.
Indications for Therapy in Newly Diagnosed AL
Guideline: Treatment should be initiated immediately in virtually all patients with systemic AL amyloidosis.
Level of Evidence: III
Grade of Recommendation: A
No trials have specifically addressed this point, but it is known through randomized trials that patients with AL treated with anti–plasma cell therapy live longer and can have clinical improvement compared with those who receive either no therapy or ineffective therapy like colchicine.
Those patients who have monoclonal gammopathy of undetermined significance or smoldering myeloma with an incidental finding of a positive Congo red reaction of the bone marrow do not require therapy and have low risk of progression to vital organ involvement. Such patients should be observed periodically with amyloid-directed review of systems, serum immunoglobulin FLCs, alkaline phosphatase, troponin, NT-proBNP, and creatinine as well as with spot urine for albumin.
Initial Therapy for Patients With Systemic AL Amyloidosis
Guideline: Consider high-dose chemotherapy with ASCT in selected patients.
Level of Evidence: III
Grade of Recommendation: B
In our routine practice, the first question asked is whether a patient is a candidate for high-dose chemotherapy followed by ASCT (Figure 2; Table 5). Among eligible patients, ASCT is an excellent option with potential for long-term survival. There are, however, no randomized trial data to support that it is superior therapy. On the contrary, a small phase 3 study concluded that ASCT is inferior to melphalan and dexamethasone (MDex).
On an intention-to-treat (ITT) basis, the median survival for MDex was 57 months vs 22 months for the ASCT arm. However, of the 50 patients randomized to receive ASCT, only 37 actually received the planned transplant and 9 of those died within 100 days, indicating an unacceptably high (24%) treatment-related mortality (TRM). In a 6-month landmark analysis, no difference in survival was noted between treatment arms, thus accounting for the survival disadvantage of ASCT to the very high TRM rate. In contrast, modern cohorts demonstrate a TRM of less than 5%,
Improved outcomes after autologous hematopoietic cell transplantation for light chain amyloidosis: a Center for International Blood and Marrow Transplant Research study.
In contrast to that randomized study, numerous studies support the use of ASCT in selected patients, given high response rate, durability of response, and long-term survival effect. In the 4 largest modern series on ASCT in AL amyloidosis (with or without induction), HR was achieved in 83% to 94% of patients, hematologic CR in 43% to 56%, and OR in 56% to 69%, and median OS was 6.3 to 10.9 years.
In a study focusing on AL patients surviving 10 years or more, those who underwent ASCT were less likely to require subsequent therapies compared with those receiving standard-intensity therapies.
Improved outcomes after autologous hematopoietic cell transplantation for light chain amyloidosis: a Center for International Blood and Marrow Transplant Research study.
High-dose melphalan and stem cell transplantation for patients with AL amyloidosis: trends in treatment-related mortality over the past 17 years at a single referral center.
High-dose melphalan and stem cell transplantation for patients with AL amyloidosis: trends in treatment-related mortality over the past 17 years at a single referral center.
Our eligibility criteria for ASCT are provided in Table 5. In our practice, we use a troponin T level of 0.06 ng/mL or more (or high-sensitivity troponin level ≥75 ng/L) as an exclusion factor, given a 28% 100-day all-cause mortality among these patients in contrast to a 7% all-cause mortality among those with a value below that threshold.
Collection of stem cells for storage can be considered in selected younger patients with high cardiac risk as they may become transplant eligible if organ function recovers with standard-intensity therapies.
Guideline: Dose-attenuated conditioning chemotherapy is not recommended for sicker patients.
Level of Evidence: III
Grade of Recommendation: C
In an effort to treat more patients with ASCT, dose-attenuated melphalan has been employed in patients with worse performance status, more organs involved, significant cardiac involvement, and older age. Consistently, this approach has resulted in lower HR rates including lower CR rates, inferior PFS and OS, and higher TRM rate.
Inferior survival and higher TRM in patients receiving an attenuated melphalan dose are not surprising because these patients are more frail. However, attenuated melphalan dose was an independent predictor for poor outcomes in the 2 largest studies of ASCT in AL amyloidosis from BU and Mayo Clinic.
In contrast, the UK group reported that an attenuated melphalan dose did not affect HR, OR, and OS, although in a quarter of the patients, the melphalan dose was unknown.
Long-term survival appears to be unsurpassed if ASCT is performed in select patients at high-volume transplant centers with a low TRM, especially if CR is achieved.
Patients with immunoglobulin light chain amyloidosis undergoing autologous stem cell transplantation have superior outcomes compared with patients with multiple myeloma: a retrospective review from a tertiary referral center.
In contrast, for those patients who have significant comorbidities meriting consideration of reduction of the conditioning melphalan dose (with the exception of reduced dose melphalan for patients with eGFR <30 mL/min per 1.73 m2), transplant is likely not the preferred initial option.
Guideline: Induction therapy before ASCT is recommended in all transplant-eligible patients.
Level of Evidence: III
Grade of Recommendation: C
Our recommendation for induction therapy in transplant-eligible patients is now broadened to include all patients, regardless of the degree of bone marrow plasmacytosis, given improvement in standard-intensity therapies and emerging data on the favorable benefit-risk balance of induction therapy. Moreover, several months are typically required to get a patient to transplant,
and it would be appropriate to reduce the load of the amyloidogenic light chains in the meantime to prevent further organ damage.
A small single-center randomized trial comparing 2 cycles of bortezomib-dexamethasone induction followed by ASCT (n=28) vs ASCT alone (n=28) has reported improved 1-year HR and CR rates favoring the induction arm (86% and 68% vs 54% and 36%, respectively).
Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial.
Moreover, the respective 2-year OS rates were 95% and 69%, and the respective 2-year PFS rates were 81% and 51%. A phase 2 study with 50 transplant-eligible patients assessed the impact of 4 cycles of bortezomib-dexamethasone induction before ASCT.
The study failed to meet its primary end point because of a high dropout (30%), mainly as a result of treatment-related toxicity, which can be explained by enrollment in inexperienced centers for management of AL amyloidosis and the use of twice-weekly bortezomib.
A retrospective study by our group explored the role of induction therapy among 415 patients who underwent ASCT between 1996 and 2011.
Induction therapy was given to 35% of the cohort, half of which was in the form of corticosteroids only. Induction therapy did not affect post-ASCT HR or CR rate in those with 10% or less plasmacytosis. However, among those with more than 10% plasmacytosis, induction therapy significantly improved the post-ASCT response rate, with CR nearly doubled from 18% to 34%. In multivariate analysis, having no induction therapy was associated with a shorter survival, irrespective of the plasma cell burden.
Other reports on the benefit of induction therapy exist,
although they are limited by selection bias and low-level strength of evidence. Another study from the Pavia group reported the clinical outcomes of bortezomib induction followed by ASCT among 40% of patients who did not achieve a satisfactory response to cyclophosphamide, bortezomib, and dexamethasone (CyBorD) and were deemed transplant eligible.
In the era of effective therapies, we recommend that induction therapy should be offered to all patients to increase the likelihood of a deep response after ASCT. Daratumumab-CyBorD is our recommended pre-ASCT induction, given its high efficacy and acceptable toxicity, as found in the ANDROMEDA study (discussed in detail in the non–transplant therapy section later). Alternatively, CyBorD can be offered as induction when daratumumab is not available. We recommend against twice-weekly bortezomib, which has a higher adverse effect profile, as therapy-related toxicity or organ deterioration while the patient is receiving induction therapy may adversely affect eligibility for ASCT.
The role of ASCT in patients who achieved CR to induction therapy remains unanswered. At this time, we recommend stem cell collection, whereas a decision on whether to pursue early ASCT should be made on an individual basis. Patients who may see greater benefit of early ASCT in this scenario are those with high-risk FISH abnormalities or concomitant active myeloma, but a definitive answer is lacking.
Guideline: Patients who did not achieve at least VGPR after ASCT should be offered an alternative therapy.
Level of Evidence: III
Grade of Recommendation: B
The concept of consolidation after ASCT has been assessed in several studies. Although it is a semantic distinction, achievement of less than VGPR after ASCT should be regarded as treatment failure and alternative therapy should be offered. However, the literature refers to therapy after ASCT with no disease progression as consolidation, usually in the context of aiming at deeper response.
Tandem cycles of high-dose melphalan and autologous stem cell transplantation increases the response rate in AL amyloidosis [erratum appears in Bone Marrow Transplant. 2007;40(6):607].
performed a prospective trial testing whether a second (tandem) ASCT could induce CR in patients who had not achieved CR after the first ASCT. There were 62 patients enrolled, and 27 patients achieved CR to first transplant. Of the 22 who did not achieve CR and could be considered for a second ASCT, 17 patients proceeded with this therapy and 5 more patients achieved CR. Although tandem ASCT may improve depth of response, its toxicity and the presence of alternative therapies make the tandem transplant model rarely used.
Two phase 2 trials tested the impact of consolidation. In these trials, patients not achieving CR received consolidative thalidomide with or without dexamethasone
Risk-adapted autologous stem cell transplantation with adjuvant dexamethasone +/- thalidomide for systemic light-chain amyloidosis: results of a phase II trial.
Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis.
or bortezomib and dexamethasone. In the study of thalidomide with or without dexamethasone, 31 patients began consolidation, but only 52% completed 9 months of treatment; 42% achieved a deeper HR. By ITT (which includes patients who died before response assessment was made), the HR and CR rates were 71% and 36%.
Risk-adapted autologous stem cell transplantation with adjuvant dexamethasone +/- thalidomide for systemic light-chain amyloidosis: results of a phase II trial.
In the other study, 6 cycles of bortezomib and dexamethasone were given to 23 patients. Of these, 18 patients had improvement in their response depth, including 12 patients (52%) who achieved a CR.
Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis.
We published our experience with consolidation after ASCT in 72 patients, representing 15% of patients who underwent ASCT in our center between 2005 and 2017.
Consolidation was almost evenly divided between proteasome inhibitor (PI), immunomodulatory drug (IMiD), and PI-IMiD combination. Patients who received consolidation had a lower day +100 post-ASCT CR or VGPR than those who did not (35% vs 84%). With consolidation, the rate of CR or VGPR improved to 58%, mainly because of improvement in CR rate.
Guideline: Maintenance therapy after ASCT should be considered for patients with myeloma phenotype or high-risk FISH abnormalities.
Level of Evidence: V
Grade of Recommendation: D
Because there are no trials or series addressing this question, a recommendation on post-ASCT maintenance therapy is driven by expert opinion only. The goal of maintenance therapy is to provide continuation of response with low-intensity therapy. In MM, maintenance therapy with lenalidomide or bortezomib has been able to improve disease control, and for lenalidomide, survival benefit has been found in several studies as well as in a meta-analysis.
Most patients with AL do not have concomitant symptomatic myeloma; however, for those patients with concomitant myeloma (as defined by SLiM-CRAB criteria), maintenance therapy after ASCT should also take into consideration the myeloma part of the disease. Lenalidomide could be considered in those with concern for early relapse, assuming adequate cardiac reserve. In addition, patients with high-risk FISH abnormalities [del17p, t(4;14), t(14;16), t(14;20), gain 1q] tend to relapse early,
Interphase fluorescence in situ hybridization in untreated AL amyloidosis has an independent prognostic impact by abnormality type and treatment category.
and maintenance therapy, preferably with PI, should also be considered in such patients. In our cohort of an ASCT population, maintenance therapy is given to approximately 5% of patients.
Guideline: For patients on hemodialysis, ASCT is feasible, especially if renal allograft is being considered.
Level of Evidence: IV
Grade of Recommendation: B
Once an AL patient has started dialysis, it is unlikely that renal function will recover without a renal allograft. Two studies have reported that ASCT can be safely performed in these patients with comparable outcome to those without end-stage renal disease (ESRD). The first study from BU reported on outcomes of 15 patients with ESRD undergoing ASCT for AL amyloidosis between 1994 and 2000.
The CR rate was 53%, and TRM was seen in 2 patients (13%). The OS was not different between the ESRD group and the non-ESRD group, but median survival was only 25 months, reflecting the early experience with ASCT. The second study from our group assessed the impact of timing of dialysis in AL patients undergoing ASCT. The 8 patients who had been on dialysis for more than 30 days before ASCT had similar outcome to those who never required dialysis.
These patients had the highest level of cardiac biomarkers, reflecting the impaired glomerular filtration rather than the cardiac status. Therefore, ASCT can be performed safely in hemodialysis patients, as long as there is attention to dose adjustment of melphalan and supportive care medications. Assessment of cardiac status to determine ASCT eligibility should follow other heart functional means rather than cardiac biomarkers.
Guideline: ASCT in patients with underlying lymphoproliferative disease or IgM monoclonal protein should be considered for eligible patients.
Level of Evidence: III
Grade of Recommendation: B
Limited information exists to guide treatment. The largest transplant series is from Mayo Clinic, in which 38 patients with an IgM monoclonal protein underwent ASCT.
Most patients were conditioned with melphalan alone (84%), whereas 16% of patients received BCNU-etoposide-cytarabine-melphalan (BEAM) conditioning. The HR rate was 92%, and the CR rate was 18%. Renal response was seen in 65% of patients and cardiac response in 60%. The median PFS and OS were 4 years and 9 years, respectively.
Initial Therapy for Patients Ineligible for Stem Cell Transplant
Guideline: Daratumumab in combination with bortezomib, cyclophosphamide, and dexamethasone is the new standard of care for transplant-ineligible newly diagnosed AL amyloidosis patients.
Level of Evidence: I
Grade of Recommendation: A
At the time of writing of the consensus statement, the initial results from the ANDROMEDA study were presented. This is the largest randomized controlled trial to date in AL amyloidosis with 388 patients. Newly diagnosed AL patients were randomly assigned to daratumumab (anti-CD38 monoclonal antibody) in combination with CyBorD (investigational arm, n=195) or CyBorD (control arm, n=193). CyBorD was given for 6 cycles in each arm and daratumumab in standard schedule and dosing up to a total of 24 cycles. Patients with Mayo stage 3b were excluded. The median duration of treatment was 9.6 months for daratumumab-CyBorD and 5.3 months for CyBorD. The HR and CR rates were significantly higher in the investigational arm compared with the control arm (HR, 92% vs 77%; CR, 53% vs 18%). However, the investigators used a modified CR definition in that study, which included negative serum or urine immunofixation and involved light chain below the upper limit of normal, irrespective of normalization of serum FLC ratio. The 6-month cardiac and renal response rates favored the treatment arm (cardiac response, 42% vs 22%; renal response, 54% vs 27%). The toxicity profile was similar between arms, but the rate of pneumonia was 8% in the daratumumab-CyBorD arm compared with 4% in the CyBorD arm. The main design caveat of this study is the longer treatment duration in the daratumumab-CyBorD arm compared with the control arm, which affects the interpretation of some of the study end points.
Given these results, daratumumab in combination with CyBorD was recently approved by the Food and Drug Administration, making this combination the preferred initial therapy for AL amyloidosis.
Guideline: In the absence of access to frontline daratumumab, an acceptable first-line therapy for transplant-ineligible patients is CyBorD or bortezomib, melphalan, and dexamethasone (BMDex).
Level of Evidence: II for BMDex; III for CyBorD
Grade of Recommendation: A
Bortezomib success in AL amyloidosis probably stems from a higher sensitivity of AL plasma cells to proteasome inhibition owing to toxic light chain–induced cellular stress.
In a randomized study comparing BMDex (n=53) with MDex (n=56), the BMDex arm achieved higher HR rate (79% vs 52%), higher VGPR/CR rate (64% vs 39%), and longer PFS or OS compared with the MDex arm, providing high-level evidence of proof for the importance of bortezomib as initial therapy for AL amyloidosis.
However, the bulk of the experience with bortezomib in the upfront setting comes from retrospective studies. A summary of the major studies assessing bortezomib in combination with alkylator and dexamethasone in the upfront setting is listed in Table 6. The HR rate is 60% to 80%, with CR in the 20% to 25% range. The largest study on first-line bortezomib comes from the UK group, in which 915 patients were mostly treated with CyBorD between 2010 and 2017.
Response data were available for 819 patients. On ITT analysis, the HR and CR rates were 65% and 25%, respectively. The median OS was 6 years. A third of the study population died without progression to second-line therapy, and of the remaining patients, 55% did not require second-line therapy at the 7-year landmark.
Table 6Bortezomib Combinations in Newly Diagnosed AL Amyloidosis
Data were modified from original data, if needed, to reflect intention-to-treat analysis (patients who died before response assessment are considered nonresponders).
Data were modified from original data, if needed, to reflect intention-to-treat analysis (patients who died before response assessment are considered nonresponders).
A matched comparison of cyclophosphamide, bortezomib and dexamethasone (CVD) versus risk-adapted cyclophosphamide, thalidomide and dexamethasone (CTD) in AL amyloidosis.
Bortezomib-based chemotherapy reduces early mortality and improves outcomes in patients with ultra-high-risk light-chain amyloidosis: a retrospective case control study.
a CR, complete response; HR, hematologic response; ITT, intention to treat; OR, organ response.
b Data were modified from original data, if needed, to reflect intention-to-treat analysis (patients who died before response assessment are considered nonresponders).
c Data not reported in the original publication and generated from the original study data set for the manuscript.
In resource-limited areas, CyBorD (or other bortezomib-containing regimens) should continue to be the standard of care for newly diagnosed AL amyloidosis patients (Figure 3). The choice between CyBorD and BMDex (or other bortezomib-containing regimens) is not fully guided as there is no comparison between the various regimens. In the United States, CyBorD is the standard, given its early introduction
Interphase fluorescence in situ hybridization in untreated AL amyloidosis has an independent prognostic impact by abnormality type and treatment category.
it may be reasonable to consider BMDex in the face of t(11;14). In contrast, if there is a plan for stem cell harvest and possible future ASCT, melphalan should be avoided or limited as it can deleteriously affect the ability to mobilize stem cells.
Guideline: Bortezomib should be administered subcutaneously once weekly at an initial dose of 1.3 to 1.6 mg/m2. Lower initial dose (0.7-1.0 mg/m2) can be considered in those with advanced cardiac disease.
Level of Evidence: III
Grade of Recommendation: B
In a phase 1/2 study using single-agent bortezomib in the relapsed setting, once-weekly bortezomib at a dose of 1.6 mg/m2 was associated with a lower toxicity profile compared with twice-weekly bortezomib at a dose of 1.3 mg/m2, including fewer cardiac events and orthostatic hypotension and less dose modification.
The twice-weekly bortezomib was possibly linked to death in 2 of 34 patients but none in the 18 patients treated with once-weekly bortezomib. Moreover, the CR rate was higher in the once-weekly bortezomib group. Lower bortezomib doses (0.7-1.0 mg/m2) led to fewer adverse events but also lower response rate.
The Greek group reported outcomes for dose-adjusted bortezomib-dexamethasone (bortezomib 1.3 mg/m2 and dexamethasone 20 mg weekly) for patients with advanced cardiac stage, age older than 70 years, low performance status, low systolic blood pressure (<100 mm Hg), or preexisting neuropathy.
Long-term outcomes of primary systemic light chain (AL) amyloidosis in patients treated upfront with bortezomib or lenalidomide and the importance of risk adapted strategies.
These patients had similar HR, CR, and OR rates compared with those who received full-dose bortezomib-dexamethasone (bortezomib 1.3 mg/m2 and dexamethasone 40 mg on days 1, 4, 8, and 11 every 21 days). The 3-month death rate was significantly lower in the dose-adjusted group compared with the full-dose group (4.5% vs 36%), despite worse baseline characteristics. In an unselected AL population not eligible for ASCT, we reported that bortezomib was associated with increased risk of early death compared with MDex after accounting for the number of involved organs, dFLC, and Mayo stage.
However, this observation should be taken cautiously, given the retrospective nature of the study, leading to potential selection bias and lack of data on treatment intensity in many patients treated in outside facilities.
Our overall recommendation is to administer bortezomib once weekly rather than twice weekly, with close monitoring for toxic effects including cardiac toxicity, hypotension, and neuropathy. In patients with advanced heart disease (Mayo stage 3b or New York Heart Association class III/IV), an initial lower dose of bortezomib can be considered and increased if tolerated. The dexamethasone weekly dose should be adjusted to organ involvement and performance status to avoid excess toxicity. This is particularly important in patients with advanced heart disease or nephrotic syndrome, in which dexamethasone can aggravate fluid retention.
Guideline: Duration of induction is at least 6 cycles in patients with no coexisting MM or high-risk FISH abnormalities.
Level of Evidence: III
Grade of Recommendation: B
There are no randomized trials that address the optimal duration of therapy. However, given the typical low clonal burden, therapy is generally administered for a limited period. The median number of cycles in clinical practice is 5,
which is the basis for our recommendation for at least 6 cycles of therapy in most patients (Figure 3). However, patients who achieved a rapid response with a plateau in response (including involved FLC level) may be offered fewer than 6 induction cycles.
Guideline: Patients with concomitant symptomatic MM or with high-risk FISH abnormalities should receive induction for 6 to 12 months with consideration of maintenance therapy.
Level of Evidence: IV
Grade of Recommendation: C
There is considerable lack of data on the management of AL amyloidosis patients with concomitant symptomatic myeloma (SLiM-CRAB features) or high-risk FISH abnormalities. These 2 subgroups compose approximately 10% of AL amyloidosis patients each and overlap each other.
Bone marrow plasma cells 20% or greater discriminate presentation, response, and survival in AL amyloidosis [erratum appears in Leukemia. 2020;34(10):2819].
As discussed before, whereas the short-term survival is dictated by the organ pattern and the degree of heart involvement, the plasma cell clone features, such as the attainment of hematologic CR, are important for long-term survival.
High-risk FISH abnormalities predict worse outcomes in myeloma patients, but their role in the AL population is not fully defined, given their rarity. In a multicenter study of 44 AL patients with del17p, the 2 independent predictors for survival were cardiac stage and response to therapy.
Patients with del17p in more than 50% of the plasma cells had a trend toward inferior survival.
With the reservation of data paucity, management of AL amyloidosis patients with concomitant symptomatic myeloma or high-risk FISH abnormalities should consider employment of myeloma treatment schemes in terms of duration of therapy and the use of maintenance therapy. We recommend 6 to 12 cycles of therapy in these patients to align with the general recommendation on induction therapy in transplant-ineligible myeloma patients. Because transplant-ineligible AL amyloidosis patients are often frail, one needs to balance the putative risk of myeloma “high-risk features” with the known toxic effects of therapy in AL patients. Because IMiDs are typically poorly tolerated in patients with significant cardiac involvement, if maintenance is considered in these patients, bortezomib or ixazomib maintenance may be preferred.
Initial Therapy in Certain Subpopulations of Interest
Guideline: Patients with t(11;14) have an inferior HR and survival after bortezomib-based therapy, and alternative therapies should be considered early if HR is suboptimal.
Level of Evidence: III
Grade of Recommendation: B
Translocation t(11;14) is present in approximately 50% of AL amyloidosis patients.
Interphase fluorescence in situ hybridization in untreated AL amyloidosis has an independent prognostic impact by abnormality type and treatment category.
Several studies have reported that patients harboring this aberration and who were treated with bortezomib have lower response rate and inferior PFS and OS compared with non-t(11;14) patients treated with bortezomib.
Interphase fluorescence in situ hybridization in untreated AL amyloidosis has an independent prognostic impact by abnormality type and treatment category.
However, the overall management of these patients should follow the treatment guidelines of the general AL amyloidosis population, with change in therapy if adequate response is not achieved.
Guideline: In patients with neuropathy, bortezomib should be avoided.
Level of Evidence: I
Grade of Recommendation: A
Bortezomib can severely aggravate autonomic or peripheral neuropathy, and its use should be discouraged in those with grade 2 or worse neuropathy (≥severe paresthesias or mild weakness interfering with daily function). Options in this population of patients include MDex,
Guideline: In patients on hemodialysis, attention is required for dose modifications.
Level of Evidence: III
Grade of Recommendation: C
Patients on long-term dialysis require adjustment of therapy for their renal impairment. Daratumumab has no renal clearance and is not dialyzable, and thus no dose adjustment to renal function is needed. It can be given after dialysis unless the patient is volume overloaded. In that case, it should be given before dialysis so the volume can be removed. Subcutaneous daratumumab may overcome the fluid overload that can be seen with intravenous administration of daratumumab.
Cyclophosphamide should be capped at 300 mg per dose. It should be given after dialysis because it can be removed with dialysis. Whereas bortezomib and dexamethasone do not require renal dose adjustments, melphalan dose should be reduced 30% to 50%, depending on the severity of the renal dysfunction. Attention should also be given to dose adjustment of supportive care medications, such as acyclovir and sulfamethoxazole/trimethoprim, both of which should be given after dialysis.
Guideline: Non-ASCT therapies for AL patients with underlying lymphoproliferative disease or IgM monoclonal gammopathy yield lower responses, and guidance on optimal therapy is lacking.
Level of Evidence: IV
Grade of Recommendation: C
IgM-associated AL amyloidosis is a rare clinical entity with distinctive clinical characteristics.
Some cases may be “localized forms,” in which there is only nodal or soft tissue involvement without visceral involvement. These cases can merely be observed, with no indication for systemic therapy. Chemotherapy is more often reserved for those cases in which there is typical amyloid deposition in viscera. Historically, regimens have been borrowed from both the myeloma and the Waldenström macroglobulinemia armamentarium but were not tested systematically. These treatments include cladribine, fludarabine, rituximab, chlorambucil, cyclophosphamide, vincristine, doxorubicin, melphalan, corticosteroids, PIs, IMiDs, and ASCT.
European collaborative study defining clinical profile outcomes and novel prognostic criteria in monoclonal immunoglobulin M-related light chain amyloidosis.
However, IgM amyloidosis is characterized by lower response rate and poorer survival when adjusted to Mayo cardiac stage compared with non-IgM AL amyloidosis.
European collaborative study defining clinical profile outcomes and novel prognostic criteria in monoclonal immunoglobulin M-related light chain amyloidosis.
European collaborative study defining clinical profile outcomes and novel prognostic criteria in monoclonal immunoglobulin M-related light chain amyloidosis.
In a study of 75 patients with IgM amyloidosis, 3 distinct morphologic-genomic subtypes were found: lymphoplasmacytic (63%), pure plasma cell neoplasm (23%), and other (14%).
Compared with the pure plasma cell neoplasm type, patients with the lymphoplasmacytic type had a higher degree of marrow involvement and a higher degree of cardiac involvement, and all were positive for the MYD88L265P and CXCR4 mutations. Patients with pure plasma cell neoplasm were exclusively positive for t(11;14). Survival was not different between lymphoplasmacytic and pure plasma cell neoplasm types, but comparison is limited by small numbers. This study hypothesized that the lower HR in IgM amyloidosis compared with non-IgM amyloidosis is tied to these different subtypes and that if therapy will be guided by the underlying clone, response rate should improve.
We encourage referral of patients with IgM amyloidosis to an amyloidosis center to optimize diagnosis and management in an effort to improve survival in this rare subset of patients.
Treating Relapsed or Refractory AL Amyloidosis
Guideline: For patients not achieving hematologic VGPR (and for some not achieving hematologic CR), one should move down the relapsed/refractory management algorithm.
Level of Evidence: II
Grade of Recommendation: A
As discussed in the first-line therapy section, the ideal is to achieve hematologic CR because clone persistence can cause organ progression or less substantial organ improvement. The importance of balancing the desire to obtain the deepest responses and therapy-related toxicity cannot be overemphasized.
Guideline: Salvage therapy for patients previously achieving VGPR or better should be considered in the face of rising dFLC before the development of organ progression, even if hematologic progression is not met.
Level of Evidence: III
Grade of Recommendation: C
The decision on when to change therapy in the face of inadequate response or to reinstitute therapy for relapsed disease is a matter of ongoing debate.
The median time between ASCT and second-line therapy was 2 years. At the time of second-line therapy, the median dFLC was 100 mg/L, being 42% of the dFLC at the time of diagnosis. The dFLC at second- line therapy was lower in the 2009-2016 period compared with the 1997-2008 period (70 mg/L vs 120 mg/L), probably representing the increase in availability of effective therapies in recent years as well as a lower dFLC threshold to restart therapy. Organ progression was noted in 63% of the patients. On multivariate analysis, dFLC of 50 mg/L or more and organ progression at second-line therapy were adversely associated with survival. The importance of initiation of second-line therapy before organ progression was also reported by Palladini et al.
In this study, 92 patients required second-line therapy, at a median dFLC of 55 mg/L. Cardiac and renal progression was noted in 22% and 12% of patients. The only independent predictor for survival was cardiac progression. Unfortunately, organ function deterioration during second-line therapy is seen in half of the patients and, in addition to the risk of death, is also associated with an increase in medical cost.
Guideline: Daratumumab-based therapy is the preferred salvage therapy in patients not refractory to daratumumab.
Level of Evidence: II
Grade of Recommendation: A
There are considerable data from prospective and retrospective studies to support daratumumab use as second-line therapy, given high efficacy and good tolerability (Figure 4). Table 7 summarizes the important clinical data on daratumumab in AL amyloidosis in the relapsed/refractory setting. Hematologic responses are seen in most patients, with the rate of VGPR or better at approximately 60% to 80% and CR in approximately 10% to 40% of patients. Responses are rapid, within 1 to 3 months of therapy, and are lasting. It is unlikely that response will improve beyond what has been achieved within the first 3 months of therapy.
Data were modified from original data, if needed, to reflect intention-to-treat analysis (patients who died before response assessment are considered nonresponders).
Data were modified from original data, if needed, to reflect intention-to-treat analysis (patients who died before response assessment are considered nonresponders).
Daratumumab is effective in the relapsed or refractory systemic light-chain amyloidosis but associated with high infection burden in a frail real-life population.
a CR, complete response; DD, daratumumab-dexamethasone; DVD, daratumumab-bortezomib-dexamethasone; HR, hematologic response; ITT, intention to treat; OR, organ response.
b Data were modified from original data, if needed, to reflect intention-to-treat analysis (patients who died before response assessment are considered nonresponders).
Daratumumab as monotherapy or in combination with dexamethasone (often given as premedication) is sufficient in most patients. Overall, combination with other agents (such as bortezomib or IMiD) is usually not necessary as data do not suggest that it leads to clear improvement in response depth. Duration of therapy is not well defined.
Several predictors for response and survival among daratumumab-treated patients were reported. In 1 study, the dFLC after 1 infusion (either as absolute number or as percentage reduction) was the only parameter to predict response.
In a larger study of 106 patients, a dFLC greater than 180 mg/L at therapy initiation was an independent poor predictor for VGPR or better response. The presence of dFLC greater than 180 mg/L, high urine albumin to creatinine ratio (>220 mg/mmol), and cardiac stage 3b were independent predictors for poor PFS.
The finding of high albumin to creatinine ratio to predict inferior PFS was explained by loss of daratumumab in the urine in patients with nephrotic-range proteinuria. Indeed, the authors described 7 patients with suspected or confirmed daratumumab in the urine, suggesting that heavy proteinuria causes lower availability of daratumumab, affecting its efficacy.
Daratumumab was well tolerated in all assessed trials. In the 2 prospective studies, the rate of infusion-related reactions was 23% and 52%, mostly as grade 1 or grade 2. Other adverse effects include infections, fatigue, cardiac arrhythmia, congestive heart failure, lymphopenia, diarrhea, anemia, and thrombocytopenia. Daratumumab is associated with the development of hypogammaglobulinemia (which may be present at treatment onset and further exacerbated by therapy). The use of intravenous immunoglobulin may be justified in those who experienced serious infections after therapy and in whom serum IgG is below 500 to 600 mg/dL, but this practice was not assessed for efficacy.
Guideline: Bortezomib-based regimen or ixazomib-based regimen is the preferred salvage therapy in daratumumab-refractory and bortezomib-sensitive patients.
Level of Evidence: III
Grade of Recommendation: B
Proteasome inhibitor–based therapy remains the preferred salvage therapy after daratumumab failure, given better results for a PI-based therapy in relapse/refractory AL amyloidosis and better tolerability compared with IMiD-based therapy (Figure 4).
Data on bortezomib in relapse/refractory amyloidosis were extensively reviewed in our prior mSMART consensus statement for AL amyloidosis.
The maximum tolerated dose was 4 mg. Patients were heavily pretreated, and 70% had previously received bortezomib. The HR was 52%, and CR was 10%. Responses were higher in PI-naïve patients. In the Tourmaline-AL1 phase 3 study, 168 PI-sensitive patients with relapse/refractory disease were randomized between ixazomib-dexamethasone and 1 of 5 physician’s choice salvage regimens (mostly chosen were MDex and lenalidomide-dexamethasone).
Primary results from the phase 3 tourmaline-AL1 trial of ixazomib-dexamethasone versus physician's choice of therapy in patients (pts) with relapsed/refractory primary systemic AL amyloidosis (RRAL).
The study did not meet its primary end point of superior HR in the ixazomib-dexamethasone group (ixazomib-dexamethasone, 53%; physician’s choice, 51%). However, patients treated with ixazomib-dexamethasone had better CR rate (26% vs 18%) and OR (36% vs 11%), longer time to treatment failure (10 vs 5 months), and longer PFS (11 vs 7 months) but no OS advantage. This study, despite its limitations, brings ixazomib-dexamethasone as a plausible treatment option for PI-sensitive relapse/refractory AL amyloidosis. Given the low incidence of neuropathy, ixazomib-dexamethasone (as well as MDex) can be used in these patients instead of bortezomib to reduce further neurologic decline.
Guideline: Among daratumumab- and bortezomib-refractory patients, lenalidomide or pomalidomide in combination with dexamethasone is the preferred salvage therapy.
Level of Evidence: III
Grade of Recommendation: B
The use of IMiD in AL amyloidosis is challenging because of poor tolerability at standard dosing. Thalidomide is not recommended in the treatment of AL amyloidosis because of high toxicity. Lenalidomide is also not well tolerated in AL amyloidosis and generally should be restricted to use in the relapsed/refractory setting. Studies with lenalidomide in combination with dexamethasone included newly diagnosed as well as relapse/refractory patients, which may affect interpretation of the results.
A lenalidomide dose greater than 15 mg/d was not tolerated, and the dose was often reduced to 5 to 10 mg/d. The most common toxic effects encountered in these trials include fatigue, neutropenia, thrombocytopenia, rash, infections, and venous thromboembolism. An increase in NT-proBNP and worsening renal function were also frequently seen and required close monitoring, treatment interruptions, and dose adjustments. Lenalidomide in combination with an alkylator and dexamethasone yielded slightly better HR of 40% to 60%, with CR of approximately 10% and infrequent ORs in most studies.
Lenalidomide, melphalan and dexamethasone in a population of patients with immunoglobulin light chain amyloidosis with high rates of advanced cardiac involvement.
Lenalidomide in combination with melphalan and dexamethasone in patients with newly diagnosed AL amyloidosis: a multicenter phase 1/2 dose-escalation study.
A pomalidomide and dexamethasone combination was assessed in a total 87 relapse/refractory AL amyloidosis patients in 3 prospective studies, finding HR of 44% to 61%, CR of 3% to 30%, and OR of 7% to 17%.
Cardiac response assessment was usually not feasible because of a paradoxical rise in NT-proBNP as seen with lenalidomide.
Guideline: Options for third-line salvage therapy in AL amyloidosis are limited.
Level of Evidence: IV
Grade of Recommendation: C
Options for salvage therapy in AL amyloidosis after the aforementioned treatments have been used are limited. Carfilzomib has been tested in a phase 1 study but was associated with significant cardiac toxicity and therefore is not recommended in cardiac patients.
Venetoclax, a BCL-2 inhibitor, was found in MM to be active mainly among those with t(11;14), a genetic aberration present in approximately half of AL patients. Data on its efficacy and safely in AL are limited. We reported on the outcomes of 12 AL patients treated with venetoclax either as a single agent or in combination.
Most patients had t(11;14). Of the 8 evaluable patients for response, 7 patients responded, all with a VGPR or CR. Therapy was well tolerated. The use of venetoclax in t(11;14) AL amyloidosis warrants further assessment, given data from MM and these results. Other options to consider include second ASCT in eligible patients,
Third Pillar: Supportive Therapy for AL Amyloidosis
Providing supportive care for patients with AL amyloidosis is challenging and requires a multidisciplinary approach based on the predominant involved organs and symptoms. A palliative care team is invaluable in counseling patients with advanced illness on symptom management, in providing psychosocial and spiritual support for patients and families, and in assisting with establishment of goals of care and advance care planning. This aspect of care is pivotal and should be addressed at the same time as therapy.
Guideline: Diuretics are the mainstay of management of volume overload due to congestive heart failure, nephrotic syndrome, or therapy.
Level of Evidence: IV
Grade of Recommendation: D
Guideline: Beta blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers should be used with great caution in cardiac amyloidosis.
Level of Evidence: V
Grade of Recommendation: D
Patients with cardiac amyloidosis typically have severe diastolic dysfunction with a nondilated ventricle, leading to increased filling pressures. Although the ejection fraction is preserved in most patients, stroke volume is reduced and relatively fixed because of restrictive filling. Patients with advanced cardiac amyloidosis are often dependent on higher heart rates to maintain cardiac output. The use of standard medical therapy for heart failure with reduced ejection fraction, specifically beta blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, often worsens patients’ clinical status. Beta blockade may cause profound hypotension and worsen cardiac output and should be avoided. Afterload reduction with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers also tends to be poorly tolerated in patients with cardiac AL amyloidosis, especially in those who have orthostatic hypotension. Diuretics are the mainstay of care, with the best results achieved with a combination of loop diuretics and mineralocorticoid receptor antagonists, such as spironolactone. Metolazone or periodic thoracentesis may be considered in select cases.
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