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Treatment of AL Amyloidosis: Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) Consensus Statement 2020 Update

      Abstract

      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.

      Abbreviations and Acronyms:

      AH (heavy chain amyloidosis), AL (light chain amyloidosis), ASCT (autologous stem cell transplant), BMDex (bortezomib, melphalan, and dexamethasone), BU (Boston University), CR (complete response), CyBorD (cyclophosphamide, bortezomib, and dexamethasone), dFLC (difference between involved and uninvolved immunoglobulin free light chains), eGFR (estimated glomerular filtration rate), ESRD (end-stage renal disease), FISH (fluorescence in situ hybridization), FLC (free light chain), HR (hematologic response), iFLC (involved free light chain), IMiD (immunomodulatory drug), ITT (intention to treat), MDex (melphalan and dexamethasone), MFC (multiparametric flow cytometry), MM (multiple myeloma), MRD (minimal residual disease), NT-proBNP (N-terminal brain natriuretic peptide), OR (organ response), OS (overall survival), PI (proteasome inhibitor), PFS (progression-free survival), PR (partial response), TRM (treatment-related mortality), VGPR (very good partial response)
      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,
      • Dasari S.
      • Theis J.D.
      • Vrana J.A.
      • et al.
      Amyloid typing by mass spectrometry in clinical practice: a comprehensive review of 16,175 samples.
      with an incidence of approximately 1 case per 100,000 person-years.
      • Kyle R.A.
      • Larson D.R.
      • Kurtin P.J.
      • et al.
      Incidence of AL amyloidosis in Olmsted County, Minnesota, 1990 through 2015.
      Other forms of systemic amyloidosis are listed in Table 1.
      • Benson M.D.
      • Buxbaum J.N.
      • Eisenberg D.S.
      • et al.
      Amyloid nomenclature 2018: recommendations by the International Society of Amyloidosis (ISA) nomenclature committee.
      Typing of the amyloid is imperative because treatment strategies are dependent on the identity of the precursor protein.
      • Brambilla F.
      • Lavatelli F.
      • Di Silvestre D.
      • et al.
      Reliable typing of systemic amyloidoses through proteomic analysis of subcutaneous adipose tissue.
      ,
      • Vrana J.A.
      • Gamez J.D.
      • Madden B.J.
      • Theis J.D.
      • Bergen 3rd, H.R.
      • Dogan A.
      Classification of amyloidosis by laser microdissection and mass spectrometry–based proteomic analysis in clinical biopsy specimens.
      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
      Type of amyloidosisPrecursor protein componentClinical presentation
      AL
      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.
      (previously referred to as primary amyloidosis)
      κ or λ immunoglobulin light chainSystemic or localized; see text
      AHγ, μ, α, δ, ε immunoglobulin heavy chainSystemic or localized; see text
      ATTR
       Wild-type ATTR
      TTR refers to transthyretin, previously known as prealbumin.
      (age-related amyloidosis)
      Normal transthyretinRestrictive cardiomyopathy; carpal tunnel syndrome

      Lumbar spinal stenosis

      Biceps tendon rupture
       Variant ATTR
      TTR refers to transthyretin, previously known as prealbumin.
      (also referred to as hereditary ATTR)
      Mutant transthyretinPolyneuropathy phenotype, cardiomyopathy phenotype, and mixed phenotype; leptomeningeal involvement; vitreous opacities
       AA (previously referred to as secondary amyloidosis)Serum amyloid ARenal presentation most common; associated with chronic inflammatory conditions; underlying disease is typically acquired, but hereditary in case of familial periodic fever syndromes
       ALECT2Leukocyte chemotactic factor 2Acquired; renal or liver presentation
       Αβ2Mβ2-microglobulinAcquired in patients on long-term dialysis; carpal tunnel syndrome, large joint arthropathy
       AApoA-IVApolipoprotein A-IVAcquired; renal or cardiac amyloidosis
      Rare hereditary amyloidosis types
       AGel; also known as familial amyloidosis, Finnish typeGelsolinTriad of corneal lattice dystrophy, facial nerve paralysis, and cutis laxa
       AFibFibrinogen α-chainUsually renal presentation
       ALysLysozymeSicca syndrome, renal dysfunction, liver or spleen rupture, gastrointestinal ulcers
       AApoA-IApolipoprotein A-IMutation-dependent, can affect various organs
       AApoA-IIApolipoprotein A-IIRenal amyloidosis
       AApoC-IIApolipoprotein C-IIRenal amyloidosis
       AApoC-IIIApolipoprotein C-IIIRenal 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.
      • Cibeira M.T.
      • Sanchorawala V.
      • Seldin D.C.
      • et al.
      Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation: long-term results in a series of 421 patients.
      • Muchtar E.
      • Gertz M.A.
      • Lacy M.Q.
      • et al.
      Ten-year survivors in AL amyloidosis: characteristics and treatment pattern.
      • Sidana S.
      • Sidiqi M.H.
      • Dispenzieri A.
      • et al.
      Fifteen year overall survival rates after autologous stem cell transplantation for AL amyloidosis.
      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.
      • Lousada I.
      • Comenzo R.L.
      • Landau H.
      • Guthrie S.
      • Merlini G.
      Light chain amyloidosis: patient experience survey from the Amyloidosis Research Consortium.
      In addition, supportive care is best guided by the dominant involved organs and requires a multidisciplinary approach.
      Figure thumbnail gr1
      Figure 1Three-pillar scheme for improved survival in AL amyloidosis.
      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,
      • Dispenzieri A.
      • Buadi F.
      • Kumar S.K.
      • et al.
      Treatment of immunoglobulin light chain amyloidosis: Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus statement.
      multiple myeloma (MM),
      • Dingli D.
      • Ailawadhi S.
      • Bergsagel P.L.
      • et al.
      Therapy for relapsed multiple myeloma: guidelines from the Mayo Stratification for Myeloma and Risk-Adapted Therapy.
      • Gonsalves W.I.
      • Buadi F.K.
      • Ailawadhi S.
      • et al.
      Utilization of hematopoietic stem cell transplantation for the treatment of multiple myeloma: a Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus statement.
      • Mikhael J.R.
      • Dingli D.
      • Roy V.
      • et al.
      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].
      and Waldenström macroglobulinemia.
      • Kapoor P.
      • Ansell S.M.
      • Fonseca R.
      • et al.
      Diagnosis and management of Waldenström macroglobulinemia: Mayo Stratification of Macroglobulinemia and Risk-Adapted Therapy (mSMART) guidelines 2016.

      First Pillar: Early Recognition

      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.
      • Lousada I.
      • Comenzo R.L.
      • Landau H.
      • Guthrie S.
      • Merlini G.
      Light chain amyloidosis: patient experience survey from the Amyloidosis Research Consortium.
      ,
      • Kourelis T.V.
      • Kumar S.K.
      • Go R.S.
      • et al.
      Immunoglobulin light chain amyloidosis is diagnosed late in patients with preexisting plasma cell dyscrasias.
      • Kyle R.A.
      • Gertz M.A.
      Primary systemic amyloidosis: clinical and laboratory features in 474 cases.
      • McCausland K.L.
      • White M.K.
      • Guthrie S.D.
      • et al.
      Light chain (AL) amyloidosis: the journey to diagnosis.
      The initial barrier to diagnosis is the patient’s self-interpretation of symptoms.
      • McCausland K.L.
      • White M.K.
      • Guthrie S.D.
      • et al.
      Light chain (AL) amyloidosis: the journey to diagnosis.
      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.
      • McCausland K.L.
      • White M.K.
      • Guthrie S.D.
      • et al.
      Light chain (AL) amyloidosis: the journey to diagnosis.
      Notably, patients with renal involvement usually have a more straightforward pathway to diagnosis, and many are diagnosed within 6 months from symptom onset.
      • McCausland K.L.
      • White M.K.
      • Guthrie S.D.
      • et al.
      Light chain (AL) amyloidosis: the journey to diagnosis.
      This may be explained by the routine use of kidney biopsy in patients with proteinuria.
      • Muchtar E.
      • Dispenzieri A.
      • Lacy M.Q.
      • et al.
      Overuse of organ biopsies in immunoglobulin light chain amyloidosis (AL): the consequence of failure of early recognition.
      Nonetheless, patients with heart involvement are those who are in the greatest need of early diagnosis to improve outcome.

      Presentation and Organ Involvement

      Fatigue is the most common symptom, reported by 80% of patients.
      • McCausland K.L.
      • White M.K.
      • Guthrie S.D.
      • et al.
      Light chain (AL) amyloidosis: the journey to diagnosis.
      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,
      • Gertz M.A.
      • Comenzo R.
      • Falk R.H.
      • et al.
      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.
      but more than half of the patients with renal AL amyloidosis present with nephrotic-range proteinuria.
      • Muchtar E.
      • Gertz M.A.
      • Kyle R.A.
      • et al.
      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.
      • Eirin A.
      • Irazabal M.V.
      • Gertz M.A.
      • et al.
      Clinical features of patients with immunoglobulin light chain amyloidosis (AL) with vascular-limited deposition in the kidney.
      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.
      • Dispenzieri A.
      • Gertz M.A.
      • Kumar S.K.
      • et al.
      High sensitivity cardiac troponin T in patients with immunoglobulin light chain amyloidosis.
      • Dispenzieri A.
      • Gertz M.A.
      • Kyle R.A.
      • et al.
      Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis.
      • Dispenzieri A.
      • Gertz M.A.
      • Kyle R.A.
      • et al.
      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.
      • Gertz M.A.
      • Kyle R.A.
      Hepatic amyloidosis: clinical appraisal in 77 patients.
      • Kristen A.V.
      • Giannitsis E.
      • Lehrke S.
      • et al.
      Assessment of disease severity and outcome in patients with systemic light-chain amyloidosis by the high-sensitivity troponin T assay.
      • Palladini G.
      • Barassi A.
      • Klersy C.
      • et al.
      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.
      • Palladini G.
      • Campana C.
      • Klersy C.
      • et al.
      Serum N-terminal pro-brain natriuretic peptide is a sensitive marker of myocardial dysfunction in AL amyloidosis.
      • Palladini G.
      • Hegenbart U.
      • Milani P.
      • et al.
      A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis.
      • Wechalekar A.D.
      • Gillmore J.D.
      • Wassef N.
      • Lachmann H.J.
      • Whelan C.
      • Hawkins P.N.
      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.
      • Muchtar E.
      • Dispenzieri A.
      • Lacy M.Q.
      • et al.
      Overuse of organ biopsies in immunoglobulin light chain amyloidosis (AL): the consequence of failure of early recognition.
      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.
      • Dasari S.
      • Theis J.D.
      • Vrana J.A.
      • et al.
      Amyloid typing by mass spectrometry in clinical practice: a comprehensive review of 16,175 samples.
      ,
      • Vrana J.A.
      • Gamez J.D.
      • Madden B.J.
      • Theis J.D.
      • Bergen 3rd, H.R.
      • Dogan A.
      Classification of amyloidosis by laser microdissection and mass spectrometry–based proteomic analysis in clinical biopsy specimens.
      Alternative typing methods include antigen-antibody–based analyses, such as immunofluorescence, immunohistochemistry, and immunogold.
      • Fernandez de Larrea C.
      • Verga L.
      • Morbini P.
      • et al.
      A practical approach to the diagnosis of systemic amyloidoses.
      ,
      • Schonland S.O.
      • Hegenbart U.
      • Bochtler T.
      • et al.
      Immunohistochemistry in the classification of systemic forms of amyloidosis: a systematic investigation of 117 patients.
      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.
      • Rezk T.
      • Gilbertson J.A.
      • Mangione P.P.
      • et al.
      The complementary role of histology and proteomics for diagnosis and typing of systemic amyloidosis.
      It cannot be overemphasized that the presence of a monoclonal protein in a patient with amyloidosis does not prove AL type.
      • Connors L.H.
      • Sam F.
      • Skinner M.
      • et al.
      Heart failure resulting from age-related cardiac amyloid disease associated with wild-type transthyretin: a prospective, observational cohort study.
      • Geller H.I.
      • Singh A.
      • Mirto T.M.
      • et al.
      Prevalence of monoclonal gammopathy in wild-type transthyretin amyloidosis.
      • Gillmore J.D.
      • Maurer M.S.
      • Falk R.H.
      • et al.
      Nonbiopsy diagnosis of cardiac transthyretin amyloidosis.
      • Phull P.
      • Sanchorawala V.
      • Connors L.H.
      • et al.
      Monoclonal gammopathy of undetermined significance in systemic transthyretin amyloidosis (ATTR).
      • Pinney J.H.
      • Whelan C.J.
      • Petrie A.
      • et al.
      Senile systemic amyloidosis: clinical features at presentation and outcome.
      • Sidiqi M.H.
      • Dasari S.
      • McPhail E.D.
      • et al.
      Monoclonal gammopathy plus positive amyloid biopsy does not always equal AL amyloidosis.
      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.
      • Kourelis T.V.
      • Kyle R.A.
      • Dingli D.
      • et al.
      Presentation and outcomes of localized immunoglobulin light chain amyloidosis: the Mayo Clinic experience.
      ,
      • Mahmood S.
      • Bridoux F.
      • Venner C.P.
      • et al.
      Natural history and outcomes in localised immunoglobulin light-chain amyloidosis: a long-term observational study.
      At Mayo Clinic, approximately 7% of cases of AL amyloidosis are localized.
      • Kourelis T.V.
      • Kyle R.A.
      • Dingli D.
      • et al.
      Presentation and outcomes of localized immunoglobulin light chain amyloidosis: the Mayo Clinic experience.

      Evaluation of Patients With AL Amyloidosis

      Screening for a monoclonal protein (M-protein) is done by serum and urine electrophoresis/immunofixation studies and serum free light chain (FLC) assay.
      • Katzmann J.A.
      • Kyle R.A.
      • Benson J.
      • et al.
      Screening panels for detection of monoclonal gammopathies.
      More recently at Mayo Clinic, immunofixation has been replaced by the mass spectrometry method (Mass-Fix).
      • Mills J.R.
      • Kohlhagen M.C.
      • Dasari S.
      • et al.
      Comprehensive assessment of M-proteins using nanobody enrichment coupled to MALDI-TOF mass spectrometry.
      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.
      • Dispenzieri A.
      • Larson D.R.
      • Rajkumar S.V.
      • et al.
      N-glycosylation of monoclonal light chains on routine MASS-FIX testing is a risk factor for MGUS progression.
      Despite the typical low clonal burden, at least 1 abnormality is found in virtually all patients.
      • Muchtar E.
      • Gertz M.A.
      • Kyle R.A.
      • et al.
      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.
      • Merlini G.
      • Stone M.J.
      Dangerous small B-cell clones.

      Prognosis 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
      • Muchtar E.
      • Gertz M.A.
      • Kumar S.K.
      • et al.
      Improved outcomes for newly diagnosed AL amyloidosis between 2000 and 2014: cracking the glass ceiling of early death.
      and long-term
      • Muchtar E.
      • Gertz M.A.
      • Lacy M.Q.
      • et al.
      Ten-year survivors in AL amyloidosis: characteristics and treatment pattern.
      survival. The number of involved organs
      • Muchtar E.
      • Gertz M.A.
      • Kyle R.A.
      • et al.
      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].
      and hepatic
      • Kyle R.A.
      • Greipp P.R.
      • O'Fallon W.M.
      Primary systemic amyloidosis: multivariate analysis for prognostic factors in 168 cases.
      and autonomic
      • Dingli D.
      • Tan T.S.
      • Kumar S.K.
      • et al.
      Stem cell transplantation in patients with autonomic neuropathy due to primary (AL) amyloidosis.
      involvement also influence survival. The plasma cell clone becomes relevant for long-term survival.
      • Muchtar E.
      • Gertz M.A.
      • Lacy M.Q.
      • et al.
      Ten-year survivors in AL amyloidosis: characteristics and treatment pattern.
      ,
      • Kyle R.A.
      • Greipp P.R.
      • O'Fallon W.M.
      Primary systemic amyloidosis: multivariate analysis for prognostic factors in 168 cases.
      Whereas improvement in survival was noted at Mayo Clinic and the UK National Amyloidosis Center during past decades,
      • Kumar S.K.
      • Gertz M.A.
      • Lacy M.Q.
      • et al.
      Recent improvements in survival in primary systemic amyloidosis and the importance of an early mortality risk score.
      ,
      • Wechalekar A.D.
      • Gillmore J.D.
      • Hawkins P.N.
      Systemic amyloidosis.
      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.
      • Ravichandran S.
      • Lachmann H.J.
      • Wechalekar A.D.
      Epidemiologic and survival trends in amyloidosis, 1987–2019.
      The high early death rate explains why newly diagnosed patients tend to fare worse than patients with relapsed or refractory AL
      • Warsame R.
      • Bang S.M.
      • Kumar S.K.
      • et al.
      Outcomes and treatments of patients with immunoglobulin light chain amyloidosis who progress or relapse postautologous stem cell transplant.
      and why the risk factors for death are different during the first year and after the first year.
      • Kyle R.A.
      • Greipp P.R.
      • O'Fallon W.M.
      Primary systemic amyloidosis: multivariate analysis for prognostic factors in 168 cases.
      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.
      • Muchtar E.
      • Gertz M.A.
      • Kumar S.K.
      • et al.
      Improved outcomes for newly diagnosed AL amyloidosis between 2000 and 2014: cracking the glass ceiling of early death.

      Cardiac Staging

      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).
      • Dispenzieri A.
      • Gertz M.A.
      • Kyle R.A.
      • et al.
      Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis.
      The stage 3 in this model was later subdivided into 2 substages (3a and 3b), using a higher cutoff of NT-proBNP.
      • Palladini G.
      • Sachchithanantham S.
      • Milani P.
      • et al.
      A European collaborative study of cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL amyloidosis.
      This European modification of the Mayo 2004 model is successful in identifying high-risk patients for early death
      • Muchtar E.
      • Therneau T.M.
      • Larson D.R.
      • et al.
      Comparative analysis of staging systems in AL amyloidosis.
      as well as better performance in those with low estimated glomerular filtration rate (eGFR) and atrial arrhythmia.
      • Dittrich T.
      • Benner A.
      • Kimmich C.
      • et al.
      Performance analysis of AL amyloidosis cardiac biomarker staging systems with special focus on renal failure and atrial arrhythmia.
      Serum immunoglobulin FLCs are prognostic
      • Dispenzieri A.
      • Lacy M.Q.
      • Katzmann J.A.
      • et al.
      Absolute values of immunoglobulin free light chains are prognostic in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation.
      • Kumar S.
      • Dispenzieri A.
      • Katzmann J.A.
      • et al.
      Serum immunoglobulin free light-chain measurement in primary amyloidosis: prognostic value and correlations with clinical features.
      • Wechalekar A.D.
      • Wassef N.L.
      • Gibbs S.D.
      • et al.
      A new staging system for AL amyloidosis incorporating serum free light chains, cardiac troponin-T and NT-ProBNP.
      and have been incorporated into the Mayo 2012 staging system.
      • Kumar S.
      • Dispenzieri A.
      • Lacy M.Q.
      • et al.
      Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements.
      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.
      • Muchtar E.
      • Kumar S.K.
      • Gertz M.A.
      • et al.
      Staging systems use for risk stratification of systemic amyloidosis in the era of high-sensitivity troponin T assay.
      A conversion table for all cardiac biomarkers by the various cardiac models can be viewed in Table 3.
      Table 2Cardiac Risk Models in AL Amyloidosis
      dFLC, difference between involved and uninvolved immunoglobulin free light chains; NT-proBNP, N-terminal brain natriuretic peptide.
      Troponin (μg/L)NT-proBNP (ng/L)OtherStages
      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.
      Hazard ratio for death
      Data are derived from Supplemental Table 2 of reference number 54.
      Mayo 2004 model
      • Dispenzieri A.
      • Gertz M.A.
      • Kyle R.A.
      • et al.
      Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis.
      ,
      • Dispenzieri A.
      • Gertz M.A.
      • Kyle R.A.
      • et al.
      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.
      ,
      • Comenzo R.L.
      • Reece D.
      • Palladini G.
      • et al.
      Consensus guidelines for the conduct and reporting of clinical trials in systemic light-chain amyloidosis.
      • Venner C.P.
      • Gillmore J.D.
      • Sachchithanantham S.
      • et al.
      A matched comparison of cyclophosphamide, bortezomib and dexamethasone (CVD) versus risk-adapted cyclophosphamide, thalidomide and dexamethasone (CTD) in AL amyloidosis.
      • Shen K.N.
      • Zhang C.L.
      • Tian Z.
      • et al.
      Bortezomib-based chemotherapy reduces early mortality and improves outcomes in patients with ultra-high-risk light-chain amyloidosis: a retrospective case control study.
      ≥0.035≥3321Reference
      22.5 (1.9-3.5)
      36.7 (5.0-9.1)
      European 2015 modification of Mayo 2004 model
      • Palladini G.
      • Sachchithanantham S.
      • Milani P.
      • et al.
      A European collaborative study of cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL amyloidosis.
      ≥0.035≥332Stage 3 only: NT-proBNP >8500 ng/L1Reference
      22.5 (1.9-3.5)
      3
      dFLC, difference between involved and uninvolved immunoglobulin free light chains; NT-proBNP, N-terminal brain natriuretic peptide.
      4.9 (3.6-6.8)
      3
      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.
      11.1 (8.1-15.4)
      Revised Mayo 2012 model
      • Kumar S.
      • Dispenzieri A.
      • Lacy M.Q.
      • et al.
      Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements.
      ≥0.025≥1800dFLC ≥180 mg/L1Reference
      21.7 (1.2-2.3)
      34.1 (3.1-5.5)
      46.3 (4.8-8.3)
      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.
      Table 3Conversion Table for the Various Cardiac Biomarkers Used Across the 3 Cardiac Risk Models
      BNP, brain natriuretic peptide; NT-proBNP, N-terminal brain natriuretic peptide.
      ,
      Conversion data are obtained from original papers as well as by conversion tool between troponin T and high-sensitivity troponin T.60
      ModelTroponin T (μg/L)Troponin I (μg/L)High-sensitivity troponin T (ng/L)NT-proBNP (ng/L)BNP (ng/L)
      Mayo 2004 model≥0.035≥0.1≥50≥332≥81
      European 2015 modification of Mayo 2004 model≥0.035≥0.1≥50≥332≥81
      >8500>700
      Revised Mayo 2012 model≥0.025≥0.07≥40≥1800≥400
      a BNP, brain natriuretic peptide; NT-proBNP, N-terminal brain natriuretic peptide.
      b Conversion data are obtained from original papers as well as by conversion tool between troponin T and high-sensitivity troponin T.
      • Muchtar E.
      • Kumar S.K.
      • Gertz M.A.
      • et al.
      Staging systems use for risk stratification of systemic amyloidosis in the era of high-sensitivity troponin T assay.
      Echocardiographic parameters, such as ejection fraction, longitudinal left ventricular strain,
      • Bellavia D.
      • Pellikka P.A.
      • Al-Zahrani G.B.
      • et al.
      Independent predictors of survival in primary systemic (AL) amyloidosis, including cardiac biomarkers and left ventricular strain imaging: an observational cohort study.
      and stroke volume index,
      • Milani P.
      • Dispenzieri A.
      • Scott C.G.
      • et al.
      Independent prognostic value of stroke volume index in patients with immunoglobulin light chain amyloidosis.
      are prognostic as well. However, they may be limited by variability in local expertise and imaging protocols.

      Renal Staging

      Palladini et al
      • Palladini G.
      • Hegenbart U.
      • Milani P.
      • et al.
      A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis.
      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),
      • Palladini G.
      • Dispenzieri A.
      • Gertz M.A.
      • et al.
      New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes.
      as is discussed later, and thus they carry a significant impact on survival throughout the disease course.

      Prognostic Impact of Plasma Cell Burden and Biology

      The median bone marrow plasmacytosis is 10%.
      • Muchtar E.
      • Gertz M.A.
      • Kumar S.K.
      • et al.
      Improved outcomes for newly diagnosed AL amyloidosis between 2000 and 2014: cracking the glass ceiling of early death.
      Patients with more than 10% marrow plasmacytosis have a worse outcome than those with 10% or less marrow plasmacytosis.
      • Kourelis T.V.
      • Kumar S.K.
      • Gertz M.A.
      • et al.
      Coexistent multiple myeloma or increased bone marrow plasma cells define equally high-risk populations in patients with immunoglobulin light chain amyloidosis.
      ,
      • Tovar N.
      • Rodriguez-Lobato L.G.
      • Cibeira M.T.
      • et al.
      Bone marrow plasma cell infiltration in light chain amyloidosis: impact on organ involvement and outcome.
      We recently refined the independent worse outcome to patients with 20% or more bone marrow plasma cells.
      • Muchtar E.
      • Gertz M.A.
      • Kourelis T.V.
      • et al.
      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.
      • Dittus C.
      • Uwumugambi N.
      • Sun F.
      • Sloan J.M.
      • Sanchorawala V.
      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,
      • Bochtler T.
      • Hegenbart U.
      • Kunz C.
      • et al.
      Translocation t(11;14) is associated with adverse outcome in patients with newly diagnosed AL amyloidosis when treated with bortezomib-based regimens.
      • Dumas B.
      • Yameen H.
      • Sarosiek S.
      • Sloan J.M.
      • Sanchorawala V.
      Presence of t(11;14) in AL amyloidosis as a marker of response when treated with a bortezomib-based regimen.
      • Muchtar E.
      • Dispenzieri A.
      • Kumar S.K.
      • et al.
      Interphase fluorescence in situ hybridization in untreated AL amyloidosis has an independent prognostic impact by abnormality type and treatment category.
      whereas trisomies
      • Muchtar E.
      • Dispenzieri A.
      • Kumar S.K.
      • et al.
      Interphase fluorescence in situ hybridization in untreated AL amyloidosis has an independent prognostic impact by abnormality type and treatment category.
      ,
      • Warsame R.
      • Kumar S.K.
      • Gertz M.A.
      • et al.
      Abnormal FISH in patients with immunoglobulin light chain amyloidosis is a risk factor for cardiac involvement and for death.
      and del17p
      • Wong S.W.
      • Hegenbart U.
      • Palladini G.
      • et al.
      Outcome of patients with newly diagnosed systemic light-chain amyloidosis associated with deletion of 17p.
      are poor prognostic markers in AL amyloidosis.

      Second Pillar: Anti–Plasma Cell Therapy

      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,
      • Brenner D.A.
      • Jain M.
      • Pimentel D.R.
      • et al.
      Human amyloidogenic light chains directly impair cardiomyocyte function through an increase in cellular oxidant stress.
      ,
      • Mishra S.
      • Guan J.
      • Plovie E.
      • et al.
      Human amyloidogenic light chain proteins result in cardiac dysfunction, cell death, and early mortality in zebrafish.
      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.
      • Gertz M.A.
      • Comenzo R.
      • Falk R.H.
      • et al.
      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.
      ,
      • Palladini G.
      • Dispenzieri A.
      • Gertz M.A.
      • et al.
      New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes.
      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
      Response typeCriteria
      Hematologic response
      • Palladini G.
      • Dispenzieri A.
      • Gertz M.A.
      • et al.
      New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes.
       Complete responseNegative serum and urine immunofixation and normal serum immunoglobulin κ/λ FLC ratio
       Very good partial responsedFLC <40 mg/L
       Partial responsedFLC decrease of >50%
       No responseLess than a partial response
      Organ response
      • Gertz M.A.
      • Comenzo R.
      • Falk R.H.
      • et al.
      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.
      ,
      • Palladini G.
      • Dispenzieri A.
      • Gertz M.A.
      • et al.
      New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes.
       Cardiac responseDecrease of NT-proBNP by >30% and 300 ng/L (if baseline NT-proBNP >650 ng/L)
       Renal responseAt 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 response50% 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),
      • Palladini G.
      • Dispenzieri A.
      • Gertz M.A.
      • et al.
      New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes.
      VGPR or better is set as the realistic treatment goal, which can be achieved in 40% to 80% of the patients by modern therapies.
      • Muchtar E.
      • Gertz M.A.
      • Kumar S.K.
      • et al.
      Improved outcomes for newly diagnosed AL amyloidosis between 2000 and 2014: cracking the glass ceiling of early death.
      ,
      • Palladini G.
      • Sachchithanantham S.
      • Milani P.
      • et al.
      A European collaborative study of cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL amyloidosis.
      ,
      • Manwani R.
      • Cohen O.
      • Sharpley F.
      • et al.
      A prospective observational study of 915 patients with systemic AL amyloidosis treated with upfront bortezomib.
      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.
      • Manwani R.
      • Cohen O.
      • Sharpley F.
      • et al.
      A prospective observational study of 915 patients with systemic AL amyloidosis treated with upfront bortezomib.
      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.
      • Muchtar E.
      • Gertz M.A.
      • Lacy M.Q.
      • et al.
      Refining amyloid complete hematological response: quantitative serum free light chains superior to ratio.
      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.
      • Milani P.
      • Basset M.
      • Nuvolone M.
      • et al.
      Indicators of profound hematologic response in AL amyloidosis: complete response remains the goal of therapy.
      ,
      • Sarosiek S.
      • Zheng L.
      • Sloan J.M.
      • Quillen K.
      • Brauneis D.
      • Sanchorawala V.
      Comparing measures of hematologic response after high-dose melphalan and stem cell transplantation in AL amyloidosis.
      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%.
      • Cibeira M.T.
      • Sanchorawala V.
      • Seldin D.C.
      • et al.
      Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation: long-term results in a series of 421 patients.
      ,
      • Sidiqi M.H.
      • Aljama M.A.
      • Buadi F.K.
      • et al.
      Stem cell transplantation for light chain amyloidosis: decreased early mortality over time.
      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.
      • Muchtar E.
      • Gertz M.A.
      • Lacy M.Q.
      • et al.
      Ten-year survivors in AL amyloidosis: characteristics and treatment pattern.

      Timing of HR

      The importance of the timing of the HR is best provided by the HR criteria.
      • Palladini G.
      • Dispenzieri A.
      • Gertz M.A.
      • et al.
      New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes.
      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.
      • Muchtar E.
      • Jevremovic D.
      • Dispenzieri A.
      • et al.
      The prognostic value of multiparametric flow cytometry in AL amyloidosis at diagnosis and at the end of first-line treatment.
      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.
      • Sidana S.
      • Muchtar E.
      • Sidiqi M.H.
      • et al.
      Impact of minimal residual negativity using next generation flow cytometry on outcomes in light chain amyloidosis.
      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.
      • Kastritis E.
      • Kostopoulos I.V.
      • Theodorakakou F.
      • et al.
      Next generation flow cytometry for MRD detection in patients with AL amyloidosis.
      In that study, patients with MRD-negative disease were more likely to achieve OR and less likely to experience hematologic relapse.

      Organ Response Goals

      The current OR criteria are based on reduction in organ parameter and are binary, that is, response vs no response (Table 4).
      • Gertz M.A.
      • Comenzo R.
      • Falk R.H.
      • et al.
      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.
      The likelihood of achieving OR and a longer survival is proportional to the depth of the HR.
      • Palladini G.
      • Dispenzieri A.
      • Gertz M.A.
      • et al.
      New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes.
      ,
      • Manwani R.
      • Cohen O.
      • Sharpley F.
      • et al.
      A prospective observational study of 915 patients with systemic AL amyloidosis treated with upfront bortezomib.
      ,
      • Kaufman G.P.
      • Dispenzieri A.
      • Gertz M.A.
      • et al.
      Kinetics of organ response and survival following normalization of the serum free light chain ratio in AL amyloidosis.
      ,
      • Muchtar E.
      • Dispenzieri A.
      • Leung N.
      • et al.
      Depth of organ response in AL amyloidosis is associated with improved survival: grading the organ response criteria.
      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.
      • Muchtar E.
      • Dispenzieri A.
      • Leung N.
      • et al.
      Depth of organ response in AL amyloidosis is associated with improved survival: grading the organ response criteria.
      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.
      • Kyle R.A.
      • Greipp P.R.
      Primary systemic amyloidosis: comparison of melphalan and prednisone versus placebo.
      • Kyle R.A.
      • Greipp P.R.
      • Garton J.P.
      • Gertz M.A.
      Primary systemic amyloidosis. Comparison of melphalan/prednisone versus colchicine.
      • Kyle R.A.
      • Gertz M.A.
      • Greipp P.R.
      • et al.
      A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine.
      • Skinner M.
      • Anderson J.
      • Simms R.
      • et al.
      Treatment of 100 patients with primary amyloidosis: a randomized trial of melphalan, prednisone, and colchicine versus colchicine only.
      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).
      • Jaccard A.
      • Moreau P.
      • Leblond V.
      • et al.
      High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis.
      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%,
      • Cibeira M.T.
      • Sanchorawala V.
      • Seldin D.C.
      • et al.
      Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation: long-term results in a series of 421 patients.
      ,
      • Sidiqi M.H.
      • Aljama M.A.
      • Buadi F.K.
      • et al.
      Stem cell transplantation for light chain amyloidosis: decreased early mortality over time.
      ,
      • D'Souza A.
      • Dispenzieri A.
      • Wirk B.
      • et al.
      Improved outcomes after autologous hematopoietic cell transplantation for light chain amyloidosis: a Center for International Blood and Marrow Transplant Research study.
      ,
      • Sharpley F.A.
      • Petrie A.
      • Mahmood S.
      • et al.
      A 24-year experience of autologous stem cell transplantation for light chain amyloidosis patients in the United Kingdom.
      suggesting inappropriate selection of patients in that study, which in turn limits its conclusions.
      Figure thumbnail gr2
      Figure 2Treatment algorithm for transplant-eligible newly diagnosed AL amyloidosis patients. ASCT, autologous stem cell transplant; BMPCs, bone marrow plasma cells; CR, complete response; CrCl, creatinine clearance; CyBorD, cyclophosphamide, bortezomib, dexamethasone; FISH, fluorescence in situ hybridization; MEL200, melphalan 200 mg/m2 conditioning; mSMART, Mayo Stratification of Myeloma and Risk-Adapted Therapy; VGPR, very good partial response.
      Table 5Mayo Eligibility Criteria for Autologous Stem Cell Transplant
      “Physiologic” age ≤70 years
      Performance score ≤2
      Systolic blood pressure ≥90 mm Hg
      Caution as well for patients with systolic blood pressure <100 mm Hg.
      Troponin T level <0.06 ng/mL (or high-sensitivity troponin T level <75 ng/mL)
      Creatinine clearance ≥30 mL/min
      Selected patients may become eligible for autologous stem cell transplant with cardiac and renal transplant.
      (unless on long-term dialysis)
      New York Heart Association class I/II
      a Caution as well for patients with systolic blood pressure <100 mm Hg.
      b Selected patients may become eligible for autologous stem cell transplant with cardiac and renal transplant.
      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.
      • Cibeira M.T.
      • Sanchorawala V.
      • Seldin D.C.
      • et al.
      Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation: long-term results in a series of 421 patients.
      ,
      • Sharpley F.A.
      • Petrie A.
      • Mahmood S.
      • et al.
      A 24-year experience of autologous stem cell transplantation for light chain amyloidosis patients in the United Kingdom.
      • Gutierrez-Garcia G.
      • Cibeira M.T.
      • Rovira M.
      • et al.
      Improving security of autologous hematopoietic stem cell transplant in patients with light-chain amyloidosis.
      • Tandon N.
      • Muchtar E.
      • Sidana S.
      • et al.
      Revisiting conditioning dose in newly diagnosed light chain amyloidosis undergoing frontline autologous stem cell transplant: impact on response and survival.
      The actuarial 15-year survival rate in our center among patients undergoing ASCT is 30%,
      • Sidana S.
      • Sidiqi M.H.
      • Dispenzieri A.
      • et al.
      Fifteen year overall survival rates after autologous stem cell transplantation for AL amyloidosis.
      a figure that is expected to be higher with improvements in outcomes in recent years.
      • Muchtar E.
      • Gertz M.A.
      • Kumar S.K.
      • et al.
      Improved outcomes for newly diagnosed AL amyloidosis between 2000 and 2014: cracking the glass ceiling of early death.
      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.
      • Muchtar E.
      • Gertz M.A.
      • Lacy M.Q.
      • et al.
      Ten-year survivors in AL amyloidosis: characteristics and treatment pattern.
      Guideline: Select candidates for ASCT on the basis of troponin level, systolic blood pressure, renal function, functional status, and physiologic age.
      Level of Evidence: III
      Grade of Recommendation: B
      In early experience with ASCT, day 100 TRM was approximately 15% to 20%,
      • Sidiqi M.H.
      • Aljama M.A.
      • Buadi F.K.
      • et al.
      Stem cell transplantation for light chain amyloidosis: decreased early mortality over time.
      ,
      • D'Souza A.
      • Dispenzieri A.
      • Wirk B.
      • et al.
      Improved outcomes after autologous hematopoietic cell transplantation for light chain amyloidosis: a Center for International Blood and Marrow Transplant Research study.
      ,
      • Tsai S.B.
      • Seldin D.C.
      • Quillen K.
      • et al.
      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.
      but with better careful selection, it has gradually declined to a single-digit percentage, reaching as low as 1% to 4% in high-volume centers.
      • Sidiqi M.H.
      • Aljama M.A.
      • Buadi F.K.
      • et al.
      Stem cell transplantation for light chain amyloidosis: decreased early mortality over time.
      ,
      • Sharpley F.A.
      • Petrie A.
      • Mahmood S.
      • et al.
      A 24-year experience of autologous stem cell transplantation for light chain amyloidosis patients in the United Kingdom.
      ,
      • Tsai S.B.
      • Seldin D.C.
      • Quillen K.
      • et al.
      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.
      • Gertz M.
      • Lacy M.
      • Dispenzieri A.
      • et al.
      Troponin T level as an exclusion criterion for stem cell transplantation in light-chain amyloidosis.
      ,
      • Gertz M.A.
      • Lacy M.Q.
      • Dispenzieri A.
      • et al.
      Refinement in patient selection to reduce treatment-related mortality from autologous stem cell transplantation in amyloidosis.
      Another important contraindication to ASCT is low systolic blood pressure.
      • Mollee P.N.
      • Wechalekar A.D.
      • Pereira D.L.
      • et al.
      Autologous stem cell transplantation in primary systemic amyloidosis: the impact of selection criteria on outcome.
      ,
      • Wechalekar A.D.
      • Schonland S.O.
      • Kastritis E.
      • et al.
      A European collaborative study of treatment outcomes in 346 patients with cardiac stage III AL amyloidosis.
      Patients with significantly impaired creatinine clearance are at risk for post-ASCT dialysis.
      • Fadia A.
      • Casserly L.F.
      • Sanchorawala V.
      • et al.
      Incidence and outcome of acute renal failure complicating autologous stem cell transplantation for AL amyloidosis.
      ,
      • Leung N.
      • Kumar S.K.
      • Glavey S.V.
      • et al.
      The impact of dialysis on the survival of patients with immunoglobulin light chain (AL) amyloidosis undergoing autologous stem cell transplantation.
      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.
      • Cibeira M.T.
      • Sanchorawala V.
      • Seldin D.C.
      • et al.
      Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation: long-term results in a series of 421 patients.
      ,
      • Tandon N.
      • Muchtar E.
      • Sidana S.
      • et al.
      Revisiting conditioning dose in newly diagnosed light chain amyloidosis undergoing frontline autologous stem cell transplant: impact on response and survival.
      ,
      • Gertz M.A.
      • Lacy M.Q.
      • Dispenzieri A.
      • et al.
      Risk-adjusted manipulation of melphalan dose before stem cell transplantation in patients with amyloidosis is associated with a lower response 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.
      • Cibeira M.T.
      • Sanchorawala V.
      • Seldin D.C.
      • et al.
      Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation: long-term results in a series of 421 patients.
      ,
      • Tandon N.
      • Muchtar E.
      • Sidana S.
      • et al.
      Revisiting conditioning dose in newly diagnosed light chain amyloidosis undergoing frontline autologous stem cell transplant: impact on response and survival.
      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.
      • Sharpley F.A.
      • Petrie A.
      • Mahmood S.
      • et al.
      A 24-year experience of autologous stem cell transplantation for light chain amyloidosis patients in the United Kingdom.
      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.
      • Cibeira M.T.
      • Sanchorawala V.
      • Seldin D.C.
      • et al.
      Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation: long-term results in a series of 421 patients.
      • Muchtar E.
      • Gertz M.A.
      • Lacy M.Q.
      • et al.
      Ten-year survivors in AL amyloidosis: characteristics and treatment pattern.
      • Sidana S.
      • Sidiqi M.H.
      • Dispenzieri A.
      • et al.
      Fifteen year overall survival rates after autologous stem cell transplantation for AL amyloidosis.
      ,
      • Dispenzieri A.
      • Seenithamby K.
      • Lacy M.Q.
      • et al.
      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.
      • Cibeira M.T.
      • Sanchorawala V.
      • Seldin D.C.
      • et al.
      Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation: long-term results in a series of 421 patients.
      ,
      • Jaccard A.
      • Moreau P.
      • Leblond V.
      • et al.
      High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis.
      ,
      • Tandon N.
      • Muchtar E.
      • Sidana S.
      • et al.
      Revisiting conditioning dose in newly diagnosed light chain amyloidosis undergoing frontline autologous stem cell transplant: impact on response and survival.
      ,
      • Gertz M.
      • Lacy M.
      • Dispenzieri A.
      • et al.
      Troponin T level as an exclusion criterion for stem cell transplantation in light-chain amyloidosis.
      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,
      • Afrough A.
      • Saliba R.M.
      • Hamdi A.
      • et al.
      Impact of induction therapy on the outcome of immunoglobulin light chain amyloidosis after autologous hematopoietic stem cell transplantation.
      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).
      • Huang X.
      • Wang Q.
      • Chen W.
      • et al.
      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.
      • Minnema M.C.
      • Nasserinejad K.
      • Hazenberg B.
      • et al.
      Bortezomib-based induction followed by stem cell transplantation in light chain amyloidosis: results of the multicenter HOVON 104 trial.
      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.
      • Hwa Y.L.
      • Kumar S.K.
      • Gertz M.A.
      • et al.
      Induction therapy pre-autologous stem cell transplantation in immunoglobulin light chain amyloidosis: a retrospective evaluation.
      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,
      • Afrough A.
      • Saliba R.M.
      • Hamdi A.
      • et al.
      Impact of induction therapy on the outcome of immunoglobulin light chain amyloidosis after autologous hematopoietic stem cell transplantation.
      ,
      • Landau H.
      • Lahoud O.
      • Devlin S.
      • et al.
      Pilot study of bortezomib and dexamethasone pre- and post-risk-adapted autologous stem cell transplantation in AL amyloidosis.
      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.
      • Basset M.
      • Milani P.
      • Nuvolone M.
      • et al.
      Sequential response-driven bortezomib-based therapy followed by autologous stem cell transplant in AL amyloidosis.
      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.
      • Minnema M.C.
      • Nasserinejad K.
      • Hazenberg B.
      • et al.
      Bortezomib-based induction followed by stem cell transplantation in light chain amyloidosis: results of the multicenter HOVON 104 trial.
      Induction therapy may render transplant-ineligible patients eligible for transplant with improvement in organ function.
      • Manwani R.
      • Hegenbart U.
      • Mahmood S.
      • et al.
      Deferred autologous stem cell transplantation in systemic AL amyloidosis.
      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.
      Sanchorawala et al
      • Sanchorawala V.
      • Wright D.G.
      • Quillen K.
      • et al.
      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
      • Cohen A.D.
      • Zhou P.
      • Chou J.
      • et al.
      Risk-adapted autologous stem cell transplantation with adjuvant dexamethasone +/- thalidomide for systemic light-chain amyloidosis: results of a phase II trial.
      • Landau H.
      • Hassoun H.
      • Rosenzweig M.A.
      • et al.
      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%.
      • Cohen A.D.
      • Zhou P.
      • Chou J.
      • et al.
      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.
      • Landau H.
      • Hassoun H.
      • Rosenzweig M.A.
      • et al.
      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.
      • Al Saleh A.S.
      • Sidiqi M.H.
      • Sidana S.
      • et al.
      Impact of consolidation therapy post autologous stem cell transplant in patients with light chain amyloidosis.
      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.
      • Kumar S.K.
      • Rajkumar V.
      • Kyle R.A.
      • et al.
      Multiple myeloma.
      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,
      • Muchtar E.
      • Dispenzieri A.
      • Kumar S.K.
      • et al.
      Interphase fluorescence in situ hybridization in untreated AL amyloidosis has an independent prognostic impact by abnormality type and treatment category.
      ,
      • Bochtler T.
      • Hegenbart U.
      • Kunz C.
      • et al.
      Prognostic impact of cytogenetic aberrations in AL amyloidosis patients after high-dose melphalan: a long-term follow-up study.
      ,
      • Bochtler T.
      • Hegenbart U.
      • Kunz C.
      • et al.
      Gain of chromosome 1q21 is an independent adverse prognostic factor in light chain amyloidosis patients treated with melphalan/dexamethasone.
      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.
      • Casserly L.F.
      • Fadia A.
      • Sanchorawala V.
      • et al.
      High-dose intravenous melphalan with autologous stem cell transplantation in AL amyloidosis–associated end-stage renal disease.
      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.
      • Leung N.
      • Kumar S.K.
      • Glavey S.V.
      • et al.
      The impact of dialysis on the survival of patients with immunoglobulin light chain (AL) amyloidosis undergoing autologous stem cell transplantation.
      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.
      • Sidiqi M.H.
      • Buadi F.K.
      • Dispenzieri A.
      • et al.
      Autologous stem cell transplant for IgM-associated amyloid light-chain amyloidosis.
      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.
      • Oliva L.
      • Orfanelli U.
      • Resnati M.
      • et al.
      The amyloidogenic light chain is a stressor that sensitizes plasma cells to proteasome inhibitor toxicity.
      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.
      • Kastritis E.
      • Leleu X.
      • Arnulf B.
      • et al.
      Bortezomib, melphalan, and dexamethasone for light-chain 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.
      • Manwani R.
      • Cohen O.
      • Sharpley F.
      • et al.
      A prospective observational study of 915 patients with systemic AL amyloidosis treated with upfront bortezomib.
      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
      CR, complete response; HR, hematologic response; ITT, intention to treat; OR, organ response.
      Reference, yearNo.≥2 organsMayo 2004 stage (1/2/3a/3b)HR/CR (%), ITT
      Data were modified from original data, if needed, to reflect intention-to-treat analysis (patients who died before response assessment are considered nonresponders).
      OR (%), ITT
      Data were modified from original data, if needed, to reflect intention-to-treat analysis (patients who died before response assessment are considered nonresponders).
      Median follow-up (mo)Median survival
      Manwani et al,
      • Manwani R.
      • Cohen O.
      • Sharpley F.
      • et al.
      A prospective observational study of 915 patients with systemic AL amyloidosis treated with upfront bortezomib.
      2019
      915Median 2 organs16/33/37/1465/25 (n=819)12-month:

      Heart 32.5

      Kidney 15.4

      Liver 30
      23; 32 for living patients6 years
      Palladini et al,
      • Palladini G.
      • Sachchithanantham S.
      • Milani P.
      • et al.
      A European collaborative study of cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL amyloidosis.
      2015
      230Not provided18/33/29/2060/23Heart 17

      Kidney 25

      Liver 32
      25 for living patients3-year 55%
      Muchtar et al,
      • Muchtar E.
      • Gertz M.A.
      • Kumar S.K.
      • et al.
      Improved outcomes for newly diagnosed AL amyloidosis between 2000 and 2014: cracking the glass ceiling of early death.
      2017
      22228%7/35/34/2460/21
      Data not reported in the original publication and generated from the original study data set for the manuscript.
      Heart 19
      Data not reported in the original publication and generated from the original study data set for the manuscript.


      Kidney 25

      Liver 14
      33 for living patients
      Data not reported in the original publication and generated from the original study data set for the manuscript.
      21 months
      Data not reported in the original publication and generated from the original study data set for the manuscript.
      Venner et al,
      • Venner C.P.
      • Gillmore J.D.
      • Sachchithanantham S.
      • et al.
      A matched comparison of cyclophosphamide, bortezomib and dexamethasone (CVD) versus risk-adapted cyclophosphamide, thalidomide and dexamethasone (CTD) in AL amyloidosis.
      2014
      69Median 2.512/30/32/2671/40.5Not reported as ITT12.71-year 65.2%
      Shen et al,
      • Shen K.N.
      • Zhang C.L.
      • Tian Z.
      • et al.
      Bortezomib-based chemotherapy reduces early mortality and improves outcomes in patients with ultra-high-risk light-chain amyloidosis: a retrospective case control study.
      2019
      62Median 23b 45%52/37Heart 352430 months
      Jaccard et al,
      • Jaccard A.
      • Comenzo R.L.
      • Hari P.
      • et al.
      Efficacy of bortezomib, cyclophosphamide and dexamethasone in treatment-naive patients with high-risk cardiac AL amyloidosis (Mayo Clinic stage III).
      2014
      60Median 2All stage 368/15Heart 3211.8Not reached
      Diaz-Pallares et al,
      • Diaz-Pallares C.
      • Lee H.
      • Luider J.
      • et al.
      Cyclophosphamide, bortezomib and dexamethasone (CyBorD) for the treatment of newly diagnosed AL amyloidosis: impact of response on survival outcomes.
      2020
      34Not providedNot provided91/26.56-month:

      Heart 19

      Kidney 32
      24; 40 for living patientsNot reached
      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
      • Mikhael J.R.
      • Schuster S.R.
      • Jimenez-Zepeda V.H.
      • et al.
      Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis.
      and possible better tolerance compared with BMDex. However, because response to MDex is not affected by t(11;14),
      • Muchtar E.
      • Dispenzieri A.
      • Kumar S.K.
      • et al.
      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.
      • Sidana S.
      • Tandon N.
      • Gertz M.A.
      • et al.
      Impact of prior melphalan exposure on stem cell collection in light chain amyloidosis.
      Figure thumbnail gr3
      Figure 3Treatment algorithm for transplant-ineligible newly diagnosed AL amyloidosis patients. ASCT, autologous stem cell transplant; BMDex, bortezomib, melphalan, dexamethasone; BMPCs, bone marrow plasma cells; CR, complete response; CyBorD, cyclophosphamide, bortezomib, dexamethasone; FISH, fluorescence in situ hybridization; PR, partial response; VGPR, very good partial response.
      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.
      • Reece D.E.
      • Hegenbart U.
      • Sanchorawala V.
      • et al.
      Efficacy and safety of once-weekly and twice-weekly bortezomib in patients with relapsed systemic AL amyloidosis: results of a phase 1/2 study.
      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.
      • Kastritis E.
      • Roussou M.
      • Gavriatopoulou M.
      • et al.
      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.
      • Muchtar E.
      • Gertz M.A.
      • Kumar S.K.
      • et al.
      Improved outcomes for newly diagnosed AL amyloidosis between 2000 and 2014: cracking the glass ceiling of early death.
      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,
      • Muchtar E.
      • Gertz M.A.
      • Kumar S.K.
      • et al.
      Improved outcomes for newly diagnosed AL amyloidosis between 2000 and 2014: cracking the glass ceiling of early death.
      ,
      • Manwani R.
      • Cohen O.
      • Sharpley F.
      • et al.
      A prospective observational study of 915 patients with systemic AL amyloidosis treated with upfront bortezomib.
      ,
      • Jaccard A.
      • Comenzo R.L.
      • Hari P.
      • et al.
      Efficacy of bortezomib, cyclophosphamide and dexamethasone in treatment-naive patients with high-risk cardiac AL amyloidosis (Mayo Clinic stage III).
      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.
      • Muchtar E.
      • Gertz M.A.
      • Kourelis T.V.
      • et al.
      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.
      • Cibeira M.T.
      • Sanchorawala V.
      • Seldin D.C.
      • et al.
      Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation: long-term results in a series of 421 patients.
      • Muchtar E.
      • Gertz M.A.
      • Lacy M.Q.
      • et al.
      Ten-year survivors in AL amyloidosis: characteristics and treatment pattern.
      • Sidana S.
      • Sidiqi M.H.
      • Dispenzieri A.
      • et al.
      Fifteen year overall survival rates after autologous stem cell transplantation for AL amyloidosis.
      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.
      • Wong S.W.
      • Hegenbart U.
      • Palladini G.
      • et al.
      Outcome of patients with newly diagnosed systemic light-chain amyloidosis associated with deletion of 17p.
      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.
      • Muchtar E.
      • Dispenzieri A.
      • Kumar S.K.
      • et al.
      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.
      • Bochtler T.
      • Hegenbart U.
      • Kunz C.
      • et al.
      Translocation t(11;14) is associated with adverse outcome in patients with newly diagnosed AL amyloidosis when treated with bortezomib-based regimens.
      • Dumas B.
      • Yameen H.
      • Sarosiek S.
      • Sloan J.M.
      • Sanchorawala V.
      Presence of t(11;14) in AL amyloidosis as a marker of response when treated with a bortezomib-based regimen.
      • Muchtar E.
      • Dispenzieri A.
      • Kumar S.K.
      • et al.
      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,
      • Merlini G.
      • Dispenzieri A.
      • Sanchorawala V.
      • et al.
      Systemic immunoglobulin light chain amyloidosis.
      carfilzomib (in nonadvanced cardiac patients),
      • Manwani R.
      • Mahmood S.
      • Sachchithanantham S.
      • et al.
      Carfilzomib is an effective upfront treatment in AL amyloidosis patients with peripheral and autonomic neuropathy.
      and daratumumab.
      • Deshpande S.
      • Gertz M.A.
      • Dispenzieri A.
      • Kumar S.S.
      • Parikh S.A.
      • Muchtar E.
      Daratumumab as successful initial therapy for AL amyloidosis with nerve involvement.
      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.
      • Sidana S.
      • Larson D.P.
      • Greipp P.T.
      • et al.
      IgM AL amyloidosis: delineating disease biology and outcomes with clinical, genomic and bone marrow morphological features.
      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.
      • Sidana S.
      • Larson D.P.
      • Greipp P.T.
      • et al.
      IgM AL amyloidosis: delineating disease biology and outcomes with clinical, genomic and bone marrow morphological features.
      • Sachchithanantham S.
      • Roussel M.
      • Palladini G.
      • et al.
      European collaborative study defining clinical profile outcomes and novel prognostic criteria in monoclonal immunoglobulin M-related light chain amyloidosis.
      • Sissoko M.
      • Sanchorawala V.
      • Seldin D.
      • et al.
      Clinical presentation and treatment responses in IgM-related AL amyloidosis.
      • Terrier B.
      • Jaccard A.
      • Harousseau J.L.
      • et al.
      The clinical spectrum of IgM-related amyloidosis: a French nationwide retrospective study of 72 patients.
      • Wechalekar A.D.
      • Lachmann H.J.
      • Goodman H.J.
      • Bradwell A.
      • Hawkins P.N.
      • Gillmore J.D.
      AL amyloidosis associated with IgM paraproteinemia: clinical profile and treatment outcome.
      However, IgM amyloidosis is characterized by lower response rate and poorer survival when adjusted to Mayo cardiac stage compared with non-IgM AL amyloidosis.
      • Sidana S.
      • Larson D.P.
      • Greipp P.T.
      • et al.
      IgM AL amyloidosis: delineating disease biology and outcomes with clinical, genomic and bone marrow morphological features.
      The response rate in the major studies was 32% to 82%, with a CR rate at 0% to 20%.
      • Sidana S.
      • Larson D.P.
      • Greipp P.T.
      • et al.
      IgM AL amyloidosis: delineating disease biology and outcomes with clinical, genomic and bone marrow morphological features.
      • Sachchithanantham S.
      • Roussel M.
      • Palladini G.
      • et al.
      European collaborative study defining clinical profile outcomes and novel prognostic criteria in monoclonal immunoglobulin M-related light chain amyloidosis.
      • Sissoko M.
      • Sanchorawala V.
      • Seldin D.
      • et al.
      Clinical presentation and treatment responses in IgM-related AL amyloidosis.
      • Terrier B.
      • Jaccard A.
      • Harousseau J.L.
      • et al.
      The clinical spectrum of IgM-related amyloidosis: a French nationwide retrospective study of 72 patients.
      • Wechalekar A.D.
      • Lachmann H.J.
      • Goodman H.J.
      • Bradwell A.
      • Hawkins P.N.
      • Gillmore J.D.
      AL amyloidosis associated with IgM paraproteinemia: clinical profile and treatment outcome.
      Response was higher with use of bortezomib, rituximab-based chemoimmunotherapy, and IMiDs compared with a single-agent alkylator.
      • Sachchithanantham S.
      • Roussel M.
      • Palladini G.
      • et al.
      European collaborative study defining clinical profile outcomes and novel prognostic criteria in monoclonal immunoglobulin M-related light chain amyloidosis.
      • Sissoko M.
      • Sanchorawala V.
      • Seldin D.
      • et al.
      Clinical presentation and treatment responses in IgM-related AL amyloidosis.
      • Terrier B.
      • Jaccard A.
      • Harousseau J.L.
      • et al.
      The clinical spectrum of IgM-related amyloidosis: a French nationwide retrospective study of 72 patients.
      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%).
      • Sidana S.
      • Larson D.P.
      • Greipp P.T.
      • et al.
      IgM AL amyloidosis: delineating disease biology and outcomes with clinical, genomic and bone marrow morphological features.
      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.
      • Palladini G.
      • Merlini G.
      When should treatment of AL amyloidosis start at relapse? Early, to prevent organ progression.
      ,
      • Sanchorawala V.
      Delay treatment of AL amyloidosis at relapse until symptomatic: devil is in the details.
      We assessed the timing of initiation of second-line therapy among 235 patients who initially were treated with ASCT.
      • Hwa Y.L.
      • Warsame R.
      • Gertz M.A.
      • et al.
      Delineation of the timing of second-line therapy post-autologous stem cell transplant in patients with AL amyloidosis.
      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.
      • Palladini G.
      • Milani P.
      • Foli A.
      • et al.
      Presentation and outcome with second-line treatment in AL amyloidosis previously sensitive to nontransplant therapies.
      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.
      • Hari P.
      • Lin H.M.
      • Asche C.V.
      • et al.
      Treatment patterns and health care resource utilization among patients with relapsed/refractory systemic light chain amyloidosis.
      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.
      • Sanchorawala V.
      • Sarosiek S.
      • Schulman A.
      • et al.
      Safety, tolerability, and response rates of daratumumab in relapsed AL amyloidosis: results of a phase 2 Study.
      Figure thumbnail gr4
      Figure 4Treatment algorithm for patients with relapsed or refractory AL amyloidosis. ASCT, autologous stem cell transplant; CyBorD, cyclophosphamide, bortezomib, dexamethasone; Len-Dex, lenalidomide, dexamethasone; Pom-Dex, pomalidomide, dexamethasone.
      Table 7Daratumumab in Relapsed/Refractory AL Amyloidosis
      CR, complete response; DD, daratumumab-dexamethasone; DVD, daratumumab-bortezomib-dexamethasone; HR, hematologic response; ITT, intention to treat; OR, organ response.
      No.DesignMedian time from diagnosisPrior lines, medianNo. of cycles, medianMedian time to best responseHR/CR (%), ITT
      Data were modified from original data, if needed, to reflect intention-to-treat analysis (patients who died before response assessment are considered nonresponders).
      OR (%), ITT
      Data were modified from original data, if needed, to reflect intention-to-treat analysis (patients who died before response assessment are considered nonresponders).
      Median follow-up (mo)Median survival
      Kimmich et al,
      • Kimmich C.R.
      • Terzer T.
      • Benner A.
      • et al.
      Daratumumab for systemic AL amyloidosis: prognostic factors and adverse outcome with nephrotic-range albuminuria.
      2020 (DD portion)
      106Retrospective29 months25 (14 infusions)Not provided64/8Cardiac 6 months: 22

      Renal 6 months: 24
      21.225.6 months
      Kimmich et al,
      • Kimmich C.R.
      • Terzer T.
      • Benner A.
      • et al.
      Daratumumab for systemic AL amyloidosis: prognostic factors and adverse outcome with nephrotic-range albuminuria.
      2020 (DVD portion)
      62Retrospective5 months15 (14 infusions)Not provided66/11Cardiac 6 months: 26

      Renal 6 months: 24
      16.7Not reached
      Chung et al,
      • Chung A.
      • Kaufman G.P.
      • Sidana S.
      • et al.
      Organ responses with daratumumab therapy in previously treated AL amyloidosis.
      2020
      72Retrospective21 months2Not providedNot provided77/40 (72% evaluable)Cardiac 55 (54% evaluable)

      Renal 52 (53% evaluable)
      27Not reached; 2-year 86.7%
      Abeykoon et al,
      • Abeykoon J.P.
      • Zanwar S.
      • Dispenzieri A.
      • et al.
      Daratumumab-based therapy in patients with heavily-pretreated AL amyloidosis.
      2019
      44Retrospective4 years385.7 months83/80/17Cardiac 61

      Renal 50

      Liver 7
      10.2Not reached
      Roussel et al,
      • Roussel M.
      • Merlini G.
      • Chevret S.
      • et al.
      A prospective phase 2 of daratumumab in previously treated systemic light chain amyloidosis (AL) patients.
      2020
      40Prospective23 months36Not provided55/7.5Renal 31

      Cardiac 25
      26.4Not reached; 2-year 74%
      Sanchorawala et al,
      • Sanchorawala V.
      • Sarosiek S.
      • Schulman A.
      • et al.
      Safety, tolerability, and response rates of daratumumab in relapsed AL amyloidosis: results of a phase 2 Study.
      2020
      22Prospective48 months2103 months90/41Renal 67

      Cardiac 50
      20 for survivors28 months
      Van de Wyngaert et al,
      • Van de Wyngaert Z.
      • Carpentier B.
      • Pascal L.
      • et al.
      Daratumumab is effective in the relapsed or refractory systemic light-chain amyloidosis but associated with high infection burden in a frail real-life population.
      2020
      15Retrospective21 months2123 months80/40Renal 33

      Cardiac 33
      7.9Not provided
      Schwotzer et al,
      • Schwotzer R.
      • Manz M.G.
      • Pederiva S.
      • et al.
      Daratumumab for relapsed or refractory AL amyloidosis with high plasma cell burden.
      2019
      10Retrospective11.9 months380% 9 cycles2 months90/20Cardiac 50

      Renal 0
      10Not provided
      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.
      • Roussel M.
      • Merlini G.
      • Chevret S.
      • et al.
      A prospective phase 2 of daratumumab in previously treated systemic light chain amyloidosis (AL) patients.
      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.
      • Kimmich C.R.
      • Terzer T.
      • Benner A.
      • et al.
      Daratumumab for systemic AL amyloidosis: prognostic factors and adverse outcome with nephrotic-range albuminuria.
      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.
      • Dispenzieri A.
      • Buadi F.
      • Kumar S.K.
      • et al.
      Treatment of immunoglobulin light chain amyloidosis: Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus statement.
      In studies with exclusively or predominantly relapse/refractory patients, the HR was 70% to 80%, and the CR rate was 15% to 40%.
      • Reece D.E.
      • Hegenbart U.
      • Sanchorawala V.
      • et al.
      Efficacy and safety of once-weekly and twice-weekly bortezomib in patients with relapsed systemic AL amyloidosis: results of a phase 1/2 study.
      ,
      • Kastritis E.
      • Wechalekar A.D.
      • Dimopoulos M.A.
      • et al.
      Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis.
      ,
      • Wechalekar A.D.
      • Lachmann H.J.
      • Offer M.
      • Hawkins P.N.
      • Gillmore J.D.
      Efficacy of bortezomib in systemic AL amyloidosis with relapsed/refractory clonal disease.
      Ixazomib was also assessed in relapse/refractory AL amyloidosis. In a phase 1/2 study, 27 patients were treated with ixazomib.
      • Sanchorawala V.
      • Palladini G.
      • Kukreti V.
      • et al.
      A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis [erratum appears in Blood. 2020;135(13):1071].
      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).
      • Dispenzieri A.
      • Kastritis E.
      • Wechalekar A.D.
      • et al.
      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.
      • Dispenzieri A.
      • Lacy M.Q.
      • Zeldenrust S.R.
      • et al.
      The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis.
      • Palladini G.
      • Russo P.
      • Foli A.
      • et al.
      Salvage therapy with lenalidomide and dexamethasone in patients with advanced AL amyloidosis refractory to melphalan, bortezomib, and thalidomide.
      • Sanchorawala V.
      • Wright D.G.
      • Rosenzweig M.
      • et al.
      Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial.
      On ITT, HR was 38% to 47%, and CR was 0% to 21%. The ORs were infrequent, as high as 21%.
      • Dispenzieri A.
      • Lacy M.Q.
      • Zeldenrust S.R.
      • et al.
      The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis.
      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.
      • Dinner S.
      • Witteles W.
      • Afghahi A.
      • et al.
      Lenalidomide, melphalan and dexamethasone in a population of patients with immunoglobulin light chain amyloidosis with high rates of advanced cardiac involvement.
      • Kastritis E.
      • Terpos E.
      • Roussou M.
      • et al.
      A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis.
      • Kumar S.K.
      • Hayman S.R.
      • Buadi F.K.
      • et al.
      Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial.
      • Moreau P.
      • Jaccard A.
      • Benboubker L.
      • et al.
      Lenalidomide in combination with melphalan and dexamethasone in patients with newly diagnosed AL amyloidosis: a multicenter phase 1/2 dose-escalation study.
      • Palladini G.
      • Russo P.
      • Milani P.
      • et al.
      A phase II trial of cyclophosphamide, lenalidomide and dexamethasone in previously treated patients with AL amyloidosis.
      • Sanchorawala V.
      • Patel J.M.
      • Sloan J.M.
      • Shelton A.C.
      • Zeldis J.B.
      • Seldin D.C.
      Melphalan, lenalidomide and dexamethasone for the treatment of immunoglobulin light chain amyloidosis: results of a phase II trial.
      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%.
      • Dispenzieri A.
      • Buadi F.
      • Laumann K.
      • et al.
      Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis.
      • Palladini G.
      • Milani P.
      • Foli A.
      • et al.
      A phase 2 trial of pomalidomide and dexamethasone rescue treatment in patients with AL amyloidosis.
      • Sanchorawala V.
      • Shelton A.C.
      • Lo S.
      • Varga C.
      • Sloan J.M.
      • Seldin D.C.
      Pomalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 1 and 2 trial.
      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.
      • Cohen A.D.
      • Landau H.
      • Scott E.C.
      • et al.
      Safety and efficacy of carfilzomib (CFZ) in previously-treated systemic light-chain (AL) amyloidosis.
      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.
      • Sidiqi M.H.
      • Al Saleh A.S.
      • Leung N.
      • et al.
      Venetoclax for the treatment of translocation (11;14) AL amyloidosis.
      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,
      • Quillen K.
      • Seldin D.C.
      • Finn K.T.
      • Sanchorawala V.
      A second course of high-dose melphalan and auto-SCT for the treatment of relapsed AL amyloidosis.
      elotuzumab in combination with an IMiD,
      • Iqbal S.M.
      • Stecklein K.
      • Sarow J.
      • Krabak M.
      • Hillengass J.
      • McCarthy P.
      Elotuzumab in combination with lenalidomide and dexamethasone for treatment-resistant immunoglobulin light chain amyloidosis with multiple myeloma.
      and bendamustine.
      • Lentzsch S.
      • Lagos G.G.
      • Comenzo R.L.
      • et al.
      Bendamustine with dexamethasone in relapsed/refractory systemic light-chain amyloidosis: results of a phase II study.

      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.
      • Berk J.L.
      • Keane J.
      • Seldin D.C.
      • et al.
      Persistent pleural effusions in primary systemic amyloidosis: etiology and prognosis.
      Patients with cardiac amyloidosis are at risk for intracardiac thrombi
      • Dubrey S.
      • Pollak A.
      • Skinner M.
      • Falk R.H.
      Atrial thrombi occurring during sinus rhythm in cardiac amyloidosis: evidence for atrial electromechanical dissociation.
      ,
      • Feng D.
      • Syed I.S.
      • Martinez M.
      • et al.
      Intracardiac thrombosis and anticoagulation therapy in cardiac amyloidosis.