Table of contents :

• immunoglobulin (protein AL) : light chain amyloid
• AH : heavy chain amyloid
• AL / primary amyloidosis / light chain amyloidosis / secondary and familial amyloidosis / myeloma or macroglobulinemia^ref (this is not secondary amyloid)
• AL : localized bladder and bronchus

• "atypical myeloma" urine light chain + and marrow < 10% plasma cells
• adult nondiabetic nephrotic syndrome (30%; AL amyloidosis accounts for 10% of cases). When adult patients are seen with nephrotic syndrome, amyloidosis, as well as nil disease, membranoproliferative glomerulonephritis, and membranous glomerulopathy must be considered in the differential diagnosis
• hepatomegaly (24%). Amyloid involving the liver occurs in approximately 16% of patients and is characterized by palpable hepatomegaly, elevation of the serum alkaline phosphatase, and no imaging abnormalities by CT or magnetic resonance imaging (MRI). Symptoms may be limited to early satiety and weight loss. The clinician’s responsibility is to obtain immunofixation of the serum and the urine in addition to the usual studies for hepatitis, primary biliary cirrhosis, and other infiltrative liver disorders.
• congestive heart failure (22%). 50% of patients presenting with amyloidosis have demonstrable nonischemic cardiomyopathy. The symptoms can range from easy fatigability to overt CHF. This diagnosis must be entertained in any patient with cardiac symptoms of fatigue without a history of ischemia such as exertional angina or a previously documented AMI. The electrocardiogram (EKG) may show a pseudo-infarction pattern, and patients may be incorrectly diagnosed as having a silent ischemic syndrome. The findings on echocardiography, which include thickening of the heart walls, can be misinterpreted as ventricular hypertrophy. Any patient with unexplained cardiac symptoms without valvular disease, coronary artery disease, or long-standing hypertension should be considered for possible amyloidosis. We have seen patients referred to cardiologists with overt heart failure undergo cardiac catheterization, be found to have normal coronary arteries, and then be dismissed from further evaluation with no follow-up.
• symptomatic sensorimotor peripheral neuropathy (17%). The neuropathy can be both axonal and demyelinating (chronic inflammatory demyelinating polyneuropathy). Symptoms occur primarily in the lower extremities, and sensory changes are greater than motor changes. There is often a 2-year delay between the onset of symptoms and the recognition of amyloid. Important clues include: half of the patients have associated carpal tunnel syndrome, and a number of them will have autonomic syndrome (12%). Autonomic failure manifests as alternating diarrhea and constipation, pseudo-obstruction with vomiting, orthostatic hypotension, and impotence. The neuropathy is frequently painful, requiring analgesics. Gabapentin and amytriptyline often fail to provide benefit. These patients may be recognized to have a monoclonal gammopathy but are often misdiagnosed as having monoclonal gammopathy of undetermined significance (MGUS)–associated neuropathy without proper diagnostic testing to exclude amyloid. Isolated amyloidosis presenting with lumbosacral radiculoplexopathy^ref
• amyloidoma : localized space-occupying lesions amyloid nodules
• bone^{ref1, ref2}
• Meckel's cave^ref
• vertebral axis
• spine^ref
• craniovertebral junction^ref
• C2^ref
• sacrum^ref
• soft tissue :
• salivary glands
• gluteus^ref
• lung^ref
• brain parenchyma^{ref1, ref2}
• skull base^{ref1, ref2}
• gasserian ganglion / trigeminal^{ref1, ref2, ref3, ref4, ref5}
• orbital^{ref1, ref2}
• soft tissues of the legs^ref
• mediastinum
• nasopharynx^ref
• larynx
• urinary bladder
• gastrointestinal tract
Pambuccian et al^ref described a 78-year-old man with a scapular amyloidoma, in whom disease progressed within several months to symptomatic generalized amyloidosis with IgM- monoclonality (light chain disease). Laeng et al^ref found IgH gene rearrangement in 2 of 7 cases of nervous system amyloidomas suggestive of an underlying B-cell neoplasia.
Therapy : treatment is conservative and is based on excision and local therapy, although local relapses are possible with airway compromise. Amyloid deposits along the respiratory tract are best treated using endoscopic laser resection with possible stent implantation. Diffusely distributed tracheobronchial amyloidosis, considered unsuitable for bronchoscopic intervention, can obtain long-lasting benefit from external-beam radiation therapy. Amyloid of the bladder and urethra has been reported to benefit from local instillation of DMSO. Cutaneous amyloidosis can also be treated with topical application of DMSO.
• amyloid purpura appears in a minority of patients with amyloidosis. The purpura typically occurs above the nipple line and is often seen in the webbing of the neck, the face, and the eyelids. Factor X deficiency, resulting from the binding of factor X to amyloid fibrils, is thought to be one cause of the bleeding diathesis that may occur in patients with amyloidosis^ref

• serum protein electrophoresis (sensitivity = 500-2000 mg/L) is inadequate for screening since 20% of patients with amyloidosis will not have an intact immunoglobulin protein in the serum or a level too low to demonstrate a spike on the electrophoretic pattern. Only approximately 25% of patients with AL have "measurable" disease as defined by a serum protein electrophoresis M-spike of 10 g/L^{ref1, ref2}. The pie chart gives the immunoglobulin heavy (A, G, D, M) and light chain seen at diagnosis (K = kappa, L = Lambda, 0 = none) :


• serum and 24-hour urine immunofixation (sensitivity = 150-500 mg/L) : nearly 90% will have a detectable monoclonal light chain, a higher sensitivity than amyloid stains performed on routine biopsy specimens such as fat (73%) or the bone marrow (72%). Light chains in the urine are obscured by the albuminuria. Urine M proteins in amyloidosis (g/24 hr) :


• immunoglobulin-free light chain (FLC) nephelometric assay (Freelite^®; The Binding Site Limited, Birmingham, UK; sensitivity < 0.5 mg/L)^{ref1, ref2, ref3} will be abnormal in 75% of the remaining patients in support of a tentative diagnosis of amyloidosis. > 50% of patients with AL have "measurable disease" (ie, an FLC of > 100 mg/L)^{ref1, ref2, ref3, ref4}. These antisera recognize epitopes of FLCs but do not detect light chains associated with an intact immunoglobulin molecule. Patients who had negative serum immunofixation showed an abnormal FLC ratio in 85% of k and 80% of l patients. When there was no monoclonal protein in the serum or in the urine by immunofixation, the FLC technique detected a k protein in 86% of k amyloid and a l in 30% of l amyloid. The detection of FLCs by the nephelometric system is particularly important in those patients who do not have light chains by immunofixation. We routinely measure the light chain in the serum of all patients, both to confirm its immunoglobulin light chain origin as well as to monitor therapy. Nearly 10% of patients who were thought to have immunoglobulin light chain amyloid had amyloid due to other types, including 5% with fibrinogen amyloid and 4% with transthyretin mutations^ref. Inherited amyloidosis should be considered in all patients before therapy is initiated. The typing of the amyloid deposit is important because the different forms are clinically indistinguishable from each other. Renal amyloid due to long standing infection (AA) presents to the clinician identically to primary renal amyloid. Amyloid neuropathy due to a mutation of TTR presents with all the same clinical features of neuropathy seen in primary systemic amyloidosis. The tissues all appear the same by light and electron microscopy^{ref1, ref2}.
• biopsy verification of the diagnosis is required : compared with Congo-red–based light microscopy, immunoelectron microscopy (IEM) of abdominal fat aspirates was equally sensitive (75% to 80%) but significantly more specific (100% vs 80%; P < .001)^ref
  
• invasive biopsies : all patients with amyloid nephrotic syndrome, amyloid cardiomyopathy, amyloid liver disease, or amyloid neuropathy can be confirmed with biopsy of the kidney, heart, liver, or sural nerve. Biopsies of the kidney and liver carry a risk of bleeding and often necessitate overnight hospitalization for the patient. Case reports exist of severe bleeding following liver biopsy and, rarely, hepatic rupture. These small risks can be avoided if the clinician is aware that amyloid is a likely diagnosis
• noninvasive biopsies : techniques exist that are easier and less expensive and that result in minimal risk to the patient.
• bone marrow trephine biopsy : Congo red staining of a will demonstrate amyloid in at least 60% of patients^ref. A marrow biopsy is required since amyloid deposits are rarely seen in the marrow aspirate
• subcutaneous fat aspirate demonstrates amyloid deposits in 70–80% of patients. Because of the very low prevalence of amyloid, use of the fat aspirate as a screening tool in patients presenting with peripheral neuropathy in the absence of a monoclonal protein disorder has an extremely low yield^ref.
• fat⁺ marrow⁺ 62%
• fat⁺ marrow– 11%
• fat^– marrow⁺ 15%
• fat^– marrow^– 13%
• minor salivary gland biopsies and gingival biopsies^ref
• rectal biopsy still remains a sensitive diagnostic technique
• immunohistochemical staining of the biopsied amyloid deposits with k and l antisera to re-affirm the diagnosis is appropriate^ref.
• mass spectroscopic screening of small samples to determine the subunit protein of amyloid. It should also be kept in mind that nearly 3% of adults have MGUS. In patients who have intact immunoglobulin proteins in the serum with no detectable free light chain (FLC), the possibility of an incidental MGUS with a non-immunoglobulin form of amyloid must be kept in mind :
• inherited forms of renal amyloidosis due to a mutant fibrinogen Aa chain have been described. This presentation is easily confused with nephrotic syndrome associated with light chain amyloid. Immunostains of available tissue for deposits of fibrinogen or transthyretin, which cause inherited amyloidosis, are important to reliably exclude a non-immunoglobulin form of amyloid.
• amyloid cardiomyopathy occurs with high frequency in men over the age of 80, so-called senile cardiac (systemic) amyloid.
• there is an inherited form of amyloid specific to African-Americans. A mutation of transthyretin is carried by 3.9% of African-Americans, which would translate to 1.3 million adults in the USA. African-American men over the age of 70 with cardiac amyloidosis should be screened for mutant transthyretin (Ile 122). Immunohistochemical characterization of amyloid deposits is helpful in confirming the subunit protein comprising the amyloid^ref
• all amyloid deposits contain P (pentagonal) component. P component is a glycoprotein comprising 20% of the amyloid fibril by weight. If the k and l results are negative, testing for transthyretin, fibrinogen, and occasionally lysozyme and apoA is warranted^ref

Prognosis : the median survival is approximately 2 years and is < 6 months when there is significant cardiac disease. 10-yr OS = 22%;

• 24-hour urine protein is an easily assessed end point
• the most common cause of death in amyloid is cardiac, either due to progressive congestive cardiomyopathy or sudden death due to ventricular fibrillation or asystole. Clinical outcome in patients and their likelihood of responding to treatment is, in large part, determined by the extent of cardiac involvement at diagnosis^ref.
• clinical presence of congestive heart failure with a median survival of 3 months
• echocardiography with Doppler studies of diastolic function was critical in the assessment of patients newly diagnosed with AL. The recent introduction of strain echocardiography has added significant sensitivity in the assessment of cardiac function in AL^ref. Echocardiography is routinely done in all newly diagnosed patients and every 6 months during therapy. The presence of heart failure is associated with a median survival of only 6 months and is the most important clinical predictor of survival. Echocardiography allows measurement of both the EF and the IVS thickness, both of which are important in predicting outcomes in patients with amyloid. Doppler echocardiography is used to measure diastolic performance and relaxation of the ventricle during diastole. If the deceleration time is 150 ms or less by Doppler, the 1-year survival is 49%. New measures of myocardial injury that are more reproducible than the echo have recently been introduced. In the 1970s, clinical assessment was supplanted by the use of 2-dimensional echocardiography. Echocardiography is limited, however, in that reproducibility is often operator-dependent, and measurement of the thickness of the left ventricular wall can vary by 2 to 3 mm without reflecting a real change in the extent of amyloid deposition
• measurement of serum troponin T, a sensitive marker for ischemic cardiac injury^ref, has been shown to be a powerful predictor of survival in amyloidosis patients, both those treated conventionally^ref as well as those who become candidates for stem cell transplantation^ref. Serum troponin levels < 0.03, 0.03-0.1, and > 0.1 have permitted classification of AL patients into 3 groups of approximately equal size with differing survivals. One could question whether the association between cardiac troponin T and FLC is due to impaired renal clearance since both cardiac troponin T and FLC are affected by renal clearance^{ref1, ref2}, but renal function was not prognostic in PBSCT patients, nor was it significantly different between groups^ref.
• N terminal fragment of pro-brain natriuretic peptide (NT-Pro BNP) is produced when the atria are dilated^ref. Elevation of the NT-Pro BNP has been shown to be predictive of survival following a diagnosis of amyloid. Combining the troponin with the NT-Pro BNP level has resulted in a new staging system. These 2 tests should be measured in all newly diagnosed patients with amyloidosis. It has been demonstrated that the NT-proBNP is a sensitive marker for cardiac amyloidosis^ref. These cardiac biomarkers can now be used to predict outcomes in cardiac AL^ref. The serialized measurement of NT-proBNP parallels the extent of cardiac response following chemotherapy^ref. Moreover, these responses correlated with free light chain reduction, predictive of organ response. The correlation with traditional echocardiography was poor.
The ability to accurately assess cardiac improvement raises important future questions. How much free light chain reduction is really required for an organ response in amyloidosis? Does a 50% reduction in free light chain levels predict a superior outcome as it does in MM, or does the light chain have to be completely eradicated in order to prevent further amyloid deposition in tissues? Since cardiac function can improve without a reduction in the wall thickness by echo, is the myocardial dysfunction in amyloidosis not directly related to fibril deposition but soluble intermediates that are rapidly cleared following successful chemotherapy?
• serum level of ß₂-microglobulin : although a weaker prognostic indicator, levels > 2.7 µg/mL predict shorter survival

• complete response (CR) :
• serum and urine negative for a monoclonal protein by immunofixation
• free light chain ratio normal. Anyway absolute levels of immunoglobulin FLC appear to be more relevant than the FLC ratio in PBSCT recipients. Attainment of a low absolute level of involved immunoglobulin FLC—rather than a percentage reduction—is the best immunoglobulin FLC predictor for hematologic response, organ response, and overall survival after PBSCT. The pretransplantation immunoglobulin FLC has prognostic value for overall long-term survival and appears to be associated with more advanced disease^ref
• marrow contains < 5% plasma cells
• partial response (PR) :
• if serum M component > 0.5 g/dL, a 50% reduction
• if light chain in the urine with a visible peak and > 100 mg/day and 50% reduction
• if free light chain > 10 mg/dL (given the assay imprecision, it is recommended that serum free light chain (FLC) values below 10 mg/dL, are not considered criteria for evaluation of hematologic response. In addition, the / ratio in patients with renal failure may be reduced by retention of healthy polyclonal free light chains. Caution should also be used in interpreting data between laboratories and if antisera batches vary over time) and 50% reduction
• progression :
• from CR, any detectable monoclonal protein or abnormal free light chain ratio (light chain must double)
• from PR or stable response, 50% increase in serum M protein to > 0.5 g/dL or 50% increase in urine
• M protein to > 200 mg/day; a visible peak must be present
• free light chain increase of 50% to > 10 mg/dL
• stable : no CR, no PR, no progression

• serum protein electrophoresis : unlike those with multiple myeloma, AL patients frequently do not have a quantifiable immunoglobulin protein in the serum
• serial measurement of the urine M protein can be fraught with difficulty, particularly in those patients who have albuminuria from renal amyloidosis
• nephelometric assay for immunoglobulin FLCs is an adjunct to assess response to therapy. Organ response parallels changes in the serum FLC assay. A 50% reduction indicates a hematologic response and a normalization of the level to reflect a complete hematologic response. This technique has been incorporated into evaluation of response at most amyloidosis treatment centers^ref. There is one report from the UK in which the authors evaluated the role of changes of serum FLC, predominantly in a nonhematopoietic transplantation setting. These authors found that the 5-year OS was more than doubled in patients achieving a 50% decline in serum FLC regardless of the therapeutic strategy^ref. Sanchorawala et al recently demonstrated that FLC improvement correlated with complete hematologic response and were more readily detected early after treatment than were changes in immunofixation and bone marrow studies^ref. FLC testing would make more patients evaluable for hematologic response and would also be more predictive for outcome than immunofixation and bone marrow studies due to the inherent subjectivity in interpreting the former and the sampling variability in the latter. In patients with AL who underwern high-dose chemotherapy with peripheral blood stem cell transplantation (PBSCT), there was a significantly higher risk of death in patients with higher baseline FLC (hazard ratio 2.6, P < .04). Baseline FLC correlated with serum cardiac troponin levels, and higher FLC levels were associated with more organs involved by amyloid, suggesting that high FLC levels may be associated with more advanced disease. The percent FLC reduction did not predict for survival, but the absolute level of FLC achieved after therapy did. Normalization of FLC level after PBSCT predicted for both organ response and complete hematologic response. Achievement of FLC response was a better predictor of survival than achievement of complete hematologic response or normalization of the FLC ratio^ref
• radiolabeled SAP is a specific tracer for amyloid and can monitor amyloid load serially, but its availability outside the UK is limited.

• newly diagnosed patients with AL amyloidosis eligible for HDM/SCT did not benefit from initial treatment with oral melphalan and prednisone, and there was a survival disadvantage for patients with cardiac involvement if HDM/SCT was delayed by initial oral chemotherapy^ref
• high-dose melphalan (HDM) followed by autologous peripheral blood stem cell transplantation (PBSCT) is presently considered the most effective treatment for AL amyloidosis. Despite previous anecdotal reports, the paper by Comenzo and collaborators of the Boston University Amyloid Treatment and Research Program in 1996 ignited interest and introduced this procedure in the care of AL patients. The initial enthusiasm was soon tempered by the severe treatment-related mortality (TRM) caused by the toxic effects of the high-dose chemotherapy (melphalan) on organs severely compromised by amyloid disease. However, transplant-related mortality is high, ranging between 13% (in referral centers)^{ref1, ref2} and 43% (in a French retrospective multicenter study)^ref. The survival benefit of high-dose melphalan has been attributed to a patient-selection bias^ref, but a case–control study suggested a survival advantage for high-dose melphalan plus hematopoietic stem-cell rescue as compared with conventional treatment^ref. The number of organs involved at the time of transplantation was prognostic, as confirmed in several subsequent studies. These findings strongly indicated the need for a risk-adapted approach with careful patient selection and attenuation of the dose of intravenous melphalan based on age and organ involvement. These aspects were thoroughly reviewed in 2002 by Comenzo and Gertz who analyzed the outcome of the single-center and multicenter trials^ref. The Boston Group^ref and the Mayo Clinic group^ref have recently reviewed their experience with HSCT for patients with amyloidosis. Only 16-50% of AL patients are eligible for PBSCT. 2 proposed risk-adapted approaches for patient selection and dose adaptation for high-dose melphalan.
• good risk :
• any age, all criteria met (2)
• 1 or 2 organs involved
• no cardiac involvement
• creatinine clearance >= 51 ml/min
• melphalan dosing :
• 200 mg/m² if <= 60 y
• 140 mg/m² if 61-70 y
• 100 mg/m² if >= 71 y
• all of the following :
• age < 65 y
• LVEF > 0.45
• LVE
• lack of pleural effusions
• SBP >= 90 mmHg
• P_O2 > 95%, room air
• PST <= 2 unless due to neuropathy
• stem cell collection >= 2.5 x 10⁶ cells/kg
• melphalan dosing : 200 mg/m²
• intermediate risk
• age < 71; either criteria
• 1 or 2 organs involved (must include cardiac or renal with creatinine clearance < 51 ml/min)
• asymptomatic or compensated cardiac involvement
• melphalan dosing :
• 140 mg/m² if <= 60 y
• 100 mg/m² if 61-70 y
• all of the following :
• lack of pleural effusions
• SBP >= 90 mmHg
• P_O2 > 95%, room air
• PST <= 2 unless due to neuropathy
• and any of the following .
• age 65-80 y
• LVEF > 40%
• HSC collection >= 2.0 x 10⁶ cells/kg
• melphalan dosing : 140 mg/m²
• poor risk/negligible
• either criteria :
• 3 organs involved
• advanced cardiac involvement
• therapy :
• melphalan and prednisone
• clinical trials
• any of the following :
• age > 80 y
• uncompensated congestive heart failure
• LVEF < 40%
• persistent pleural effusions
• SBP < 90 mmHg
• P_O2 < 95%, room air
• PST > 3
These criteria do not include poweful prognostic cardiac markers, troponins and the amino-terminal of the natriuretic peptide type B (NT-proBNP), which are useful in stratifying the risk in patients undergoing PBSCT. It is expected that these markers will soon be integrated in the selection criteria.
• blood stem cell mobilization and collection: previous exposure to alkylating agents impairs hematopoietic stem cell collection. A total dose of melphalan exceeding 200 mg significantly reduces the ability to mobilize CD34⁺ cells. Contrary to the common experience in MM, deaths have been reported during mobilization and leukapheresis of AL patients with cardiac or multiorgan involvement^ref. Overall, the major complication rate is approximately 15% in AL patients. To minimize the risk of toxicity it is recommended that only G-CSF be used for mobilization since its use in combination with cyclophosphamide is associated with increased cardiac morbidity, a significantly higher number of aphereses required for CD34 harvesting, greater need of hospitalization, and increased toxicity^ref. The recommended G-CSF dose is 6 µg/kg every 12 hours for 5 days^ref, but 16 µg/kg given in a single dose or in 2 divided doses for 3 days has also been reported^ref. The recommended optimal dose of CD34⁺ cells in AL patients is > 5 x 10⁶ CD34⁺ cells/kg^ref. Contamination of the apheretic product with clonotypic immunoglobulin-positive plasma cells has been demonstrated, but CD34 selection is not presently recommended.
• conditioning: in most of the cases with AL, the clone size is modest: the median percentage in bone marrow is 5–7%; therefore, debulking with VAD (vincristine, doxorubicin, dexamethasone [Dex]) or other regimens, as done in multiple myeloma, seems unnecessary. Possible benefits from VAD treatment before PBSCT have been claimed. Evidence from a randomized clinical trial indicates that the delay associated with pretransplant cytoreduction, using oral melphalan and prednisone (MP), is likely to allow disease progression^ref. Conditioning is nowadays performed with intravenous melphalan using a risk-adapted dose modification. Total body irradiation (TBI) (550 cGy) followed by PBSCT was investigated in a small feasibility study: TRM was 15% in patients with poor- or intermediate-risk disease^ref. However, TBI is considered to produce significant cardiac toxicity. Tandem intermediate-dose (140 mg/m²) melphalan is feasible in selected AL patients in whom a prior uneventful transplantation produced a partial hematologic response that did not translate into organ response. This strategy has been successfully used in 2 patients who achieved a partial response at 3 months after the first transplant; both patients attained complete remission.
• transplant-related complications : PBSCT is associated with substantial morbidity and TRM (100 days after day 0) that are related to the dose of intravenous melphalan and the number of organs involved. The cause of death varies according to the eligibility criteria adopted by each center. Of the 277 patients who completed treatment in the Boston trials, 36 (13%) died within 100 days: 15 (42%) from cardiac-related causes (9 from sudden death or arrhythmia and 6 from heart failure), a further 9 (25%) from sepsis, and the remaining from various causes^ref. Of the 9 patients who died within day 100 at the Mayo Clinic, 4 died of gastrointestinal tract bleeding with multiorgan failure, and the other 5 died of cardiac arrhythmia, pulmonary embolism, disseminated aspergillosis, pneumonia and aspiration pneumonia^ref. Fatal cardiac arrhythmias and severe respiratory depression immediately after infusion of hematopoietic stem cells have been reported, suggesting dimethyl sulfoxide (DMSO) carries a much greater risk in the presence of amyloid cardiomyopathy. In addition, gastrointestinal bleeding is frequently seen in patients with AL, particularly in those with multiorgan involvement or on hemodialysis. Morbidity is also very high. Grade > 2 toxicities (National Cancer Institute Common Toxicity Criteria [NCI-CTC]) reported in a group of 152 patients were nausea and vomiting (46%), diarrhea (46%), mucositis (46%), peripheral edema (19%), renal toxicity (18%), sepsis (16%), hepatic toxicity (14%), pulmonary edema (13%), gastrointestinal bleeding (7%), and non-gastrointestinal bleeding (7%).5 Acute renal failure is a frequent (up to 21%) but often, in approximately 50%, reversible complication. Factors predicting transplant-associated acute renal failure included creatinine clearance, proteinuria, cardiac amyloidosis, melphalan dose and sepsis. Opportunistic infections secondary to T cell depression can be seen at 3 months post-transplantation. The risk-adapted approach has contributed to reducing the TRM from the early 30–40% to the current 13–14%. As these criteria are further refined by experience, and as new prognostic markers became available and supportive therapy improves, it is expected that TRM will decrease further. Indeed, the TRM observed at the Mayo Clinic in 2003 was as low as 6%.
• hematologic and clinical response^ref : the clonal (complete or partial) response rate is between 50% and 60% with a complete remission obtained in about one-third of the patients. Complete hematologic (clonal) response is positively associated with the dose of melphalan^ref. Clinical response rates vary from 34% to 55%, strongly depending on the time passed since the transplantation: renal response may require > 1 year. Clinical response was seen in about 70% of those who had a hematologic response. Among 73 patients who achieved a complete hematologic response, organ responses were renal (29/46, 63%), gastrointestinal and liver (26/46, 57%), neuropathy (17/36, 47%), soft tissue (1/9, 11%), and most notably, more than one fourth (6/22, 27%) of patients with cardiac involvement showed improvement^ref. A complete hematologic response is associated with long-term survival and amelioration of organ dysfunction, which translates into improved quality of life^ref. This unsurpassed outcome might be biased by the patient selection. However, a case-matched control study comparing overall survival of 63 AL patients undergoing PBSCT with 63 patients not undergoing transplantation (52 received alkylating-based oral chemotherapy) showed a significantly prolonged survival in PBSCT patients^ref. The outcome of the ongoing randomized French trial comparing PBSCT versus oral melphalan and Dex will illuminate this very important point. > 80 of the 100 planned patients have been enrolled as of April 30, 2004.
Outcome of high (200 mg/m²)/modified (100–140 mg/m²) dose melphalan followed by peripheral blood stem cell transplantation (PBSCT) (studies reporting 20 or more patients published in year 2000 or later are listed) :

patients treated	HDM 200 mg/m2	TRM within 100 days from melphalan administration	clonal  response  (partial +  complete)	complete  response	organ  response	organ resp./  clonal resp.	center,  year, reference
66	38	9/66 (14%)	33/66 (50%)	NR	32/66 (48%)	23/33 (70%)	single center, 2002ref
22	14	3/22 (14%)	13/22 (59%)	8/22 (36%)	10/22 (45%)	10/13 (77%)	2-centers, 2004 (study performed at the Pavia Amyloidosis Centre and at the National Cancer Institute, Milan, data unpublished)
20	9	7/20 (35%) (after new selection criteria and prophylactic measures were introduced in January 1999, TRM decreased from 50% (5/10) to 20% (2/10))	56%	28%	organ response was listed according to organs and not to patients (renal 46%, cardiac 25%, liver 50%, neurologic 0%)	NR	single center, 2004ref
277 (includes consecutive patients from 6 separate trials over 8 years, please note that 122 patients received an intermediate dose of melphalan (100–140 mg/m2))	155	36/277 (13%)	NR	73/238 (31%) (hematologic response was evaluated at 1 year: in 39 patients 1 year had not passed since treatment)	80/238 (34%)	48/73 (66%)	single center, 2004ref

Of 171 AL patients, the OR rates were 75% in the high-dose group and 53% in the intermediate-dose group although TRM was the same in both groups (approximately 15%). Reducing the melphalan dose appeared to render more AL patients eligible for HSCT but sacrificed an element of response^ref.
• maintenance therapy : at present there are no data on the utility of maintenance therapy with corticosteroids or interferon after PBSCT.
• allogeneic bone marrow HSCT : allogeneic and syngeneic BMT have been performed in sporadic cases with reported hematologic complete remission and improved proteinuria. However, selection criteria currently applied for candidates for allogeneic transplants and the toxicity of GvHD severely limit their applicability. Non-myeloablative allografting is still experimental in multiple myeloma and no data are available in AL. Although single-arm studies have suggested high response rates^ref, a recent phase 3 study was unable to demonstrate a survival benefit for patients undergoing transplantation (Jaccard A, Moreau P, Leblond V, et al. Autologous stem cell transplantation (ASCT) versus oral melphalan and high-dose dexamethasone in patients with AL (primary)amyloidosis: results of the French Multicentric Randomized Trial (MAGandIFM Intergroup). Blood.2005;106: 127a. Abstract 421). The NT-proBNP will allow risk assessment in future trials to ensure that arms are balanced for cardiac involvement.
• colchicine has no role in the treatment of AL^{ref1, ref2}
• conventional melphalan and prednisone (MP) : in the mid-1990s, two randomized trials showed that standard-dose chemotherapy with melphalan and prednisone could prolong survival in patients with AL amyloidosis^{ref1, ref2}, but clinical responses were rare and overall survival was extended by only a few months. Controlled studies indicate that patients given MP therapy benefited, compared to those treated with placebo or colchicine, showing that colchicine has no role in the treatment of AL. In the latest of these studies, a response assessed by organ function and monoclonal protein concentration was observed in 28% of patients treated with MP, and in 30% of them it was obtained after > 1 year^ref. Patients who responded to MP survived longer than non-responders (50 months vs 36 months, P = 0.03). The retrospective review of the Mayo Clinic experience of melphalan-based therapy of AL showed that responses were never seen in patients whose serum creatinine was > 3 mg/dL or whose alkaline phosphatase concentration was more than four times the upper reference limit. Patients with amyloid cardiomyopathy can respond to MP and achieve long survival, while patients with neuropathy rarely benefit from this regimen. The median time to attain a response with melphalan was approximately 1 year, and among responders, 78% survived 5 years. Furthermore, all the 30 patients who survived for 10 years received melphalan-based therapy. At the Pavia Amyloidosis Centre we have used MP to treat 207 consecutive patients with advanced disease unable to bear more-toxic regimens. According to the criteria outlined above, a response was observed in 40% of patients and translated into a significant survival advantage: median survival 18 months for non-responding versus 72 months in responding patients (P < 0.001). Ten percent of patients with heart involvement had a clinical improvement. The median time to achieve a response was 7 months. Although MP is the best-tolerated regimen, this slow response is an important disadvantage since many patients, especially those with rapidly progressive disease, may die due to inexorable amyloid deposition before they have had the chance to respond. The patients who are unable to tolerate prednisone due to advanced cardiac involvement may benefit from low-dose continuous oral melphalan. However, this regimen is not innocuous, since melphalan-based therapies carry the potential (actuarial risk 21%) for the development of late myelodysplasia or acute leukemia. At the UK National Amyloidosis Centre 33 AL patients were treated with intravenous melphalan 25 mg/m² on day 1 associated with Dex 20 mg po daily on days 1–4 every 28 days, as first-line therapy. These patients were selected on the basis of not being fit enough to receive VAD, either due to age, poor performance status, severe amyloid cardiomyopathy or neuropathy. Clonal response, complete or partial, was observed in 46% of patients, with a TRM of 18%. Survival data are not available since the median follow-up was only 8 months^ref. This high TRM may reflect the poor-risk patient population treated and/or an excessive dose of melphalan. The addition of multiple alkylating agents to MP is not indicated according to the data from a prospective randomized trial^ref.
• high-dose dexamethasone-based regimens : a rapid response to therapy is essential in AL amyloidosis. In multiple myeloma VAD may induce a quick clonal response in patients with previously untreated or refractory disease. However, this regimen presents potential problems in AL patients: vincristine can severely exacerbate autonomic or peripheral neuropathy; due to its potential cardiac toxicity doxorubicin cannot be used in patients with overt heart failure; and the intensive high-dose Dex can cause severe fluid retention in patients with renal and cardiac amyloidosis or trigger severe, often fatal, ventricular arrhythmias. There are anecdotal reports of beneficial effects, especially in patients with nephrotic syndrome, although the regimen has not been assessed in a randomized controlled trial. At the UK National Amyloidosis Centre, 98 AL patients selected without symptomatic heart failure, autonomic neuropathy or severe peripheral neuropathy were treated with a median of 4 cycles of standard VAD or CVAMP (cyclophosphamide, vincristine, adriamycin, methyl-prednisolone) as first-line therapy. A clonal response was observed in 53 patients, as defined by a fall in the amyloidogenic class of serum FLC concentration by more than 50%, with improvement of the involved organ in half of patients. TRM was 7%, which is significant considering that these patients were selected for the lack of 2 important prognostic factors: symptomatic heart involvement and autonomic neuropathy. In 11 of the 53 responding patients (21%) there was subsequent clonal progression after a median time of 20 months (range 7–54)^ref. Results obtained in the treatment of multiple myeloma indicated that Dex accounted for most (80%) of the plasma cell reduction achieved with VAD and avoided the potential toxicity of vincristine and adriamycin. Pulsed high-dose Dex, as used in the VAD regimen, has been reported to benefit AL patients with varying response rates. The recently concluded Southwest Oncology Group (SWOG) trial (S9628) comprised 87 eligible and analyzable patients. Treatment consisted of pulse Dex as in the VAD regimen for 3 cycles followed by maintenance Dex (40 mg x 4 days/mo) and IFN-a (5 million units thrice weekly)^ref. The most common dose limiting toxicity (> grade 2) was increased edema/fluid overload in 12%, requiring dose reduction. Hematologic response was achieved in 53% patients with, notably, 24% complete response. This translated into 45% responses in any organ: renal 39%, soft tissue 25%, gastrointestinal 18%, hepatic 13%, cardiac 12%, and neurological 3%. The median progression-free survival was 27 months and overall survival 31 months. The toxicity of Dex used with the same schedule of the VAD regimen in AL patients is substantial (TRM 7%). A Dex-modified, milder, less toxic schedule (40 mg x 4 days every 21 days) induced organ response in 35% of patients in a median time of 4 months, without significant toxicity^ref. Most of the responses were observed in patients with kidney involvement and rarely in patients with heart involvement.
• standard-dose melphalan + high-dose dexamethasone (MDex) (monthly courses of oral melphalan (10 mg/m² of body-surface area on days 1 to 4) plus high-dose oral dexamethasone (40 mg per day on days 1 to 4) for up to 18 treatment courses if no severe adverse effects occurred). The dose of melphalan was adjusted during the first three courses in order to induce mild cytopenia (white-cell count, <3000 per cubic millimeter) at midcourse. Prophylaxis with proton-pump inhibitors and trimethoprim–sulfamethoxazole (one double-strength tablet thrice weekly) was recommended. In 46 poor-risk patients who were ineligible for PBSCT (70% had severe, symptomatic heart involvement, and 52% had > 2 organs involved) produced hematologic response in 67% (in a median time of 4.5 months) with 33% complete remission and functional improvement of the target organs in 48%^ref. Subsequent hematologic progression was observed in 3 of the 31 responding patients (10%) after 15, 26 and 41 months; 2 of these patients regained complete remission after 2 more courses of MDex. All other responsive patients maintained the response after a median time of 24 months (range 12–48). 5 patients had severe adverse events, but none died. TRM was low (4%). The response rate observed in this poor risk series compares favorably with that achievable in unselected patients with MP and also with the results obtained with Dex plus interferon, with VAD or intermediate-dose melphalan/PBSCT. Despite advanced functional impairment, the hematologic response translated into improved function of the organs involved by the disease in almost half of the patients and resulted in a significant survival benefit. Most importantly, heart failure resolved in 6 of 32 cases (19%). These results indicate that this regimen may be a potential front-line therapy in selected patients. After a median follow-up of 3 years, the estimated median overall survival was 22.2 months in the group assigned to receive high-dose melphalan and 56.9 months in the group assigned to receive melphalan plus high-dose dexamethasone (P=0.04). Among patients with high-risk disease, overall survival was similar in the two groups. Among patients with low-risk disease, there was a nonsignificant difference between the two groups in overall survival at 3 years (58% in the group assigned to receive high-dose melphalan vs. 80% in the group assigned to receive melphalan plus high-dose dexamethasone; P=0.13). The outcome of treatment of AL amyloidosis with high-dose melphalan plus autologous stem-cell rescue was not superior to the outcome with standard-dose melphalan plus dexamethasone^ref
• thalidomide is poorly tolerated in AL amyloidosis, causing fatigue, progressive edema, cognitive difficulties, constipation, neuropathy, syncope due to bradycardia, and thromboembolic complications including some not frequently reported for other patient populations such as exacerbation of peripheral and pulmonary edema and worsening of renal function. Severe side effects impeded dose escalation above 200–300 mg/day and caused thalidomide withdrawal in 25%–50% of the patients^{ref1, ref2}. We used a combination of intermediate-dose Dex (Dex 20 mg on days 1–4, every 21 days) with thalidomide given continuously (100 mg daily, with 100 mg increments up to 400 mg) to treat 31 AL patients who did not respond to or relapsed after first-line therapy. Only 11 patients (35%) tolerated 400 mg/day and received thalidomide for a median of 5.7 months (range: 4–14 months). The remaining 20 patients (65%) did not reach the target dose and received thalidomide (median dose 200 mg/day, range: 100–300 mg/day) for a median of 3 months (range: 0.5–13 months). Hematologic and organ response were correlated with the dose of thalidomide, overall hematologic response was observed in 15 patients (48%), of whom 6 (19%) attained a complete response, and organ response in 8 patients (26%). Median time to response was 3.6 months (range: 2.5–8.0 months). Hematologic response to treatment resulted in a significant survival benefit (P = 0.01). Overall, 20 patients experienced severe (CTC grade  3) treatment-related toxicity: symptomatic bradycardia (8 patients; 26%), sedation/fatigue (4; 13%), constipation (2; 7%), acute dyspnea (2; 7%), deep venous thrombosis, skin lesions, epilepsy and renal failure (1 patient each; 3%, each). TRM was 3%. A study recently presented by the UK National Amyloidosis Centre (H.J.B. Goodman, personal communication) included 80 patients with AL in whom cytotoxic therapy had either been ineffective or deemed too toxic to pursue. Thalidomide was taken for a median of 6 months (0.4–34), at a median dose of 100 mg/day (50–600). Thalidomide was used alone in 51 patients, with Dex in 8, and in combinations with alkylating agents in the remaining patients. Somnolence, constipation and/or neuropathy occurred in 50 patients (62%), symptomatic sinus bradycardia in 4 (5%), 3 had venous thromboses and 1 had a major arterial clot. Thalidomide was discontinued due to adverse effects in 25 patients (31%). There was no TRM. Partial hematologic response was observed in 24/44 (55%) patients treated with thalidomide alone and in 18/26 (69%) of those treated with any combination. No complete response was observed. Incidentally, the authors noticed that thalidomide appeared to increase all non-clonal light chains. Thus, data of serum FLC concentration need to be evaluated carefully. Organ function improved or remained stable in 26% of the 62 evaluable cases, and SAP scintigraphy showed regression of amyloid in 9 of the 50 evaluable patients. 17 patients on thalidomide died of progressive disease. This study indicates that lower doses of thalidomide are better tolerated but also produce fewer and incomplete hematologic responses. Overall, it seems that the combination of thalidomide and Dex may represent a valid option for refractory and relapsed patients. Due to the fragility of these patients, lower doses of thalidomide should be used and careful monitoring of the organ toxicity is necessary. At our center, we found monthly Holter monitoring helpful in detecting and treating bradycardia promptly.

• lenalidomide + bortezomib, are both active in advanced and refractory multiple myeloma. The ability of these drugs, in combination with dexamethasone, to rapidly reduce the level of the monoclonal protein makes them an attractive option also for AL patients, although more data on response duration and toxicity are needed
• allogenic HSCT : in a series of 19 patients including 4 syngeneic, 8 reduced-intensity conditioning, and 7 full-dose allogeneic transplants; 10 were T-cell–depleted grafts. The follow-ups are short, and only 4 patients are currently alive after 36 months. Complete responses were seen in 10 patients. The treatment-related mortality was 40%. As in all registry studies, it suffers from the fact that there are 11 centers reporting on 19 patients. In amyloidosis, the natural history of the disease may vary among centers.5 The patient selection and the total number of patients evaluated at these centers as potential allogeneic transplant recipients cannot be known. Nonetheless, it represents the largest number of patients reported, and it is important for the scientific community to be aware of the feasibility of allogeneic transplant and its potential for graft versus tumor, as 5 of 7 patients with complete remission (CR) had chronic graft-versus-host disease (cGvHD). The data are of insufficient power to justify the use of this technique in clinical practice, and it must remain the subject of scientifically conducted clinical trials^ref
• the iodinated anthracycline, 4'-iodo-4'deoxydoxorubicin, used at a low, nonmyelosuppressive and nontoxic dosage, has produced responses in 6 of 40 (15%) patients in a multicenter trial. Strategies to combine 4'-iodo-4'-deoxydoxorubicin with chemotherapy to suppress precursor production and promote amyloid resorption would be a rational approach
• along the same line, in an effort to promote amyloid resorption, small molecules targeting the common fibrillar architecture and common protective elements have been designed and tested in animal models and Phase II clinical trials. A compound able to crosslink serum SAP and clear it from circulation is under evaluation in patients with systemic amyloidoses, including a few patients with AL, at the UK National Amyloidosis Centre.
• anti-TNF-a therapy, in the form of etanercept, in 16 patients with advanced AL produced symptomatic improvement in most of them, and half had objective responses, notably in those with macroglossia^ref. Larger trials are ongoing to evaluate the role and best dosage of etanercept in the management of AL.
• rituximab may be considered in patients with AL amyloidosis and IgM monoclonal protein.
• immunotherapy, both active and passive, is another challenging and promising approach. Dendritic cell-based idiotype vaccination has shown no side effects, but limited clinical activity. AL-amyloid burden can be markedly reduced in mice by passive immunization with an anti-L chain murine monoclonal antibody specific for an amyloid-related epitope^ref. A humanized antibody is being produced for a Phase I/II clinical trial in patients with AL.
• eprodisate (Kiacta^®, Neurochem) is a negatively charged, sulfonated molecule of low molecular weight that has structural similarities to heparan sulfate^ref (Gervais F, Morissette C, Kong X. Proteoglycans and amyloidogenic proteins in peripheral amyloidosis. Curr Med Chem Immun Endocr Metab Agents 2003;3:361-70). The compound, a member of a new class of agents that interfere with interactions between amyloidogenic proteins and glycosaminoglycans^ref, inhibits the development of amyloid deposits in the tissues in mouse models of AA amyloidosis. Eprodisate slows the decline of renal function in AA amyloidosis^ref

Supportive treatment aimed at improving or palliating organ function, maintaining quality of life, and prolonging survival whilst specific therapy has time to take effect has an important impact on survival. Supportive care should be considered a fundamental part of an integrated treatment approach to these patients and requires the coordinated expertise of several specialists who are familiar with this disease.

• the mainstay of the treatment of amyloid cardiomyopathy is salt restriction and careful administration of diuretics, such as furosemide, scrupulously avoiding aggravation of intravascular volume contraction (due to concomitant nephrotic syndrome) and postural hypotension. If furosemide becomes ineffective in controlling edema, the addition of metolazone or spironolactone can be beneficial. Patients with reduced stroke volume can benefit from afterload reduction with angiotensin-converting enzyme inhibitors. However, these agents should be used with great caution, starting at the lowest effective dose, escalating carefully and withdrawing if postural hypotension develops. Digoxin is not generally helpful, with the possible exception in patients with atrial fibrillation and rapid ventricular response. Calcium channel blockers can aggravate the congestive heart failure. Patients with recurrent syncope may require permanent pacemaker implantation. Menacing ventricular arrhythmias benefit from treatment with amiodarone. In patients with end-stage heart failure, heart transplantation is the only life-saving procedure, which may allow subsequent treatment to control the amyloidogenic clone. Several patients have been transplanted at the Mayo Clinic and at the Boston University Amyloid Center. The main problem is recurrence of amyloid in the transplanted organ as well as progression in other organs. For this reason heart transplantation must be followed by anti-clone therapy. Although the long-term survival is statistically inferior to that of patients with non-amyloid heart disease, the actuarial 5-year survival appears to be 50%. Carefully selected patients, without other significant organ involvement, can benefit from this procedure
• orthostatic systemic arterial hypotension is difficult to manage. The use of a waist-high, fitted elastic leotard is helpful. In our experience fluoricortisone is poorly tolerated because of aggravation of fluid retention. Midodrine can be helpful: the full dosage, 10 mg 3 times a day, should be reached gradually starting from the lower dose of 2.5 mg daily, and its renal excretion requires attention in patients with renal failure. Its main adverse effect is supine hypertension. Continuous noradrenaline infusion has been reported to be a successful treatment of severe hypotension refractory to conventional treatment.
• therapy of renal amyloidosis (light chain nephropathy) is limited to the control of the edema by diuretics. The main damaging mechanism is progressive tubular injury caused by glomerular protein loss. The use of angiotensin-converting enzyme inhibitors, in an attempt to reduce proteinuria, is reasonable, although their efficacy has not been proven. Treatment of hypercholesterolemia should be considered. Renal vein thrombosis is rarely, if ever, seen in these nephrotic patients and prophylactic anticoagulation is not recommended. End-stage renal failure is treated by dialysis. Both peritoneal dialysis and hemodialysis are equally effective. If the disease is not controlled by chemotherapy, extrarenal progression of amyloidosis is the main cause of death. Renal transplantation should be offered on a case-by-case basis to patients without symptomatic extrarenal involvement.
• diarrhea is a common and incapacitating problem. Octreotide decreases diarrhea both in its short-acting form (starting with 50 µg twice a day up to 100 µg thrice a day) and its long-acting depository form (10, 20 and 30 mg doses, administered every 4 weeks, adjusting the dosage to the response of diarrhea). The patient’s social life can be improved by palliative diverting ostomies. Chronic intestinal pseudo-obstruction is usually refractory to treatment. Adequate oral or intravenous feeding is mandatory in patients with significant undernourishment. Patients who present with severe liver failure may be considered for liver transplantation. Successful sequential liver and stem cell transplantations have been reported.
• neuropathic pain is difficult to control. Gabapentin (starting with 300 mg daily and with daily increments up to 1800 mg), although well tolerated, often fails to relieve pain. Non-nephrotoxic analgesics may be used as adjuvant agents.
• bleeding in AL amyloidosis is frequent and multifactorial. Factor X deficiency dramatically improves following effective chemotherapy, including PBSCT, or after splenectomy.

• heart : mean interventricular septal thickness decreased by 2 mm, 20% improvement in ejection fraction, improvement by 2 NYHA classes without an increase in diuretic use, and no increase in wall thickness
• kidney : 50% decrease (at least 0.5 g/day) of 24-hr urine protein (urine protein must be > 0.5 g/day pretreatment); creatinine and creatinine clearance must not worsen by > 25% over baseline
• liver : 50% decrease in abnormal alkaline phosphatase value; decrease in liver size radiographically at least 2 cm
• nerve : improvement in electromyogram nerve conduction velocity (rare)

Organ disease progression :
 

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