AL Amyloidosis

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15.1. Introduction

Figure 15.1 A. AL amyloidosis showing formation of amyloid fibrils from FLC domains. B. Classic facial features with periorbital purpura. (Courtesy of PN Hawkins).

Figure 15.2 A. AL amyloidosis in the heart showing thickening of the left ventricular walls leading to heart failure. B. AL amyloidosis showing macroglossia that occurs in 20% of patients. (Courtesy of PN Hawkins).

Figure 15.3 A. Serum from a patient with AL amyloidosis showing a nephrotic pattern on SPE. B. Serum IFE (sIFE) reveals a small (nonquantifiable) monoclonal λ protein in the β/γ region. (Courtesy of RA Kyle and JA Katzmann).

Figure 15.4 A. UPE and B. urine IFE (uIFE) from the same patient as in Figure 15.3, showing a monoclonal λ protein band. (Courtesy of RA Kyle and JA Katzmann).

AL amyloidosis (primary systemic amyloidosis) is a protein conformation disorder characterised by the accumulation of monoclonal free light chains (FLCs), or their fragments, as amyloid deposits (Figure 15.1A). Typically, these patients present with heart or renal failure, although the skin, peripheral nerves and other organs may also be involved (Figures 15.1B - 15.2) ^[1][2][3].

Median survival used to be little more than 18 months, but with improved chemotherapy and better monitoring techniques (particularly using sFLCs) median survival is now 6-8 years in patients with good responses to treatment. A slowly growing clone of plasma cells secrete the monoclonal FLCs, which are typically λ type (κ to λ frequency: 1:2). It is of interest that clonal plasma cells from patients with renal deposits more commonly have the 6α Vλ light chain variable region genes, while those with cardiac and multisystem disease have the 1c, 2α2 and 3r Vλ genes, although associations with other genes may be found ^[4].

AL amyloidosis is one-fifth as common as multiple myeloma (MM) with an annual incidence of 9 per million, i.e., there are approximately 600 new patients per year in the UK and 2,500 in the USA. The median age of presentation is 70 years and its occurrence is rare before age 40. Men represent between 60% and 65% of patients and less than 10% have associated MM.

The presence of a monoclonal protein in the serum and urine of patients is a common finding and an important diagnostic feature. However, the underlying monoclonal gammopathies can be subtle and are undetectable in 5-20% of patients, depending upon the sensitivity of the electrophoretic method used. Figure 15.3 shows the serum abnormalities in a patient with AL amyloidosis. Serum protein electrophoresis (SPE) indicates a typical nephrotic pattern (low albumin, elevated α2 and low γ fraction), but there is no observable monoclonal spike. Serum immunofixation electrophoresis (sIFE) shows some polyclonal immunoglobulin in the γ fraction and a λ protein that migrates in the β/γ region. This band is too small to be quantified by scanning densitometry of the SPE gel since it is undetectable against the background proteins. Figure 15.4 shows the urine protein electrophoresis (UPE) from the same patient. It contains a considerable amount of protein, particularly albumin, and there is a small monoclonal spike. IFE indicates a monoclonal λ protein against a background of polyclonal κ and λ FLCs. The monoclonal band is difficult to quantify by UPE and is of modest use for the purpose of disease monitoring.

15.2. sFLCs at disease presentation

Figure 15.5 Comparison of electrophoretic tests and sFLC immunoassays in 262 patients with AL amyloidosis studied at the UK National Amyloidosis Centre. Only 3% were quantifiable by SPE.

Figure 15.6 Diagnostic accuracy of different assays in AL amyloidosis. Electrophoretic test results in serum (A) and urine (B) were based on 430 patients studied at The Mayo Clinic. sFLCs (C) are from 262 patients at The UK National Amyloidosis Centre.

Figure 15.7 sFLCs in 262 patients with AL amyloidosis at diagnosis, 282 normal sera, 224 patients with LCMM and 28 patients with NSMM.

Figure 15.8 Diagnostic sensitivity of sFLCs and IFE in 95 patients with AL amyloidosis. Numbers refer to the samples in each category. (Courtesy of RA Kyle and JA Katzmann).

Figure 15.9 sFLCs in 95 patients with AL amyloidosis and 282 normal serum samples. The patients are divided into the diagnostic categories shown in Figure 15.8. (Courtesy of JA Katzmann).

Figure 15.10 Overall survival according to baseline sFLCs in 119 patients with AL amyloidosis.* Median values of sFLCs - 152 mg/L. (This research was originally published in Blood ^[5] © the American Society of Hematology).

Abnormal sFLCs are not a diagnostic test for AL amyloidosis; that is the preserve of tissue biopsies and DNA tests. However, FLCs are frequently abnormal and act as a useful initial screening tool alongside sIFE; if positive, they are essential for monitoring patients; if negative, the diagnosis of AL amyloidosis should be questioned.

The incidence of abnormal sFLC measurements has been assessed by many centres. The first study was from the National Amyloidosis Centre in London, UK. In a retrospective analysis of stored serum, 98% of 262 patients had abnormal sFLC concentrations at the time of clinical presentation ^[6]. In contrast, only 3% of patients had serum concentrations of monoclonal FLCs that were quantifiable by SPE. Many patients had elevated FLCs in the urine but as discussed in Chapters 3 and 24, serum measurements are preferable. Comparisons of the results with electrophoretic tests are shown in Figures 15.5 and 15.6.

Comparison of the sFLC results from individual patients is shown in Figure 15.7 alongside normal serum samples. Concentrations of FLCs in the AL amyloidosis patients are similar to those observed in nonsecretory multiple myeloma (NSMM) but lower than those found in light chain multiple myeloma (LCMM). Classification into κ or λ types by FLC immunoassays agreed fully with IFE and bone marrow phenotyping (in the 207/262 samples that were available). In most patients, the concentrations of monoclonal FLCs were within the range of 30-500 mg/L. There was no correlation of sFLC concentrations with intact monoclonal immunoglobulins, when present.

The diagnostic accuracy of traditional serum and urine tests has been compared with sFLC assays in a study from The Mayo Clinic ^[7]. Samples from 95 patients with AL amyloidosis were selected, based upon whether serum or urine samples were positive or negative for monoclonal proteins by IFE and bone marrow immunohistochemistry. For samples that were serum and urine positive by IFE, the sensitivity of sFLC immunoassays was marginally lower (Figures 15.8 and 15.9). In those patients whose sera were IFE negative for κ or λ, the sFLC results showed a sensitivity of 95% and 100%, respectively. In patients whose samples were negative by sIFE and uIFE (but confirmed by bone marrow tests), sFLCs had a sensitivity of 86%. In the bone marrow negative group of 4 patients, sFLCs were not diagnostic.

The study above was based on samples from deliberately selected diagnostic groups. A further study was undertaken to evaluate FLC assays in 34 unselected patients with AL amyloidosis who had undergone peripheral blood stem cell transplant (PBSCT) ^[8]. Of the 34 patients, at the time of transplantation, 26 were abnormal by sIFE, 28 by uIFE and 24 by both sIFE and uIFE. However, only 19 and 17 patients had monoclonal protein concentrations that could be quantified by SPE and UPE, respectively. Overall, only about half of the patients who had undergone transplantation could be evaluated by serum or urine monoclonal proteins. In contrast, changes in sFLCs could be used for assessing all 34 patients although, in 4 patients, the concentrations were within the normal range.

Similar results were found by Akar et al. ^[9][10] in 169 patients with AL amyloidosis, who were evaluated for the utility of sFLC immunoassays. Elevated concentrations of κ or λ FLCs were found in 96% and 94% of patients respectively, higher than by any other individual test. However, monoclonality, as defined by κ/λ ratios was less sensitive: 89% for κ patients and 73% for λ patients. For the κ patients, sensitivity was higher than other tests but for λ patients sIFE and uIFE were more sensitive (79% and 92% respectively). The conclusions were similar to those from Katzmann et al. ^[7], described above: 1) sFLC measurements are a useful screening test and supplement other tests; 2) the quantitative nature of the FLC immunoassays has value in monitoring patients; and 3) FLC tests are complementary to IFE and other tests used in AL amyloidosis. Indeed, this is reflected in recent guidelines specifically addressing the use of sFLC assessment ^[11], (Chapter 25).

An audit of the utility of different diagnostic tests in AL amyloidosis, performed throughout 2003, was published by Katzmann et al. ^[12] (Table 15.1). In 110 newly diagnosed patients, FLC κ/λ ratios were the most sensitive test and, in combination with sIFE, identified 109 of the patients. Urine tests failed to identify the remaining patient, who was negative by serum tests.

Table 15.1. Sensitivity of different diagnostic tests and their combinations in 110 patients with AL amyloidosis at the time of disease diagnosis.

Many other groups have also reported that a high proportion of AL amyloidosis patients have abnormal sFLC κ/λ ratios. Studies by Palladini et al. ^[13] with 115 patients, Morris et al. ^[14] with 31 patients, and Bochtler et al. ^[15] with 133 patients, reported abnormality rates of 76%, 97% and 87%, respectively. A recent and detailed screening study ^[16] showed a detection rate of 88.3% of the sFLC assay for AL amyloidosis. Combination of sFLC, SPE and sIFE showed a combined sensitivity of 97.1%. Addition of urine studies to the serum screening panel elevates this detection to 98.1%. This illustrates that in some rare instances, AL amyloidosis might be detected exclusively by urine studies ^[13] and why 24h-urine IFE is additionally recommended by the IMWG guidelines ^[11] when screening for AL amyloidosis (Chapter 25). All authors agreed that the sFLC assays were most useful for subsequent patient monitoring.

In the studies described above, there was little correlation between the concentrations of sFLCs detected by immunoassays and SPE or IFE (Figure 15.9). Some patients had surprisingly high concentrations of FLCs by immunoassay but IFE was normal. It is possible that the FLCs were polymerised in some of the samples and this may have inhibited the formation of narrow bands on the electrophoretic gels. This has been observed in sera from patients with NSMM (see Figure 9.2).

Discordant results:

In 3-15% of patients, sFLCs are normal by immunoassay but detectable by sIFE. Theoretical explanations include:

While these three issues should be considered when curious results are seen, in practice, they have not been the cause of any observed discrepancies between properly measured results of sFLC and sIFE tests.

In rare patients both sFLCs and sIFE are normal. Explanations include:

15.3. Initial sFLC measurements correlate with survival

In MM, the baseline concentrations of sFLC correlate with outcome. The same is apparent for AL amyloidosis. In a study of 119 patients being treated with PBSCT, Dispenzieri et al. ^[5] showed that sFLC concentrations above the median value of 152 mg/L were associated with shorter survival times than those patients with values below the median (Figure 15.10). A four parameter staging system has recently been reported ^[17].

Clinical case history No 5

Clinical case history No 5. AL amyloidosis identified by FLC analysis when electrophoretic tests were doubtful [18].
A 40-year-old woman, with spontaneous bruises, asthenia, abdominal pains and a possible cardiomyopathy, was investigated for suspicion of AL amyloidosis. Abdominal fat biopsy showed Congo Red positivity. SPE showed hypogammaglobulinaemia but no monoclonal proteins. IFE showed a weak λ band without a corresponding intact immunoglobulin (Figure 15.11). A weak λ arc was also visible by serum immunoelectrophoresis. Quantitative immunoglobulin measurements were: IgG 4.9 g/L; IgA 1.02 g/L and IgM 0.32 g/L indicating hypogammaglobulinaemia. sFLC analysis showed: κ 7.8 mg/L; λ 210 mg/L and κ/λ ratio 0.04. Nephelometric FLC quantification was therefore clearly abnormal and provided a measurable parameter for subsequent disease monitoring. In contrast, FLCs were barely detectable by conventional electrophoretic assays.
	Figure 15.11 Clinical Case history No 5. SPE scan and IFE of the patient’s serum. A weak λ band is visible. (Courtesy of Dr Lucile Musset).

15.4. Monitoring patients with AL amyloidosis

Figure 15.12 I¹²³ labelled serum amyloid P scans in a 52-year-old woman, viewed posteriorly. Reduction of AL deposits in the liver and spleen after one year of chemotherapy can be seen. Serum κ FLCs reduced from 551 mg/L to 52 mg/L over the same period. (Courtesy of PN Hawkins).

Figure 15.13 Comparison of disease status from serum amyloid P scans and serum FLCs in 127 patients with AL amyloidosis before and 12 months after commencing chemotherapy. The mean percentage of remaining FLCs in each group are indicated (Kruskal-Wallis test: p <0.0001). (Courtesy of PN Hawkins).

Figure 15.14 Kaplan- Meier probability of survival in 137 patients with AL amyloidosis showing that a reduction of sFLCs by greater than 50% following chemotherapy was associated with increased survival. (Courtesy of PN Hawkins).

Figure 15.15 Kaplan-Meier probability of survival in 65 patients with advanced AL amyloidosis treated with CTD based upon haematological responses. (This research was originally published in Blood ^[19] © the American Society of Hematology).

Figure 15.16 Kaplan-Meier probability of survival in 81 patients with severe AL amyloidosis treated with melphalan and dexamethasone. A 25% reduction of sFLCs was associated with increased survival. (This research was originally published in Blood ^[20] © the American Society of Hematology).

Figure 15.17 Kaplan-Meier probability of prolonged survival in 204 patients with AL amyloidosis treated with VAD regiments according to sFLC responses. (Courtesy of PN Hawkins).

“The introduction of the serum immunoglobulin free light chain assay has revolutionized our ability to assess hematological responses in patients with low tumor burden.......”

“The Freelite serum free light chain assay represents a landmark advance in the management of AL amyloidosis.....”

The aim of therapy in AL amyloidosis is to suppress the monoclonal plasma cell clone that produces the amyloidogenic FLC. When the supply of amyloid-forming protein is reduced, the balance between amyloid deposition and clearance may be favourably altered. Although complete suppression of the clonal plasma cells is desirable, reduction in the amyloidogenic sFLC concentrations by 50-70% is often sufficient to lead to stabilisation or regression of amyloid deposits.

Using SPE, the depositing monoclonal FLCs can rarely be quantified in serum. In the study by Lachmann et al. ^[6], only 3% of patients had sufficiently high concentrations of monoclonal sFLCs to be quantitated by SPE (Figure 15.5) so patients could not be reliably monitored (see Figure 15.18 as an example). This had previously led to the use of I¹²³-labelled serum amyloid P scans (SAP scans) as an alternative method of assessment. Uptake of the radiolabelled protein into amyloid deposits allows identification of the affected organs and the amounts deposited. Furthermore, uptake varies with time, in parallel with changes in clinical status. This is seen in patients during treatment with chemotherapy and is compared with the concentrations of sFLCs in Figures 15.12 and 15.18.

Investigations by Lachmann et al. ^[6] in 137 patients with AL amyloidosis confirmed the important relationship between amyloid deposits seen on the scans and sFLC concentrations. Patients were divided into 3 groups dependent upon whether the SAP scans of the amyloid deposits showed regression, no change, or progression following chemotherapy. There was a good correlation with changes in sFLC concentrations during the same period (Figure 15.13). This indicated that sFLC measurements could provide a simple measure of changes in disease status in patients with AL amyloidosis.

The importance of sFLC measurements for assessing chemotherapy in AL amyloidosis has been demonstrated repeatedly. The first study was a retrospective analysis of 164 patients by Lachmann et al. ^[6]. Patients received high-dose melphalan, intermediate or low-dose therapy and all were monitored with SAP scans and blood tests on a six-monthly basis. Stored blood samples were analysed for sFLCs in the 137 patients who survived at least 6 months. Results showed that a reduction in the amyloidogenic FLCs by 50% or more following chemotherapy, was associated with a 10-fold survival advantage. There was an 88% probability of survival for 5 years if the sFLCs had fallen by more than 50%, compared with 39% if the sFLCs had reduced by less than 50% (p <0.001) (Figure 15.14). Median survival was 15 months in the 27 patients whose sFLCs showed no response (p <0.0001). A greater than 50% fall in sFLC was more significantly related to good outcome than any other clinical or biochemical measure, while reductions by >90% were associated with the best survival.

As a result of these observations, the authors made several recommendations on the use of sFLC measurements, most of which were incorporated into UK and international guidelines (Chapter 25):

     1. In order to minimise the toxicity associated with chemotherapy, measurements of the sFLC should be made approximately 2
         weeks after each course of chemotherapy. This should assist with decision-making about continuation of treatment.

     2. It may be appropriate to discontinue chemotherapy at an early stage if the amyloidogenic FLC concentrations have:

           a. Fallen to within the normal range.

           b. Fallen to a plateau level for at least a month.

           c. Fallen by 50-70% and toxicity or adverse effects are deemed to render further chemotherapy undesirable.

           d. Not fallen significantly after three courses of treatment, suggesting that alternative treatments should be considered.

Other large studies have confirmed the utility of sFLC for monitoring responses to chemotherapy. Wechalekar et al. ^[19] used an approach of risk-adapted therapy using cyclophosphamide, thalidomide and dexamethasone in 65 patients with advanced disease. Responses of sFLCs were divided into complete, partial (>50% reduction) and no response. The differences in survival between the groups was clear (p <0.001) (Figure 15.15).

Tan et al. ^[20] reviewed 81 patients who were unsuitable for PBSCT and had received melphalan and dexamethasone alone. A 25% reduction in sFLCs (difference between involved and uninvolved) predicted prolonged overall survival that was not reached at 30 months compared with 11.3 months median survival for non-responders (p <0.0001) (Figure 15.16). More recently, Goodman et al. ^[23] reviewed 204 patients treated with VAD like regimens and showed the prolonged survival benefits of sFLC responses (p <0.0001) (Figure 15.17). While complete suppression of the clonal plasma cells is desirable, reduction in the amyloidogenic sFLC concentrations by 50-70% is often sufficient to lead to stabilisation or regression of amyloid deposits. Continuation of toxic chemotherapy when FLC concentrations have responded may be unnecessary or even harmful. Risk-adapted therapy, based upon early changes in FLCs, may become common practice.

Clinical case history No 6

Clinical case history No 6. Use of sFLCs to monitor a patient with AL amyloidosis.
A 49-year-old man presented with congestive cardiac failure. After establishing a diagnosis of AL amyloidosis, he was given a heart transplant. He was subsequently treated with melphalan and prednisolone for a year, but then gradually developed increasing autonomic neuropathy with gastrointestinal symptoms, weight loss, hypotension and proteinuria. A cardiac biopsy showed evidence of amyloid in the graft. Two years after his initial presentation, he was given high dose melphalan and a PBSCT. This was successful as judged by diminishing proteinuria from 5.5 to 2.3 g per day over the following months and more stable blood pressure. The patient regained some weight, returned to jogging and was relatively well for the following few years. During his 6th year of illness, he gradually became short of breath, lost weight and renal function worsened. Deterioration continued with an episode of aspiration pneumonia followed by syncopal episodes. End-stage renal failure finally developed and he died seven and a half years after the initial presentation. Throughout his illness, he had a low level of monoclonal IgGκ protein in his serum, detectable only by IFE. Changes in its concentration had not been sufficient to act as a useful clinical marker (Figure 15.18). Retrospective analysis of serum samples showed that a monoclonal κ FLC had been present at different stages of his disease. It was present in greatly elevated concentrations at presentation but fell following the PBSCT and was undetectable for several years. It then recurred, as minor symptoms developed. Investigations at that time were normal and it was considered that the amyloidosis remained under control. In retrospect, rising FLC concentrations indicated otherwise. Subsequently, symptoms progressed in parallel with rising κ sFLC levels but the monoclonal IgGκ, detectable by IFE, remained unchanged. Development of progressive renal and cardiac failure indicated the terminal phase of the illness and he became too ill to be treated with chemotherapy. Perhaps, if FLC results had been available before the final illness, earlier treatment with chemotherapy could have produced a favourable outcome.
	Figure 15.18 Changes in SAP scans and serum monoclonal proteins during the disease course of a patiewnt with AL amyloidosis. M&P: melphalan and prednisolone; ESRF: end stage renal failure. (Courtesy of PN Hawkins).

15.5. Stem cell transplantation and sFLCs

The first study in this setting was undertaken by the Mayo Clinic ^[8], in which 34 patients with AL amyloidosis were assessed following PBSCT. Seventy-five percent of patients could be evaluated for clinical responses by serum or urine electrophoretic tests, whereas all could be assessed using sFLC concentrations. sFLCs were either the only marker for measurement, or decreased before the other tests in 21 of the 34 patients. Overall, changes in FLC concentrations showed a better correlation with changes in organ function than changes in electrophoretic tests.

A subsequent study by the same authors ^[5] showed that there was a higher risk of death with high baseline sFLC (see section 15.3 above). Furthermore, reduction post-transplant, was a more powerful predictor of survival than complete haematological responses (Figure 15.19). Other studies have shown similar results when monitoring reductions in sFLC ratios or concentrations ^[24][25]. All agree that FLC quantification should be standard practice for monitoring AL amyloidosis patients undergoing PBSCT.

15.6. Solid organ transplantation and sFLCs

Figure 15.19 Absolute value of sFLCs after PBSCT. (A. Distribution of levels 100 days after PBSCT, B. overall survival by sFLCs at day 100 and C. at 1 year (This research was originally published in Blood ^[5] © the American Society of Hematology).

Figure 15.20 Sustained fall in sFLCs following chemotherapy and cardiac transplantation. (Reproduced with permission of Haematologica and A Mignot ^[26]).

Renal transplanation. There are no substantial publications on the role of sFLCs in patients with AL amyloidosis and renal failure. Since the kidneys are the most common site of amyloid deposition it is likely that serum rather than urine measurements of FLCs would be helpful in monitoring and predicting organ damage. Furthermore, renal transplantation is helpful in patients with advanced renal disease. Wechalekar et al. ^[19] reported on 16 patients who had renal transplantation and indicated that the median survival was at least 7.4 years despite a very poor haematological response to chemotherapy in many. sFLC measurements for assessing disease relapse with damage to the transplant are likely to be helpful.

Cardiac transplantation. This is a controversial procedure in AL amyloidosis because of recurrence of amyloid in the graft and shortage of donors. However, it has been used when amyloid deposits in other organs are not too severe. Gillmore et al. ^[27] reported on 5 patients with heart and stem cell transplantation and showed substantial survival benefits (for an example see Figure 15.18). Mignot et al. ^[26] reported successful suppression of monoclonal λ sFLCs by 80% using melphalan and dexamethasone followed by cardiac transplantation. In spite of initial severe cardiac failure, recovery of organ function and AL amyloidosis control remained good at 2 years with normal sFLC concentrations (Figure 15.20). The early and rapid fall in monoclonal sFLCs was a useful guide to the success of the subsequent transplantation.

15.7. Brain naturetic peptide (NT-proBNP) and sFLCs in AL amyloidosis

An important link between cardiac dysfunction in AL amyloidosis and falling sFLC concentrations was observed by Palladini and colleagues ^[28][29]. Fifty-one AL amyloidosis patients with symptomatic myocardial involvement were given chemotherapy and monitored for sFLCs and the amino-terminal fragment of naturetic peptide type B (NTproBNP), a sensitive marker of myocardial dysfunction in AL amyloidosis. During treatment, 22 patients had a reduction of sFLCs by more than 50%, including 9 patients who had disappearance of monoclonal immunoglobulins by IFE and there was a corresponding reduction of NT-proBNP levels (p <0.001). Survival was better in responders than non responders (p <0.001). In some patients with sFLC reductions, the heart failure resolved without concomitant reduction of wall thickness at echocardiography.

These observations suggest that the amyloidogenic precursors equate to the circulating monoclonal FLCs. Of particular interest was the rapid improvement in heart failure, supporting a toxic effect. Further evidence has come from in-vitro studies of cardiac myocytes, where direct toxicity of amyloidogenic FLCs has been observed. It further emphasises the utility of the FLC assays and the importance of rapidly reducing their concentrations in patients with heart failure. In addition, although correlated, changes in sFLCs and NT-proBNP levels were independent markers of survival.

15.8. sFLCs in renal failure complicating AL amyloidosis

Renal failure frequently complicates AL amyloidosis and inevitably leads to increased serum concentrations of the amyloidogenic FLC even when the disease is not progressing. However, increases also occur in the concentrations of the non-depositing FLC (Chapter 20.1). Under these circumstances, the κ/λ ratio is a good determinant of disease progression. Furthermore, changes in the alternate FLC can be used to assess changes in renal function. This is illustrated in a patient with AL amyloidosis caused by a κ-secreting plasma cell clone (Figure 15.21).

It should be noted that the normal range for κ/λ ratio changes slightly in patients with renal failure. As renal function deteriorates, fewer FLCs are cleared through the glomeruli and more are removed by pinocytosis in other tissues. This reduces the clearance rate of κ more than λ, so the median value for the normal κ/λ ratio increases slightly (Chapter 20).

Clinical case history No 7

Clinical case history No 7. Use of the κ/λ ratio to assess AL amyloidosis in a patient with renal impairment.
A patient with AL amyloidosis was treated with cyclophosphamide and vincristine, adriamycin (doxorubicin), methyl-prednisolone (C-VAMP), after which serum κ FLC concentrations increased and then remained stable for six months before increasing further (Figure 15.21). Serum creatinine concentrations changed in a similar manner suggesting that a reduction in renal clearance could account for the rise in κ concentrations. However, the κ/λ ratio steadily increased over the same period, indicating a clonal increase in κ concentrations. The κ/λ ratio then increased sharply which suggested that the deteriorating renal function was due to increased amyloid deposition. A renal transplant was then successfully performed. These results illustrate a typical dilemma facing the clinician managing these patients. The deteriorating renal function could be due to one or more factors. However, the steadily rising κ/λ ratio indicated a recurrence of the FLC clone leading to renal deposition of amyloid. Clearly, the κ/λ ratio should be carefully monitored, but it is not clear whether this is the only consideration. As renal function deteriorates, a greater proportion of the circulating sFLCs are due to failure of renal clearance rather than de-novo synthesis. The additional circulating amounts of depositing FLCs might accelerate amyloid formation. The depositing FLC concentrations can be estimated by subtraction of the non-depositing FLC concentrations (polyclonal). Indeed, it has been suggested that this should replace κ/λ ratios when monitoring patients with MM. Guidelines for the diagnosis and monitoring of AL amyloidosis are described in Chapter 25.
	Figure 15.21 Changes in sFLCs and renal function in a patient with monoclonal κ AL amyloidosis. (Courtesy of PN Hawkins).

References