Light chain amyloidosis 2012: a new era

Authors

  • Moshe E. Gatt,

    Corresponding author
    • Department of Haematology, Hadassah Hebrew University Medical Centre, Jerusalem, Israel
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  • Giovanni Palladini

    1. Amyloidosis Research and Treatment Centre, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
    2. Department of Molecular Medicine, University of Pavia, Pavia, Italy
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Correspondence: Moshe E. Gatt, Department of Haematology, Hadassah Hebrew University Medical Centre, POB 12000, Jerusalem 91120, Israel. E-mail: rmoshg@hadassah.org.il

Summary

AL amyloidosis patients with multi-organ and particularly cardiac involvement have historically been considered to have a bad prognosis. The introduction of autologous stem cell transplantation was associated with unacceptable toxicity in high-risk patients, but responding patients have prolonged overall survival. Toxicities can be decreased by careful patient selection, but this reduces the applicability of this treatment modality to a limited number of patients. Efforts are therefore needed to design novel more effective regimens, with the use of new medications, such as thalidomide, lenalidomide and bortezomib, next generation immunomodulatory drugs and proteasome inhibitors. Their combination with dexamethasone and alkylating agents show promising results, allowing a high percentage of remission and subsequent event-free and overall survival, even in a significant proportion of high risk, poor prognosis populations. This review includes the state-of-the-art treatment for AL amyloidosis patients as of 2012, in light of the progress in management of this disease during recent years.

Systemic immunoglobulin light chain amyloidosis (AL) is a protein mis-folding disease caused by aggregation and tissue deposition of monoclonal light chains produced by a bone marrow plasma cell clone (Merlini et al, 2012; a, Merlini & Stone, 2006). The cornerstones of appropriate management of patients with AL amyloidosis are (i) correct amyloid typing, (ii) accurate risk stratification and (iii) timely evaluation of response to therapy (Palladini & Merlini, 2011a). Several types of systemic amyloidoses (AL, reactive to chronic inflammation, hereditary, senile) have overlapping clinical presentations and non-AL amyloidosis can also occur in the presence of a monoclonal gammapathy, given the high prevalence of the latter condition (Anesi et al, 2001; Lachmann et al, 2002; Comenzo et al, 2006). The demonstration that amyloid deposits are formed by light chains is mandatory before starting treatment for AL amyloidosis.

Light microscopy immunohistochemistry can consistently identify amyloid A (AA) amyloidosis. However, conventional immunohistochemistry, as well as immunofluorescence on renal biopsies, is unreliable in AL, when performed with commercial antibodies (Satoskar et al, 2007). Nevertheless, at referral centres using custom-made antibodies, light microscopy immunohistochemistry can be a valuable tool for amyloid characterization (Schönland et al, 2012). We routinely rely on immuno electron microscopy performed on abdominal fat aspirates and organ biopsies (Arbustini et al, 2002). This technique co-localizes the antibody and the amyloid fibril, thus increasing specificity, and correctly identified the amyloid type in more than 99% of cases in a series of 537 patients referred to our centre for suspected systemic amyloidosis (Verga et al, 2010). Modern proteomics makes typing of amyloid a direct matter, and several approaches based on two-dimensional electrophoresis (Lavatelli et al, 2008, 2011), laser capture microdissection (Vrana et al, 2009), and Multidimensional Protein Identification Technology (Brambilla et al, 2012) have been developed. The proteomic approach to amyloid typing has the advantage of not requiring prior hypotheses on the nature of the deposited protein (Lavatelli & Vrana, 2011).

AL amyloidosis is not only a haematological malignancy as patients also have multiorgan dysfunction, which determines prognosis and renders them more susceptible to treatment toxicity. This should always be kept in mind when designing a therapeutic strategy. The presence and extent of heart involvement is the major prognostic determinant, and cardiac dysfunction is best assessed by the cardiac biomarkers N-terminal pro-natriuretic peptide type-B (NT-proBNP) and troponins (Dispenzieri et al, 2003a; Palladini et al, 2003). A staging system based on these biomarkers (Dispenzieri et al, 2004a), which has been recently revised (Kumar et al, 2012a), allows accurate discrimination of low-risk (candidates for aggressive treatment that have prolonged survival if they respond to therapy), intermediate-risk, and high-risk (who are very fragile and often die before having a chance to respond to therapy) patients (Table I). Furthermore, haematological response is assessed by measuring changes in the concentration of circulating free light chains (FLCs), and cardiac response and progression are defined by decreases or increases in NT-proBNP (Table 1) (Palladini et al, 2010a,b). As AL amyloidosis is a progressive disease, response to treatment needs to be assessed early, in order to rapidly start rescue therapies in non-responders.

Table 1. Updated international society of amyloidosis criteria for cardiac staging and for haematological and cardiac response
Standard staging system (Dispenzieri et al, 2004a)The system is based on NT-proBNP (cut-off point 332 ng/l) and cTnT (cut-off point 0·035 ng/ml). Stage I, II, and III, patients have none, one or two markers above the cut-off points, respectively
Revised staging system (Kumar et al, 2012a)The revised staging system is based on NT-proBNP (cut-off point 1800 ng/l), cTnT (cut-off point 0·025 ng/ml), and dFLC (cut-off point 180 mg/l). Stage I, II, III, and IV patients have none, one, two or three markers above the cut-off points, respectively
Type of response (Palladini et al, 2012b)Definition
  1. dFLC, difference in concentration between involved (amyloidogenic) and uninvolved free light chain; eGFR, estimated glomerular filtration rate; FLC, circulating free light chain; iFLC, involved (amyloidogenic) free light chain; NT-proBNP, N-terminal natriuretic peptide type-B; cTnI/cTnT, cardiac Troponin I/T.

  2. a

    Caution should be used in interpreting NT-proBNP changes in subjects treated with immune modulatory drugs and in those with a >25% decrease in glomerular filtration rate.

Complete responseNegative serum and urine immunofixation and normal FLC κ/λ ratio
Very good partial responsedFLC <40 mg/l
Partial responsedFLC decrease >50%
No responseOther
NT-proBNP responsea>30% and >300 ng/l reduction in subjects with baseline NT-proBNP ≥650 ng/l

Being a plasma cell-related disorder, it may be found secondary to multiple myeloma (MM) in 10–15% of patients, conferring worse prognosis (Desikan et al, 1997; Rajkumar et al, 1998a,b; Madan et al, 2010a). Alternatively, it may be found isolated as a primary disease that rarely progresses to MM (Rajkumar et al, 1998a). Whereas in MM the clinical scenario is dominated by myeloma end-organ damage, such as bone lesions and tubular kidney disease, in AL amyloidosis the clinical scenario and prognosis are contingent upon the organ dysfunction caused by the amyloidogenic light chain (Merlini, 2012). Some relatively large MM retrospective series failed to show significance of the presence of asymptomatic amyloid deposits in the bone marrow, thus correlating the patient's prognosis to the MM primary disease (Petruzziello et al, 2010; Siragusa et al, 2011), whereas others did show such clinical significance (Vela-Ojeda et al, 2009). Treatment approaches to primary AL often follow and mimic MM protocols, aimed at suppressing the clone with chemotherapy (Palladini & Merlini, 2011a). In the recent era, novel agents used in MM are finding their place in the therapeutic armamentarium.

Primary AL is a rare disease, and large controlled patient trials are therefore difficult to conduct (Comenzo et al, 2012). Given the fact that multiorgan failure has a wide clinical spectrum, these subjects are particularly susceptible to treatment toxicity. Thus, various single arm trials have different populations, which are difficult to compare (Gertz, 2010).

Lessons learned from clinical observations confirm the hypothesis that it is not solely the deposition of large material in the tissues that cause organ injury (Merlini & Bellotti, 2003; Merlini & Westermark, 2004; Phipps et al, 2010), but more so the toxicity of the specific circulating light chains (LC). The goal of treatment is the prompt elimination of the amyloidogenic LC by targeting the plasma cell clone with chemotherapy, while minimizing toxicity of therapy (Gertz et al, 2010; Merlini et al, 2012). Reductions in the concentration of the circulating FLC by an effective treatment can rapidly result in a marked clinical improvement and prolonged survival, sometimes better than its proliferative counterpart disease, MM. These responses to therapy on one hand, and the patients' sensitivity to various agents on the other, raise the question of which strategy is the best to choose for the newly diagnosed or relapsed AL patient. This review discusses the role of most recently reported agents, and argues for the use of tailored approaches in light of these latest advances in AL treatment.

Conventional-dose chemotherapy

Alkylating agents are the major chemotherapies used in MM and subsequently safely and effectively employed in AL (Kyle et al, 1997). Although treatment with melphalan and prednisone is very well tolerated and prolongs survival compared to untreated patients, responses are rare (~30%) and are reached slowly, sometimes requiring more than 1 year (Skinner et al, 1996; Kyle et al, 1997). Following the observation that high-dose dexamethasone was rapidly effective in AL amyloidosis (Dhodapkar et al, 1997), in 1999 a trial of combined oral melphalan and dexamethasone (MDex) in patients who were not eligible for autologous stem cell transplantation (ASCT), obtained encouraging haematological response rates of 67% [complete remission (CR) 33%], with a low (4%) treatment-related mortality (TRM) (Palladini et al, 2004, 2007). The median survival of patients treated with MDex was 5·1 years, thus leading to this therapy becoming a widely acceptable first line treatment, which is presently considered to be standard therapy for patients who do not receive stem cell transplants (Gertz, 2010).

However, cardiac patients with advanced heart involvement did not tolerate high-dose dexamethasone, and lowering the dose from 40 to 20 mg on days 1–4 was associated with a significantly lower CR rate (16% vs. 31%) (Palladini et al, 2010c). Other trials of MDex in patients with advanced cardiac involvement showed extremely disappointing results, in that 26% of patients died during treatment, and the haematological response rate was only 44% (Dietrich et al, 2010), with a very short median survival (Lebovic et al, 2008). It is of note that the latter two trials included more patients with advanced cardiac involvement than the first report, indicating that although MDex is safe and effective in intermediate risk patients, it cannot overcome the poor prognosis of subjects with advanced cardiac involvement.

In addition, intermediate dose IV melphalan results in significant toxicity. The Australian trial using melphalan 20 mg/m2 for high-risk patients was terminated early due to excessive myelotoxicity and no evidence of response benefit (Mollee et al, 2012).

Bendamustine, a combined alkylator and purine analogue, has been shown to exert a beneficial effect even in heavily pretreated patients (Damaj et al, 2012). Subsequently, this agent was also tested as salvage therapy combined with prednisone in 11 relapsed/refractory AL patients (Milani et al, 2012); six patients responded, one achieved a very good partial responses (VGPR) and five achieved partial responses (PR). Four patients experienced severe cytopenias.

In conclusion, conventional-dose therapy (oral MDex) has shown efficacy in AL patients, and thus has become the golden standard for treatment, especially in medically frail patients. However, newer agents and combination treatments are showing promising superior results, as will be discussed further.

Autologous stem cell transplantation

ASCT was first reported by Comenzo et al (1998) as a major breakthrough in the treatment of AL amyloidosis, following its use in MM. Melphalan 200 mg/m2 was reported to induce a 76% haematological response rate, with an additional 33% achieving a CR, while TRM was 12–13% (Gertz et al, 2004; Skinner et al, 2004). The median survival of transplanted patients was 4·7 years (Sanchorawala et al, 2007a). The main caveat to these first reports was that patients with advanced organ damage were exposed to an unacceptably high risk (more than 40%) of TRM, particularly in multicentre settings (Moreau, 1999). Since then, efforts have been made to improve selection of candidates for ASCT and to stratify them according to risk (Palladini & Merlini, 2011b). A retrospective study recently showed that, since 2006, refinement of eligibility criteria resulted in a marked decrease of TRM (12% vs. 7%) (Gertz et al, 2010).

Reduction of the melphalan dose may be suitable for patients with moderate cardiac dysfunction, but results in a lower haematological response rate (53%) (Gertz et al, 2004), and in one report a 50% reduction of the dose (Cibeira et al, 2011) still resulted in TRM that was higher than previously reported (16%) (Cibeira et al, 2011; Madan et al, 2012). In a trial of ASCT in which the dose of melphalan was reduced according to age, echocardiographic evidence of heart involvement and renal function, the haematological response rate was 60% (CR 20%), demonstrating only 4% TRM, which was limited to patients with cardiac involvement (Cohen et al, 2007). A more recent trial from the same group, with similar criteria for melphalan dose adjustment, reported a 14% TRM rate, all in patients with cardiac amyloidosis, and the haematological response rate was 52% (CR 22%) (Landau et al, 2010). The total number of patients in each trial group was low, thus highlighting the difficulty of comparison among patient groups. Overall, there is no evidence that reduced-intensity ASCT (melphalan 100–150 mg/m2) is superior to non-myeloablative chemotherapy in AL amyloidosis, while retaining a significant TRM.

An additional major difficulty encountered was a high initial mortality rate (17%) during induction chemotherapy and during the period of stem cell mobilization (Schonland et al, 2010a). Of those that could be transplanted, the haematological response rate was 83% (CR 57%). The overall intent-to-treat haematological response rate was 72% (CR 46%). Another recent report (Madan et al, 2010b) showed that giving induction chemotherapy as in MM before ASCT resulted in no benefit, but also no detrimental effect. Thus it seems that there is no role for induction chemotherapy if a patient is planned for front line ASCT. However, as will be further discussed, it may be advisable to combine ASCT with a short course of a bortezomib-based protocol either before or after transplantation.

The tandem use of ASCT has also been reported (Quillen et al, 2011), although in only 11 patients, of which three achieved a CR, and with no TRM. The use of a modified high-dose melphalan regimen given in two cycles in a selected population with preserved performance status and cardiac function (>45% ejection fraction, EF) was recently updated (Sanchorawala et al, 2011) to yield a fairly low TRM of 10%, and an overall survival (OS) of 68 months. Thirty percent of patients had heart involvement, thus showing once again that careful patient selection, even in the setting of a multicentre study, can lead to prolonged OS with acceptable TRM.

A major advance in risk stratification was seen using cardiac biomarkers (Table 1). Subjects with elevated cardiac troponin T (cTnT; >60 ng/l) or cardiac troponin I (cTnI; >100 ng/l) had a higher risk of TRM (7% vs. 28% for cTnT and 3% vs. 25% for cTnI), despite melphalan dose adjustment based on clinical and echocardiographic criteria (Dispenzieri et al, 2004b; Gertz et al, 2008). These observations suggest that patient stratification based on standard clinical and echocardiographic criteria is inadequate to guide the choice of treatment, and that elevated cTn should be an exclusion criterion for ASCT.

Stratification according to N-terminal probrain natriuretic peptide (NTproBNP) and cTn may also be employed. An update on patients transplanted with high dose melphalan showed that even patients with cardiac involvement (with up to New York Heart Association grade III and EF >40% enrolled), and patients with cardiac stage III, using the criteria designated by cardiac biomarkers, could be treated using this modality (Madan et al, 2012). Although the staging definition by BNP and cTnI, i.e. stage I (normal biomarkers, BNP < 100 pg/ml and cTnI < 0·1 ng/ml), II (one elevated biomarker) or III (both biomarkers elevated), in this study did not discriminate TRM, the overall TRM was 16%. Nevertheless, achieving a good response required no reduction in the melphalan dosage. A recent follow up of 499 transplanted patients show that those who have a serum troponin T >0·06 ng/ml or an NT-proBNP >5000 pg/ml (not on dialysis) should not be considered acceptable candidates for stem cell transplantation due to an unacceptable early mortality rate. Application of these selection criteria is capable of reducing TRM to <2% (Gertz et al, 2012).

An update on long term survival for patients attaining CR post-ASCT show the estimated probability of OS for patients in CR was as high as 86% at 5 years. Patients who did not achieve a CR had a short median event-free survival of 2 years [95% confidence interval (CI) 1·6–2·7], as compared with 8·3 years for patients in CR (P < 0·0001) (Cibeira et al, 2011). In another series with long term follow up, 44% of patients survived more than 10 years (Cordes et al, 2012).

Overall these promising results in well selected patients show that ASCT may still be an established first line modality in low-intermediate risk AL patients.

Having said that, the only head-to-head randomized controlled trial evaluation of active treatments in AL amyloidosis, is the French trial comparing MDex and ASCT (Jaccard et al, 2007). This study failed to demonstrate an advantage in terms of haematological response rate (67% vs. 68%) for ASCT over MDex (Jaccard et al, 2007). Of note, in this trial TRM was relatively high (24%), perhaps obscuring the beneficial effects of ASCT, had a more strict patient selection been used, reflecting a higher risk patient population or failure to reduce chemotherapy doses appropriately. Nonetheless, the last updated results, with a longer follow-up of >5 years after last recruitment, did not find any superiority in the intensive arm in survival or remission duration, even in the landmark analysis eliminating TRM (Jaccard et al, 2010).

The outcome of this study, as well as the promising results obtained with newer treatments, particularly those incorporating novel agents, require the exact role of ASCT in AL amyloidosis to be reconsidered, and the need for more randomized trials.

In addition, it is noteworthy that only a small fraction of patients with AL amyloidosis are eligible for ASCT with full high-dose melphalan (200 mg/m2): only 14% of patients enrolled in the prospective Alchemy study in UK (Dr A. Wechalekar, University College London, UK, personal communication) and 12% of patients followed up at the Pavia Amyloid Centre. Recently, conditioning regimens incorporating bortezomib resulted in improved disease-free survival and OS without affecting engraftment. In AL, this has not been studied, although there are ongoing trials showing promising results (Table 2, discussed below).

Table 2. Future and ongoing studies in AL amyloidosis
Clinical trials.gov identifierAllocationaPatientbPhaseUse of chemotherapycUse of novel agentsdAccrual beginningEstimated endLocation
  1. Source: http://clinicaltrials.gov/ct2/results?term=amyloidosis+treatment.

  2. a

    S, single armed; R, Randomized.

  3. b

    ND, newly diagnosed; RR, relapsed refractory.

  4. c

    Mel, Melphalan; Dex, dexamethasone; Cyclo, cyclophosphamide; Bend, Bendamustine.

  5. d

    B, Bortezomib; L, Lenalidomide; T, Thalidomide; M, MLN9708 (oral proteasome inhibitor); P, Pomalidomide; EGCG, Dietary Supplement With Epigallocatechin Gallate; S, SAP (Serum Amyloid P) Depleter GSK2315698.

  6. e

    Phase III multiple centre worldwide study planned.

NCT01383759SNDI/IIASCT with HDMelB6/20116/2013NY, USA
NCT01083316SNDIIBD followed by ASCTB9/200912/2013Boston, MA, USA
NCT01273844SNDIIBD followed by ASCTB12/201012/2014China, Jiangsu
NCT01277016RNDIIIMel/Dex+/− B1/20111/2013European Myeloma Network
NCT01078454RNDIIMel/Dex+/− B11/20105/2011Multicentre USA
NCT00679367SRRIIMel/DexB5/20085/2013Boston, MA, USA
NCT01318902SRRIeNoM3/20111/2014Multicentre USA, Canada, Europe
NCT00890552SND/RRIIMel/DexL4/200912/2012Stanford, CA, USA
NCT01194791SND Cyclo/DexL10/201012/2015Multicentre Spain
NCT01570387SRRI/IIDexP2/20122/2013Boston, MA, USA
NCT01510613SRRIIDexP2/20122/2013Pavia, Italy
Other agents
NCT01406314SSINoS10/20116/2012Cambridge, UK
NCT01222260SSIIBendNo7/201111/2013Pittsburgh, USA
NCT01511263RRIINoEGCG1/201212/2013Pavia, Italy

Taken together, the results of ASCT are established over long periods of follow-up, showing substantial responses and prolonged OS. However, TRM is still a caveat. Studies using biomarkers suggest that patient stratification based on standard clinical criteria is inadequate to guide the choice of treatment, where TRM was >25% in patients with elevated cTn. Accurate baseline risk assessment of cardiac biomarkers is thus the cornerstones for careful patient selection. Consequently, only a minority of patients (20–30%) will be eligible for ASCT.

Allogeneic peripheral blood stem cell transplantation and organ transplantation

Transplantation of the organs involved by amyloidosis may prolong survival, improve quality of life, and render patients with advanced disease eligible for aggressive specific treatment. The main concerns with organ transplantation are recurrence of amyloidosis in the graft and progression in other organs. Organ transplant can be considered in patients who attain CR, but have irreversible end-stage organ damage. Available data indicate that kidney transplant can be offered to patients with AL amyloidosis with sustained CR (Bansal et al, 2012). Heart transplant followed by ASCT or other effective chemotherapy can be the only effective option for young patients with isolated, severe cardiac involvement (Gillmore et al, 2006; Maurer et al, 2007; Lacy et al, 2008; Sack et al, 2008; Dey et al, 2010; Sattianayagam et al, 2010).

Allogeneic bone marrow transplant has been attempted in relatively few cases, aiming at obtaining sustained remissions and possibly a cure in young patients. However, this approach was associated with a very high (40%) TRM (Schönland et al, 2006).

Novel agents – present and future

There are numerous studies regarding the use of novel agents with or without the addition of conventional chemotherapy. These include mostly the immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and the proteasome inhibitor bortezomib. Most trials are small, the population heterogeneous (multiorgan involvement, newly diagnosed and relapsed/refractory), and long term follow-up is limited. Figure 1, based on the information provided in the text, shows the response rates for various treatment modalities in AL. Note these were never compared, include only haematological assessment criteria, and the follow up time for the novel agents regimens is short, as well as the number of patients in each trial; However, there is a trend for treatment responses to be as good as ASCT, particularly assuming that patient selection for these trials included not only relapsed and refractory patients, but also higher risk patients than those included in ASCT trials.

Figure 1.

Response rate for various treatment modalities in AL Amyloidosis†. *Newly diagnosed; **Previously treated or refractory; */**Both populations. The number of patients included in each trial are given in parentheses. MDex, Melphalan + Dexamethasone; ASCT, autologous stem cell transplantation; Thal, Thalidomide; Pom, pomalidomide; Dex, dexamethasone; CyDex, cyclophosphamide + dexamethasone; HR, haematological remission; CR, complete remission. †Included are trials and reports for both newly diagnosed and relapsed patients, provided there was >10 patients reported. References are cited in the main text.

IMiDs

This group of immune-modulator agents, has been shown to produce significant responses (albeit the time to response may be delayed as compared with other modalities) in MM patients (Mitsiades et al, 2011; Palumbo & Anderson, 2011). Therefore, its activity was assessed in AL patients.

Thalidomide

As a single agent, thalidomide has limited efficacy (Dispenzieri et al, 2003b; Seldin et al, 2003). Combined with dexamethasone, thalidomide (TDex) yielded a 48% haematological response rate (CR 19%) in relapsed/refractory patients (Palladini et al, 2005). Toxicity was substantial, with 65% of subjects experiencing serious adverse events (SAE), including symptomatic bradycardia (26%), fatigue and constipation (Palladini et al, 2005). In an attempt to improve the response rate and to reduce the time to response in patients with advanced cardiac amyloidosis, thalidomide was combined with melphalan and attenuated dexamethasone; however, 27% of patients died on treatment and only 36% achieved haematological response (Palladini et al, 2009a). Adjuvant TDex was used in patients who obtained less than CR after ASCT and improved the quality of response in 42% of cases (Cohen et al, 2007).

Thalidomide in the newly diagnosed patient and combined with alkylators

The addition of cyclophosphamide to thalidomide and dexamethasone (CTD) resulted in a 74% haematological response rate (CR in 21%) (Wechalekar et al, 2007). The ‘real world’ prospective follow up (‘Alchemy registry’) of 250 patients treated as of September 2009, most of whom had received CTD as upfront therapy (77% of patients), demonstrated that although 33% managed to achieve a CR/VGPR, after a median follow up of 7 months, 29% of patients died, and 50% of treated patients had to be hospitalized for treatment toxicities (Gillmore et al, 2012). Renal organ responses were also poor. Most common toxicities were fluid retention and sedation, and TRM was 4%. A retrospective comparison showed that MDex and CTD have similar activity (Gillmore, et al 2009). Although recent observations in multiple myeloma indicate that also CTD negatively affects stem cell mobilization (Auner et al, 2010), this regimen may be preferred over MDex in young patients in whom a subsequent ASCT may be considered. It is also important to note that an early switch of non-responding 91 patients by three cycles of CTD in the ‘Alchemy’ trial enabled them to be salvaged by second line therapy (84% bortezomib containing regimens), allowing better responses, and consequently prolonged and comparable OS with first line CTD responders (Wechalekar et al, 2012). Thus, a policy of early assessment of response and switch to alternate therapy should be employed.

Lenalidomide

It is difficult to separate trials for newly diagnosed and relapsed refractory patients, as they are usually reported together. Two parallel trials investigated the efficacy of lenalidomide and dexamethasone in AL amyloidosis in the relapsed refractory setting: doses of lenalidomide higher than 15 mg were poorly tolerated and the haematological response rates ranged from 41% to 47% (Sanchorawala et al, 2007b; Dispenzieri et al, 2007). Furthermore, although patients were almost all pretreated with chemotherapy by ASCT, of those who achieved CR, 60% were durable, even off-therapy (Sanchorawala et al, 2010a). In patients pretreated with chemotherapy/bortezomib and even refractory to thalidomide, lenalidomide still exerted a beneficial effect, with a haematological response of 41%. However, this improvement was accompanied by significant toxicity, especially in patients with high cTn (Palladini et al, 2012a). Another recent trial of relapsed/refractory patients showed 50% haematological response, consistent with the previous reports of lenalidomide efficacy (Dietrich et al, 2012).

Lenalidomide combined with alkylator agents

Lenalidomide has been added to MDex, producing a haematological response in 58% of patients and CR in 23% (Moreau et al, 2010). In this trial, the maximum tolerated dose of lenalidomide was 15 mg. In another trial of relatively heavily pretreated patients, the addition of lenalidomide at 10 mg to MDex was associated with substential grade 3–4 toxicities, both fatigue and haematological, and a relatively modest effect of 50% partial haematological responses and no CRs to date (Patel et al, 2011). In a small study including 12 newly diagnosed patients, this combination was shown to be less toxic, with 3/12 patient experiencing a CR (Afghahi et al, 2011).

Lenalidomide has likewise been combined with cyclophosphamide and dexamethasone in three independent studies (Kumar et al, 2012b; Palladini et al, 2012b; Kastritis et al, 2012). The rate of haematological response ranged from 40% to 77%, being lower in pretreated subjects, and CR were rare (8–11%). In all these trials, lenalidomide toxicity was prominent (SAE 60–86%) and mainly characterized by cytopenia, fatigue and fluid retention. However, it is a relevant option for patients refractory to bortezomib and other chemotherapeutic agents. Available data indicate that the quality of response to this combination increases over time. It is likely that in AL amyloidosis, as in MM, prolonged exposure to lenalidomide may improve patient outcome. Trials to assess the value of maintenance therapy in this disease are warranted.

Pomalidomide

Pomalidomide is a newer thalidomide analogue, with a potent anti-myeloma activity and encouraging responses in MM patients who are relapsed/refractory to thalidomide and lenalidomide (Lacy et al, 2011). In AL it was also tested in 33 heavily pretreated patients, also including patients previously treated with thalidomide and lenalidomide, and showed a 48% haematological response rate, with 3% CR reported (Dispenzieri et al, 2012). Most patients had cardiac involvement. Treatment was relatively well tolerated, with only three patients discontinuing therapy due to toxicity.

Safety issues for IMiDs

Recently, concern has risen over possible renal and cardiac toxicity of IMiDs. In a retrospective analysis from the Boston University group, 66% of patients exposed to lenalidomide developed renal dysfunction, which was reversible in 44% of cases (Specter et al, 2011). This taken into consideration, lenalidomide was reported to be reasonably well-tolerated in patients with associated end-stage renal disease and dialysis, in a small series of seven patients (Sanchorawala et al, 2010b), but none managed to discontinue dialysis as a result of this regimen. In addition, an increase of cardiac biomarkers BNP and NTproBNP has been reported with the use of IMiDs (Palladini et al, 2009b; Gibbs et al, 2009; Tapan et al, 2010). The reason for this phenomenon is not clear. It is usually asymptomatic, and does not imply treatment failure (Tapan et al, 2010), but was also correlated with negatively affected survival (Dispenzieri et al, 2010; Tapan et al, 2010). Thus, in patients taking IMiDs, elevated biomarkers should be followed and assessed as per their dynamics, and not their absolute values (Tapan et al, 2010). Another safety concern comes from long term follow-up of MM patients, showing elevated hazard ratios for secondary malignancies in patients treated with lenalidomide, especially after ASCT with high dose melphalan (Dimopoulos et al, 2012). Given the prolonged survival in AL after ASCT, this issue should be taken into consideration in the relapsed patients after ASCT setting.

In summary, all IMiDs show well established and durable activities in AL patients, both in the upfront and relapsed setting, yet CR rates seem lower than those reported by other modalities. It should be noted that time to haematological response with IMiDs is longer than that observed with bortezomib, but delayed long term CR rates have been observed. Thus, when a fast response is needed, it may not be the agent of preference, but is a good choice for prolonged treatment.

Proteasome inhibitors

The proteasome inhibitor bortezomib is active in MM. Changes in serum FLC blood levels in responding MM patients occur rapidly, thus making it an attractive treatment agent in AL as well. In preclinical studies, plasma cells are particularly sensitive to proteasome inhibition (Bianchi et al, 2009). Amyloidogenic plasma cells synthesize a misfolded light chain which causes proteasome overload and increased sensitivity to bortezomib (Oliva et al, 2010). Bone marrow purified plasma cells from amyloid patients were shown to be twice as vulnerable to bortezomib inhibition (Oliva et al, 2012) than those of MM patients. Thus, bortezomib may represent prototype for a targeted therapy for AL amyloidosis (Sitia et al, 2007). In AL amyloidosis, bortezomib has proven to be an important therapeutic agent, as currently reported in several small series and trials.

Bortezomib

Similarly to lenalidomide, it is difficult to separate trials for newly diagnosed and relapsed refractory patients, as those are usually reported together. Bortezomib as a single agent was prospectively evaluated in a phase I/II dose-escalation study, and was well tolerated at up to 1·6 mg/m2 once weekly and 1·3 mg/m2 twice weekly (Comenzo et al, 2010; Reece et al, 2011). The haematological response rate was 39% (CR 11%) at lower doses, 69% (CR 38%) at 1·6 mg/m2 once weekly, and 67% (CR 24%) at 1·3 mg/m2 twice weekly (Comenzo et al, 2010). Time to response was shorter with the twice weekly schedule (median 0·7 vs. 2·1 months), but the once weekly schedule was better tolerated (SAE 50% vs. 79%) (Comenzo et al, 2010). The combination of bortezomib and dexamethasone (BDex) produced high haematological response rates (80–94%) (Kastritis et al, 2007; Wechalekar et al, 2008a). A retrospective study of 94 patients, reported a 71% haematological response rate (CR 25%, 47% in previously untreated subjects) (Kastritis et al, 2010). Median time to haematological response was relatively short: 1·7 months (Kastritis et al, 2010). In this study, SAE were observed in 29% of cases, most common being fluid retention and hypotension, and TRM was 3% (Kastritis et al, 2010). A smaller series of patients (n = 26) was reported from a multicentre retrospective analysis outside the context of a clinical trial (Lamm et al, 2011) and showed similar results of 54% response and 31% CR with the use of BDex.

In most clinical trials, patients with severe cardiac involvement are excluded. In 38 patients with stage III cardiac disease, reduced doses of bi-weekly BDex (1 mg/m2 and 8 mg respectively) were administered. Twenty-one patients achieved a haematological remission after a median of three cycles, yet 18 of all 38 patients died during the treatment, reflecting the severity of their disease as measured by high levels of NT-proBNP prior to treatment (Schonland et al, 2010b), defining a very-high risk group that is difficult to salvage even with an effective treatment.

Bortezomib combined with alkylator agents

Adding cyclophosphamide to BDex (CyBorD) yielded an unprecedented VGPR/CR in 16 of 17 treated patients (Venner et al, 2012), with minor toxicity. This was also observed in other centres in 25 newly diagnosed and relapsed patients (Tovar et al, 2012). The largest series to-date of 43 patients receiving this combination resulted in haematological remission of 81·4% with CR of 42% (frontline patients, 66·5% CR). These results translated into an estimated 2-year progression-free survival (PFS) of 98% (Mikhael et al, 2012). In another series of 35 patients treated initially with BDex and continued treatment with the addition of cyclophosphamide, 50% had cardiac stage III disease. Of these high risk patients, 86% achieved a rapid response (median 2–3 months) and prolonged PFS (Maramattom et al, 2011). Finally, dissecting the pooled analysis of 44 very high risk patients with stage III cardiac AL (median NTproBNP of 4362 ng/l), treated with once weekly bortezomib combined with cyclophosphamide and dexamethazone as upfront therapy, a haematological remission was achieved in 68% and estimated 1-year OS of 65% (Jaccard et al, 2012). In all series onset of response was rapid.

Patients receiving BDex plus alkylators (17 patients cyclophosphamide and 33 melphalan) resulted in fair responses, mostly in patients with stage I or II cardiac disease, as compared with those with stage III (67% response and 40% respectively) (Palladini et al, 2011a). In another series with 16 subjects treated with MDex plus bortezomib (BMDex), 15 responded (94%, CR 38%), with manageable toxicity, although dose adjustments were often required (Zonder et al, 2009).

Of note, in the landmark (matched case–controlled) analysis of 33 newly diagnosed patients treated with BMDex versus well-matched 66 treated patients with MDex, the median survival was 24 months, similar in both groups (Palladini et al, 2012c). This study included a high proportion of patients with advanced cardiac dysfunction, resulting in high rate (almost 20%) mortality in the first 3 months. Indeed, while the intention-to-treat analysis did not show differences in terms of response rate between MDex and BMDex, in a 3-month landmark analysis excluding early deaths, the rate of CR/VGPR was significantly higher in the BMDex cohort (52% vs. 29%). These data highlight the need for randomized clinical trials, stratified according to the severity of cardiac involvement (one such trial is now ongoing).

Safety issues for bortezomib

Apart from worsening heart failure, which has been reported in MM patients (Enrico et al, 2007) and in some patients reported in the series above, a major concern regarding treatment with bortezomib is its common side effect of causing peripheral neuropathy. AL patients already suffer from neuropathy, and therefore caution should be employed with its use. In MM, subcutaneous administration has resulted in similar efficacy but with less neuropathy (Moreau et al, 2011). A small series of 11 AL patients treated subcutaneously has shown a promising safety profile similar to that found in MM (Gibbs et al, 2012).

Combined bortezomib and ASCT

Combined modalities using adjuvant therapy with BDex has been attempted in subjects who obtained less than CR after ASCT (69% of newly diagnosed patients), substantially improving the quality of response (Landau et al, 2010). The overall response rate in patients with residual light chains post-transplant achieved 90% deeper response, with 74% achieving sCR (Landau et al, 2012). This is usually achieved after the first course of consolidation. A complementary approach of administering two cycles of BDex before and as conditioning for ASCT also yielded very good response rates of haematological remission in 9/18 patients after the induction, and all 11 patients evaluable after the ASCT attained a CR/VGPR (Sanchorawala et al, 2012a).

Other proteasome inhibitors

A trial of a novel oral proteasome inhibitor (MLN9708) for relapsed patients has also been initiated. Preliminary results from a Phase I study in nine relapsed refractory patients showed VGPR/PR in 3/2 patients with acceptable toxicities (Sanchorawala et al, 2012b). A phase III trial for relapsed/refractory patients has recently begun in multiple centres worldwide.

In conclusion, bortezomib as a proteasome inhibitor, has been shown to have strong and probably the most rapid effect in AL. Given that data regarding organ response is lacking, due to the short follow-up time, it is difficult to assess and compare the various trials, and to compare bortezomib to the IMiDs. However, there seems to be a trend towards better and faster haematological responses using bortezomib-based regimens as compared with IMiDs (Fig 1). Thus, for high-risk patients, and those where a rapid response is sought, the use of bortezomib (preferably combined with an alkylator) in the upfront setting is advocated.

Other agents

Interestingly, 7% of AL patients have a clonal IgM. In older series, most were treated with chemotherapy or ASCT. However, these patients tend to be older, and respond to rituximab, a monoclonal anti CD20 antibody based protocol (Wechalekar et al, 2008b; Gertz et al, 2011). Recently, a series of 10 patients with IgM-AL amyloidosis has been reported (Palladini et al, 2011b), all treated with the combination of BDex and the addition of rituximab. Haematological response was achieved in 78% of patients, including three refractory to previous rituximab. Similar to Waldenström macroglobulinemia, this regimen holds promising results for a rare subset of AL patients.

Duration of treatment using novel agents

The aim of treatment in AL amyloidosis should be prolonging survival by inducing reversal of amyloid-related organ dysfunction, particularly cardiac. Most clinical trials are lacking data as to the duration of treatment using novel agents in AL. In MM, maintenance treatment has been shown to prolong disease-free survival and sometimes OS (Ludwig et al, 2012). However, AL is usually a consequence of small plasma cell clones. Patients with primary AL amyloidosis, unlike subjects with MM, do not only have a haematological malignancy, but also have organ damage, which makes them more susceptible to treatment-related toxicity. Thus, treatment goal should be reached at the lowest possible side effect costs. Indeed, it has been shown that subjects who attain CR, do not have a survival advantage over those who reach PR plus a cardiac response defined as NT-proBNP reduction, at least in the first 4 years after diagnosis (Wechalekar et al, 2008a). Nevertheless, it remains to be established whether once organ dysfunction has improved, further treatment aimed at improving the quality of response, or even maintenance therapy, will result in improved survival.

Alternative approaches to treating AL amyloidosis

The mainstay of AL amyloidosis treatment is the suppression of synthesis of the amyloid protein with chemotherapy. Nevertheless, alternative strategies are being explored, aimed at reducing the amyloidogenic propensity of the precursor and directly targeting the amyloid deposits. The use of polyphenols as anti-amyloid compounds is also being considered with interest (Ferreira et al, 2011, 2012). Following the observations that (-)-epigallocatechin-3-gallate (EGCG), the main polyphenolic constituent of green tea, reduces cerebral amyloidosis in Alzheimer transgenic mice (Rezai-Zadeh et al, 2005), and inhibits fibril formation of amyloid- (Ehrnhoefer et al, 2008), Dr Werner Hunstein, former professor of haematology at the University of Heidelberg, who was suffering from AL amyloidosis, observed an improvement in his cardiac symptoms while he was purposely drinking high amounts of green tea (Hunstein, 2007). The clinical activity of EGCG was then confirmed in retrospective case series both in AL amyloidosis and in transthyretin-related amyloidosis (ATTR) (Mereles et al, 2010; Kristen et al, 2012). A randomized clinical trial is ongoing to evaluate the ability of EGCG in promoting regression of residual cardiac damage in patients with AL amyloidosis who have completed chemotherapy.

Pepys et al (2002) investigated the possibility of promoting resorption of amyloid deposits by depleting serum amyloid P component (SAP), a common constituent of amyloid deposits thought to protect them from resorption, with a palindromic compound, CPHPC (R-1-[6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl] pyrrolidine-2-carboxylic acid), a competitive inhibitor of SAP binding to amyloid fibrils. A pilot clinical study of CPHPC, showed promising results in subjects with hereditary fibrinogen amyloidosis (Gillmore et al, 2010). More recently, the same group showed that administration of anti-human-SAP antibodies to mice with amyloid deposits containing human SAP triggers resorption of visceral amyloid deposits (Bodin et al, 2010).

These alternative approach trials are ongoing, availing an appealing synergistic initiative to the present treatment of AL Amyloidosis.

Changes in survival – the beginning of a new era

When vital organs are targeted by the amyloidogenic light chains, it ultimately leads to the patient's death especially when there is cardiac involvement (60–70% of patients), with 3–6 months' OS without treatment (Obici et al, 2005). With the advances in supportive care as well as the rapid use of effective therapy, the survival curves of responding patients have become even better than that seen for MM patients. Recent reports of patient cohorts on long-term survival are encouraging. However, early deaths due to advanced, irreversible cardiac dysfunction at presentation remain an unsolved problem. A retrospective European collaborative study of 347 Patients with Mayo stage III disease (Wechalekar et al, 2011), mostly treated with MDex or thalidomide based regimens, still showed encouraging results. The haematological responses on an intention-to-treat basis were seen in more than 40% of patients, and for responding patients, the OS at 12 months from response evaluation was 74% for CR, 52% for PR and 18% for non responders. Thus, even patients with severe heart disease may benefit from treatment, provided they survive long enough for the treatment to exert its action. Even in elderly patients, a response may translate to better OS: 38 patients with a median age of 78 years, of which 37% had stage III disease (Venner et al, 2011), were treated mostly with CTD. Median OS for the entire cohort was 10·7 months, 45% died within 1 year of diagnosis. Yet, once again, attaining a VGPR, correlated with a statistically significant improvement in OS compared with patients who did not achieve this milestone (median not reached vs 9·8 months).

The largest series of patients was reported along 40 years of follow up (Kumar et al, 2011). Two thousand one hundred and eighteen patients were divided into four cohorts based on date of diagnosis; 1966–76 (n = 121), 1977–86 (n = 343), 1987–96 (n = 636) and 1997–2006 (n = 1017). The median OS from diagnosis for the four cohorts were 0·9, 1·2, 1·2 and 1·5 years respectively, P < 0·001. Nevertheless, from 2003 to 2006, the OS of 463 patients followed at this time period shows 42% survival at 4 years. These observations of early mortality emphasize the need for early diagnosis, and treatments of rapid action in this disadvantaged subset of patients.

Early diagnosis can be achieved by increasing the awareness of the disease amongst haematologists. As AL amyloidosis is a rare disease a population-based screening is not feasible. Nevertheless, there are subjects at relatively high risk of developing this disease who merit special attention. For instance, it is known that evolution to AL amyloidosis accounts for ∼10% of all progressions in patients with a monoclonal gammopathy of undetermined significance (Kyle et al, 2002, 2004), and the risk is particularly high in subjects with an altered FLC κ/λ ratio. In these patients, attention should be paid to the onset of early signs of amyloid-related organ involvement, such as the appearance of elevated NT-proBNP, albuminuria, elevated alkaline phosphatase or γ-glutamil-transpeptidase, onset of hypotension or resolution of hypertension, bilateral carpal tunnel syndrome, unexplained weight loss and fatigue (Merlini et al, 2012).

The future of novel agents holds great promise for both newly-diagnosed and relapsed/refractory patients. In the next few years, multiple agents are to be tested and re-assessed prospectively (Table 2). Early diagnosis allowing timely intervention remains the major key towards outcome improvement.

Is it time to prefer one approach over the other?

To date, there is no consensus regarding the optimal care for newly diagnosed patients. Figure 1 shows a comparison of different reports utilizing the available agents. Very few controlled trials comparing different therapeutic approaches exist in AL amyloidosis, and none include novel agents or biomarker-based risk stratification. Thus, it is vital that as many patients as possible be included in the ongoing clinical trials. One must consider the fact that each report has a different number and nature of patients, and includes different stages as well as newly diagnosed and relapsed subsets. The first randomized trial for novel agents in AL is still ongoing for newly diagnosed patients treated with BMDex versus MDex.

Cardiac staging (Table 1) with both NT-proBNP and cTn, and recently with the addition of light chain levels (Kumar et al, 2012a) before ASCT have gained large experience as first line therapy for eligible patients (Gertz, 2010; Palladini & Merlini, 2011b; Merlini et al, 2012). Patients can be divided into three groups according to their cardiac stage: low, intermediate and high risk.

Indications for treatment of AL amyloidosis outside clinical trials are given, based on evidence for uncontrolled studies and retrospective series (Fig 2). The choice of treatment should be based on risk-stratification. Low-risk patients with normal cTn, can be considered for ASCT. However, the very high rate of good quality responses observed with the stem cell-sparing regimen CyBorD (Mikhael et al, 2012; Venner et al, 2012), suggest that even these selected patients could not be transplanted frontline, but may be offered this combination instead. If CyBorD fails to induce a good quality response, then it is advisable to proceed to transplant. Bortezomib (or thalidomide) and dexamethasone can be used to improve the rate of CR after transplantation (Cohen et al, 2007; Landau et al, 2012).

Figure 2.

Treatment flowchart for patients with AL amyloidosis who are not enrolled in clinical trials. We suggest early haematological response re-assessment (after two-three cycles), and early switch/addition of therapy according to the response. Response criteria and risk assessment as previously revised (Palladini & Merlini, 2011a). ASCT, autologous stem cell transplant; BDex, bortezomib and dexamethasone; BMDex, bortezomib, melphalan and dexamethasone; CR, complete response; CyBorD, cyclophosphamide, bortezomib and dexamethasone; CTD, cyclophosphamide, thalidomide and dexamethasone; cTn, cardiac troponin; MDex, melphalan and dexamethasone; TDex, thalidomide and dexamethasone.

Approximately 50% of patients with AL amyloidosis are low-intermediate risk subjects who are not eligible for ASCT. If the reason making them ineligible for ASCT is potentially reversible, stem cell sparing regimens, such as CyBorD or CTD, should be preferred. Otherwise, BMDex could be used. The choice of second-line therapy depends on the regimen used frontline. Lenalidomide or pomalidomide combination should be considered in subjects already exposed to alkylators and bortezomib, whereas bortezomib should be used in patients who have not yet been exposed to this agent.

No treatment has proved able to overcome the poor prognosis of high-risk subjects. Nevertheless, in a small series, an unprecedented survival was reported for stage III subjects treated with CyBorD (Venner et al, 2012). Due to its very favourable toxicity profile, MDex with low-dose (20 mg/d) dexamethasone, could be also considered in this setting.

We suggest early haematological FLC response re-assessment (after two-three cycles), and early switch/addition of therapy according to the response.

Novel agents hold promise to achieve significant haematological responses as high as ASCT CR rates, but time curves are currently too short to conclude these will be durable. However, they may rapidly become the future first line treatment.

Acknowledgements

We thank Prof Giampaolo Merlini for his invaluable help in writing this manuscript. GP is partly supported by Grant N. 9965 from the Associazione Italiana per la Ricerca sul Cancro Special Program Molecular Clinical Oncology.

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