Review Hematology 4

Light chain in the era of novel agents

K. Beel, MD, PhD1

The development of new immunomodulatory therapies and their implementation in the treatment of mul- tiple myeloma in the past years, offer new perspectives for the treatment of other plasma dyscrasias. Light chain amyloidosis is historically associated with a very poor prognosis, despite the small size of the monoclonal plasma cell population, due to progressive deposition in vital organs. Hence, advances in treatment are eagerly awaited. Luckily, myeloma patients are paving the way for light chain amyloidosis treatment, clearly demonstrating that immunomodulatory drugs and proteasome inhibitors are capable of controlling plasma cell proliferation. Two recently published trials have shown a remarkable survival benefit with CyBorD, a bortezomib containing regimen in light chain amyloidosis, possibly setting a new standard for the treatment of this . In this article, we review current insights in the pathogenesis, diagnostic challenges, prognostic markers and available treatments for light chain amyloidosis. (Belg J Hematol 2013;4(4):120-126)

Introduction Systemic light chain amyloidosis (AL) is caused by a malities occur both in MM and in AL. The translocation small clone of plasma cells, synthesising immunoglob- t(11;14) is more frequent in AL (40-50%), but in contrast ulin light chain polypeptides, which are prone to mis- to MM, it is associated with a worse prognosis, as is folding and interstitial deposition as insoluble β-sheet the presence of cyclin D1 overexpression. Of interest, fibrils. Without treatment, the associated proteotoxicity marrow plasma cells of amyloidosis patients exert an inevitably leads to progressive failure and death. intermediate gene expression profile between a normal AL occurs in approximately one case per 100 000 per- and a myeloma signature.4 sons in western countries, similar to chronic myeloid leukaemia, with a mean age of 63 years at diagnosis. Pathogenesis Historically, AL had a very poor prognosis, with a me- The process of amyloid formation is not completely dian survival of thirteen months.1 Although AL is the understood. Like Parkinson’s disease and Alzheimer’s, most common type of systemic amyloidosis; hereditary, AL is a proteopathy, meaning that changes in senile and secondary forms exist and should not be conformation induce toxicity through highly ordered confused with AL because of the different therapies amyloid β-sheet depositions. AL amyloidosis is inher- indicated. An overlap with multiple myeloma (MM) ently linked to the adoptive immune response in jawed exists, as 20% of AL patients meet the criteria for vertebrates. Immunoglobulin formation in the plasma myeloma and up to 30% of myeloma patients have cell relies on recombination and somatic gene mutations. minor amyloid deposition.2 As opposed to other plasma However, genetic plasticity has its downside and amy- cell disorders, a 1:3 κ:λ ratio is found in AL, which loid formation could be considered the price for the supports the concept that λ light chains are intrinsically acquisition of a sophisticated adoptive immune system. more amyloi-dogenic than κ.3 Some cytogenetic abnor- It is assumed that the amyloid deposition process was

1Department of Haematology, Ziekenhuisnetwerk Antwerpen (ZNA), Antwerp, Belgium. Please send all correspondence to: K. Beel, MD, PhD, Ziekenhuisnetwerk Antwerpen (ZNA), Department of Haematology, Middelheim, Lindendreef 1, 2020 Antwerp, Belgium, tel: +32 3 230 34 95, email: [email protected]. Conflict of interest: The author has nothing to disclose and indicates no potential conflict of interest. Key words: diagnosis and treatment of AL amyloidosis, novel agents in AL amyloidosis, systemic immunoglobulin light chain amyloidosis.

Belgian Journal of Hematology Volume 4, Issue 4, December 2013 120 Review Hematology

clinical: high index of suspicion nephrotic range proteinuria, non-ischemic cardiomyopathy, , autonomic neuropathy with weight loss, unexplained hepatomegaly

histological: obtain biopsy fine needle aspiration of abdominal fat: noninvasive, fast, cheap (sensitivity 88%, specificity 97%)9

or minor labial salivary gland (sensitivity 50%), or bone marrow biopsy (sensitivity 60%,)7,8 or rectum, or renal biopsy staining and red-green under polarized light microscopy or 10 nm fibrils on electron microscopy possible future gold standard with amyloid typing capacity: laser dissection with mass spectrometry9

laboratory: demonstrate monoclonal gammopathy electrophoresis + serum immunophenotyping + serum FLC + urine EP/IFE = 98% sensitivity bone marrow biopsy with plasma cell count (median plasma cell precentage is 7%)

+ -

organ distribution: determine extent of disease (no uniform scoring criteria) molecular: typing of non AL amyloidosis -screen the heart with biomarkers troponin T and NT-proBNP <-> low sensitivity for EKG hereditary mutations in amyloid (TTR) (voltage loss), echocardio (atrial septum thickening), or cardiac MRI or direct amyloid fibril sequencing ($) -screen the kidneys with serum creatinine and 24h urine collection -screen other organs guided by signs & symptoms: EMG, pulmonary function, liver biopsy full body scan: SAP scintigraphy (only abroad, does not detect cardiac involvement)11

Figure 1. Diagnostic algorithm for light chain amyloidosis. selected during evolution, as a last resort to prevent Diagnosis misfolded from interaction with physiological The diagnosis of AL can be challenging and a high processes, by concentrating them in certain tissues.5 index of suspicion is required by all physicians, since Some mutations in the genes, encoding the variable AL is a systemic disease with a variable phenotype. domain of the light chains, can cause thermodynamic, A diagnostic delay results in more organ impairment, hydrophobic or electrostatic instability, giving rise to which jeopardises treatment tolerability, which in turn an amyloidogenic light chain. Up to 28 different amy- has a negative impact on prognosis. A diagnostic algo- loidogenic proteins have been recognised in humans, rithm is presented in Figure 1. but only a few are common.6 Once the secondary structure of an α-helix-rich , typical of most The four most frequent presentations of AL are nephrotic proteins, refolds and forms more β-sheet structures, syndrome with preserved glomerular filtration rate, non- peptides start to associate in an antiparallel way, allow- ischemic cardiomyopathy, autonomic (orthostatism) or ing continued amyloid polymerisation. Besides immu- peripheral neuropathy (carpal tunnel) and hepatomegaly noglobulin light chains, many stabilising proteins are with cholestasis.8 Kidney involvement is most frequent, present in amyloid fibrils, such as the serum amyloid but cardiac involvement is most dangerous. Fatigue (in protein (SAP) and . Specific char- 68%), peripheral oedema (in 62%) and weight loss (in acteristics (‘tropism’), e.g. matrix components glycos- 43%) are the most common systemic symptoms. Diar- aminoglycans and proteoglycans in the target organ, rhoea, due to gastro-intestinal amyloid deposition, occurs play a role in the amyloid deposition. As an example, the in 9%. Macroglossia (in 14%) or periorbital ecchymosis 6a λ light chain is classically mentioned as preferentially (raccoon eye) (in 11%) are rare, but pathognomonic for associated with kidney involvement. However, later AL, as is the shoulder-pad-sign (in 15%), caused by studies have shown that some cases involve the heart.7 periarticular amyloid infiltration. Factor X absorption

Belgian Journal of Hematology Volume 4, Issue 4, December 2013 121 4 of amyloid deposits and capillary fragility increase the for monitoring response in the vast majority of patients risk of bleeding.3 A biopsy needs to be obtained to con- and normalisation of the serum FLC ratio is a strong firm a clinical suspicion of amyloidosis. Fine needle predictor of survival. Classically, the more organs invol- aspiration of abdominal fat is the preferred diagnostic ved the worse the prognosis, but cardiac involvement test, as it is non-invasive, fast and cheap with a high has the greatest impact on survival with >70% of AL sensitivity (88%) and specificity (97%).3 Confirmation patients dying of amyloid cardiomyopathy. Dispenzieri of AL by the demonstration of a monoclonal gammopa- et al. developed the Mayo cardiac staging system, based thy and/or exclusion of other types of amyloidosis is on Troponin T and NT-pro-BNP levels, both sensitive important, to spare patients unnecessary . and reliable markers of cardiac function. Troponin T Common types of amyloidosis besides AL are senile, correlates with cardiac damage and NT-pro-BNP with hereditary (ATTR) and wall strain.8 Prognosis and survival differ significantly (AA) secondary to chronic . Senile amyloi- between patients with 0 (stage I), 1 (stage II) or 2 (stage dosis classically occurs in old men with isolated cardiac III) elevated markers.11 A reduction of 30% of NT-pro- involvement and the treatment is merely supportive. BNP with treatment qualifies as response and normal- Hereditary ATTR amyloidosis, particularly common in isation of NT-pro-BNP correlates with improved survival. African-Americans (3%), is a contra-indication for che- These biomarkers are less reliable for cardiac monitoring motherapy and requires liver transplantation. Molecular in the presence of renal failure, but in this case, they analysis of hereditary mutations in amyloid proteins and provide a composite view on both organ systems.12 With direct amyloid fibril sequencing can be performed, at a treatment, cardiac function starts to improve before the considerable expense, at the NHS amyloidosis Centre resorption of amyloid deposits, indicating that circulat- in London. Hereditary amyloidosis has a low penetrance ing amyloid precursors exert reversible organ toxicity. and a variable presentation in different family members, Therefore monitoring these biomarkers of cardiac func- further confounding the diagnosis.9 The mere presence tion is more useful for follow-up than echocardiographic of a serum or urine monoclonal protein leads to misdiag- measurement of wall thickening.13 The haematological nosis in 10%, as a coincidental monoclonal gammopathy disorder and organ damage are currently measured by of unknown significance (MGUS) is not uncommon in the combination of serum FLC and cardiac biomarkers patients with other types of amyloidosis.6 Moreover, the troponin T and NT-pro-BNP, which are easy and power- absence of a detectable serum monoclonal protein does ful tools for evaluation of prognosis and response to not exclude systemic amyloidosis. The last step in the therapy.14 Some authors recommend annual measure- diagnostic process is defining the extent of the disease. ment of NTpro-BNP and urinary albumin in all MGUS Localised amyloidosis is first suspected on the basis of patients with an abnormal FLC ratio.15 Other prognos- its location. It usually presents in the skin, larynx, brain, tic factors are the number of organs involved, the level bladder or as solitary pulmonary nodules. Life expec- of FLC at diagnosis, serum uric acid, male gender, tancy is normal and these patients should be referred weight loss and beta2-microglobulin, but these are not for laser therapy. A systematic clinical exam, followed validated.7 by directed organ screening helps to establish the extent of the disease. Iodinated serum amyloid P scintigraphy Treatment (SAP-scan) is a diagnostic tool for imaging organ distri- The goal of treatment is rapid reduction of the plasma bution at diagnosis or follow-up. However, its availability cell clone and elimination of circulating free light chains, is limited and cardiac involvement cannot be detected.10 in order to rescue organ function before irreversible damage has occurred, while supporting organ function Response monitoring and prognosis in a multidisciplinary way and to extend survival. There Hematologic response to therapy and the presence and is a clear relationship between hematologic response, the extent of cardiac involvement are significant inde- organ response and survival.16 Ideally, future treatments pendent prognostic factors in AL.3 Hematologic response should also contain fibril directed therapies, to prevent predicts and precedes organ response by a median of fibril formation and promote resorption of amyloid twelve months and is the goal of treatment. Before the deposits. advent of serum free light chain (FLC) nephelometry, The paucity of randomised trials and the heterogeneity measurement of hematologic response was difficult.7 of the disease challenge treatment recommendations. My- The serum FLC assay now represents a powerful tool eloma treatments seem to provoke a higher toxicity in AL

Belgian Journal of Hematology Volume 4, Issue 4, December 2013 122 Review Hematology

Table 1. Selected therapeutic trials in light chain amyloidosis

Regimen Patients (pretreated) Hematologic Response Complete Response Reference

Dex 25 (0) 40% 16% Gertz et al. 199924

Mel - Dex 89 (0) 68% 33% Palladini et al. 200418, Jaccard et al. 200722

ASCT 200 Mel 275 (0) 76% 33% Gertz et al. 200419

ASCT 100-140 Mel 173 (0) 53% 18% Gertz et al. 200419

Thal - Dex 31 (31) 48% 19% Palladini et al. 200525

Cy - Thal - Dex 75 (44) 74% 21% Wechalekar et al. 200726

Len - Dex 34 (31) 47% 21% Sanchorawala et al. 200727

Mel - Len - Dex 26 (0) 58% 23% Moreau et al. 201028

Cy - Len - Dex 35 (11) 60% 11% Kumar et al. 201229

Pom - Dex 33 (29) 47% 0% Dispenzieri et al. 201230

Bortezomib 70 (70) 69% 38% Reece et al. 201131

Bor - Dex 18 (7) 94% 44% Kastritis et al. 200732

Bor - Mel - Pred 16 (0) 94% 56% Gasparetto et al. 201033

Cy - Bor - Dex 17 (7) 94% 71% Mikhael et al. 201234

Cy - Bor - Dex 43 (23) 81% 40% Venner et al. 201235

Dex=dexamethasone, Mel=melphalan, ASCT=autologous stem cell transplantation, Thal=thalidomide, Cy=cyclophosphamide, Len=lenalidomide, Pom=pomalidomide, Bor=bortezomib

patients and treatment should be individualised based Deaths have been reported during stem cell mobilisation on age, frailty, organ dysfunction and treatment toxicities. in AL patients with cardiac disease. To minimise the risk of toxicity, granulocyte-colony stimulating factor Chemotherapy and stem cell transplantation (G-CSF) alone is recommended for mobilisation.20 Me- The first randomised trial in amyloidosis was melphalan dian time to organ response after ASCT is twelve months. plus prednisone versus placebo in 1978.17 This combi- In experienced centres, where strict selection criteria nation induced complete remission (CR) rates of 30%. are implemented, median survival in AL after ASCT is Replacing prednisone with dexamethasone improved eight years.21 However, the use of ASCT in AL remains response rates and survival (33% CR, 48% organ re- controversial, as the only randomised trial in amyloi- sponse, 5.1 years overall survival (OS)).18 However, in dosis treatment was a French multicentre trial on mel- patients with cardiac amyloidosis Mel-Dex is clearly phalan plus dexamethasone and ASCT, which showed ineffective. High dose melphalan (200 mg/m2) followed no superiority of Mel-Dex/ASCT over Mel-Dex alone.22 by autologous stem cell transplantation has improved Yet this trial was hampered by low patient numbers, outcome in a proportion of eligible patients. A pilot study the inclusion of patients with severe organ damage, with autologous stem cell transplantation (ASCT) was low experience with ASCT for AL at investigation sites performed in 1996.18 The high treatment related mor- and lack of randomisation for cardiac involvement.23 tality in this fragile population (especially with cardiac involvement) was reduced by attenuating the melphalan Novel agents conditioning dose (100-140 mg/m2) in frail patients Mel-Dex has a low CR rate and ASCT is limited to a but at the price of lower response and survival rates.19 minority of patients. Therefore, the search for therapies

Belgian Journal of Hematology Volume 4, Issue 4, December 2013 123 4 for AL continues. A selection of trials in treatment-naïve and dexamethasone.35 Larger phase III studies are cur- and relapsed AL patients is listed in Table 1. rently underway. The results of the addition of an imid to the steroid and Both studies are retrospective, have a limited number alkylating agent backbone are promising, but renal and of patients and a short follow-up. Despite these limita- cardiac toxicity, as well as the risk of venous thrombo- tions, these studies show that CyBorD has the poten- embolism are cause for concern. For lenalidomide, high- tial to change the natural course of the disease, through er doses than 15 mg per day are poorly tolerated in rapid and durable reduction of the culprit plasma cell patients with systemic AL. clone, and to reverse the poor outcome in patients with cardiac involvement. The use of bortezomib as induc- Since the first investigations with bortezomib, it’s became tion therapy renders some originally ineligible patients clear that this agent could represent a major break- eligible for transplantation. An important question to through in the treatment of AL, as bortezomib induces be answered in future prospective trials (as in myeloma) rapid reduction of monoclonal light chains with potent is whether ASCT is still mandatory for AL patients in hematologic and organ (especially cardiac) responses and stable CR after treatment with a bortezomib containing is well tolerated. However, dose reductions are required regimen. A European phase II trial is being developed in certain patients, especially in cases with neuropathy for patients with Mayo stage III cardiac disease, with or cardiac symptoms. attenuated bortezomib doses. CyBorD can be adminis- tered in Belgium, if bortezomib is obtained in compas- After impressive response rates in myeloma, CyBorD sionate use. The pharmaceutical company provides (the combination of cyclophosphamide, bortezomib and twelve compassionate use administrations per doctor dexamethasone) has been explored in light chain amy- per year. However, patient registration in a data survey loidosis. In May 2012, two independent groups reported would be highly recommendable, as this would at least on this therapy scheme. Mikhael et al. (Mayo clinic, allow a retrospective study. International collaboration Toronto) reported on a retrospective analysis of seven- is required to accrue enough patients in prospective teen patients with AL amyloidosis, ten of which were clinical trials. A Hovon trial opened in 2012, comparing treatment naive, who were treated with two to six cycles dexamethasone plus bortezomib versus dexamethasone of bortezomib 1.5 mg/m2 weekly or 1.3 mg/m2 on days alone as an induction therapy before ASCT. However, 1,4,8,11, cyclophosphamide 300 mg orally weekly and we believe that most treating physicians do not feel com- dexamethasone 40 mg weekly, before autologous stem fortable about withholding bortezomib from patients cell transplantation in eligible patients, as an alterna- with AL amyloidosis. tive to those ineligible and as salvage therapy for re- Future treatments will probably involve lapsed patients.34 They report unprecedented results, against Serum Amyloid Protein (SAP) or the tertiary with 94% hematologic responses and a 71% CR rate. structure of amyloid.36 SAP stabilises amyloid fibrils Renal response was observed in half of the patients. and promotes fibrillogenesis. Humanised monoclonal anti-SAP antibodies have been developed and are cur- Median duration of response was 22 months. Three rently being tested in phase I/II trials. Antibodies against ineligible patients became eligible after CyBorD. Low light chain fibril compounds are also being tested in a grade neuropathy was the major side effect, which phase I/II trial. could be managed by changing to weekly bortezomib. Venner et al. (London National amyloidosis Centre) Supportive organ care reported on 43 patients, of which 20 were treatment Organ function starts to improve several months after naive, who were treated with biweekly bortezomib, the achievement of a hematologic CR, but continues dexamethasone and cyclophosphamide. Hematologic to improve over time. Meanwhile, a multidisciplinary response rate was 81.4% with a CR rate of 39.5%. Stem approach is important for providing optimal individu- cell collection remained successful after eight cycles of alised supportive treatment. bortezomib 1.3 mg/m2 (1,4,8,11), dexamethasone 20 mg Patients with diastolic dysfunction are best treated with (1,2,4,5,8,9,11,12) and cyclophosphamide 350 mg/m2 a combination of loop diuretics and spironolactone. orally (d1,8,15). In the 20 patients with Mayo stage III Angiotensin converting (ACE) inhibitors can cardiac disease, the OS at two years was 94.4%, im- worsen cardiac symptoms, unless used to treat hyper- proving the ten month median survival with melphalan tension. Anticoagulation should be considered to prevent

Belgian Journal of Hematology Volume 4, Issue 4, December 2013 124 Review Hematology

Key messages for clinical practice

• A fast and accurate diagnosis of light chain amyloidosis requires a high index of suspicion and is crucial to prevent end-stage organ failure. • Cardiac involvement and response to treatment are the most important prognostic factors in light chain amyloidosis. • Serum FLC and cardiac biomarkers troponin T and NT-pro-BNP are elegant and powerful tools for the evaluation of prognosis and response to therapy in light chain amyloidosis. • CyBorD looks promising as standard treatment for light chain amyloidosis. The role of autologous stem cell transplantation in the era of novel agents remains to be determined.

atrial thrombosis, but bleeding is a risk. Digoxin is achieved by a combination of cytotoxic chemotherapy, contra-indicated for atrial fibrillation in AL patients, as targeted and immunologic approaches to prevent amy- this seems to bind to amyloid deposits with increased loid deposition and promote fibril resorption.8 toxicity. Calcium channel blockers can aggravate con- gestive heart failure and beta-blockers have shown to References increase mortality in cardiac AL. Amiodarone is best 1. Kyle RA, Gertz MA, Greipp PR, et al. Long-term survival (10 years or more) in tolerated. For severe nephrotic syndrome, diuretics are 30 patients with primary amyloidosis. Blood 1999;93:1062-6. the mainstay of therapy. ACE inhibitors can be consid- 2. Hawkins PN, Myers MJ, Epenetos AA, et al. Specific localisation of imaging ered to reduce proteinuria, but caution is warranted in of amyloid deposits in vivo using 123I-labeled serum amyloid P component. the case of poor cardiac output or hypotension. Octreo- J Exp Med 1988;167:903-13. tide is effective for the treatment of diarrhoea. Renal 3. Merlini G, Palladini G. Advances in AL amyloidosis. Hematology Education: transplantation can be considered after ASCT and the education program for the annual congress of the European Hematology results in prolonged survival. Heart transplantation Association 2008;2:287-93. has been carried out before and after ASCT with accept- 4. Abraham RS, Ballman KV, Dispenzieri A, et al. Functional gene expression able outcomes in small series.7 analysis of clonal plasma cells identifies a unique molecular profile for light chain amyloidosis. Blood 2005;105:794-803. Conclusion 5. Sukhanova A, Poly S, Shemetov A, et al. Implications of Protein Structure Systemic AL is a life-threatening disease and prompt Instability: From Physiological to Pathological Secondary Structure. Biopolymers diagnosis is required to allow intensive treatment in 1997;8:577-88. order to preserve organ, especially cardiac, function. 6. Sipe JD, Benson MD, Buxbaum JN, et al. Amyloid fibril protein nomenclature: The expanding myeloma armamentarium is improving 2010 recommendations for the nomenclature committee of the International AL treatment, but specific large randomised trials in Society of Amyloidosis. Amyloid 2010;17:101-4. amyloidosis are urgently needed. To date there are no 7. Dispenzieri A, Gertz MA, Buadi F. What do I need to know about immuno- approved drugs for the treatment of light chain amyloi- globulin light chain (AL) amyloidosis? Blood Reviews 2012;26:137-54. dosis. Because of the rarity and the heterogeneity of 8. Merlini G, Seldin D, Gertz MA. Amyloidosis: Pathogenesis and New Therapeutic the disease, internationally joint efforts will be required Options. J Clin Oncol 2011;29:1924-33. for prospective AL studies. The field is now mature for 9. Loo D, Mollee P, Renaut P, et al. Proteomics in Molecular Diagnosis: Typing of large scale international collaborations. Such a network Amyloidosis. J Biomed Biotechnol 2011;1-9. of amyloidosis referral centres is currently working on 10. Hawkins PN, Myers MJ, Epenetos AA, et al. Specific localisation of imaging a framework to facilitate clinical research in AL amyloi- of amyloid deposits in vivo using 123I-labeled serum amyloid P component. dosis (XIII International Symposium on Amyloidosis, J Exp Med 1988;167:903-13. May 2012, Groningen). One important task for future 11. Dispenzieri A, Gertz MA, Kyle RA, et al. Serum cardiac troponins and N- trials will be to determine the role of ASCT in AL. terminal pro-brain natriuretic peptide: a staging system for primary systemic With the advent of novel agents, the field of amyloidosis amyloidosis. J Clin Oncol 2004;22:3751-7. has entered an exciting era. A real prospect of cure 12. Dispenzieri A, Kyle R, Merlini G, et al. International Myeloma Working Group emerges on the horizon and this will probably be guidelines for serum-free light chain analysis in multiple myeloma and related

Belgian Journal of Hematology Volume 4, Issue 4, December 2013 125 4

disorders. Leukemia 2009;23:215-24. primary amyloidosis (AL). Blood 2005;105:2949-51. 13. Palladini G, Lavatelli F, Russo P, et al. Circulating amyloidogenic free light 26. Wechalekar AD, Goodman HJ, Lachmann HJ, et al. Safety and efficacy of chains and serum N-terminal natriuretic peptide type B decrease simultaneously risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic in association with improvement of survival in AL. Blood 2006;107(10):3854-8. AL amyloidosis. Blood 2007:109(2): 457-64. 14. Wechalekar AD, Wassef NL, Gibbs SD, et al. A new staging system for AL 27. Sanchorawala V, Wright DG, Rosenzweig M, et al. Lenalidomide and dexa- amyloidosis incorporating serum free light chains, cardiac troponin-T and NT- methasone in the treatment of AL amyloidosis: results of a phase II trail. Blood pro-BNP. Blood 2009;114:abstr 2796. 2007;109:492-6. 15. Merlini G, Wechalekar AD, Palladini G. Systemic light chain amyloidosis: an 28. Moreau P, Jaccard A, Benboubker L, et al. Lenalidomide in combination with update for treating physicians. Blood 2013;121(26):5124-30. melphalan and dexamethasone in patients with newly-diagnosed light-chain-(AL) 16. Dispenzieri A, Lacy MQ, Katzmann JA, et al. Absolute values of immunoglobulin amyloidosis: A multicentre phase I/II dose escalation study. Blood 2010;116:4777-82. free light chains are prognostic in patients with primary systemic amyloidosis 29. Kumar SK, Hayman SR, Buadi FK, et al. Lenalidomide, cyclophosphamide, undergoing peripheral blood stem cell transplantation. Blood 2006;107:3378-83. and dexamethasone (CRd) for light chain amyloidosis: long-term results from a 17. Kyle RA, Greipp PR. Primary systemic amyloidosis: comparison of melphalan phase II trial. Blood 2012;119:4860-7. and prednisone versus placebo. Blood 1978;52(4):818-27. 30. Dispenzieri A, Buadi F, Laumann K, et al. Activity of pomalidomide in patients 18. Palladini G, Perfetti V, Obici L, et al. Association of melphalan and high-dose with immunoglobulin light-chain amyloidosis. Blood 2012;119:5397-5404. dexamethasone is effective and well tolerated in patients with AL (primary) amy- 31. Reece DE, Hegenbart U, Sanchorawala V, et al. Efficacy and safety of weekly loidosis who are ineligible for stem cell transplantation. Blood 2004;103(8):2936-8. and twice-weekly bortezomib in patients with relapsed systemic AL amyloidosis: 19. Gertz MA, Lacy MQ, Dispenzieri A, et al. Risk-adjusted manipulation of melpha- results of a phase I/II study. Blood 2011;118(4)865-73. lan dose before stem cell transplantation in patients with amyloidosis is associated 32. Kastritis E, Anagnostopoulos A, Roussou M, et al. Treatment of light chain with a lower response rate. Bone Marrow Transplantation 2004;34:1035-1. (AL) amyloidosis with the combination of bortezomib and dexamethasone. Hae- 20. Sanchorawala V. Role of high-dose melphalan and autologous peripheral matologica 2007;92:1351-8. blood stem cell transplantation in AL amyloidosis. Am J Res 2012;2(1):9-17. 33. Gasparetto C, Sanchorawala V, Snyder RM, et al. Use of melphalan (M)/ 21. Gertz MA, Lacy MQ, Dispenzieri A, et al. Transplantation for amyloidosis. dexamethasone (D)/bortezomib in AL amyloidosis. J Clin Oncol (ASCO Meet Curr Opin Oncol 2007;19(2):136-41. abstract) 2010;28(suppl. 15): 8024 22. Jaccard A, Moreau P, Leblond V, et al. High-dose melphalan versus melphalan 34. Mikhael JR, Schuster SR, Jimenez-Zepeda VH, et al. Cyclophosphamide-bort- plus dexamethasone for AL amyloidosis. N Engl J Med 2007:357(11):1083-93. ezomib-dexamethasone (CyBorD) produces rapid and complete hematologic 23. Rosenzweig M, Landau H. Light chain (AL) amyloidosis: update on diagnosis response in patients with AL amyloidosis. Blood 2012;119(19):4391-4. and management. Journal of Hematology & Oncology 2011;4(47):1-8. 35. Venner CP, Lane T, Foard D, et al. Cyclophosphamide, bortezomib, and 24. Gertz MA, Lacy MQ, Lust JA, et al. Phase II trial of high-dose dexamethasone dexamethasone therapy in AL amyloidosis is associated with high clonal response for untreated patients with primary systemic amyloidosis. Med Oncol 1999;16:104-9. rates and prolonged progression-free survival. Blood 2012;119(19):4387-90. 25. Palladini G, Perfetti V, Perlini S, et al. The combination of thalidomide and 36. Bodin K, Ellmerich S, Kahan MC, et al. Antibodies to human serum amyloid intermediate-dose dexamethasone is an effective treatment for patients with P component eliminate visceral amyloid deposits. Nature 2010;468(7320):93-7.

Belgian Journal of Hematology Volume 4, Issue 4, December 2013 126