2010-April-Guidelines for use of serum free light chain assays

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Chapter

25

SECTION 4 - General applications of free light chain assays

Guidelines for use of serum free light chain assays

Contents

International and national guidelines for identifying and managing patients with plasma cell dyscrasias are published and updated on a regular basis. These are widely adopted for assessing new patients and for patient entry into clinical trials. This chapter provides an overview of key available guidelines with an emphasis on recommendations relating to the serum free light chain (sFLC) component (identified in blue).


25.3._International_Myeloma_Working_Group_guidelines_for_monoclonal_gammopathy_of_undetermined_significance_and_smouldering_multiple_myeloma_.282010.29

25.1. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders

Comprehensive guidelines were published in 2003 [1], subsequently updated in 2006 [2] and further clarified in 2009 [3] and 2010 [4]. The criteria comprise the following:

Monoclonal gammopathy of undetermined significance (MGUS)
All three criteria must be met:
  • Serum monoclonal protein <30g/L
  • Clonal bone marrow plasma cells <10%, and
  • Absence of end-organ damage such as hypercalcaemia, renal insufficiency, anaemia, and bone lesions that can be attributed to the plasma cell proliferative disorder
Smouldering (asymptomatic) multiple myeloma (SMM)
Both criteria must be met:
  • Serum monoclonal protein (IgG or IgA) ≥30g/L and/or clonal bone marrow plasma cells ≥10%, and
  • Absence of end-organ damage such as lytic bone lesions, anaemia, hypercalcalcaemia, or renal failure that can be attributed to the plasma cell proliferative disorder
Multiple myeloma (MM)
All three criteria must be met except as noted:
  • Clonal bone marrow plasma cells ≥10%
  • Presence of serum and/or urinary monoclonal protein (except in patients with nonsecretory multiple myeloma (NSMM)), and
  • Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:
    • Hypercalcaemia: serum calcium ≥11.5 mg/dL or
    • Renal insufficiency: serum creatinine >1.73 mmol/L
    • Anaemia: normochromic, normocytic with a haemoglobin value of >2 g/dL below the lower limit of normal or a haemoglobin value <10 g/dL
    • Bone lesions: lytic lesions, severe osteopenia or pathological fractures

Classification criteria for the less common plasma cell dyscrasias (some of which do not yet include the use of sFLCs) are described in Chapter 18.

25.2. International Myeloma Working Group: guidelines for serum free light chain analysis in multiple myeloma and related disorders (2009)

These guidelines, published in 2009 [5], discuss published evidence for the utility and application of the sFLC assays for most plasma cell disorders and include symptomatic MM, NSMM, light chain multiple myeloma (LCMM), SMM, MGUS, solitary plasmacytoma and AL Amyloidosis. Furthermore, these guidelines highlight key recommendations for the use of the sFLC assays in screening, prognosis and in the assessment of patient response to treatment. Specific emphasis is placed on distinguishing between proven utility and those potential utilities which remain under investigation.

Screening

sFLC assays are recommended to be used in combination with serum protein electrophoresis (SPE) and serum immunofixation electrophoresis (IFE) to screen for pathological monoclonal plasmaproliferative disorders other than AL amyloidosis, which additionally requires a 24-hour urine IFE.

Prognosis

It is recommended that baseline sFLC assay results are obtained at diagnosis for all patients with MGUS, SMM or active MM, solitary plasmacytoma and AL amyloidosis. Highly abnormal results have been shown to be prognostic in virtually every plasma cell disorder. Notably, in MGUS, SMM and plasmacytoma, a highly abnormal sFLC result indicates a substantial risk of progression to systemic disease.

Monitoring and response assessment

sFLC assays are recommended for the quantitatitve monitoring of patients with oligosecretory plasma cells disorders, including patients with AL amyloidosis, oligosecretory myeloma and in nearly two-thirds of patients previously classified as NSMM. Furthermore, in the absence of urinary evaluations or FLC measurements, light chain escape can be missed and so these tests should be performed periodically. Baseline results of sFLC testing are required prior to initiating new chemotherapy regimens for all patients with MM to determine if a stringent complete response has been attained after a complete response has been achieved. Despite limited published data validating the use of sFLC assays in patients with light chain deposition disease, the personal experience of the guidelines' authors confirms their utility in these cases.

25.3. International Myeloma Working Group guidelines for monoclonal gammopathy of undetermined significance and smouldering multiple myeloma (2010)

For patients with MGUS, the size of the monoclonal protein, type of monoclonal protein, sFLC ratio, as well as the proportion of aberrant plasma cells within the bone marrow are helpful in identifying patients who are at increased risk of progression [6][7][8][9][10]. International Myeloma Working Group (IMWG) guidelines [4] now recommend that patients with MGUS should be risk stratified at diagnosis to optimise counseling and follow up using a risk stratification model incorporating the following 3 risk factors: serum monoclonal immunoglobulin size (≥15 g/L); serum monoclonal immunoglobulin type (IgA or IgM) and an abnormal sFLC κ/λ ratio (Table 25.1 and Chapter 19) . For patients with low-risk MGUS, a baseline bone marrow examination or skeletal radiography is not routinely indicated. For patients with intermediate- and high-risk MGUS a bone marrow aspirate and biopsy should be carried out at baseline to rule out an underlying plasma cell malignancy [4].

MGUS risk group Criteria Absolute risk* (%) Recommended follow-up
Low Serum M-protein (<15 g/L)

IgG subtype

Normal sFLC ratio (0.26-1.65)		 2 6 months initially, and if stable, follow up every 2-3 years or when symptoms suggestive of a plasma cell malignancy arise
Low-intermediate Any one risk factor present 10 6 months initially, then annually and upon any change in the patient's clinical condition
High-intermediate Any two risk factors present 18
High All three risk factors present 27

Table 25.1 Summary of MGUS risk groups and recommended follow-up. *of progression at 20 years accounting for death as a competing risk. Risk factors are defined as: serum monoclonal immunoglobulin size (≥15 g/L); serum monoclonal immunoglobulin type (IgA or IgM) and an abnormal sFLC κ/λ ratio

For patients with SMM, the guidelines recommend initial laboratory tests to confirm the diagnosis (SPE, 24-hour urine collection for electrophoresis), and to rule out MM (full blood cell count, calcium, and creatinine), at baseline and after 2 to 3 months. Baseline sFLC measurements are required for risk stratification and a baseline bone marrow biopsy and skeletal survey are mandatory. If the results are stable, the studies should be repeated every 4-6 months for 1 year, and if stable, the follow-up period can be lengthened to every 6 to 12 months [4].

25.4. UK Myeloma Forum and Nordic Myeloma Study Group: guidelines for the investigation of newly detected M-proteins and management of monoclonal gammopathy of undetermined significance (2009)

These 2009 guidelines [11] recommend SPE and urine protein electrophoresis (UPE) analysis in patients with a clinical presentation suspicious for monoclonal gammopathy: elevated erythrocyte sedimentation rate, anemia, hypercalcemia, renal failure and high or low serum concentrations of total immunoglobulins or the individual classes. IFE analysis is advised, in the absence of a detectable M-protein, where there is a strong clinical suspicion of underlying plasma cell dyscrasia.

Where urine samples are unavailable, sFLC analysis is required for the detection of NSMM and certain cases of AL amyloidosis and LCMM. sFLC analysis is also advised where serum immunoglobulin levels are low and no serum M-protein is identified. Alternatively a urine sample may be requested for IFE.

The guidelines also discuss the current evidence for differential diagnosis of monoclonal gammopathies, including the definitions for diagnosis, as stated in Section 25.1 [1]. Added to this is emphasis on low level M-protein concentrations usually being observed with MGUS, although commenting that some patients within this group will have AL amyloidosis, LCMM or solitary plasmacytoma. The guidelines further discuss prognosis and risk factors for MGUS and its malignant transformation. The value of the sFLC κ/λ ratio, along with M-protein level and immunoglobulin type, in differentiating high and low risk of malignant transformation is discussed [12].

According to these guidelines [11], the frequency of monitoring MGUS patients considered at low risk, particularly those with low paraprotein concentrations, could be reduced if actual life expectancy is low and all lymphoproliferative diseases other than MGUS have been excluded. This is in agreement with the IMWG guidelines (see Section 25.3 above) [4]. For those patients with longer life expectancies, higher M-protein levels, and non-IgG subtypes, monitoring every 3-4 months within the first year was considered advisable and thereafter once or twice yearly in the absence of symptoms of progression. For patients with an abnormal baseline sFLC ratio or significant Bence Jones proteinuria, the risk of renal failure is increased, and more frequent monitoring along with ample hydration was recommended.

25.5. International Myeloma Working Group: guidelines for standard investigative workup of patients with suspected multiple myeloma (2011)

sFLC analysis is recommended as part of the standard investigative workup in all newly diagnosed patients with plasma cell dyscrasias [13]. It was noted that sFLC testing is particularly important in patients with NSMM, LCMM, as well as in patients with oligosecretory myeloma. Measurement of urine FLC levels is not recommended.

25.6. International Myeloma Working Group: guidelines for risk stratification in multiple myeloma (2011)

Evaluation of prognostic factors and risk stratification in newly-diagnosed patients is important to define treatment strategies, compare outcome of therapeutic trials and predict survival from diagnosis. The 2011 IMWG guidelines for risk stratification [14] state that the International staging system (ISS) [15], incorporating serum albumin and β2-microglobulin, is applicable as a prognostic system in the majority of settings. High serum β2-microglobulin and ISS stages II and III are considered to predict higher risk disease (Table 25.2). In addition, cytogenetics and FISH analysis play an important and independent role in risk stratification.

Other additional factors may have a significant role in risk stratification as individual factors. These include extramedullary or plasmablastic disease, plasma cell leukaemia, renal failure, lactate dehydrogenase (LDH), IgA, high sFLCs and an abnormal κ/λ ratio.

Stage Criteria Median Survival
I Serum β2M <3.5mg/L. Serum albumin ≥35g/L 62 months
II* Not stage I or III 44 months
III Serum β2M ≥5.5mg/L 29 months

Table 25.2 International Staging System. *There are 2 categories for stage II: serum β2M <3.5mg/L but serum albumin <35g/L; or serum β2M 3.5 to <5.5mg/L, irrespective of the serum albumin level.

Earlier staging systems included concentrations of monoclonal immunoglobulins. It has now been realised that these have little relevance to MM outcome. For IgG MM this may be due to variable recycling by FcRn receptors (Chapters 10 and 32). In contrast, elevated sFLC concentrations and abnormal κ/λ ratios do relate to disease stage and outcome (Chapters 11 and 12). This may relate to their more constant clearance rate, capacity to cause renal damage (Chapter 13) and their association with IgH translocations [16].

25.7. International Myeloma Working Group: uniform response criteria for multiple myeloma (2011)

These guidelines summarise the current response criteria in MM (Table 25.3) [17]. It is proposed that all future clinical trials in MM follow these guidelines for reporting results. They are largely based on the IMWG uniform response criteria [18], with additional clarifications [3][17]. Incorporation of sFLC assays has enabled greater inclusion of patients who do not have measurable disease on serum and urine protein electrophoresis, and provided stricter definitions of complete response [19].

Response subcategory
 Response criteria
Complete response (CR)
  • Negative IFE of serum and urine, and
  • Disappearance of any soft tissue plasmacytomas, and
  • <5% plasma cells in bone marrow
  • In patients in whom the only measurable disease is by sFLC levels, CR is defined as a normal FLC ratio (0.26-1.65) in addition to the CR criteria listed above
Stringent complete response (sCR)
CR as defined above plus
  • Normal FLC ratio, and
  • Absence of clonal plasma cells by immunohistochemistry or 2-4 colour flow cytometry
Immunophenotypic CR
sCR plus
  • absence of phenotypically aberrant plasma cells in bone marrow with a minimum of one million of total bone marrow cells analyzed by multiparametric flow cytometry (with ≥4 colours)
Molecular CR
CR plus
  • Negative ASO-PCR, sensitivity 10-5
Very good partial response (VGPR)
  • Serum and urine M-protein detectable by IFE but not on electrophoresis, or
  • ≥90% reduction in serum M-protein plus urine M-protein <100 mg per 24 hours
  • In patients in whom the only measurable disease is by sFLC levels, VGPR is defined as a >90% decrease in the difference between involved and uninvolved sFLC levels
Patial response (PR)
  • ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg per 24 hours
  • In patients in whom the only measurable disease is by sFLC levels, PR is defined as a ≥50% decrease in the difference between involved and uninvolved sFLC levels
  • If serum and urine M-protein are unmeasurable, and sFLCs are also unmeasurable, ≥50% reduction in bone marrow plasma cells is required in place of M-protein, provided baseline percentage was ≥30%
  • In addition to the above criteria, if present at baseline, ≥50% reduction in the size of soft tissue plasmacytomas is also required
Stable disease (SD)
Not meeting criteria for CR, VGPR, PR or progressive disease
Progressive disease (PD)
  • Increase of 25% from lowest response value in any one or more of the following:
    • Serum M-protein (absolute increase must be ≥5 g/L) and/or
    • Urine M-protein (absolute increase must be ≥200 mg/24 hours) and/or
    • In patients in whom the only measurable disease is by sFLC levels, the difference between involved and uninvolved sFLC levels (absolute increase must be >100 mg/L)
    • If serum and urine M-protein are unmeasurable, and sFLCs are also unmeasurable, bone marrow plasma cell percentage (absolute % must be ≥10%)
  • Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas
  • Development of hypercalcaemia (corrected serum calcium >11.5 mg/dL) that can be attributed solely to the plasma cell proliferative disorder

Table 25.3 IMWG: uniform response criteria for MM
Note that all response categories require two consecutive assessments made at any time before the institution of any new therapy. CR, PR and SD categories also require no known evidence of progressive or new bone lesions if radiographic studies were performed. VGPR and CR categories require serum and urine studies regardless of whether disease at baseline was measurable on serum, urine, both or neither. Radiographic studies are not required to satisfy these response requirements. Bone marrow assessments need not be confirmed. For PD, serum M-protein increases of ≥10 g/L are sufficient to define relapse if starting M-protein is ≥50 g/L. ASO-PCR: Allele-specific oligonucleotide polymerase chain reaction.


It is recommended that patients undergoing therapy be tracked monthly for the first year of new therapy and every alternate month thereafter. Patients with measurable disease by SPE or UPE (defined as serum monoclonal protein ≥10 g/L; urine monoclonal protein ≥200 mg/24 hours), or both, will be assessed for response based only on these two tests, and not by FLC assays. In these patients, FLC assays are only required for assessment of stringent complete response [20].

In patients in whom the only measurable disease is by sFLC levels (defined as involved FLC ≥100 mg/L, provided the FLC ratio is abnormal), the definition of partial or very good partial sFLC response requires subtraction of the tumour ("involved") FLC from the non-tumour ("uninvolved") FLC. This difference calculation provides an interpretable result when the non-tumour FLC is either below the detection limit or fluctuating widely. It is also helpful when interpreting high concentrations of the alternate FLC that are seen in patients with impaired renal function (Chapter 20.2).

25.8. British Committee for Standards in Haematology: guidelines on the diagnosis and management of multiple myeloma (2010)

British guidelines on the diagnosis and management of MM published in 2006 [21] have undergone major revision and are now available online [22]. These guidelines include the following uses of sFLC measurements:

Investigation and diagnosis

Assessment of sFLCs is recommended as part of the diagnostic work up of patients where there is a strong suspicion of myeloma but in whom routine serum protein electrophoresis is negative. sFLCs are also recommended in requests for which urine has not been sent to the laboratory (Chapters 23 and 24)). Quantification of sFLCs and κ/λ ratio is recommended in the initial investigation of patients with LCMM, NSMM and oligosecretory disease (Chapters 8, 9 and 11).

Measuring response to therapy

sFLC assays are recommended to assess response in all patients with LCMM, NSMM and oligosecretory disease (Chapters 23 and 24). Quantification of sFLCs and κ/λ ratio is recommended in the initial investigation of patients with LCMM, NSMM and oligosecretory disease (Chapters 8, 9 and 12). sFLCs should also be used to monitor patients with renal impairment. Response to therapy should be defined using the IMWG uniform response criteria (see Section 25.7). The stringent complete response category is recommended only for use in a clinical trial setting.

Monitoring SMM

Monitoring of patients with SMM should include regular clinical assessment and monoclonal protein measurement, including sFLC analysis when indicated.

25.9. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: multiple myeloma (2011)

sFLC assays (Freelite™) are recommended by the NCCN Clinical Practice Guidelines in Oncology for use in the intial diagnostic workup of MM and related disorders [23].

25.10. European Society of Medical Oncology: recommendations for diagnosis, treatment and follow-up of multiple myeloma (2009)

sFLC measurements are useful for identifying and monitoring patients with NSMM [24]. Furthermore, sFLC determination can be used as well as or instead of urine electrophoresis in follow up.

25.11. International Society of Amyloidosis: definition of organ involvement and response to treatment in AL amyloidosis (2010)

Uniform criteria for the definition of organ involvement and response to treatment in AL amyloidosis were first published in 2005 [25], and subsequently updated in 2010 at the 12th International Symposium on Amyloidosis (Table 25.4) [26][27][28]. The definition of measurable absolute concentration of involved FLC was revised to a >50 mg/L difference between involved and uninvolved FLC concentrations (dFLC). Patients with a dFLC below the threshold (50 mg/L) remain eligible for clinical trials but are evaluable only for CR as well as organ response [26].

Response subcategory
 Response criteria
Complete response (CR)
  • Negative IFE of serum and urine, and
  • Normal FLC ratio, and
  • <5% plasma cells in bone marrow
Very good partial response (VGPR)
  • absolute value of the difference between involved and uninvolved sFLC concentrations is <40 mg/L
Partial response (PR)
  • >50% decrease in the difference between involved and uninvolved sFLC levels
No response
  • Other

Table 25.4 International Society of Amyloidosis criteria for haematological response

25.12. British Committee for Standards in Haematology: guidelines on the diagnosis and management of AL amyloidosis (2004)

The report includes the following recommendations [29]:

Investigation of suspected AL amyloidosis

Initial invesetigation should confirm the diagnosis of amyloidosis on tissue biopsy and this should be followed by investigations to establish the type of amyloid present, including quantitative sFLC assays (Chapter 15).

Monitoring AL amyloidosis

Response to treatment should be monitored with sFLC assays. The sFLC assays appear to be the most sensitive method for monitoring the clonal disease in AL amyloidosis patients. Treatment should be continued until the clonal disease has been suppressed by at least 50-75%, or until plateau (Chapter 15).


Chapter 24 Back to Contents Page Chapter 26

References

  1. ↑ 1.0 1.1 Kyle R, Child JA, Anderson K, Barlogie B, Bataille R, Bensinger W, et al. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol 2003;121:749-57 PMID: 12780789
  2. ↑ Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, et al. International uniform response criteria for multiple myeloma. Leukemia 2006;20:1467-73 PMID: 16855634
  3. ↑ 3.0 3.1 Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia 2009;23:3-9 PMID: 18971951
  4. ↑ 4.0 4.1 4.2 4.3 4.4 Kyle RA, Durie BG, Rajkumar SV, Landgren O, Blade J, Merlini G, et al. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia 2010;24:1121-7 PMID: 20410922
  5. ↑ Dispenzieri A, Kyle R, Merlini G, Miguel JS, Ludwig H, Hajek R, et al. International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders. Leukemia 2009;23:215-24 PMID: 19020545
  6. ↑ Kyle RA, Therneau TM, Rajkumar SV, Remstein ED, Offord JR, Larson DR et al. Long-term follow-up of IgM monoclonal gammopathy of undetermined significance. Blood 2003;102:3759-64 PMID: 12881316
  7. ↑ Blade J, Lopez-Guillermo A, Rozman C, Cervantes F, Salgado C, Aguilar JL et al. Malignant transformation and life expectancy in monoclonal gammopathy of undetermined significance. Br J Haematol 1992;81:391-4 PMID: 1390212
  8. ↑ Cesana C, Klersy C, Barbarano L, Nosari AM, Crugnola M, Pungolino E et al. Prognostic factors for malignant transformation in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. J Clin Oncol 2002;20:1625-34 PMID: 11896113
  9. ↑ Rajkumar SV, Kyle RA, Therneau TM, Melton LJ, III, Bradwell AR, Clark RJ et al. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood 2005;106:812-7 PMID: 15855274
  10. ↑ Perez-Persona E, Vidriales MB, Mateo G, Garcia-Sanz R, Mateos MV, de Coca AG et al. New criteria to identify risk of progression in monoclonal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells. Blood 2007;110:2586-92 PMID: 17576818
  11. ↑ 11.0 11.1 Bird J, Behrens J, Westin J, Turesson I, Drayson M, Beetham R, et al. UK Myeloma Forum (UKMF) and Nordic Myeloma Study Group (NMSG): guidelines for the investigation of newly detected M-proteins and the management of monoclonal gammopathy of undetermined significance (MGUS). Br J Haematol 2009;147:22-42 PMID: 19673884
  12. ↑ Rajkumar SV. MGUS and smoldering multiple myeloma: Update on pathogenesis, natural history and management. Hematology Am Soc Hematol Educ Program 2005:340-5 PMID: 16304401
  13. ↑ Dimopoulos M, Kyle R, Fermand JP, Rajkumar SV, San MJ, Chanan-Khan A et al. Guidelines for standard investigative workup: report of the International Myeloma Workshop Consensus Panel 3. Blood 2011 PMID: 21292778
  14. ↑ Munshi NC, Anderson KC, Bergsagel PL, Shaughnessy J, Palumbo A, Durie B et al. Guidelines for risk stratification in multiple myeloma: report of the International Myeloma Workshop Consensus Panel 2. Blood 2011 PMID: 21292777
  15. ↑ Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Blade J, et al. International staging system for multiple myeloma. J Clin Oncol 2005;23:3412-20 PMID: 15809451
  16. ↑ Kumar S, Zhang L, Dispenzieri A, Van WS, Katzmann JA, Snyder M et al. Relationship between elevated immunoglobulin free light chain and the presence of IgH translocations in multiple myeloma. Leukemia 2010;24:1498-505 PMID: 20520636
  17. ↑ 17.0 17.1 Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood 2011 PMID: 21292775
  18. ↑ Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, et al. International uniform response criteria for multiple myeloma. Leukemia 2006;20:1467-73 PMID: 16855634
  19. ↑ Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, et al. International uniform response criteria for multiple myeloma. Leukemia 2006;20:1467-73 PMID: 16855634
  20. ↑ Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, et al. International uniform response criteria for multiple myeloma. Leukemia 2006;20:1467-73 PMID: 16855634
  21. ↑ Smith A, Wisloff F, Samson D. Guidelines on the diagnosis and management of multiple myeloma 2005. Br J Haematol 2006;132:410-51 PMID: 16412016
  22. ↑ Bird J, Owen R, D'sa S, Snowden J, Pratt G, Littlewood T et al. Guidelines on the diagnosis and management of multiple myeloma http://www.bcshguidelines.com/4_HAEMATOLOGY_GUIDELINES.html
  23. ↑ Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Multiple Myeloma V.1.2011. © 2010 National Comprehensive Cancer Network, Inc. All rights reserved [1]
  24. ↑ Harousseau JL, Dreyling M. Multiple myeloma: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2009;20:97-9 PMID: 17491042
  25. ↑ Gertz MA, Comenzo R, Falk RH, Fermand JP, Hazenberg BP, Hawkins PN, et al. Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, 18-22 April 2004. Am J Hematol 2005;79:319-28 PMID: 16044444
  26. ↑ 26.0 26.1 Gertz MA, Merlini G. Definition of organ involvement and response to treatment in AL amyloidosis: an updated consensus opinion. Amyloid 2010;17:CP-Ba
  27. ↑ Palladini G, Merlini G. Transplantation vs. conventional-dose therapy for amyloidosis. Curr Opin Oncol 2011;23:214-20 PMID: 21178616
  28. ↑ Palladini G, Dispenzieri A, Gertz MA, Wechalekar A, Hawkins P, Schonland SO et al. Validation of the criteria of response to treatment in AL amyloidosis. Blood 2010;116:1364a
  29. ↑ Bird JM, Cavenagh J, Samson D, Mehta A, Hawkins P, Lachmann H. Guidelines on the diagnosis and management of AL amyloidosis. Br J Haematol 2004;125:681-700 PMID: 15180858
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