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

There are several new International and National guidelines for identifying and managing patients with plasma cell dyscrasias. These are being widely adopted for assessing new patients and for patient entry into clinical trials. This chapter provides an overview with an emphasis on the serum FLC component (identified in blue). Classification criteria for the less common plasma cell dyscrasias (some of which do not yet include the use of serum FLCs) are described in Chapter 18 .

25.1. International Guidelines for the classification of MM and MGUS

The most recent guidelines were published in 2003 [1] and comprise the following:-

Symptomatic multiple myeloma
  • M-protein in serum and/or urine.
  • Bone marrow (clonal) plasma cells or plasmacytoma.
  • Related organ or tissue impairment (end organ damage, including bone lesions*).
Nonsecretory multiple myeloma
  • No M-protein in serum and urine with immunofixation.
  • Bone marrow clonal plasmacytosis >10% or plasmacytoma.
  • Related organ or tissue impairment (end organ damage, including bone lesions*).
Asymptomatic myeloma (smouldering myeloma)
  • M-protein in serum >30g/L: and/or
  • Bone marrow clonal plasma cells >10%.
  • No symptoms, related organ or tissue impairment (no end organ damage, including bone lesions*).
Monoclonal gammopathy of undetermined significance (MGUS)
  • M-protein in serum <30g/L.
  • Bone marrow clonal plasma cells <10% and low level of plasma cell infiltration in a trephine biopsy (if done).
  • No evidence of other B-cell proliferative disorders.
  • No related organ or tissue impairment (no end organ damage, including bone lesions).


*Criteria for end organ damage in MM - CRAB (Calcium increased, Renal insufficiency, Anaemia or Bone lesions).
Calcium levels increased: serum calcium >0.25mmol/L above the upper limit of normal or >2.75mmol/L.
Renal insufficiency: creatinine >173mmol/L.
Anaemia: haemoglobin 2g/dL below the lower limit of normal or haemoglobin <10g/dL.
Bone lesions: lytic lesions or osteoporosis with compression fractures.
Others: symptomatic hyperviscosity, AL amyloidosis, recurrent bacterial infections (>2 episodes in 12 months).

25.2. UK Myeloma Forum, Nordic Myeloma Study Group and the British Committee for Standards in Haematology

The guidelines [2] include the following use of serum FLC measurements:-

Investigation and diagnosis.

Quantification of serum FLCs and κ/λ ratio can be used as an alternative to measuring urine FLCs. Serum FLCs are particularly useful for the diagnosis of LCMM and patients in whom the serum and urine is negative on IFE (NSMM) (Chapter 8 and Chapter 9).

Measuring responses to therapy.

Serum FLCs are useful for monitoring LCMM and NSMM (Chapter 8 and Chapter 9). Serum FLCs may also be helpful in monitoring responses in the many patients with IIMM (Chapter 10). Because of the short half-life of sFLCs this can give an earlier indication of response to therapy than changes in intact monoclonal immunoglobulins.

25.3. International Staging System for Multiple Myeloma

In May 2005, the International Staging System (ISS) for Multiple Myeloma was published [3]. This is based upon serum albumin and serum β2 microglobulin alone (Table 25.1). Because of its detailed analysis, wide international agreement and simplicity, it is likely to be adopted quickly .

Earlier staging systems included concentrations of monoclonal immunoglobulins. It has now been realised that they have little relevance to MM outcome. For IgG MM this may be due to variable recycling by FcRn receptors (Chapter 10 and 32). However, monoclonal sFLC concentrations and abnormal κ/λ ratios do relate to disease stage and outcome (Chapter 11 and 12). This may be because their clearance rate is constant and because they cause renal damage which influences mortality (Chapter 13).


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 25.1 New 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.

25.4. New “Uniform Response Criteria for MM” incorporating FLCs

There have been extensive international discussions on guidelines that utilise the high sensitivity of serum FLC measurements [4][5][6]. One important new recommendation is to change the way that the κ/λ ratios are reported. Subtraction of the tumour FLC from the non-tumour FLC provides a single value that is easy to report and understand. It also provides an interpretable result when the non-tumour FLC is either below the detection limit or is fluctuating widely. It is similarly helpful when interpreting high concentrations of the alternate FLC that are seen in patients with impaired renal function (Chapter 20.2). Limited clinical studies indicate no loss of clinical utility. The response criteria include the following FLC guidelines (Tables 25.2, 25.3. 25.4, 25.6 and 25.7):-


1.
Facilitate precise comparisons of efficacy between new treatment and strategies in trials
2.
Incorporation of the serum free light chain assays
3.
Stricter definitions of complete response
4.
Incorporate standard definition of near compete response.
5.
Stricter definition of disease progression
6.
Enable greater inclusion of patients with oligo-secretory and nonsecretory disease
7.
Provide clarifications, improve detail, and correct inconsistencies in prior response criteria

Table 25.2. Rationale for the development of uniform response criteria

1.
Presence of an M-component* in serum and/or urine plus clonal plasma cells in the bone marrow and/or a documented clonal plasmacytoma
Plus one or more of the following:**
2.
Calcium elevation (>11.5 gms/dL)
3.
Renal insufficiency (creatinine>2mg /dL)
4.
Anemia (Hemoglobin <10g /dL or 2g <normal)
5.
Bone disease (lytic or osteopenic)

Table 25.3. Diagnostic criteria for multiple myeloma requiring systemic therapy

* In patients with no detectable M-component, serum FREELITE chain (FLC) assays can substitute and satisfy this criterion. For patients with no serum or urine M-component, the baseline bone marrow must have >30% plasma cells. These patients are referred to as "nonsecretory myeloma".
** Must be attributable to the underlying plasma cell disorder


Laboratory tests for measurement of M proteins.

Serum M-protein level is quantitated using densitometry on SPE except in cases where the SPE is felt to be unreliable such as in patients with IgA monoclonal proteins migrating in the beta region. If SPE is not available for routine M-protein quantitation during therapy, then nephelometry or turbidimetry can be accepted. However, this must be explicitly reported; nephelometry can be used only for individual patients to assess response; SPE and nephelometric values cannot be used interchangeably.

Urine M protein measurement is estimated using 24-hour UPE only. Random or 24 hour urine tests measuring κ and λ FLC measurements are not reliable and are not recommended.
Definitions of measurable disease

Response criteria for all categories and subcategories of response except CR are applicable only to patients who have “measurable” disease defined by at least one of the following 3 measurements:-
  Serum M protein =/>1 gm/dL (> 10 gm/L)
  Urine M protein =/>200 mg/24 hours
  Serum FLC assay: Involved FLC =/> 10 mg/dL (>100 mg/L)

Response criteria for complete response (CR)

These are applicable to patients who have abnormalities on one of the three measurements below. Note that patients who do not meet any of the criteria for measurable disease as listed can only be assessed for stringent CR and cannot be assessed for any of the other response categories:-
  Serum M protein on IFE
  Urine M protein on IFE
  Normal serum FLC κ/ λratio (<0.26 or >1.65)

Follow-up to meet criteria for partial response or stable disease

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” as defined above by SPE and UPE, need to be followed by both SPE and UPE for response assessment and categorization.

Except for assessment of complete response, patients with measurable disease restricted to the SPE will need to be followed only by SPE; correspondingly patients with measurable disease restricted to UPE will need to be followed only by UPE.

Patients with measurable disease in either SPE or UPE, or both, will be assessed for response only based on these two tests and not by FLC assays. FLC response criteria are only applicable to patients without measurable disease in the serum or urine, and to fulfill the requirements in the category of stringent CR.

To be considered CR, both serum and urine IFE must be done and be negative regardless of the size of baseline M protein in the serum or urine; patients with negative UPE values pre-treatment still require UPE testing to confirm CR and exclude light chain (or Bence-Jones) escape.

Skeletal survey is required only if clinically indicated; Bone marrow is required only for categorization of CR, and for patients with nonsecretory disease.

Table 25.4. Practical Details of Response Evaluation

Response Subcategory
 Response Criteria
Complete Response (CR)
  • Negative IFE in the serum and urine and:-
  • Disappearance of any soft tissue plasmacytomas and:-
  • < 5% plasma cells in bone marrow
Stringent CR (sCR)
CR as defined above plus:-
  • Normal FLC ratio and:-
  • Absence of clonal cells in BM by immunohistochemistry or immunofluresence
Very Good Partial Response (VGPR)
Serum and urine M-component detectable by IFE but SPE-ve or:-
90% or greater reduction in serum M-component and urine M-component <100 mg per 24 hours
Patial Response
50% reduction of serum M protein and:-
  • Reduction in 24-hour urinary M protein by =/>90% or to =/<200mg per 24 hours and
  • If present at baseline, a =>50% reduction in size of soft tissue plasmacytomas
  • If the serum and urine M-protein are unmeasureable*, a >50% decrease in difference between involoved and uninvolved FLC levels is required in place of the M-protein criteria
  • If serum and urine M-protein are unmeasureable, and sFLCs are also normal, =/> 50% reduction in plasma cells is required in place of M-protein, provided baseline BM plasma cell percentage is =/> 30%
Stable Disease
Not meeting criteria for complete response, near complete response, partial response, or progressive disease

Table 25.5. International Myeloma Working Group Uniform Response Criteria: Complete Response and Other Response Categories.
Note that all response categories require two consecutive assessments done at anytime before the institution of any new therapy. *Refer to Table 25.4 for definitions of measurable disease.

Timing
 Recommended testing of M-component, serum FLcs and CRAB features
Post-Induction
At least assesment pre-harvest. If harvest occurs during induction then assessment should be immediately pre-transplant.
Post-Harvest
At least one assessment post-harvest if cytoreductive therapy used for harvest and/or if patient proceeding directly to maintenance only.
Post-Transplant
One measurement required at =/<100 days. This re-staging requires bone marrow biopsy.

Table 25.6. Response Evaluation for Patients proceeding to Stem Cell Harvesting and Transplantation

Relapse Subcategory
 Relapse Criteria
Progressive disease.*
(Includes primary progressive disease and disease progression on or off therapy; To be used for calculation of the time to progression and progression-free survival endpoints.)
Any one or more of the following:
  • Increase of =/>25% from baseline in
- Serum M-component and/or (the absolute increase must be =/>0.5g/dL)
- Urine M-component and/or (the absolute increase must be =/>200mg/24 hours
- Difference between involved and uninvolved FLC levels. The absolute increase must be >10 mg/dL.
- Bone marrow plasma cell %. The absolute % must be =/> 10%.
PLUS and one or more of:

Direct indicators of increasing disease and/or end organ dysfunction (CRAB features)**

  1. Development of new soft tissue plasmacytomas or bone lesions
  2. Definite increase in size of exisitng plasmacytoma or bone lesions. A definite increase is defined as a 50% (and at least 1 cm) increase as measured serially by the sum of the products of the cross diameters of the measurable lesion
  3. Hypercalcemia (>11mg/dL)
  4. Decrease in haemoglobin of 20g/L or more
  5. Rise in serum creatinine by 2mg/dL or more
Relaspe from CR.*
(To be used only if the endpoint studied is "Disease free survival"; otherwise CR patients should also be evaluated using criteria for progressive disease).
Any one or more of the following:
  • Reappearance of serum and urine M protein by IFE, SPE or UPE
  • Development of =/5% plasma cells in the bone marrow
  • Appearance of any other sign of progression (i.e. new plasmacytoma, lytic bone lesion, or hypercalcemia see below)

Table 25.7. International Myeloma Working Group Uniform Response Criteria: Disease Progression and Relapse from Complete response*
* All relapse categories require two consecutive assessments done at anytime before the institution of any new therapy. **Patients developing two or more of the CRAB features without increases in monoclonal protein or free light chain levels are also considered to have progressive disease.

25.5. National Comprehensive Cancer Network.

Serum FLCs are included in the Clinical Practice Guidelines in Oncology: Multiple myeloma 2007 [7] based upon the New “Uniform Response Criteria for MM” described in Section 25.4 above.

25.6. European Society of Medical Oncology Recommendations.

European Society of Medical Oncology (ESMO) Recommendations for diagnosis, treatment and follow-up of multiple myeloma state serum FLC measurements are useful for identifying and monitoring patients with NSMM [8].

25.7. USA National Academy of Clinical Biochemistry Guidelines.

Serum FLCs are included in the guidelines for the use of tumour markers in monoclonal gammopathies. Serum FLC measurements are useful for the diagnosis and follow up of NSMM, MGUS and AL amyloidosis. They are more sensitive than urine tests in patients with LCMM and in other patients with MM who may have coexistent SLE or renal impairment [9].

25.8. Guidelines for AL amyloidosis.

A Consensus Opinion from the 10th International Symposium on Amyloid and Amyloidosis.[10] Definition of Organ Involvement and Treatment Response in Immunoglobulin Light Chain Amyloidosis (AL):

Complete response (CR)
Serum and urine negative for a monoclonal protein by IFE.
Serum FLC κ/λ ratio normal.
Marrow contains < 5% plasma cells.
Partial response (PR)
If serum M component > 0.5g/dL, a 50% reduction.
If FLCs in the urine with a visible peak and =>100 mg/day, a 50% reduction.
If serum FLC >10 mg/dL (100mg/L): reduction by =>50 %.
Progression
From CR, any detectable monoclonal protein or abnormal FLC κ/λ ratio (light chain must double).
From PR or stable response, 50% increase in serum M protein to > 0.5g/dL or 50% increase in urine M protein to > 200mg/day; a visible peak must be present.
Serum FLC increase of 50% to >10mg/dL.
Stable disease

No CR, no PR, no progression

UK Guidelines for AL Amyloidosis. [11] (Similar guidelines have been adopted in France [12]).

The report includes comments on serum FLC measurements as follows:-

  1. Serum FLCs are abnormal in 98% of patients with systemic AL amyloidosis including those that cannot be identified by conventional methods. Patients should be assessed for serum FLCs during the diagnostic procedure.
  2. Serum FLC measurements appear to be the most effective current method of monitoring patients.
  3. Changes in amyloid load correlate with changes in FLC concentrations and with survival.
  4. Treatment should be continued, when feasible, until serum FLC concentrations have fallen by at least 50-75%.
  5. Treatment strategies are best guided by their early effect on concentrations of serum FLCs.

25.9. Guidelines for assessing outcome in MGUS.

Until recently there have been no useful markers for predicting outcome in MGUS because they lacked statistical power. Recently, Rajkumar et al. [4] have shown that the combination of immunoglobulin MGUS class, its quantity above or below 15g/L and the presence or absence of an abnormal FLC κ/λ ratio can be used for risk stratification (Table 19.2). Data from this study is likely to be used in future guidelines for MGUS management [13].


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References

  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. ↑ 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
  3. ↑ 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
  4. ↑ 4.0 4.1 Rajkumar SV, Kyle RA. Conventional therapy and approach to management. Best Pract Res Clin Haematol 2005; 18: 585 – 601 PMID: 16026739
  5. ↑ Kumar S, Gertz MA, Hayman SR, Lacy MQ, Dispenzieri A, Zeldenrust SR, et al. Use of the serum free light chain assay in assessment of response to therapy in multiple myeloma: Validation of recently proposed response criteria in a prospective clinical trial of lenalidomide plus dexamethasone for newly diagnosed multiple myeloma. Blood 2005; 106: 3479a
  6. ↑ 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
  7. ↑ Anderson KC, Alsina M, Bensinger W, Biermann JS, Chanan-Khan A, Comenzo RL, et al. Multiple myeloma. Clinical practice guidelines in oncology. J Natl Compr Canc Netw 2007; 5: 118 – 47 PMID: 17335683
  8. ↑ Harousseau JL. Multiple myeloma: ESMO Clinical Recommendations for diagnosis, treatment and follow-up. Ann Oncol 2007; 18: ii44 – 6 PMID: 17491042
  9. ↑ Gupta S, Comenzo RL, Hoffman BR, Fleisher M. National Academy of Clinical Biochemistry guidelines for the use of tumor markers in monoclonal gammopathies. [1]
  10. ↑ 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
  11. ↑ 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
  12. ↑ Jaccard A, Moreau P, Aucouturier P, Ronco P, Fermand J-P, Hermine O. Amylose immunoglobulinique. Hematologie 2003; 9: 485 – 95
  13. ↑ Mayo Medical Laboratories. Laboratory analysis for monoclonal gammopathies. Mayo Communique 2007; 32: 1 – 4
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