An article by Prof. Dr. med. Dirk Peetz:
INSTAND EQAS Expert & INSTAND e.V. Board - Treasurer; Head Physician, Institut for Laboratory Medicine Helios Klinikum Berlin-Buch GmbH
The EQA scheme 243 Gammopathies contains essential elements for the diagnosis and follow-up of multiple myeloma. Its parameters are “Detection of the monoclonal protein (qualitative), free light chains type kappa and lambda (quantitative and quotient)” and the antibody detections IgA, IgG, and IgM.
The S3 guideline Diagnostics, therapy, and follow-up care for patients with monoclonal gammopathy of undetermined significance (MGUS) or multiple myeloma [1] published by the Association of the Scientific Medical Societies in Germany (AWMF), the German Cancer Society (DKG) and the German Cancer Aid Foundation (DKH) in February 2022, which is well worth reading, clearly describes the use of these and other parameters. The Onkopedia guideline on multiple myeloma [2] from the German Society for Hematology and Medical Oncology (DGHO), Austrian Society for Hematology & Medical Oncology (OeGHO), Swiss Society for Hematology (SGH+SSH) and Swiss Society for Medical Oncology (SMO/SSOM/SGMO) is also highly recommended and well worth reading.
The overview presented here summarizes the relevant diagnostic criteria, most of which are based on laboratory medical examinations.
Initial and follow-up diagnostics if there is sufficient clinical suspicion:
Detection of organ dysfunctions
- e.g., creatinine/renal dysfunction
Detection of myeloma-associated phenomena
- e.g., immunoglobulins/antibody deficiency or LDH, indirect bilirubin, haptoglobin if autoimmune haemolysis is suspected
Detection of the monoclonal protein in serum and, if necessary, in urine
- Protein electrophoresis or capillary zone electrophoresis
- with quantification of the paraprotein (from the area of the M gradient) at initial diagnosis and during the course of treatment to monitor the response to therapy - Immunofixation with IgG/A/M and Kappa/Lambda
- extend to IgD/E if G/A/M negative and monoclonal kappa or lambda present
- If there is sufficient clinical suspicion, carry out immunofixation and kappa/lambda measurement even if there is no M gradient in the electrophoresis - Quantifying urine tests always from 24-hour urine collection
- Quantitative determination of free kappa and lambda light chains in serum incl. ratio at the time of initial diagnosis and for follow-up monitoring
- No standard determination of free light chains in urine during follow-up
Cellular detection:
- Microscopic leukocyte differentiation at diagnosis and progression
- Proportion of (atypical) plasma cells - Bone marrow examination for initial diagnosis
- with aspiration cytology and histology
- Flow cytometry, if applicable
- Immunohistochemistry on bone marrow aspirate for plasma cell quantification and detection of light chain restriction and aberrant antigen expression (e.g. CD56, cyclin D1) - Cytogenetics and molecular diagnostics
- See guideline for details
Classification primarily on the basis of laboratory diagnostic criteria:
- Monoclonal gammopathy of undetermined significance of the non-IgM type
- Monoclonal serum protein <30g/L
- Clonal plasma cells in the bone marrow <10%
- No end-organ damage attributable to plasma cell proliferation (hypercalcemia, renal insufficiency, anemia, or bone lesions - CRAB criteria, see symptomatic multiple myeloma) - Asymptomatic (smouldering) myeloma
- Monoclonal serum protein >30g/L (or >500mg/24 in urine) and/or 10-60% clonal plasma cells in the bone marrow
- No end-organ damage or amyloidosis - Symptomatic multiple myeloma
- >10% clonal BM plasma cells or biopsy-proven plasmacytoma with >1 myeloma-defining criteria
- End organ damage due to plasma cell proliferation - CRAB criteria:
Calcium >110 mg/L or >10 mg/L above upper reference range limit (hypercalcemia)
Renal with creatinine >177 µmol/L or creatinine clearance <40 ml/min (renal insufficiency)
- Anemia with hemoglobin <100g/L or >20g/L below the lower reference range limit (anemia)
- Bone with >1 osteolysis in X-ray, CT, PET/CT (bone lesions)
- One of the following biomarkers: ≥60% clonal BM plasma cells, free light chain ratio >100 and/or 1 focal MRI lesion
Assessment of treatment response/progress/relapse based on laboratory parameters in accordance with the recommendations of the International Myeloma Working Group (IMWG):
- Stringent complete response (sCR)
- Normal FLC ratio
- Absence of clonal cells in BM biopsy (immunohistochemistry κ/λ ratio ≤4:1 or ≥1:2) - Complete Response (CR)
- Negative immunofixation (serum and urine) confirmed by second test
- Normal FLC ratio
- <5% plasma cells in the bone marrow
- No soft tissue manifestations - Nearly Complete Response (nCR, not included in IMWG, supplemented by guideline)
- Positive immunofixation serum and/or urine
- No detection of monoclonal protein/M gradients in electrophoresis (serum or 24-hour urine collection)
- No soft tissue manifestations
- independent of the plasma cell content in the bone marrow; or serologic CR with unknown bone marrow status - Very Good Partial Response (VGPR)
- Serum and/or urine M protein or LK detectable in urine
- ≥90% reduction in serum M protein (M gradient)
- Urine M protein <100 mg/24h
- ≥90% reduction in the difference between affected and unaffected free light chain - Partial Response (PR)
- ≥50% reduction in serum M protein (M gradient) and reduction in light chain excretion in 24-hour urine (by ≥ 90% or <200 mg/24h)
- If serum and urine M-protein not measurable: decrease of ≥ 50% in difference “affected” and “not affected” FLC (instead of M-protein criteria)
- If FLC not measurable: ≥50% reduction of KM plasma cells if initial ≥30%
- ≥50% reduction in the size of soft tissue manifestations - Minimal Response (MR)
- 25-49% reduction in serum M protein (M gradients)
- 50-89% reduction in light chain excretion in 24-hour urine, but still ≥ 200 mg/day
- ≥50% reduction in the size of soft tissue manifestations - Stable Disease (SD)
- None of the previous criteria nor those of disease progression are met
- is considered a non-response - Progressive disease (PD, one or more of the following criteria)
- Increase in M protein serum or urine (M gradient) ≥25% compared to nadir, absolute increase by at least ≥5 g/l (serum) and/or light chain excretion ≥200 mg/day (urine)
(with initial serum M protein value of ≥ 50 g/l increase of ≥10 g/l)
- If serum and urine M protein cannot be measured: increase of ≥ 25% in difference between “affected” and “unaffected” FLC, absolute increase of at least ≥100 mg/l (instead of M protein criteria)
- Increase in KM plasma cells ≥25% compared to nadir, absolute increase by ≥10% (only asecretory processes)
- New bone lesions or soft tissue manifestations or increase in size ≥50% compared to nadir (sum of orthogonal diameters of >1 lesion or ≥50% increase in longest diameter of an existing lesion >1 cm)
- ≥50% increase in circulating plasma cells (at least 200 cells/ μL), if this is the only measurable variable
Prognostic factors of multiple myeloma:
- International Staging System (ISS) and revised ISS
- Stage I: b2-microglobulin < 3.5 mg/l and serum albumin ≥ 3.5 g/dl and cytogenetics standard risk andLDH ≤ upper normal value
- Stage II: neither stage I nor stage III
- Stage III: b2-microglobulin ≥ 5.5 mg/l and cytogenetics high risk or LDH > upper normal value - Genetic high-risk situation
- Del17p >20% of the sorted plasma cells (FISH)
- TP53 mutation (independent of allele fraction)
- Biallelic del(1p32)
- t(4;14) or t(14;16) or t(14;20) in combination with gain/amp 1q or monoallelic del (1p32)
- Gain 1q (independent of copy number) in combination with del(1p32), t(4;14)/t(14;16)/t(14;20).
Laboratory diagnostics is a decisive step in the diagnosis and treatment of multiple myeloma and, in addition to precise diagnosis and prognostic assessment, enables optimal therapy planning and monitoring. In addition to the EQA scheme 243 Gammopathies, INSTAND also regularly uses samples from patients with multiple myeloma in various other hematological EQA schemes and contributes to external quality assurance to ensure high-quality diagnostics:
EQAS 212 Haematology 07 - Blood Smear Analysis - Haematology 07 - Blood Smear Analysis - INSTAND e.V. (instand-ev.de)
Prof. Dr. med. Dr. phil. Torsten Haferlach │ Prof. Dr. med. Wolfgang Kern
Assessment and diagnosis, differentiation in %, ery-, leuko-, thrombocyte morphology
EQAS 214 Haematology 12 - Immunophenotyping 02 - Haematology 12 - Immunophenotyping 02 - INSTAND e.V. (instand-ev.de)
Dr. med. Richard Schabath│ Prof. Dr. med. Wolfgang Kern
Immunophenotypic diagnostics
EQAS 218 Haematology 09 - Bone Marrow Cytology - Haematology 09 - Bone Marrow Cytology - INSTAND e.V. (instand-ev.de)
Prof. Dr. med. Dr. phil. Torsten Haferlach│ Prof. Dr. med. Winfried Gassmann
Assessment and diagnosis - online under the virtual microscope
EQAS 243 Gammopathies - Gammopathies - INSTAND e.V. (instand-ev.de)
Prof. Dr. med. Dirk Peetz │ Dr. med. Christoph Niederau
Free light chains type kappa (quantitative), free light chains type lambda (quantitative), gammopathies, IgA, IgG, IgM, kappa/lambda (quotient)
EQAS 292 Tumor Markers - Tumor Markers - INSTAND e.V. (instand-ev.de)
Prof. Dr. med. Stefan Holdenrieder │ Prof. Dr. med. Dirk Peetz
b2-microglobulin and 20 other tumor markers
EQAS 765 Molecular Oncology 09 - TP53 - Molecular Oncology 09 - TP53 - INSTAND e.V. (instand-ev.de)
Prof. Dr. Karl-Anton Kreuzer│ Dr. rer. nat. Eva Lorsy
TP53 Mutation(s), TP53 nomenclature
References:
[1] Oncology guideline program (German Cancer Society, German Cancer Aid, AWMF): Diagnostics, therapy, and follow-up care for patients with monoclonal gammopathy of unclear significance (MGUS) or multiple myeloma, long version 1.0, 2022, AWMF register number: 018/035OL, https://www.leitlinienprogramm-onkologie.de/leitlinien/multiples-myelom/. (Zugriff am 12.10.2024)
[2] Körtum M et al. Onkopedia guideline multiple myeloma. Status October 2024. https://www.onkopedia.com/de/onkopedia/guidelines/multiples-myelom/ (Zugriff am 12.10.2024)