Abstract
The determination of monoclonal protein (M-protein) by SPE, IFE and SFLC assay is fundamental in the diagnosis of Plasma cell proliferative disorder (PCPD). In the present study, we seek to assess the diagnostic performance and concordance of these three techniques in un-treated PCPD patients. All new patients with dysproteinemia and/or suspected PCPD were included in this retrospective observational study. The baseline parameters were retrieved from electronic medical records. SPE was performed on gel electrophoresis system; monoclonal component was identified by IFE. SFLC assays were performed by nephelometry using a latex-enhanced immunoassay. Total 402 patients of PCPD were included (10.9% of MGUS/SMM and 89.1% of multiple myeloma). The combination of SPE + rSFLC (ratio of kappa/lambda light chain) and SPE + IFE + rSFLC was able to detect M-protein across all subgroups of patients. In 61 patients, rSFLC values were within normal range (54.5% of MGUS/SMM and 10.3% of MM) and was more commonly seen with IgG lambda M-protein (57.4% vs. all-others). The median dFLC value, among these patients, was higher for MM than MGUS/SMM patients (23.8 vs. 14.4 mg/L, respectively). The combination of SPE and rSFLC can be reliably used to detect M-protein in PCPD patients. In a small subgroup of MM patients, despite the presence of an intact immunoglobulin (M-protein), the rSFLC is not abnormal. Historically, these patients should respond better to treatment. However, a further follow-up analysis with more number of such patients would be advantageous for better understanding.
Keywords: Plasma cell dyscrasia, IgG lambda, M-protein, rSFLC, dFLC
Introduction
Plasma cell proliferative disorders (PCPD) are generally distinguished from other hematopoietic neoplasms by the presence of a secreted monoclonal immunoglobulin i.e. M-protein [1]. The disease includes disorders such as Multiple myeloma (MM), plasmacytoma, plasma cell leukemia, AL-amyloidosis, smouldering multiple myeloma (SMM) and monoclonal gammopathy of undetermined significance (MGUS). The accurate classification of the disease is augmented by the qualitative and quantitative estimation of the secreted M-protein [1]. The detection and measurement of M-protein also helps in stratification of risk progression and monitoring response to therapy [2]. The diagnostic armamentarium to detect the presence of M-protein includes serum protein electrophoresis (SPE), immunofixation electrophoresis (IFE), and quantitative serum free light chain measurement (SFLC). The utility of urine electrophoresis and immunofixation is limited to specific diagnostic condition e.g. AL amyloidosis [3].
The most reliable and widely-used screening tests to detect and quantitate M-protein in a suspected patient of monoclonal gammopathy, are SPE and SFLC ratio (rSFLC) [2]. Immunofixation electrophoresis is, traditionally, used to characterize the M-protein. In certain patients, the M-protein estimation by SPE and/or IFE is in-apparent and the SFLC assay has increased the diagnostic sensitivity in such situations [4]. However, further & final diagnosis of the disease requires a number of other serologic, hematologic, radiologic investigations and a bone marrow examination.
In the present study, we identified a cohort of 402 un-treated patients of PCPD and analyzed the results of SPE, IFE and SFLC assay. The purpose of the study was to assess the diagnostic performance and concordance of SPE, IFE and SFLC assay in our group of patients.
Materials & Methods
Patients
We retrospectively queried the database for all new patients (first-timers) with dysproteinemia or who underwent bone marrow examination for the clinical suspicion of multiple myeloma (September 2018–February 2021). Clinical and baseline laboratory parameters were retrieved from the electronic medical records. The study has been approved by institutional ethics committee.
M-protein Screening Test
The M-protein screening panel (SPE, IFE and SFLC assay) was performed within 30 days of the diagnosis. The SPE was performed on semi-automated gel electrophoresis system HYDRASYS™ (SEBIA) and the monoclonal component was identified by IFE with HYDRAGEL™ (SEBIA) kit. SFLC assays were performed by nephelometry (Siemens BN Prospec system) using a latex-enhanced immunoassay (Freelite™; The Binding Site Group Ltd, Birmingham). An abnormal SPE (positive M-protein) was defined by the presence of a quantifiable M-spike (by densitometry) or a distinct band in γ region. Serum samples with markedly increased β or α-2 fraction were considered as positive, if consecutive serum IFE and/or SFLC ratio was also abnormal (Fig. 1). The IFE assessed the monoclonal component for γ (IgG), α (IgA), μ (IgM), κ (kappa) and λ (lambda) immunoglobulin chains. The antisera for δ (IgD) and ε (IgE) immunoglobulin chains were not available and hence, not tested. The SFLC assay reported κ (kappa) and λ (lambda) FLC concentration, and the SFLC ratio (rSFLC) was calculated. The diagnostic range of rSFLC result was taken as 0.26–1.65 (and 0.31–3.10 in patients with impaired renal function).
Fig. 1.
A Photomicrograph of bone marrow biopsy section (Hematoxylin & Eosin stained, 10X) shows relatively dense cellular area below bony trabeculae; B Corresponding immunohistochemistry staining using antibody against CD138 (Thermofisher Scientific) highlights the plasma cell aggregate (40X); C Serum protein electrophoresis (HYDRASYS™, Sebia) gel shows a test panel of fifteen samples, in which samples in lane 16, 24 and 26 show discrete bands in corresponding gamma region, while the sample in lane 25 shows a dense band near and overlying to beta region; D Serum immunofixation eletrophoresis (HYDRAGEL™,Sebia) gel shows a test panel of the four samples, for which the corresponding electrophoresis gel is shown in C. The samples run in lane 16, 25 and 26 of the electrophoresis gel show a discrete band/s against lambda light chain region, IgA kappa regions and IgG lambda regions, respectively
Bone Marrow Examination
Bone marrow aspirate/imprint smears were stained with May Grunwald Giemsa (MGG) stain and microscopically examined. The hematoxylin & eosin (H&E) stained bone marrow biopsy section were reviewed and immunohistochemistry using CD138 polyclonal antibody (Thermofisher Scientific) was used on as-and-when required basis (Fig. 1). The final diagnosis was based on the recommended established guidelines [1]. The diagnostic sensitivity was calculated for each of the three screening tests and their combinations.
Results
Patients
We analysed the data from 402 patients of plasma cell proliferative disorder, which included 44 patients (10.9%) of MGUS/SMM and 358 (89.1%) patients of Multiple Myeloma. All these patients had results of SPE, IFE and SFLC analysis within 30 days of the diagnosis and no patients had been treated prior to undergoing these investigations. The baseline characteristics are listed in Table 1.
Table 1.
Patient’s characteristics (n = 402)
| Characteristic | MGUS/SMM | MM | ||
|---|---|---|---|---|
| Total | IIMM | LCMM | ||
| Number of patients (n) | 44 | 358 | 276 (77.1%) | 78 (21.8%) |
| Median age (years) | 63 | 59 | 60 | 55.5 |
| Less than 40 years (%) | 2 (4.5) | 23 (6.4) | 19 (6.9) | 4 (5.1) |
| Between 40 and 60 years | 18 (40.9) | 183 (51.1) | 132 (47.8) | 49 (62.8) |
| More than 60 years | 24 (54.6) | 152 (42.5) | 125 (45.3) | 25 (32.1) |
| M:F | 1.9 | 2.1 | 2.4 | 1.4 |
| Presence of renal impairment ( %)* | 17 (31.8) | 148 (41.3) | 95 (34.4) | 52 (66.6) |
| Median | ||||
| Hb (g/dl) | 9.8 | 8.2 | 6.2 | 8.2 |
| TLC (× 109/L) | 7.5 | 7.2 | 7.0 | 8.4 |
| Platelet (× 109/L) | 192 | 165 | 164.5 | 165 |
| Immunoglobulin type | ||||
| IgG Kappa ( %) | 24 (54.5) | 133 (37.2) | 133 (48.2) | NA |
| IgG Lambda ( %) | 18 (40.9) | 83 (23.2) | 83 (30.1) | NA |
| IgA Kappa ( %) | 1 (2.2) | 29 (8.1) | 29 (10.5) | NA |
| IgA Lambda ( %) | 1 (2.2) | 28 (7.8) | 28 (10.1) | NA |
| Light chain only (%) | Nil | 78 (21.8) | 37 (47.4) | |
| Kappa light chain (%) | Nil | 37 (10.3) | NA | 41 (52.6) |
| Lambda light chain (%) | Nil | 41 ( 11.5) | NA | NA |
| Biclonal (%) | Nil | 3 (0.8) | 3 (1.1) | NA |
| Undetermined ?NSMM (%) | Nil | 4 (1.1) | NA | |
| Median Kappa (mg/L) | 121 | 74.7 | 66.4 | 91.3 |
| Median Lambda (mg/L) | 63.9 | 32.9 | 25.5 | 479 |
| Median SFLC ratio | 1.66 | 2.50 | 2.88 | 0.05 |
| Median dFLC (mg/L) | 46.5 | 813.8 | 479.25 | 8209 |
*histopathologically not attributed to plasma cell disorder
MGUS/SMM, monoclonal gammopathy of undetermined significance/smouldering multiple myeloma; MM, multiple myeloma; IIMM, intact immunoglobulin multiple myeloma; LCMM, light chain multiple myeloma; NA, not applicable
Disease and M-protein Subtype
Based on the immunoglobulin type, 276 (77.1%) patients were diagnosed as intact immunoglobulin multiple myeloma (IIMM) and 78 (21.8%) patients were as light chain multiple myeloma (LCMM). In 4 patients (1.1%), no immunoglobulin type can be identified using SPE/IFE, however the rSFLC was markedly abnormal, range 0.007–118.6 (?Non-secretory multiple myeloma, NSMM). Among the MM patients, IgG kappa type M-protein (37.2%) was most frequent followed by IgG lambda type (23.2%) and light chain type (21.8%). Similarly, IgG kappa type (54.5%) M-protein is also predominated in MGUS patients, followed by IgG lambda type (40.9%). No patient with light chain type M-protein was detected in the group of MGUS/SMM. Between the IIMM and LCMM patients, renal impairment was more frequently seen in the latter group of patients (34.4% vs. 66.6%, Table 1).
Sensitivity of M-protein Screening Tests
The diagnostic sensitivities of these tests to detect M-protein were calculated individually and as well as in combination by using the formula (number of patients in which M-protein was found through respective technique or techniques/ total number of patients in which M-protein was found). The results for them, were as—SPE 89.7%, IFE 98.8%, rSFLC 89.6%, SPE + rSFLC 100%, and SPE + IFE + rSFLC 100% (Table 2). The diagnostic sensitivity of SPE was higher to detect M-protein in IIMM patients in comparison to the LCMM patients (95.6% vs. 71.8%). On the other hand, the sensitivity to detect M-protein by rSFLC was better in LCMM (100% vs. 86.6% in IIMM). The combination of SPE + rSFLC and SPE + IFE + rSFLC was able to detect M-protein across all subgroups of myeloma patients.
Table 2.
Diagnostic sensitivities of protein electrophoresis, immunofixation electrophoresis and free light chain ratio
| Present study | Katzmann et al. Clin Biochem Rev [2] | Jeong et al. Clin Chem Lab Med [7] | ||||||
|---|---|---|---|---|---|---|---|---|
| IIMM (n = 276) | LCMM (n = 78) | Total (n = 358) | MM (n = 467) | Total (n = 1851) | IIMM (n = 159) | LCMM (n = 49) | Total (n = 210) | |
| SPEP (%) | 95.6 | 71.8 | 89.7 | 87.6 | 79 | 96.9 | 61.2 | 87.6 |
| IFE (%) | 100 | 100 | 98.8 | 94.4 | 87 | 99.3 | 75.5 | 92.9 |
| rSFLC (%) | 86.6 | 100 | 89.6 | 96.8 | 74.3 | 87.4 | 98 | 90 |
| SPEP + rSFLC (%) | 100 | 100 | 100 | 100 | 94.3 | 100 | 100 | 100 |
| SPEP + IFE + rSFLC (%) | 100 | 100 | 100 | 100 | 97.4 | 100 | 100 | 100 |
Patients with Normal SFLC Ratio
In this cohort, 61 patients were found to have normal SFLC ratio (rSFLC). It was more frequently observed in MGUS/SMM patients (24/44 pateints, 54.5%). Among the MM patients, 10.3% (37/358) patients showed normal ratio and all of these were of IIMM patients. This finding was more commonly observed in IgG lambda type M-protein (35/61, 57.4% vs. others).
Discussion
Our findings pertaining to the diagnostic capabilities of the different screening tests to detect an M-protein, are similar to the previous literatures (Table 2). Different screening tests, namely SPE, IFE and rSFLC, have their own different lower threshold to detect the M-protein (0.3 g/dl for SPE, 0.1 g/dl for IFE and 1 mg/l for SFLC). Thus, no single method/technique is sufficient to detect the M-protein in each and every patient. The diagnostic sensitivities of the different screening tests are comparable, altogether, except for the fact that the in four patients, the type of M-protein cannot be identified. In these four patients, the IFE results were negative (along with SPE results) and the rSFLC was markedly abnormal (range: 0.007–118.6). All these patients were categorised as Undetermined myeloma type (?Non-secretory myeloma) and were not included in the LCMM patients subgroup. The diagnosis of “true” non-secretory multiple myeloma is relatively challenging and many of such patients can be categorized as oligo-sectretors/FLC-restricted MM, as is present in our cohort [5]. However, as was reported by Katzmann et al. [2] and further widely practiced worldwide, the combination of SPE and rSFLC reliably detect M-protein across all myeloma subgroup in our cohort as well.
The comparative analysis of IIMM and LCMM patients concurs that the sensitivity of rSFLC to detect M-protein is much higher than the SPE alone in LCMM group. In the light of the frequent presence of renal impairment in LCMM patients (66.6% vs. 34.4% in IIMM), our findings get reinforced by the fact that the diagnostic utility of urine FLC measurement is unreliable in early- or oligo-secretory LCMM disease [6]. In contrast, IIMM group of patients showed a better diagnostic sensitivity of SPE (95.6%) versus rSFLC (71.8%). Although similar results had also been reported [2, 7–9], the utility of SFLC assay in these patients is manifolds, as it not only helps to define stringent complete response, but also is required for early detection of relapse with light chain escape.
In our cohort, 10.3% (37/358) of myeloma patients did not have an abnormal rSFLC results and this was exclusively seen among IIMM patients (37/276, 13.4%). Similar findings were also highlighted by other investigators (Table 3). The exact reason for this, is not well-known and multiple factors, like polyclonal free-light chain elevation, antigen excess, light-chain polymerisation and un-recognisable epitopes might interplay and impact on it [3, 10–12]. The presence of abnormal rSFLC at presentation had been reported as independent marker of outcome with more extreme ratios predicted worse overall and progression-free survival [9, 13]. Similar findings had also been described in MGUS patients [14]. It was also observed that in this small subgroup of patients, the median dFLC (difference between involved minus uninvolved light chain) value was higher in MM than MGUS/SMM patients (23.8 vs. 14.4 mg/L, respectively). The utility of dFLC had been established in the assessment of treatment response at specific scenario (e.g. AL Amyloidosis etc.), however use of these values in the diagnostic setting is not well described [15]. In our series, we noticed that there is a notable difference between the dFLC values of the MM and MGUS/SMM patients who had normal rSFLC result, at the time of diagnosis, however, a definite diagnostic (or prognostic) role of this, as a biomarker, can only be answered by evaluating it in a much larger number of patients.
Table 3.
Characteristics of patients with normal SFLC ratio (n = 61)
| Disease conditions | Present study | Jeong et al. Clin Chem Lab Med 2013 [7] | Dispenzieri et al. Blood 2008 [8] | Snozek CL et al. Leukemia 2008 [9] | ||
|---|---|---|---|---|---|---|
| MGUS/SMM | MM | Total | No. of MM patients with normal rSFLC (%) | |||
| Number of patients (% of total) | 24 (54.5%) | 37 (10.3%) | 61 (15.2%) | 21 (12.9%) | 16 (4.9%) | 39 (4.9%) |
| Number of patients with renal impairment | 11 | 11 | 22 | NA | NA | NA |
| Immunoglobulin type | ||||||
| IgG Kappa | 6 | 9 | 15 | NA | NA | NA |
| IgG Lambda | 16 | 19 | 35 | |||
| IgA Kappa | 1 | 4 | 5 | |||
| IgA Lambda | 1 | 4 | 5 | |||
| Light chain only | Nil | Nil | Nil | |||
| Biclonal | Nil | 1 | 1 | |||
| Median Kappa (mg/L) | 96.2 | 27.7 | 44.4 | NA | NA | NA |
| Median Lambda (mg/L) | 72.2 | 45.6 | 48.1 | |||
| Median SFLC ratio | 1.26 | 0.99 | 1.18 | |||
| Median dFLC (mg/L) | 14.4 | 23.8 | 21.8 | |||
Virtually all cases of MM are preceded by an MGUS and the M-protein isotype (IgG vs. non-IgG MGUS) affects the likelihood of an MGUS progressing into MM [14, 16, 17]. Historically, IgG subtype M-protein is most frequently encountered in MM patients, followed by IgA, Light chain and IgD subtypes [18]. In our analysis, light chain subtype was second most common form following IgG subtype myeloma. In contrast to MM, IgA subtype of M-protein is markedly less frequent in MGUS/SMM group of patients (4.4% vs. 15.9% in the former). In patients with normal rSFLC, it was IgG lambda subtype M-protein, which was most frequently observed (more often in MGUS than MM). Literature review did not bring forth any plausible explanation for such peculiarity. Even, the presence or absence of renal impairment, in our cohort, did not show any prejudice in this small group of patients.
Multiple myeloma is traditionally being considered as a disease of relatively older age [19]. The data from Indian population showed a relatively younger median age of disease presentation [20, 21]. Our results also revealed that the median age of patients is less in comparison to western data. However, the proportion of patients less than 40 years of age is not as high as was reported in Indian subpopulation [20]. Renal impairment was relatively more frequent in our myeloma patients [18], which could be attributed to the late presentation of patients to our hospital (tertiary care centre).
In conclusion, being in agreement, our results strengthen the fact that combination of SPE and rSFLC can be reliably used to detect M-protein in suspected patients of myeloma. The diagnosis can be further established by additional investigations, including bone marrow examination. There is a small subgroup of MM patients, in which despite the presence of an intact immunoglobulin (M-protein), the rSFLC is not abnormal. Based on the available evidences, these patients should respond favourably (against patients with abnormal rSFLC results). However, a detailed diagnostic (genetic, serological) workup and follow-up of such patients could be advantageous for further understanding.
Acknowledgements
Mr. Ashok Kumar, Mr. Manoj Singh, Mr. Kaushal, Mr. Rahul, Mr. Manoj Sarkar and Mr. Ramdev from the Myeloma Lab, Department of Hematology, SGPGIMS, Lucknow, for performing the SPE, IFE and SFLC assays.
Author contributions
MKS, VP and SD: data retreivement, MKS, DC, RG, KR: manuscript writing, AG, SK, RK, SN: patient recruitment and management.
Availability of data and material
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Declarations
Ethical Approval
The study was approved by institutional ethics committee.
Consent to Participate
An informed consent was taken.
Consent to Publication
An informed consent was taken.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.