| Abstract|| |
Multiple myeloma (MM) is associated with the secretion of a unique monoclonal protein (M-protein) due to overproduction of immunoglobulin (Ig) by a clone of abnormally proliferating plasma cells. However, in 4% of the cases more than one M-protein can be found. This category of gammopathies is called "double monoclonal gammopathies." Here, we present a rare case of MM with double monoclonal gammopathy, where the presence of both M-proteins was observed in the single sharp peak on capillary zone electrophoresis (CZE). Further the interference of Hook effect is also discussed. Double monoclonal gammopathies need to be identified to increase diagnostic accuracy and reliability, and to get a better understanding of the disease pathogenesis and progression.
Keywords: Capillary electrophoresis, double monoclonal gammopathy, hook effect, multiple myeloma
|How to cite this URL:|
Saijpaul R, Khurana V, Verma R, Kaushik S. Single monoclonal spike characterized as double monoclonal gammopathy in a patient with multiple myeloma: A rare finding. Indian J Pathol Microbiol [Epub ahead of print] [cited 2023 Mar 27]. Available from: https://www.ijpmonline.org/preprintarticle.asp?id=368581
| Introduction|| |
Multiple Myeloma (MM) is a part of a range of disorders called as monoclonal gammopathies. It represents a malignant proliferation of plasma cells derived from a single clone. The malignant plasma cells exist primarily not only in the bone marrow but can also be seen in the peripheral blood and other tissues especially in the later stages of the disease. MM is most commonly characterized by the secretion of a monoclonal immunoglobulin (Ig) protein or M-protein by the abnormal plasma cells in the serum or urine, detected by serum/urine protein electrophoresis (SPEP/UPEP) as a single sharp band/peak (M-band/M-spike) mostly in the gamma region. About 4% of monoclonal gammopathies present as double monoclonal gammopathies involve the production of two distinct M-proteins from the abnormal plasma cells. The most common combination reported is IgG and IgA (53%), followed by IgM and IgG (24%). Double monoclonal gammopathies can be associated with conditions like double monoclonal gammopathy of undetermined significance (DGUS), MM, as well lymphoproliferative disorders like leukemia and lymphoma. Here, we present a rare case of MM with double monoclonal gammopathy, where the presence of both M-proteins was observed in the single sharp peak on capillary zone electrophoresis (CZE).
| Case History|| |
A 54-year-old female presented with the complaints of backache and progressive generalized weakness since 1.5 months. There was no other significant history. On examination marked pallor was present with vitals within normal range. Laboratory blood investigations performed on Vitros 5600 (Ortho Clinical Diagnostics) revealed the patient to have markedly increased serum total protein and calcium levels, reversal of the albumin–globulin ratio, and elevated renal parameters. Rest of the biochemical parameters were normal. Hematological investigations revealed the patient to be anemic with an increased erythrocyte sedimentation rate (ESR). Urine was negative for Bence Jones proteins. SPEP and Immunotyping (IT) were performed by Capillary electrophoresis on Minicap flex-piercing (Sebia, France). SPEP revealed a single sharp peak in the gamma region [Figure 1]a. To identify the M-protein secreted and for characterization of the type of heavy and light chains IT was performed. The presence of monoclonal Ig protein IgG-kappa corresponding to the single sharp peak in SPEP was seen [Figure 1]b. Considering a very high total protein concentration and M-protein concentration more than 2 gm/dl, as per manufacturer recommendations, IT was run under "hypergamma mode," which is the automatic dilution mode of the machine to get a more accurate quantitative estimation of M-protein concentration [Figure 2]a. No significant change was observed. Following the next step of the recommendation, the sample was diluted manually (1:3) and IT was run again. Interestingly, here the presence of two distinct MP was revealed – IgG-kappa and IgA-kappa, corresponding to the single sharp peak on SPEP [Figure 2]b. The M-protein was quantified to be 4.1 g/dl. Nephelometric measurements of serum Ig and free light chains performed on analyzer BN2 (Siemens) confirmed our findings. [Table 1] shows the reports of the blood investigations done for the patient. The bone marrow biopsy was suggestive of plasma cell myeloma with clonal plasma cells forming 20% of all nucleated cells including binucleate and immature forms. On Immunohistochemistry, plasma cells were positive for CD138 with kappa restriction. Flow cytometry done suggested plasma cell myeloma with kappa restriction, revealing 21.4% cells gated showing strong positivity for CD38, CD138, and CD 56. For radiological examination, x-rays performed showed evidence of lytic lesions in the skull, bilateral proximal femur, and shaft of the left femur [Figure 3]. A diagnosis of MM with double monoclonal gammopathy was made. Unfortunately, the patient was lost to follow-up and further treatment details could not be elucidated.
|Figure 1: (a) Serum protein electrophoresis performed on capillary electrophoresis (Sebia Minicap flex-piercing) revealing a single sharp peak in the gamma region (M-protein concentration – 4.1 g/dl). (b) IT performed on capillary electrophoresis (Sebia Minicap flex-piercing) showing evidence of monoclonal IgG-k|
Click here to view
|Figure 2: IT performed on capillary electrophoresis (Sebia Minicap flex-piercing) under "hypergamma mode" showing evidence of Monoclonal IgG-k. (a) IT performed on capillary electrophoresis (Sebia Minicap flex-piercing) with sample diluted 1:3 manually showing evidence of monoclonal IgG-k and IgA-k. (The electrophoretogram is represented in black, while the IT performed in presence of respective antiserum as mentioned, is represented in blue.)|
Click here to view
|Figure 3: Radiological examination (a) x-ray bilateral thigh – AP view, (b) x-ray skull – lateral view, and (c) x-ray pelvis with bilateral hip|
Click here to view
| Discussion|| |
MM is characterized as a malignancy involving terminally differentiated plasma cells secreting unique monoclonal Ig. The exact etiology of the disease is not known. Disease pathophysiology is influenced by the tumor microenvironment and genetic events. Double monoclonal gammopathies involve the presence of two M-proteins in serum and/or urine. These distinct proteins may arise either from two distinct plasma cell clones or from clonally related plasma cells after they have undergone class switching and can be detected either at initial presentation or during the course of the treatment, especially after therapy with high-dose immunosuppressants and post stem cell transplantation. The M-proteins secreted may have dissimilar heavy and light chains, or, similar heavy chains with dissimilar light chains, or dissimilar heavy chains and similar heavy chains. True biclonal gammopathy is a small subgroup of double monoclonal gammopathy, where the M-proteins secreted always have different heavy as well as light chains with different variable regions, thus providing conclusive evidence that the two proteins are indeed the products of two separate clones.
Double monoclonal as well as biclonal gammopathy associated cases have previously been reported by Yadav et al., Kancharla et al., Banerjee et al., and Pradhan et al. among others, but what makes our case unique is the presence of two types of M-protein in the single sharp peak on electrophoresis discovered on IT. Another factor encountered in this case, is the hook effect because of the markedly increased total serum protein values, which may have resulted in masking of one type of monoclonal Ig by the other type (IgA by IgG) as seen in IT performed on untreated sample. Double monoclonal gammopathy could only be uncovered after IT was performed in the sample dilution, performed manually.
While diagnosis of double monoclonal gammopathy does not really change the course of treatment for the patient or the patient outcome, it is important that we identify a case of double monoclonal gammopathy as such a report that reflects the diagnostic accuracy and reliability of the analytic procedure performed. As it is known, the distinct M-proteins may be present at initial presentation itself or might develop during the course of the treatment, the knowledge, if present at the time of diagnosis, can aid in better evaluation of response of the disease to therapy. Subsequent measurements of both the M-proteins at the time of diagnosis as well as follow-ups can assist in making better treatment choices, as the synchronicity or lack thereof, of the response of the all clonal proteins to therapy can be assessed. A better understanding of the disease pathogenesis and progression may also be achieved as the exact etiology of MM is still not clearly known.
Authors would like to acknowledge Dr. Bidhan Chandra Koner and Dr. Anjali Sharma for their sincere efforts in the compilation of this case report.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Kumar SK, Rajkumar V, Kyle RA, van Duin M, Sonneveld P, Mateos MV, et al
. Multiple myeloma. Nat Rev Dis Primers 2017;3:17046. doi: 10.1038/nrdp. 2017.46
Sharma S, Gupta P, Aggarwal R, Malhotra P, Minz RW, Bansal F. Demystifying biclonal gammopathy: A pathologist's perspective. Lab Med 2019;50:357-63.
Mahto M, Balakrishnan P, Koner BC, Lali P, Mishra TK, Saxena A. Rare case of biclonal gammopathy. Int J Case Rep Images 2011;2:11-4.
Srinivasan VK, Bhagat P, Bansal F, Chhabra S. Occurrence of double monoclonal bands on protein electrophoresis: An unusual finding. Indian J Hematol Blood Transfus 2016;32(Suppl 1):184-8.
Khalid A, Shahbaz I. Double gammopathy of undetermined significance-a first case report from Pakistan. J Hematol Thrombo Dis 2019;7:297.
Yadav A, Reddy R, Malathi M. Multiple myeloma with biclonal gammopathy of IgA kappa variant: A case report. Biochem Anal Biochem 2017;6:345.
Kancharla P, Patel E, Hennrick K, Ibrahim S, Goldfinger M. A rare presentation of biclonal gammopathy in multiple myeloma with simultaneous extramedullary involvement: A case report. Case Rep Oncol 2019;122:537-42.
Banerjee A, Pimpalgaonkar K, Christy AL. A rare case of multiple myeloma with biclonal gammopathy. J Clin Diagn Res 2016;10:BD03-4.
Pradhan D, Arora P, Gami A, Kaur N. Immunoglobulin G kappa biclonal gammopathy associated with multiple myeloma, plasmacytoma and cast nephropathy. J Cancer Res Ther 2015;11:660.
Room No. 205, Department of Biochemistry, Maulana Azad Medical College, Bahadur Shah Zafar Marg, New Delhi - 110 002
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]