CLB-08643; No. of pages: 5; 4C: Clinical Biochemistry xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Clinical Biochemistry journal homepage: www.elsevier.com/locate/clinbiochem
Characteristics of unexpected protein bands in multiple myeloma patients after autologous stem cell transplantation Soo-Kyung Kim a, Tae-Dong Jeong a, So Young Kim a, Woochang Lee a,⁎, Sail Chun a, Cheol Won Suh b, Won-Ki Min a a b
Departments of Laboratory Medicine, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Republic of Korea Departments of Oncology, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Republic of Korea
a r t i c l e
i n f o
Article history: Received 4 July 2013 Received in revised form 30 December 2013 Accepted 13 February 2014 Available online xxxx Keywords: Free light chain ratio Immunofixation electrophoresis Multiple myeloma Unexpected protein band
a b s t r a c t Objectives: The aim of this study is to investigate the characteristics of unexpected protein bands (UPBs) in patients with multiple myeloma (MM). Design and methods: Individuals diagnosed with MM (n = 193) were enrolled. Their medical records and IFE patterns were reviewed. Results: Of the patients that underwent ASCT, 54% developed UPBs. The median time for UPB appearance and duration was 1.8 and 5.7 months, respectively. IFE revealed 74.1% of UPBs to be of the immunoglobulin G type and 72.2% to be of the κ-type. At UPB appearance, 42.6% of patients were defined as sCR or CR, and 50.0% of the patients satisfying the CR criteria had an abnormal FLC ratio. Of the patients who developed UPBs, five relapsed. Among these, four patients showed disappearance of the previous IFE oligoclonality and reappearance of the original paraprotein at relapse. Conclusions: Close follow-up of UPBs is critical for evaluating MM therapeutic response and disease progression. The presence of monoclonal bands may indicate relapse of disease, but in the vast majority of cases with UPBs, it does not; instead, it most likely represents a transient phenomenon caused by the immune response. © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Introduction Multiple myeloma (MM) is characterized by the presence of paraproteins, immunologically identical monoclonal antibodies generated by clonal proliferation of plasma cells. Although MM-related paraproteins can switch isotypes during relapse, paraproteins usually remain unchanged throughout disease progression [1]. The recommended clinical laboratory tests for the diagnosis and follow-up of MM include complete blood cell count, determination of calcium and creatinine levels, serum free light chain (FLC) assay, urine or serum protein electrophoresis (EP), immunofixation electrophoresis (IFE), cytogenetic tests, and others [2–4]. Paraproteins can be identified by EP and IFE, although EP is not sensitive enough to detect small amounts of paraproteins and immunoglobulin (Ig) heavy and light chain class. Consequently, the initial EP should always be performed in combination with IFE to confirm monoclonality, and to determine the Ig heavy and light chain class [5].
⁎ Corresponding author at: Department of Laboratory Medicine, University of Ulsan College of Medicine and Asan, Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Republic of Korea. Fax: +82 2 478 0884. E-mail address: [email protected] (W. Lee).
The widespread use of autologous stem cell transplantation (ASCT) and the introduction of novel drugs have contributed enormously to the treatment outcome and prognosis of MM [6,7]. However, in patients who have undergone ASCT, the isotypes and locations of IFE bands frequently differ from that observed at diagnosis [1,8,9], which can complicate the interpretation of results. For these reasons, this study aimed to investigate the characteristics and clinical implications of unexpected protein bands (UPBs) by retrospective review of medical records and serum or urine IFE test results of MM patients who had undergone ASCT. Methods Study population A retrospective study was conducted on MM patients treated at the Asan Medical Center in Seoul, Korea from January 2007 to January 2012. A total of 193 patients were included in the study. Of these, 100 patients (49 males and 51 females; median age 59 years) underwent ASCT and 93 MM patients (54 males and 39 females; median age 70) did not undergo ASCT. Induction chemotherapy was implemented as prescribed by a physician. The study was approved by the Institutional Review Board of the Asan Medical Center, in accordance with the World Medical Association's (WMA) Declaration of Helsinki.
http://dx.doi.org/10.1016/j.clinbiochem.2014.02.015 0009-9120/© 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Please cite this article as: Kim S-K, et al, Characteristics of unexpected protein bands in multiple myeloma patients after autologous stem cell transplantation, Clin Biochem (2014), http://dx.doi.org/10.1016/j.clinbiochem.2014.02.015
2
S.-K. Kim et al. / Clinical Biochemistry xxx (2014) xxx–xxx
Immunofixation electrophoresis The Beckman Paragon Electrophoresis System (Beckman Coulter, Fullerton, CA, USA) was used for detection of paraprotein isotypes from January 2007 to April 2009, and the Hydragel 4IF reagent set (Sebia, Paris, France) was used from April 2009 to January 2012. In our laboratory, the lower limit of detection of an M-protein on an immunofixation gel was 12 mg/dL. UPBs were defined by the appearance of Ig bands in different locations or by the presence of different isotypes. Each UPB was categorized as either oligoclonal bands or an isotype switch. The presence of two or more discrete Ig bands of the same isotype was interpreted as oligoclonal bands. The presence of a protein band with a heavy or light chain type that was different from the original paraprotein was interpreted as an isotype switch. Measurement of hemoglobin, calcium, creatinine and free light chain Patients' hemoglobin, calcium, and creatinine levels at diagnosis were determined. Hemoglobin was measured by an XE-2100 (Sysmex, Kobe, Japan). Creatinine and calcium were measured by a TBA 200FR (Toshiba Medical Systems, Tokyo, Japan). A serum FLC measurement (Freelite™; Binding Site Ltd., Birmingham, UK) was performed by Siemens Dade Behring Nephelometer II analyzer System (BNII). All assays were performed following the manufacturer's instructions. Statistical analyses Statistical analysis was performed using the SPSS software (version 19.0; SPSS Inc., Chicago, IL, USA). A chi-square test was used to analyze the difference in UPB incidence between the ASCT and non-ASCT group. An independent sample t-test was used to analyze UPB incidence based on age, initial hemoglobin, serum creatinine, and calcium levels. Fisher's exact test was used to analyze UPB incidence based on the use of novel or conventional drugs. A P value b0.05 was considered to indicate statistical significance. Results Patients Of the 100 patients who had undergone ASCT, 65 patients received novel agents. Among these novel treatments, PAD (bortezomib, doxorubicin, and dexamethasone) was the most frequently used regimen, in 36/65 patients (55%). Thirty-five patients were treated with conventional drugs only. Of these patients, 27/35 (77%) were treated with a VAD (vincristine, doxorubicin, and dexamethasone) regimen. Unexpected protein bands
undergo ASCT (P b 0.001). In patients who underwent ASCT, the median time for the appearance and duration of UPBs was 1.8 months (range 0.7–26.4 months) and 5.7 months (range 0.9–25.9 months), respectively. The most common heavy chain isotype was IgG, observed in 74.1%, and the most common light chain isotype was κ, observed in 72.2% of the patients (Table 1). Oligoclonal bands were observed in 38/54 (70.4%) patients with UPBs and an isotype switch was noted in 16 (29.6%) patients (Table 2). Based on the type of induction chemotherapy, UPBs appeared in 24/35 (68.6%) patients treated with conventional drugs and 30/65 (46.2%) patients treated with novel drugs. The incidence of UPBs in patients treated with novel drugs was significantly lower than that of patients treated with conventional drugs (P = 0.037). To determine the association between UPB and clinical status, response criteria according to the International Myeloma Working Group (IMWG) at the time of UPB appearance and disappearance were evaluated. At the moment UPB appeared, the response criteria were categorized as a stringent complete response (sCR) in 10 (18.5%), complete response (CR) in 13 (24.1%), very good partial response (VGPR) in 6 (11.1%), partial response (PR) in 9 (16.7%), stable disease (SD) in 12 (22.2%), progressive disease (PD) in 3 (5.6%), and relapse in 1 (1.9%) patient. UPBs disappeared in 37/54 patients. The other 17 patients had persistent UPB until the last follow-up or loss to followup. In 37 patients, evaluation of the response criteria at the time of UPB disappearance resulted in categorization as sCR of 13 (35.1%), CR of 10 (27.0%), VGPR of 5 (13.5%), PR of 1 (2.7%), and SD of 8 (21.6%) patients. Age, hemoglobin, calcium, and creatinine levels at diagnosis For the 54 patients with UPBs, the median age at diagnosis was 60 (range 40–70), and median hemoglobin, calcium, and creatinine levels were 10.3 g/dL (range 6.2–17.1 g/dL), 9.2 mg/dL (range 7.4–13.0 mg/dL), and 0.9 mg/dL (range 0.4–10.6 mg/dL), respectively. For 46 patients without UPBs, the median age at diagnosis was 59 (range 46–68), and median hemoglobin, calcium, and creatinine levels were 9.5 g/dL (range 5.4–14.0 g/dL), 9.1 mg/dL (range 7.4–14.1 mg/dL), and 1.0 mg/dL (range 0.4–6.8 mg/dL), respectively. No differences were found in the age (P = 0.558), and hemoglobin (P = 0.103), calcium (P = 0.295), and creatinine (P = 0.542) levels, between the groups. Free light chain ratio At the time of UPB onset, 48 patients were analyzed by FLC assay, and 25 (52.1%) showed an abnormal FLC ratio (FLCR). Fourteen patients had an FLCR higher than the normal range, which indicates overproduction of κ light chains. However, of these patients, only four showed κ-type UPB, another four patients had λ-type UPB, and six
UPBs were detected in 54% of patients that underwent ASCT (Fig. 1), while UPBs were detected in only 5/93 patients (5.4%) that did not Table 1 Isotypes and their frequency of unexpected protein bands (UPBs) in 54 multiple myeloma patients who developed UPBs after autologous stem cell transplantation.
Fig. 1. Representative serum immunofixation electrophoresis (IFE) of a patient who underwent autologous stem cell transplantation (ASCT) for management of multiple myeloma. (A) Free λ monoclonal band at diagnosis. (B) IgG κ and λ type bands detected two months after ASCT.
Subtype
Number of patients (% frequency)
IgG κ IgG κ and IgG λ Free λ IgG λ IgG κ and free λ Free κ and free λ Free κ IgG κ and IgA λ IgM λ IgA λ
18 (33.3) 9 (16.7) 7 (13.0) 6 (11.1) 6 (11.1) 3 (5.6) 2 (3.7) 1 (1.9) 1 (1.9) 1 (1.9)
Please cite this article as: Kim S-K, et al, Characteristics of unexpected protein bands in multiple myeloma patients after autologous stem cell transplantation, Clin Biochem (2014), http://dx.doi.org/10.1016/j.clinbiochem.2014.02.015
S.-K. Kim et al. / Clinical Biochemistry xxx (2014) xxx–xxx
3
Table 2 Clinical data and characteristics of unexpected protein bands for the multiple myeloma patients who had an isotype switch determined by immunofixation electrophoresis after treatment. Case number
Age (years)
Sex
16 23 37 38 39 46 53 55 58 63 67 75 76 81 82 87 106 141 149
51 59 66 65 49 60 62 52 45 64 58 60 53 40 59 60 68 74 67
F M F M F F F F M F M F F F F F M F M
Primary chemotherapy
VD PAD VAD VAD, PAD HD dexa, PAD HD dexa, PAD HD dexa, VAD HD dexa, PAD VAD, PAD TD HD dexa, PAD TD TD, VAD VAD, VD TD TD MP, TD MP HD dexa
ASCT
Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No No No
Isotype Original monoclonal band
UPB
IgD λ IgG λ IgD λ IgG κ IgG κ Free κ Free λ IgA κ IgG κ IgG κ Free κ IgA κ IgA λ IgG λ IgG κ IgA κ IgG λ IgG κ Free λ
IgG κ IgG κ IgM λ Free λ Free λ IgG λ IgG κ IgG κ IgG λ IgA λ Free κ, free λ IgG κ IgG λ Free κ Free L IgG κ, IgG λ Free λ IgG λ IgG κ
UPB duration (months) 14.6 4.2 18.1 3.9 19.8 NA 6.5 0.9 2.4 1.4 13.6 6.9 3.0 2.0 NA NA 6.7 1.7 2.0
ASCT, autologous stem cell transplantation; F, female; HD dexa, high dose dexamethasone; M, male; MP, melphalan and prednisone; NA, not applicable; PAD, bortezomib, doxorubicin, and dexamethasone; TD, thalidomide and dexamethasone; UPB, unexpected protein band; VAD, vincristine, doxorubicin, and dexamethasone; VD, bortezomib and dexamethasone.
had both κ- and λ-type UPB. Eleven patients had an FLCR lower than the normal range. Of these 11 patients, 3 had κ-type UPB, 1 had λ-type UPB, and 7 had both κ- and λ-type UPB. Excluding patients who were lost to follow-up or who had persistent UPB, 37 patients had UPB disappearance at the follow-up period. Among these, 34 patients were analyzed by FLC assay. At the time of UPB disappearance, 13 (38.2%) patients showed an abnormal FLCR. Relapse Twelve patients relapsed during ASCT follow-up, and IFE tests were performed on 11/12 at the time of relapse. Among these 11 relapsed patients, 5 had UPBs after ASCT and 6 did not have UPBs after ASCT. In other words, among the 54 patients who developed UPBs, 5 (9.3%) patients relapsed, and among the 46 patients who did not develop UPBs, 6 (13.0%) patients relapsed. Of the five patients who developed UPBs and experienced relapse afterwards, four had UPBs that appeared after ASCT but disappeared at the time of relapse, with the reappearance of paraprotein bands similar to those at diagnosis (Fig. 2). The other patient was diagnosed with a newly formed plasmacytoma in the chest wall and testis. His IFE showed a constant UPB isotype and location, even at the time of relapse. The characteristics of relapsed patients are described in Table 3. Discussion The aim of the present study was to report our experience with a series of 193 MM patients, which is one of the largest cohorts examined
to determine the relevant characteristics of UPBs in this patient population. As ASCT is a common treatment option, detection of UPBs with an IFE test has increased concomitantly, making IFE interpretation more difficult. In this study, the incidence of UPBs was 54% in patients that underwent ASCT, compared to 5.4% in subjects that did not. These results are in agreement with those of previous reports of UPB incidence in the ASCT group as 10–73% [8–10]. Median onset and duration of UPB in this study resembled those of numerous reports of a median onset at 2–11.5 months after ASCT, and the median duration as 3–22 months [8–10]. The current response criteria were defined without considering UPB; thus, there have been difficulties interpreting response criteria in patients with UPB. According to the IMWG response criteria, CR is defined as negative immunofixation of the serum and urine. However, in cases with UPB, negative M-protein other than UPB on immunofixation would be a more appropriate criterion. In this study, CR was defined using IFEs with UPB without M-protein at diagnosis and disappearance of any soft tissue plamacytoma and BM plasma cells of b5%. Patients who satisfied the CR criteria and had normal FLCR (0.26–1.65) were defined as sCR [11]. At the appearance of UPB, 42.6% of the patients belonged to sCR or CR. A previous study reported that at UPB appearance, 35.8% of the patients were CR [10]. However, if we consider UPB on IFE, 23 cases defined as CR or sCR would be redefined as 15 VGPR and 8 PR. Therefore, the UPB should be examined carefully, since misinterpretation of UPB to M-protein would lead to a misdiagnosis of poorer response criteria. In the UPB group, 50.0% of the patients satisfying CR criteria had abnormal FLCR, having similar frequency to the previous studies reporting
Fig. 2. Serum immunofixation eletrophoresis (IFE) patterns of a patient who underwent autologous hematopoietic stem cell transplantation (ASCT) and relapsed. (A) Free λ monoclonal band at diagnosis. (B) IgG κ type UPB observed six months after ASCT. (C) Disappearance of UPBs and reappearance of the paraprotein band similar to that of the diagnosis observed at relapse.
Please cite this article as: Kim S-K, et al, Characteristics of unexpected protein bands in multiple myeloma patients after autologous stem cell transplantation, Clin Biochem (2014), http://dx.doi.org/10.1016/j.clinbiochem.2014.02.015
4
S.-K. Kim et al. / Clinical Biochemistry xxx (2014) xxx–xxx
Table 3 Characteristics of unexpected protein bands for the multiple myeloma patients who relapsed after treatment. Case number
Age (years)
Sex
7 10 12 16 19 31 35 37 40 44 54 60
63 47 47 51 52 65 46 66 60 68 63 46
M M M F F F M F F F M M
PrimaryChemotherapy
PAD CP PAD VD VAD VAD VAD, PAD VAD HD dexa, PAD VAD, PAD HD dexa, VAD HD Dexa, PAD, MPT
Isotype Original monoclonal band
UPB
IgG κ IgA κ IgA κ IgD λ IgG κ Free λ IgA κ IgD λ IgG κ Free κ IgG λ Free λ
– IgG κ – IgG κ – IgG κ IgG κ IgM λ Free λ – – –
UPBonset afterASCT(months)
UPB duration(months)
Relapseonset afterASCT(months)
– 4.7 – 5.1 – 0.9 1.9 1.1 2.1 – – –
– 5.7 – 14.6 – 1.6 4.4 18.1 10.5 – – –
10 11 16 45 11 30 7 19 32 34 24 16
CP, cyclophosphamide and prednisone; F. female; HD dexa, high-dose dexamethasone; M, male; MPT, melphalan, prednisone, and thalidomide; PAD, bortezomib, doxorubicin, and dexamethasone; UPB, unexpected protein band; VAD, vincristine, doxorubicin, and dexamethasone; VD, bortezomib and dexamethasone.
57–72.7% [12,13]. UPB light chain isotype and FLCR had no correlation, while only 28.6% of the κ-type UPB had increased FLCR and 9.1% of the λ-type UPB had decreased FLCR. This discordance between the light chain involved in UPB and FLCR has been reported previously [13]. Further studies will be required to ascertain the current definition of sCR and its prognostic relevance. Comparing the response criteria at the time of UPB appearance and at the time of UPB disappearance, nine (24.3%) patients, who were neither defined as sCR nor CR, changed to sCR or CR after UPB disappearance. Fourteen (37.8%) patients maintained sCR or CR. One (2.7%) patient changed from CR to SD and one (2.7%) patient had persistent SD. The frequent occurrence of monoclonal gammopathies with an abnormal FLCR following bone marrow transplantation has long been known [14]. The B-cell system is regenerated at an accelerated rate, leading to normalization of immunoglobulin serum levels within months after transplantation [14]. However during this reconstitution period, a number of immunoglobulin aberrations may develop, affecting both the levels of the various immunoglobulin classes and the antibody repertoire [14]. Therefore, the presence of UPBs is a reflection of physiological response occurring during reorganization of humoral immunity after immune suppression [15]. The mechanism responsible for the restricted antibody response may be due to normal recapitulation of B-cell ontogeny, or they may result from a malfunctioning T-cell system and a disturbance of T–B cell cooperation [16]. One explanation for the higher incidence of UPBs in patients who had undergone ASCT could be that myeloablative treatment followed by stem cell rescue probably results in higher tumor reduction leading to a more powerful immune reconstitution than induction chemotherapy not followed by ASCT [17]. The most frequently observed isotype in this study was IgG κ. When stem cells of B cell lineage rearrange IgG light chain, either κ loci may be utilized. If a nonfunctional gene is produced, rearrangement of the second κ chain locus ensues, and if the rearrangement again does not result in a functional product, λ light chains will be rearranged [18]. This ultimately results in a 2/1 proportion of κ/λ light chains in normal serum IgGs. A similar ratio would be expected in the regenerating bone marrow; therefore, κ predominance suggests that UPBs are attributable to a physiological regeneration process [14]. We investigated the incidence rate of UPBs based on induction chemotherapy regimens. UPBs were detected significantly more often in patients treated with conventional drugs than patients treated with novel drugs. Our results differ from those of Fernandez et al., who reported higher UPB incidence in patients treated with novel drugs than in those treated with conventional drugs (60.0 vs. 11.1%) [17]. The difference from our study may be derived from different categorization of patients. In their study, patients were divided into two groups based on a novel vs. conventional chemotherapy regimen, and ASCT history was not considered when grouping the patients.
Relapse rates were similar between the UPB (9.3%) and non-UPB (13.0%) groups. Therefore, UPBs does not contribute to relapse. Patients with UPBs showed a characteristic IFE pattern at relapse. At the time of relapse, UPBs disappeared and paraprotein bands similar to those at diagnosis reappeared. In addition, this study examined hemoglobin, calcium, and creatinine levels between UPB and non-UPB groups to identify any difference during disease progression. However, no significant differences were noted. In conclusion, the appearance of UPBs is regarded as an epiphenomenon following treatment of MM patients that does not seem to be derived from malignant plasma cells. To discriminate UPBs from the monoclonal band of relapse, it is important to compare the location and isotype of the present band with that at diagnosis. Moreover, the patient's clinical findings should always be considered when interpreting IFE.
Conflict of interest The authors declare that there are no conflicts of interest regarding publication of this article.
References [1] Hall SL, Tate J, Gill D, Mollee P. Significance of abnormal protein bands in patients with multiple myeloma following autologous stem cell transplantation. Clin Biochem Rev 2009;30:113–8. [2] Palumbo A, Sezer O, Kyle R, Miguel JS, Orlowski RZ, Moreau P, et al. International myeloma working group guidelines for the management of multiple myeloma patients ineligible for standard high-dose chemotherapy with autologous stem cell transplantation. Leukemia 2009;23:1716–30. [3] Dimopoulos M, Terpos E, Comenzo RL, Tosi P, Beksac M, Sezer O, et al. International myeloma working group consensus statement and guidelines regarding the current role of imaging techniques in the diagnosis and monitoring of multiple myeloma. Leukemia 2009;23:1545–56. [4] Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia 2009;23:3–9. [5] Rajkumar SV, Kyle RA, Connor RF. Recognition of monoclonal proteins. UpToDate; 2012. [6] Cavo M, Baccarani M. The changing landscape of myeloma therapy. N Engl J Med 2006;354:1076–8. [7] Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood 2008;111:2516–20. [8] Zent CS, Wilson CS, Tricot G, Jagannath S, Siegel D, Desikan KR, et al. Oligoclonal protein bands and ig isotype switching in multiple myeloma treated with highdose therapy and hematopoietic cell transplantation. Blood 1998;91:3518–23. [9] Hovenga S, de Wolf JT, Guikema JE, Klip H, Smit JW, Smit Sibinga CT, et al. Autologous stem cell transplantation in multiple myeloma after vad and edap courses: a high incidence of oligoclonal serum igs post transplantation. Bone Marrow Transplant 2000;25:723–8. [10] Sucak G, Suyanı E, Ozkurt ZN, Yeğin ZA, Aki Z, Yagci M. Abnormal protein bands in patients with multiple myeloma after haematopoietic stem cell transplantation: does it have a prognostic significance? Hematol Oncol 2010;28:180–4.
Please cite this article as: Kim S-K, et al, Characteristics of unexpected protein bands in multiple myeloma patients after autologous stem cell transplantation, Clin Biochem (2014), http://dx.doi.org/10.1016/j.clinbiochem.2014.02.015
S.-K. Kim et al. / Clinical Biochemistry xxx (2014) xxx–xxx [11] Katzmann JA, Clark RJ, Abraham RS, Bryant S, Lymp JF, Bradwell AR, et al. Serum reference intervals and diagnostic ranges for free κ and free λ immunoglobulin light chains: relative sensitivity for detection of monoclonal light chains. Clin Chem 2002;48:1437–44. [12] Alejandre ME, Pavlovsky MA, Remaggi G, Corrado C, Fernandez I, Milone G, et al. Serum free light chains and oligoclonal bands in patients with multiple myeloma and autologous stem cell transplantation. Clin Chem Lab Med 2012;50:1093–7. [13] De Larrea CF, Cibeira MT, Elena M, Arostegui JI, Rosiñol L, Rovira M, et al. Abnormal serum free light chain ratio in patients with multiple myeloma in complete remission has strong association with the presence of oligoclonal bands: implications for stringent complete remission definition. Blood 2009;114:4954–6. [14] Hammarstrom L, Smith CIE. Frequent occurrence of monoclonal gammopathies with an imbalanced light-chain ratio following bone marrow transplantation. Transplantation 1987;43:447–9.
5
[15] Alejandre ME, Madalena LB, Pavlovsky MA, Facio ML, Corrado C, Milone G, et al. Oligoclonal bands and immunoglobulin isotype switch during monitoring of patients with multiple myeloma and autologous hematopoietic cell transplantation: a 16-year experience. Clin Chem Lab Med 2010;48:727–31. [16] Mitus AJ, Stein R, Rappeport JM, Antin JH, Weinstein HJ, Alper CA, et al. Monoclonal and oligoclonal gammopathy after bone marrow transplantation. Blood 1989;74:2764–8. [17] Fernandez de Larrea C, Tovar N, Cibeira MT, Arostegui JI, Rosinol L, Elena M, et al. Emergence of oligoclonal bands in patients with multiple myeloma in complete remission after induction chemotherapy: association with the use of novel agents. Haematologica 2011;96:171–3. [18] Hieter PA, Korsmeyer SJ, Waldmann TA, Leder P. Human immunoglobulin kappa light-chain genes are deleted or rearranged in lambda-producing b cells. Nature 1981;290:368–72.
Please cite this article as: Kim S-K, et al, Characteristics of unexpected protein bands in multiple myeloma patients after autologous stem cell transplantation, Clin Biochem (2014), http://dx.doi.org/10.1016/j.clinbiochem.2014.02.015
Contents lists available at ScienceDirect
Clinical Biochemistry journal homepage: www.elsevier.com/locate/clinbiochem
Characteristics of unexpected protein bands in multiple myeloma patients after autologous stem cell transplantation Soo-Kyung Kim a, Tae-Dong Jeong a, So Young Kim a, Woochang Lee a,⁎, Sail Chun a, Cheol Won Suh b, Won-Ki Min a a b
Departments of Laboratory Medicine, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Republic of Korea Departments of Oncology, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Republic of Korea
a r t i c l e
i n f o
Article history: Received 4 July 2013 Received in revised form 30 December 2013 Accepted 13 February 2014 Available online xxxx Keywords: Free light chain ratio Immunofixation electrophoresis Multiple myeloma Unexpected protein band
a b s t r a c t Objectives: The aim of this study is to investigate the characteristics of unexpected protein bands (UPBs) in patients with multiple myeloma (MM). Design and methods: Individuals diagnosed with MM (n = 193) were enrolled. Their medical records and IFE patterns were reviewed. Results: Of the patients that underwent ASCT, 54% developed UPBs. The median time for UPB appearance and duration was 1.8 and 5.7 months, respectively. IFE revealed 74.1% of UPBs to be of the immunoglobulin G type and 72.2% to be of the κ-type. At UPB appearance, 42.6% of patients were defined as sCR or CR, and 50.0% of the patients satisfying the CR criteria had an abnormal FLC ratio. Of the patients who developed UPBs, five relapsed. Among these, four patients showed disappearance of the previous IFE oligoclonality and reappearance of the original paraprotein at relapse. Conclusions: Close follow-up of UPBs is critical for evaluating MM therapeutic response and disease progression. The presence of monoclonal bands may indicate relapse of disease, but in the vast majority of cases with UPBs, it does not; instead, it most likely represents a transient phenomenon caused by the immune response. © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Introduction Multiple myeloma (MM) is characterized by the presence of paraproteins, immunologically identical monoclonal antibodies generated by clonal proliferation of plasma cells. Although MM-related paraproteins can switch isotypes during relapse, paraproteins usually remain unchanged throughout disease progression [1]. The recommended clinical laboratory tests for the diagnosis and follow-up of MM include complete blood cell count, determination of calcium and creatinine levels, serum free light chain (FLC) assay, urine or serum protein electrophoresis (EP), immunofixation electrophoresis (IFE), cytogenetic tests, and others [2–4]. Paraproteins can be identified by EP and IFE, although EP is not sensitive enough to detect small amounts of paraproteins and immunoglobulin (Ig) heavy and light chain class. Consequently, the initial EP should always be performed in combination with IFE to confirm monoclonality, and to determine the Ig heavy and light chain class [5].
⁎ Corresponding author at: Department of Laboratory Medicine, University of Ulsan College of Medicine and Asan, Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Republic of Korea. Fax: +82 2 478 0884. E-mail address: [email protected] (W. Lee).
The widespread use of autologous stem cell transplantation (ASCT) and the introduction of novel drugs have contributed enormously to the treatment outcome and prognosis of MM [6,7]. However, in patients who have undergone ASCT, the isotypes and locations of IFE bands frequently differ from that observed at diagnosis [1,8,9], which can complicate the interpretation of results. For these reasons, this study aimed to investigate the characteristics and clinical implications of unexpected protein bands (UPBs) by retrospective review of medical records and serum or urine IFE test results of MM patients who had undergone ASCT. Methods Study population A retrospective study was conducted on MM patients treated at the Asan Medical Center in Seoul, Korea from January 2007 to January 2012. A total of 193 patients were included in the study. Of these, 100 patients (49 males and 51 females; median age 59 years) underwent ASCT and 93 MM patients (54 males and 39 females; median age 70) did not undergo ASCT. Induction chemotherapy was implemented as prescribed by a physician. The study was approved by the Institutional Review Board of the Asan Medical Center, in accordance with the World Medical Association's (WMA) Declaration of Helsinki.
http://dx.doi.org/10.1016/j.clinbiochem.2014.02.015 0009-9120/© 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Please cite this article as: Kim S-K, et al, Characteristics of unexpected protein bands in multiple myeloma patients after autologous stem cell transplantation, Clin Biochem (2014), http://dx.doi.org/10.1016/j.clinbiochem.2014.02.015
2
S.-K. Kim et al. / Clinical Biochemistry xxx (2014) xxx–xxx
Immunofixation electrophoresis The Beckman Paragon Electrophoresis System (Beckman Coulter, Fullerton, CA, USA) was used for detection of paraprotein isotypes from January 2007 to April 2009, and the Hydragel 4IF reagent set (Sebia, Paris, France) was used from April 2009 to January 2012. In our laboratory, the lower limit of detection of an M-protein on an immunofixation gel was 12 mg/dL. UPBs were defined by the appearance of Ig bands in different locations or by the presence of different isotypes. Each UPB was categorized as either oligoclonal bands or an isotype switch. The presence of two or more discrete Ig bands of the same isotype was interpreted as oligoclonal bands. The presence of a protein band with a heavy or light chain type that was different from the original paraprotein was interpreted as an isotype switch. Measurement of hemoglobin, calcium, creatinine and free light chain Patients' hemoglobin, calcium, and creatinine levels at diagnosis were determined. Hemoglobin was measured by an XE-2100 (Sysmex, Kobe, Japan). Creatinine and calcium were measured by a TBA 200FR (Toshiba Medical Systems, Tokyo, Japan). A serum FLC measurement (Freelite™; Binding Site Ltd., Birmingham, UK) was performed by Siemens Dade Behring Nephelometer II analyzer System (BNII). All assays were performed following the manufacturer's instructions. Statistical analyses Statistical analysis was performed using the SPSS software (version 19.0; SPSS Inc., Chicago, IL, USA). A chi-square test was used to analyze the difference in UPB incidence between the ASCT and non-ASCT group. An independent sample t-test was used to analyze UPB incidence based on age, initial hemoglobin, serum creatinine, and calcium levels. Fisher's exact test was used to analyze UPB incidence based on the use of novel or conventional drugs. A P value b0.05 was considered to indicate statistical significance. Results Patients Of the 100 patients who had undergone ASCT, 65 patients received novel agents. Among these novel treatments, PAD (bortezomib, doxorubicin, and dexamethasone) was the most frequently used regimen, in 36/65 patients (55%). Thirty-five patients were treated with conventional drugs only. Of these patients, 27/35 (77%) were treated with a VAD (vincristine, doxorubicin, and dexamethasone) regimen. Unexpected protein bands
undergo ASCT (P b 0.001). In patients who underwent ASCT, the median time for the appearance and duration of UPBs was 1.8 months (range 0.7–26.4 months) and 5.7 months (range 0.9–25.9 months), respectively. The most common heavy chain isotype was IgG, observed in 74.1%, and the most common light chain isotype was κ, observed in 72.2% of the patients (Table 1). Oligoclonal bands were observed in 38/54 (70.4%) patients with UPBs and an isotype switch was noted in 16 (29.6%) patients (Table 2). Based on the type of induction chemotherapy, UPBs appeared in 24/35 (68.6%) patients treated with conventional drugs and 30/65 (46.2%) patients treated with novel drugs. The incidence of UPBs in patients treated with novel drugs was significantly lower than that of patients treated with conventional drugs (P = 0.037). To determine the association between UPB and clinical status, response criteria according to the International Myeloma Working Group (IMWG) at the time of UPB appearance and disappearance were evaluated. At the moment UPB appeared, the response criteria were categorized as a stringent complete response (sCR) in 10 (18.5%), complete response (CR) in 13 (24.1%), very good partial response (VGPR) in 6 (11.1%), partial response (PR) in 9 (16.7%), stable disease (SD) in 12 (22.2%), progressive disease (PD) in 3 (5.6%), and relapse in 1 (1.9%) patient. UPBs disappeared in 37/54 patients. The other 17 patients had persistent UPB until the last follow-up or loss to followup. In 37 patients, evaluation of the response criteria at the time of UPB disappearance resulted in categorization as sCR of 13 (35.1%), CR of 10 (27.0%), VGPR of 5 (13.5%), PR of 1 (2.7%), and SD of 8 (21.6%) patients. Age, hemoglobin, calcium, and creatinine levels at diagnosis For the 54 patients with UPBs, the median age at diagnosis was 60 (range 40–70), and median hemoglobin, calcium, and creatinine levels were 10.3 g/dL (range 6.2–17.1 g/dL), 9.2 mg/dL (range 7.4–13.0 mg/dL), and 0.9 mg/dL (range 0.4–10.6 mg/dL), respectively. For 46 patients without UPBs, the median age at diagnosis was 59 (range 46–68), and median hemoglobin, calcium, and creatinine levels were 9.5 g/dL (range 5.4–14.0 g/dL), 9.1 mg/dL (range 7.4–14.1 mg/dL), and 1.0 mg/dL (range 0.4–6.8 mg/dL), respectively. No differences were found in the age (P = 0.558), and hemoglobin (P = 0.103), calcium (P = 0.295), and creatinine (P = 0.542) levels, between the groups. Free light chain ratio At the time of UPB onset, 48 patients were analyzed by FLC assay, and 25 (52.1%) showed an abnormal FLC ratio (FLCR). Fourteen patients had an FLCR higher than the normal range, which indicates overproduction of κ light chains. However, of these patients, only four showed κ-type UPB, another four patients had λ-type UPB, and six
UPBs were detected in 54% of patients that underwent ASCT (Fig. 1), while UPBs were detected in only 5/93 patients (5.4%) that did not Table 1 Isotypes and their frequency of unexpected protein bands (UPBs) in 54 multiple myeloma patients who developed UPBs after autologous stem cell transplantation.
Fig. 1. Representative serum immunofixation electrophoresis (IFE) of a patient who underwent autologous stem cell transplantation (ASCT) for management of multiple myeloma. (A) Free λ monoclonal band at diagnosis. (B) IgG κ and λ type bands detected two months after ASCT.
Subtype
Number of patients (% frequency)
IgG κ IgG κ and IgG λ Free λ IgG λ IgG κ and free λ Free κ and free λ Free κ IgG κ and IgA λ IgM λ IgA λ
18 (33.3) 9 (16.7) 7 (13.0) 6 (11.1) 6 (11.1) 3 (5.6) 2 (3.7) 1 (1.9) 1 (1.9) 1 (1.9)
Please cite this article as: Kim S-K, et al, Characteristics of unexpected protein bands in multiple myeloma patients after autologous stem cell transplantation, Clin Biochem (2014), http://dx.doi.org/10.1016/j.clinbiochem.2014.02.015
S.-K. Kim et al. / Clinical Biochemistry xxx (2014) xxx–xxx
3
Table 2 Clinical data and characteristics of unexpected protein bands for the multiple myeloma patients who had an isotype switch determined by immunofixation electrophoresis after treatment. Case number
Age (years)
Sex
16 23 37 38 39 46 53 55 58 63 67 75 76 81 82 87 106 141 149
51 59 66 65 49 60 62 52 45 64 58 60 53 40 59 60 68 74 67
F M F M F F F F M F M F F F F F M F M
Primary chemotherapy
VD PAD VAD VAD, PAD HD dexa, PAD HD dexa, PAD HD dexa, VAD HD dexa, PAD VAD, PAD TD HD dexa, PAD TD TD, VAD VAD, VD TD TD MP, TD MP HD dexa
ASCT
Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No No No
Isotype Original monoclonal band
UPB
IgD λ IgG λ IgD λ IgG κ IgG κ Free κ Free λ IgA κ IgG κ IgG κ Free κ IgA κ IgA λ IgG λ IgG κ IgA κ IgG λ IgG κ Free λ
IgG κ IgG κ IgM λ Free λ Free λ IgG λ IgG κ IgG κ IgG λ IgA λ Free κ, free λ IgG κ IgG λ Free κ Free L IgG κ, IgG λ Free λ IgG λ IgG κ
UPB duration (months) 14.6 4.2 18.1 3.9 19.8 NA 6.5 0.9 2.4 1.4 13.6 6.9 3.0 2.0 NA NA 6.7 1.7 2.0
ASCT, autologous stem cell transplantation; F, female; HD dexa, high dose dexamethasone; M, male; MP, melphalan and prednisone; NA, not applicable; PAD, bortezomib, doxorubicin, and dexamethasone; TD, thalidomide and dexamethasone; UPB, unexpected protein band; VAD, vincristine, doxorubicin, and dexamethasone; VD, bortezomib and dexamethasone.
had both κ- and λ-type UPB. Eleven patients had an FLCR lower than the normal range. Of these 11 patients, 3 had κ-type UPB, 1 had λ-type UPB, and 7 had both κ- and λ-type UPB. Excluding patients who were lost to follow-up or who had persistent UPB, 37 patients had UPB disappearance at the follow-up period. Among these, 34 patients were analyzed by FLC assay. At the time of UPB disappearance, 13 (38.2%) patients showed an abnormal FLCR. Relapse Twelve patients relapsed during ASCT follow-up, and IFE tests were performed on 11/12 at the time of relapse. Among these 11 relapsed patients, 5 had UPBs after ASCT and 6 did not have UPBs after ASCT. In other words, among the 54 patients who developed UPBs, 5 (9.3%) patients relapsed, and among the 46 patients who did not develop UPBs, 6 (13.0%) patients relapsed. Of the five patients who developed UPBs and experienced relapse afterwards, four had UPBs that appeared after ASCT but disappeared at the time of relapse, with the reappearance of paraprotein bands similar to those at diagnosis (Fig. 2). The other patient was diagnosed with a newly formed plasmacytoma in the chest wall and testis. His IFE showed a constant UPB isotype and location, even at the time of relapse. The characteristics of relapsed patients are described in Table 3. Discussion The aim of the present study was to report our experience with a series of 193 MM patients, which is one of the largest cohorts examined
to determine the relevant characteristics of UPBs in this patient population. As ASCT is a common treatment option, detection of UPBs with an IFE test has increased concomitantly, making IFE interpretation more difficult. In this study, the incidence of UPBs was 54% in patients that underwent ASCT, compared to 5.4% in subjects that did not. These results are in agreement with those of previous reports of UPB incidence in the ASCT group as 10–73% [8–10]. Median onset and duration of UPB in this study resembled those of numerous reports of a median onset at 2–11.5 months after ASCT, and the median duration as 3–22 months [8–10]. The current response criteria were defined without considering UPB; thus, there have been difficulties interpreting response criteria in patients with UPB. According to the IMWG response criteria, CR is defined as negative immunofixation of the serum and urine. However, in cases with UPB, negative M-protein other than UPB on immunofixation would be a more appropriate criterion. In this study, CR was defined using IFEs with UPB without M-protein at diagnosis and disappearance of any soft tissue plamacytoma and BM plasma cells of b5%. Patients who satisfied the CR criteria and had normal FLCR (0.26–1.65) were defined as sCR [11]. At the appearance of UPB, 42.6% of the patients belonged to sCR or CR. A previous study reported that at UPB appearance, 35.8% of the patients were CR [10]. However, if we consider UPB on IFE, 23 cases defined as CR or sCR would be redefined as 15 VGPR and 8 PR. Therefore, the UPB should be examined carefully, since misinterpretation of UPB to M-protein would lead to a misdiagnosis of poorer response criteria. In the UPB group, 50.0% of the patients satisfying CR criteria had abnormal FLCR, having similar frequency to the previous studies reporting
Fig. 2. Serum immunofixation eletrophoresis (IFE) patterns of a patient who underwent autologous hematopoietic stem cell transplantation (ASCT) and relapsed. (A) Free λ monoclonal band at diagnosis. (B) IgG κ type UPB observed six months after ASCT. (C) Disappearance of UPBs and reappearance of the paraprotein band similar to that of the diagnosis observed at relapse.
Please cite this article as: Kim S-K, et al, Characteristics of unexpected protein bands in multiple myeloma patients after autologous stem cell transplantation, Clin Biochem (2014), http://dx.doi.org/10.1016/j.clinbiochem.2014.02.015
4
S.-K. Kim et al. / Clinical Biochemistry xxx (2014) xxx–xxx
Table 3 Characteristics of unexpected protein bands for the multiple myeloma patients who relapsed after treatment. Case number
Age (years)
Sex
7 10 12 16 19 31 35 37 40 44 54 60
63 47 47 51 52 65 46 66 60 68 63 46
M M M F F F M F F F M M
PrimaryChemotherapy
PAD CP PAD VD VAD VAD VAD, PAD VAD HD dexa, PAD VAD, PAD HD dexa, VAD HD Dexa, PAD, MPT
Isotype Original monoclonal band
UPB
IgG κ IgA κ IgA κ IgD λ IgG κ Free λ IgA κ IgD λ IgG κ Free κ IgG λ Free λ
– IgG κ – IgG κ – IgG κ IgG κ IgM λ Free λ – – –
UPBonset afterASCT(months)
UPB duration(months)
Relapseonset afterASCT(months)
– 4.7 – 5.1 – 0.9 1.9 1.1 2.1 – – –
– 5.7 – 14.6 – 1.6 4.4 18.1 10.5 – – –
10 11 16 45 11 30 7 19 32 34 24 16
CP, cyclophosphamide and prednisone; F. female; HD dexa, high-dose dexamethasone; M, male; MPT, melphalan, prednisone, and thalidomide; PAD, bortezomib, doxorubicin, and dexamethasone; UPB, unexpected protein band; VAD, vincristine, doxorubicin, and dexamethasone; VD, bortezomib and dexamethasone.
57–72.7% [12,13]. UPB light chain isotype and FLCR had no correlation, while only 28.6% of the κ-type UPB had increased FLCR and 9.1% of the λ-type UPB had decreased FLCR. This discordance between the light chain involved in UPB and FLCR has been reported previously [13]. Further studies will be required to ascertain the current definition of sCR and its prognostic relevance. Comparing the response criteria at the time of UPB appearance and at the time of UPB disappearance, nine (24.3%) patients, who were neither defined as sCR nor CR, changed to sCR or CR after UPB disappearance. Fourteen (37.8%) patients maintained sCR or CR. One (2.7%) patient changed from CR to SD and one (2.7%) patient had persistent SD. The frequent occurrence of monoclonal gammopathies with an abnormal FLCR following bone marrow transplantation has long been known [14]. The B-cell system is regenerated at an accelerated rate, leading to normalization of immunoglobulin serum levels within months after transplantation [14]. However during this reconstitution period, a number of immunoglobulin aberrations may develop, affecting both the levels of the various immunoglobulin classes and the antibody repertoire [14]. Therefore, the presence of UPBs is a reflection of physiological response occurring during reorganization of humoral immunity after immune suppression [15]. The mechanism responsible for the restricted antibody response may be due to normal recapitulation of B-cell ontogeny, or they may result from a malfunctioning T-cell system and a disturbance of T–B cell cooperation [16]. One explanation for the higher incidence of UPBs in patients who had undergone ASCT could be that myeloablative treatment followed by stem cell rescue probably results in higher tumor reduction leading to a more powerful immune reconstitution than induction chemotherapy not followed by ASCT [17]. The most frequently observed isotype in this study was IgG κ. When stem cells of B cell lineage rearrange IgG light chain, either κ loci may be utilized. If a nonfunctional gene is produced, rearrangement of the second κ chain locus ensues, and if the rearrangement again does not result in a functional product, λ light chains will be rearranged [18]. This ultimately results in a 2/1 proportion of κ/λ light chains in normal serum IgGs. A similar ratio would be expected in the regenerating bone marrow; therefore, κ predominance suggests that UPBs are attributable to a physiological regeneration process [14]. We investigated the incidence rate of UPBs based on induction chemotherapy regimens. UPBs were detected significantly more often in patients treated with conventional drugs than patients treated with novel drugs. Our results differ from those of Fernandez et al., who reported higher UPB incidence in patients treated with novel drugs than in those treated with conventional drugs (60.0 vs. 11.1%) [17]. The difference from our study may be derived from different categorization of patients. In their study, patients were divided into two groups based on a novel vs. conventional chemotherapy regimen, and ASCT history was not considered when grouping the patients.
Relapse rates were similar between the UPB (9.3%) and non-UPB (13.0%) groups. Therefore, UPBs does not contribute to relapse. Patients with UPBs showed a characteristic IFE pattern at relapse. At the time of relapse, UPBs disappeared and paraprotein bands similar to those at diagnosis reappeared. In addition, this study examined hemoglobin, calcium, and creatinine levels between UPB and non-UPB groups to identify any difference during disease progression. However, no significant differences were noted. In conclusion, the appearance of UPBs is regarded as an epiphenomenon following treatment of MM patients that does not seem to be derived from malignant plasma cells. To discriminate UPBs from the monoclonal band of relapse, it is important to compare the location and isotype of the present band with that at diagnosis. Moreover, the patient's clinical findings should always be considered when interpreting IFE.
Conflict of interest The authors declare that there are no conflicts of interest regarding publication of this article.
References [1] Hall SL, Tate J, Gill D, Mollee P. Significance of abnormal protein bands in patients with multiple myeloma following autologous stem cell transplantation. Clin Biochem Rev 2009;30:113–8. [2] Palumbo A, Sezer O, Kyle R, Miguel JS, Orlowski RZ, Moreau P, et al. International myeloma working group guidelines for the management of multiple myeloma patients ineligible for standard high-dose chemotherapy with autologous stem cell transplantation. Leukemia 2009;23:1716–30. [3] Dimopoulos M, Terpos E, Comenzo RL, Tosi P, Beksac M, Sezer O, et al. International myeloma working group consensus statement and guidelines regarding the current role of imaging techniques in the diagnosis and monitoring of multiple myeloma. Leukemia 2009;23:1545–56. [4] Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia 2009;23:3–9. [5] Rajkumar SV, Kyle RA, Connor RF. Recognition of monoclonal proteins. UpToDate; 2012. [6] Cavo M, Baccarani M. The changing landscape of myeloma therapy. N Engl J Med 2006;354:1076–8. [7] Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood 2008;111:2516–20. [8] Zent CS, Wilson CS, Tricot G, Jagannath S, Siegel D, Desikan KR, et al. Oligoclonal protein bands and ig isotype switching in multiple myeloma treated with highdose therapy and hematopoietic cell transplantation. Blood 1998;91:3518–23. [9] Hovenga S, de Wolf JT, Guikema JE, Klip H, Smit JW, Smit Sibinga CT, et al. Autologous stem cell transplantation in multiple myeloma after vad and edap courses: a high incidence of oligoclonal serum igs post transplantation. Bone Marrow Transplant 2000;25:723–8. [10] Sucak G, Suyanı E, Ozkurt ZN, Yeğin ZA, Aki Z, Yagci M. Abnormal protein bands in patients with multiple myeloma after haematopoietic stem cell transplantation: does it have a prognostic significance? Hematol Oncol 2010;28:180–4.
Please cite this article as: Kim S-K, et al, Characteristics of unexpected protein bands in multiple myeloma patients after autologous stem cell transplantation, Clin Biochem (2014), http://dx.doi.org/10.1016/j.clinbiochem.2014.02.015
S.-K. Kim et al. / Clinical Biochemistry xxx (2014) xxx–xxx [11] Katzmann JA, Clark RJ, Abraham RS, Bryant S, Lymp JF, Bradwell AR, et al. Serum reference intervals and diagnostic ranges for free κ and free λ immunoglobulin light chains: relative sensitivity for detection of monoclonal light chains. Clin Chem 2002;48:1437–44. [12] Alejandre ME, Pavlovsky MA, Remaggi G, Corrado C, Fernandez I, Milone G, et al. Serum free light chains and oligoclonal bands in patients with multiple myeloma and autologous stem cell transplantation. Clin Chem Lab Med 2012;50:1093–7. [13] De Larrea CF, Cibeira MT, Elena M, Arostegui JI, Rosiñol L, Rovira M, et al. Abnormal serum free light chain ratio in patients with multiple myeloma in complete remission has strong association with the presence of oligoclonal bands: implications for stringent complete remission definition. Blood 2009;114:4954–6. [14] Hammarstrom L, Smith CIE. Frequent occurrence of monoclonal gammopathies with an imbalanced light-chain ratio following bone marrow transplantation. Transplantation 1987;43:447–9.
5
[15] Alejandre ME, Madalena LB, Pavlovsky MA, Facio ML, Corrado C, Milone G, et al. Oligoclonal bands and immunoglobulin isotype switch during monitoring of patients with multiple myeloma and autologous hematopoietic cell transplantation: a 16-year experience. Clin Chem Lab Med 2010;48:727–31. [16] Mitus AJ, Stein R, Rappeport JM, Antin JH, Weinstein HJ, Alper CA, et al. Monoclonal and oligoclonal gammopathy after bone marrow transplantation. Blood 1989;74:2764–8. [17] Fernandez de Larrea C, Tovar N, Cibeira MT, Arostegui JI, Rosinol L, Elena M, et al. Emergence of oligoclonal bands in patients with multiple myeloma in complete remission after induction chemotherapy: association with the use of novel agents. Haematologica 2011;96:171–3. [18] Hieter PA, Korsmeyer SJ, Waldmann TA, Leder P. Human immunoglobulin kappa light-chain genes are deleted or rearranged in lambda-producing b cells. Nature 1981;290:368–72.
Please cite this article as: Kim S-K, et al, Characteristics of unexpected protein bands in multiple myeloma patients after autologous stem cell transplantation, Clin Biochem (2014), http://dx.doi.org/10.1016/j.clinbiochem.2014.02.015
