Expert Review of Molecular Diagnostics Downloaded from informahealthcare.com by Emory University on 04/21/15 For personal use only.
Review
Serum free light chain analysis in the diagnosis and management of multiple myeloma and related conditions Expert Rev. Mol. Diagn. 14(1), 55–66 (2014)
Maria Stella Graziani1 and Giampaolo Merlini*2 1 Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy 2 Department of Molecular Medicine, University of Pavia, Foundation Scientific Institute San Matteo, Amyloidosis Research and Treatment Center, V.le Golgi 19, 27100, Pavia, Italy *Author for correspondence: Tel.: +39 0382 502 995 Fax: +39 0382 502 990 [email protected]
The serum free light chain (FLC) assay is an important tool in the management of patients with monoclonal gammopathies. MEDLINE, the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews from January 2000 through July 2013, were used as data sources. The available evidence is rather weak. For screening of multiple myeloma and related conditions, the association of the FLC assay with the traditional serum tests avoids urine study. Screening for immunoglobulin light-chain (AL) amyloidosis or other rare syndromes requires the urine examination. FLC measurement is used in the assessment of the risk of progression of precursor diseases to overt myeloma, and for risk stratification in solitary plasmacytoma, multiple myeloma and AL amyloidosis. In patients with oligosecretory myeloma and AL amyloidosis, the quantification of FLC is essential for monitoring and categorization of response to therapy. Further studies with improved design are warranted to strengthen the available evidence. KEYWORDS: Bence-Jones protein • monoclonal gammopathies • oligosecretory myeloma • screening • urinalysis
Free light chain (FLC) measurement in serum has become commercially available, almost 12 years ago [1], and since its appearance an important amount of data has been accumulated on the role of this test in the management of monoclonal gammopathies. Detection and measurement of the monoclonal proteins or monoclonal components (MC), are integral parts of the diagnosis and monitoring of these diseases and have been traditionally performed by serum and urine electrophoresis (s-PE, uPE) and immunofixation (s-IFE, u-IFE) [2]. The FLC immunometric assay is based on the recognition of epitopes exposed only on light chains that are not bound to the heavy chains of the immunoglobulins (FIGURE 1). Plasma cells synthesize approximately 40% excess of light chains to allow proper assembly of the intact immunoglobulin molecules. Serum k FLCs are normally monomeric while l FLCs tend to be dimeric, although both can form higher polymeric forms [3]. Serum FLCs www.expert-reviews.com
10.1586/14737159.2014.864557
are rapidly cleared and metabolized by the kidney: dimeric FLC, more frequently l than k, are cleared in 3–6 h, and monomeric FLCs, usually k, are cleared in 2–4 h. The shorter serum half-life for k gives a median k/l FLC ratio of approximately 0.6. Clearance can be prolonged to 2–3 days in end-stage renal failure [4,5]. FLC renal catabolic rates and, by inference, tubular absorption rates range from 1 to 30 g/day [6,7]. Reduction in glomerular filtration rate and impairment of renal tubular function, both, commonly observed in myeloma, affect renal tubular absorption [5]. Therefore, the relation between Bence-Jones protein (BJP) excretion and tumor cell mass is likely to be complex. The shorter half-life of FLC compared to the complete immunoglobulin allows a closer monitoring of the clone changes during therapy. The assay consists of two separate measurements, one for kFLC and one for lFLC chains, plus the calculation of the ratio
2014 Informa UK Ltd
ISSN 1473-7159
55
Review
Graziani & Merlini
Exposed surface
κFLC
Exposed surface
Hidden surface
Expert Review of Molecular Diagnostics Downloaded from informahealthcare.com by Emory University on 04/21/15 For personal use only.
Antigen binding sites
Hinge region
Target of sFLC immunoassays
Heavy chain
λFLC
published [11]. The present review focuses mainly on the guidelines proposed by international bodies for plasma cell dyscrasias, since they are widely applied in clinical practice and analyzes primary studies in this context. The applications of the FLC assay in other lymphoproliferative diseases have been recently reviewed elsewhere [12]. Screening Multiple myeloma & related disorders
The utility of the FLC assay in the diagnosis of MM and related conditions was examined in the International Myeloma Light Working Group (IMWG) guidelines [13], chain Variable issued in 2009. Although, it is acknowldomain edged that the primary studies available at the time of the guidelines preparaFigure 1. An antibody molecule showing the heavy and light chain structure, together with free k and l free light chains. tion were heterogeneous in many FLC: Free light chain. aspects, precluding a proper meta-analReproduced with permission from [201]. ysis, the document indicates that the screening strategies for plasma cell between the two light chains (rFLC) [1]. The reference inter- disorders, others than immunoglobulin light-chain (AL) vals of FLCs have been reported (kFLC: 3.3–19.4 mg/l; amyloidosis, could be based on serum tests only (s-PE, slFLC: 5.7–26.3 mg/l) and the k/l FLC ratio (rFLC) is a IFE and serum FLC) with no need for urine examination, sensitive marker of clonal FLC production (rFLC diagnostic thus facilitating the diagnostic procedures [13]. One large range: 0.26–1.65) [8]. Patients with renal impairment can study reported that serum studies (s-PE, s-IFE and have rFLC slightly above the reference range with no other serum FLC) missed two (0.5%) of the 428 monoclonal evidence of monoclonal proteins [9]. This reflects a change in gammopathies with urinary monoclonal proteins, and these the dynamics of serum FLC clearance in renal failure. As the two cases required no medical intervention [14]. A subsekidneys fail, less FLC are cleared through that way, and the quent study from the same group examined the best screennon-preferential reticuloendothelial route is responsible for ing strategy for MC detection [15] and showed that serum an increasing proportion of the FLC clearance. This results tests (s-PE, s-IFE and rFLC) could detect 100% of the in a closer serum half-life for the two FLCs types, and the patients with MM, macroglobulinemia and smoldering mulFLC ratio becomes increasingly influenced by the underlying tiple myeloma (SMM), and 97.1% of monoclonal gammopproduction rates by plasma cells. Since k producing cells are athy of undetermined significance (MGUS). A more approximately twice as many as l ones, this results in a simplified strategy including only s-PE and rFLC could median k/l FLC ratio of 1.1 in serum, with a 100% range detect 100% of patients with MM and macroglobulinemia, of 0.37–3.1 in patients with kidney failure [10]. This modi- but missed one of 199 patients with SMM and 59 of fied ‘renal reference range’ was effective for identifying 524 patients with MGUS. Actually, several reports indicate patients with multiple myeloma (MM) and end stage renal that rFLC improves the s-PE sensitivity and specificity in failure [10]. detecting the monoclonal protein [16–18]. A strategy based on Since the time this assay became available, a vast number serum tests only (even the simplified one, not including of primary studies have been undertaken to clarify the role of s-IFE), is an efficient initial diagnostic screening for highFLC measurement in the management of MM and related tumor-burden plasma cell disorders such as MM, SMM disorders. In this review we will consider the role of FLC and macroglobulinemia. In the same year of the IMWG recmeasurement in screening, risk stratification and treatment ommendations, a European guideline was published [19]. follow-up in MM and related conditions. MEDLINE, the This guideline recommends, for screening purposes, to perCochrane Central Register of Controlled Trials and the form the serum and urine electrophoresis and immunofixaCochrane Database of Systematic Reviews from January tion, and to use FLC as an adjunctive test when urine 2000 through July 2013, were used as data source. An sample is not available or when a clinical suspicion still evidence-based systematic review of the literature regarding exists in presence of a negative immunofixation. The the use of serum FLC analysis for diagnosis, management IMWG and the European guidelines are discrepant on this and prognosis of plasma cell dyscrasias has been recently aspect. Carbohydrate
56
Constant domain
Expert Rev. Mol. Diagn. 14(1), (2014)
Serum free light chains in plasma cell dyscrasias
Expert Review of Molecular Diagnostics Downloaded from informahealthcare.com by Emory University on 04/21/15 For personal use only.
AL amyloidosis
The IMWG guidelines indicate that screening for AL amyloidosis should include serum tests (s-PE, s-IFE and rFLC) and urine examination (u-PE and u-IFE) both [13], based on the evidence that elimination of the urine study would have missed a number of cases [14]. The indication was in agreement with a previous UK guideline on the management of AL amyloidosis [20]. Three primary studies [15,21,22], showed that in order to reach the best sensitivity for the detection of the MC in AL amyloidosis, u-IFE was necessary. The number of missed cases (most often l clones) was not particularly elevated (i.e., 6% [21]); this, however, could have had important clinical consequences given the severity of the disease and the absolute need for an early diagnosis of this dreadful condition [23].
Review
SMM patients who progress to symptomatic myeloma within 2 years, the so-called ‘high-risk SMM’ [28], in view of the potential benefits of early treatment [29]. Two recent papers reported that patients with SMM with a rFLC ‡100 are at high risk of developing overt MM within 24 months [30,31]. Multiple myeloma
In newly diagnosed myeloma patients, the utility of the rFLC has been demonstrated to predict survival in primary studies [32–34]. Thus, it was proposed to incorporate the rFLC into the International Staging System with cut points of 32 [33]. The 2011 IMWG specific guidelines on risk stratification in MM [35] are more cautious and state that although the rFLC for prognostication in MM patients may be useful under some circumstances, the general applicability is unknown.
Rare syndromes
Rare diseases, such as the POEMS syndrome, light chain deposition disease (LCDD) and plasmacytoma, are usually associated with small B-cell clones [24]. Systemic effects caused by clone expansion are therefore minimal, but the synthesized protein can be very toxic for several organs. In these cases, a prompt recognition of the presence of the MC can quickly address the correct diagnosis; as a consequence, there is a great need to use the most sensitive techniques to detect the MC. Katzmann et al. included a number of these disorders (plasmacytoma, POEMS syndrome and LCDD) in their study [15]; no screening strategy could identify 100% of these patients. For plasmacytomas, the highest sensitivity (89.7%) was reached by s-PE + s-IFE + rFLC or + u-IFE; for POEMS syndrome the maximal sensitivity (96.8%) was obtained with s-IFE alone; in the 18 patients with LCDD the best sensitivity (83.3%) was achieved using all serum and urine tests.
AL amyloidosis
Several studies have shown that in patients with AL amyloidosis, the burden of the amyloidogenic light chain is a powerful prognostic feature [36,37]. The difference between involved and uninvolved light chain (dFLC) has been integrated together with the cardiac biomarkers troponin and natriuretic peptide type B in a powerful staging system for risk stratification of these patients [38]. The risk cut point is dFLC of 180 mg/l. Solitary plasmacytoma
The evidence to recommend rFLC measurement at baseline in patients with solitary plasmacytoma comes from a Mayo Clinic study [39], which reported that patients with abnormal rFLC were at higher risk of progression (44 vs 26% in 5 years). The best risk cut points for rFLC are 4.0. Monitoring
Risk assessment Monoclonal gammopathy of undetermined significance
A specific guideline was issued by IMWG [25] on the risk factors for progression of MGUS. On the basis of the primary study, demonstrating that rFLC is an independent risk factor for progression in MGUS patients [26], the IMWG formally recommends the tridimensional model for prognostication, which includes MC size, immunoglobulin isotype, and rFLC. For this purpose, the best risk cut points of rFLC coincide with the universal reference range (0.26–1.65) [26]. Smoldering MM
Baseline rFLC was identified as a risk factor for progression to MM or related disorders for SMM patients as well [27]; therefore, its measurement was included in the IMWG guidelines on risk factors for progression [25]. The tridimensional model for SMM patients includes bone marrow plasma cells percentage, MC size and rFLC. The best risk cut points for rFLC are 8.0. Recently, particular attention has been devoted in discovering biomarkers that could identify with ‡80–90% accuracy www.expert-reviews.com
Monoclonal gammopathy of undetermined significance & smoldering multiple myeloma
The purpose of monitoring patients with MGUS or SMM is to identify the progression to a malignant disorder at an early stage. However, while the rFLC at diagnosis is correlated with risk of progression toward malignancy, there is no evidence that measuring the FLC during follow-up produces clinical benefit. The IMWG and the European guidelines on monitoring and management of patients with MGUS or SMM do not include FLC measurement in the laboratory parameters to be monitored during follow-up [13,19,25,40]. For monitoring purposes, these guidelines recommend the MC quantification by s-PE or u-PE; however, in patients with light chain only MGUS or SMM, the MC protein can be difficult to detect by electrophoretic methods, so the FLC measurement in these cases could be helpful in monitoring the disease. Multiple myeloma
Patients with oligosecretory myeloma (serum MC
Review
Serum free light chain analysis in the diagnosis and management of multiple myeloma and related conditions Expert Rev. Mol. Diagn. 14(1), 55–66 (2014)
Maria Stella Graziani1 and Giampaolo Merlini*2 1 Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy 2 Department of Molecular Medicine, University of Pavia, Foundation Scientific Institute San Matteo, Amyloidosis Research and Treatment Center, V.le Golgi 19, 27100, Pavia, Italy *Author for correspondence: Tel.: +39 0382 502 995 Fax: +39 0382 502 990 [email protected]
The serum free light chain (FLC) assay is an important tool in the management of patients with monoclonal gammopathies. MEDLINE, the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews from January 2000 through July 2013, were used as data sources. The available evidence is rather weak. For screening of multiple myeloma and related conditions, the association of the FLC assay with the traditional serum tests avoids urine study. Screening for immunoglobulin light-chain (AL) amyloidosis or other rare syndromes requires the urine examination. FLC measurement is used in the assessment of the risk of progression of precursor diseases to overt myeloma, and for risk stratification in solitary plasmacytoma, multiple myeloma and AL amyloidosis. In patients with oligosecretory myeloma and AL amyloidosis, the quantification of FLC is essential for monitoring and categorization of response to therapy. Further studies with improved design are warranted to strengthen the available evidence. KEYWORDS: Bence-Jones protein • monoclonal gammopathies • oligosecretory myeloma • screening • urinalysis
Free light chain (FLC) measurement in serum has become commercially available, almost 12 years ago [1], and since its appearance an important amount of data has been accumulated on the role of this test in the management of monoclonal gammopathies. Detection and measurement of the monoclonal proteins or monoclonal components (MC), are integral parts of the diagnosis and monitoring of these diseases and have been traditionally performed by serum and urine electrophoresis (s-PE, uPE) and immunofixation (s-IFE, u-IFE) [2]. The FLC immunometric assay is based on the recognition of epitopes exposed only on light chains that are not bound to the heavy chains of the immunoglobulins (FIGURE 1). Plasma cells synthesize approximately 40% excess of light chains to allow proper assembly of the intact immunoglobulin molecules. Serum k FLCs are normally monomeric while l FLCs tend to be dimeric, although both can form higher polymeric forms [3]. Serum FLCs www.expert-reviews.com
10.1586/14737159.2014.864557
are rapidly cleared and metabolized by the kidney: dimeric FLC, more frequently l than k, are cleared in 3–6 h, and monomeric FLCs, usually k, are cleared in 2–4 h. The shorter serum half-life for k gives a median k/l FLC ratio of approximately 0.6. Clearance can be prolonged to 2–3 days in end-stage renal failure [4,5]. FLC renal catabolic rates and, by inference, tubular absorption rates range from 1 to 30 g/day [6,7]. Reduction in glomerular filtration rate and impairment of renal tubular function, both, commonly observed in myeloma, affect renal tubular absorption [5]. Therefore, the relation between Bence-Jones protein (BJP) excretion and tumor cell mass is likely to be complex. The shorter half-life of FLC compared to the complete immunoglobulin allows a closer monitoring of the clone changes during therapy. The assay consists of two separate measurements, one for kFLC and one for lFLC chains, plus the calculation of the ratio
2014 Informa UK Ltd
ISSN 1473-7159
55
Review
Graziani & Merlini
Exposed surface
κFLC
Exposed surface
Hidden surface
Expert Review of Molecular Diagnostics Downloaded from informahealthcare.com by Emory University on 04/21/15 For personal use only.
Antigen binding sites
Hinge region
Target of sFLC immunoassays
Heavy chain
λFLC
published [11]. The present review focuses mainly on the guidelines proposed by international bodies for plasma cell dyscrasias, since they are widely applied in clinical practice and analyzes primary studies in this context. The applications of the FLC assay in other lymphoproliferative diseases have been recently reviewed elsewhere [12]. Screening Multiple myeloma & related disorders
The utility of the FLC assay in the diagnosis of MM and related conditions was examined in the International Myeloma Light Working Group (IMWG) guidelines [13], chain Variable issued in 2009. Although, it is acknowldomain edged that the primary studies available at the time of the guidelines preparaFigure 1. An antibody molecule showing the heavy and light chain structure, together with free k and l free light chains. tion were heterogeneous in many FLC: Free light chain. aspects, precluding a proper meta-analReproduced with permission from [201]. ysis, the document indicates that the screening strategies for plasma cell between the two light chains (rFLC) [1]. The reference inter- disorders, others than immunoglobulin light-chain (AL) vals of FLCs have been reported (kFLC: 3.3–19.4 mg/l; amyloidosis, could be based on serum tests only (s-PE, slFLC: 5.7–26.3 mg/l) and the k/l FLC ratio (rFLC) is a IFE and serum FLC) with no need for urine examination, sensitive marker of clonal FLC production (rFLC diagnostic thus facilitating the diagnostic procedures [13]. One large range: 0.26–1.65) [8]. Patients with renal impairment can study reported that serum studies (s-PE, s-IFE and have rFLC slightly above the reference range with no other serum FLC) missed two (0.5%) of the 428 monoclonal evidence of monoclonal proteins [9]. This reflects a change in gammopathies with urinary monoclonal proteins, and these the dynamics of serum FLC clearance in renal failure. As the two cases required no medical intervention [14]. A subsekidneys fail, less FLC are cleared through that way, and the quent study from the same group examined the best screennon-preferential reticuloendothelial route is responsible for ing strategy for MC detection [15] and showed that serum an increasing proportion of the FLC clearance. This results tests (s-PE, s-IFE and rFLC) could detect 100% of the in a closer serum half-life for the two FLCs types, and the patients with MM, macroglobulinemia and smoldering mulFLC ratio becomes increasingly influenced by the underlying tiple myeloma (SMM), and 97.1% of monoclonal gammopproduction rates by plasma cells. Since k producing cells are athy of undetermined significance (MGUS). A more approximately twice as many as l ones, this results in a simplified strategy including only s-PE and rFLC could median k/l FLC ratio of 1.1 in serum, with a 100% range detect 100% of patients with MM and macroglobulinemia, of 0.37–3.1 in patients with kidney failure [10]. This modi- but missed one of 199 patients with SMM and 59 of fied ‘renal reference range’ was effective for identifying 524 patients with MGUS. Actually, several reports indicate patients with multiple myeloma (MM) and end stage renal that rFLC improves the s-PE sensitivity and specificity in failure [10]. detecting the monoclonal protein [16–18]. A strategy based on Since the time this assay became available, a vast number serum tests only (even the simplified one, not including of primary studies have been undertaken to clarify the role of s-IFE), is an efficient initial diagnostic screening for highFLC measurement in the management of MM and related tumor-burden plasma cell disorders such as MM, SMM disorders. In this review we will consider the role of FLC and macroglobulinemia. In the same year of the IMWG recmeasurement in screening, risk stratification and treatment ommendations, a European guideline was published [19]. follow-up in MM and related conditions. MEDLINE, the This guideline recommends, for screening purposes, to perCochrane Central Register of Controlled Trials and the form the serum and urine electrophoresis and immunofixaCochrane Database of Systematic Reviews from January tion, and to use FLC as an adjunctive test when urine 2000 through July 2013, were used as data source. An sample is not available or when a clinical suspicion still evidence-based systematic review of the literature regarding exists in presence of a negative immunofixation. The the use of serum FLC analysis for diagnosis, management IMWG and the European guidelines are discrepant on this and prognosis of plasma cell dyscrasias has been recently aspect. Carbohydrate
56
Constant domain
Expert Rev. Mol. Diagn. 14(1), (2014)
Serum free light chains in plasma cell dyscrasias
Expert Review of Molecular Diagnostics Downloaded from informahealthcare.com by Emory University on 04/21/15 For personal use only.
AL amyloidosis
The IMWG guidelines indicate that screening for AL amyloidosis should include serum tests (s-PE, s-IFE and rFLC) and urine examination (u-PE and u-IFE) both [13], based on the evidence that elimination of the urine study would have missed a number of cases [14]. The indication was in agreement with a previous UK guideline on the management of AL amyloidosis [20]. Three primary studies [15,21,22], showed that in order to reach the best sensitivity for the detection of the MC in AL amyloidosis, u-IFE was necessary. The number of missed cases (most often l clones) was not particularly elevated (i.e., 6% [21]); this, however, could have had important clinical consequences given the severity of the disease and the absolute need for an early diagnosis of this dreadful condition [23].
Review
SMM patients who progress to symptomatic myeloma within 2 years, the so-called ‘high-risk SMM’ [28], in view of the potential benefits of early treatment [29]. Two recent papers reported that patients with SMM with a rFLC ‡100 are at high risk of developing overt MM within 24 months [30,31]. Multiple myeloma
In newly diagnosed myeloma patients, the utility of the rFLC has been demonstrated to predict survival in primary studies [32–34]. Thus, it was proposed to incorporate the rFLC into the International Staging System with cut points of 32 [33]. The 2011 IMWG specific guidelines on risk stratification in MM [35] are more cautious and state that although the rFLC for prognostication in MM patients may be useful under some circumstances, the general applicability is unknown.
Rare syndromes
Rare diseases, such as the POEMS syndrome, light chain deposition disease (LCDD) and plasmacytoma, are usually associated with small B-cell clones [24]. Systemic effects caused by clone expansion are therefore minimal, but the synthesized protein can be very toxic for several organs. In these cases, a prompt recognition of the presence of the MC can quickly address the correct diagnosis; as a consequence, there is a great need to use the most sensitive techniques to detect the MC. Katzmann et al. included a number of these disorders (plasmacytoma, POEMS syndrome and LCDD) in their study [15]; no screening strategy could identify 100% of these patients. For plasmacytomas, the highest sensitivity (89.7%) was reached by s-PE + s-IFE + rFLC or + u-IFE; for POEMS syndrome the maximal sensitivity (96.8%) was obtained with s-IFE alone; in the 18 patients with LCDD the best sensitivity (83.3%) was achieved using all serum and urine tests.
AL amyloidosis
Several studies have shown that in patients with AL amyloidosis, the burden of the amyloidogenic light chain is a powerful prognostic feature [36,37]. The difference between involved and uninvolved light chain (dFLC) has been integrated together with the cardiac biomarkers troponin and natriuretic peptide type B in a powerful staging system for risk stratification of these patients [38]. The risk cut point is dFLC of 180 mg/l. Solitary plasmacytoma
The evidence to recommend rFLC measurement at baseline in patients with solitary plasmacytoma comes from a Mayo Clinic study [39], which reported that patients with abnormal rFLC were at higher risk of progression (44 vs 26% in 5 years). The best risk cut points for rFLC are 4.0. Monitoring
Risk assessment Monoclonal gammopathy of undetermined significance
A specific guideline was issued by IMWG [25] on the risk factors for progression of MGUS. On the basis of the primary study, demonstrating that rFLC is an independent risk factor for progression in MGUS patients [26], the IMWG formally recommends the tridimensional model for prognostication, which includes MC size, immunoglobulin isotype, and rFLC. For this purpose, the best risk cut points of rFLC coincide with the universal reference range (0.26–1.65) [26]. Smoldering MM
Baseline rFLC was identified as a risk factor for progression to MM or related disorders for SMM patients as well [27]; therefore, its measurement was included in the IMWG guidelines on risk factors for progression [25]. The tridimensional model for SMM patients includes bone marrow plasma cells percentage, MC size and rFLC. The best risk cut points for rFLC are 8.0. Recently, particular attention has been devoted in discovering biomarkers that could identify with ‡80–90% accuracy www.expert-reviews.com
Monoclonal gammopathy of undetermined significance & smoldering multiple myeloma
The purpose of monitoring patients with MGUS or SMM is to identify the progression to a malignant disorder at an early stage. However, while the rFLC at diagnosis is correlated with risk of progression toward malignancy, there is no evidence that measuring the FLC during follow-up produces clinical benefit. The IMWG and the European guidelines on monitoring and management of patients with MGUS or SMM do not include FLC measurement in the laboratory parameters to be monitored during follow-up [13,19,25,40]. For monitoring purposes, these guidelines recommend the MC quantification by s-PE or u-PE; however, in patients with light chain only MGUS or SMM, the MC protein can be difficult to detect by electrophoretic methods, so the FLC measurement in these cases could be helpful in monitoring the disease. Multiple myeloma
Patients with oligosecretory myeloma (serum MC
