A rare case of IgDλ/λ free Multiple Myeloma as a virtuous example of collaboration between clinical activity and laboratory medicine

A rare case of IgDλ/λ free Multiple Myeloma as a virtuous example of collaboration between clinical activity and laboratory medicine | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report A rare case of IgDλ/λ free Multiple Myeloma as a virtuous example of collaboration between clinical activity and laboratory medicine Mauro Sasso, Candida Rosaria Germano, Vanda Staffella, Luigi Ceci, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4641430/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract BACKGROUND : IgD Multiple Myeloma (MM) is a rare hematological neoplasm characterized by an aggressive course compared to the other isotypes of Myeloma; its laboratory findings are usually anemia, presence of Bence Jones protein (BJP), hypogammaglobulinemia, lack of a monoclonal peak on serum protein electrophoresis (SPE), renal failure, osteolytic lesions. CLINICAL CASE : A 72-year-old man with bone pain presented to the Hematology Unit because of bone pain and laboratory tests showing a Monoclonal Component type λ and normocytic anemia (Hemoglobin level 10.5 g/dL). A conventional skeletal radiography of cranium and spine in toto was performed and showed multiple discopathies, sacroiliitis and bilateral coxarthrosis. RESULTS : Laboratory tests performed in Clinical Pathology and Microbiology Unit showed hypogammaglobulinemia, acute renal failure (s-creatinine 2.86 mg/dL, eGFR 39,01 mL/min), s-calcium 9.3 mg/L, serum Free Light Chains ratio 0,0044, presence of BJP type λ, a peak of 19.7 g/L in SPE. Serum immunofixation (sIFE) performed by anti-IgD and λ free serum showed a monoclonal IgDλ band and a monoclonal λ free band. Nuclear Magnetic Resonance (NMR) imaging showed cervical-dorso-lumbar and pelvic osteolysis, while osteomedullary biopsy showed a 70% plasma cell infiltration. Symptomatic IgDλ MM was diagnosed: the symptomatic findings where anemia and bone disease. CONCLUSION : The 72-year-old patient of our clinical case presented at diagnosis some features commonly present in IgD MM. In this case, the laboratory adopted new diagnostic protocols in order to make a correct diagnosis; the hematological parameters, SPE and sIFE were monitored for 56 months. New therapies have been shown to improve outcomes in this disease and a recent revision of recommendations has contributed to good clinical practice for patients with relapsed/refractory MM. IgD Multiple Myeloma Daratumumab immunofixation electrophoresis DIRA test Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 BACKGROUND Multiple Myeloma (MM) is a hematologic neoplasm characterized by an abnormal clonal proliferation of plasma cells in bone marrow that are responsible for the production of one or more Monoclonal Components (CM), i.e., complete or incomplete Immunoglobulins (Ig), represented by the heavy chains G, A, D, E and/or the light chains κ and λ detectable in serum and/or urine. MM accounts for about 10% of all hematologic malignancies, and IgD MM is a rare subtype of the disease as it accounts for about 2% of diagnosed cases worldwide [ 1 – 3 ]. In particular, in Italy MM accounts for 1.6% of all diagnosed cancers in men and 1.5% in women, with an incidence (expressed as Standardized Direct Rate (TSD) pop Eur13) of 11.1 cases/100,000 per year in men and 7.7 cases/100,000 per year in women. National estimates for 2020 speak of just over 2,700 new cases of myeloma each year among women and about 3,000 among men [ 4 ]. In Apulia, from 2014 to 2019, there were 1969 new diagnosis of MM (1.69% of total new cancer diagnoses), including 211 new cases (2.06% of the new diagnoses) in the province of Barletta-Andria-Trani (BAT) alone. The regional TSD of incidence/100,000 population is 10.35 for men (12.2 in BT province, mean age 69.9) and 8.02 for women (10.42 in BT, mean age 69.4). The TSD of mortality for both male and female patients is 5.31 in Apulia and 4.35 in BT, with an identical mean age of 76.6 years [ 5 ]. The International Myeloma Working Group (IMWG) criteria for the diagnosis of MM are based on the presence of ≥ 10% clonal bone marrow plasma cells or a biopsy-proven plasmacytoma plus evidence of one or more multiple myeloma defining events (MDE): CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) attributable to the plasma cell disorder, bone marrow clonal plasmacytosis ≥ 60%, serum involved/uninvolved free light chain (sFLC) ratio ≥ 100 (provided involved sFLC is ≥ 100 mg/L), or > 1 focal lesion > 5 mm on magnetic resonance imaging. CRAB criteria are declined as follows: elevated serum Calcium (Ca) levels (Ca > 11 mg/dL or greater at the upper limit of the reference range), renal failure (creatinine clearance 1.77 mg/dL), anemia (hemoglobin (Hb) levels < 10 g/dL or 2 g less than the lower limit of the reference range) [ 6 ]. Clinical and laboratory findings at the onset of IgD MM disease are similar to those of other myeloma types (bone pain, renal failure, and osteolytic bone lesions), but the clinical course is more aggressive. The laboratory typical findings of IgD MM are hypercalcemia, normocytic normochromic anemia, the presence of Bence Jones Proteinuria (BJP), and a SPE showing hypogammaglobulinemia but no monoclonal peaks [ 1 , 7 , 8 ]. Some studies reported a median survival between 13,7 and 21 months [ 9 ]. The isotype of the CM involved, patient's age, comorbidities, performance status and previous treatment in case of relapse provide useful elements for diagnostic, prognostic and therapeutic purposes [ 10 ]. The therapeutic landscape of MM has evolved significantly with the approval of numerous novel agents including immunomodulatory drugs (IMiDs) (Thalidomide, Lenalidomide, and Pomalidomide, Iberdomide), proteosome inhibitors (PIs) such as Bortezomib, Carfilzomib and Ixazomib and monoclonal Antibodies (mAb), targeting CD38 (Daratumumab, Isatuximab) and anti-SLAMF7 (Elotuzumab). Daratumumab is a human monoclonal antibody isotype IgG1κ anti-CD38, produced in a mammalian cell line (Chinese Hamster Ovary) by recombinant DNA technology. The clinical case reported in this paper is the first case of IgD MM diagnosed in the Local Health Authority of Barletta-Andria-Trani (ASL BT) thanks the virtuous path of collaboration between the teams of Hematology Unit, "Dimiccoli" Hospital, Barletta (BT) and the protidology sector of Clinical Pathology and Microbiology Unit, "L. Bonomo" Hospital, Andria (BT). METHODS SPE were performed by capillary technology (CZE) on Capillarys 3 Tera instrumentation (Sebia S.r.l., Bagno a Ripoli (FI), Italy). The immunotyping of CMs on serum (sIFE) and BJP on urine (uIFE) was performed, strictly following the Sebia company's operational protocols, using agarose gel on Hydrasys II (Sebia) instrumentation. Using the same instrumentation, drug interference was evaluated using the Hydrashift Daratumumab kit (Sebia). Densitometric scanning of the gel obtained with uIFE allowed quantification of BJP. Measurement of β2microglobulin (β2M), free light chains kappa (sFLCκ) and lambda (sFLCλ) in serum was performed using the BNII nephelometer (Siemens Healthcare S.r.l., Milan, Italy) and reagents from the same Siemens Healthcare company. Measurement of other analytes was carried out using the following instrumentation: LIAISON XL (Diasorin S.p.A., Saluggia (VC), Italy) for ferritin (Fer) by chemiluminescence method; the Beckman platform (Beckman Coulter. Brea, Calif., United States) for serum IgG, IgA, IgM and C-Reactive Protein (CRP) by immunoturbidimetric method, serum and urinary creatinine (Crea) by kinetic method (Jaffé), protein (serum and urinary) and calcium (Ca) by colorimetric method, transaminases (AST, ALT) by modified IFCC enzyme kinetic method, Lactate Dehydrogenase (LDH) by modified Waker method. The complete blood count (CBC) was performed by using Yumizen H2500 instrumentation (Horiba Ltd, Kyoto, Kyoto Prefecture, Japan). Data were graphically processed using Microsoft Excel software, version 18.2304.1202.0 from Microsoft 365 (Microsoft Corporation, Redmond, United States). Historical patient analytical data were accessed using information stored on DNLAB software version 5.2 (Dedalus S.p,a., Florence, Italy) and Phoresis software version 9.2 (Sebia). CLINICAL CASE A 72-year-old man with bone pain presented to the Hematology Unit of Barletta (BT) Hospital because of bone pain and laboratory tests showing a Monoclonal Component type λ and normocytic anemia (Hemoglobin level 10.5 g/dL). A conventional skeletal radiography of cranium and spine in toto was performed and showed multiple discopathies, sacroiliitis and bilateral coxarthrosis. Therefore, hematochemical examinations were scheduled and showed: Crea 2.86 mg/dL, eGFR 39.01 mL/min/1.73 m², Ca 9. 3 mg/L, Fer 433.9 ng/mL, β2M 8.55 mg/L, IgG 702 mg/dL, IgA 54 mg/dL, IgM 22 mg/dL, sFLCκ 11 mg/L, sFLCλ 2510 mg/L, sFLCκ/sFLCλ ratio (rFLC) 0.0043, proteinuria 15282 mg/24h, and the presence of a CM in the γ zone of the EF of 1.97 g/dL (19.7 g/L) (Fig. 1 a). The sIFE performed with standard anti-IgG, anti-IgA, anti-IgM, anti-κ and anti-λ antisera identified two CM reactive only with anti λ (Fig. 1 b), so it was necessary to perform a second sIFE with anti-IgD, anti-IgE. anti-λ and anti-λ free antisera that showed the presence of one CM isotype IgDλ and a second CM reactive only with anti λ free antiserum (Fig. 1 c). The uIFE showed marked positivity for Bence Jones type λ protein (Fig. 1 d). The osteomedullary biopsy revealed markedly increased plasma cells (70% of total marrow cellularity), with an anatomicopathologic stage III (infiltration versus intertrabecular spaces: 56%), a negative congo red staining, ruling out the presence of amyloid . Echocardiogram was conclusive for hypertensive heart disease with preserved global systolic function, signs of mild diastolic dysfunction, no evidence of pericardial effusion, absence of hemodynamically significant valvulopathy, ventricular ejection fraction of 60%. A Whole-Body Low-Dose Computed Tomography (WBLDCT) was performed and showed absence of lytic lesions, while the Magnetic Resonance Imaging (MRI)showed the presence of cervical-dorso-lumbar and pelvic osteolysis (Fig. 2 ). Total body positron emission tomography (PET) investigation documented a slight increase in the concentration of the metabolic tracer at the level of left scapula spine and left iliac bone coincident with two lytic lesions of 8 and 12 mm, respectively. Therefore, the diagnosis of IgDλ MM symptomatic with anemia and bone disease was made. The patient was considered frail and not eligible for Autologous Stem-Cell Transplantation (ASCT) on the basis of IMWG frailty score, which consists of a geriatric assessment (GA, Geriatric Assessment) combining three scales: the Katz Activity of Daily Living (ADL), the Lawton Instrumental Activity of Daily Living (IADL) and the Charlson Comorbidity Index (CCI) with the patient's age, comorbidities and functional status [ 11 ]. The patient was treated with VMP scheme (Bortezomib - Melphalan - Prednisone) for nine cycles, obtaining a VGPR (Very Good Partial Response) [ 2 ]: after therapy, the IgDλ monoclonal component in the γ zone of SPE was not quantified, bone marrow plasma cell percentage was 5%, the 24 hour proteinuria was negative, the value of creatinine and Hb was 1.65 mg/dL and 12.4 g/dL respectively. The patient received monthly infusions of zoledronic acid with a dose adjustement according to creatinine clearance. Approximately ten months after the end of the first line of therapy, there was a worsening renal function (reappearance of proteinuria, BJP > 500 mg/24h), so the patient was suspected of having relapsed disease. A osteo medullary biopsy was performed, and showed plasma cell infiltration of 20%, while FISH (Fluorescent In Situ Hybridization) analysis revealed the presence of amp 1q21 [ 1 , 12 , 13 ]. On Nuclear Magnetic Resonance, residual areas of altered signal at the spine, pelvis and proximal third of the femurs were documented (Fig. 3 ). As a consequence, on november 2021, a second line therapy according DRd (Daratumumab - Lenalidomide - Dexamethasone) scheme was adopted. The outcome was summarized in Table 1 . Table 1 Laboratory diagnostics and therapy responses Date CM (g/L) sIFE DIRA uIFE BJP24h (mg/24h) rFLC Therapy Therapy response 2019-10-02 19,7 IgDλ + λfree NP λ NP 0,0043 1° accesso - 2019-12-17 9,5 IgDλ + λfree NP λ NP 0,01189 VMP - 2020-01-07 6,8 IgDλ + λfree NP λ NP 0,02 VMP - 2020-03-18 6,4 NP NP NP NP NP VMP - 2020-05-27 5,3 IgDλ NP NP NP 0,01808 VMP - 2020-09-29 3,9 IgDλ NP λ NP 0,03106 VMP - 2020-11-18 2,7 NP NP NP NP NP VMP - 2021-01-27 1,7 NP NP NP NP NP VMP - 2021-09-03 NQ IgDλ + λfree NP NP NP 0,02527 VMP - 2022-01-17 NQ IgDλ NP λ 133,5 0,04241 VMP VGPR 2022-03-14 ASS IgDλ + λfree NP NP 125,9 0,06355 AZ SD 2022-04-05 NQ NP NP NP NP NP AZ SD 2022-06-07 NQ IgDλ + λfree NP NP NP NP AZ SD 2022-09-27 NP NP NP λ + CM NP NP AZ PD 2023-03-15 NQ IgDλ + λfree NP λ 556 NP AZ PD 2023-11-30 3,9 IgDλ + λfree NP λ 1017,2 0,281 AZ PD 2024-01-09 4,4 IgDλ + λfree NP NP 996 0,22676 AZ PD 2019-10-02 NP NP NP NP NP 0,31974 DRd - 2019-12-17 1,5 NP NP NP NP 0,38913 DRd - 2020-01-07 NP NP NP NP NP 0,44311 DRd - 2020-03-18 NQ IgGκ ? NP NP NP 0,42685 DRd - 2020-05-27 NQ IgGκ ? NP λ 42,2 0,59448 DRd - 2020-09-29 Susp NP NP NP NP 0,71087 DRd - 2020-11-18 NQ IgGκ ? NP λ 10,8 NP DRd - 2021-01-27 NQ IgGκ ? NP λ NQ 0,54286 DRd - 2021-09-03 ASS λ + λ NP NP DRd - 2022-01-17 ASS NP NP NP NP NP DRd - 2022-03-14 NP NP NP Neg 486,7 NP DRd - 2022-04-05 ASS NP NP NP 475 0,5416 DRd CR 2022-06-07 ASS NP NP NP NP 0,88544 DRd - 2022-09-27 ASS Neg + Neg NP 0,75248 DRd CR 2023-03-15 NP NP NP Neg 627,38 NP DRd - 2023-11-30 ASS Neg + Neg 657,8 NP DRd CR Abbreviations uIFE: urinary immunofixation; sIFE: serum immunofixation; BJP24h: quantification of Bence Jones Protein in the 24h collection; CM: Monoclonal component quantization in serum electrophoresis; NP: Not Performed; NQ: Not Quantifiable (peak <1 g/L); DIRA: Daratumumab Interference Reflex Assay Test; Prot24h: 24 hours proteinuria; FLC: Free Light Chain; rFLC: serum FLCκ/FLCλ ratio; Susp: CM suspected presence reported; VMP, Bortezomib, Melphalan, Prednisone; AZ: Zoledronic Acid; DRd: Daratumumab, Lenalidomide, Dexamethasone; SD: Stable Disease; VGPR: Very Good Partial Response; PD: Progression Disease; CR: Complete Response Data analysis shows that rFLC (reference range 0.26–1.95) was always in favor of the λ chains, and λ chains were present in the urine sample. Moreover, there was a progressive decrease of the SPE monoclonal peak, and BJP quantization by densitometric scanning of the gel electrophoretic tracing of uIFE (Fig. 1 e), the disappearance of IgDλ MC, and the appearance of an IgGκ MC with a suspected pharmacological origin (Fig. 1 f). Indeed, Daratumumab Interference Reflex Assay (DIRA) test (Fig. 1 h) confirmed suspected daratumumab interference, enabling the effective separation of daratumumab bands from residual endogenous M-proteins In conclusion, in this clinical case, the appearance of a CM isotype λ, then negated, the absence of BJP, together with the evaluation of other hematochemical data, deposed in favor of a Complete Response (CR) (Table 1 ) [ 6 ]. DISCUSSION This article reports on the first-ever case of IgD MM documented in ASL BT thanks to the use of new technologies and the development of diagnostic algorithms. IgD-mediated MM is rare hematologic disease affecting predominantly male patients with a mean age of 59 years (54–65 years) [ 14 ]. The diagnosis of this disease is complex because of the low titer of the paraprotein involved (0–10 mg/dL) and its half-life is2.8 days [ 1 , 14 ], so it is often not detectable on electrophoretic trace but only in sIFE [ 15 , 16 ]. Unfortunately, some laboratories do not provide for the use of anti-IgD antisera in sIFE, so the risk of IgD MM being misdiagnosed or confused with Light Chain Deposition Disease (LCDD) is high, as evidenced by the case of our patient for whom tests performed at outside laboratories had shown the presence of MC consisting of λ chains only. In order to avoid interpretative errors, as recommended in literature [ 16 , 17 ], whenever sIFE shows only the monoclonal κ or λ band after immunotyping with standard anti IgG, IgA, IgM, κ and λ antisera, it is necessary to process the test sample with anti IgD, IgE, λ free and κ, with a serum/diluent ratio of 1:1.5. In our experience, unlike what has been reported by other authors, we consider the use of a diluent in order to optimize gel electrophoretic run and avoid false positives [ 18 ]. This procedure has allowed us to detect 5 patients with IgD MC isotype and 2 with IgE isotype in the last 4 years. In the case illustrated, the severe renal impairment required a rapid measurement of BJP concentration [ 19 – 23 ], that is a useful parameter for evaluating the efficacy of therapeutic schemes. Therefore, a new operative procedure, schematized in the flow chart in Fig. 4 , for performing urine electrophoresis on the 24-hour urine collection in order to quantify BJP and/or complete MC by densitometric scanning of the electrophoretic run on agarose gel was agreed upon between the Units. This clinical case presented at diagnosis with some features typical of IgD MM: light chain λ subtype [ 1 , 9 ], normocytic normochromic anemia [ 1 , 2 ], Bence Jones proteinuria and impaired renal function [ 14 ], 1q21 amplification [ 24 ], osteolytic lesions, generalized weakness, fatigue and bone pain, marked decrease in uninvolved immunoglobulin classes [ 1 , 2 ] and also the clinical signs of aggressive disease [ 14 ]. From a biochemical point of view, hypercalcemia, elevated creatinine levels, LDH, β2M and CRP concentrations are detected more often in IgD MM compared with all other subtypes [ 17 , 25 ]. The biochemical and hematological parameters of the patient of our clinical case were collected from the diagnosis up to the present day (Table 2 ). In the 56 months observation period, in particular, we recorded consistently high values of Crea (reference range 0.45–1.25 mg/dL) and β2M (reference range 1,09–2.53 mg/L), decreased eGFR (11 measurements, data not shown, reference range 95–150 ml/min), proteinuria (reference value < 150 mg/24h), CRP slightly altered (reference value < 0.80 mg/dL), anemia (reference range Hb 13.7–17.5 g/dL) and immunoparesis (suppression of uninvolved immunoglobulins): the measurement of serum immunoglobulins revealed decreased concentrations of IgA (reference range 70–400 mg/dL) and IgM (reference range 40–230 mg/dL) in all determinations performed, while IgG serum level (reference range 700–1600 mg/dL) was within the reference range in only two out of eight assays. Unlike what is reported in literature, in this clinical case calcium serum levels (reference range 8.8–10.2 mg/dL) were always normal. In addition, LDH, alkaline phosphatase (ALP) and aspartate and alanine transaminase (AST and ALT) were always within the reference range and the serum ferritin level was always above the upper limit (reference range 10–300 ng/mL) (data not shown). Table 2 Main hematochemical tests in follow-up Date Ca (mg/dL) Crea (mg/L) CRP (mg/dL) Hb (g/dL) β2M (ng/L) IgG (mg/dL) IgA (mg/dL) IgM (mg/dL) 2019-10-02 9,3 2,86 1,01 9,8 8,55 702 54 22 2019-10-14 NP 2,81 NP 8.7 NP NP NP NP 2019-12-03 9,4 2,01 NP 9,5 NP NP NP NP 2019-12-17 9,4 1,98 4,87 9,3 5,35 524 36 < 25 2020-01-07 9,4 1,76 0,38 10,4 4,7 592 38 < 22 2020-01-21 9,5 1,76 0,21 NP NP NP NP NP 2020-02-11 9,5 1,7 NP 10.9 NP NP NP NP 2020-03-18 9,9 1,83 NP 11.8 NP NP NP NP 2020-04-22 9,8 1,84 NP 11,2 NP NP NP NP 2020-05-27 9,4 1,9 NP 11 NP NP NP NP 2020-06-25 9,5 1,84 NP 11,1 NP NP NP NP 2020-07-27 NP 1,97 NP 11 NP NP NP NP 2020-09-29 9,4 1,7 NP 12,2 NP 693 47 15 2020-11-18 9,7 1,65 NP 12,4 3,67 720 59 24 2021-01-27 9,7 1,72 0,71 13 3,79 819 76 30 2021-03-01 9,4 1,71 NP 13,1 NP NP NP NP 2021-04-29 9,5 1,91 NP 13,7 NP NP NP NP 2021-05-31 9,4 2,34 NP 13,1 NP NP NP NP 2021-07-07 10,2 2,85 NP 12,7 NP NP NP NP 2021-07-17 9,4 2,47 NP 12,2 5,53 883 71 21 2021-09-03 NP NP NP 13.1 NP NP NP NP 2021-09-10 9 1,89 NP NP NP NP NP NP 2021-10-11 NP 1,88 NP 13 NP NP NP NP 2021-10-14 9,5 1,62 NP 12.4 NP NP NP NP 2021-11-08 9,6 1,98 NP 12.4 NP NP NP NP 2021-11-24 9 2,06 NP 12 NP NP NP NP 2021-12-20 9,4 2,22 NP 10.5 NP NP NP NP 2022-01-17 9,3 1,68 6,51 11.3 5,44 411 7 22 2022-02-14 8,7 1,62 NP 11 NP NP NP NP 2022-02-28 8,1 1,74 NP 12.1 NP NP NP NP 2022-03-14 9,3 1,51 0,72 12.5 4,05 376 8 < 22 2022-04-05 8,5 1,48 0,75 11.3 4,69 341 8 < 22 2022-05-10 9 1,54 NP 12.2 NP NP NP NP 2022-06-07 9,7 1,75 NP 12.1 NP NP NP NP 2022-07-05 9,4 1,69 NP 11.2 NP NP NP NP 2022-08-02 9,7 1,55 NP 11,4 NP NP NP NP 2022-08-30 9,4 1,61 NP 10.5 NP NP NP NP 2022-09-27 9,6 1,62 NP 11,5 NP NP NP NP 2022-10-25 9,3 1,51 NP 11.2 NP NP NP NP 2022-11-27 9,3 1,49 NP 11.3 NP NP NP NP 2022-12-21 8,9 1,44 NP 10.4 NP NP NP NP 2023-01-18 9,1 1,42 NP 10.7 NP NP NP NP 2023-01-30 NP 1,3 NP 11,5 NP NP NP NP 2023-02-15 9 1,37 NP NP NP NP NP NP 2023-03-15 9,5 1,41 2,44 NP 4,49 371 < 7 < 21 2023-04-12 9,4 1,52 NP NP NP NP NP NP 2023-05-10 9 1,57 NP NP NP NP NP NP 2023-06-30 9,4 2 NP 10,2 NP NP NP NP 2023-08-02 8,9 1,9 NP NP NP NP NP NP 2023-09-04 9,7 1,6 NP NP NP NP NP NP 2023-10-02 8,9 1,4 NP NP NP NP NP NP 2023-10-31 8,7 1,7 NP NP NP NP NP NP 2023-11-30 8,4 1,6 NP NP NP NP NP NP 2024-01-09 9 1,6 0,74 NP 5,61 376 24 < 20 2024-02-06 9,1 1,6 NP NP NP NP NP NP 2024-02-23 9,1 1,5 0,50 NP 4.3 434 31 10 2024-03-27 9,0 1,8 NP 12,9 NP NP NP NP Abbreviations Ca: calcemia; Crea: serum creatinine; CRP: C-Reactive Protein; β2M: serum β2-Microglobulina; Hb: hemoglobin; IgA, IgG, IgM: serum immunoglobulins; NP: Not Performed In any case, laboratory tests should always be correlated with clinical manifestations, imaging examinations, and bone marrow biopsy investigations. In IgD MM, electrophoretic patterns showing the marked decrease of the γ-globulin zone and absence of monoclonal peaks have been widely documented [ 1 , 8 , 26 ]. In our case at diagnosis, theoretically, two peaks corresponding to the two MCs IgDλ and λ free should have been evident [ 15 , 16 ]; instead, only a peak of 19.3 g/L, representative of sFLCλ (2510 mg/L, rFLC 0.0044), was detected on the electrophoresis trace, while the IgD paraprotein peak was undetectable due to its low serum levels [ 29 ]. Confirming this interpretation, the peak gradually decreased, until it disappeared, in proportion to the decrease in sFLCλ concentration, i.e., the increase in rFLC (Fig. 5 ). The latter parameter is compared with the results of immunofixations and serum electrophoresis in Table 1 . The sIFE initially showed two IgDλ and λ free CMs, then only one λ free isotype MC was evident until the test resulted negative, while BJP λ disappeared in urine, in accordance with the response to the treatment plan. Recent advances in diagnosis and treatment have improved outcomes in patients with IgD MM, although the clinical course is thought to be aggressive [ 3 , 14 ]. Patients affected by IgD MM have a poor prognosis compared with other MM subtypes, with a median survival of 13 to 21 months [ 9 ]. Some studies suggest the use of bortezomib as a first-line drug because it effectively prolongs survival time [ 27 ], especially in younger patients [ 28 ]. Since patients with IgD MM have a shorter median survival compared to other subtypes [ 28 , 29 ], according to some authors, the use of bortezomib could improve the prognosis especially in younger patients [ 30 ]. In a retrospective study [ 14 ] of 149 patients, an Overall Response Rate (ORR) was observed in 125 (83.9%), while 24 (15.4%) had progressive or stable disease, with median Overall Survival (mOS) ranging from 9 to 62 months. Novel Agents (NA = Bortezomib, Thalidomide and Lenalidomide) were administered to 111 (74.4%) patients, achieving a mOS of 23 months (range = 15-38.6). Conventional therapeutic agents like Melphalan, Vinblastine, Vincristine, Epirubicin and Ifosfamide were administered to 38 (25.5%) patients, resulting in an mOS of 14 months (range = 12.5–17). Data showed that bortezomib-based treatment protocols showed a higher Overall Response Rate (ORR = 94%, CR = 52%) than non-bortezomib-based treatment protocols (ORR = 77.8%, CR = 27.7%). In our case, the patient underwent therapy according to VMP scheme (Bortezomib -Melphalan - Prednisone) obtaining a VGPR. The introduction of anti-CD38 monoclonal antibody (mAb) in the treatment of MM also improved the outcome in IgD MM patients [ 14 ]. Daratumumab is a human IgG1κ mAb that at the recommended dosage (1800 mg/sc for 8 weeks, then every 2 weeks for 16 weeks, and then every 4 weeks thereafter) reaches peak serum concentrations and it is easily detectable in most SPE and sIFE. In our case, the diagnostic challenge was the question of whether the appearance of an IgGκ MC represented an isotypic switch or was an interference of the monoclonal drug administered. The answer to the diagnostic question was provided by the introduction of the new DIRA test, which allowed us to report with certainty that the monoclonal peak visible in SPE was caused by the administered drug. Patients with Relapsed/Refractory Multiple Myeloma (RRMM) require treatments that induce a good depth and duration of response essential to achieve stabilization of quality of life. A recent review by Durer et al. [ 33 ] provided a set of recommendations for good clinical practice for RRMM patients that starts with careful consideration of disease-related (biochemical or clinical relapse, cytogenetic risk, aggressiveness) and host-related (age, performance status, comorbidities, frailty, bone marrow reserve, transplant eligibility, preferences, caregiver availability) factors in addition to treatment-related factors (type of drugs, number of prior lines, depth and duration of response, toxicity, and prior complications). The recommendations for good clinical practice reported by Durer follow the EMN (European Myeloma Network) recommendations for MM. CONCLUSIONS The continuous exchange of information and constant collaboration between the Protidology Sector of the Clinical Pathology and Microbiology Unit and the Myeloma Group of the Hematology Unit, the recent acquisition of new analytical instrumentation, and the lived experience have enabled an important implementation in support of clinical activity: the case, in fact, highlights the importance of know-how in the evaluation of electrophoretic tracings, the standardization of diagnostic pathways, and their constant updating in response to clinical needs. The positive aspect is the extension of the new protocols to other clinical cases. Today, recognition of IgD MM, BJP assay on urine specimen, and evaluation of drug interference in IFE are professional assets of the Units and have become a role model in our professional activities. Declarations ETHICS STATEMENT Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. All procedures performed in volving human participants were in accordance with ethical standards to the 1964 Declaration of Helsinki and its subsequent amendments or comparable ethical standards. The participant provided his written informed consent to participate in this study. Written Informed Consent was obtained for the publication of any potentially identifiable data included in this article. FUNDING The authors declare that did not receive support from any organization for the submitted work and no funding was received to assist with the preparation of this manuscript. CONFLICT OF INTEREST All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript. DATA AVAILABILITY STATEMENT The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the contact author. ACKNOWLEDGMENTS We would like to thank Dr. Francesco Cuccaro, Chief Doctor of Epidemiology and Statistics Unit, ASL BT and all the Operators of the Cancer Registry of the Region Apulia, with special reference to Drs. Rossella Bruni and Lucia Bisceglia of the Epidemiology Area and Care Intelligence, AReSS Apulia. AUTHOR CONTRIBUTIONS Conceptualization: Mauro Sasso and Candida Rosaria Germano; Methodology: Mauro Sasso; Software: Mauro Sasso; Validation: Mauro Sasso and Candida Rosaria Germano; Data curation: Mauro Sasso; Writing - original draft preparation: Mauro Sasso; Writing -review and editing: Mauro Sasso, Candida Rosaria Germano and Vanda Staffella; Supervision: Luigi Ceci and Giuseppe Tarantini. All authors have read and agreed to the published version of the manuscript. References El Maataoui A, Fares S, Taoufik A (2021) Immunoglobulin D-Lambda Multiple Myeloma, and a Review of the Literature. Clin Med Rev Case Rep 8:341–344. https://doi.org/10.12998%2Fwjcc.v9.i11.2576 Djidjik R, Lounici Y, Chergeulaine K et al (2015) IgD multiple myeloma: clinical, biological features and prognostic value of the serum free light chain assay. Pathol Biol (Paris) 63:210–214. https://doi.org/10.1016/j.patbio.2015.06.002 Ongoren S, Erdogan I, Salihoglu A et al (2015) IgD multiple myeloma, descriptive report of eight cases, single centre experience. Clin Lymphoma Myeloma Leuk 31:17. https://doi.org/10.1186/1756-9966-31-17 Gruppo di Lavoro AIOM, Fondazione AIRTUM, PASSI AIOMPASSI, D’Argento SIAPEC (2020) IAP I numeri del cancro in Italia. https://www.aiom.it/wp-content/uploads/2020/10/2020_Numeri_Cancro-operatori_web.pdf , Accesso Aprile 2024 AReSS RT, Puglia, ASL BT (2022) Quinto rapporto del Registro Tumori della ASL BT. https://www.sanita.puglia.it/documents/36008/18585903/Registro+tumori+2022.pdf/dfce6dc9-3d25-42d3-bb2d-952bd1f033d5 . Accesso Luglio 2023 Rajkumar SV (2020) Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am J Hematol 95:548–567. https://doi.org/10.1002/ajh.25791 Gao L, Li Q, Kang J, Li C, Zhou J (2015) Non-secreting multiple myeloma switches to IgD of lambda type: a case report and review of literature. Int J Clin Exp Med 8:16984–16990 Pandey S, Kyle RA (2013) Unusual myelomas: a review of IgD and IgE variants. Oncol (Williston Park) 27(8):798–803 Zagouri F, Kastritis E, Symeonidis AS et al (2014) Immunoglobulin D myeloma: clinical features and outcome in the era of novel agents. Eur J Haematol 92:308–312. https://doi.org/10.1111/ejh.12255 AIOM (2017) Linee guida 2017 per il Mieloma Multiplo. https://www.aiom.it/linee-guida/mieloma-2017/ . Accesso Aprile 2024 Palumbo A, Bringhen S, Mateos M-V et al (2015) Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood 125(13):2068–2074. https://doi.org/10.1182/blood-2014-12-615187 Ho PJ, Campbell LJ, Gibson J et al (2002) The biology and cytogenetics of multiple myeloma. Rev Clin Exp Hematol 63:276–300 Sive J, Cuthill K, Hunter H et al (2021) Guidelines on the diagnosis, investigation and initial treatment of myeloma: a British Society for Haematology/UK Myeloma Forum Guideline. Brit J Haematol 193:245–248. https://doi.org/10.1111/bjh.17410 Selene II, Jose JA, Khalil MJ et al (2019) Presentation Patterns, Diagnostic Markers, Management Strategies, and Outcomes of IgD Multiple Myeloma: A Systematic Review of Literature. Cureus 11(2):e4011. https://doi.org/10.7759/cureus.4011 Misra A, Mishra J, Chandramohan J et al (2016) Old but Still Relevant: High Resolution Electrophoresis and Immunofixation in Multiple Myeloma. Indian J Hematol Blood Transfus 32(1):10–17. https://doi.org/10.1007/s12288-015-0605-3 Robier C, Piribauer M, Beham-Schmid C et al (2017) IgD-λ myeloma with extensive free light-chain excretion: a diagnostic pitfall in the identification of monoclonal gammopathies. Clin Chem Lab Med 55(7):e137–e139. https://doi.org/10.1515/cclm-2016-0653 Benchekroun L, Ouzzif Z, Bouabdillah M et al (2011) Myélome multiple à immunoglobuline D [Multiple myeloma with D immunoglobulin]. Ann Biol Clin (Paris) 69(5):581–587. https://doi.org/10.1684/abc.2011.0617 Hejl C, Mestiri R, Carmoi T et al (2018) IgE monoclonal gammopathy: A case report and literature review. Clin Biochem 51:103–109. https://doi.org/10.1016/j.clinbiochem.2017.09.015 Natali P et al (2021) Revisione e aggiornamento del documento di consenso SIBioC per la ricerca e quantificazione della proteina di Bence Jones. Bioch Clin 45(1):75–86 International Myeloma Working Group (2003) Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders. Br J Haematol 121:749–757 Durie BGM, Harousseau JL, Miguel JS et al (2006) International uniform response criteria for multiple myeloma. Leukemia 20:1467–1473. https://doi.org/10.1038/sj.leu.2404284 Rajkumar SV, Dimopoulos MA, Palumbo A et al (2014) International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 15:538–548. https://doi.org/10.1016/s1470-2045(14)70442-5 Kumar S, Paiva B, Anderson KC et al (2016) International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol 17:328–346. https://doi.org/10.1016/s1470-2045(16)30206-6 Lu J, Lu J, Chen W et al (2014) Chinese Medical Doctor Association Hematology Branch. Clinical features and treatment outcome in newly diagnosed Chinese patients with multiple myeloma: results of a multicenter analysis. Blood Cancer J 4(8):e239. https://doi.org/10.1038%2Fbcj.2014.55 Reece DE, Vesole DH, Shrestha S et al (2010) Outcome of patients with IgD and IgM multiple myeloma undergoing autologous hematopoietic stem cell transplantation: a retrospective CIBMTR study. Clin Lymphoma Myeloma Leuk 10(6):458–463. https://doi.org/10.3816%2FCLML.2010.n.078 Troiano T, Brescia V, De Marinis L et al (2022) Case Report: A case of IgD lambda/lambda Multiple Myeloma in patient with acute renal failure and without monoclonal spike in serum electrophoresis. Front Hematol 1:1–5. https://doi.org/10.11613%2FBM.2024.020801 Xu YL, Zhao WH, Tang ZY et al (2019) J. Guillain-Barré syndrome in a patient with multiple myeloma after bortezomib therapy: A case report. World J Clin Cases 7(18):2905–2909. https://doi.org/10.12998/wjcc.v7.i18.2905 Lu J, Lu J, Chen W et al (2016) More frequent IgD and reduced CD200 expression in Chinese patients younger than 50 years old with multiple myeloma: a multicenter analysis. Drug Des Devel Ther 10:3673–3679. https://doi.org/10.2147/dddt.s100062 Modi J, Kamal J, Eter A et al (2015) Immunoglobulin D Multiple Myeloma With Rapidly Progressing Renal Failure. J Clin Med Res 7(8):653–655. https://doi.org/10.14740%2Fjocmr2210w He QL, Meng SS, Yang JN et al (2021) Immunoglobulin D-λ/λ biclonal multiple myeloma: A case report. World J Clin Cases 9(11):2576–2583. https://doi.org/10.12998/wjcc.v9.i11.2576 McCudden C, Axel AE, Slaets D et al (2016) Monitoring multiple myeloma patients treated with daratumumab: teasing out monoclonal antibody interference. Clin Chem Lab Med 54(6):1095–1104. https://doi.org/10.1515/cclm-2015-1031 McCudden C, Axel AE, Slaets D et al (2015) Assessing clinical response in multiple myeloma (MM) patients treated with monoclonal antibodies (mAbs): validation of a daratumumab IFE reflex assay (DIRA) to distinguish malignant M-protein from therapeutic antibody. Poster 8590. https://cerbaresearch.com/app/uploads/2024/03/Cerba-Research-Poster-Assessing-Clinical-Response-in-Multiple-Myeloma-Patients-Treated-With-Monoclonal-Antibodies.pdf . Accesso Aprile 2024 Durer C, Durer S, Lee S et al (2020) Treatment of relapsed multiple myeloma: Evidence-based recommendations. Blood Rev 39:100616. https://doi.org/10.1016/j.blre.2019.100616 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4641430","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":325147200,"identity":"700cb0d5-b596-4788-9e3e-72c584328a13","order_by":0,"name":"Mauro Sasso","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3klEQVRIiWNgGAWjYJADxgcMDBYJINYBYrUwGzAwSCQwsAG1EKuHTQKmBa81uu1nzD58YKiTl+8/fKzixx+JPP75DYyHP+DRYnYmx3jmDIbDhhtupKXd7G2TKJY4RsBhZgdyjJl5GA4wbpDgMbvB2yCR2EBQy/k3IC119vP7z5gV/vkjkTifoJYbYFuYExsO5Jgx87BJJG4grOVZMeMMg8PJQL8kS8sC/WJ4DKj9DF6HJW9m+FBRZzu///DBj2/+2OTJHT58+EMFHi0QYIDCY2wgqGEUjIJRMApGAX4AAFmjUbv5X383AAAAAElFTkSuQmCC","orcid":"","institution":"Local Health Authority in Barletta- Andria-Trani (ASL BT)","correspondingAuthor":true,"prefix":"","firstName":"Mauro","middleName":"","lastName":"Sasso","suffix":""},{"id":325147203,"identity":"c645a4f3-ee87-4b28-8ec4-fa78f65b21c6","order_by":1,"name":"Candida Rosaria Germano","email":"","orcid":"","institution":"Local Health Authority in Barletta- Andria-Trani (ASL BT)","correspondingAuthor":false,"prefix":"","firstName":"Candida","middleName":"Rosaria","lastName":"Germano","suffix":""},{"id":325147209,"identity":"c8205181-e9c8-4a79-b924-3c501f48a791","order_by":2,"name":"Vanda Staffella","email":"","orcid":"","institution":"Local Health Authority in Barletta- Andria-Trani (ASL BT)","correspondingAuthor":false,"prefix":"","firstName":"Vanda","middleName":"","lastName":"Staffella","suffix":""},{"id":325147213,"identity":"259d1e04-675d-4911-b62b-677ad7704a10","order_by":3,"name":"Luigi Ceci","email":"","orcid":"","institution":"Local Health Authority in Barletta- Andria-Trani (ASL BT)","correspondingAuthor":false,"prefix":"","firstName":"Luigi","middleName":"","lastName":"Ceci","suffix":""},{"id":325147221,"identity":"b3d00e37-8be7-4482-b1cf-ddb2a75ebfe8","order_by":4,"name":"Giuseppe Tarantini","email":"","orcid":"","institution":"Local Health Authority in Barletta- Andria-Trani (ASL BT)","correspondingAuthor":false,"prefix":"","firstName":"Giuseppe","middleName":"","lastName":"Tarantini","suffix":""}],"badges":[],"createdAt":"2024-06-26 09:07:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4641430/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4641430/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":61176917,"identity":"b41b2f23-af58-4b9e-9f5d-d2590294f808","added_by":"auto","created_at":"2024-07-26 15:49:10","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":136194,"visible":true,"origin":"","legend":"\u003cp\u003eElectrophoresis and immunofixation patterns. \u003cstrong\u003e(a)\u003c/strong\u003e sEF 2019-10-02: a CM in the γ zone is visible. \u003cstrong\u003e(b)\u003c/strong\u003e sIFE 2019-10-02 with standard anti-IgG, anti-IgA, anti-IgM, anti-κ and anti-λ antisera: two monoclonal free light chains isotype λ are evident. \u003cstrong\u003e(c)\u003c/strong\u003e sIFE 2019-10-02 with anti-IgD, anti-IgE, anti-λ and anti-λ free antisera: CM isotype IgDλ and monoclonal free light chain isotype λ free is shown. \u003cstrong\u003e(d) \u003c/strong\u003euIFE; marked positivity for λ-type BJP.\u003cstrong\u003e (e)\u003c/strong\u003e uEF for quantification of BJP. \u003cstrong\u003e(f)\u003c/strong\u003e sEF 2022-11-27: no peak related to CM IgDλ; a peak of suspected pharmacological origin appeared. \u003cstrong\u003e(g)\u003c/strong\u003e sIFE 2022-11-27 with standard anti-IgG, anti-IgA, anti-IgM, anti-κ and anti-λ antisera: a CM isotype IgGκ and a monoclonal free light chain isotype λ are shown. \u003cstrong\u003e(h)\u003c/strong\u003e DIRA test 2022-11-27: presence of a monoclonal free light chain isotype λ, the IgGκ highlighted with sIFE is the monoclonal antibody Daratumumab administered for therapy. \u003cstrong\u003eAbbreviations \u003c/strong\u003eCM: Monoclonal Component; BJP: Bence Jones protein; DIRA test: Daratumumab Interference Reflex Assay test; sEF: serum electrophoresis; uEF: urinary protein electrophoresis; sIFE: serum \u0026nbsp;immunofixation; uIFE: urinary immunofixation\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-4641430/v1/a01a259b8cdac721b75b063b.png"},{"id":61176920,"identity":"abc81f0a-134c-42c7-9ec7-0c8bdd2f0ad7","added_by":"auto","created_at":"2024-07-26 15:49:10","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":286531,"visible":true,"origin":"","legend":"\u003cp\u003eImaging diagnosis 2019-10-18: Nuclear Magnetic Resonance showed cervical-dorso-lumbar and pelvic osteolysis\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-4641430/v1/f4aade9e12dccb497a83c029.png"},{"id":61176916,"identity":"07c4aa4d-6bd5-46fd-afee-278aec000286","added_by":"auto","created_at":"2024-07-26 15:49:10","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":117322,"visible":true,"origin":"","legend":"\u003cp\u003eRelapse diagnosis 2021-11-04. Residual areas of altered signal at the spine, pelvis and proximal third of the femurs were documented onNuclear Magnetic Resonance\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-4641430/v1/521edb651e11b0b9199c7c34.png"},{"id":61176919,"identity":"ffb0ab8c-3692-4796-b1c4-dc6bc5dc188c","added_by":"auto","created_at":"2024-07-26 15:49:10","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":55790,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart for requesting urinary protein electrophoresis\u003c/p\u003e","description":"","filename":"Fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-4641430/v1/798da627e87cba3c5fd1a146.png"},{"id":61178151,"identity":"acb6c148-ea8c-4b87-a416-0a15dab510d2","added_by":"auto","created_at":"2024-07-26 15:57:10","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":116576,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of the decrease in monoclonal peak measured (in g/L) on electrophoretic trace and the increase of rFLC during follow-up\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations \u003c/strong\u003eFLC: Free Light Chain; rFLC: serum FLCκ/FLCλ ratio; NEG: Monoclonal Component absent; EF: serum electrophoresis\u003c/p\u003e","description":"","filename":"Fig5.png","url":"https://assets-eu.researchsquare.com/files/rs-4641430/v1/894a2a0489ea581987450f24.png"},{"id":95801645,"identity":"7ae5bbb2-ee5c-46d6-9d54-37a0a52dc7bf","added_by":"auto","created_at":"2025-11-13 08:25:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2039450,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4641430/v1/7fa3b76e-bcfc-4371-b1c9-42aee3de6bd6.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A rare case of IgDλ/λ free Multiple Myeloma as a virtuous example of collaboration between clinical activity and laboratory medicine","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eMultiple Myeloma (MM) is a hematologic neoplasm characterized by an abnormal clonal proliferation of plasma cells in bone marrow that are responsible for the production of one or more Monoclonal Components (CM), i.e., complete or incomplete Immunoglobulins (Ig), represented by the heavy chains G, A, D, E and/or the light chains κ and λ detectable in serum and/or urine.\u003c/p\u003e \u003cp\u003eMM accounts for about 10% of all hematologic malignancies, and IgD MM is a rare subtype of the disease as it accounts for about 2% of diagnosed cases worldwide [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn particular, in Italy MM accounts for 1.6% of all diagnosed cancers in men and 1.5% in women, with an incidence (expressed as Standardized Direct Rate (TSD) pop Eur13) of 11.1 cases/100,000 per year in men and 7.7 cases/100,000 per year in women. National estimates for 2020 speak of just over 2,700 new cases of myeloma each year among women and about 3,000 among men [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn Apulia, from 2014 to 2019, there were 1969 new diagnosis of MM (1.69% of total new cancer diagnoses), including 211 new cases (2.06% of the new diagnoses) in the province of Barletta-Andria-Trani (BAT) alone. The regional TSD of incidence/100,000 population is 10.35 for men (12.2 in BT province, mean age 69.9) and 8.02 for women (10.42 in BT, mean age 69.4). The TSD of mortality for both male and female patients is 5.31 in Apulia and 4.35 in BT, with an identical mean age of 76.6 years [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe International Myeloma Working Group (IMWG) criteria for the diagnosis of MM are based on the presence of \u0026ge;\u0026thinsp;10% clonal bone marrow plasma cells or a biopsy-proven plasmacytoma plus evidence of one or more multiple myeloma defining events (MDE): CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) attributable to the plasma cell disorder, bone marrow clonal plasmacytosis\u0026thinsp;\u0026ge;\u0026thinsp;60%, serum involved/uninvolved free light chain (sFLC) ratio\u0026thinsp;\u0026ge;\u0026thinsp;100 (provided involved sFLC is \u0026ge;\u0026thinsp;100 mg/L), or \u0026gt;\u0026thinsp;1 focal lesion\u0026thinsp;\u0026gt;\u0026thinsp;5 mm on magnetic resonance imaging. CRAB criteria are declined as follows: elevated serum Calcium (Ca) levels (Ca\u0026thinsp;\u0026gt;\u0026thinsp;11 mg/dL or greater at the upper limit of the reference range), renal failure (creatinine clearance\u0026thinsp;\u0026lt;\u0026thinsp;40 mL/min/1.73 m\u0026sup2; or serum creatinine\u0026thinsp;\u0026gt;\u0026thinsp;1.77 mg/dL), anemia (hemoglobin (Hb) levels\u0026thinsp;\u0026lt;\u0026thinsp;10 g/dL or 2 g less than the lower limit of the reference range) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eClinical and laboratory findings at the onset of IgD MM disease are similar to those of other myeloma types (bone pain, renal failure, and osteolytic bone lesions), but the clinical course is more aggressive. The laboratory typical findings of IgD MM are hypercalcemia, normocytic normochromic anemia, the presence of Bence Jones Proteinuria (BJP), and a SPE showing hypogammaglobulinemia but no monoclonal peaks [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Some studies reported a median survival between 13,7 and 21 months [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe isotype of the CM involved, patient's age, comorbidities, performance status and previous treatment in case of relapse provide useful elements for diagnostic, prognostic and therapeutic purposes [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The therapeutic landscape of MM has evolved significantly with the approval of numerous novel agents including immunomodulatory drugs (IMiDs) (Thalidomide, Lenalidomide, and Pomalidomide, Iberdomide), proteosome inhibitors (PIs) such as Bortezomib, Carfilzomib and Ixazomib and monoclonal Antibodies (mAb), targeting CD38 (Daratumumab, Isatuximab) and anti-SLAMF7 (Elotuzumab). Daratumumab is a human monoclonal antibody isotype IgG1κ anti-CD38, produced in a mammalian cell line (Chinese Hamster Ovary) by recombinant DNA technology.\u003c/p\u003e \u003cp\u003eThe clinical case reported in this paper is the first case of IgD MM diagnosed in the Local Health Authority of Barletta-Andria-Trani (ASL BT) thanks the virtuous path of collaboration between the teams of Hematology Unit, \"Dimiccoli\" Hospital, Barletta (BT) and the protidology sector of Clinical Pathology and Microbiology Unit, \"L. Bonomo\" Hospital, Andria (BT).\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003eSPE were performed by capillary technology (CZE) on Capillarys 3 Tera instrumentation (Sebia S.r.l., Bagno a Ripoli (FI), Italy).\u003c/p\u003e \u003cp\u003eThe immunotyping of CMs on serum (sIFE) and BJP on urine (uIFE) was performed, strictly following the Sebia company's operational protocols, using agarose gel on Hydrasys II (Sebia) instrumentation.\u003c/p\u003e \u003cp\u003eUsing the same instrumentation, drug interference was evaluated using the Hydrashift Daratumumab kit (Sebia).\u003c/p\u003e \u003cp\u003eDensitometric scanning of the gel obtained with uIFE allowed quantification of BJP.\u003c/p\u003e \u003cp\u003eMeasurement of β2microglobulin (β2M), free light chains kappa (sFLCκ) and lambda (sFLCλ) in serum was performed using the BNII nephelometer (Siemens Healthcare S.r.l., Milan, Italy) and reagents from the same Siemens Healthcare company.\u003c/p\u003e \u003cp\u003eMeasurement of other analytes was carried out using the following instrumentation: LIAISON XL (Diasorin S.p.A., Saluggia (VC), Italy) for ferritin (Fer) by chemiluminescence method; the Beckman platform (Beckman Coulter. Brea, Calif., United States) for serum IgG, IgA, IgM and C-Reactive Protein (CRP) by immunoturbidimetric method, serum and urinary creatinine (Crea) by kinetic method (Jaffé), protein (serum and urinary) and calcium (Ca) by colorimetric method, transaminases (AST, ALT) by modified IFCC enzyme kinetic method, Lactate Dehydrogenase (LDH) by modified Waker method.\u003c/p\u003e \u003cp\u003eThe complete blood count (CBC) was performed by using Yumizen H2500 instrumentation (Horiba Ltd, Kyoto, Kyoto Prefecture, Japan).\u003c/p\u003e \u003cp\u003eData were graphically processed using Microsoft Excel software, version 18.2304.1202.0 from Microsoft 365 (Microsoft Corporation, Redmond, United States).\u003c/p\u003e \u003cp\u003eHistorical patient analytical data were accessed using information stored on DNLAB software version 5.2 (Dedalus S.p,a., Florence, Italy) and Phoresis software version 9.2 (Sebia).\u003c/p\u003e "},{"header":"CLINICAL CASE","content":"\u003cp\u003eA 72-year-old man with bone pain presented to the Hematology Unit of Barletta (BT) Hospital because of bone pain and laboratory tests showing a Monoclonal Component type λ and normocytic anemia (Hemoglobin level 10.5 g/dL). A conventional skeletal radiography of cranium and spine in toto was performed and showed multiple discopathies, sacroiliitis and bilateral coxarthrosis.\u003c/p\u003e\u003cp\u003eTherefore, hematochemical examinations were scheduled and showed: Crea 2.86 mg/dL, eGFR 39.01 mL/min/1.73 m², Ca 9. 3 mg/L, Fer 433.9 ng/mL, β2M 8.55 mg/L, IgG 702 mg/dL, IgA 54 mg/dL, IgM 22 mg/dL, sFLCκ 11 mg/L, sFLCλ 2510 mg/L, sFLCκ/sFLCλ ratio (rFLC) 0.0043, proteinuria 15282 mg/24h, and the presence of a CM in the γ zone of the EF of 1.97 g/dL (19.7 g/L) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). The sIFE performed with standard anti-IgG, anti-IgA, anti-IgM, anti-κ and anti-λ antisera identified two CM reactive only with anti λ (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb), so it was necessary to perform a second sIFE with anti-IgD, anti-IgE. anti-λ and anti-λ free antisera that showed the presence of one CM isotype IgDλ and a second CM reactive only with anti λ free antiserum (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec). The uIFE showed marked positivity for Bence Jones type λ protein (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ed).\u003c/p\u003e\u003cp\u003eThe osteomedullary biopsy revealed markedly increased plasma cells (70% of total marrow cellularity), with an anatomicopathologic stage III (infiltration versus intertrabecular spaces: 56%), a negative congo red staining, ruling out the presence of amyloid .\u003c/p\u003e\u003cp\u003eEchocardiogram was conclusive for hypertensive heart disease with preserved global systolic function, signs of mild diastolic dysfunction, no evidence of pericardial effusion, absence of hemodynamically significant valvulopathy, ventricular ejection fraction of 60%.\u003c/p\u003e\u003cp\u003eA Whole-Body Low-Dose Computed Tomography (WBLDCT) was performed and showed absence of lytic lesions, while the Magnetic Resonance Imaging (MRI)showed the presence of cervical-dorso-lumbar and pelvic osteolysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Total body positron emission tomography (PET) investigation documented a slight increase in the concentration of the metabolic tracer at the level of left scapula spine and left iliac bone coincident with two lytic lesions of 8 and 12 mm, respectively.\u003c/p\u003e\u003cp\u003eTherefore, the diagnosis of IgDλ MM symptomatic with anemia and bone disease was made. The patient was considered \u003cem\u003efrail\u003c/em\u003e and not eligible for Autologous Stem-Cell Transplantation (ASCT) on the basis of IMWG frailty score, which consists of a geriatric assessment (GA, Geriatric Assessment) combining three scales: the Katz Activity of Daily Living (ADL), the Lawton Instrumental Activity of Daily Living (IADL) and the Charlson Comorbidity Index (CCI) with the patient's age, comorbidities and functional status [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe patient was treated with VMP scheme (Bortezomib - Melphalan - Prednisone) for nine cycles, obtaining a VGPR (Very Good Partial Response) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]: after therapy, the IgDλ monoclonal component in the γ zone of SPE was not quantified, bone marrow plasma cell percentage was 5%, the 24 hour proteinuria was negative, the value of creatinine and Hb was 1.65 mg/dL and 12.4 g/dL respectively. The patient received monthly infusions of zoledronic acid with a dose adjustement according to creatinine clearance.\u003c/p\u003e\u003cp\u003eApproximately ten months after the end of the first line of therapy, there was a worsening renal function (reappearance of proteinuria, BJP \u0026gt; 500 mg/24h), so the patient was suspected of having relapsed disease. A osteo medullary biopsy was performed, and showed plasma cell infiltration of 20%, while FISH (Fluorescent In Situ Hybridization) analysis revealed the presence of amp 1q21 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. On Nuclear Magnetic Resonance, residual areas of altered signal at the spine, pelvis and proximal third of the femurs were documented (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eAs a consequence, on november 2021, a second line therapy according DRd (Daratumumab - Lenalidomide - Dexamethasone) scheme was adopted. The outcome was summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eLaboratory diagnostics and therapy responses\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e\u003ccolgroup cols=\"9\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDate\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCM (g/L)\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003esIFE\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDIRA\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003euIFE\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBJP24h\u003c/p\u003e \u003cp\u003e(mg/24h)\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003erFLC\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eTherapy\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eTherapy response\u003c/p\u003e \u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2019-10-02\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19,7\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIgDλ + λfree\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eλ\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0,0043\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1° accesso\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2019-12-17\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9,5\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIgDλ + λfree\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eλ\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0,01189\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eVMP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2020-01-07\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6,8\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIgDλ + λfree\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eλ\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0,02\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eVMP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2020-03-18\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6,4\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eVMP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2020-05-27\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5,3\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIgDλ\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0,01808\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eVMP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2020-09-29\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3,9\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIgDλ\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eλ\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0,03106\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eVMP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2020-11-18\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2,7\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eVMP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2021-01-27\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1,7\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eVMP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2021-09-03\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNQ\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIgDλ + λfree\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0,02527\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eVMP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2022-01-17\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNQ\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIgDλ\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eλ\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e133,5\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0,04241\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eVMP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eVGPR\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2022-03-14\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eASS\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIgDλ + λfree\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e125,9\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0,06355\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAZ\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2022-04-05\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNQ\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAZ\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2022-06-07\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNQ\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIgDλ + λfree\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAZ\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2022-09-27\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eλ + CM\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAZ\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2023-03-15\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNQ\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIgDλ + λfree\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eλ\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e556\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAZ\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2023-11-30\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3,9\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIgDλ + λfree\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eλ\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1017,2\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0,281\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAZ\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2024-01-09\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4,4\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIgDλ + λfree\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e996\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0,22676\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAZ\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2019-10-02\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0,31974\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDRd\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2019-12-17\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1,5\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0,38913\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDRd\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2020-01-07\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0,44311\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDRd\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2020-03-18\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNQ\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIgGκ ?\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0,42685\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDRd\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2020-05-27\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNQ\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIgGκ ?\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eλ\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e42,2\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0,59448\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDRd\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2020-09-29\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSusp\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0,71087\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDRd\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2020-11-18\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNQ\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIgGκ ?\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eλ\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10,8\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDRd\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2021-01-27\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNQ\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIgGκ ?\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eλ\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNQ\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0,54286\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDRd\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2021-09-03\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eASS\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eλ\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eλ\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDRd\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2022-01-17\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e 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align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNeg\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e486,7\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDRd\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2022-04-05\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eASS\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e475\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0,5416\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDRd\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eCR\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2022-06-07\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eASS\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0,88544\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDRd\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2022-09-27\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eASS\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNeg\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNeg\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0,75248\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDRd\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eCR\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2023-03-15\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNeg\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e627,38\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDRd\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2023-11-30\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eASS\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNeg\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNeg\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e657,8\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDRd\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eCR\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"9\"\u003e\u003cp\u003e\u003cstrong\u003eAbbreviations\u0026nbsp;\u003c/strong\u003euIFE: urinary immunofixation; sIFE: serum immunofixation; BJP24h: quantification of Bence Jones Protein in the 24h collection; CM: Monoclonal component quantization in serum electrophoresis; NP: Not Performed; NQ: Not Quantifiable (peak \u0026lt;1 g/L); DIRA: Daratumumab Interference Reflex Assay Test; Prot24h: 24 hours proteinuria; FLC: Free Light Chain; rFLC: serum FLCκ/FLCλ ratio; Susp: CM suspected presence reported; VMP, Bortezomib, Melphalan, Prednisone; AZ: Zoledronic Acid; DRd: Daratumumab, Lenalidomide, Dexamethasone; SD: Stable Disease; VGPR: Very Good Partial Response; PD: Progression Disease; CR: Complete Response\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003c/div\u003e\u003cp\u003eData analysis shows that rFLC (reference range 0.26–1.95) was always in favor of the λ chains, and λ chains were present in the urine sample. Moreover, there was a progressive decrease of the SPE monoclonal peak, and BJP quantization by densitometric scanning of the gel electrophoretic tracing of uIFE (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ee), the disappearance of IgDλ MC, and the appearance of an IgGκ MC with a suspected pharmacological origin (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ef). Indeed, Daratumumab Interference Reflex Assay (DIRA) test (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eh) confirmed suspected daratumumab interference, enabling the effective separation of daratumumab bands from residual endogenous M-proteins In conclusion, in this clinical case, the appearance of a CM isotype λ, then negated, the absence of BJP, together with the evaluation of other hematochemical data, deposed in favor of a Complete Response (CR) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis article reports on the first-ever case of IgD MM documented in ASL BT thanks to the use of new technologies and the development of diagnostic algorithms.\u003c/p\u003e \u003cp\u003eIgD-mediated MM is rare hematologic disease affecting predominantly male patients with a mean age of 59 years (54\u0026ndash;65 years) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The diagnosis of this disease is complex because of the low titer of the paraprotein involved (0\u0026ndash;10 mg/dL) and its half-life is2.8 days [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], so it is often not detectable on electrophoretic trace but only in sIFE [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Unfortunately, some laboratories do not provide for the use of anti-IgD antisera in sIFE, so the risk of IgD MM being misdiagnosed or confused with Light Chain Deposition Disease (LCDD) is high, as evidenced by the case of our patient for whom tests performed at outside laboratories had shown the presence of MC consisting of λ chains only. In order to avoid interpretative errors, as recommended in literature [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], whenever sIFE shows only the monoclonal κ or λ band after immunotyping with standard anti IgG, IgA, IgM, κ and λ antisera, it is necessary to process the test sample with anti IgD, IgE, λ free and κ, with a serum/diluent ratio of 1:1.5. In our experience, unlike what has been reported by other authors, we consider the use of a diluent in order to optimize gel electrophoretic run and avoid false positives [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. This procedure has allowed us to detect 5 patients with IgD MC isotype and 2 with IgE isotype in the last 4 years.\u003c/p\u003e \u003cp\u003eIn the case illustrated, the severe renal impairment required a rapid measurement of BJP concentration [\u003cspan additionalcitationids=\"CR20 CR21 CR22\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], that is a useful parameter for evaluating the efficacy of therapeutic schemes. Therefore, a new operative procedure, schematized in the flow chart in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, for performing urine electrophoresis on the 24-hour urine collection in order to quantify BJP and/or complete MC by densitometric scanning of the electrophoretic run on agarose gel was agreed upon between the Units.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThis clinical case presented at diagnosis with some features typical of IgD MM: light chain λ subtype [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], normocytic normochromic anemia [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], Bence Jones proteinuria and impaired renal function [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], 1q21 amplification [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], osteolytic lesions, generalized weakness, fatigue and bone pain, marked decrease in uninvolved immunoglobulin classes [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] and also the clinical signs of aggressive disease [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. From a biochemical point of view, hypercalcemia, elevated creatinine levels, LDH, β2M and CRP concentrations are detected more often in IgD MM compared with all other subtypes [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe biochemical and hematological parameters of the patient of our clinical case were collected from the diagnosis up to the present day (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In the 56 months observation period, in particular, we recorded consistently high values of Crea (reference range 0.45\u0026ndash;1.25 mg/dL) and β2M (reference range 1,09\u0026ndash;2.53 mg/L), decreased eGFR (11 measurements, data not shown, reference range 95\u0026ndash;150 ml/min), proteinuria (reference value\u0026thinsp;\u0026lt;\u0026thinsp;150 mg/24h), CRP slightly altered (reference value\u0026thinsp;\u0026lt;\u0026thinsp;0.80 mg/dL), anemia (reference range Hb 13.7\u0026ndash;17.5 g/dL) and immunoparesis (suppression of uninvolved immunoglobulins): the measurement of serum immunoglobulins revealed decreased concentrations of IgA (reference range 70\u0026ndash;400 mg/dL) and IgM (reference range 40\u0026ndash;230 mg/dL) in all determinations performed, while IgG serum level (reference range 700\u0026ndash;1600 mg/dL) was within the reference range in only two out of eight assays. Unlike what is reported in literature, in this clinical case calcium serum levels (reference range 8.8\u0026ndash;10.2 mg/dL) were always normal. In addition, LDH, alkaline phosphatase (ALP) and aspartate and alanine transaminase (AST and ALT) were always within the reference range and the serum ferritin level was always above the upper limit (reference range 10\u0026ndash;300 ng/mL) (data not shown).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMain hematochemical tests in follow-up\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCa (mg/dL)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCrea (mg/L)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCRP (mg/dL)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHb\u003c/p\u003e \u003cp\u003e(g/dL)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eβ2M (ng/L)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIgG (mg/dL)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eIgA (mg/dL)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIgM (mg/dL)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2019-10-02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9,3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2,86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1,01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9,8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8,55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e702\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2019-10-14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2,81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e 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colname=\"c3\"\u003e \u003cp\u003e1,7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2020-03-18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9,9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1,83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e 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colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2020-06-25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9,5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1,84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11,1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e 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colname=\"c3\"\u003e \u003cp\u003e1,72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0,71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3,79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e819\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2021-03-01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9,4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1,71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e 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colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2021-07-07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10,2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2,85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12,7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e 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colname=\"c3\"\u003e \u003cp\u003e1,88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2021-10-14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9,5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1,62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e 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colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2021-12-20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9,4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2,22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e 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colname=\"c3\"\u003e \u003cp\u003e1,51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0,72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4,05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e376\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2022-04-05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8,5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1,48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0,75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4,69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e341\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2022-05-10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1,54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e 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colname=\"c8\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2022-08-02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9,7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1,55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11,4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e 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colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2022-12-21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8,9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1,44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e 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\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2023-01-30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1,3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11,5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2023-02-15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1,37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2023-03-15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9,5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1,41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2,44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4,49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e371\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2023-04-12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9,4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1,52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2023-05-10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1,57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2023-06-30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9,4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10,2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2023-08-02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8,9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1,9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2023-09-04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9,7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1,6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2023-10-02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8,9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1,4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2023-10-31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8,7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1,7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2023-11-30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8,4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1,6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2024-01-09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1,6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0,74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5,61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e376\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2024-02-06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9,1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1,6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2024-02-23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9,1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1,5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0,50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e434\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2024-03-27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9,0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1,8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12,9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003e\u003cb\u003eAbbreviations\u003c/b\u003e Ca: calcemia; Crea: serum creatinine; CRP: C-Reactive Protein; β2M: serum β2-Microglobulina; Hb: hemoglobin; IgA, IgG, IgM: serum immunoglobulins; NP: Not Performed\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn any case, laboratory tests should always be correlated with clinical manifestations, imaging examinations, and bone marrow biopsy investigations.\u003c/p\u003e \u003cp\u003eIn IgD MM, electrophoretic patterns showing the marked decrease of the γ-globulin zone and absence of monoclonal peaks have been widely documented [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn our case at diagnosis, theoretically, two peaks corresponding to the two MCs IgDλ and λ free should have been evident [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]; instead, only a peak of 19.3 g/L, representative of sFLCλ (2510 mg/L, rFLC 0.0044), was detected on the electrophoresis trace, while the IgD paraprotein peak was undetectable due to its low serum levels [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Confirming this interpretation, the peak gradually decreased, until it disappeared, in proportion to the decrease in sFLCλ concentration, i.e., the increase in rFLC (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). The latter parameter is compared with the results of immunofixations and serum electrophoresis in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The sIFE initially showed two IgDλ and λ free CMs, then only one λ free isotype MC was evident until the test resulted negative, while BJP λ disappeared in urine, in accordance with the response to the treatment plan.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eRecent advances in diagnosis and treatment have improved outcomes in patients with IgD MM, although the clinical course is thought to be aggressive [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Patients affected by IgD MM have a poor prognosis compared with other MM subtypes, with a median survival of 13 to 21 months [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSome studies suggest the use of bortezomib as a first-line drug because it effectively prolongs survival time [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], especially in younger patients [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Since patients with IgD MM have a shorter median survival compared to other subtypes [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], according to some authors, the use of bortezomib could improve the prognosis especially in younger patients [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. In a retrospective study [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] of 149 patients, an Overall Response Rate (ORR) was observed in 125 (83.9%), while 24 (15.4%) had progressive or stable disease, with median Overall Survival (mOS) ranging from 9 to 62 months. Novel Agents (NA\u0026thinsp;=\u0026thinsp;Bortezomib, Thalidomide and Lenalidomide) were administered to 111 (74.4%) patients, achieving a mOS of 23 months (range\u0026thinsp;=\u0026thinsp;15-38.6). Conventional therapeutic agents like Melphalan, Vinblastine, Vincristine, Epirubicin and Ifosfamide were administered to 38 (25.5%) patients, resulting in an mOS of 14 months (range\u0026thinsp;=\u0026thinsp;12.5\u0026ndash;17). Data showed that bortezomib-based treatment protocols showed a higher Overall Response Rate (ORR\u0026thinsp;=\u0026thinsp;94%, CR\u0026thinsp;=\u0026thinsp;52%) than non-bortezomib-based treatment protocols (ORR\u0026thinsp;=\u0026thinsp;77.8%, CR\u0026thinsp;=\u0026thinsp;27.7%).\u003c/p\u003e \u003cp\u003eIn our case, the patient underwent therapy according to VMP scheme (Bortezomib -Melphalan - Prednisone) obtaining a VGPR.\u003c/p\u003e \u003cp\u003eThe introduction of anti-CD38 monoclonal antibody (mAb) in the treatment of MM also improved the outcome in IgD MM patients [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Daratumumab is a human IgG1κ mAb that at the recommended dosage (1800 mg/sc for 8 weeks, then every 2 weeks for 16 weeks, and then every 4 weeks thereafter) reaches peak serum concentrations and it is easily detectable in most SPE and sIFE. In our case, the diagnostic challenge was the question of whether the appearance of an IgGκ MC represented an isotypic switch or was an interference of the monoclonal drug administered. The answer to the diagnostic question was provided by the introduction of the new DIRA test, which allowed us to report with certainty that the monoclonal peak visible in SPE was caused by the administered drug.\u003c/p\u003e \u003cp\u003ePatients with Relapsed/Refractory Multiple Myeloma (RRMM) require treatments that induce a good depth and duration of response essential to achieve stabilization of quality of life. A recent review by Durer et al. [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] provided a set of recommendations for good clinical practice for RRMM patients that starts with careful consideration of disease-related (biochemical or clinical relapse, cytogenetic risk, aggressiveness) and host-related (age, performance status, comorbidities, frailty, bone marrow reserve, transplant eligibility, preferences, caregiver availability) factors in addition to treatment-related factors (type of drugs, number of prior lines, depth and duration of response, toxicity, and prior complications). The recommendations for good clinical practice reported by Durer follow the EMN (European Myeloma Network) recommendations for MM.\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eThe continuous exchange of information and constant collaboration between the Protidology Sector of the Clinical Pathology and Microbiology Unit and the Myeloma Group of the Hematology Unit, the recent acquisition of new analytical instrumentation, and the lived experience have enabled an important implementation in support of clinical activity: the case, in fact, highlights the importance of know-how in the evaluation of electrophoretic tracings, the standardization of diagnostic pathways, and their constant updating in response to clinical needs. The positive aspect is the extension of the new protocols to other clinical cases. Today, recognition of IgD MM, BJP assay on urine specimen, and evaluation of drug interference in IFE are professional assets of the Units and have become a role model in our professional activities.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eETHICS STATEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. All procedures performed in volving human participants were in accordance with ethical standards to the 1964 Declaration of Helsinki and its subsequent amendments or comparable ethical standards. The participant provided his written informed consent to participate in this study. Written Informed Consent was obtained for the publication of any potentially identifiable data included in this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare\u0026nbsp;that did not receive support from any organization for the submitted work and no funding was received to assist with the preparation of this manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONFLICT OF INTEREST\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDATA AVAILABILITY STATEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the contact author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eACKNOWLEDGMENTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank Dr. Francesco Cuccaro, Chief Doctor of Epidemiology and Statistics Unit, ASL BT and all the Operators of the Cancer Registry of the Region Apulia, with special reference to Drs. Rossella Bruni and Lucia Bisceglia of the Epidemiology Area and Care\u0026nbsp;Intelligence, AReSS Apulia.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization: Mauro Sasso and Candida Rosaria Germano; Methodology: Mauro Sasso; Software: Mauro Sasso; Validation: Mauro Sasso and Candida Rosaria Germano; Data curation: Mauro Sasso; Writing - original draft preparation: Mauro Sasso; Writing -review and editing: Mauro Sasso, Candida Rosaria Germano and Vanda Staffella; Supervision: Luigi Ceci and Giuseppe Tarantini. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eEl Maataoui A, Fares S, Taoufik A (2021) Immunoglobulin D-Lambda Multiple Myeloma, and a Review of the Literature. Clin Med Rev Case Rep 8:341\u0026ndash;344. https://doi.org/10.12998%2Fwjcc.v9.i11.2576\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDjidjik R, Lounici Y, Chergeulaine K et al (2015) IgD multiple myeloma: clinical, biological features and prognostic value of the serum free light chain assay. 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Clin Chem Lab Med 54(6):1095\u0026ndash;1104. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1515/cclm-2015-1031\u003c/span\u003e\u003cspan address=\"10.1515/cclm-2015-1031\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcCudden C, Axel AE, Slaets D et al (2015) Assessing clinical response in multiple myeloma (MM) patients treated with monoclonal antibodies (mAbs): validation of a daratumumab IFE reflex assay (DIRA) to distinguish malignant M-protein from therapeutic antibody. 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Blood Rev 39:100616. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.blre.2019.100616\u003c/span\u003e\u003cspan address=\"10.1016/j.blre.2019.100616\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"IgD Multiple Myeloma, Daratumumab, immunofixation, electrophoresis, DIRA test","lastPublishedDoi":"10.21203/rs.3.rs-4641430/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4641430/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBACKGROUND\u003c/strong\u003e: IgD Multiple Myeloma (MM) is a rare hematological neoplasm characterized by an aggressive course compared to the other isotypes of Myeloma; its laboratory findings are usually anemia, presence of Bence Jones protein (BJP), hypogammaglobulinemia, lack of a monoclonal peak on serum protein electrophoresis (SPE), renal failure, osteolytic lesions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCLINICAL CASE\u003c/strong\u003e: A 72-year-old man with bone pain presented to the Hematology Unit because of bone pain and laboratory tests showing a Monoclonal Component type λ and normocytic anemia (Hemoglobin level 10.5 g/dL). A conventional skeletal radiography of cranium and spine in toto was performed and showed multiple discopathies, sacroiliitis and bilateral coxarthrosis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRESULTS\u003c/strong\u003e: Laboratory tests performed in Clinical Pathology and Microbiology Unit showed hypogammaglobulinemia, acute renal failure (s-creatinine 2.86 mg/dL, eGFR 39,01 mL/min), s-calcium 9.3 mg/L, serum Free Light Chains ratio 0,0044, presence of BJP type λ, a peak of 19.7 g/L in SPE. Serum immunofixation (sIFE) performed by anti-IgD and λ free serum showed a monoclonal IgDλ band and a monoclonal λ free band. Nuclear Magnetic Resonance (NMR) imaging showed cervical-dorso-lumbar and pelvic osteolysis, while osteomedullary biopsy showed a 70% plasma cell infiltration. Symptomatic IgDλ MM was diagnosed: the symptomatic findings where anemia and bone disease.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONCLUSION\u003c/strong\u003e: The 72-year-old patient of our clinical case presented at diagnosis some features commonly present in IgD MM. In this case, the laboratory adopted new diagnostic protocols in order to make a correct diagnosis; the hematological parameters, SPE and sIFE were monitored for 56 months.\u003c/p\u003e\n\u003cp\u003eNew therapies have been shown to improve outcomes in this disease and a recent revision of recommendations has contributed to good clinical practice for patients with relapsed/refractory MM.\u003c/p\u003e","manuscriptTitle":"A rare case of IgDλ/λ free Multiple Myeloma as a virtuous example of collaboration between clinical activity and laboratory medicine","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-26 15:49:05","doi":"10.21203/rs.3.rs-4641430/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5952e927-298d-43a3-a952-6562472d4e05","owner":[],"postedDate":"July 26th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-12T13:54:02+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-26 15:49:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4641430","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4641430","identity":"rs-4641430","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}