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EFLM Seminar Mab Therapy in Multiple Myeloma Handouts.Pdf M-protein diagnostics of Multiple Myeloma patients treated with biologics EFLM webinar March 27th 2018 JFM (Hans) Jacobs Radboud university medical center (The Netherlands) Laboratory Specialist Medical Immunology ([email protected]) Moderated by Christopher McCudden (Ottawa, Canada) Monoclonal gammopathy/plasma cell dyscrasia (e.g. multiple myeloma) Plasma Cell Bone marrow Peripheral blood B lymphocyte Serum protein electrophoresis (SPE) the separation of charged proteins in an electrical field Anode Albumin + Pole a1: - Orosomucoid - a1 Antitrypsin a2: - Haptoglobin - a2 Macroglobulin - a Lipoprotein - Ceruloplasmin b: - Transferrin - Hemopexin - C3 Complement - b Lipoprotein - Immunoglobulins (IgA) Cathode g: - Immunoglobulins (IgG) - Pole • SPE characterized by albumin, α1-, α2-, β- and γ-fraction • Band-intensity corresponds to its concentration M-protein diagnostics, gel electrophoresis M-protein = Myeloma protein = Paraprotein = Monoclonal component = M spike #1 normal #1 #2 Serum #2 Alb α-1 IgG-κ α-2 #2 M-protein β Normal γ ELP G A M κ λ Densitometry Serum protein Immunofixation electrophoresis (SPE) electrophoresis (IFE) Quantification Detection Typing/Characterisation Monoclonal gammopathy / Plasma cell dyscrasia Amyloidosis (AL) Lymphoma Smouldering myeloma Multiple Myeloma 18% 11% (167) 4% (55) 6% (87) (273) Solitary or extramedullary plasmacytoma 1% (23) Waldenström’s Macroglobulinemia 3% (43) Other MGUS 6% (93) 51% (769) Biclonal IgA (21%) (1%) IgE (0.01%) Nonsecretory myeloma (3%) FLC 15% IgD (1%) IgG (59%) Diagnosed at Mayo Clinic 2002 M-protein quantification: Why? M-protein quantification is required for Classification: f.e. MGUS, smouldering myeloma (sMM) or multiple myeloma (MM) Staging of symptomatic myeloma (stage I, II and III) To monitor disease / therapy-response / or disease evolution (f.e. from MGUS > sMM > MM) Durie et al. Leukemia 2006 Rajkumar et al. Blood 2015 M-protein quantification: How? IgG-kappa M-protein ‘M-spike’ 20% of total serum protein T G A M κ λ Alb. α-1 α-2 β γ SPE Immunofixation SPE scanning densitometry For example: • Total serum protein = 80 g/L • M-spike = 20% of total serum protein • IgG-kappa M-protein = 16 g/L Dutch External Quality Assessment (EQA) M-protein diagnostics National program organized by Radboudumc (75 participating labs) 2011.1A 100% IgG-kappa IgG-kappa Mean: 42.4 g/L VC: 13 % ELP G A M κ2011.2C λ >95% IgG-kappa IgG-kappa Mean: 2.7 g/L VC: 29 % 2011.4B 92% IgG-kappa IgG-kappa Mean: 5.5 g/L VC: 40 % ELP G A M κ λ Monitoring patients, requires good test reproducibility… ELP G A M K L (n=75 labs) Mean: 6.9 g/L 2009.3A CV: 23 % Mean: 6.7 g/L 2009.4A CV: 22 % Mean: 6.4 g/L 2010.4A CV: 22 % Mean: 6.4 g/L 2012.1A CV: 22 % Over 5 measurements average within-lab VC : 14 % Mean: 6.4 g/L 2014.3B CV: 23 % ELP G A M K L Free Light Chain biology Kappa Lambda Bone marrow and lymphoid organs Kidney Polyclonal FLCs produced approx. 500 mg/day Capacity to absorb and metabolize 10-30 gram/day T1/2 varies from 2-6 hrs to (2-3 days with renal failure) FLC normal ranges (Freelite, TBS) Kappa: 3.3 – 19.4 mg/L Lambda: 5.7 – 26.3 mg/L Ratio: 0.26 – 1.65 Katzmann et al. Clin Chem 2002 Monoclonal gammopathy Amyloidosis (AL) Lymphoma Smouldering myeloma Multiple Myeloma 18% 11% (167) 4% (55) 6% (87) (273) Solitary or extramedullary plasmacytoma 1% (23) Waldenström’s Macroglobulinemia 3% (43) Other MGUS 6% (93) 51% (769) Biclonal IgA (21%) (1%) IgE (0.01%) Nonsecretory myeloma (3%) Free Light Chain λ or κ FLC 15% IgD (1%) IgG (59%) Diagnosed at Mayo Clinic 2002 Multiple myeloma and renal impairment hyperCalcemia, Renal impairment, Anemia, Bone disease (CRAB diagnostic criteria MM) Multiple myeloma at initial presentation Block urine flow • 18-50% renal impairment (serum creat ↑) Interstit. inflam. • 12-15% acute renal failure • 8% become dialysis dependent Pathology • Cast nephropathy (myeloma kidney) • Light chain (AL) amyloidosis • Light chain deposition disease • Hypercalcemia • Nephrotoxic drugs • Hyperviscosity syndrome … Dimopoulos et al. J Clin Oncol 2010 Basnayake et al. Kidney Int 2011 Monoclonal Free Light Chains: not always a monoclonal band ‘hidden epitope’ Free Light Chain λ or κ Bence Jones proteins The very first cancer biomarker: The Lancet; 1847 ‘When urine is heated, a white cloud appears and a precipitate forms. The precipitate disappears on boiling and reappears on cooling...’ Henry Bence Jones ELP G A M κ λ FLC FLC κ λ FLC’s = short T1/2 = low serum concentration = often no ‘M-spike’… No M-protein… no monoclonal gammopathy? ELP G A M κ λ If clinical suspicion of: FLC multiple myeloma AL amyloidosis sFLC nephelometry REF values (freelite) Patient Bead Free kappa: 3,3 – 19,4 mg/l 192 mg/l Free lambda: 5,7 – 26,3 mg/l 6.6 mg/l Bead Ratio: 0,26 – 1,65 29 Diagnosis: FLC kappa plasmacytoma-Th12 Dispenzieri et al. Leukemia 2009 M-protein diagnostics: summary ‘hidden epitope’ Free Light Chain λ or κ 85% intact M-protein 15% LCMM Bead • Early detection LCMM • Improved monitoring • Prognostic value Bead Immunoassay (neph/turb/elisa) Sensitivity 500-2.000 mg/L 150-500 mg/L Sensitivity 1-3 mg/L ‘Diagnostic requirement: additional band’ ‘Diagnostic requirement: abnormal FLC κ/λ ratio’ Bradwell et al. 2001 Clin Chem ‘immunoassay for quantification of FLC’ Drayson et al. 2001 Blood ‘identifying and monitoirng ‘non-secretory MM’ Dispenzieri et al. 2009 Leukemia ‘FLC in international guidelines’ M-protein diagnostics: screening, diagnosis and staging AL Amyloidosis Lymphoma Smouldering myeloma Multiple Myeloma 11% 4% 6% 18% plasmacytoma 1% Waldenström’s Macroglobulinemia 3% Other Diagnosed at Mayo Clinic 2002 MGUS 6% (93) 51% Diagnostic criteria Disease staging * * Or myeloma defining event. Rajkumar et al. Lancet Oncology 2014. M-protein diagnostics: follow-up and response evaluation MGUS MM Progression to MM 1st relapse 2nd relapse Diagnosis Diagnosis Durie et al. Leukemia 2006 Rajkumar et al. Blood 2015 Improved treatment regimes for MM patients Daratumumab IMWG guideline: Ludwig et al. Leukemia 2013 Tumor specific antibodies Carter et al. Nat Rev Cancer 2007 Anti-cancer antibodies used in the clinic* 1. Direct tumor cell killing 2. Immune-mediated tumor cell killing 3. Vascular and stromal cell ablation Daratumumab 2015 CD38 Multiple myeloma Elotuzumab 2015 SLAMF7 Multiple myeloma 4. Immune modulation tumor micro-environm. *List is not extensive… Scott et al. Nat Rev Cancer 2012 Monoclonal antibody therapy in multiple myeloma Daratumumab Elotuzumab Touzeau et al. Review. Leukemia 2017 Production and humanization of monoclonal antibodies ‘…momab’ ‘…ximab’ ‘…zumab’ ‘…umab’ Risk of loss of specificity Risk of immunological rejection Techniques: 1) Merge binding portion of monoclonal mouse antibody with human antibody producing DNA. Use cell cultures to express this DNA product 2) Genetically engineered mice that produce ‘human’ antibodies / Human hybridomas Biologics for MM patients in clinical practice Lokhorst et al. NEJM 2015 Lonial et al. NEJM 2015 Mateos et al. NEJM 2018 Daratumumab Mechanisms of effect expansion Immunomodulatory effects Laubach et al. Clin Cancer Research 2015 Van de Donk et al. Blood 2018 Daratumumab pharmacokinetics daratumumab Human IgG1-kappa mAb biologic 16 mg/kg 16 mg/kg 16 mg/kg Weekly Every 2 wks Every 4 wks Reaching serum [dara] up to 1 g/L Xu et al. Clin Phar Ther 2017 Clemens et al. Clin Pharmacokinet 2017 Daratumumab and M-protein interference 1A Patient 1 B Patient 1 Before Daratumumab After Daratumumab IMWG response criteria (Durie et al. 2006) a.o. IFE negative… Enlarged γ-region Enlarged γ-region M-spike M-spike 10.6 g/L 20.4 g/L Dara-spike 0.4 g/L Before After daratumumab daratumumab Patient 1 Patient 1 Daratumumab Before daratumumab After daratumumab spiked in saline PE G A M κ λ G κ λ G κ λ SP G κ SP G κ Van de Donk et al. Clin Chem Lab Med 2016 Abrogate interference using mAb against biological DIRA ‘DARA shift-assay’ Daratumumab-specific Immunofixation Reflex Assay McCudden et al. Clin Chem Lab Med 2016 Indication to use DIRA or similar shift-assay Before After daratumumab daratumumab (+ M-protein comigrates with dara) Perform DIRA SP G κ SP G κ (or similar shift assay) Daratumumab Hydrashift assay (=pos example) Adapted from Van de Donk et al. Blood 2018 Outlook: synergistic effect of combined mAb in MM patients ?? Alternative techniques to multiplex M-protein / mAb monitoring Adpated from Touzeau et al. Review. Leukemia 2017 Zajec et al. J Proteome Res 2018 Willrich et al. CCLM 2016 Daratumumab does not interfere with serum FLC testing Rosenberg et al. Clin Biochem 2016 Dira spiked sample in Dutch EQA Dara spiked at 5 g/L 100% IgG-kappa M-protein Mean M-spike (n=66): 4.9 g/L Inter-lab CV: 22 % M-spike 5.2 g/L All participants report a normal [FLC-kappa]: which is in line with observation of Rosenberg et al.: no monoclonal FLC kappa in Daratumumab Dara spiked at 1 g/L 98% IgG-kappa M-protein Mean M-spike (n=44): 1.7 g/L Inter-lab CV: 46% Many labs don’t spike such small M-proteins and reported <2 g/L Can mAb’s used for other indications also interfere with serum protein electrophoresis? Theoretically yes, but they often go unnoticed…. Daratumumab in MM patients Adalimumab (α-TNF) in Rheumatoid Arthritis • SPE performed to monitor disease • SPE not commonly performed in RA • Dara dosed at high concentrations • Adalimumab dosed at lower concentrations (16 mg/kg i.v. weekly in first 8 weeks) (40 mg s.c. weekly or every 2 weeks) • Hypogamma globulinemia • Hypergamma globulinemia (caused by disease process and therapy) (caused by disease process) Low background: High background: easy to detect small bands difficult to detect small bands McCudden et al.
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