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Diagnostico y seguimiento de pacientes con Mieloma múltiple.

Diagnostico y seguimiento de pacientes con Mieloma múltiple. Hospital Universitario 12 de octubre. Hematología. 2014. Criterios diagnosticos del Mieloma multiple. Gamapatia Monoclonal de Significado incierto (MGUS). Mieloma Multiple asintomatica (SMM). Mieloma Multiple

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Diagnostico y seguimiento de pacientes con Mieloma múltiple.

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  1. Diagnostico y seguimiento de pacientes con Mieloma múltiple. Hospital Universitario 12 de octubre. Hematología. 2014

  2. Criterios diagnosticos del Mieloma multiple. Gamapatia Monoclonal de Significadoincierto (MGUS) Mieloma Multiple asintomatica (SMM) Mieloma Multiple sintomatica 30 g/L serum • y/o •  10% • y • Ausente Componente Monoclonal. Células plasmaticas En MO (%) Daño orgánicoa Presente(suero/orina) y > 10%* y Presente < 30 g/L serum y < 10% y Ausente -Calcioniveleselevados: calico serico >11 mg/dl ( > 2·75 mmol/l) -Insuficiencia renal: creatinina> 2mg/dl (>173 mmol/l) -Anemia: hemoglobina2 g/dl menor del limite normal o hemoglobina<10 g/dl -lesionesoseas: lesions liticas o osteoporosis con fracturas de compression (MRI o CT) Otras: hiperviscosidadsintomatica, amiloidosis, infecciónbacterianarecurrente (> 2 en 12m) BJH 2003, 121:74

  3. Masa Tumoral 100% La búsqueda del nivel de reducción antitumoral relacionado con la curación Reducción 50% (EEF válido) EEF (-) 10-15% MGUS MM indolente Inmunofijación: Dintel de detección EMR+ Enfermedad Residual Detectable por CMF o PCR EMR <10-6 Enfermedad Residual Negativa, ¿Otros Focos de Enfermedad? EMR (-) PET/TAC (-) = ¿ALTA PROBABILIDAD DE CURACIÓN? Remisión parcial (RP) MBRP Remisión completa RC estricta (RCs) RC IF RC molecular

  4. 10 Asimptomatico Sintomatico Mieloma activo 5 Recaida M protein (g/dL) Refractariorecaida MGUS or smouldering myeloma Plateauremision 2 Time Modelo propuesto del curso de la enfermedad en MM. Induccion Transplante Consolidación Maintenimiento No infrecuente 3-5 eventos de Recaída /Progresión MGUS = monoclonal gammopathy of undetermined significance. Durie BGM. Concise review of the disease and treatment options. Multiple myeloma; 2008/2009. Available from: http://myeloma.org/pdfs/cr08-eng_f1web.pdf.

  5. Pico monoclonal – inmunofijación. (suero /orina) Células plasmáticas en MO. PCR -ASO Inmunofenotipo CMF Plamocitomas Ratio FLC RC estricta (RCs) RC molecular MBRP Remisión parcial (RP) RC IF Remisión completa RC + ASO-PCR negativo (sensibilidad 10-5) RCs+ ausencia de CP (clonales) aberrante fenotípico en MO con un minimo de 1 millón de células en MO analizadas por CMF ( > 4 colores). RC + ratio FLC normal Ausencia de CP por IHQ o CMF (2 a 4 colores) > 50% reducción del PM y reducción en orina 24 > 90% o < 200 mg/24. Si el PM es no medible, > 50% de disminución en la diferencia entre el nivel de FLC comprometida y no comprometida, es requerida en lugar del criterio del PM. Si el PM en suero y orina son no medibles y FLC no son medibles, Se utiliza la reducción de CP >50% en MO, partiendo de un nivel basal >30%. Una reducción >50% en el tamaño de plasmocitomas IF en suero y orina negativo. CP en MO <5%. Desaparición de plasmacitomas. PM detectable en IF. PM no detectable en EEF. Reducción >90% en PM + orina 24h <100mg.

  6. Guidelines for standard investigative workup: diagnosisDimopoulos MA, et al for the International Myeloma Workshop Consensus Panel 3 (Blood 2011) Hipercalcemia, Renal alteración, B2M, LDH BQ: calcio, creatinine, B2M y LDH. Anemia, neutropenia, trombocitopenia. Hemograma y frotis de sangreperiferico. Dolor, astenia, comorbilidades (Corazon, pulmon, renal, PNP y enf hepatica), sintomasamiloide. Historia clinica y examen fisico Pruebas de laboratorio Diagnostico y seguimiento

  7. Guidelines for standard investigative workup: diagnosisDimopoulos MA, et al for the International Myeloma Workshop Consensus Panel 3 (Blood 2011) Oligosecretory, Prognosis Medida de cadenasligeraslibres. Identification of Bence Jones Proteinuria Orina de 24 horas: electrophoresis e inmunofijación Identification & quantitation of MC in serum* Electroforesis de proteinas sericas, inmunofijación + cuantificación de inmunoglobulinas.

  8. Electroforesis de proteínas e inmunofijación.

  9. Proteínas séricas.

  10. Proteínas séricas.

  11. Proteínas séricas.

  12. Proteínas en la orina.

  13. exposed surface exposed surface hidden surface antigen binding Previously hinge region sites hidden surface and antibody heavy chain target carbohydrate light chain Serum free-light-chains vs. heavy-light-chains Kappa or lambda sFLC Heavy/light chains • sFLC: Important in non-secretory, oligosecretory and light-chain MM; & Risk of progressionin MGUS and SMM • The novel Hevylite™ assay enables to accurately measure each isotype-specific heavy and light chain • - specific measurement of the monoclonal (intact) Ig • - measures suppression of the uninvolved HLC-pairs (immune paresis) Leukemia 2013;27hgf

  14. Guidelines for standard investigative workup: diagnosisDimopoulos MA, Kyle RA and Jagannath S for the International Myeloma Workshop Consensus Panel 3 TAC PET-TAC Serie osea IRM Evaluaciónradiologica

  15. MagneticResonanceImaging (MRI) Dimopoulos MA for the International Myeloma Workshop Consensus Panel 3 ((Blood 2011) Mandatory: - Presumed Diagnosis of Solitary plasmacytoma - Detailed evaluation of a painful sekeletal area - Suspicion of cord compression - Pre-Kyphoplastia Recommended - Smoldering(asymptomatic) myeloma - Vertebral collapse in the context of osteoporosis - Non secretorymyeloma Consider: - Screening of spineorpelvicplasmacytomasin symptomatic MM - Identification of diffuse pattern (prognosis) BM involvement and its pattern: focal, diffuse or variegated *Whole MRI: experienceisnotyetestablished

  16. MRI in Smoldering Multiple Myeloma Whole-body MRI: focal lesions in 28% 149 patients with smoldering MM MRI of the spine: focal lesions in 22% 37 patients with smoldering MM ≤ 1 1.0 > 1 0.8 Median TTP Median TTP: NR Median TTP: 15 mo 0.6 Progression-free survival Median TTP: 13 mo 0.4 Median TTP: NR 0.2 Median TTP: 13 m Log-rank P < .001 Log-rank P = .0001 0 0 6 12 18 24 30 36 42 48 54 60 Time Since MRI Treatment (months) Kartritis E, et al. Leukemia 2012 (Epub) Hillengass J, et al. J Clin Oncol 2010;28:1606-1610 Diffusion-weighted MRI ( detects the diffusion of water particles through tissues): functional image of the tumor Abnormal MRI  biphosphonates?, Close monitoring?, Start therapy?......... No consensus! Similar results: Moulopoulos, J Clin Oncol 1995; Mariette Br J Haematol 1999; Heuck ASH 2011 & Hillengass ASH 2012

  17. Otherimagingtechniques CT scan: - WhenMRI unavailableorcontraindicated (metal devices) - Bonepainwithoutlyticlessions - To clarify lytic lessions: ribs, sternum & scapulae - To clarify the extent of softtissues & risk of fracture - To plan radiotherapyorsurgery Low-dosewholebody CT PET-scan:Not recommended for routine use* Selected cases: • Suspected extramedullardisease • Evaluation of ribbonelesions • High LDH • Bence Jones Scape • Rapidlyrecurrentdisease *PET: Lack of standardization: False + (infection and/or inflammation) & false - (high-dose steroids)

  18. Impacto del Post-ASCT PET-CT Negativo en resultados clinicos. PFS accordingto PET-SUV post-ASCT PET-CT OS accordingto PET-SUV post ASCT PET-CT 1.00 1.00 PET-SUV100%reduction 79% 0.75 0.75 PET-SUV 100%reduction 66% PET-SUV <100%reduction 0.50 47% 0.50 PET-SUV <100%reduction 0.25 32% 0.25 Log rank P value = 0.017 Log rank P value = 0.0184 0.00 0.00 0 12 24 36 48 60 0 12 24 36 48 60 Months Months PET-CT is a reliable technique for predicting long-term outcomes. PET-CT, positron emission tomography–computed tomography; SUV, standardized uptake value Zamagni E et al. Blood. 2011;118:5989.

  19. Impact of post-ASCT PET-CT negativity on clinical outcome PFS OS PET-SUV 100% reduction 79% PET-SUV 100% reduction 66% PET-SUV <100% reduction 47% 32% PET-SUV <100% reduction Logrank P-value=0.0184 Logrank P-value=0.017 Complete FDG suppression at PET/CT after ASCT ……Longer PFS & OS PET-CT:a reliable technique for predicting long-term outcomes Zamagni et al. Blood 2011;118(23):5989 Early identification of non-responding patients: > 3 PET focal lesions at Day 7 first cycle of induction inferior PFS & OS (Bartel et al. Blood 2009;114(10): 2068-2076; Usmani et al. Blood 2013. Epub (ahed of print) PET-CT, positron emission tomography - computed tomography

  20. Guidelines for standard investigative workup: diagnosisDimopoulos MA, et al for the International Myeloma Workshop Consensus Panel 3 (Blood 2011) % infiltración de células plasmáticas. Médula ósea aspirado /Biopsia.

  21. Examen de la médula ósea

  22. Analisis del clon tumoral.: Morfologia, citogeneticamolecular,citometria de flujo y Biologia molecular.

  23. Genetic markers with prognostic significance FISH analysis IGH translocations Gene expressionprofiling t(4;14) t(14;16) SNP-basedmappingarray TC classification t(11;14) Molecular classifications (UAMS & Hovon) 16q deletions Genomic imbalances 12p deletions Non-hyperdiplid 1q gains 1q gains 17 gene-model (Arkansas group) 5q gains 1p deletions 15 gene-model (Intergroupe Francophone) Monosomy 13 17p deletions Prognosis is influenced by association with other abnormalities & number of involved cells Perez-Simon, Blood 1999; Fonseca Blood 2003; Chang Blood 2005; Gutierrez Leukemia 2007; Avet- Loiseau JCO 2010 & Blood 2011; Boyd Leukemia 2011, Kumar Blood 2012; Zhan Blood 2006, Saughnessy Blood 2007; Deacaux Blood 2008; Broyl Blood 2010; Tapper JCO 2011:

  24. Diagnostic Bone Marrow analysis by Flow Cytometry: Distinction between myelomatous & normal PC Normal PC Myelomatous PC CD19 CD45 CD56 In 92 % of MM patients the PC have a aberrant phenotype (Mateo G et al. J Clin Oncol; 2008). Sensitivity10-4

  25. MGUS MM Clonal Poly-Clonal versus MM patients showed <5%poly-PC Clonal & Polyclonal PC coexist The most powerful single criteria for differential diagnosis (even in stage I MM) Differential diagnosis between MM and MGUS Based on the distribution of clonal and Polyclonal PC: Analysis of the PC compartment 1. Ocqueteau M, Am J Pathol 1998, 152: 1655

  26. P = .003 5 years 1,0 82% 0,8 0,6 % Time to progression 42% Median: 73 months 0,4 8% 0,2 Median: not reached 0,0 0 24 48 72 96 120 Months Effect of Prognostic Index on TTP in Smoldering MM: by immunophenotype plus immunoparesis” > 95% aPC/BMPC + paresis n = 39 (28 progr.) Median: 23 months > 95% aPC/BMPC or paresis n = 22 (10 progr.) No adverse factors n = 28 (1 progr.) Pérez-Persona E, et al. Blood. 2007;110:2586-2592.

  27. Immunophenotypic investigation of MRD in MM by Multiparametric Flow cytometry Advantages Disadvantages • Heterogeneous BM infiltration* • Only PC compartment1 • No tumor antigens2 • Lack of standardization • Applicability: >90% • Speed • Simplicity • Sensitivity: 10-4 - 10-5 * Extramedullary Relapses 1 MM: expansion of malignant PC (hallmark of MM)  changes in this tumor cell compartment  Clinically meaningful 2 Aberrant phenotypes for discrimination between Myelomatous and normal PC

  28. What is the value of Immunophenotypic Response in MM patients in conventional CR after HDT/ASCT?

  29. Impact on survival of MRD by Immnunophenotyping in BM obtained 3m after ASCT in CR patients (IFx-) (n=147) PFS OS 87% 62% 59% 100 100 30% 80 80 Median: 71m 60 60 Medians: NR 40 40 20 20 p< 0.001 Median: 37m p= 0.009 Months Months 0 0 0 25 50 75 100 125 0 20 40 60 80 100 120 140 MRD negative (n=94) MRD positive (n=53) GEM 2000 trial Paiva B et al; Blood. 2008, 112: 4017-4023

  30. Immunophenotypic Remission ( GEM 2000 & 2005) (1113 pts) The better the quality of the response the longer the survival PFS OS Immunop. CR vs CR: P = 0.007 100 100 Immunop. CR vs CR: P < 0.001 Immun. CR 80 80 CR Immun. CR VGPR 60 60 PR CR VGPR 40 40 PR 20 20 months months PR, n=364 Immunophenotypic CR, n=193 CR, 292 VGPR, n=164 0 0 Median f/u: 46 months (updated) Paiva et al; Blood. 2008, JCO 2011 0 25 50 75 100 125 0 25 50 75 100 125

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