los nuevos criterios de diagnóstico para el mieloma...

X Congreso Nacional del Laboratorio Clínico Zaragoza 19/21 de Octubre de 2016

Juan José Lahuerta. Servicio de Hematología. HU 12 de Octubre, Madrid PETHEMA/ Grupo Español de Mieloma Múltiple

Los Nuevos Criterios de Diagnóstico para el Mieloma Múltiple Sintomático, desde una Perspectiva Crítica

SIMPOSIO: NUEVAS PERSPECTIVAS EN EL MANEJO DEL MIELOMA MÚLTIPLE

David Pérez Surribas. Laboratorio Pasteur, Andorra

Congreso Nacional del Laboratorio Clínico 2016

Myeloma Pathogenesis Model multistep process: the genetic-acumulation cascade

Bergsagel LP & Kuehl WM. Journal of Clinical Oncology 2005;23:6333-38 & Morgan G (modified), Nature 2012

Tumor Diversity


CXCR4

MM y MICROAMBIENTE MEDULAR

Células del estroma

SDF1

1-integrinas

ICAM-2

CD138

VCAM-1

VLA-4

ICAM-1

LFA-1

CD44

Célula de

MM

Matriz extracelular Fibronectina, laminina

IL-6

IGF-1

VEGF

TNF

La adhesión celular induce resistencia a drogas

- Detención del ciclo celular ( p27);

- Inhibición de la apoptosis ( FLIP-1 –inhibidor FAS -)

- Protección del daño a DNA inducido por fármacos

La adhesion de la CP induce sobreexpresión de 53 genes (11 regulados by NFkB)

NFkB

Aumento de la Proliferación

Aumento act. Osteoclástica

Crecimiento y migración de cls de MM

Mejora de la integración del MM en el nicho medular

β1-integrinas: VLA-4 (CD49d),VLA-5 (CD49e),VLA-6 (CD49f)

San Miguel, Hematol J. 2003 (suppl 3)


Daño Óseo

Enfermedad Osea

RANK

Osteoclasto Células del estroma

RANKL

C

P Osteoblasto

Célula de Mieloma

DKK1 FRZB

Via Wnt

Deposición de Inmunoglobulinas

Amiloidosis AL (Mutaciones estructurales específicas K/λ Poshusta TL. PLoS ONE. 2009;4:e5169

Cadenas ligeras Cadenas ligeras y pesadas solo cadenas pesadas

Enfermedad Renal

Inmunodeficiencia

Descenso +de células B CD19+ y T CD4+/CD8

Células Dendríticas: múltiples alts. funcionales

Células T:- Inversión CD4:CD8 ratio, Expansión oligoclonal de

CD4/CD8, Reducción de poblaciones γδT, -Trastornos en las

poblaciones T-reguladoras

Células B: hipogammaglobulinemia por supresión de cls. B CD19

Células NK: defectos funcionales, expresión alterada de

receptores


Phenotypic alterations of bone marrow hematopoietic cells are often present in newly

diagnosed symptomatic múltiple myeloma (47%) and smoldering MM (33%) untreated

patients

Matarraz S et al. Haematologica 2012;97:1608-11

16/80 (20%) of MGUS or smoldering MM untreated patients demonstrate early

dysmopoietic morphological features* usually seen in MDS

Korde N et al. ASH2012#1805

Myelodysplasia-associated Immunophenotypic Alterations of Bone Marrow Cells in MGUS or Untreated Smoldering and active MM

* Early dyspoietic features observed in CD34+ MEGA patients compared to CD34- MEGA patients include: hypolobulated megakaryocytes (100% vs. 43%, p=0.0005), micromegakaryocytes (100% vs. 36%, p= 0.0001), bone marrow hypercellularity (48% vs. 38%, p=0.006), and higher myeloblast numbers identified by CD34+ immunostaining (2.8% vs. 1.4%, p=0.005). one patient was identified as having an emerging inv(3) or a t(3;3)


Available Therapies for MM

MM Research Foundation. MM Disease Overview. 2011.

Rajkumar. ASCO 2012 Education Session.

Treatment of

Relapsed Disease Induction Consolidation / Maintenance

ASCT

if eligible*

Supportive Care

*Transplant eligibility may impact initial treatment decisions

Treatment Options

Conventional chemotherapy (e.g., alkylating agents)

Steroids (corticosteroids)

Autologous stem cell transplant (ASCT)

“Novel” agents (proteasome inhibitors, immunomodulatory agents, etc)


Active myeloma

Asymptomatic

2

5

10

Refractory relapse

MGUS or smouldering

myeloma Plateau remission

Symptomatic

Relapse

M p

rote

in (

g/d

L)

Time

Not infrequently 3-5 events of Relapse/Progression

Induction Transplant Consolidation Maintenance


MM: Towards a New Model of Clinical Evolution

present frontline therapeutic sequence better PFS, better quality of life, better response in RR, better survival probability

PR CR MRD - PET/TC -

Symptomatic myeloma

OS

Induction

consolidation maintenance

±ASCT

Late Relapse

early treatment in biological progression?

most effective rescue treatments

?

Asymptomatic relapse was less frequent before 2000 than in more recent years (26.3 vs 55.4%) Fernández de

Larrea C et al. Bone Marrow Transplant. 2013 Sep 30. [Epub ahead of print]


Criterios de Consenso ¿Una Norma Absoluta?

Los planteamientos de consenso facilitan la estructuración de ensayos clínicos, su normalización y en consecuencia la interpretación y la comparabilidad de los resultados de la investigación clínica.

Pero la realidad clínica de la enfermedad con mucha frecuencia rompe el marco de los “axiomas”? de consenso

El consenso es también un instrumento de alivio utilizado para acordar respuestas a preguntas con respuesta desconocida

Por eso, tan importante como conocer las nuevas definiciones consensuadas por la comunidad científica y académica, es tener conciencia de sus limitaciones.


1. IMWG consensus criteria for response and minimal residual disease assessment in MM. Lancet Oncol. 2016 Aug;17(8):e328-46. 2. IMWG consensus . Treatment of MM with high-risk cytogenetics. Blood. 2016 Jun 16;127(24):2955-62. 3. IMWG recommendations for the diagnosis and management of myeloma-related renal impairment. J Clin Oncol. 2016 May 1;34(13):1544-57. 4. IMWG recomendations: Management of relapsed MM. Leukemia. 2016 May;30(5):1005-17. 5. IMWG validation: Geriatric assessment in MM patients. Haematologica. 2016 Jun 16. pii: haematol.2016.148189. [Epub ahead of print]. 6. IMWG ASBMT, EBMT, BMTCTN Consensus Conference. Cell Transplantation in Patients with Relapsed MM. Biol Blood Marrow Transplant. 2015 Dec;21:2039-51. 7. IMWG consensus statement. Role of magnetic resonance imaging in the management of patients with MM. J Clin Oncol. 2015 Feb 20;33(6):657-64. 8. IMWG updated criteria for the diagnosis of MM. Lancet Oncol. 2014 Nov;15(12):e538-48. 9. IMWG consensus statement. Renal Insufficiency in newly-diagnosed MM. Anticancer Res. 2014 Aug;34(8):4299-306. 10. IMWG recommendations for global myeloma care. Leukemia. 2014 May;28(5):981-92. 11. IMWG consensus statement for the management, treatment, and supportive care of patients with MM not eligible for ASCT. J Clin Oncol. 2014 Feb 20;32:587-600. 12. IMWG consensus on risk stratification in MM. Leukemia. 2014 Feb;28(2):269-77. 13. IMWG recommendations for the treatment of MM-related bone disease. J Clin Oncol. 2013 Jun 20;31(18):2347-57. 14. IMWG consensus statement. Plasma cell leukemia: diagnostic requirements, response criteria and treatment. Leukemia. 2013 Apr;27(4):780-91. 15. IMWG consensus on maintenance therapy in MM. Blood. 2012 Mar 29;119(13):3003-15. 16. IMWG consensus approach to the treatment of MM patients who are candidates for ASCT. Blood. 2011 Jun 9;117(23):6063-73. 17. IMWG consensus Panel 3. Consensus recommendations for standard investigative workup. Blood. 2011 May 5;117(18):4701-5. 18. IMWG consensus Panel 2. Recommendations for risk stratification in MMPanel 2. Blood. 2011 May 5;117(18):4696-700. 19. IMWG consensus Panel 1. Consensus recommendations for the uniform reporting of clinical trials. Blood. 2011 May 5;117(18):4691-5. 20. IMWG consensus statement. Renal impairment in patients with MM. J Clin Oncol. 2010 Nov 20;28(33):4976-84. 21. IMWG consensus statement regarding the current status of allogeneic stem-cell transplantation for MM. J Clin Oncol. 2010 Oct 10;28(29):4521-30. 22. IMWG consensus. MGUS and smoldering (asymptomatic) MM. Leukemia. 2010 Jun;24(6):1121-7. 23. IMWG consensus perspectives on stem cell collection following initial therapy. Blood. 2009 Aug 27;114(9):1729-35. 24. IMWG consensus statement and guidelines regarding the current status of stem cell collection. Leukemia. 2009 Oct;23(10):1904-12. 25. IMWG guidelines for the management of MM patients ineligible for standard HDC/ASCT. Leukemia. 2009 Oct;23(10):1716-30. 26. IMWG consensus and guidelines regarding the current role of imaging techniques in the diagnosis and monitoring of MM. Leukemia. 2009 Sep;23:1545-56 27. IMWG guidelines for serum-free light chain analysis in MM and related disorders. Leukemia 2009 Feb;23(2):215-24. 28. IMWG consensus statement. The role of vertebral augmentation in MM. Leukemia 2008 Aug;22(8):1479-84. 29. IMWG. The use of biochemical markers of bone remodeling in MM. Leukemia. 2010 Oct;24(10):1700-12. 30. IMWG. International uniform response criteria for MM. Leukemia. 2006 Sep;20(9):1467-73. 31. IMWG. Criteria for the classification of monoclonal gammopathies, MM and related disorders. Br J Haematol. 2003 Jun;121(5):749-5.

International Myeloma Working Group Guías/Proclamaciones de Consenso para el Manejo del MM Congreso Nacional del Laboratorio Clínico 2016

Guías Clínicas y Definiciones por Consenso en MM Mas Instituciones

Italian MM Group. Bone Marrow Transplant

Italian Society of Hematology

Italian Society of Experimental Hematology

Italian Group for Bone Marrow Transplantation (GITMO)

Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA)

German Study Group on Multiple Myeloma (DSMM)

American Society of Blood and Marrow Transplantation

European Society of Blood and Marrow Transplantation (EBMT)

Blood and Marrow Transplant Clinical Trials Network

European Society for Clinical Cell Analysis

Cancer Care Ontario Hematology Disease Site Group

Center for International Blood and Marrow Transplantation Research

Italian Myeloma criteria for PET Use

Asia-Pacific Hematology Consortium

Surgeon's Committee of the Chinese Myeloma Working Group

Mayo Clinic Group (Minnesota, Arizona, and Florida)

European Myeloma Network

British Committee for Standards in Haematology

UK Myeloma Forum

National Comprehensive Cancer Network (NCCN)

PETHEMA/Spanish MM Group

Panel on Clinical Endpoints in Multiple Myeloma.

Scientific Advisors. International Myeloma Foundation.

American Society of Clinical Oncology

Nordic Myeloma Study Group Laboratories

International Multiple Myeloma Consortium

Canadian Agency for Drugs and Technologies in Health

Intergroupe Francophone du Myélome

The Singapore Myeloma Study Group


Monoclonal gammopathy of undetermined significance (MGUS) - M-protein in serum <30 g/l - Bone marrow clonal plasma cells <10% and low level of plasma cell infiltration in a trephine biopsy (if done).

No evidence of other B-cell proliferative disorders - No related organ or tissue impairment (AL amyloid and the IgM paraprotein–related neurological syndromes would be instances of

‘MG associated with…..)

Asymptomatic myeloma (smouldering myeloma) - M-protein in serum ≥ 30 g/l, and/or - Bone marrow clonal plasma cells ≥10% - No related organ or tissue impairment (no end organ damage, including bone lesions) or symptoms

Symptomatic multiple myeloma. - M-protein in serum and/or urine - Bone marrow (clonal) plasma cells* or plasmacytoma - Related organ or tissue impairment (end organ damage, including bone lesions) *If flow cytometry is performed, most plasma cells (> 90%) will show a ‘neoplastic’ phenotype. Some patients may have no symptoms but have related organ or tissue impairment.

Criteria for the Classification of Monoclonal Gammopathies, Multiple Myeloma and Related Disorders

A report of the International Myeloma Working Group. British Journal of Haematology 2003;121: 749.757


Lancet Oncol 2014; 15: e538–48

….These updated are based on the identification of biomarkers associated with near inevitable development of CRAB features in patients who would otherwise be regarded as having smouldering multiple myeloma……



….The IMWG recommends the implementation of these criteria in routine practice and in future clinical trials,….


IMWG Updated Criteria for the Diagnosis of Multiple Myeloma

Issues for Discussion

1) New Early Myeloma-defining Biomarkers ….identification of biomarkers associated with near inevitable development of CRAB features in patients who would otherwise be regarded as having smouldering multiple myeloma

2) Definition of Renal Failure …..clarify and update the underlying laboratory and radiographic variables that fulfil the criteria for the presence of myeloma-defining CRAB features


“Unnecessary” Treatment with Melphalan, Cyclophosphamide or Thalidomide Probably has no Benefit in Indolent Multiple Myeloma

1. Hjorth M, et al. Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I--a randomized study. Myeloma Group of Western Sweden. Eur J Haematol. 1993 Feb;50(2):95-102.

2. Hjorth M, et al. Initial treatment in multiple myeloma: no advantage of multidrug chemotherapy over melphalan-prednisone. The Myeloma Group of Western Sweden. Br J Haematol. 1990 Feb;74(2):185-91

3. Riccardi A, et al. Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer. 2000 Apr;82(7):1254-60.

4. Rajkumar SV, et al. Thalidomide as initial therapy for early-stage myeloma. Leukemia. 2003 Apr; 17(4):775-9.

5. Detweiler-Short K, et al. Long-term results of single-agent thalidomide as initial therapy for asymptomatic (smoldering or indolent) myeloma. Am J Hematol. 2010 Oct;85(10):737-40.


Revised IMWG Diagnostic Criteria Identify Smouldering MM at Imminent Risk of Progression

Central Criteria: If reliable biomarkers associated with roughly an 80% probability of progression to MM within 2 years were identified, such patients should be regarded as having MM and offered therapy. These data should be validated (ie, substantiated by more than two independent studies

Basis

1. The proportion of ultra-high risk patients who do not progress within 2 years (up to 20%) was regarded to be reasonable

2. The results of end-organ damage, especially acute renal failure or pathological fracture, were judged to be unacceptably severe, with risk of substantial long-term morbidity.

Rajkumar SV et al. Lancet Oncol 2014; 15: e538–48


Consensus or Clinical Evidence?

Consensus Criteria: “If reliable biomarkers associated with roughly an 80% probability of progression to MM within 2 years were identified, such patients should be regarded as having MM and offered therapy…”

Concern: There is no experience about current treatments for MM improve the prognosis in patients with risk factors used for high-risk asymptomatic myeloma patients definition

Evidence: A (PETHEMA/GEM Spanish*) randomised trial done in 2013 reported that early therapy for smouldering multiple myeloma can extend overall survival, ………

* Mateos MV et al. N Engl J Med 2013; 369: 438–47. Rajkumar SV et al. Lancet Oncol 2014; 15: e538–48


Revised IMWG diagnostic criteria for multiple myeloma and smouldering multiple myeloma

Any one or more of the following biomarkers of malignancy: Clonal bone marrow plasma cell percentage* ≥60%

Involved:uninvolved serum free light chain ratio ≥100

>1 focal lesions on MRI studies

Rajkumar SV et al. N Engl J Med 2011; 365:474-475

Definition of Multiple Myeloma



Clonal Bone Marrow Plasma Cell Percentage* ≥60% Quality of Criteria

* Clonality should be established by showing κ/λ-light-chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used

First study 6 of 276 patients. PFS 7.7 months; 5 of the 6 patients (83%) patients had progressed or died by 14 months.

Kyle RA et al.N Engl J Med 2007;356:2582-90

Extension study 21 of 651 patients /(1996-2010). PFS: 7 months; 95% patients progressed to symptomatic myeloma within 2 y.


Uninvolved Serum Free Light Chain Ratio ≥100 Quality of Criteria

Larsen JT Leukemia 2013; 27: 941–46

Retrospective analysis of predictive value of the serum (FLC) assay in 586 patients with SMM diagnosed between 1970 to 2010. A serum involved/uninvolved FLC ratio ≥ 100 was used to define high-risk SMM, which included 15% (n=90) of the total cohort

Risk of progression to MM within the first 2 years in 90 patients with an FLC ratio ≥ 100: 72% (79% to MM or AL)


> 1 Focal Lesions on MRI Studies Quality of Criteria

Hillengass J et al. Prognostic significance of focal lesions in whole-body magnetic resonance imaging in patients with asymptomatic MM. J Clin Oncol 2010; 28: 1606–10

0 or 1 FL vs > 1 FL “The series include 16 patients with initial plasma cell tumor plus evidence of systemic disease according to other factors, of which 14 also had corresponding osteolysis ….”

pag 1608*

1 FL: TTP 13 months, 65% of patients had progressed at 2 years

“FLs were present in 42 (28%) of 149 patients (> 1 FL n=23). In 16 patients with initial plasma cell tumor, nine had merely one of these lesions in wb-MRI, and seven showed additional FLs…..”

*In 16 patients, a localized plasma cell tumor plus evidence of systemic disease according to other factors, such as elevated monoclonal protein or percentage of plasma cells in bone marrow, were present. None of the patients had signs of bone disease besides one with osteolysis caused by the plasma cell tumor…..pag 1607


Ultra Risk SMM, Now Active MM Validation of Criteria (In 96 patients with SMM and ≥ 18 mo. of follow-up)

Kastritis E et al. Leukemia 2013; 27: 947–53

Clonal bone marrow plasma cell percentage* ≥60% Bone marrow PC 60%: 7 (8%) of 98 patients. PFS 15 months. At 2 years, ~̴ 60% of MM progression (approximate value taken from the a actuarial curve, data not included explicitly in the article)

Uninvolved serum free light chain ratio ≥100 Free Ligh Chain ratio ≥ 100: 3-4? of 98 patients (not explicity stated)

>1 focal lesions on MRI studies

- It has not been used the original criterion (>1FL) - For 8 of 37 patients with abnormal MRI (focal or diffuse): TTP 15 mo. At 2 years, ~̴ 65% of MM progression. (not explicity stated)


A pesar de la falta de calidad de los datos utilizados por el IMWG para justificar el tratamiento de los pacientes con MM Indolente de Ultra-Alto

riesgo,

Sigue siendo razonable tratar a estos pacientes

Ya que existe evidencia que justifica el tratamiento de casos con MM indolente cuyo riesgo de progresión a MM activo se sitúa entre el 50% y el 65% a los 2 años


Mateos MV et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. Engl J Med 2013 Aug 1;369(5):438-47

QUIREDEX. A Randomised, Controlled, GEM/PETHEMA Phase 3 Trial

¿Qué Evidencia?


QuiRedex: Len-dex vs no treatment

Ammendment on August 2011: Stop treatment at 2 years of treatment

* Low-dose Dex will be added at the moment of biological progression

Induction

Nine 4-week cycles

Maintenance

Therapeutic abstention

Therapeutic abstention

Control arm (n = 66)

Lenalidomide 25 mg/daily during 21d every 28 d

Dexamethasone 20 mg D1-D4 and D12-D15 every 28 d

Treatment arm (n = 60)

Lenalidomide 10 mg/daily during 21 d every month*


QuiRedex: Len-dex vs no Treatment follow-up of 40 months

Median TTP: 21m;

37 Progressions (59%)

Median TTP: NR

Progressions 7%,

4 pts: symptomatic PD


TTP was significantly improved in the treatment versus the observation group according to both risk models (Mayo criteria: HR 0·21, p<0·0001; Spanish criteria: 0·27, p<0·0001; both criteria: 0·24) The agreement between the two risk models is complete: in the control arm each model separately identifies patients at 50% risk of progressing to MM at 2 years

Mayo risk model: M-component ≥ 30 g/L and plasma cell bone marrow infiltration ≥ 10%

Pethema/GEM risk model : aberrant PC in bone marrow by FMC ≥95% plus immunoparesis

Mateos MV et al. Lancet Oncol. 2016 Aug;17(8):1127-36

QuiRedex: Len-dex vs no Treatment Time to Progression According to the Mayo and Spanish Risk Models Congreso Nacional del Laboratorio Clínico 2016

IMWG Criteria: Potential Future Biomarkers for Diagnosis of Multiple Myeloma

2-year probability of progression

High levels of circulating plasma cells1 80%

Abnormal plasma cell immunophenotype ≥95% plus immunoparesis2,3 50%

Evolution of smouldering multiple myeloma4* 65%

Cytogenetic subtypes: t (4;14), 1q amp, or del 17p5, 6 50%

High bone marrow plasma cell proliferative rate7 80%

Unexplained decrease in creatinine clearance by ≥25% accompanied by a rise in urinary monoclonal protein or serum free light-chain concentrations

Not known

*Increase in serum monoclonal protein by ≥10% on each of two successive evaluations within a 6-month period


1) Bianchi Get al. Leukemia 2013;27: 680–85. 2) Perez-Persona E, et al. Br J Haematol 2010; 148: 110–14. 3) Rawstron AC, et al, Haematologica 2008; 93: 431–38. 4) Rosinol L, et alBr J Haematol 2003; 123: 631–36. 5) Rajkumar SV, et al Leukemia 2013; 27: 1738–44. 6) Neben K, J Clin Oncol 2013; 31: 4325–32. 7) Madan S, et al. Mayo Clin Proc 2010; 85: 300.


Evolving Changes in Disease Biomarkers and Risk of Early Progression in SMM, 2016

The study include 190 patients with smoldering multiple myeloma diagnosed at Mayo Clinic (1973 – 2014)

Risk factor patients progressing within 2 years

Clonal Bone Marrow Plasma Cells ≥20% (BMPC) 44/91 (48.4%)

Evolving Monoclonal Protein Only (eMP) 37/58 (63.8%)

Evolving Hb Only (eHb) 31/48 (64.6%)

Both eMP and eHb 22/27 (81.5%)

eMP, eHb and BMPC 20% 19/21 (90.5%)

Ravi P et al. Blood Cancer Journal 2016;6:e454

• Evolving change in monoclonal protein level was defined as ⩾10% increase in serum monoclonal protein (M) and/or immunoglobulin (Ig) (M/Ig) within the first 6 months of diagnosis (only if M-protein ⩾3 g/dl) and/or ⩾ 25% increase in M/Ig within the first 12 months, with a minimum required increase of 0.5 g/dl in M-protein and/or 500 mg/dl in Ig.

• Evolving change in hemoglobin was defined as ⩾ 0.5 g/dl decrease within 12 months of diagnosis.


Imaging Techniques in the Diagnosis of Symptomatic MM. Is not the Time for PET/ CT?

“Increased uptake on PET-CT alone is not adequate for the diagnosis of multiple myeloma; evidence of underlying osteolytic bone destruction is needed on the CT portion of the examination”.

Rajkumar SV. Lancet Oncol 2014;15:e538-48


18F-FDG PET/CT Focal, But not Osteolytic, Lesions Predict the Progression of Smoldering Myeloma to Active Disease

The risk of progression of those with positive PET/CT was 3.00 (95% confidence interval 1.58–5.69, P = 0.001), with a median TTP of 1.1 versus 4.5 years for PET/CT-negative patients.

The probability of progression within 2 years was 58% for positive versus 33% for negative patients.

In conclusion, PET/CT positivity significantly increased the risk of progression of SMM to MM. PET/CT could become a new tool to define high-risk SMM.

Zamagni E et al. Leukemia (2016) 30, 417–422


PET/CT in the Diagnostic Evaluation of Smoldering MM Identification Of Patients Needing Therapy

PET-CT + and underlying osteolysis (n = 16) TTP 21 mo.

PET-CT negative (n = 106) TTP 60 mo.

P = 0.004

PET-CT positive patients

n Probability of progression at 2 years

P

With underlying osteolysis

16 87%

0.31

PET-CT uptake but no osteolysis

9 61%

Siontis B et al. Blood Cancer Journal 2015; 5, e364


1. ¿Por qué el IMWG recomienda tratar únicamente los MMI de muy alto riesgo (de transformación a MM Activo), sin una validación previa en ensayos clínicos?

2. ¿Por qué se eligió el 80% de riesgo de transformación a los 2 años para la indicación terapéutica, y se sustentó con datos inconsistentes?

3. ¿Por qué no se considera la opinión de los pacientes (y de sus médicos)

4. ¿Por qué no se ha establecido un procedimiento para incorporar actualizaciones con la suficiente agilidad?

IMWG Diagnostic Criteria ¿Porqué? Congreso Nacional del Laboratorio Clínico 2016

Definition of Renal Failure Revised IMWG Criteria for Diagnosis of Myeloma


Renal insufficiency: creatinine clearance <40 mL per min or serum creatinine >2 mg/dL

Clarifications Only renal failure caused by light-chain cast nephropathy (based on typical histological changes or

presumptive diagnosis based on the presence of high involved FLC levels, typically >1500 mg/L) is regarded as a myeloma-defining events

Although other forms of renal damage (eg, AL amyloidosis, monoclonal immunoglobulin deposition disease, lightchain Fanconi syndrome, monoclonal gammopathy associated membranoproliferative glomerulonephritis) can occur in multiple myeloma, this association is not characteristic of multiple myeloma and can be seen with other types of plasma cell dyscrasias…..(monoclonal gammopathy of renal significance)……….. We recommend a renal biopsy to clarify the underlying cause of the renal failure in patients with suspected cast nephropathy


Revised IMWG Criteria for Diagnosis of Myeloma: Definition of Renal Failure Congreso Nacional del Laboratorio Clínico 2016

Dangerous Small B-cell Clones

Merlini G & Stone MJ. Blood 2006;108:2520-2530 (modified)

Clo

n

Siz

e

MM, WM, NHL, CLL

Clin

ical

exp

ress

ion

d

ue

to

th

e c

lon

e

bone lesions anemia, hypercalcemia

infections systemic symptoms

none

Clin

ical

exp

ress

ion

d

ue

to

th

e c

lon

e

Kydney-, heart-, liver-failure,

dysautonomia, vasculitis, purpura

polyneuropathy, hemolytic anemia

cold sensitivity, hyperviscosity


The type of kidney damage is determined mainly by the innate characteristics of the monoclonal protein as well as by where (tubules, interstitium, glomeruli, vessels) are deposited, independent of its concentration or tumor burden. In these conditions, the progression of the clone is not required

In MM other Forms of Renal Damage are Possible, but.. The Cast Nephropathy is not Exclusive of MM

• Bridoux F et al. Diagnosis of monoclonal gammopathy of renal significance. Kidney International (2015) 87, 698–711 • Rosner MH et al. Paraprotein–Related Kidney Disease: Diagnosing and Treating Monoclonal Gammopathy of Renal Significance.

Clin J Am Soc Nephrol. 2016 Aug 15. pii: CJN.02920316. [Epub ahead of print]


The Treatment of Gammopathy Different of MM, Including SMM, in which the Paraprotein Produce Organ Damage,

is not Considered by the IMWG Criteria

Rapid suppression of the secretion of nephrotoxic MIg has been shown to favorably impact renal and patient survival in most diseases associated with MGRS, including AL amyloidosis, light-chain deposition disease, immunotactoid glomerulopathy, and proliferative glomerulonephritis with monoclonal Ig deposits.1-4 *MGRS: monoclonal gammopathy of renal significance

1) Leung N, Dispenzieri A, Fervenza FC et al. Renal response after high-dose melphalan and stem cell transplantation is a favorable marker in patients with primary systemic amyloidosis. Am J Kidney Dis 2005; 46: 270–277. 2) Lorenz EC, Gertz MA, Fervenza FC et al. Long-term outcome of autologous stem cell transplantation in light chain deposition disease. Nephrol Dial Transplant 2008; 23: 2052–2057. 3) Bridoux F, Hugue V, Coldefy O et al. Fibrillary glomerulonephritis and immunotactoid (microtubular) glomerulopathy are associated with distinct immunologic features. Kidney Int 2002; 62: 1764–1775. 4) Guiard E, Karras A, Plaisier E et al. Patterns of noncryoglobulinemic glomerulonephritis with monoclonal Ig deposits: correlation with IgG subclass and response to rituximab. Clin J Am Soc Nephrol 2011; 6: 1609–1616.


Consenso científico: definición del paradigma actual por acuerdo de la comunidad científica

“Consenso significa que mucha gente dice colectivamente lo que nadie cree de forma individual” (Abba Eban)

"Históricamente, la pretensión de consenso es una manera de evitar el debate afirmando

el asunto ya está resuelto. (Michael Crichton)

Y no olvidar que hace tiempo hubo consenso acerca de que el mundo era plano….

Is there Consensus on Consensus?

Kiladjian JJ & Gale PG. Leukemia 2016; 30: 1229


los nuevos criterios de diagnóstico para el mieloma...

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