mieloma multiplo: dal sospetto diagnostico alle terapie innovative · 2019-12-12 · mieloma...
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Massimo Massaia
SC Ematologia - AO S. Croce e Carle – Cuneo, Italy
Laboratorio di Immunologia dei Tumori del Sangue, CeRMS - Torino, Italy
AO S.Croce e Carle
Cuneo
Mieloma Multiplo:
dal sospetto diagnostico alle terapie innovative
MEDICINA INTERNA 2019: Clinica e Ricerca si incontrano Auditorium Fondazione Ferrero
Alba, 29-30 Novembre 2019
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DISCLOSURES:
MASSIMO MASSAIA
Come da nuova regolamentazione della Commissione Nazionale per la Formazione Continua del Ministero della Salute, è
richiesta la trasparenza delle fonti di finanziamento e dei rapporti con soggetti portatori di interessi commerciali in campo
sanitario.
• Fondi per la ricerca da aziende con interessi commerciali in campo sanitario: Gilead, Novartis
• Partecipazione ad Advisory Board: AbbVie, Janssen
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MM is the tip of the iceberg of
an antibody-mediated immune reaction went wrong
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What are the hallmarks of an antibody-mediated immune
reaction went wrong?
• Ig amount & clonality (serum & urine)
• The amount of plasma cells producing the monoclonal Ig (BM & PB)
• The tissue damage induced by the monoclonal Ig
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MM is a continuous disease
symptomatic
myeloma
progressive
myeloma MGUS smoldering
myeloma clonotypic
Ag-experienced B cell
How do we intercept this threat?
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MM is a continuous disease
MGUS smoldering
myeloma clonotypic
Ag-experienced B cell
How do we intercept this threat?
by chance!!!
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MM is a continuous disease
MGUS smoldering
myeloma clonotypic
Ag-experienced B cell
How do we intercept this threat?
by chance!!!
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Tools to predict MGUS progression
Rajkumar V et al., Blood. 2005; 106(3): 812–81
5
21
37
58 1) M-protein <1.5 g/dL; 2) IgG (non-IgA/IgM) 3) normal FLC
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MM is a continuous disease
MGUS smoldering
myeloma clonotypic
Ag-experienced B cell
How do we intercept this threat?
by chance!!!
![Page 10: Mieloma Multiplo: dal sospetto diagnostico alle terapie innovative · 2019-12-12 · Mieloma Multiplo: dal sospetto diagnostico alle terapie innovative MEDICINA INTERNA 2019: Clinica](https://reader030.vdocuments.com.br/reader030/viewer/2022040309/5f2dd97f1158990e1f0c1b73/html5/thumbnails/10.jpg)
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1.9 5.1 10 median times
to progression
Kyle RA et al., Leukemia (2010) 24, 1121–1127
Progression risk stratification for SMM patients
Risk factors: 1) abnormal FLC ratio; 2) BMPC >10%; 3) serum M protein > 3 g/dl.
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MM is a continuous disease
symptomatic
myeloma
progressive
myeloma MGUS smoldering
myeloma clonotypic
Ag-experienced B cell
How do we intercept this threat?
by EO damage
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Monoclonal peak
Normal Multiple Myeloma
Plasma cell proliferation
Serum Protein Electrophoresis
Anemia
Renal failure
Skeletal lesions
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The seed:
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Tumor initiating events in MM
via dysregulation of the G1/S cell cycle checkpoint.
adapted from Pawlyn C et al., Nat Rev Cancer. 2017 Aug 24;17(9):543-556
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The seed:
The clonal cell burden is important: • M protein • FLC • BMPC (>10%; MC/BMPC ratio)
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The soil:
Bone marrow microenvironment
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Hematopoietic cells • Hematopoietic stem cells
• Hematopoietic progenitors
• Erythrocytes
• Megakaryocytes/platelets
• Lymphocytes
• Monocytes/macrophages
• Dendritic cells
• Endothelial cells
Nonhematopoietic cells • Vascular cells
• Pericytes
• Stromal/reticular cells
• Fibroblasts
• Osteoblasts
• Osteoclasts
• Marrow adipocytes
Fibrous proteins • Collagen
• Laminin
• Fibronectin
• Elastin
Proteoglycans • Heparan sulfate proteoglycans
• Small leucine-rich repeat proteoglycans
(such as decorin,biglycan, fibromodulin, lumican)
Glycosaminoglycans • Hyaluronan
SIBLING proteins • Such as osteopontin, bone sialoprotein and dentin matrix
protein-1
Adhesion molecules • VLA-4, VLA-5
• LFA-1, VCAM-1, ICAM-1
• Syndecan-1 (CD138)
Cytokines • IL-1b
• IL-3
• IL-6
• IL-10
• IL-15
• IL-21
• TNF-a
• SDF1
• TGF-b
• bFGF
• SCF
• Ang-1
• BAFF
• RANKL
• PTHrP
• SDF-1
• MIP-1a
Growth factors • IGF-1
• VEGF
• TGF-b
• bFGF
• HGF
• Ang-1
Other factors • MMPs
• TIMPs
• Calcium
Bone marrow microenvironment
cellular
component
soluble
component
extracellular matrix
component
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genetic
alterations
microenvironment
perturbation
immune
dysregulation
MGUS indolent
myeloma
overt
myeloma
progressive
myeloma
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Pawlyn C et al., Nat Rev Cancer. 2017 Aug 24;17(9):543-556
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Benmebarek MR, et al., Int J Mol Sci. 2019;20(6):1283. Published 2019 Mar 14.
CAR-T cell design
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Timmers M et al., Front Immunol. 2019 Jul 16;10:1613.
CAR-T cell therapy in MM
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Charrot S et al. Hemasphere. 2019 Mar 19;3(2):e188.
CAR-T trials registered at clinicaltrials.gov (Dec 2018)
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Geographical distribution of CAR-T trials registered at clinicaltrials.gov
Charrot S et al. Hemasphere. 2019 Mar 19;3(2):e188.
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adapted from Panowski S, et al., MAbs. 2014 Jan-Feb;6(1):34-45.
ADR (drug/antibody ratio) according to non-site vs site-specific conjugation
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The therapeutic window is improved by ADC
Panowski S, et al., MAbs. 2014 Jan-Feb;6(1):34-45.
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