Embed Size (px)
Citation preview
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
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
MM is the tip of the iceberg of
an antibody-mediated immune reaction went wrong
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
MM is a continuous disease
symptomatic
myeloma
progressive
myeloma MGUS smoldering
myeloma clonotypic
Ag-experienced B cell
How do we intercept this threat?
MM is a continuous disease
MGUS smoldering
myeloma clonotypic
Ag-experienced B cell
How do we intercept this threat?
by chance!!!
MM is a continuous disease
MGUS smoldering
myeloma clonotypic
Ag-experienced B cell
How do we intercept this threat?
by chance!!!
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
MM is a continuous disease
MGUS smoldering
myeloma clonotypic
Ag-experienced B cell
How do we intercept this threat?
by chance!!!
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.
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
Monoclonal peak
Normal Multiple Myeloma
Plasma cell proliferation
Serum Protein Electrophoresis
Anemia
Renal failure
Skeletal lesions
The seed:
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
The seed:
The clonal cell burden is important: • M protein • FLC • BMPC (>10%; MC/BMPC ratio)
The soil:
Bone marrow microenvironment
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
genetic
alterations
microenvironment
perturbation
immune
dysregulation
MGUS indolent
myeloma
overt
myeloma
progressive
myeloma
Pawlyn C et al., Nat Rev Cancer. 2017 Aug 24;17(9):543-556
Benmebarek MR, et al., Int J Mol Sci. 2019;20(6):1283. Published 2019 Mar 14.
CAR-T cell design
Timmers M et al., Front Immunol. 2019 Jul 16;10:1613.
CAR-T cell therapy in MM
Charrot S et al. Hemasphere. 2019 Mar 19;3(2):e188.
CAR-T trials registered at clinicaltrials.gov (Dec 2018)
Geographical distribution of CAR-T trials registered at clinicaltrials.gov
Charrot S et al. Hemasphere. 2019 Mar 19;3(2):e188.
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
The therapeutic window is improved by ADC
Panowski S, et al., MAbs. 2014 Jan-Feb;6(1):34-45.
