Mieloma Multiplo: dal sospetto diagnostico alle terapie innovative
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Mieloma Multiplo:
dal sospetto diagnostico alle terapie innovative
Massimo Massaia
SC Ematologia - AO S. Croce e Carle – Cuneo, Italy
Laboratorio di Immunologia dei Tumori del Sangue, CeRMS - Torino, Italy
MEDICINA INTERNA 2019: Clinica e Ricerca si incontrano
Auditorium Fondazione Ferrero
Alba, 29-30 Novembre 2019
AO S.Croce e Carle
Cuneo
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
clonotypic smoldering symptomatic progressive
Ag-experienced B cell MGUS myeloma myeloma myeloma
How do we intercept this threat?
MM is a continuous disease
clonotypic smoldering
Ag-experienced B cell MGUS myeloma
by chance!!!
How do we intercept this threat?
MM is a continuous disease
clonotypic smoldering
Ag-experienced B cell MGUS myeloma
by chance!!!
How do we intercept this threat?
Tools to predict MGUS progression
58
1) M-protein
MM is a continuous disease
clonotypic smoldering
Ag-experienced B cell MGUS myeloma
by chance!!!
How do we intercept this threat?
Progression risk stratification for SMM patients
1.9 5.1 10 median times
to progression
Risk factors:
1) abnormal FLC ratio;
2) BMPC >10%;
3) serum M protein > 3 g/dl.
Kyle RA et al., Leukemia (2010) 24, 1121–1127MM is a continuous disease
by EO damage
clonotypic smoldering symptomatic progressive
Ag-experienced B cell MGUS myeloma myeloma myeloma
How do we intercept this threat?Normal Multiple Myeloma
Plasma cell proliferation
Monoclonal
peak
Serum Protein Electrophoresis Renal failure
Anemia
Skeletal lesionsThe 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):543-556The seed: The clonal cell burden is important: • M protein • FLC • BMPC (>10%; MC/BMPC ratio)
The soil: Bone marrow microenvironment
Bone marrow microenvironment
cellular extracellular matrix soluble
component component component
Hematopoietic cells Fibrous proteins Cytokines Growth factors
• Hematopoietic stem cells • Collagen • IL-1b • IGF-1
• Hematopoietic progenitors • Laminin • IL-3 • VEGF
• Erythrocytes • Fibronectin • IL-6 • TGF-b
• Megakaryocytes/platelets • Elastin • IL-10 • bFGF
• Lymphocytes Proteoglycans • IL-15 • HGF
• Monocytes/macrophages • Heparan sulfate proteoglycans • IL-21 • Ang-1
• Dendritic cells • Small leucine-rich repeat proteoglycans • TNF-a Other factors
• Endothelial cells (such as decorin,biglycan, fibromodulin, lumican) • SDF1 • MMPs
Nonhematopoietic cells Glycosaminoglycans • TGF-b • TIMPs
• Vascular cells • Hyaluronan • bFGF • Calcium
• Pericytes SIBLING proteins • SCF
• Stromal/reticular cells • Such as osteopontin, bone sialoprotein and dentin matrix • Ang-1
• Fibroblasts protein-1 • BAFF
• Osteoblasts • RANKL
Adhesion molecules
• Osteoclasts • PTHrP
• VLA-4, VLA-5
• Marrow adipocytes • SDF-1
• LFA-1, VCAM-1, ICAM-1
• MIP-1a
• Syndecan-1 (CD138)indolent overt progressive
MGUS
myeloma myeloma myeloma
genetic
alterations
microenvironment
perturbation
immune
dysregulationPawlyn C et al., Nat Rev Cancer. 2017 Aug 24;17(9):543-556
CAR-T cell design
Benmebarek MR, et al., Int J Mol Sci. 2019;20(6):1283. Published 2019 Mar 14.CAR-T cell therapy in MM
Timmers M et al., Front Immunol. 2019 Jul 16;10:1613.CAR-T trials registered at clinicaltrials.gov (Dec 2018)
Charrot S et al. Hemasphere. 2019 Mar 19;3(2):e188.Geographical distribution of CAR-T trials registered at clinicaltrials.gov
Charrot S et al. Hemasphere. 2019 Mar 19;3(2):e188.ADR (drug/antibody ratio) according to non-site vs site-specific conjugation
adapted from Panowski S, et al., MAbs. 2014 Jan-Feb;6(1):34-45.The therapeutic window is improved by ADC
Panowski S, et al., MAbs. 2014 Jan-Feb;6(1):34-45.lavatoicuneo@gmail.com
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