Mieloma Multiplo: dal sospetto diagnostico alle terapie innovative · 2019-12-12 · Mieloma...

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.

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