Myeloma Basics

Rodger Tiedemann

M.D., Ph.D., F.R.A.C.P., F.R.C.P.A.

Assist. Professor of Medicine, University of TorontoSenior Scientist & Staff Physician, Ontario Cancer Institute

Princess Margaret Hospital

Overview

Pre-Bcell

NaiveB cell

Interfollicular area

Immature B-cell

ProgenitorB-cell

What are plasma cells?

Follicular area

FDC

Lymph Node

Germinal CentreB-cell development

Ag

Pre-Bcell

NaiveB cell

Follicular B blast

Centroblast

Centrocyte

MarginalZone

MemoryB-cells

Plasma cell

ExtrafollicularB-Immunoblast

Interfollicular area

Immature B-cell

ProgenitorB-cell

What are plasma cells?

Follicular area

FDC

Ag

Lymph Node

Germinal Centre

SHM+

class switching

Germs

IgM IgG IgA

B-cell affinity maturation

What are antibodies?

light chain – κ, λ

heavy chain – G, A, M, E, D

What is an M-protein? SPEP

Polyclonal smear

M-spike

Normal antibody repertoire

Myeloma antibodies

Understanding your Bloodwork

• Donna Reece9:30-10:15

Stepwise progressionStepwise progression

MGUSSmoldering

MMActiveMM

Extramedullary

Clonal cellsClonal cells

PC > 10%PC > 10%

End organ damageEnd organ damage

BM independentBM independent

InternationaI Working Group (IWG) diagnostic criteria

MMAn M-protein

(in serum or urine) +

Marrow plasmacytosis or soft tissue

plasmacytoma (clonal) +

End-organ damage: ‘CRAB’

SMM

Serum M-protein ≥3.0 g/dL

and / orMarrow plasma cells ≥10%

(clonal) +

No related organ or tissue impairment

MGUS

Serum M-protein <3.0 g/dL +

Marrow plasma cells <10% +

No related organ damage No other B cell NHL or

amyloidosis

MGUS

=Monoclonal gammopathy of undetermined significance

• prevalence increases with age: • 3.2% at >50yo• 5.3% at >70yo• 7.5% at >85yo

• on average, 1% risk per year of progression to Multiple Myeloma or lymphoma (7x risk ‘normal’ population)

• virtually all MM patients probably had MGUS before MM

MM Features

• Calcium elevation• Renal disease• Anemia• Bone disease

• M-protein(often >30g/l in serum)IgG > IgA > IgD or Light chain only

• Clonal plasma cells(often >10% in BM)

Smith. Br J Haematol. 2005;132:410.

What causes plasma cells to become malignant?

Chromosomal changes in MM

Hypodiploid < 45

Hyperdiploid >46/47 Near tetradiploid >75

Pseudodiploid 44/45 – 46/47

Leif BergsagelLeif Bergsagel

  

 

                                                               

                              

Marta ChesiMarta Chesi

5+ recurrent chromosome translocations (breakages) in MM

15%

5%2%

15%

1%

55%

3%3%

1%

FGFR3/MMSET

c-MAF

MAF-B

MAF-A

CYCLIN D1

CYCLIN D2

CYCLIN D3

OTHER

HYPERDIPLOID

9 Types of Myeloma

IgH translocationHyperdiploid

Pre-Bcell

NaiveB cell

Mantlezone

Follicular B blast

Centroblast

Centrocyte

MarginalZone

MemoryB-cells

ExtrafollicularB-Immunoblast

Interfollicular area

Immature B-cell

ProgenitorB-cell

What causes Multiple Myeloma?

Follicular area

FDC

Ag

Lymph Node

Germinal Centre

SHM+

class switching

IgM IgG IgA

MGUSMultipleMyeloma

Increased risk of MM in individuals exposed to:

• A-bomb• Radiation (e.g. radiologists & nuclear power plant workers• Pesticides? (evidence not compelling)• Benzene? (evidence not compelling)• Risk modified by gender & race

What sparks the first mutation(s) that lead to MM?

??????“break”

Erroneous DNA repair?

attempted repair“break”

insult

Prognosis in MM?

International Staging System (ISS)

1 Serum ß2 microglobulin <3.5 mg/dL +Serum albumin ≥ 3.5 g/dL

2 Not 1 or 3*

3 Serum ß2 microglobulin >5.5 mg/dL

International Staging System vs OS

R. Fonseca et al. Blood 2003

Chromosomal abnormalities (by FISH)

t(4;14)

t(14;16)13

-17p13.1

Shaughnessy, J. D. et al. Blood 2007;109:2276-2284

Gene expression-defined high-risk signature

What medicines are available?

Alkylating agents

Dr “Danny” BergsagelDr “Danny” Bergsagel

melphalanmelphalan cyclophosphamidecyclophosphamide prednisoneprednisone dexamethasonedexamethasone

Glucocorticosteroids

19581958 19671967

Previous standard of care: circa 1999

< 70y< 70y(Vincristine) (Adriamycin)

Dexamethasone

(Vincristine) (Adriamycin)

Dexamethasone

> 70y> 70y ??

inductioninduction consolidationconsolidation maintenancemaintenance

Repeat?Repeat?

MelphalanPrednisoneMelphalanPrednisone

Melphalan 200mg/m2

with autologous SCTMelphalan 200mg/m2

with autologous SCT?steroid

?interferon?steroid

?interferon

IMiDs: Thalidomide, Lenalidomide and Pomalidomide

Lenalidomide15-25 mg/d

MyelosuppressionSkin rash

DVT

NNHO O

O

NH2

Structurally similar, but functionally different, both qualitatively and quantitatively

N

N

O

O

O

O

Thalidomide100-200 mg/d

NeuropathyConstipation

SedationDVT

Pomalidomide 1-4 mg/d

N

O

O

NH

O

O

N H 2

MOA of IMiDS

Teo SK, AAPS Journal. 2005; 07(01):  Teo SK, AAPS Journal. 2005; 07(01): 

NH

ONH

O

OO

H

H

HN

NH

OHN

O

O

NH

O

N

O O

O

Carfilzomib

Irreversible

Proteasome (Thr)

NH

HN B

O

OH

OH

O

N

N CH

CH

O

HN

R

O

HN B

HOOH

Bortezomib

Slowly reversible

(Thr or Ser protease)

Proteasome Inhibitors

Proteasome inhibition

Xproteasome

Myeloma cell

trash

Proteasome inhibited(e.g. with Velcade)

Trash++

How can these drugsbe best used?

Many patients do well with Revlimid induction & transplantE4A03: Overall Survival after 4x Rev/Dex + Auto SCT

P=NS

Su

rviv

al P

rob

ab

ility

0

20

40

60

80

100

Time in Months

0 6 12 18 24 30 36

50 50 49 48 47 35 20

40 40 40 38 37 32 21

Numbers at RiskRD

Rd

Rd

RD 92%

3-year OS rate

HDM+Transplant following 4 cycles of RD vs. Rd

Transplant N = 90

(median age: 57 years)

Median F/U: 36 months

Rajkumar et al, 2008.

Lenalidomide (Revlimid) does not overcome classical high-risk

0

.2

.4

.6

.8

1

PFS

0 10 20 30 40 50

time (months)

Standard Risk

High Risk P < 0.001median 18.5 months

median 36.5 months

Rev/DexRev/Dex

Bortezomib improves outcome (OS) in high-risk MM, including t(4;14).

Low risk MM, no t(4;14) or -17pLow risk MM, no t(4;14) or -17p High risk MM, t(4;14)High risk MM, t(4;14)

Bortezomib added to TT3 but absent from TT2Bortezomib added to TT3 but absent from TT2

Pineda-Roman et al., Br J Haematol. 2008 Mar;140(6):625-34 Pineda-Roman et al., Br J Haematol. 2008 Mar;140(6):625-34

OS

TT3TT3 TT2TT2TT2 + ThalTT2 + Thal

TT3TT3

TT2TT2

TT2 + ThalTT2 + Thal

MM response rates: new drugs and combinationsMM response rates: new drugs and combinations

% of patientsresponding

Old regimens New regimens

Current Approaches for the Newly Diagnosed Patient

• Dr Keith Stewart1:00-1:45

• Dr Donna Reece1:00-1:45

What to do at Relapse