Transcript No Slide Title

Multiple Myeloma
Monitoring and Therapy
Angela Dispenzieri, M.D.
IMF Patient Workshop November 3, 2014
Scottsdale, Arizona
Rochester, Minnesota
Mayo Clinic College of Medicine
Mayo Clinic Comprehensive Cancer Center
Jacksonville, Florida
Multiple Myeloma
Plasma cell malignancy
Calcium
Renal
Anemia
Bone
Making the diagnosis of
multiple myeloma
Not all increases in plasma cells
are myeloma
• MGUS – Monoclonal Gammopathy of Unknown
Significance
Precancer
Cousin diseases
• Smoldering myeloma
Localized
• Solitary Plasmacytoma
cancer
• Multiple myeloma
• Primary systemic amyloidosis
• POEMS syndrome
• Waldenström’s macroglobulinemia
What tests should be done with new
diagnosis of multiple myeloma?
1. Protein electrophoresis of blood and
urine and quantitative immunoglobulin
2. Serum immunoglobulin free light chain
3. Blood hemoglobin, creatinine, calcium,
albumin, beta-2 microglobulin, and LDH
4. Bone radiographs
5. Bone marrow aspirate with FISH and
immunophenotype
Prognostic factor
Important to monitor for
complications and to establish
response therapy
Multiple Myeloma
Staging and Prognosis
Myeloma Staging Systems
• Durie Salmon: IA-IIIB
• Size of M-protein, extent of anemia,
calcium, kidney function, and
number of bone lesions
• International staging system: I-III
• Blood albumin and beta-2
microglobulin
Most Important Prognostic
Factors
• Age
• Frailty
• Renal function
• Myeloma stage
• Myeloma cells
• FISH (fluorescent in situ
hybridization) of myeloma cells
• Aberrant flow phenotype
• Gene expression profiling
msmart.org
TUMOR BIOLOGY: DISEASE AGGRESSIVENESS
Myeloma Risk-Stratification
Standard-Risk
All other FISH
including:
 Trisomies
 t(11;14) (CCND1)
 t(6;14) (CCND3)
Intermediate-Risk
 t(4;14) (FGFR3/
MMSET)
High-Risk
 Del 17p
 t(14;16) (C-MAF)
 t(14;20) (MAF-B)
 High risk GEP
*Presence of trisomies ameliorates high risk
What do we mean by ‘prognostic’
factors?
• Different patients’ myeloma acts may
vary very significantly—almost like
different diseases!
• Markers to help differentiate those
patients with the ‘gentlest’ myeloma
from those with the ‘meanest’
myeloma
Treating Complications of
Myeloma
Signs & Symptoms in 1027 Newly
Diagnosed Myeloma Patients
80
Percent of patients
70
79
73
60
50
66
40
30
32
20
19
10
13
12
0
Bone Bone
lesions pain
Hb<12
g/dL
Kyle et al Mayo clinic Proc. 2003;78:21-33
Fatigue Cr >2 Ca >11 Wt loss
mg/dL mg/dL (>9 kg)
Complications of Myeloma
COMPLICATION
• Painful bone
lesions
• Kidney failure
TREATMENT
• Pain medications,
physical therapy,
rarely surgery and
radiation
• Fluids,
± plasmapheresis,
± dialysis
• High calcium
• Zolendronic acid,
fluids
Treating Multiple Myeloma
The good news….
….there are many treatment
options
The bad news….
….there are many treatment
options
Only Clinical Trials Will
Provide Answers.
Different Drugs Available Now
Corticosteroids
Alkylators
IMiDs
Prednisone
Melphalan
Dexamethasone
Prednisolone
Proteasome
inhibitors
Other
Thalidomide
Bortezomib
(Velcade)
Doxorubicin
Cyclophosphamide
Lenaldiomide
(Revlimid)
Carfilzomib
(Kyprolis)
Cisplatin
Bendamustine
Pomalidomide
(Pomalyst)
Etoposide
Mix and match to make recipes against myeloma
Different Drugs Available Now +
New Drugs Likely Coming Soon
Corticosteroids
Alkylators
IMiDs
Proteasom
e inhibitors
Prednisone
Melphalan
Thalidomide
Bortezomib
Dexamethasone
Cyclophosphamide
Lenaldiomide
Carfilzomib
Prednisolone
Bendamustine
Pomalidomide
Ixazomib
Other
Doxorubicin
Cisplatin
Etoposide
Oprozomib
•
•
•
•
Monoclonal Antibodies: Elotuzumab, Daratumumab, SAR 650984
Kinase Inhibitors: Afuresertib, Dinaciclib
Kinesin Spindle Protein Inhibitor: ARYY520
Histone deacetylase inhibitors: pabinostat, vorinostat
The Anatomy of a Myeloma
Therapeutic Plan
General Treatment Strategy
YOUNG AND FIT
ELDERLY OR
FRAIL
Rd, CVD, VRD, PAD,
VTD, CTD
Rd, MPV, MPT
2. Stem cell collection
For 1-2 transplants
--
3. Stem cell transplant
1 or 2 transplants
--
4. Consolidation
Controversial
--
5. Maintenance
Controversial
Controversial
6. Relapse 1, 2, 3, etc
Many options
Many options
1. Induction
20
How to use Drugs Against
Myeloma?
• 1-at a time?
• 2-at a time?
• 3-at a time?
• 4-at a time?
• More at a time?
• High-dose with stem cell support?
Myeloma Risk-Stratification
Standard-Risk
 Trisomies
 t(11;14)
 t(6;14)
Excellent Outcome
Intermediate-Risk*
 t(4;14)
Bortezomib Critical
*Presence of trisomies ameliorates high risk
High-Risk*




Del 17p
t(14;16)
t(14;20)
GEP defined highrisk
CR appears critical
msmart.org
Monitoring Disease
1. Symptoms
2. Blood
3. Urine
4. Radiographic images
5. Bone marrow
Bone marrow
Blood stream
Antibodies
Immunoglobulins
Fight
infection
Harmful
Use
Myeloma
Plasma
cells
cells
a.k.a.
Monoclonal antibody
M-protein
M-spike
Eat away at bones
Myeloma protein
Crowd bone marrow
causing anemia
Immunoglobulin
Ig
Myeloma:
Poison kidneys
Antibody Proteins
Light chains
Heavy chains
• Two light chains
• Kappa or
• Lambda
• 5 heavy chains
• IgA or
• IgG or
• IgD or
• IgM and IgE
Abnormal Serum Protein
Electrophoresis
Normal
g/L
35
M-spike
14
21
21
g/L
Serum Immunofixation (IFE)
Bone marrow
Bone marrow
Blood stream
Myeloma protein
Oligosecretory
Little protein
secreted
Myeloma
cells
Light chain
secreted (no
heavy chain)
No protein
secreted
Non-secretory
Bence Jones
Or light chain
myeloma
Most
myeloma cases
Urine protein electrophoresis
Urine
Total urine protein =
2.8 g/24 hours
Immunoglobulin Free Light Chains
Light chains
FREE
Light chains
hidden
surface
exposed surface
Previously
hidden
surfaces
Heavy chains
Intact Immunoglobulin
Free Light Chains
Antisera recognize epitopes of FLC’s, but do not detect light chains associated with intact
immunoglobulin
What is the immunoglobulin free
light chain ratio?
Normal
range
for ratio
Serum FLC Lambda (mg/L)
100000
Clonal l
10000
1000
100
10
Clonal k
1
0.1
0.1
normal
range for
k&l
1
10
100
1000
Serum FLC Kappa (mg/L)
10000
100000
Know your proteins and other
things
• Know your monoclonal protein type
• IgG kappa, IgG lambda, IgA kappa,
IgA lambda, kappa only, lambda
only, IgD kappa, IgD lambda
• Know which test(s) your doctor is
following and the starting amount of
your monoclonal protein
• Hemoglobin, creatinine, and calcium
Myeloma Response Measurement
Partial
Response
Very good
partial
response
Complete
response
Stringent
complete
response
Blood
M-protein
50%
reduction
90%
reduction
Complete
disappearance
Complete
disappearance
Urine Mprotein
90%
reduction
< 100
mg/24
hours
Complete
disappearance
Complete
disappearance
Serum
immunoglobulin FLC
Us if no
other
measure
NA
NA
Normal ratio
Bone
marrow
plasma cells
NA
NA
< 5%
Complete
disappearance
Date
10/7/2011
6/7/2011
2/7/2011
10/7/2010
6/7/2010
Obs
2/7/2010
10/7/2009
6/7/2009
Pom
-dex
2/7/2009
10/7/2008
6/7/2008
Sunitinib
2/7/2008
10/7/2007
6/7/2007
Vel
-dex
2/7/2007
10/7/2006
Obs
6/7/2006
2/7/2006
10/7/2005
ASCT
6/7/2005
Dendr
vaccine
2/7/2005
10/7/2004
6/7/2004
2/7/2004
10/7/2003
6/7/2003
2/7/2003
10/7/2002
4
3.5
3
2.5
2
1.5
1
0.5
0
6/7/2002
Thal
-dex
2/7/2002
10/7/2001
6/7/2001
2/7/2001
M-spike
Mr. W.: Going Strong 13 years
after diagnosis
Diagnosed in February 2001
DSS 3A; ISS 2; Normal FISH and Cytogenetics
Best response was VGPR after second ASCT
Relapsed myeloma
ASCT
CTXpred
MLN
9708
Obs
34
What are goals of therapy?
Need to weigh
Survival
Quality of Life
Side-effects
Response
Imaging in Myeloma
D
• Simple bone radiographs
• CT bone
• PET-CT
• MRI
C
T1
T1 +gad
Treating Complications of
Myeloma Therapy
Managing Complications of Therapy
Cortico-steroids
Alkylators
IMiDs
Proteasome
inhibitors
Prednisone
Melphalan
Thalidomide
Bortezomib
Dexame-thasone
Cyclophosphamide
Lenaldiomide
Carfilzomib
Prednisolone
Pomalidomide
Insomnia, mood
Low blood
Constipation
Hunger, diabetes
Fatigue
Diarrhea
Infection
Rash
Blood clots
Prevention is the best therapy.
Tell your doctor if side-effects
Neuropathy
Fatigue
Low platelets
Infection
Survival for MM patients has
doubled to tripled past 15
years due to new treatments!
The landscape is changing for
patients with myeloma thanks
to investigators all over the
world and patients like you,
who are willing to participate in
clinical trials.
Thank You for Your Attention