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Management of Multiple Myeloma: The Changing Paradigm
Myeloma 101: Disease Overview
Craig Emmitt Cole, MDUniversity of Michigan Comprehensive Cancer Center
Red Blood Cells
White Blood Cells
Platelet Cells
Bone Marrow Stem Cell
LymphGlands
Lymph Cells
PlasmaCells
Antibody Proteins
Bone MarrowBlood Factory
Anatomy and Biology (just a little….)What are Blood Cancers, What IS Multiple
Myeloma?
Antibody Proteins
Bone MarrowBlood Factory
Red Blood Cells
White Blood Cells
Platelet Cells
LymphGlands
Lymph Cells
PlasmaCells
Bone Marrow Stem Cell
LYMPHOMA
LEUKEMIA
MULTIPLE MYELOMAMonoclonalM-proteins
Lightchains
Antibody Anatomy
HeavychainsFree Light Chains
Multiple Myeloma Today
CML, chronic myeloid leukemia; CLL, chronic lymphocytic leukemia; MM, multiple myeloma; NHL, non-Hodgkin lymphoma.Leukemia & Lymphoma Society. Facts 2014-2015. Available at: http://www.lls.org/#/resourcecenter/freeeducationmaterials/generalcancer/facts. Accessed April 6, 2015. Siegel RL et al. CA Cancer J Clin. 2016;66:7.
Multiple Myeloma and Common Symptoms
About 10% to 20% of patients with newly diagnosed myeloma will
not have any symptoms.
Low Blood Counts• Anemia is present in 60%
at diagnosis• May lead to anemia and
infection
WeaknessFatigueInfection
Decreased Kidney Function• Occurs in over half of
myeloma patients
Bone Damage• Affects 85% of patients• Leads to fractures
Bone Turnover• Leads to high levels of
calcium in blood (hypercalcemia)
Weakness
Bone pain
Loss of appetite
Weight loss
Multiple Myeloma Complications. http://www.themmrf.org/multiple-myeloma/multiple-myeloma-complicationsAccessed April 14, 2016.Campbell K. Nurs Times. 2014;110:12.
Key Steps to Takeon Your Journey
Laboratory tests and diagnosis
Staging and prognosis
Obtain a second opinion
Treatment
The promise of precision medicine
Diagnosing Myeloma: Learn Your Labs!
CBC • Number of red blood cells, white blood cells, and platelets
CoMP• Measure levels of albumin, calcium, lactate dehydrogenase
[LDH], blood urea nitrogen [BUN], and creatinine. Assess function of kidney, liver, and bone status and the extent of disease.
Beta2MicroG
• Determine the level of a protein that indicates the presence/extent of MM and kidney function
IFE • Identify the type of abnormal antibody proteins: IgG, IgA, κ,or λ
SPEP • Detect the presence and level of M protein
SFLC • Freelite® test measures free light chains (kappa or lambda) in blood
UPEP • Detect Bence-Jones proteins (otherwise known as myeloma light chains) in Urine
24-hr Urine
Analysis• Determine the presence and levels of M protein and Bence Jones
protein in the Urine
CBC, complete blood count; CMP, complete metabolic panel; B2M; beta-2 microglobulin; SPEP, serum protein electrophoresis;IFE, immunofixation electrophoresis; SFLC, serum free light chain assay; UPEP, urine protein electropheresis;
Blood and Urine Tests
Q: Where Do We Start Lookingfor Myeloma?
A: Monoclonal Protein!
Albuminγ ZoneProteins
α ZoneProteins
β ZoneProteins
Plasma Cells
Lightest Heaviest
IgGIgGIgG IgAIgAIgA IgMIgMIgM
Serum Protein ElectrophoresisNormal
Antibodies
Plasma
γ ZoneProteinsAlbumin
α ZoneProteins
β ZoneProteins
Monoclonal Plasma Cells
Lightest Heaviest
Serum Protein ElectrophoresisMonoclonal Gammopathy
Plasma
Monoclonal protein
IgGKappa
M-Protein
IgGKappa
M-Protein
Treatment
γ ZoneProteinsAlbumin
α ZoneProteins
β ZoneProteins
Monoclonal Plasma Cells
Lightest Heaviest
Serum Protein ElectrophoresisMonoclonal Gammopathy Light Chains
Plasma
Monoclonal protein
Monoclonal Light Chain
protein
• Serum free light chains (FLC) blood test uses κ and λantibodies against specific areas that are exposed on FLCs.
• FLCs independently quantify the two light chain types.
• Clonality can be identified by the demonstration of an abnormal ratio of κ : λ FLCs.
Normal Range
κ light-chain-only multiple myeloma
λ light-chain-only multiple myeloma
Hutchison, C. A. et al. (2009) Serum free light chain assessment in monoclonal gammopathy and kidney disease Nat. Rev. Nephrol. doi:10.1038/nrneph.2009.151
Light Chain Monoclonal GammopathyDetection: Serum Free Light Chains
• In 17% of patients with myeloma only produce a light chains.
KappaLt.
Chain
LambdaLt.
Chain
KappaLt.
Chain
LambdaLt.
Chain
Ratio: 1Ratio: 1.06
Light Chain Monoclonal Gammopathy
NormalNormalwith inflammation
1.00mg/dL 1.00mg/dL1.80mg/dL 1.70mg/dL
Ratio: 1.06
Light Chain Monoclonal Gammopathy
LambdaLt.
Chain
KappaLt.
Chain
KappaLt.
ChainMM
Ratio: >100Positive Kappa Monoclonal Serum Light Chains
Normalwith inflammation
178.80mg/dL 0.50mg/dL
KappaLt.
Chain LambdaLt.
Chain
Light Chain Monoclonal Gammopathy
1.00mg/dL 1.00mg/dL
KappaLt.
Chain
After therapy of MMRestore normal Light Chains
Ratio:100Ratio:1
Diagnosing Myeloma: Know Your Imaging Tests!
X-ray MRI CT scan PET scan
Conventional x-rays reveal punched-out lytic lesions, osteoporosis, or fractures in 75% of
patients.
MRI & PET/CT appear to be more sensitive (85%) than skeletal x-rays for the detection of small lytic bone lesions.
Assess changes in the bone structure and determine the number and size of tumors in the bone
Diagnosing Myeloma: Know Your Bone Marrow Tests!
Karyotyping
FISH (fluorescence in situ hybridization)
MM cell
Chromosome
Jamshidi needle
Bone marrow
Skin
Hip bone
Bone Marrow Aspiration and
Biopsy
Cytogenetic Analysis
What’s inside those Myeloma Cells:FISH (fluorescence in situ hybridization)
Chromosome 7
Serum levels of 2 –Microglobulin are of Prognostic Importance in Myeloma
2 –Microglobulin
The higher the 2 Microglobulin = the more plasma cells and/or the
worse the kidney function.
Putting the Results Together
Staging and Prognosis
Bone marrow analysis
Bone marrow analysis
Imaging resultsImaging results
Blood and urine
test results
Blood and urine
test results
Stage IIIStage II
Multiple Myeloma Staging
Greipp PR et al. J Clin Oncol. 2005;23:3412.
β2 –MicroglobulinB2M
Stage I
Albumin3.5 g/dL
B2M <3.5 mg/dL B2M >5.5Neither stage I
nor stage III
High Risk Intermediate Risk Standard Risk
How Aggressive Is My Myeloma?
*Based on the Updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) Consensus Guidelines 2013Mikhael JR et al. Mayo Clin Proc. 2013;88:360.
0
60
40
80
20
Risk Level* (Degree of Aggressiveness)
3 4–5 10Survival (years)
FISH• del 17p• t(14;16)• t(14;20)
GEP• High-risk signature
FISH• t(4;14)*
Cytogenetic• del 13 or hypodiploid• PCLI ≥3%
All others including:• Hyperdiploid• t(11;14)• t(6;14)
Pat
ient
s af
fect
ed (%
)
Revised International Staging System for Multiple Myeloma
Prognostic Factor Stage I Stage II Stage IIIISS Stage• I -Serum β2-microglobulin <3.5 mg/L, serum
albumin >3.5 g/dL• II- Not ISS stage I or III• III- Serum 2-microglobulin >5.5 mg/L
ISS Stage I ISS Stage II ISS Stage III
AND/OR AND AND
LDHNormal Serum LDH: <the upper limit of normalHigh Serum LDH: > the upper limit of normal
Normal High
AND/OR AND AND/OR
Cytogenetic*High Risk:
• del(17p) • t(4;14) • t(14;16)
Standard risk No high-risk CA
No high Risk High Risk
*Based on the Updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) Consensus Guidelines 2013 Mikhael JR et al. Mayo Clin Proc. 2013;88:360.
Not R-ISS Stage I or III
Palumbo et al. JCO. September 10, 2015 vol. 33 no. 26 2863-2869
The Promise of Precision Medicine…
Starts With Genomics
How Do We Match the Right Myeloma Medicines to Each Patient?
Precision Medicine
• Gene expressionprofiling [GEP]
• Whole-genome/ whole-exomesequencing)
• Next-generation sequencing
MM cell
Chromosome
DNA
Personalizing medical care with DNA testing of many different genes (genomics) at the same time
Genomictesting
Tailoredtreatment
Bone marrow tissue samplesNewly diagnosed → relapse
MMRF CoMMpassSM Study: Advancing Personalized
Medicine Research• Landmark study focusing
on the genomics of myeloma
• Goals: – Learn which patients
respond best to which therapies
– Achieve better treatments targeted to each patient’s biological makeup
• 1,000 newly diagnosed patients will be followed for at least 10 years
For more information call the MMRF at 866-603-6628
or visit www.themmmrf.org.
Enrollment complete!
Interpreting results
Interpreting results
Know Your Myeloma Genomics
Tissue banking
(NDMM to RRMM)
Tissue banking
(NDMM to RRMM)
What tests are available?
What tests are available?
Is it available to me?
Is it available to me?
MGUS or Smoldering Myeloma
Active myeloma
Up Front Therapy
PlateauRemission
Asymptomatic
Relapse
Salvage Therapy
RefractoryTherapy
Symptomatic
BriefPlateau
Relapse
Refractory Relapse
ProgressiveMyeloma
Time
Dis
ease
Bur
den
(M-P
rote
in)
The Typical Course of Myeloma
• Auto Transplant• Novel Therapies• Maintenance Therapy
No anemia or bone lesions.
Normal calcium levels and
kidney function.
Possible anemia, bone lesions, high calcium levels, or reduced kidney function.
Myeloma is not
responsive to therapy.
0
2
4
6
IgGKappa
M-Protein
After Establishing a MM Diagnosis, Find Out From Your Doctor...
IgGKappa
M-Protein
What is your response to
therapy?
Treatment
Treatment Overview
Overview of Treatment ApproachMGUS
Close monitoring (observation)
Smoldering MM
Close monitoring (observation)
If high risk: possible myeloma drugs?
Active myeloma
Initial therapy• Myeloma drugs• High-dose chemotherapy/
stem cell transplantation (option, if possible)
Maintenance optionTherapies for relapsed/refractory myeloma
If bone loss: bisphosphonates
Bone loss: bisphosphonates+
other supportive treatments
Clinical trial participation should be considered.
Hideshima T, Anderson KC. Nature Rev Cancer. 2002;2:927.Hideshima T et al. Blood. 2004;104:607.Hideshima T, Anderson KC. Nat Rev Cancer. 2007;7:585.
Currently Available Therapies Targeting Myeloma Cells in the Bone Marrow Microenvironment
Bone marrowstromal cell
VCAM-1, fibronectinICAM-1 LFA-1 MUC-1
VLA-4
IL-6, VEGFIGF-1, SDF-1BAFF, APRIL,
BSF-3
TNFTGFVEGF
NF-�B
NF-B
Adhesion molecules
NF-B
Smad, ERK
JAK/STAT3
MEK/ERK
PI3-K
GSK-3FKHR
Caspase-9NF-BmTOR
Bad
PKC
Bcl-xLMcl-1
MEK/ERKp27Kip1
NF-BBcl-xL
IAPCyclin-D
MM cell
SurvivalAnti-apoptosis
Cell cycle
SurvivalAnti-apoptosis
Cell cycle
Proliferation
SurvivalAnti-apoptosis
Akt
Migration
ProliferationAnti-apoptosis
Cytokines
Raf
FGFR3
Adhesion
CD40
CS1
BAFF-R
VEGFR
,
Cytokines, growth factors
Targeting MM cell
Targeting MM cell and BM micro-
environment
Proteasome inhibitors: Velcade, Kyprolis, Ixazomib
IMiDs:Thalomid, Revlimid,
PomalystHDAC inhibitor:
Farydak, Ricolinostat
CD138
IGF1R
CD38
C56
T
NK
M
Antibodies to cell surface targets:
DaratumumabElotuzumabIsatuximab
1962 1983 1986 1996 2012
Evolution of Multiple Myeloma Treatment: 10 New Drugs Approved in ≤12 Years
1984 2003 2006 2007
VAD, vincristine, doxorubicin, dexamethasone; IMiD, immunomodulatory drug; HDAC, histone deacetylase.
2013
Chemotherapy
Steroid Transplant
IMiD
Bone supportProteasome inhibitor
HDAC inhibitor
2015
Conventional Therapy Novel Therapy
BisphosphonatesMelphalan
and prednisone
VAD
High-dose dexamethasone
High-dose chemotherapy with
autologous stem cell support
Kyprolis
High-dose melphalan
High-dose chemotherapy with autologous bone
marrow transplant
Velcade
Thalomid
Revlimid
Doxil
Pomalyst
Farydak
Ninlaro
2016
Empliciti
Darzalex
Monoclonal Antibody
Novel Therapies and Immunotherapy
Continuing Evolution of Multiple Myeloma Treatment: New Classes and Targets
PLD, peglylated liposomal doxorubicin; IMiD, immunomodulatory drug; HDAC, histone deacetylase; KSP, kinesin spindle protein, SINE, selective inhibitor of nuclear export*Not yet FDA-approved; only available in clinical trials†Treatments studied in MMRC trials‡FDA-approved for a non-MM indication
20122003 2006 2007 2013 2015 2016+
Doxil
Kyprolis
Velcade
Thalomid
Revlimid
Pomalyst
Farydak Isatuximab*†
Atezolizumab* †
Nivolumab‡
Vaccines*
Ninlaro
Darzalex
Empliciti
Pembrolizumab‡
Filanesib*
CAR-T*
Selinexor* †
Oprozomib*
Proteasome inhibitor
IMiD
Chemotherapy
Vaccines
Adoptive T cell therapy Checkpoint inhibitors
HDAC inhibitor Monoclonal Antibody SINE
KSP inhibitor
Selected Novel Drugs Being Explored in Clinic Trials
Third/ Fourth-generation
agents
Proteasome inhibitors
IMIDs
marizomib, oprozomib, ixazomib
CC-220
Novel classes of
Therapy
Monoclonal antibodies anti-CD38, anti–CD-138 conjugate, anti-BCMA conjugate, antiCS1-conjugate
Check Point Inhibitors Durvalumab, Atezolizumab, PembrolizumabNivolumab
BTKi Ibrutinib, AVL-292
HDAC inhibitors panobinostat,* romidepsin, ricolinostatPleiotropic Pathway Modifier CC:122
Kinesin Spindle Inh ARRY
CDK PD0332991, SCH727965, AT7519
BCL antagonist ABT263
HSP90 Ganetespib (STA-9090)
SINE XPO antagonist KPT-330 (Selinexor)
FGFR3 TKI258, MFGR1877S
17p mutated Idasanutlin
Clinical Trials
Advancements in Survival from Multiple Myeloma
Blood (ASH Annual Meeting Abstracts) 2011 118: Abstract 2948; AACR Annual Meeting, April 20, 2016; New Orleans, LA.; Abstract 5231.
• With new biology based medications response rates for newly diagnosed myeloma are now 91 to 98%.
54,963
74,814
2004
2011
People in the United States living with,or in a remission from Multiple Myeloma
19,851More People
Have Survived
• From 2011 to 2022, expect the number of patients living with myeloma to increase by 55%(from 76,000-119,000), due to improvements in prognosis.
2015
95,874
• New myeloma cases among men and women ages 40 to 79 years will increase by 28% (from 16,000-21,000) by 2022.
Summary
Be an informed and empowered patient!
Multiple myeloma can have numerous effects on the body
Genomics is growing and may lead to personalized treatments
Survival improving because of new drugs and new combinations of drugs
Treatment paradigm will continue to change with the approval of additional novel agents
MMRF Resources
MMRF CoMMunity Gatewaywww.mmrfcommunitygateway.org
Multiple Myeloma Disease Overview brochure
Multiple Myeloma Treatment Overview brochure
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