Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida

Multiple MyelomaMonitoring and Therapy

Angela Dispenzieri, M.D.IMF Patient Workshop November 4, 2014

Mayo Clinic College of MedicineMayo Clinic Comprehensive Cancer Center

Multiple MyelomaStaging 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

TUMOR BIOLOGY: DISEASE AGGRESSIVENESSMyeloma Risk-Stratification

Del 17p

t(14;16) (C-MAF)

t(14;20) (MAF-B)

High risk GEP

All other FISH including:

Trisomies

t(11;14) (CCND1)

t(6;14) (CCND3)

t(4;14) (FGFR3/ MMSET)

High-RiskIntermediate-RiskStandard-Risk

msmart.org

*Presence of trisomies ameliorates high risk

What do we mean by ‘prognostic’ factors?

• Different patients’ myeloma acts almost like different diseases!

• Markers to help differentiate those patients with the ‘gentlest’ myeloma from those with the ‘meanest’ myeloma

Myeloma Risk-Stratification

Del 17p t(14;16) t(14;20)

GEP defined high-risk

Trisomies

t(11;14)

t(6;14)

t(4;14)

High-Risk*Intermediate-Risk*Standard-Risk

msmart.org*Presence of trisomies ameliorates high risk

CR appears criticalBortezomib CriticalExcellent Outcome

Treating Multiple Myeloma

The good news….

The bad news….

….there are many treatment options

….there are many treatment options

Only Clinical Trials Will Provide Answers.

Different Drugs Available Now

Cortico-steroids

Alkylators IMiDs Proteasome inhibitors

Other

Prednisone Melphalan ThalidomideBortezomib

(Velcade)Doxo-rubicin

Dexame-thasone

Cyclophos-phamide

Lenaldiomide(Revlimid)

Carfilzomib(Kyprolis)

Benda-mustine

PrednisolonePomalidomide

(Pomalyst)Etoposide

Cisplatin

Mix and match to make recipes against myeloma

Different Drugs Available Now + New Drugs Likely Coming Soon

Cortico-steroids

Alkylators IMiDs Proteasome inhibitors

Other

Prednisone Melphalan Thalidomide BortezomibDoxo-rubicin

Dexame-thasone

Cyclophos-phamide

Lenaldiomide CarfilzomibCisplatin

PrednisoloneBenda-mustine

Pomalidomide Ixazomib Etoposide

Oprozomib

• Monoclonal Antibodies: Elotuzumab, Daratumumab, SAR 650984• Kinase Inhibitors: Afuresertib, Dinaciclib• Kinesin Spindle Protein Inhibitor: ARYY520• Histone deacetylase inhibitors: pabinostat, vorinostat

Monitoring Disease

1. Symptoms

2. Blood

3. Urine

4. Radiographic images

5. Bone marrow

Complications of Myeloma

COMPLICATION

• Painful bone lesions

• Kidney failure

• High calcium

TREATMENT

• Pain medications, physical therapy, rarely surgery and radiation

• Fluids, ± plasmapheresis, ± dialysis

• Zolendronic acid, fluids

Managing Complications of Therapy

Cortico-steroids Alkylators IMiDs Proteasome inhibitors

Prednisone Melphalan Thalidomide Bortezomib

Dexame-thasone Cyclophos-phamide

Lenaldiomide Carfilzomib

Prednisolone Pomalidomide

Insomnia, mood Low blood Constipation Neuropathy

Hunger, diabetes Fatigue Diarrhea Fatigue

Infection Rash Low platelets

Blood clots Infection

Prevention is the best therapy. ll your doctor if side-effects

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

AntibodiesImmunoglobulins

Plasma cells

Bone marrow

Fight infection

a.k.a. M-component

M-proteinM-spike

Myeloma proteinImmunoglobulin

Ig

HarmfulUse

Myeloma: Poison kidneys

Eat away at bonesCrowd bone marrow

causing anemia

Myeloma cells

Blood stream

Antibody Proteins

• Two light chains• Kappa or• Lambda

• 5 heavy chains• IgA or• IgG or• IgD or• IgM and IgE

Heavy chains

Light chains

Abnormal Serum Protein Electrophoresis

35 14 g/L 21 21 g/L

Normal M-spike

Serum Immunofixation (IFE)

Myeloma protein

Myeloma cells

Bone marrow

No protein secreted

Non-secretory

Oligosecretory

Little protein secreted

Bence JonesOr light chain

myeloma

Light chain secreted (no heavy chain)

Mostmyeloma cases

Bone marrow Blood stream

Urine protein electrophoresis

Total urine protein = 2.8 g/24 hours

Urine

Antibody Proteins

Heavy chains

Light chainsFREE

Light chains

Intact Immunoglobulin

Free Light Chains

exposed surface

hidden surface

Previouslyhidden

surfaces

Antisera recognize epitopes of FLC’s, but do not detect light chains associated with intact immunoglobulin

0.1

1

10

100

1000

10000

100000

0.1 1 10 100 1000 10000 100000

Serum FLC Kappa (mg/L)

Se

rum

FL

C L

am

bd

a (

mg

/L)

What is the immunoglobulin free light chain ratio? Normal

range for ratio

normalrange for k & l

Clonal k

Clonal l

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

PR VGPR CR sCR

BloodM-protein

50% reduction

90% reduction

Complete disappearance

Complete disappearance

Urine M-protein

90% reduction

< 100 mg/24 hours

Complete disappearance

Complete disappearance

Serum immunoglo-bulin FLC

Us if no other

measureNA NA Normal ratio

Bone marrow plasma cells

NA NA < 5%Complete

disappearance

Mr. W.: Going Strong 13 years after diagnosis

00.5

11.5

22.5

33.5

4

2/7/

2001

6/7/

2001

10/7

/200

1

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2002

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2

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1

Date

M-s

pike

Thal-dex

ASCT

Vel-dex

ASCT

Suni-tinib

Pom-dex

CTX-pred

Obs Obs

Dendrvaccine

Obs

Diagnosed in February 2001DSS 3A; ISS 2; Normal FISH and Cytogenetics Best response was VGPR after second ASCT

Relapsed myeloma

27

MLN9708

Imaging in Myeloma

• Simple bone radiographs

• CT bone

• PET-CT

• MRI

T1 T1 +gad

C

D

What are goals of therapy?

Need to weigh

Survival

Quality of Life

ResponseSide-effects

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