Dr. Alan Teh , 2012

Multiple Myeloma

Sarah Newbury, the first reported patient with multiple myeloma.

A) Bone destruction in the sternum. (B) The patient with fractured femurs and right humerus. (C) Bone destruction involving the femur.

Timeline depicting the history and treatment of multiple myeloma from 1844 to the present.

Kyle R A , Rajkumar S V Blood 2008;111:2962-2972

Myeloma is a blood cancerIncidence : 0.7M/0.5 F per

100,000 population (NCR, 2003)

Median age: 60 years1/10 as common as leukaemias

What Is Multiple Myeloma?

Causes

Is not known for sureDecline in the immune systemBiological factorsCertain occupationsExposure to certain chemicals Exposure to radiationVirus

7

What Is Multiple Myeloma?Cancer of plasma cells.Plasma cells come from B lymphocytes, and

produce antibodies (immunoglobulins). Myeloma cells produce abnormal

immunoglobulins.– Overproduce monoclonal protein or paraprotein.– Ineffective immunoglobulins.– Leads to decreased bone marrow function. – Destruction of bone tissue.

Plasma Cell

Mechanism of diseasePlasma cell proliferation - > anemia, bone

marrow suppression, infection risk

Osteoclasts - > boney lesions, fractures, increased blood calcium

Paraprotein, hypercalcemia -> renal failure

Hypercalcemia – polyuria, thirst, drowsiness, coma

MM: Clinical PresentationsAnemia - 73 percentBone pain - 58 percentElevated creatinine - 48 percentFatigue/generalized weakness - 32 percentHypercalcemia- 28 percentWeight loss - 24 percent, one-half of whom

had lost ≥ 9 kgEarly stage - asymptomatic

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Common Sites for Bone InvolvementSkullSpine

ThoracicLumbarVertebrae

PelvisLong bones Spinal cord –

compression can occur

http://www.emedicine.com/Radio/topic460.htm#section~Introduction

Slowly evolving cancerMGUS

Monoclonal Gammopathy of Unknown Significance

Asymptomatic myeloma

Symptomatic myeloma

Risk of MGUS Myeloma

Risk groupRelative

RiskRisk @ 20

yrs

Lowest risk: 1. M protein < 1.5 g/dL2. IgG subtype3. Normal FLC ratio

1 5%

Any 1 factor abnormal 5.4 21%

Any 2 factors abnormal 10.1 37%

All 3 factors abnormal 20.8 58%

Rajkumar, V et al. Blood . 2005

When I told a friend that I have cancer, he replied "I thought you were an Aries?".

Symptomatic myeloma= CRABhyperCalcaemiaRenal insufficiencyAnaemiaBone lesions

DiagnosisParaprotein (M-protein)

serum protein electrophoresis24 hr urine protein electrophoresisserum Free light chain

Bone marrow biopsyplasma cellschromosome analysis: Karyotyping, FISH

ImagingX Rays, MRI, PET scan

SPEP: Normal

SPEP: M-protein, M-spike

Bone Marrow

Cytogenetics

FISH

Normal Skull Xray

Lytic Bone Lesion

MM: PET Scan

Staging for MMInternational staging system (ISS) 

Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL

Stage II — neither stage I nor stage IIIStage III — B2M ≥5.5 mg/L

Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months

Cytogenenetics, FISHHigh risk (median survival 25 months): Intermediate risk (median survival 42

months)Standard risk (median survival 50 months)

What's the difference between God and a doctorGod doesn't think he’s a doctor

Cancer cures smoking, eventually

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Previous Challenges in MM Treatment • Currently incurable in most patients.• Long-term complete responses are rare. • Median survival with standard therapy

about 3 years.• Autologous stem cell transplant may

prolong progression free survival, but it’s not curative.

• Treatment of relapse:– No standard therapy. – Existing options inadequate.

New treatment options needed.

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MM Treatment OptionsConventional chemotherapy:

Melphalan Doxorubicin Cyclophosphamide

• Radiation therapy

• Stem cell transplantation:

– Autologous– Allogenic

• Novel therapeutics: – Thalidomide – Lenalidomide – Bortezomib

Thalomid® Prescribing Information, Revlimid® Prescribing Information; Velcade® Prescribing Information

• Steroid therapy: – Dexamethasone – Prednisone

MM: Treatment DecisionsIndications for treatmentRisk stratification

- age- co-morbidities

Eligibility for stem cell transplantation

Smoldering (asymptomatic) myelomaDeferral of chemotherapy until progression to

symptomatic diseaseFollow these patients closely, every 3 to 4

months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium

Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop

MM: Indications for TreatmentAnemia (hemoglobin <10 g/dL or 2 g/dL

below normal)Hypercalcemia (serum calcium >11.5 mg/dL)Renal insufficiency (serum creatinine>2

mg/dL)Lytic bone lesions or severe osteopeniaExtramedullary plasmacytoma

Current Frontline Options

Conventional chemotherapySurvival ≤ 3 yrs

TransplantationProlongs survival 4-5 yrs

Novel agents targeting stromal interactions and associated signaling pathways have superiority over conventional chemotherapy- increased % total responders- increased depth of response

Myeloma treatment optionsEra of Novel therapy as frontline >

Conventional chemotherapy

Autologous transplantation (high dose chemotherapy and stem cell rescue) still an option for younger patients

Current Frontline Options

Examples of current Novel agent combinations:

Thalidomide based : TD, CTD, MPT

Bortezomib (Velcade) based: Vdex, VMP, CVD, PAD, VRD

Lenalidomide (Revlimid) based: LenDex, Lendex

Younger patientsTimingUpfront after initial therapy with

novel agentsSalvage for relapseSingle vs Tandem (Double)Low TRM - <3%

Autologous transplantation

Autologous transplant - ineligible Age >70 yearsSignificant comorbities (organ

function)Poor performance status

Allogeneic transplantationGenerally not recommended (outside

of clinical trials)High incidence of GVHDHigh TRM (> 40%)

RadiotherapySurgeryBone care – bisphosphonatesTransfusionsGrowth factors Treatment and prevention of

infections Monitoring, management and

prevention of s/e

Other treatment / Supportive care

Myeloma survival by decade

Assessment of response

Impact of Novel Therapies on Survivorship Care

Unexpected new long-term complicationsSecond cancersLong-term maintenance for survivors:

quality of lifeFamily/social problemsFinancial/insurance concernsOther

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Optimizing Survival: Importance of Health MaintenanceMM patients are expected to live longerProper health maintenance contributes

toward longer survival and quality of life

RelapseBiochemical

- significant increase in M-proteinClinical

- CRAB criteriaImportance of monitoring and

follow-up

Hope New drugs on the horizonCarfilzomibPomalidomidePanobinostatVorinostatElotuzumabOld drugs with new useBendamustine

Be informedhttp://myeloma.orgGroup support

meetingssupport groups

http://malaysianmedicine.com – Myeloma Support Group

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