Multiple Myeloma PPT.pdf full understanding

Myeloma full understanding of concepts

1. Multiple Myeloma
Dr. James Nyamataga, MD
Tutorial Assistant and Myeloma Research Fellow
Department of Haematology, MUHAS
1

2. OUTLINE
•Introduction to MM
•Pathogenesis
•Clinical Features
•Diagnosis
•Treatments overview
•Summary
3/5/2025 2

3. INTRODUCTION
•Neoplastic proliferation of clonal plasma cells
•Increased production of monoclonal proteins
•Causing end organ damage/complications
❖bone lesions>>lytic
❖high calcium levels in the blood
❖Anaemia
❖Renal damage and
❖immunosuppression
3

4. Multiple Myeloma - Epidemiology
•Common Plasma cell dyscrasias
•2% of all cancers and 2% cancer related mortalities
•The second most common blood cancer
•Number 1 blood cancer in Black Americans
•Males are more affected
•Median age of onset is 65 years

5. HEMATOLOGICAL MALIGANCIES
5
AML
MDS
Lymphomas or Myeloma
Chronic leukemias/MPN
ALL

6. •Primaryroleinhumoralimmunity
•Produceasingleidiotype-specific
immunoglobulin
•Normallyfoundinlownumbers(3-5%)in
thebonemarrowandinreticulo-
endothelialtissues,notcirculatingin blood
•Appearance–
–Ovalshape,deeplybasophiliccytoplasm,witha
perinuclearhalo
–Thenucleusiseccentricwithcoarsechromatin
condensation(so-calledclockfacepattern)
WhatIsAPlasmaCell?

7. PLASMA CELL STRUCTURE
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8. Plasma cell development
3/5/2025 https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.01821/full 8

9. NormalPlasmaCellDevelopment
KuehlandBersagelNatRevCancer2004;2:175.

10. ClonalEvolution:MGUStoMMtoPCL

11. EpidemiologyofMultipleMyeloma
•~35,730newcasesand12,590deathsfromMMareexpectedinthe
UnitedStatesin2023
•Slightlymorecommoninmenthaninwomen
•1.8%ofallnewcancercasesinUS
•Medianageatdiagnosisis69yrs
AmericanCancerSociety.Cancerfactsandfigures2023.AccessedAugust24, 2023

12. MM- PRIMARY EVENTS
.
12
IGH gene
Translocation
• t(4:14)
•t(6:14)
•t(11:14)
•t(14:16)
•t(14:20)
Hyperdiploidy •Trisomies of Odd chromosome numbers

13. MM- SECONDARY EVENTS
.
13
•NRAS, KRAS, BRAF
MAPK
•CYLD, TRAF3
NFkB
•TP53, ATM, ATR
DNA repair
•IRF4, EGR1
Plasma differentiation
•DIS3, FAM463
RNA metabolism

14. MM- Clinical Features
C R A B
Increase in
blood Calcium
Renal damageAnaemia Bone damage
PathogenesisRelease of
Ca2+ from
damaged bone
into blood
stream
-Abnormal M-
protein
-High blood
Ca2+
-Infections
-NSAIDs
-Decrease
erythropoiesis
-osteoclast
activation
-Block
Osteoblast
Symptoms and
signs
-Fatique
-Mental
confusion
-Dehydration
-constipation
-Weakness
-Renal damage
-Fatique -Fatique Bone pain
-Fracture
-nerve
compression

15. Diagnostic Evaluation
•Blood
-CBC with differential
-SPEP and Immunofixation
- Beta 2-macroglobulin, LDH, Albumin, BUN, Creatine
-Quantitative immunoglobins
-Serum-free light chain assay
•Urine: 24-hr UPEP and Immunofixation
•Imaging: CT scan, PET scan, X-rays, MRI
•BMA+Trephine: cytology, cytogenetics, FISH, gene profiling.
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16. Diagnostic Criteria
Criteria 1 Criteria 2
Bone marrow monoclonal plasmacytosis ≥
10%
OR
Biopsy-proven bony/extramedullary
plasmacytoma
-Presence of CRAB
-Bone marrow monoclonal
plasmacytosis ≥ 60%
-FLC ≥ 100
-At least one or more focal lesion
on MRI
-One or more osteolytic lesions on
skeletal radiography, CT , or PET-
CT
CRITERIA 1
ANY
ONE OF
CRITERI
A 2
MM

17. UpdatedIMWGCriteriaforDiagnosis
*S:60%clonalBMplasmacells
Li:seruminvolvedfreelightchainratio>
100
M:MRIskeleton>1focallesion(>5mm
size)
C:Calciumelevation(>11mg/dLor>1mg/dL
higherthanULN)
R:Renalinsufficiency(creatinineclearance< 40
mL/minorserumcreatinine>2mg/dL)
A:Anemia(Hb<10g/dLor2g/dL<normal)B:
Bonedisease(≥1lyticlesionsonskeletal
radiography,CT,orPET-CT)
MGUS
▪Mprotein<3g/Dl
▪Clonalplasmacells
inBM< 10%
▪NoSLiM-CRAB
SmolderingMyeloma
▪Mprotein:≥3g/dL
(serum)or
≥500mg/24hrs(urine)
▪ClonalplasmacellsinBM≥
10%to60%
▪NoSLiM-CRAB
MultipleMyeloma
▪Underlyingplasmacell
proliferative disorder
AND >1SLiM-CRAB
feature

18. R-ISS for risk stratification of MM at diagnosis
Stage Criteria
R-ISS I1. ISS Stage I (β2M < 3.5 mg/L and serum albumin ≥ 3.5 g/dL)
2. Standard-risk chromosomal abnormalities t(6:14), t(11:14)
3. Normal LDH levels
R-ISS II1. Neither R-ISS I nor R-ISS III
R-ISS III1. ISS Stage III (β2M ≥ 5.5 mg/L)
2. High-risk chromosomal abnormalities t(4;14), t(14;16), or
del(17p)]
3. Elevated LDH levels
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19. Treatment Goals
Stabilizing Palliative Remission-
Inducing
Curative
Intent Addressing life
threatening/eme
rgency events
Relieving
discomfort
-Slowing or
arresting the
course myeloma
-Permanent
remission
Examples plasmapheresis
-Hemodialysis
-Reduce
hypercalcemia
-Infection
control
-Radiotherapy
-Blood products
transfusion
-Orthopaedic
procedures
-Myeloma
induction drugs
-High dose
chemotherapy
and Stem cell
transplant
Time to decideHrs to Days Days Weeks to
Months
Weeks to
Months

20. Approved drugs used in Multiple Myeloma
IMiDs PI Glucocortic
oids
Anti CD38
moabs
BisAbs CAR-T cellsADC
Thalidomide
Lenalidomid
e
Pomalidomid
e
Bortezom
ib
Carfilzomi
b
Ixazomib
Dexametha
sone
Daratumu
mab
Isatuximab
Teclistamab
Elranatama
b
Talquetama
b
Idecabtagen
e vicleucel
Ciltabtagene
autoleucel
Bleranta
mab
mafadoti
n

21. Plasma/Myeloma cell surface antigen
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22. Supportive care
•Bone protection: Bisphosphonates, kyphoplasty,
•Antipain: opioids
•VTE prophylaxis
•Neuropathy
•Proton pump inhibitors
•Transfusion
•Infection prophylaxis
•Psychological therapy
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23. Treatment pathyway of MM
INDUCTION THERAPY
-Combination therapy e,g VRd, Dara-VRd
CONSOLIDATION THERAPY
-High dose Melphalan and Autologous Stem Cell Transplant
MAINTENANCE THERAPY
-Lenalidomide
-Bortezomib+Lenalidomide

24. Diagnosis
and
Risk
Stratification
Fit
Unfit/Frail
or
Decline
SCT
InductionConsolidation
Managing
Relapse
Inductionfollowedbycontinuoustherapy
Maintenance
TumorBurden
MRD
MultipleMyelomaTreatmentParadigm
Costello.HematologyAmSocHematolEducProgram,2022

25. TreatmentBackbonesforMultipleMyeloma
Initial therapy
NCCNGuidelines
®.Multiplemyelomaversion2.2021.
Treatmentregimensfor
newlydiagnosedandRR
MMgenerallyconsistsof:
≥2treatmentbackbones
+
Corticosteroid
Proteasome Inhibitors
•Bortezomib
•Carfilzomib
•Ixazomib
Immunomodulatory
Agents
•Thalidomide
•Lenalidomide
•Pomalidomide
Monoclonal
Antibodies
•Daratumumab
•Elotuzumab
•Isatuximab

26. Tests for monitoring Therapy Response
Blood tests Urine testsBone
evaluation
Bone Marrow
-CBC
-M component
-Immunofixation
-Serum free light chains assays
-Creatinine
-BUN
-B2 microglubulin
-PBS
-LFTs
-UPEP
-24-hr urine for
total protein
-Creatinine,
-skeletal survey
-MRI/CT scan
-Whole body
FDG/PET scan
-Bone density
e,g DEXA scan
-BMA and
Trephine
-special tests
molecular
studies

27. Rouleaux formation
Plasma cells

28. SerumProteinElectrophoresisandImmunofixation
Normal
Abnormal

29. MyelomaBoneDisease
MRI

30. •Age
–Justanumber?
–Olderpatients
more sensitive
totoxicity;less
physicalreserve
•Performance
status
•Comorbidities
–Cardiovasculardisease
–Pulmonarydisease
–Hepaticdisease(eg,
chronichepatitisor
cirrhosis)
–Renaldisease?
FactorsAffectingTransplantationEligibility

31. FactorsAffectingTreatmentSelection
Patient-Related
•Age/frailty
•Performancestatus
•Lifestyle/ptpreferences
•Drugmetabolism
•Compliance/adherence
•Caregiversupport
•Renalinsufficiency
•Comorbidities
Disease-Related
•ISS/LDH
•Rateofrise
•Marrowburden
•CRABsymptoms
(hypercalcemia,renal
failure,anemia,bone
disease)
•Extramedullary
•Molecularcytogenetics/
genomics
Treatment-Related
•Responseto
priortherapy
(depth/duration)
•Timetorelapse
•Routeofadministration
•Singleagentvs
combination
•Adverseevents/toxicity
•Clinicaltrial availability
•Costsandcopays
•Accesstostandard
ofcaretherapies

32. MeasuringResponsetoTherapy-IMWG
ResponseType MProtein
PlasmaCellsinBone
Marrow/ Other
Stringentcompleteresponse
(sCR)
None(blood/urine)
No abnormalplasma
cells
Nofreelightchains
Completeresponse(CR) None(blood/urine)Lessthan5%
Disappearanceofsofttissue
plasmacytomas*
Verygoodpartialresponse
(VGPR)
Greaterthan90%reduction
(blood)
NA NA
Partialresponse(PR)
Greaterthan50%reduction
inblood
+
Greaterthan90%reduction
inurine
NA
Greater50%reductioninthe
sizeofsofttissue
plasmacytomas
Minimalresponse(MR):
25%-49%reductionin
bloodandreductionof
50%-89%inurine
NA
25%-49%reductioninthesize of
softtissueplasmacytomas andno
increaseinsize/number ofbone
lesions
Stabledisease(SD) Doesnotmeetcriteriaforresponseorprogressivedisease
Progressivedisease(PD)
Greaterthan25%increase
(bloodorurine)
Greaterthan10%
Otherchanges:bonelesions, soft
tissueplasmacytomas,high
calciumlevels

33. Response criteria by IMWG
Responding MM
-Minimal response
-Partial Response
-Very good partial response
-Complete response
-Stringent complete response
-MRD negativity
Non-responding MM
-Stable disease
-Progressive disease
-Relapse
-Refractory

34. Tanzania Experience
•At least 100 new cases of MM are diagnosed annually (GLOBOCAN
2020)
•Median age at diagnosis less than 65 years
•Diagnosis: SPEP, UPEP, BMA+ trephine, Skeletal survey
•RX:
Bortezomib/Thalidomide/Dexamethasone/Lenalidomide/Melphalan
•HD melphalan+ASCT done to 14 pts since 2021, in three phases, last
phase may 2024 five patients.
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35. SAMMARY
•MM is a common hematological malignancy in Tanzania
•Diagnostic, prognostications, and treatments are the main challenges
of MM in Tanzania
•Molecular Characterization of Multiple Myeloma in Tanzania has the
potential to determine the molecular and immune microenvironment
pattern in Tanzania myeloma patients
•Ultimately improve treatment outcomes of MM in Tanzania
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36. References
•Hoffbrand’s Essential Haematology 7
th
edition

37. Thank you for Listening
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