MULTIPLE MYELOMA

DR F. A. FASOLA
DEPT OF HAEMATOLOGY
COLLEGE OF MEDICINE
UNIVERSITY OF IBADAN
 Definition
• Multiple myeloma is a B-cell neoplasm in
which there is unregulated proliferation
and accumulation within the bone marrow
of a single clone of plasma cells with the
production of homogenous monoclonal
protein
 Other plasma cell dyscrasias
• Malignant plasma cell disorder
• Waldenstroms macroglobulinaemia (WM)
• Solitary plasmacytoma (SP)
• Extramedullary plasmacytoma (EMP)
• Plasma cell leaukaemia (PCL)
• Heavy chain disease (HCD)
• Benign plasma cell dyscrasias
• Monoclonal gammopathy of undetermined
significance (MGUS)
 MULTIPLE MYELOMA-Epidemiology
• MM accounts for 1.3% of all malignancies
and 10% of hematologic cancers
• 2.9% of all malignancies in blacks and
1.0% in whites,
• annual incidence per 100,000 population,
among white men and women, is 7.1 and
4.2, respectively, and among black men
and women, 14.4 and 10.2, respectively
• 2nd most common blood cancer after
lymphoma
• Median age at diagnosis: 60-65 yrs
• Rarely occurs before 40yrs
• M>F ratio 1.6:1
 Aetiology / Risk factor
• Old age
• - radiation doses
• Agric industry, exposure to grain dust, aflatoxins,
pestcides
• factory works- various chemicals e.g benzene
• FHX of autoimmune disease ,
• Xsome 14 abnormalty
• Infections (HIV, Herpes)
 Multiple Myeloma – sub-types
• • Subtypes of MM are determined based on
the kind of abnormal protein secreted
• IgG – 50-60%
• IgA – 20- 25%
• IgD – 1-2%
• IgM – 1%
• IgE - 0.5%
• Light Chain Disease only 15– 20%
• Non Secretors 1-2 %
• Combined <1%
 Pathogenesis
• Disseminated proliferation & accumulation of clonal plasma
cells ,replacing haem tissue leading to anaemia± leucopenia
• production of an abnormal immunoglobulin (immunoglobulin G
[IgG], IgM, or IgA, or, rarely, IgE or IgD) or light chain protein (kappa
or lambda): homogenous protein accumulating in
blood→hyperviscosity and excretion of light chains in urine (renal
failure), paresis of normal Ig production (recurrent infection)
• Bone destruction - predominant areas of involvement occurring in
sites of red marrow, such as the vertebral bodies and ribs.
• Tumour cells and cytokine e.g IL-6, 1L-1, TNF-β, release of calcium
from bone ‫ﺠ‬soft and fragile bone manifest with bone pain and
pathological #
• bone lesions in patients with myeloma rarely heal
• . Plasma cells are rarely seen in PBF
 pathogenesis
• typical development of the disease progress from
monoclonal gammopathy of undetermined significance,
through smoldering (asymptomatic) myeloma, to
symptomatic MM
• Clinically, symptomatic MM is characterized by end-
organ damage, generally involving hypercalcemia, renal
failure, anemia and bone lesions (CRAB features)
• Several recurrent cytogenetic abnormalities are seen
throughout the course of the disease, from the
premalignant stage of monoclonal gammopathy of
undetermined significance (MGUS) to smoldering
multiple myeloma (SMM) to end-stage MM
 Pathogenesis contd
• bone marrow microenvironment in myeloma includes osteoblasts,
osteoclasts, endothelial cells, immune cells and MM cells that
contribute to tumor growth and the bone destructive process

• Interaction leads to paracrine secretion –IL-6,IL-1,IL-11,TNF-

1a,TGFb, receptor activator of NF-kB ligand (RANKL),by BMSC

• Myeloma cells also stimulate cells in the marrow microenvironment,

particularly marrow stromal cells and T cells,
• IL-6 activate NF-Kb for myeloma cell growth and survival against
Dex- induced apoptosis

• Immune cells contribute to the bone destructive process through

production of cytokines and adhesion molecules that increase
myeloma cell growth and enhance myeloma cell chemoresistance,
increase osteoclastogenesis, suppress osteoblastogenesis,

• Angiogenesis (VEGF)-correlates with disease activity & survival

• Inhibition of T-cell function
 Presentation
• In asymptomatic patients - identified
through laboratory abnormalities such as
hypercalcemia, anemia, or proteinuria
symptomatic patients:
 Clinical features
• BHRICHAB symptomatic patients
• Bone disease: Bone pain 60% ,back ache, pathological
fracture and paraplegia (cord compression)
• Hypercalcaemia-25% nausea, vomiting, malaise,
weakness,
• Renal failure-25%. Precipitating factors include-
Dehydration, hypercalcaemia, BJP,
hyperuricaemia,sepsis, hyperviscosity, nephrotoxic
antibiotics or cytotoxic antibiotics of the kidneys
• Hyperviscosity syndrome
• IgM, IgA, cold agglutinin
• visual impairment→total loss of vision, retinal hemorrhage
• Fatigue, headache, fluctuating level of consciousness,
dizzy spell, transient ischemic attack, dyspnea
 Clinical features
• Coagulopathy-bleeding tendency
• Immune paresis- bacterial pneumonia,
pyelonephritis, recurrent infection
• BMF-anaemia is present in nearly all
patients at some point,
• Amyloidosis- CCF, macroglossia
 Investigations
• FBC-Hb↓ ,normocytic normochromic
anaemia,rouleaux,leucoerythroblastic feature
• ESR- 100mm/hr-1
• Electrolyte-↓ Anion gap; Urea ↑ ,Creatinine↑
• Calcium ↑, Uric acid ↑,PO4 normal, LDH ↑
• Protein- LFT-total serum protein ↑
• ↑Ig in 80%
• ↓Ig in 15-20% seen in those with light chain MM
only and non secretory MM
• ↓ Albumin
• Βeta 2 micrglobulin, LDH, CRP
 Investigations
• MM patients should be tested for the presence of M
proteins using a combination of tests that should include
a serum protein electrophoresis (SPEP), serum
immunofixation (SIFE), and the serum FLC assay
• A)Serum/Urine protein electrophoresis (SPE/UPE)-
M-protein in serum and urine- 80% while only in urine
not in serum-20% (UPE)
• Absent M protein in serum and urine occurs in non
secretory MM
• B) Immunofixation (serum/urine)- Identify specific Ig
class
• C) Radial immunodifusion or Nephelemetery-
quantitate the Ig level
• D) Free light chain assay FLC - useful in patients
• who lack a measurable M protein, provided the FLC ratio
is abnormal
 Investigations
• Bone marrow aspiration /biopsy –atypical plasma cell
infilteration , the only way to dx non-secretory myeloma,
plasmablast, (centrally placed nucleus abundant
cytoplasm)russell bodies,multinucleated,
• BM fluorescent in situ hybridization (FISH) probes
designed to detect cytogenetic abnormalities for (risk-
stratification)
• Trisomies, t(11;14), t(6;14) good,
• t(4;14), t(14;16), t(14;20), and del(17p) high risk
• Flowcytometer:
• Myeloma cells –high CD38, CD138;CD19 NEG, &56
pos(CD19-DC56+)
• Normal plasma cells-CD19pos/CD56 neg(CD19+CD56-)
 Investigations
• The extent of bone disease is best assessed by skeletal
survey, low-dose WB-CT or PET/CT imaging
• Radiological (x-ray-skeletal survey)-lytic lesion e.g
punched out lesion on skull ,pathological #, wedge
vertebrae collapse, generalized osteopororosis
• osteoblast (OBL) activity is severely decreased or absent
so no new bone formation unlike other disease with bone
metastasis
• no MM related x-ray change in 20 % of cases
• MRI not routine but may be used in some patients to early
detection of bone lesion to rule out focal bone marrow
lesions that can be seen before true osteolytic disease
occurs.
• low-dose whole body computed tomography (WB-CT), fluoro-
deoxyglucose (FDG) positron emission tomography/computed
tomographic scans (PET/CT), or magnetic resonance imaging (MRI).
 Bence jones protein
• monoclonal light chains in the urine
• positive in approximately half of all patients with myeloma
• In1845. Dr. Henry Bence Jones tested this urine and found a
substance in it that was precipitated by the addition of nitric acid.
• Term first used in 1880
• Its peculiar characteristics on heating: precipitation of the urine at 40
to 60 degrees C and re-dissolving of the precipitate at 100 degrees
C
• BJP is undetectable by dipsticks used to detect proteinuria since
they detect albumin and not BJP
• clean catch early morning urine sample is needed to screen for
Bence Jones proteins by urine protein electrophoresis and
immunofixation electrophoresis. A 24-hour urine catch is desirable
to accurately quantify the amount of BJP excreted
Mott cell with Russell bodies
 Old Diagnostic criteria
• Major criteria
• Plasmacytoma on tissue biopsy
• Bm plasmacytosis with >30% PC
• M-Protein spike on SEP or UEP
• IgG >3.5g/dl
• IgA>2g/dl
• BJP on concentrated urine electrophoresis
(>Ig/24hrs of ƙ or λ light chains)
 Minor criteria

• A .BM plasmacytosis 10-30 %

• B .M-protein spike
Ig G -<3.5g/dl
IgA -<2g/dl
BJP <1g/24 hrs
• C .lytic bone lesion
• D .low Ig level; Normal IgM<0.5g/L, IgA < 1g/L or
IgG < 6g/L
• Dx-1 major + 1minor criteria or 3 minor criteria
which must include a+b
• The updated criteria represent a paradigm
shift since they allow early diagnosis and
initiation of therapy before end-organ
damage.
 Diagnostic Criteria for Multiple Myeloma
• Both criteria must be met
• Clonal bone marrow plasma cells ≥10% or biopsy-proven
bony or extramedullary plasmacytoma
• Any one or more of the following MDE:MM defining event
• Evidence of end organ damage that can be attributed to
the underlying plasma cell proliferative disorder,
specifically:
• Presence of 1 or more of CRAB symptoms:
C: Calcium elevation > 11.0 mg/dL
R: Renal dysfunction (serum creatinine > 2 mg/dL)
A: Anaemia (Hb < 10 g/dL or 2 g/dL < normal)
B: Bone disease (lytic lesions or osteoporosis) one or more
osteolytic lesions on skeletal radiography, computed
tomography (CT), or positron emission tomography-CT (PET-
CT)
• Clonal bone marrow plasma cell percentage ≥ 60%
• Involved: uninvolved serum free light chain (FLC) ratio ≥100
(involved FLC level must be ≥100 mg/L)
• >1 focal lesions on magnetic resonance imaging (MRI) studies
(at least 5 mm in size) 27
 Therapy
• Inform patient and counsel patient
• Supportive
• Cytoreduction –definitive treatment
• Supportive
• Anaemia –RBC transfusion, EPO
• Leucopenia-G-CSF or GM-CSF
• Hypercalcemia-
• Pain –local irradiation or analgesics
• Osteoporosis-Biphosphonates
• Renal failure-dialysis
• Paraparesis-orthopaedic/neuro surgeon
• Hyperviscosity syndrome-plasmapheresis
 Cytoreduction
• Aim is not curative but to improve quality of life, delay
disease progression, rapid and durable disease control
with reversal of complications
• Melphalan +- prednisolone
• VAD-vincristine ,Adriamycin .dexamethasone
• Pulse dexamethasone
• Thalidomide, Lenalidomide, Pomalidomide -
TNFinhibition,T-cell- costimulatory, anti-angiogenic
• Bortezomib, Carfilzomib, Ixazomib (proteasome inhibition)
• Autologous or allogeneic SCT
• Daratumumab (anti-CD38)
• Elotuzumab
 Treatment plan
• treatment of symptomatic newly diagnosed multiple
myeloma is dictated by eligibility for ASCT and risk-
stratification
• to initiate therapy, patients must meet criteria for multiple
myeloma
• Risk stratification: Standard and high risk
• The presence of del(17p), t(4;14), t(14;16), t(14;20), gain
1q, or p53 mutation is considered high-risk multiple
myeloma
 Treatment plan
• 1. In younger, fit patients - Remission induction with three
drug-based induction treatment (bortezomib-based regimen)
given for approximately 3-4 cycles followed by autologous stem
cell transplantation (ASCT)
• Then Maintenance
• 2. Not eligible for transplant cos of age, disability,
comorbidity- Remission induction for approximately 8-12 cycles
followed by lenalidomide for maintainance therapy
• Bortezomib, lenalidomide, dexamethasone (VRd) is the
current standard of care for newly diagnosed multiple myeloma
• bortezomib-thalidomide-dexamethasone (VTd) or bortezomib-
cyclophosphamide-dexamethasone (VCd) can be used instead
of VRd
• Rx with lenalidomide/thalidomide require anti-thrombosis
prophylaxis
• In high-risk patients- daratumumab (anti- CD38) may be added
 prognosis
• Survival for myeloma is strongly related to stage
of the disease at diagnosis
• β2-microglobulin, albumin
• The International Staging System (ISS) is a
simple prognostic algorithm based on two
parameters;
• 1.high serum β2-microglobulin level reflects high
tumor mass and reduced renal function,
• 2. low serum albumin in MM is mainly caused
by inflammatory cytokines such as interleukin-6
secreted by the myeloma microenvironment
International Staging System (ISS).
• Staging Parameters MS(months)
stage 1 ß2-m <3.5mg/dl 62
ALB ≥35mg/dl
stage 2 β2-m <3.5mg/dl 44
ALB <35mg/dl
OR
β2-m 3.5-5.5mg/dl
stage 3 β2-m >5.5mg/dl 29
 Revised international staging system
for myeloma
• Stage 1
• All of the following:
• Serum albumin ≥3.5 g/dL
• Serum beta-2-microglobulin <3.5 mg/L
• No high risk cytogenetics
• Normal serum lactate dehydrogenase level
• Stage II
• Not fitting Stage I or III
• Stage III
• Both of the following:
• Serum beta-2-microglobulin >5.5 mg/L
• High risk cytogenetics [t(4;14), t(14;16), or del(17p)] or elevated
serum lactate dehydrogenase level
• Revised International Staging System
(RISS) combines elements of tumor
burden (ISS) and disease biology
(presence of high risk cytogenetic
abnormalities or elevated lactate
dehydrogenase level), to create a unified
prognostic index that and helps in clinical
care as well as in comparison of clinical
trial data
Punched out lesions in the skull
 survival
• Overall survival is affected by tumor burden (stage), biology
(cytogenetic abnormalities), and response to therapy.
• Tumor burden is assessed using the Durie Salmon Staging (DSS)
and the International Staging System (ISS)
• Disease biology is reflected by cytogenetic abnormalities
• improvement in the 5-year relative survival rate for patients with
multiple myeloma, from 29% in 1990 to 45% in 2009
• Modern therapy: the median survival in multiple myeloma is
approximately 6 -7years
• In the subset of patients eligible for ASCT, 4-year survival rates are
more than 80% ; the median overall survival (OS) - 8 years
• Among elderly patients (age >75 years), median OS is lower,
approximately 5 years.
• Autologous SCT-< 70yrs CR-30%
• Allogeneic BMT – 60% CR, but high transplant related mortality,
GVHD
 Case
• Mrs A.R.O, 65 year old retiree referred from an outside
clinic. She presented to UCH with 1-month history of
worsening back pain associated with weakness,
dizziness, dyspnea on exertion and palpitations,
• Positive findings on examination revealed moderate palor
• Investigations on examination showed the following:
• Full blood count – PCV-16%, WBC-8410, PLT – 294,000
• ESR – 140mm/hr
• SEUCR – Urea – 64 (15-45)mg/dl, Creatinine – 3.5 (0.5-
1.5)mg/dl
• Serum calcium – 13.2mg/dl (8.5-10), phospahe – 4.0
(2.5-4.5), uric acid – 13.7mg/dl (2.0-7.0)
• QUESTION????????????