MANAGEMENT OF MULTIPLE
MYELOMA
Dr Saqib Ahmad Shah PG
DEPARTMENT OF RADIATION ONCOLOGY
SKIMS
MODERATOR:- DR NAZIRAHMAD KHAN
ADDT PROF SKIMS

PLASMA
CELL
DISORDER
BENING LIKE
MGUS,CASTLE
MANS
DISESASE,ALPHA
CHAIN DISEASE
MULTIPLE
MYELOMA
AND ITS
VARIANTS
PLASMOCYTOMA
MEDULLARY AND
EXTRA MEDULLARY
AGGRESSIVE
PLASMA CELL
LEVKEMIA
INDOLENT eg
waldernstorm
macroglobinemia
1.Plasma cell
proliferation.
2.Monoclonal
protein
secretion
3.immunodeffic
iency(paraprote
nemia)

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 destrucion involving femur(reported by Dr
William Macintyre in london 1845).Autopsy by dr John Dalrymple.)
IN 1873 Rutizksy coined the term multiple myeloma.

Epidemology
The American Cancer Society has estimated 26,850 new cancer cases of
MM in the United States in 2014, with an estimated 11,240 deaths
representing 1% of all malignancies in whites and 2% in Afarican
americans.
Among hematological malignancies it constitutes 10% (2nd in number) in
USA
The mean age of affected individuals is 62 years for men (75% >70 years of age)
and 61 years for women (79% >70 years of age).
The 5-year survival rate reported in the SEER database has increased from
25% in 1975 to 34% in 2003 due to newer and more effective treatment
options available.( survilance epidemology and end results programme).
MALES more common than females(1.6:1)
India..0.5 % of all malignancies.
KASHMIR:-76/3940(0.02%) in 2014.

ETIOLOGY
• Radiation
• Occupational (Ni,agricultural chemicals,benzene,petroleum,silicon )
• Mineral oil used as laxative
• Heriditary and genetic.
• HLA-cw2 over expression
• Race (2:1)
• Repeated infections(however no evident cause
associated).
• MGUS(premalignant condition).

B cell differentiation

Pathophysiology
Indolent phase
(MGUS , smoldering myeloma, myeloma IA )
1-3 yr or longer
Overt phase
Increase in M pr
Appearance of end organ damage
6 m0- 1 yr
Plateau phase
Aggressive terminal phase
Dependent on BM
stroma
Treat effectively
Temporarily can be controlled by
chemo
Responses short lived, survival
poor

Multiple Myeloma - Cytogenetics
Deletion 17p and Abnormalities associated with
chromosome 13 carry a particularly unfavorable
prognosis & respond poorly to therapy

radiation exposure
Chr. Osteomyelitis, HHV8

Bone marrow micro environment

Clinical features
Expansion of
neoplastic cells
Secretory
proteins
Host
response

Multiple myeloma
Marrow
infiltration
Release of cytokines
Bone destruction Bone pain
Hypercalcemia
IL-6
Il 1 β
Anemia
Monoclonal protein Immune deficiency
Renal failure hyperviscosity Amylodosis Infection
Neurological
symptoms
coagulopathy
EMD

Serum Protein
Electrophoresis
Serum Protein Electrophoresis :
• Serum is placed on special paper
treated with agarose gel and exposed
to an electric current. This separates
the serum protein components into
five classifications by size and electrical
charge : serum albumin, alpha-1
globulins, alpha-2 globulins, beta
globulins, and gamma globulins.
• Immunoglobulins ( IgG, IgM, IgA)
usually migrate to gamma region but
may sometimes extend to beta region.
• SPEP should always be performed in
combination with serum
immunofixation in order to determine
clonality

SPEP
SPEP showing Monoclonal
Gammopathy
• Shows a tall “narrow” band in
gamma region – “M-Spike”
• Also, note reduction in the normal
polyclonal gamma band

SPEP
SPEP showing Polyclonal Gammopathy
• Shows a broad based peak in gamma
region .
• Seen in chronic infections,
inflammation, connective tissue
disease, lymphoproliferative disease.

Immunofixation
• More sensitive than SPEP
• Immunofixation is performed when
SPEP shows a sharp “peak” or a
plasma cell disorder is suspected
despite a normal SPEP
• Immunofixation always done to
confirm the presence of M-Protein
and to determine the type (IgM or
IgG etc and the light chain
restriction : k or λ)Unlike SPEP,
immunofixation does not give
an estimate of the size of the
M protein (ie, its serum
concentration), and thus
should be done in conjunction
with electrophoresis.

Bone marrow exaination

Skeltal survey
Skull – punched out lesions
The bone lesions - proliferation of tumor
cells, activation of osteoclasts and
suppression of osteoblasts
The bone lesions are lytic in nature and are
rarely associated with osteoblastic new
bone formation.
radioisotopic bone scanning is less useful
in diagnosis than is plain radiography.

MM & Skeletal Complications
~ 80% of patients with multiple
myeloma will have evidence of
skeletal involvement on
skeletal survey
• Vertebrae: 65%
• Ribs: 45%
• Skull: 40%
• Shoulders: 40%
• Pelvis: 30%
• Long bones: 25%
Dimopoulos M, et al. Leukemia. 2009:1-12.

.
MRI offers a sensitive means to document extent of bone marrow infiltration
and cord or root compression in patients with pain syndromes.

PET SCAN

STAGING

Prognostic factors

:
MONOCLONAL GAMMOPATHIES

Denotes presence of an M-protein in a
patient without a plasma cell or
lymphoproliferative disorder i.e;
Undetermined Significance
Monoclonal Gammopathy of Undetermined
Significance ( MGUS)

• Incidence of MGUS increases with age :
• 1% of adults in US
• 3% of adults over age 70 years
• 11% of adults over age 80 years
• 14% of adults over age 90 years
• Significance : Can progress to monoclonal
Disease
IgG or IgA MGUS
IgM MGUS
Monoclonal Gammopathy of Undetermined
Significance ( MGUS)

• Predictors of Progression :
• Size of the M-protein at the time of recognition of MGUS -
most important predictor of progression
• IgM & IgA monoclonal proteins have a greater risk of
progression than an IgG M-protein.
• Risk of progression does not go away with time!
• Risk of progression 1% per year
• CUMULATIVE RISK
• 10% at 10 years, 25% at 25 years from diagnosis
• So, Management :
MGUS - Progression

• Both criteria should be met :
• Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10
percent
• No end organ damage related to plasma cell dyscrasia (see CRAB)
• Management :
• Does not require any intervention
• Close surveillanace is necessary to ensure stability of the disease ( SPEP,
CBC, Creatinine and calcium every 3 to 4 month and Skeletal Survey
annually to pick up asymptomatic bone lesions)
Smoldering Myeloma

• Rare variant : About 1% of Myelomas
• May present with Bone lesions ( most common presenting
symptom bone pain)
• No serum or urine monoclonal protein ( diagnosis can be
missed if one is not aware of this entity, NSMM).
• Renal failure and hypercalcemia are generally lacking
• Anemia may be present
• Bone marrow biopsy must be performed in suspected cases:
Immunostaining for a monoclonal protein on bone marrow
sections may establish the diagnosis, Clonal plasma cell
population in marrow.
• Must rule out IgD and IgE myeloma
Non-Secretory Myeloma

Solitary Plasmacytoma
Localized plasma cell tumor
• Absence of a plasma cell infiltrate in random marrow biopsies
• No evidence of other bone lesions by radiographic examination
• Absence of renal failure, hypercalcemia or anemia

• Plasma cell tumors that arise outside the
bone marrow and no features of Multiple
Myeloma
• Most Common Primary Sites - Head and
Neck region: Upper air passages and
oropharynx (May involve draining lymph
nodes.
• Less Common Sites – Lymph nodes
(primary), salivary glands, spleen, liver, etc.
• 25% have small monoclonal spike
• Rare dissemination, rarer evolution to
myeloma
• Management :
• If completely resected during biopsy, no further
therapy
• If incompletely resected, radiation therapy locally
Extramedullary Plasmacytoma

All three criteria must be met
• Presence of a serum or urinary monoclonal
protein
• Presence of 10 percent or more clonal
plasma cells in the bone marrow or a
plasmacytoma
• Presence of end organ damage felt related to
the plasma cell dyscrasia, such as: CRAB :
Hypercalcemia (calcium > 11.5gm%), Renal
Insufficiency, Anemia (hgb < 10gm%) or Lytic
bone lesions
Multiple Myeloma

Multiple Myeloma
Spinal Cord Compression : oncological Emergency
Spinal cord compression occurs in 5 % of patients with multiple myeloma
( plasmacytoma or pathological fracture related)
Managed with urgent:
1. Corticosteroids
2.Neurosurgical intervention (laminectomy or
anterior decompression in pathological #) +
radiation therapy to preserve neurological function
3. Radiation therapy alone ( plasmacytoma)

*Thal/dex or dex are additional options
especially if immediate response is needed.
Clearly not transplantation
candidate based on age, performance
score, and comorbidity
BD/MPT, MPB, Len/dex
or clinical trial*
Potential transplantation
candidate
Nonalkylator-based
induction x 2 cycles
(BD/BDD/BTD/LD/BCD)
Stem cell harvest
Initial Approach to Treatment of MM

Novel Frontline Options
Immunomodulatory drugs (IMiDs)
• Thalidomide
• Lenalidomide
Proteasome inhibitors
• Bortezomib
• Carfilzomib

Thalidomide: Proposed Mechanism of Action
Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Rajkumar SV, et al. Leukemia.
2003;17:775-779. D’Amato RJ, et al.Proc Natl Acad Sci U S A. 1994;91:4082-4085.

Lenalidomide
Immunomodulatory derivative of thalidomide
More potent than thalidomide in preclinical models
• Dose-dependent decrease in TNF-α and interleukin-6
• Directly induces apoptosis, G1 growth arrest
• Enhances activity of dexamethasone
More favorable toxicity profile than thalidomide
Difficult to use in renal insufficiency ( dose adjust)
Richardson P, et al. Blood. 2003;100:3063. Hideshima T, et al. Blood. 2000;96:2943-2950.

Bortezomib:
A Reversible Proteasome Inhibitor
Chymo-
tryptic
Site
Post-
Glutamyl
Site
Tryptic
Site
b1 b2
b3
b4
b5
b6
b7
Cross section of b ring
Bortezomib
Adams J, et al. Invest New Drugs. 2000;18:109-121.
Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338.
H
N B
N
H
O
O
OH
N
N
OH
Interferes with intracellular pathway that
degrades proteins regulating cell cycle,
apoptosis,angiogenesis

Transplant candidates
Induction chemotherapy
Stem cell
transplant
Maintenance

Induction cemotherapy

Who is not a candidate for transplant ?
• Age >65 yrs
• Myeloma related organ or tissue impairment (end organ
damage) ( ROTI)
Hb 2 g /dl below the lower limit of normal
or, <10 g /dl
s. Ca - 25 mmol/l above the upper limit of
normal or, >75 mmol/ l
bone lesions- lytic lesions or osteoporosis with compression fractures
s creat - >173 µmol/ l
symptomatic hyperviscosity, amyloidosis, reccurent bac infections
(>2 episodes in 12 months)
Hence majority of
patients are not
candidates

Non transplant candidates

Rationale of SCT

Myeloablation with stem cell support
• 1.TBI (12 Gy in 8 #) and cyclophosphamide
• 2. TBI (8 Gy ) +high dose melphalan +/- Cyclo
• 3. high dose melphalan alone (140-200
mg/m2)
• High dose carboplatin /etopside /cyclo.

Total body irradiation
 Goal – as palliation in radiation sensitive disease to eradiacte
residual cancer
 Used along with stem cell support
 Technique –
1. using large field size to encompass entire body – stationary beam
Extended SSD – 200-600cmStandard SSD
LINAC

2. use less than whole body FS -
Moving beam / couch

 Rigorous dosimetry
 Use of compensators at head neck region
 Dose variation acceptible- 10 % of prescribed dose
 Supine postion , at extended SSD, using AP/PA – most
desirable
 Back up must be available
Presciption – midpoint at level of umbilicus
Dose / fractionation
 8- 10 Gy/ SF at dose rate
 12-15 Gy @ 1-5 -2 Gy / # twice or thrice daily
Complications
 Pneumonitis
fractionated regimes tolerated better

Role of maintenance therapy?
Why the question?
• Despite ↑remission rates, -no clear plateau in
the survival curves following conventional or HDT.
• Although the proportion of patients achieving CR
has increased, all patients eventually relapse.
• Various maintenance therapies have been
evaluated in MM in an effort to sustain remission.

Maintenance therapy
 Depends on type , length of induction therapy
 If steroids used- depends on type, dose,
schedule
 No standard therapy to prolong TTP.
 modest increase in only EFS not OS
Agents tried–
 low dose (50 mg )alt day prednisolone
Berenson et al. Blood 2002;99:3163.
Lenalidomide(25 mg)
Br J Haematol 2013;112:1020-34
 thalidomide 200 mg OD
Attal et al. Blood 2006;108:3289.

Role of radiation
 Mainstay of treatment prior to availability of
chemotherapy
 Present day role
Definitive
 solitary bone / extradural plasmacytoma
 Dose – 40-50 Gy @ 2 Gy / #
Palliative
 impending bone fracture- vertebra, humerus,
femur, pelvis
 spinal cord compression
For irradiation hemipelvis, monitor hemogram

Portal
 8 cm wide
 Centered
on spine
 Extends
one to two
vertebral
bodies
above and
below

• Dose- 30 Gy/ 10 #,/20 Gy/ 5 #,(30 Gy dose better than 20gy )
Radies D et al:J cli oncology:2005
• Energy- 1.25 Mv/
• Prone
• Supine- treat through table, after raising table ht to max
• Cervical spine- direct posterior field.
Thoracic spine- single post field.
• Lumbar spine/pelvis- AP – PA field / single post field

• Fractures of long bone - fixation - post op RT
• Symptomatic vertebral compression fractures-
vertebroplasty/ kyphoplasty - post op RT
• 50 % of nonambulatory cases regain ambulation after RT
• 67 % cases improve sphincter function
• 89 % - relief of back pain .
• Median duration of response 12 months
LECOVET ET AL:BR J HEMATOLOGY:1997
• For analgesia, however, avoid NSAID
• use lumbar corsets, braces for stabilising spine

Bisphosphonates
• Bisphosphonates are structural analogues of pyrophosphates that bind to
hydroxyapatite crystals in bone & inhibit osteoclast induced bone
resorption
drug IV/oral dose
pamindronate Iv 60 – 90 mg
4wkly
zoledronate iv 4 mg 4 wkly
clodronate PO 1600 mg / d
ibandronate PO 50 mg/d
Oral formulations less tolerated because of GI toxicity
Overall bisphosphonates results in 44 % relief in bone pain, 28 - 56 % decrease in
bony complications , including hypercalcemia, decrease need for EBRT.
Relatively safe & inexpensive, at least 1 yr therapy reqd for any significant
response
Zoledronic acid more
effective than pamidronate
Combining CCT well
tolerated & also improves
PFS

• However , these agents can cause
• Renal dysfunction –
Pamindronate – glomerular lesion , with proteinuria (nephrotic levels )
zolendronic acid – tubular dysfunction
• Ostenecrosis of jaw – before starting – all patients should have dental
examination
• Monitor s. calcium- if s. calcium reduced oral calcium 1000 mg daily and
Vitamin D (800 IU ) can be given
• Ensure adequate hydration – 2-3 l of liquids to promote excretion of
light chains, Ca , UA

Special clinical problems and other supportive measures
Hypercalcemia Nausea, fatigue,
confusion,
polyuria, constipation
Best approach-
admit, check
RFT,SE,Alb, Ca
IV fluids, dexam,
bisphosphonate
Renal failure Hydrate, treat hypercalcemia, reduce s
.UA,
consider hemodialysis if reasonable
evidence of good prognosis and have
not failed initial therapy
Infections Foremost cause of
death
Prophylactic use of IVIg, antibiotics not
required
Hyper viscosity Bleeding,
retinopathy,malaise,
stroke,coma
Serum M protein >
3-4 g/dl
plasmapheresis
Anemia Normocytic,
normochromic
Erythropoetin-
improves Hb by >2 g/dl

• ULTRA HIGH RISK MM.
• 25 % of MM patients are now are classfied in to UHRM.
• They include the following
• ISS 3 with clinical presentation as EMD OR Plasma cell
leukemia
• LDH high,FISH shows 17q deletion with PCLI >1%.
• SURVIVAL <2YRS
• POMALIDOMIDE(3rd generation im is used /currently
recommended)

Future therapies
• t(4,14) >>>> FGGR3 gene>>>>>dovatinib
• t(11,14)>>>cyclin d>>>>>>seleciclib,dinaciclib
• Braf mutation>>>>>>tipifaranib

THANKU