The document provides information on multiple myeloma, including its definition, history, etiology, pathogenesis, clinical presentation, investigations and staging. Some key points: - Multiple myeloma is a neoplastic proliferation of plasma cells in the bone marrow, causing osteolytic bone lesions. It is the second most common hematologic malignancy. - Clinical features include bone pain, pathological fractures, anemia, hypercalcemia and renal impairment. Diagnosis requires ≥10% plasma cells on bone marrow biopsy and evidence of end organ damage. - Investigations include serum and urine protein electrophoresis, immunofixation, skeletal survey, MRI and bone marrow biopsy to assess disease burden and abnormalities. Staging involves blood

1. PRESENTER : DR TOMIN P ZACARIAS, PGT 2ND YEAR
MODERATOR : PROF. DR SANJEEV KUMAR BHUYAN
DEPT OF ORTHOPAEDICS
GAUHATI MEDICAL COLLEGE AND HOSPITAL

2. Definition
• It is Plasma cell myeloma.
• Most common primary malignancy of bone.
• neoplastic proliferation of plasma cells derived
from a single clone.
• Due to the tumour , tumor products and host
response , it results in a number of organ
dysfunction & symptoms.

3. History
• Descriptions of disease seen even in Egyptian
mummies.
• In 1844, Samuel Solley with Bence Jones, he found
that the urinalysis of the patient showed a protein
-Bence Jones Protein.
• Rustizky in 1873 termed multiple myeloma (MM) .
• Kahler’s disease.

4. • Ellinger described about the increased serum proteins
and ESR in multiple myeloma.
• Wright and Weber in 1898 were the pioneers in
providing the X-ray features .
• Magnus Levy described amyloidosis in multiple
myeloma.
• By the 3rd and 4th decade of the 20th century first bone
marrow aspiration and then electrophoresis done.
• Grabar in 1953 identified heavy and light chains

5. Etiology
• Multifactorial
• Genetic causes
• Environmental/ occupational
• Chronic inflammations
• Radiations
• Infections

6. Multistep development model
spectrum from monoclonal gammopathy of undetermined
significance to full blown multiple myeloma.

7. Chromosomal abnormalities that are
associated :
• 13q 14 deletions
• 17p 13 deletions
• t(11,14)(q13;q32) andt(4;14)(p16;q32)
translocations.

8. • Mutation of P53 & Rb gene.
• N- ras, K-ras and B-raf mutations are most
common and combined occur in over 40%
patients.
• IL-6 may play a role in driving myeloma cell
proliferation.

9. Epidemology
• 1-4 /100000 people per year.
• Incidence in Western population is 4 times higher than
Asian population.
• 2nd most frequent hematological malignancy after non-
Hodgkin's lymphoma .
• Older persons ( 40-70 years) are more affected.
• 2% patients are younger than 40 years.
• Males are slightly more affected than females.

10. • In Multiple myeloma, the cancerous myeloma cells produce proteins that speed
up the work of the osteoclasts while slowing down the work of the osteoblasts.
• This results in soft spots in the bone known as osteolytic lesions.

11. PATHOGENESIS

12. Vicious
cycle
Osteoclast activating factors
Increased
calcium and
complications
BMSC
Osteoblast inhibiting factors

13. CLINICAL PICTURE
• Symptoms vary according to manifestation and
stage of disease .
• 30% asymptomatic and have incidental detection.
• Early disease is completely silent with gradual
development of pain.
• 1/3rd of patients are diagnosed after a history of
pathological fracture.

16. • Onset is insidious with rheumatic like pains.
• Usually back and loins.
• Intermittent and progressive .
• Eventually fatal termination due to :
1. Extensive bone marrow replacement
2. Severe anaemia
3. Thrombocytopenia
4. Haemorrhages.

17. • A rapid onset of severe pain after slight strain
indicates a pathologic fracture.
• Susceptibility to infection (like pnuemonia &
pyelonephritis ) due to Strept .pnuemoniae, stap.
aureus & klebsiella pneumonia in lungs.
• E.coli & gram negative infections in urinary tract.

18. • MYELOMA KIDNEY
• Caused by Tubular blockage by protein casts.
Myeloma kidney in the center and on the left. A normal kidney is shown on the right for
comparison. The myeloma kidney appears pale and scarred due to a combination of
deposition of casts in the tubules, inflammation and fibrosis

19. • Renal failure : -
1. Most commonly due to hypercalcemia.
2. Glomerular deposits of amyloid, Bence Jones
proteins , hyperurecamia, recurrent infections ,
NSAIDs for pain control, bisphosphonates use,
infiltration by Myeloma cells can lead to renal
failure.
• Normally light chains are reabsorbed &
catabolised, but here the tubules are damaged
by LC toxicity.

20. • Earliest manifestation will be FANCONIs
syndrome :
• It is a type 2 proximal tubular damage
• Loss of sugars,AA-, kidney fails to acidify
urine.
Urine albumin is normal because
glomeruli is normal.

21. ANEMIA:
• Normocytic , normochromic anemia seen in
~80 % pts
• Because normal marrow is replaced by
Myeloma cells.
• Reduced Hematopoiesis
Hyperviscosity syndromelike Raynauds may
develop if Myeloma component forms
cryoglobulin.[most commonly IgM,IgG3 &
IgAparaproteins]

22. CLINICAL FEATURES

25. • Neurologic manifestation :
1. Hypercalcemia = lethargy, weakness, depression,
irritability
2. Hyper viscosity = headache, fatigue, retinopathy.
3. Spine collapse leading to cord copression.
4. Infiltration of nerves byamyloid.
5. Paraplegia more common in solitary myeloma
because it may grow bigger in size.

26. Signs and symptoms of light
chain amyloidosis
CCF
HEPATOMEGALY
ENLARGED TONGUE
SKIN CHANGES
CARPELTUNNEL SYNDROME

27. POEMS SYNDROME :
POLYNEUROPATHY + ORGANOMEGALY +
ENDOCRINOPATHY + MM + SKIN CHANGES
Pathogenesis - unclear,
Osteosclerotic myeloma
Hypertrichosis
Hyperpigmentation
Skin thickening

28. RADIOGRAPHIC FINDINGS
• Conventional radiological findings in MM can include
1. Osteopenia
2. osteoporosis,
3. lytic lesions and
4. collapse fractures.
• 70-80% patients - some bone changes .
• rest will develop it during the course of disease.
• Sclerotic lesions are extremely rare and should
prompt investigations in line for POEMS syndrome or
alternate diagnosis like bony secondaries.

29. • Multiple , rounded , punched out areas found in
skull , vertebral column, ribs and pelvis.
• Less commonly long bones.
diffuse lytic lesions giving
Pepper Pot Skull / rain drop
skull

30. A-P radiograph right humerus:
diffuse lytic lesions of the right
humerus (arrowed) with old
pathological fracture distal
diaphysis (arrow).

31. • With extensive spine involvement , picture is
typical of generalised osteoporosis.
• Biconcave vertebral bodies + vertebral collapse.
• Osteolytic defect rarely observed.
Rarefaction of vertebra
Complete dissolution
Disappearing vertebra

33. • Ultrasonography abdomen to see for kidney and
hepatosplenomegaly.
• Bone scan is NOT a preferred modality for
assessing skeletal lesions in MM since , It shows
areas of bone formation only.
• The drawbacks with conventional radiology are
that it has a high false positivity .
• It can’t distinguish age related osteopenia from
MM related osteopenia or osteoporosis.

34. • Whole body CT scans have a better sensitivity
than x-rays.
• There excessive amount of radiation exposure
• poor visualisation of the marrow.
• But gives a better estimate of fracture risk.

35. • Role of MRI is coming up in a large scale now.
• MRI also gives a better understanding of the
marrow and soft tissue components .
• helps in prognosis.
• Hazard of radiation is not present with MRI.
• PET might be helpful in detecting active lesions
from inactive ones .

36. International Myeloma Working Group
( IMWG) Revised diagnostic criteria:
Multiple myeloma
Bone marrow plasma cells ≥10%
OR
bony or biopsy proven extramedullary
plasmacytoma
and
any one or more of myeloma defining
events :

37. • Myeloma defining events:
1. Evidence of end organ damage due to underlying plasma cell
proliferative disorder
♦ HyperCalcemia: >1 mg/dl higher than upper limit or >11
mg/dl
♦ Renal insufficiency: serum creatinine >2mg/dl or creatinine
clearance <40 ml/min
♦ Anemia: Hb<10 gm/dl or >2gm/dl below the lower limit of
normal
♦ Bone lesion: one or more osteolytic lesions skeletal
radiography, CT or PET-CT
2. Any one or more biomarker of malignancy including:
♦ Clonal bone marrow plasma cells ≥ 60%
♦ Free light chain ratio ≥ 100
♦ >1 focal lesions on MRI

39. LABORATORY AND STAGING
INVESTIGATIONS
1. The presence of para protein in serum and
urine :
• Serum beta 2 microglobulin
• Urine Bence jones protein
• Hyperglobulinemia
• M band on electrophoresis

40. 2. assessment of malignant plasma cells in bone
marrow
• Bone marrow aspirate and biopsy
• Sternum and ileum.
3. Bone lesions screened by skeletal survey.

41. MINIMUM BASELINE DIAGNOSTIC WORKUP
1. CBC, PERIPHERAL BLOOD SMEAR, ESR.
2. RFT and LFT including calcium and LDH levels
3. Serum protein electrophoresis (including quantification),
Immunofixation Electrophoresis
4. Routine urinalysis, 24-hour urine collection for
electrophoresis, immunofixation (desirable)
5. Bone marrow aspirate and/or biopsy
• Plasma cell percentage and morphology
• Cytogenetics or FISH( fluorescence in situ hybridisation)
6. Radiologic skeletal bone survey, including spine, pelvis,
skull, humerus and femur and ultrasound abdomen.
7. Magnetic resonance imaging in certain circumstances
8. Serum beta 2-microglobulin
9. Measurement of serum-free light chains

42. • The gold standard for demonstrating monoclonal
gammopathy is the serum and Urine immunofixation
electrophoresis (SIFE & UIFE).
• Start with Serum and Urine Protein Electrophoresis
(SPEP & UPEP) .
• SPEP = 80%
• SPEP + SIFE = 93%.
• SPEP +SIFE + UIFE = 97%.
• The remaining 3% is Non-secretory myelomas.
SENSITIVITY TO DIAGNOSIS

43. Serum Protein Electrophoresis (SPEP)
• It is important to differentiate the Monoclonal M
spike from polyclonal gammopathy which can be
present in various benign conditions.
• The M spike of MM is usually present in gamma
region but at times may be present in the beta 2
region also.

46. • Seen in only 20 % cases of multiple
myeloma.

47. Bone Marrow Biopsy
• Bone marrow plasmacytosis is to be proven by BM
aspiration and Biopsy from both iliac crests.
• Bilateral BM Biopsy is recommended.
• BM involvement is found in about 95% patients.
• In around 40% patients the levels might be below 10%.
• Hence in the presence of end organ damage, the absolute
percentage of BM plasmacytosis is not significant.

48. • Hypercalcemia is present in around 10-15% patients at
presentation .
• Major cause of reversible renal insufficiency at
presentation.
• Increased ESR is seen in 90% patients.
• LOW NORMAL ALP INSPITE EXTENSIVE BONE
DESTRUCTION.
• Serum Creatinine elevations above normal values
found in about one third of patients at presentation.

49. Other investigations
1. Serum β2 microglobulins: a marker of tumour
burden.
2. Serum LDH: has an independent prognostic
significance .
3. ESR is elevated in most cases of MM but the values
correlate neither with tumor burden nor with
treatment response.
4. C-Reactive proteins may be elevated in MM and
might be of value when infections are a presenting
feature of MM. (doesn’t correlate disease status ).

50. 5. Molecular testing
• Conventional cytogenetics and Fluorescent In situ
Hybridisation (FISH) are being used recently.
Risk Stratification system based on cytogenetics :
1. Standard-risk
• Hyperdiploidy
• t (11;14)
• t (6;14)
2. Intermediate-risk
• t (4;14)
• Deletion 13 or hypodiploidy by conventional karyotyping.
3. High-risk
• 17p deletion
• t (14;16)
• t (14;20)

51. Histology of MM
ECCENTRICALLY PLACED NUCLEUS + CART WHEEL [coarse chromatin]
In severe disease we can see mott cells & flame cells
FLAME CELL
Russell bodies

52. DUTCHER BODY
{intra nuclear}
RUSSELLBODY
{intracytoplasmic}

53. Serum Free Light Chain (SFLC) assay
• Detects the levels of κappa and lambda light chains
in the serum.
1.free kappa (0.33-1.94 mg/dL)
2.free lambda (0.57-2.63 mg/dL).
kappa to lambda ratio
• The normal ratio is 0.26 to 1.65.
• Values < 0.26 indicates a lambda light chain
disease.
• >1.65 indicates a kappa Light Chain disease.
• SFLC is also to be normal in order to claim a
Stringent Complete Response.

54. Who Classification of Plasma Cell Neoplasms
• Monoclonal gammopathy of undetermined significance (MGUS)
• Multiple Myeloma
1. Symptomatic
2. Asymptomatic (Smoldering)
3. Nonsecretory
4. Plasma Cell Leukemia
• Plasmacytoma
1. Solitary plasmacytoma of bone
2. Extra medullary plasmacytoma
• Deposition Disease
1. Primary Amyloidosis,
2. Systemic Heavy and Light Chain Disease
• Osteosclerotic Myeloma (POEMS Syndrome)

55. `

56. • Other staging systems
1.DURIE – SALMON STAGING SYSTEM
( myeloma cell mass, haemoglobin, serum calcium , severity
of lytic lesions, M component production rates, renal
function ).
2. REVISED INTERNATIONAL STAGING SYSYEM
( takes into account LDH and FLUROSCENCE IN SITU
HYBRIDISATION ).

57. Monoclonal Gammopathy of
Undetermined Significance (MGUS)
• premalignant asymptomatic stage.
• over the age of 50 year MGUS is present
in 3-4% cases
• can progress to multiple myeloma at the
rate of 1% per year.
• absence of hypercalcaemia, renal failure,
anaemia, and bone lesions (CRAB
features)

58. Diagnostic criteria for MGUS
• All three criteria must be met:
1. Serum monoclonal protein <3 gm/dl
2. Clonal bone marrow plasma cells <10%,
3. Absence of end-organ damage (CRAB)
• persons found to have MGUS should be
monitored stringently lifelong.

59. Smoldering multiple myeloma
Intermediate during the transition from MGUS to frank
symptomatic MM.
The monoclonal plasmacytosis and gammopathy has
increased to MM levels but the end organ damage that
defines MM has not yet occurred.
The diagnostic criteria for is:
1. Serum monoclonal protein (IgG or IgA) ≥ 3gm/dl
2. 24 hr urinary monoclonal protein ≥500 mg and/or
3. bone marrow plasma cells 10-60%
4. Absence of myeloma defining event or amyloidosis

60. Plasma Cell Leukaemia (PCL)
PCL occurs when there is more than 20% abnormal
plasma cells in the differential WBC lineage
or
an absolute number of more than 2x10^9/L of plasma
cells.
• This might be primary or secondary.
• Primary (approx. 60%), if the patient presents with
PCL
• secondary is if the patients progresses to PCL from
MM.

62. Extramedullary Plasmacytoma
• Commonly in nasal cavity, nasopharynx, larynx and
sinuses.
• in any location in the body .
• commonly of the IgA subtype.
• Other evidence of systemic MM should not be
present.

63. • The diagnostic criteria is:
1. No M-protein in serum and/or urine
2. Extramedullary tumour of clonal plasma
cells
3. Normal bone marrow
4. Normal skeletal survey
5. No related organ or tissue impairment (end
organ damage including bone lesions).

64. Multiple Solitary Plasmacytomas
( Less than 5% of all PCDs. )
• The diagnostic criteria for this entity are as follows:
1. No M-protein in serum and/or urine
2. More than one localized area of bone destruction or
extramedullary tumour of clonal plasma cells which
may be recurrent
3. Normal bone marrow
4. Normal skeletal survey.
5. No related organ or tissue impairment (no end organ
damage other than the localized bone lesions)

65. Goals of Therapy for Multiple myeloma
• Address pain relief & other disease symptoms
• Control disease activity -prevent further organ damage
• Debulk tumor and use internal fixation
augmented with methacrylate
• Prolong overall survival
• Preserve normal performance

66. 28
• Conventionalchemotherapy:
• Radiation therapy
• Surgical care
–
–
Autologous
Allogenic
–
–
–
Thalidomide
Lenalidomide
Bortezomib
• Stem cell transplantation:
Melphalan
Doxorubicin
Cyclophosphamide
• Steroid therapy:
– Dexamethasone
– Prednisone
• Novel therapeutics:
• Supportive Medical Therapy
MANAGEMENT

67. Indications of Rx
1. Progressive lytic lesion
2. Stage 2 &3
3. Stage 1 + Bence Jones Protein.
4. Refractory hypercalcemia.
5. Compression fractures.
6. Recurrent infections.
7. Bone marrow suppression
8. Renal failure.

68. SUPPORTIVE CARE :
• Hypercalcemia - bisphosphonate,
glucocorticoid, hydration & natriuresis.
• Bisphosphonate ( PAMIDRONATE,
ZOLENDRONIC ACID ) decreases Osteoclastic
resorption.
• fluid intake & avoid dehydration = Enhance renal
excretion of light chains .
• Acute renal failure = plasmapheresis is effective in
clearing light chains

69. • Hyper viscosity syndrome = PLASMAPHERESIS
• Patients developing neurological symptoms like
back ache, bladder & bowel incontinence = local
radiation therapy & steroids if compression is
present.
• Anemia = erythropoietin +hematinics.
• Calcitonin inhibits bone resorption.
• Certain bone lesion needs local radiation

73. • In MGUS – no active Rx , only follow up
In high risk pts done every 6 months.
• In MGUS + polyneuropathy
plasmapheresis +rituximab
• Prevention of Smoldering Myeloma to
active MM
lenalidomide +dexamethasone.

74. Smoldering MM to symptomatic MM
Give anti tumour Rx.
Patients withsolitary plasmacytosis &
extramedullary plasmacytosis
Prolonged life survival after 40Gy irradiation.

75. Drugs action & side effects :
1.Thalidomide :
• antiangiogenic effects enhances cytotoxic T cell
&NKcell
• Side effects: demyelination , phocomelia.
2. Lenalidomide : less toxic than thalidomide.
• DVT prophylaxis with aspirin, LMWH, warfarin
to be taken.

76. 3. Melphalan :
1) alkylates DNA gets broken down in an attempt to
correct it.
2) DNA cross linkage
Side effects :vomiting, hemorrhage in GIT , ulcers
4. Bortezomib :
• 26s ribosome inhibitor = cell cycle arrest &+ apoptosis.
• Side Effect = hypotension , cardiotoxicity, peripheral
neuropathy
• Herpes Zoster prophylaxis to be taken.
5. Carfilzomib : 20s ribosome inhibitor .

77. • In Patients receiving lenalidomide ,stems
cells have to be harvested before starting of
chemo as after the therapy stem cells
reduces.
• In Transplant candidates – avoid alkylating
agents like melphalan, as they damage the
stem cells. {mainly for autologous
transplant}.

78. Initial Rx :
High dose pulsed glucocorticoid is used alone
= dexa 40mg for 4 days every 2 weeks
Or
VAD combination
Vincristine = 0.4mg/d for 4 days continuous
infusion
Doxorubicin = 9mg/d for 4 days infusion
Dexa 40mg/d for 4 days per week for 3 weeks.

79. Newly diagnosed cases:
Thalidomide 200mg /d for 4 days every 2 weeks +
dexa
Or
Lenalidomide 25mg on days 1-21 every 4 weeks +
dexa
Or
Bortezomib(1.3mg/m2 on days 1,4, 8 &11)
every 3weeks + dexa
superior toxicity profile with improved efficacy
made them agents for induction.

80. Autologous transplant :
• Transplantation of patients own stem cells after
chemotherapy ,
• M/C type done for MM,
• ITS NOT CURATIVE BUT PROLONGS LIFE.
Patients <65-70 yrs
Treatment related mortality 10-20%
Response rate 80%
Long term survival40-50%.

81. Conventional allogenic
transplant :
• Healthy persons stem cells are transplanted into
affected patient.
• Patients <45-50 yrs with HLA identical donor.
• Rx related mortality 40-50%
• Long term survival20-30%.

82. Patients who arenot transplant candidates :
• Melphalan 8mg/m2/day + prednisone 25-
60mg/m2/day for 4 days/ 4-6weeks &
L- phenylalanine mustard.
Response :
Reduction in pain ,
Hypercalcemia correction ,
anemia correction,
Infections reduce

83. RELAPSED MYELOMA
lenalidomide +/- bortezomib + dexa
or
Bortezomib + liposomal doxorubicin
is also used.
• Carfilzomib + pomalidomide has shown
efficacy in relapse &refractory cases.

84. Orthopedic related Rx :
1. Pathological fracture spine has risk of cord
compression needs internal stabilization
or bracing.
2. Unrelieved cord compression needs
laminectomy & decompression.
3. Local radiation is given 3 wks later after
surgery or when wound is healed.

85. Vertebroplasty :
Open & percutaneous method using C arm or
ultrasound guidance
Materials used PMMA ( poly methyl methacrylate)

86. • Appendicular skeletal lesion are treated with
intramedullary fixation and adjuvant radiotherapy.
Solitary focus
appendicular skeleton axial skeleton
Surgical excision radiotherapy
radiotherapy

87. DIFFERENTIAL DIAGNOSIS
1. Skeletal metastasis
2. Malignant lymphoma
3. Monoclonal gammopathy of uncertain origin.
4. Waldenstrom hypergammaglobulinemia

88. Waldenström’s Macroglobulinemia
• malignancy of lymphoplasmacytoid cells that secret IgM.
• Contrast to myeloma, the disease was associated with
lymphadenopathy and hepatosplenomegaly.
• major clinical manifestation was the hyperviscosity
syndrome.
• Involves the bone marrow , but does not cause bone lesions
or hypercalcemia.

89. • MYD88 L265P somatic mutation is the most
common.
• This is now used as a diagnostic test.
• The disease is slightly more common in men .
• increased incidence with age.
• associated with demyelinating disease of the
peripheral nervous system.

91. TAKE HOME MESSAGE
• Disease of elderly
• Should suspect when elderly patient present
with bone pain or non specific symptoms such
as nausea , vomiting, malaise, weakness,
recurrent infections and weight loss.
• Survival rate increased due to availability of
non transplant options
• Remains incurable.