comprehensive details about multiple myeloma in relation to orthopedics !!!!

1. PRESENTER : DR VENKATESH V
MODERATOR :DR ABDUL RAVOOF
DR MAHESH D V

2. Definition : -
 Plasma cell myeloma
 Represent a malignant proliferation of plasma cells
derived from a single clone.
 Due to the tumour & tumor products host response to
it results in a number of organ dysfunction &
symptoms.

3. Etiology : -
 Unknown
 Seen in ppl exposed to nuclear war heads in WW 2
after a latency of 20 yrs.
 M/C seen in farmers, wood workers, leather workers,
ppl exposed to petroleum products.

4.  Chromosomal alterations with prognostic significance
are –
1. 13q 14 del , 17p 13 del
2. t(11,14)(q13;q32) translocation
3. t(4;14)(p16,q32)predom, all have been quoted to
antibody heavy chain isotype – participate in the
formation process
4. Mutation of P53 & Rb gene.

5.  Neoplastic event in myeloma may evolve earlier
B – cells than plasma cells.
IL – 6 plays a role in driving myeloma cell proliferation

6. Incidence : -
 Multiple myeloma is the second most prevalent blood
cancer after non-Hodgkin's lymphoma
 1% of all cancers and 2% of all cancer deaths.
 Age 60-65 years most common
 Occurs in men > women
 African Americans and Native Pacific Islanders have the
highest reported incidence of this disease and Asians the
lowest

7. Pathogenesis & clinical features :
 MM cells bind to bone marrow stromal cells(BMSC)
via cell surface adhesion molecules.
(+) triggers
 MM cell growth leading to drug resistance & migration
in bone marrow.
 This effect is due to direct MM cell- BMSC binding or
due to induction by cytokine like IL6, VEGF,IGF 1 &
TNF.

8.  Growth , drug resistance , migration are mediated by
Ras/raf/mitogen activated protein kinase signaling
cascade.

9.  Bone pain – 70% of presentation
 Aggrevates on movement
 Bone lesions are due to tumour proliferation & o.clast
activation
 Which destroys bone & suppress o.blast

10.  Increased clastic activity = OAFs produced by MM
cell
 Lytic lesions are due to suppressed “dickhoff 1” gene
produced by MM cell
 Bone lysis leads to raised ca2+ levels causing acute &
chronic complications.

11.  Bone lesions seen over skull, clavicle, sternum & also
collapse of vertebrae causing compression of cord.

13.  Susceptibility to infection (like pnuemonia &
pyelonephritis ) due to S.pnuemoniae, stap.aureus &
kl.pnuemoniae in lungs .
 E.coli + gr negative in urinary tract.

14.  Causes for susceptibility : -
1. Diffuse hypo gamma G
2. Hypo gamma g due to increased destruction &
reduced production
3. Suppressed normal antibody synthesis
4. Increased destruction of IgG rapidly because
production directly related to destruction.
5. Poor response to polysaccharide cell wall on bacteria
6. Granulocyte lysosome contact reduced with
decreased migration of granulocyte.
7. Reduced CD 4 count.

15.  Renal failure : -
1. m/c due to hyperca2+
2. Glomerular deposits of amyloid, BJP, hyperurecamia,
recurrent infections , NSAIDs for pain controll,
bisphosphonates use, infiltration by MM cells.
3. Always light chains are present in MM due to tubular
damage.
Normally light chains are reabsorbed & catabolised, but
here the tubules are damaged by LC toxicity.

16.  Earliest manifestation will be FANCONIs syndrome :
 It is a type 2 proximal tubular damage
 Loss of sugars, AA-, kidney fails to acidify urine.
 Albumin in urine is normal because glomeruli is
normal.

17.  ANEMIA :
 Normocytic , normochromic anemia seen in ~80 % pts
 Because normal marrow is replaced by MM cells.
 Reduced Hematopoiesis
 Decreased erythropoietin + hemolysis
 Most pts may also have megaloblastic anemia due to

18.  Hyper viscosity syndrome like Raynauds may
develop if M component forms cryoglobulin.[M/C
IgM,IgG3 & IgA paraproteins]
 Other symptoms :
 Headache , fatigue, shortness of breath, pptn of heart
failure, ataxia, vertigo, retinopathy, somnolence &
coma.
 Role of M component :
 large amt of IgG or dimerisation of IgA could be reason
for hyperviscosity
 M protein has anti I Ab specificity causes cold
agglutinin
 Or anti myelin activity causes peripheral neuropathy.

19.  Bony damage & collapse may cause cord compression,
radicular pain , loss of bowel & bladder control.
 Infiltration in peripheral nerves by amyloid causes
carpal tunnel syndrome.

20.  Neurologic symptoms :
1. Hyperca2+ = lethargy, weakness, depression
2. Hyperviscosity headache, fatigue, retinopathy
3. Spine collapse leading to cord copression
4. Infiltration of nerves by amyloid
5. Paraplegia more common in solitary myeloma
because it may grow bigger in size.

21.  May present with
1. Cord compression
2. Pathological #
3. Hyper viscosity symptoms
4. Sepsis
5. Hyper ca2+

22. Clinical Finding Underlying Cause and Pathogenetic
Mechanism
Hypercalcemia, osteoporosis,
pathologic fractures, lytic bone lesions,
bone pain
Tumor expansion, production of OAFs
by tumor cells, o.blast inhibitory factors
Renal failure Hyperca2+, light chain deposition,
amyloidosis, urate nephropathy, drug
toxicity (NSAIDs, bisphosphonates),
contrast dye
Easy fatigue—anemia Bone marrow infiltration, production of
inhibitory factors, hemolysis, decreased
hemopoeisis, decreased erythropoietin
levels
Recurrent infections Hypogammaglobulinemia, low CD4
count, decreased neutrophil migration
Neurologic symptoms Hyperviscosity, cryoglobulinemia,
hyperca2+, nerve compression, anti-
neuronal antibody, POEMS syndrome.

23. Clinical Finding Underlying Cause and Pathogenetic
Mechanism
Nausea and vomiting Renal failure, hypercalcemia
Bleeding/clotting disorder Interference with clotting factors,
antibody to clotting factors, amyloid
damage of endothelium, platelet
dysfunction, antibody coating of
platelet.

25. Diagnosis & staging : -
 Plasmacytosis >10%
 Serum /urine M component
 End organ damage
 Bone marrow plasma cells are CD 138 positive either
for Kappa or Lambda light chains.
 CLASSIC TRIAD : -
1. marrow plasmacytosis (>10%),
2. lytic bone lesions
3. serum and/or urine M component

26. Diagnostic criteria's : -
 D/D =
1. MGUS
2. SMOULDERING MYELOMA
3. SYMPTOMATIC MYELOMA
4. NON-SECRETARY MYELOMA
5. SOLITARY PLASMACYTOMA OF BONE.

27. Monoclonal gammopathy of undetermined
significance (MGUS)
M protein in serum < 30 g/L
Bone marrow clonal plasma cells < 10%
No evidence of other B cell proliferative disorders
No myeloma-related organ or tissue impairment (no end organ damage, including
bone lesions)

28. Asymptomatic myeloma (smouldering myeloma)
M protein in serum 30 g/L and/or
Bone marrow clonal plasma cells 10%
No myeloma-related organ or tissue impairment (no end organ damage, including
bone lesions)a or symptoms
Symptomatic multiple myeloma
M protein in serum and/or urine
Bone marrow (clonal) plasma cellsb or plasmacytoma
Myeloma-related organ or tissue impairment (end organ damage, including bone
lesions)

29. Nonsecretory myeloma
No M protein in serum and/or urine with immunofixation
Bone marrow clonal plasmacytosis 10% or plasmacytoma
Myeloma-related organ or tissue impairment (end organ damage, including bone
lesions)
Solitary plasmacytoma of bone
No M protein in serum and/or urinec
Single area of bone destruction due to clonal plasma cells
Bone marrow not consistent with multiple myeloma
Normal skeletal survey (and MRI of spine and pelvis if done)
No related organ or tissue impairment (no end organ damage other than solitary
bone lesion)

32.  2 variants of MM :
1. Solitary bone plasmacytosis
2. Solitary extramedullary plasmacytosis
Both are associated with = < 30 % of M component
>10 yrs of survival.

33.  Solitary bone plasmacytosis
1. Involves a single lytic lesion of bone with out marrow
plasmacytosis.
 Single extramedullary plasmacytosis
1. Involves submucosal lymphoid tissues of
nasopharynx or paranasal sinuses without marrow
plasmacytosis.

34. Clinical evaluation : -
 Tender bones : - Initially, the bone pain is intermittent;
in later stages it is continuous. Worse during the day
and aggravated by exercise and weight bearing. The
pain is better at night.
 A rapid onset of severe pain after slight strain =
indicates a pathologic fracture.

35.  Paraplegia may occur with vertebral collapse and is
more common with a solitary presentation
(plasmacytoma).
 Bacterial infections .

36.  common tetrad of multiple myeloma is CRAB
 C = Calcium (elevated)
 R = Renal failure
 A = Anemia
 B = Bone lesions

37. Signs and symptoms of light chain
amyloidosis
 CCF
 HEPATOMEGALY
 ENLARGED TONGUE
 SKIN CHANGES
 CARPEL TUNNEL SYNDROME

38.  Lab evaluation –
 Anaemia
 ESR raised
 Plasma cells > 2000 cells/Micro liter
 S.ca2+ , uric acid, BUN – raised
 P.electrophoresis – M spike { immuno-phoresis can
detect small amount of M components also }.
CHURCH SIGN

39.  Serum electrophoresis : at least 0.5g/dl to be present
for detection.

40.  24hr BJP
 S .ALP – Normal
 BJP detection done by heat test – falsely negative in
~50%.
 Pts secreting lambda light chains have shorter survival.
 Reason for shorter survival – a. due to genetic
abnormality in cell proliferation
b. More likely lambda chains causes more damage to
renal cells.
 Reversed albumin globulin ratio.

41.  Globulin may be raised in Hepatocellular , collagen
vascular & malignant diseases.
 Initially the anaemia is normochromic but with
bleeding in mass lesions anaemia becomes
HYPOCHROMIC
 Increased rouleaux formation.

42.  Normal viscosity of blood 1.8
 1 is of water + .8 times of blood is more than water.
 Symptoms of hyperviscosity usually appear when it
reaches 4 to 5 cp, corresponding to =
1. (IgM) level of at least 3 g/dL,
2. IgG level of 4 g/dL,
3. IgA level of 6 g/dL

43.  About half of patients with IgM paraprotein develop
hyper viscosity more than IgA or IgG.
 IgG3 subclass of IgG forms = temperature dependent
aggregates leading to hyperviscosity & cold
agglutination.

44. Gross specimen :
 Greyish red or dark red which bleeds freely,
 Lies in medullary portion with cortex eaten away.
 In spine may compress the cord after erosion.

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

46.  DUTCHER BODY RUSSELL BODY
{intra nuclear} {intracytoplasmic}

47.  De-differentiation classified by BARTL GRADE
1. Grade 1 = slow growing disease
2. Grade 3 = plasmablastic + aggressive course + reducd
survival.

48. Locations -

49. Classification =

50.  Prognosis depending on ß2 microglobulin =
1. ß2 M < 0.0048g/ L survival 43 months
2. ß2 M > 0.0048g/L survival 12 months.
Median survival in monthsstage

51. Radiological features :
RAIN DROP SKULL
PUNCHED OUT LESIONS PROXIMAL FEMUR
LYTIC LESION

58.  Disappearing vertebral disease :
 Lytic defects are rarely seen because collapse occurs
even before the defects are seen.
 With complete extension of rarefaction of vertebra
leading to collapse.

59.  Sclerosing form of MM :
 Round puffs = osteoporosis
 Ring like shells of density
 Due to reactive bone
Formation around the nodule
Of myeloma.

60. SCLEROSING MYELOMA BRODIES ABSCESS
Multiple or generalised Single site
Absence of fibrosis Fibrosis +
Minimal lymphocytes Abundant lymphocytes

61. Role of MRI :
 To see cord compression
 Extent of marrow infiltration
 Root compression
 Carpel tunnel syndrome
 Or To see any compressive neuropathy

62. Treatment :
 Indications of Rx ;
1. Progressive lytic lesion
2. Stage 2 &3
3. Stage 1 + BJP
4. Refractory hyper ca2
5. Compression #
6. Recurrent infections
7. Bone marrow suppression
8. Renal failure.

63. Treatment =
 In MGUS – no active Rx , only follow up once a year
with electrophoresis, CBC, RFT, s.ca2+
 In high risk pts done every 6 months.
 In MGUS + polyneuropathy = plasmapheresis +
rituximab
 Prevention of SMM to active MM – linalidomide +
dexamethasone.

64.  SMM to symptomatic MM [anemia , hyper ca2+, lytic
lesions, renal dysfunction, recurrent infections]
 Give anti tumour Rx.
 Pts with solitary plasmacytosis & extramedullary
plasmacytosis
 Prolonged life survival after 40Gy irradiation.

65.  With symptoms +/- progression =
1. Systemic Rx to control progression
2. Symp supportive care to prevent morbidity.

66. Drugs action & side effects :
 Thalidomide : antiangiogenic effects {- FGF & VEGF}
enhances cytotoxic T cell & NK cell
ADR: demyelination , phocomelia
 Lenalidomide : less toxic than thalidomide
 Melphalan : 1) alkylates DNA gets broken down in an
attempt to correct it.
2) DNA cross linkage
ADR :vomiting, hemorrhage in GIT, ulcers

67.  Bortezomib : 26s ribosome inhibitor = cell cycle arrest
& + apoptosis.
ADR = hypotension , cardiotoxicity
 Carfilzomib : 20s ribosome inhibitor .

68. Initial Rx :
 High dose pulsed glucocorticoid is used alone = dexa
40mg for 4 days every 2 weeks
 Or
 VAD combination =
 Vincristine = .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.

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

70.  Complications & preventions :
For bortezomib – HZ prophylaxis
Neuropathy prevented by giving subcut/ once weekly
administration.
For linalidomide – DVT prophylaxis with aspirin,
LMWH, warfarin

71.  Patients receiving linalidomide stems cells have to be
harvested before starting, because after therapy stem
cells reduces.
 Transplant candidates – to avoid alkylating agents –
melphalan, because they will damage the stem cells.
{mainly for autologous transplant}.

72. 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 survival 40-50%.

73. Conventional allogenic transplant :
 Healthy persons stem cells transplant into affected pt,
has the potential to cure, but available in small %.
 Patients <45-50 yrs with HLA identical donor.
 Rx related mortality 40-50%
 Long term survival 20-30%.

74.  Patients who are not transplant candidates :
1. Melphalan 8mg/m2/day + prednisone 25-
60mg/m2/day for 4 days/ 4-6weeks & L-
phenylalanine mustard.
2. Response – pain , hyerca2, anemia , infections
reduces
3. Light chain excretion reduces

75. Maintenance Rx:
 Interferon alpha – inhibits self renewal capacity of
stem cells
 Glucocorticoids : suppress IL 6 , induces apoptosis
 Thalidomide – neuro toxicity major concern
 Bortezomib

76.  RELAPSED MYELOMA : Rx with linalidomide +/-
borte + dexa.
or
 Borte + liposomal doxorubicin is also used.
 Carfilzomib + pomalidomide shown efficacy in relapse
& refractory cases.

77.  SUPPORTIVE CARE :
1. Hyperca2+ responds to bisphosphonate, gluco-
corticoid, hydration & natriuresis.
2. Bisphosphonate decreases O.clastic resorption.
3. Enhance renal excretion of light chains by fluid
intake & avoid dehydration.

78.  In acute renal failure = plasmapheresis is effective in
clearing light chains.
 PLASMAPHERESIS treatment of choice in hyper viscosity
syndrome.
 Patients developing neuro symp like back ache, bladder &
bowel incontinence needs local radiation therapy &
steroids if compression is present.
 Anemia = erythropoietin + hematinics.

79.  Calcitonin inhibits bone resorption
 Certain bone lesion needs local radiation
 Orthopedic related Rx :
1. Pathological # - spine : risk of cord compression
needs internal stabilization or bracing
2. Unrelieved cord compression needs laminectomy &
decompression
3. Local radiation given 3 wks later after Sx or when
wound is healed

80.  Vertebroplasty : indications : symptomatic vertebral
angioma , painfull vertebral tumor & osteoporosis with
loss of height of vertebra .
 Open & percutaneous method using C arm ,
ultrasound guidance.
 Materials used PMMA.

81. POEMS SYNDROME :
 POLYNEUROPATHY + ORGANOMEGALY +
ENDOCRINOPATHY + MM + SKIN CHANGES
 Pathogenesis - unclear, but high circulating levels of
the proinflammatory cytokines IL-1, IL-6, VEGF,
and TNF have been documented and levels of the
inhibitory cytokine TGF- beta are lower.

83.  Thank u !!!!

85.  In patients who are not fit for transplant :
 >70yrs with co-morbidity
 2/3 drug combinations are used.
 Melphalan(0.25mg/kg/day) +
prednisolone(1mg/kg/day for) 4 days every 4-6 weeks.
 >65yrs = thalido + melphalan gives a higher response
rate. Similarly with MP + borte