3. Definition:
Group of lymphoid neoplasms of terminally
differentiated B - cells that have in common the
expansion of a single clone of immunoglobulin
(Ig) - secreting plasma cells and a resultant
increase in serum levels of a single homogeneous
(monoclonal) Ig or itâs fragments.
Plasma CellDyscrasias
4. PlasmaCellPlasma cells :
â˘Terminally differentiated B-cells
â˘Not normally found in peripheral blood .
â˘Account for less than 3.5% of nucleated cells
in the bone marrow
â˘Oval cells with low N:C ratio. Cytoplasm is
basophilic blue. Nucleus (30-40% of the cell) is
oval or round and typically placed
eccentrically (to one side) of the cell.
â˘A clear, colorless area adjacent to the nucleus
contains Golgi apparatus
â˘Russell bodies : Globules (2-3 Îźm) of
accumulated immunoglobulins in the cytoplasm
of plasma cells. Usually round. Russell bodies
may be found in normal bonemarrow.
5. PlasmaCell
Mott cells
Plasma cells crowded with
Russell bodies.An obstruction
blocks the release of Golgi
secretions. Thesecells can be
found in any caseof chronic
plasmacytosis.
9. Clinical Manifestations
ď BONE PAIN (Pain in the
lower back, long bones
or ribs)
ď Generalized malaise,Weight
loss,
ď Anaemia,Thrombocytopenia
(Bleeding)
ď Renal failure (Light chains
and amyloid depostion)
ď Symptoms of hypercalcemia
â˘Nausea
â˘Fatigue
â˘Thirst
ď Symptoms of hyperviscosity
â˘Headaches
â˘Bruising
â˘Ischemic neurologic
symptoms
ď Hyperuricemia
ď Infections
ď Other neurologic symptoms
Peripheral neuropathy
ď Meningitis
10. ď Investigations in any suspected Monoclonal Gammopathy
should include to accurately classify the disorder:
ď Complete Blood Count ( look for anemia)
ď Comprehensive Metabolic panel
⢠Look for renal insufficiency, hypercalcemia and subtle clues like
decreased anion gap
⢠Total protein and albumin level. Determine Globulin
component. Too low globulin ( < 2gm%) or Elevated
Globulin ( > 3.5gm%) is concerning : Determine if
Polyclonal vs. Monoclonal
Investigations
11. Evaluate further with :
⢠Quantitative Immunoglobulins : Increase in all components usually,
polyclonal. Increase in single component with reciprocal decrease
of uninvolved globulin usually, may suggest monoclonal.
⢠Serum Protein Electrophoresis with immunofixation if monoclonal
gammopathy is suspected.
⢠24HR-Urine protein electrophoresis withurine immunofixation ( Serum
Free Light Chain assay (Îş/Îť ratio) may be used in place of UPEP}
⢠Bone marrow biopsy to evaluate % plasma cells if there is monoclonal
protein or abnormal UPEP or Light chain assay or if strong clinical
picture of myeloma.
⢠Skeletal survey if monoclonal gammopathy has been established
( Bone scans are usually, negative inMM)
⢠Beta-2 microglobulin andAlbumin for staging and prognosis in
MM ( once diagnosis is made).
12. Serum ProteinElectrophoresis
Serum Protein Electrophoresis:
â˘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.
â˘Immunoglobulins ( IgG, IgM, IgA) usually
migrate to gamma region but may sometimes
extend to beta region.
â˘SPEP should always be performed in
combination with serumimmunofixation in
order to determine clonality
15. Immunofixation
⢠More sensitive thanSPEP
⢠Immunofixation is performed when SPEP
shows a sharp âpeakâ 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 orÎť)
⢠Why do both SPEPand IF?Why not just IF in
initial diagnosis?
⢠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.
17. Denotes presence of an M-protein in apatient without aplasma cell or
lymphoproliferative disorder i.e;UndeterminedSignificance
Monoclonal Gammopathy ofUndetermined
Significance (MGUS)
18. ⢠Incidence of MGUSincreases with age :
⢠1%of adults inUS
⢠3%of adults overage 70years
⢠11%of adults over age80 years
⢠14%of adults over age90 years
⢠Significance:Canprogress to monoclonal Disease
IgG or IgAMGUS IgM MGUS
Monoclonal Gammopathy ofUndetermined
Significance (MGUS)
21. ⢠Both criteria should be met :
⢠Serum monoclonal protein âĽ3 g/dL and/or bone marrow plasma
cells âĽ10 percent
⢠No end organ damage related to plasma cell dyscrasia (see
CRAB)
⢠Management :
⢠Does not requireany intervention
⢠Close surveillanace is necessary to ensure stability of the
disease ( SPEP,CBC, Creatinine and calcium every 3to 4 month
and Skeletal Survey annually to pick up asymptomatic bone
lesions)
Smoldering Myeloma
22. ⢠Rarevariant :About 1%of Myelomas
⢠May present with Bone lesions ( most common presenting
symptom bone pain)
⢠No serumor urine monoclonal protein ( diagnosis canbe missed if
one is not aware of this entity, NSMM).
⢠Renalfailure and hypercalcemiaare generally lacking
⢠Anemia may bepresent
⢠Bone marrow biopsy must be performed in suspected cases:
Immunostaining for amonoclonal protein on bone marrow
sections may establish the diagnosis,Clonal plasma cell
population in marrow.
⢠Must rule out IgD and IgEmyeloma
Non-Secretory Myeloma
23. Solitary Plasmacytoma
Localized plasma celltumor
⢠Absenceof aplasma cell infiltrate in random marrow biopsies
⢠No evidenceof other bone lesions by radiographic examination
⢠Absenceof renal failure, hypercalcemia or anemia
24. ⢠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.
⢠LessCommonSites â Lymph nodes (primary),
salivary glands, spleen, liver, etc.
⢠25% have small monoclonalspike
⢠Rare dissemination, rarer evolution tomyeloma
⢠Management :
⢠If completely resected during biopsy, no
further therapy
⢠If incompletely resected, radiation therapy locally
Extramedullary
Plasmacytoma
25. All three criteria mustbe met
â˘Presence of a serum or urinary monoclonal protein
â˘Presence of 10 percent or more clonal plasma cells in
the bone marrow or a plasmacytoma
â˘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
26. Multiple Myeloma
Bone Lesions :
Conventional radiographs (Skeletal Survey)
abnormal in 80% of patients who present with
multiple myeloma
28. Multiple Myeloma
Renal Insufficiency :
Serum creatinine increased in > 50% at diagnosis Creatinine
>2g/dLin 20% of patients
Renal failure may be presenting manifestation
Major Causes:
⢠Myeloma castnephropathy
⢠Hypercalcemia
⢠Amyloidosis
⢠Radiocontrast dyein apatientwithmyeloma
29. Multiple Myeloma
Spinal Cord Compression :An Oncological
Emergency
Spinal cord compression occurs in 5 % of patients
with multiple myeloma ( plasmacytoma or
pathological fracture related)
Managed withurgent:
1.Corticosteroids
2.Neurosurgical intervention (laminectomyor
anterior decompression in pathological #) +
radiation therapy to preserve neurological
function
3.Radiation therapy alone (plasmacytoma)
30. Multiple Myeloma - Cytogenetics
Deletion 17p and Abnormalities associated with chromosome
13 carry a particularly unfavorable prognosis & respond
poorly to therapy
31. Staging
Salmon-Durie staging system for multiple myeloma
Stage I
⢠Hemoglobin level greater than 10g/dL
⢠Calciumlevel lessthan 12 mg/dL
⢠Radiograph showing normal bones or solitary plasmacytoma
⢠Low M protein values (ie, IgG<5g/dL, IgA<3g/dL, urine <4
g/24h)
Stage II
⢠Findings that fit neither stage I nor stage III criteria
Stage III
⢠Hemoglobin level lessthan 8.5 g/dL
⢠Calcium level greater than 12mg/dL
⢠Radiograph showing advanced lytic bone disease
⢠High M protein value (ie, IgG>7g/dL, IgA >5g/dL, urine >12 g/24h)
32. Sub classification Ainvolves acreatinine level lessthan 2 g/dL.
Sub classification B involves acreatinine level greater than 2 g/dL.
Median survival is asfollows:
StageI, >60 months
StageII, 41 months
StageIII, 23 months
33. Multiple Myeloma
Staging :International Staging System :
Stage I âB2M <3.5 mg/L and serum
albumin âĽ3.5 g/dL
Stage II âneither stage I nor stage III
Stage III âB2M âĽ5.5mg/L
Median overall survival for patients with ISS
stages I, II, and III are 62, 44, and 29months
34. Multiple Myeloma
Treatment Decisions:
â˘Indicationsfortreatment:presenceofanyofCRAB (bonelesionscan be
diffuse osteopeniaalone)
â˘Risk Stratification:
⢠FISH fordetection of t(4;14),t(14;16),and del17p13
⢠Conventional cytogenetics (karyotyping)fordetectionofdel13 or
hypodiploidy
⢠Thepresenceof any of the above markers defines high risk
myeloma, which encompasses the 25percent of MM patients
who haveamediansurvivalofapproximatelytwo yearsorless
despitestandardtreatment
35. Current FrontlineOptions
Conventional chemotherapy
⢠Survival ⤠3yrs
Transplantation
⢠Prolongs survival 4-5yrs
Novel agents targeting stromal interactions and associated
signaling pathways have shown promise and improved
survival.
ChngWJ,et al. CancerControl. 2005;12:91-104.
36. MM: INITIALTHERAPY
The initial therapy of patients with symptomatic myeloma
varies depending on whether patients are eligible or not
to pursue autologous hematopoietic cell transplantation
37. *Thal/dex or dex are additional options
especially if immediate responseisneeded.
Clearly non transplantation
candidate basedon age,performance
score, and comorbidity
MPT,MPV,Len/dex
or clinicaltrial*
Potential transplantation
candidate
Nonalkylator-based
induction x 4cycles
Stem cellharvest
InitialApproach toTreatment of MM
38. DETERMINING TRANSPLANT
ELIGIBILITY
Autologous hematopoietic cell transplantation (HCT)
results in superiorevent-free and overall survival rates
when comparedwith combination chemotherapy
All patients should be evaluated atdiagnosis for transplant
eligibility so that the risks and benefits of autologous HCT
canbe reviewed with those eligible
A minority of patients will be eligible for allogeneic HCT,
but the value of allogeneic approaches in myeloma remain
investigational
39. NOTEligible for Autologous HCT
Age >77years
Direct bilirubin>2.0 mg/dL (34.2 Âľmol/liter)
Serum creatinine>2.5 mg/dL (221 Âľmol/liter) unless on
chronic stable dialysis
Eastern Cooperative Oncology Group (ECOG)
performance status 3or 4 unless due to bonepain
NewYork HeartAssociation functional status Class III or
IV
40. 54
42
Attal M, et al. NEnglJMed. 1996;335:91-97. Child JA,et al. NEnglJMed.2003;348:1875-1883.
15 45 60
25
50
75
100
OS(%)
0
0
Highdose
Conventionaldose
30
Mos
20 80
25
50
75
100
Survival(%)
0
0
Intensive therapy
Standardtherapy
40 60
Mos
P =.03 by Wilcoxontest
P =.04 by log-ranktest
Transplantation vsConventional Chemotherapy
41. AutologousStemCellTransplantation
ď§ Mel 200 mg/m2 standard conditioningregimen
ď§ Sufficient performance score,and adequate liver, pulmonary,
cardiac functionneeded
ď§ Higher PRandCRrates than conventional chemotherapy
ď§ HigherOSand EFSthan conventional Rx
ď§ Advanced ageand impaired renal function are, by themselves,
not contraindications
Attal M, et al. NEnglJMed. 1996;335:91-97. NCCNPractice Guidelines. Myeloma.V.3.2010.
49. Peripheral Neuropathy Following
BortezomibTherapy inAdvanced MM
Peripheral neuropathy was reported in 90/256 (35%) patients with
MM treated with bortezomib in phase II trials
80% of patients entered these trials with preexisting
peripheral neuropathy
3%patients without vs 16% with baseline peripheral
neuropathy developed grade 3peripheral neuropathy
Richardson PG, et al. ASH 2003. Abstract 512.
50. Initial Approach to Treatment of MM
Clearly not a
transplantation candidate
MPT,MPV,Len/dex
or clinicaltrial*
Potential transplantation
candidate
Nonalkylator-based
induction
Stem cellharvest
51. FrontlineTherapy in Elderly MM Patients
For elderly patients or those who are not suitable
candidates for transplantation, MPhasbeen astandard
treatment
⢠ORR:60%
⢠Long-term CR:<5%
Trials with MP-basedcombinations reported improved
response rates and time to progression
⢠MPT
⢠VMP
NCCNPractice Guidelines. Myeloma. V.3.2010.
52. Conclusions
In elderly patients, the addition of novel agents to
standard MPhasprovided improved responserates
⢠MPalone (ORR:50%; CR:5%)
⢠MPR(50%to 95%reduction in myeloma protein in 55.6%)
⢠VMP(ORR:86%)
Careshould betaken with IMiD-based therapy to
include aspirin prophylaxisfor DVT/PE
Careshould be taken with bortezomib-based
regimens to include herpeszosterprophylaxis
53. MM & SkeletalComplications
~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.
54. TheCentral Roleof the Osteoclast in
Osteolytic BoneDestruction
Growth
factors
Direct effects on
osteoclast differentiation
Tumor cells
Osteoclast differentiation
Active
osteoclast
Osteolysis
Bone loss
Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664.
55. Mechanism of Bisphosphonate
Inhibition of OsteoclastActivity
Bisphosphonates
inhibit osteoclast
activity, and promote
osteoclast apoptosis[1]
Bisphosphonates
are releasedlocally
during boneresorption[1]
Bisphosphonatesare
concentrated under
osteoclasts[1]
Bisphosphonates maymodulate
signaling from osteoblasts
to osteoclasts
X
Newbone
Bone
ď§
ď§
Increased OPGproduction[2]
DecreasedRANKLexpression[3]
1.ReszkaAA, et al. CurrRheumatol Rep.2003;5:65-74.2. Viereck V, et al. BiochemBiophys ResCommun.
2002;291:680-686.3.PanB,et al. JBoneMiner Res.2004;19:147-154.
56. Recommended DosesandInfusion
Times
Drug Dose/Infusion
Time
Interval
Estimated CrCl > 60 mL/min
Pamidronate
Zoledronic acid
90 mg over 2-3 hrs
4 mg over 15 mins
3-4
3-4
wks
wks
Estimated CrCl 30 to < 60 mL/min
Pamidronate
Zoledronic acid
90 mg over 2-3
hrs*
Reduced dosageâ
3-4
3-4
wks
wks
Estimated CrCl < 30 mL/min
Pamidronate
Zoledronic acid
90 mg over 4-6
hrs*
Not recommended
3-4 wks
*Consider dosereduction.
â 3.5mg(CrCl50-60mL/min); 3.3mg (CrCl 40-49mL/min); 3.0mg (CrCl 30-39mL/min).
Kyle R,et al. JClinOncol.2007;25:2464-2472.
57. Bisphosphonates andOsteonecrosis
Uncommon complicationcausing
avascular necrosis of maxilla or
mandible
Suspectwith tooth or jaw pain or
exposedbone
Mayberelated to duration of
therapy
True incidence unknown
Always enquire recentdental
therapy or tooth related problems
before startingbisphosphonates
Papapetrou PD. Hormones (Athens).2009;8:96-110.