2. Indroduction
• Plasma cell disorders are a diverse group of disorders of
unknown etiology characterized by :
• Disproportionate proliferation of a single clone of B cells
• Presence of a structurally and electrophoretically
homogeneous (monoclonal) immunoglobulin or polypeptide
subunit in serum, urine, or both
3. Incidence
• Data from SEER indicate an incidence in the United States of
7.2 per 100,000 men per year and 4.6 per 100,000 women
during the period 2004 to 2008.
• India incidence is 0.3-1.9/100,000 for males and 0.4-
1.3/100,000 for females.
• Peak incidence in India is at 55 yrs roughly a decade earlier
than the western population.
• M: F is 1.4:1
• Higher incidence for african americans.
• Portion of people surviving after 5 yrs as of 2010 is 45%
• < 2% of population diagnosed at less than 40 yrs.
6. Etiology
• Environment Exposure: ionizing radiation is the strongest
single factor linked to an increased risk of multiple myeloma.
• Chemicals : Exposure to metals, especially nickel; agricultural
chemicals; benzene and petroleum products; other aromatic
hydrocarbons; agent orange; and silicon have been
considered as potential risk factors.
• Hereditary and genetic factors may predispose patients to
myeloma development.
7. Pathophysiology
• After developing in the bone
marrow, undifferentiated B cells
enter peripheral lymphoid tissues,
such as lymph nodes, spleen, and
gut (eg, Peyer patches).
• Here, they begin to differentiate
into cells, each of which can
respond to a limited number of
antigens. After encountering the
appropriate antigen, some B cells
undergo clonal proliferation into
plasma cells.
• Each clonal plasma cell line is
committed to synthesizing one
specific immunoglobulin antibody
that consists of 2 identical heavy
chains and 2 identical light chains .
8.
9. Basic Defect…
• “Plasma cell disorders are of unknown
etiology and are characterized by the
disproportionate proliferation of one clone.
The result is a corresponding increase in the
serum level of its product, the monoclonal
immunoglobulin protein (M-protein). M-
proteins may consist of both heavy and light
chains or of only one type of chain.”
11. Clinical features
• Anaemia: normocytic normochromic anaemia, due to tumor
cell involvement of the marrow as well as inadequate
erythropoietin responsiveness.
• The suppressive effects of various cytokines on erythropoiesis
and the effect of renal dysfunction on erythropoietin
production are also contributing factors.
• Renal Failure: Multifactorial
• Light chains casts causing interstial nephritis, hypercalcemia
leading to osmotic diuresis, volume depletion, and prerenal
azotemia
• light chain deposition disease : AL Amylodosis , Nsaids,
bisphosphonates and chemotherapy adds to furthur insults
12. Clinical features
• Hyper Calcemia and Bone Disease: is an unbalanced process
of increased osteoclast activity and suppressed osteoblast
activity.
• These factors include IL-1β, TNF-β (lymphotoxin), IL-6, and
macrophage inflammatory proteins-1 (MIP-1) alpha.
• The receptor activator of nuclear factor kappa B ligand
(RANKL) plays an important role in osteoclast differentiation
via its receptor located on the osteoclast membrane.
• Osteoprotegerin (OPG) , DKK-1 , activin A. is known to inhibit
osteo blastic activity .
13.
14. Clinical Features
• Recurrent Infections: Myeloma patients are at risk for
developing recurrent bacterial infections due to deficiencies
in both humoral and cellular immunity.
• Neurological Symptoms: The most common cause of
neurologic abnormalities is related to a tumor mass effect,
especially compression of the spinal cord or cranial or spinal
nerves.
• POEMS (Poly neuropathy,organomegaly,
endocrinopathy,monoclonal gammapathy,skin changes)
• Hyperviscocity :The M components in myeloma can cause
hyperviscosity and compromise circulation when the serum
immunoglobulin levels exceed certain levels.
16. DIAGNOSIS
• The first step in the evaluation includes tests to confirm the
presence, type, and quantity of monoclonal protein, as well as
the detection and quantification of clonal plasma cells.
• The second component to differentiate MGUS, SMM versus
symptomatic myeloma, is to identify end organ damage by
performing a hemogram to detect anemia, a complete
skeletal radiographic survey to detect bone lesions, and a
chemistry profile to detect renal dysfunction and
hypercalcemia.
• A third component in the investigative workup involves an
evaluation of prognostic variables including markers of tumor
burden, genomic profiles, and therapy-related changes
17. Diagnosis
• Lab investigations
CBC, RFT, S.Ca , S.Alb , Uric
acid, Beta2 microglobulin, LDH
• Presence & Characterization
of Monoclonal Proteins
Serum Protein electrophorosis,
24 hr urine protein – urine
electrophorosis, bence john
protein,
immunofixation of urine and
protein,
serum free light chain assay and
ratio
• Detect Clonal Plasma Cells
Bone Marrow biopsy,
Clonality by immunostagging
Flow cytometry
Cytogenetics
FISH ( del 13, del 17p13,
t(4.14) , t(11,14), t(14.16)
• Radiological Evaluvation
Skeletal surveys,
bone densimetry DEXA
low dose CT, whole body MRI
(STIR ,tumour burden) and PET
CT(extra osseous, solitary plama
cytoma)
18. Special scenarios
• Abd fat or rectal biopsy for amyloid
• Solitary lytic lesion biopsy
• Serum vicoscity
20. Focal multiple myeloma. (A and B) Sagittal T1 and STIR, respectively, show multiple
foci of myeloma in the thoracic spine (arrowheads) and in the manubrium (arrow).
Low T1 is indicative of plasma cells replacing the normal marrow fat, and increased
STIR corresponds to the increased cellularity of the lesions.
21. Electrophoresis (EP) /
Immunoelectrophoresis ( IEP )
• a serum or urine
sample
• gel is stained and read
• tall spike
• M proteins of identical
molecular size
• urine - B.J.Protein
30. MANAGEMENT OF SOLITARY
PLASMACYTOMA
• Solitary Plasmacytoma can be osseous or extra osseous.
• RT dose of 40-50 Gy to involved field +/- surgical stabilization.
• Follow up interval with 3-6 months .
• High local control rate with RT (79% to 95%), yet a modest
overall survival of approximately 50% at 10 years.
• Due to progression of disease to MM after 2-3 yrs, 60% of
patients. Lesser in case of EMP.
• Bulk, age and bony presentations tend towards progression to
MM.
31. RT in Solitary Plasmacytoma
• Accurate evaluation of tumor extent is an important feature of
radical RT for solitary plasmacytoma. MRI is useful to evaluate the
extent of disease both within and beyond bone.
• CT and MRI imaging should be used to determine gross tumor
volumes. Clinical target volumes (CTV) should encompass probable
routes of microscopic spread, recognizing that barriers to the
extension of local disease will vary according to anatomic location,
as will the morbidity of treating adjacent normal tissues.
• For RT of long bone lesions, while coverage of the entire involved
bone has been recommended by some authors, a study of palliative
RT to only the symptomatic area for multiple myeloma found that
recurrence in the untreated portion of the involved bone was rare,
and similarly, no marginal recurrences were seen among 30
patients with solitary plasmacytoma treated with RT that
encompassed only the tumor with a margin.
32. • Nodal failure (<4%) in SPB , EMP 10-20% nodal involvmemt.
• Nodal irradiation only if regional nodes involved (TMH)
• Planning target volumes (PTV) should account for day-to-day
setup variation and will typically add 5 to 10 mm around CTV
volumes.
• CT-based planning and the use of conformal techniques,
including intensity-modulated radiation therapy, should be
employed when needed to treat the PTV adjacent to critical
structures
33. Monoclonal Gammopathy of Undetermined
Significance (MGUS)
• Serum M protein <3
g/dL
• Bone marrow plasma
cells <10%
• Absence of anemia,
renal failure,
hypercalcemia, lytic
bone lesions
• 1% of the general
population and in about
3% of normal
individuals over 70
years of age
• 16% -malignant plasma
cell disorder
• Disease Management -
observation
34. MGUS and Smouldering MM
• have a low tumor mass and indolent disease course
presenting without specific symptoms.
• Non-IgG subtype, abnormal kappa/lambda free light chain
ratio, and serum M protein more than 1.5 g per deciliter are
associated with higher incidences of progression from MGUS
to myeloma.
• 60% chance of progression to myeloma in 20 years.
• High risk of progression from smoldering myeloma to active
MM are bone marrow plasmacytosis >30%, abnormal
kappa/lambda free light chain ratio, and serum M protein >30
g per liter (3.0 g per deciliter).
• Patients with all three adverse features have a nearly 50%
chance of progression in 2 years
35. Treatment MGUS & Smouldering
Myeloma
• Typically, patients with MGUS require no therapy. Similarly,
patients with smoldering myeloma are also not treated routinely
until disease progression or the appearance of end organ damage.
• Smouldering Myeloma trial with 119, randomised to receive
linalidomise 25mg/day (D1-21) with dexamethosone 20mg/day
(D1-4 & D12-15) 28 day cycle with 4 week interval * 9cycles VS
Observation.
• Patients in the treatment group received a maintenance regimen
(lenalidomide at a dose of 10 mg per day on days 1 to 21 of each
28-day cycle for 2 years) after completing induction treatment.
• 3-year overall survival rate (94%vs 80)
36. Multiple Myeloma
• Smouldering
Serum Monoclonal protein
IgG/A >3g/dl.
OR
Bence Jones protein
>500mg/24hrs
AND/OR
Clonal Bone marrow
plasma cells 10-60%.
AND
Absence of Myeloma
defining events. Skeletal
survey negetve
• Active
Clonal bone marrow cells
>10% or biopsy proven bony
or EMP
AND : Myeloma defining
events
o Ca++ > 11mg/dl
o Creat> 2mg/dl, Creat
cLearence <40ml/mim
o Anaemia <10g/dl
o One or more osteolytic lesion
on CT, PETCT
o Clonal bone marrow>60%
o >1focal lesion on MRI >5mm
37. Evaluation of Active MM
• CBC with diff counts
• Chemistry with BUN, creatinine
• SPEP with IFE
• Quantitative immunglobulins
• Serum B2 microglobulin
• Serum free light chains
• Skeletal survey
• MRI/PET
38. Over View of Active MM Management
Patient with myeloma
Transplant eligible
Induction therapy
2-4 cycles Induction therapy
Transplant ineligible
Induction therapy
Upfront transplant
Delayed
Transplant
maintenance
Maintenance
39. Transplant eligibility
• Age
• Biological age should be taken into account
than chronological age.
• Individualized therapy is needed in such
patients more than 65yrs.
• ECOG , renal co morbidities (not absolute
contraindication).
• Social-Economic reasons.
40. Induction Therapy for Transplant
• Aim is to achieve CR as well as to reduce the tumour burden.
• Three drug regimen is preferred over two drug regimen, two drug
can be advocated in elderly and frail, non compliant.
• Thalidomide, dexamethasone as single agent, doxorubicin,
vincristine, dexamethasone has been removed. (NCCN) .
• Melphalan to be avoided, reduce stem cell reserve.
41. • Aim is to achieve a CR or VGPR. While avoiding excessive
toxicity as well and maintaining a good QOL.
• Prolongation of remission and survival other goals.
• Melphalan can be added in elderly age group or ones where
transplant is ruled out. Relapsed cases advocated. (TMH).
42. Maintainance
• Lenalidomide & Bortezomib
• Rational is to suppress minimal residual
disease in patients with CR and to reduce
tumour burden in patients with PR
• Role is controversial.
43. Stem Cell Harvest
• Patient should be revaluvated for 2 cycles (4 CYCLES IN OUR
INSTITUTE)for assessing the tumour response (skeletal survey,
bone marrow aspirate and biopsy, lab inv)
• Stem cell is harvested from bone marrow or peripheral blood .
• Stem cell should be harvested after 4 cycles and enough has
to be collected for two transplants, (6*10^6 CD34+ cells /kg or
2*10^6 cells/Kg per transplant)
• Optimal duration for achieving maximal response is unknown,
here maintainance therapy comes into play.
44. Stem Cell Transplant Timing
• After 3-4 months of induction therapy and harvesting
adequate stem cells
• Early Transplant or delayed transplant.
• Delayed means continuation of induction therapy till stable
M-protein in serum and urine and no progression of
myeloma) followed by close observation with plans to
transplant at time of relapse.
54. Role of RT in MM
• Total body irradiation : Some high-dose chemotherapy
protocols for multiple myeloma incorporate total body
irradiation (TBI) into the conditioning regimen.
• Because of toxicity concerns (mucosal and hematologic) with
TBI, many programs use chemotherapy alone.
• (IFM [Intergroupe Francophone du Mye’lome] trial 9502)
examined
• melphalan, 200 mg/m2 alone (M200) versus melphalan 140
mg/m2 with TBI, 8 Gy in 4 fractions (M140/TBI).
• It was found that patients in the TBI-containing arm suffered
more grade 3 or 4 mucosal toxicity, heavier transfusion
requirement, and longer hospitalization stay.
55. • Hemi-Body Irradiation: Diffuse bone pain involving wide
areas of the skeleton can be effectively palliated by half-body
radiation with single doses of 5 to 8 Gy,
• The bone marrow in the unirradiated half-body serves as a
stem cell reserve and will slowly repopulate the irradiated
marrow after treatment.
• The dose for upper half-body should not exceed 8 Gy due to
lung tolerance.
• Hemi Body irradiation is rarely used.
56. Indication of RT in MM
• Pain Relief: Majority (>85%) responds to RT, 50% having
complete pain relief and radiological response in form of re-
calcification seen in half of patients (TMH).
• 40% of patients require palliative RT for pain relief.
• Doses of 10 to 20 Gy (in 5 to 10 fractions) are effective,
although the pain relief is often partial.
• There was no dose–response relationship above 10 Gy.
Recurrence of symptoms requiring further treatment was
seen in 6% of sites after a median of 16 months.
57. Adjunctive Therapy
• HyperCalcemia: pamidronate and zoledronate. S/e renal
toxicity, Osteonecrosis of jaw.
• Their mechanism of action includes the downregulation of
osteoclast activity, decreased IL-6 production, the activation
of gamma/delta T cells with antimyeloma activity, and the
induction of apoptosis of osteoclasts.
• Pamidronate 90 mg and zoledronic acid 4 mg are equipotent
in reducing bone-related problems in myeloma
• Denosumab, a RANKL-targeting antibody is efficacious
• An antibody targeting DKK-1 (BHQ-880), which improves
osteoblastic activity, and a chimeric protein targeting -activin
A (ACE-011) is currently under trials (Devita)
58. Spinal Cord Compression
• For spinal cord compression, motor improvement is expected
in approximately 50% of irradiated patients.
• A multicenter study suggested that a longer fractionated
regimen (30 Gy in 10 fractions or higher) was associated with
better neurologic recovery than 20 Gy in 5 fractions or a single
8 Gy.
59. • Hyperviscocity : Plasma Pheresis
• Anaemia : Blood transfusions
consider erythropoetin 150U/Kg or 40000U 3
times per week subcutaneous.
• Renal Dysfunction: maintain hydration, avoid NSAIDS, avoid
IV contrasts , plasma pheresis, caution using bisphosphonates.
• Infection Prophylaxis
• AntiCoagulation Measures : Aspirin 81-325mg/ day or
warfarin INR 2-3
60. Radio Immuno Therapy
• Bone seeking radiopharmaceuticals targeting the bone marrow
have been studied as an alternative to TBI.
• samarium-153-ethylene diamine tetramethylene phosphonate
(153Sm-EDTMP, or QuadrametTM).
• holmium-166-DOTMP (166Ho-1,4,7,10- tetraazacyclododecane-
1,4,7,10-tetramethylene-phosphonic acid), with a higher energy β
emission (maximum energy 1.85 MeV).
• With the ability to deliver much higher doses to the bone marrow
than TBI, in the range of 30 to 60 Gy, yet sparing the dose-limiting
normal tissues such as lung, mucosa, and kidneys.
• Disadvantage is heterogeneity of uptake.
Notes de l'éditeur
Plasma cell disorders encompass all these disorders.
This has been documented in atomic bomb survivors who have a five times greater incidence than a control group with a latent period of approximately 20 years from exposure.
(gamma [γ], mu [μ], alpha [α], delta [δ], or epsilon [ε]) , (kappa [κ] or lambda [λ]).
The dysfunctional plasma cells secrete one of these intact immunoglobulin molecules; however, there may be a discrepancy in the production of the heavy and light chains leading to an imbalance with an excess of κ or λ light chain that is excreted in the urine (Bence Jones proteinuria), or in some instances, a production of only excess κ or λ light chain molecules
Peripheral neuropathy in myeloma may be due to an
infiltrative process associated with the deposition of amyloid protein
in the paraneural or vasa nervorum; due to a metabolic abnormality
such as hypercalcemia, uremia, or hyperviscosity; or mediated by
an autoimmune process or cytokines
70% have IgG, 20% have IgA, and 5% to 10% have production of monoclonal light chains only. IgA has highrer respose rate but inferior outcome.
The measurement of serum free light chain (FLC) concentration has become an important tool to diagnose and follow the disease process, including response to therapy.
This is based on a histologic examination (Bartl grade) in which grade I suggests a slow growing disease, whereas grade III represents plasmablastic disease with
an aggressive course. Nodular or diffuse, nodular has poor prognosis.
β2-microglobulin (β2M) has been identified as one of the most consistent predictors of survival in plasma cell myeloma, defines renal damage. Value >2.5mg/l poor prognosis
SPEP: Serum protein electrophoresis is how we measure M protein> we look for a spike in SPEP in gamma region. If its polyclonal it’s a smooth curve that is increased. If its is sharp increase and look like a church steeple it is monoclonal gammopathy. The are under curve is calculated to give us the size of the M protein.
IFE is identification of type of Plasma M protein.
I fish integrated Fish , Durie Salmon stagging din predict outcomes and hence not used.
Solitary plasmacytomas of the bone involve vertebral bodies in one-third of patients and frequently affect men (70%) at a younger age (median 56 years).
Aim of induction therapy is to achieve, complete response as well to reduce tumour burden
Prophylaxix with full dose anticoagulants sucj as warfarin needed when using immuno modulators, Anti viral prophylaxix for proteosomal inhibitors.
Receptor activator of nuclear factor kappa-B ligand