Multiple myeloma

1. MULTIPLE MYELOMA
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2. INTRODUCTION
• Multiple Myeloma (also k/a Myeloma, Plasma cell
myeloma, plasmocytoma, monoclonal gammopathy
or Kahler disease )
• It is a cancer of the plasma cell characterized by a
malignant proliferation of plasma cells derived from a
single clone
• is a progressive hematologic (blood) disease.
• Plasma cell an important part of the immune system
that produces immunoglobulin (antibodies) to help
fight infection and disease.
• Most common primary malignancy of bone (~40%)
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3. INCIDENCE
• Multiple myeloma is the 2nd most prevalent blood
cancer after non-Hodgkin's lymphoma.
• Most common primary malignancy of bone
• Age group – more common in 4th to 6th decade
• Male : Female 2:1
• More in african-americans than Caucasians
• Risk factors – radiation - exposure to petroleum
products
• Average age at diagnosis is 62 years for men and 61
years for women
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4. RISK FACTORS
• Age >60.
• Exposure to pesticides ( DDT ).
• Radiation
• Wood,leather,sheet metal & nuclear industry worker
• Exposure to ptroleum products (Benzene)
• Kaposi’s sarcoma Herpes Virus(Presence of IL-6 and HHV8 )
•
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5. • Multiple myeloma is characterized by excessive numbers of abnormal
plasma cells in the bone marrow and overproduction of intact
monoclonal immunoglobulin (IgG, IgA, IgD, or IgE) or Bence-Jones
protein (free monoclonal κ and λ light chains). Hypercalcemia,
anemia, renal damage, increased susceptibility to bacterial infection,
and impaired production of normal immunoglobulin are common
clinical manifestations of multiple myeloma. It is often also
characterized by diffuse osteoporosis, usually in the pelvis, spine, ribs,
and skull.
PATHOPHYSIOLOGY

6. • 15% to 20% of patients with myeloma produce incomplete
immunoglobulins, containing only the light chain portion of the
immunoglobulin
• Primarily in the urine, rather than in the blood
(immunoelectrophoresis)
• Different from monoclonal (M) protein or paraprotein
• Absent in nonsecretory myeloma (1%)
Bence Jones proteins
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7. Classification of Myeloma
1. Monoclonal Gammopathy of Undetermined Significance
(MGUS)
2. Asymptomatic Multiple Myeloma
• Smoldering (SMM)
• Indolent (IMM)
3. Symptomatic Multiple Myeloma (MM)
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8. 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
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9. Asymptomatic Multiple Myeloma
Smoldering Multiple Myeloma
(SMM)
• Serum M protein >3 g/dL and/or
bone marrow plasma cells ≥10%
• Absence of anemia, renal failure,
hypercalcemia, lytic bone lesions
Indolent Multiple Myeloma (IMM)
• Stable serum/urine M protein
• Bone marrow plasmacytosis
• Mild anemia or few small lytic bone
lesions
• Absence of symptoms
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10. Symptomatic Multiple Myeloma (MM)
• Presence of serum/urine M protein
• Bone marrow plasmacytosis (>30%)
• Anemia, renal failure, hypercalcemia, or lytic bone lesions
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12. CLINICAL FEATURES
The pathological and clinical features of myeloma are due to:
• 1. Tissue infiltration
• 2. Production of large amount of paraprotein
• 3. Impairment of immunity.
• May be symptomatic or asymptomatic.
• Symptomatic myeloma characterized by presence of ROTI and CRAB.
• Myeloma Related Organ or Tissue Impairment.
• Calcium levels increased
• Renal failure
• Anemia
• Bone lesion
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13. Mechanism of disease
• Plasma cell proliferation - > anemia, bone marrow suppression,
infection risk
• Osteoclasts - > bony lesions, fractures, vertebral collapse, spinal cord
compression
• Paraprotein, hypercalcemia -> renal failure
• Hypercalcemia – polyuria, thirst, drowsiness, coma
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14. Clinical Manifestations of Multiple Myeloma
•BONE PAIN (Pain in the lower
back, long bones or ribs)
•Generalized malaise,Weight loss,
•Anaemia,Thrombocytopenia
(Bleeding)
• Renal failure( Light chains and
amyloid depostion)
•Symptoms of hypercalcemia
•Nausea
•Fatigue
•Thirst
•Symptoms of hyperviscosity
•Headaches
•Bruising
•Ischemic neurologic symptoms
•Hyperuricemia
•Infections
•Other neurologic symptoms
Peripheral neuropathy
•Meningitis
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15. Myeloma bone disease
• Rapid growth of myeloma cells inhibits normal bone-
forming cells osteoblasts
• production of substances that activate the cells that
resorb bone called osteoclasts is increased
Common bones affected:
 Skull
 Spine ( Thoracic ,Lumbar)
 Pelvis
 Long bones
 Spinal cord – compression can occur
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16. Diagnostic features of active or
symptomatic myeloma
Organ damage classified as “CRAB”
• C – calcium elevation (>10 mg/L)
• R – renal dysfunction (creatinine >2 mg/dL)
• A – anemia (hemoglobin <10 g/dL or ≥2 g/dL decrease from
patient’s normal)
• B – bone disease (lytic lesions or osteoporosis)
*ONE OR MORE required for diagnosis of SYMPTOMATIC
MYELOMA.
Other less common features can also be criteria for an
individual patient, including:
• Recurrent severe infections
• Neuropathy linked to myeloma
• Amyloidosis or M-component deposition
• Other unique features
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17. Bone Marrow
Tumor cells adhere to the bone marrow stromal cells (BMSCs),the structural
cells of BM.
Adherence increases the stromal cell production of the growth factor
interleukin 6 (IL-6), >continued growth and survival of the myeloma cells.
Adherence also allows the myeloma tumor cells to produce other osteoclast-
activating factors including interleukin 1-beta (IL-1β) and tumor necrosis
factor-alpha (TNF-α).
Osteoclast-stimulating factors prompt the bone marrow stromal cells and the
osteoblasts to produce growth factor-RANKL.
TNF induces osteoclast cells and increases osteoclast activity that results in the
bone disease of myeloma.
Osteoclastic activity also results in the release of certain cytokines such as IL-6,
which contribute to tumor cell growth and survival. Medrockets.com

18. Staging of Myeloma
Durie-Salmon system
clinical stage of disease (stage I, II, or III) is based on the
• levels of M protein,
• number of lytic bone lesions,
• hemoglobin values and
• serum calcium levels.
Stages are further divided (A/B) according to renal function
International Staging System (ISS)
new, simpler, more cost-effective, is based on:
• beta 2-micro globulin (β2-M) and
• albumin Medrockets.com

19. Salmon-Durie staging system for multiple myeloma
• Stage I
• Hemoglobin level greater than 10 g/dL
• Calcium level less than 12 mg/dL
• Radiograph showing normal bones or solitary plasmacytoma
• Low M protein values (ie, IgG <5 g/dL, IgA <3 g/dL, urine <4 g/24 h)
• Stage II
• Findings that fit neither stage I nor stage III criteria
• Stage III
• Hemoglobin level less than 8.5 g/dL
• Calcium level greater than 12 mg/dL
• Radiograph showing advanced lytic bone disease
• High M protein value (ie, IgG >7 g/dL, IgA >5 g/dL, urine >12 g/24 h)
• Subclassification A involves a creatinine level less than 2 g/dL.
• Subclassification B involves a creatinine level greater than 2 g/dL.
• Median survival is as follows:
• Stage I, >60 months
• Stage II, 41 months
• Stage III, 23 months
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20. Stage International Staging System Criteria
I β2-microglobulin < 3.5; albumin ≥ 3.5
II Neither stage I nor stage III values
III β2-microglobulin > 5.5

21. • The classic triad of myeloma
• Marrow plasmacytosis (>10%)
• Lytic bone lesions
• Serum and/or urine M component
• The diagnosis may be made in the absence of bone
lesions if the plasmacytosis is associated with a
progressive increase in the M component over time
or if extramedullary mass lesions develop
DIAGNOSIS
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22. Major
• І Plasmacytoma on tissue biopsy
• II = Bone marrow with greater than 30% plasma cells
• III = Monoclonal globulin spike on serum protein electrophoresis, with an immunoglobulin
(Ig) G peak of greater than 35 g/L or an IgA peak of greater than 20 g/L, or urine protein
electrophoresis (in the presence of amyloidosis) result of greater than 1 g/24 h
MINOR
• a = Bone marrow with 10-30% plasma cells
• b = Monoclonal globulin spike present but less than category III
• c = Lytic bone lesions
• d =Depressed normal Igs
The diagnosis of MM requires at least 1 major and 1 minor criterion or at least 3 minor
criteria including both a and b
DIAGNOSTIC CRITERIA
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23. • Anemia, leukopenia, thrombocytopenia
• ALb, reversed A:G ratio
• serum creat, uric acid, urea
• Abnormal coagulation
• Serum Ca
• Proteinuria and cast
• ESR
• LOW NORMAL ALKALINE PHOSPHATASE
• Red cells show rouleaux formation
• BENCE-JONES PROTEIN in urine in 30%
LABORATORY FINDINGS
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24. • Serum electrophoresis- screening method for
detection of Plasma cell disorders.
• It reveals monoclonal component (narrow band
peak: “church spike”)
• found in 98% of patients, in serum, urine or both
“M” spike or
church spike on
electrophoresis
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25. -eccentric nucleus with nucleolus
Sparse chromatin in spoke-of-wheel
fashion
Eosinophilic cytoplasm
No perinuclear halo & does not take
PMB stain well
No supporting stroma
Invading vessels seen
Microscopic appearance
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26. Radiology
Multiple, punched-out, sharply
demarceted, purely lytic lesion
without surrounding reactive
sclerosis
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27. Differential diagnosis
• Other Plasma cell disorders- MGUS (monoclonal
gammopathy of uncertain significance),
Waldenstrom`s disease
• Bone metastasis –breast, prostatic Ca
• Hyperparathyroidism
• Other reasons for renal failure-ex. chronic glomerulo-
nephritis
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28. Test Values indicating favorable prognosis
B 2-M <3 μg/mL
Albumin ≥3.5 g/dL
PCLI < 1%
CRP <6 μg/mL
LDH Age ≤60 y: 100-190 U/L
Age >60 y: 110-210 U/L
Plasmablastic
morphology
Absence of plasmablastic morphology
Chromosomal analysis
(FISH)
Normal chromosome 13
GOOD PROGNOSTIC FACTORS
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29. • Raised B2-microglobulin >4.
• Low serum albumin <3g/dl.
• Cytogenetics –ch13 deletion, hypodiploidy, T(4:14)
• Raised LDH, CRP, Cr.
• Low platelet <150 and Hb<100.
• Bone marrow plasma cell percentage ≥ 50%
• Age >70.
BAD PROGNOSTIC FACTORS
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30. Goals of Treatment
Treatment Of Myeloma
• Eradicating all evidence of disease, which may require accepting
higher levels of toxicity
• Controlling disease activity to prevent damage to other organs of
the body, using a regimen with an acceptable toxicity level
• Preserving normal performance and quality of life for as long as
possible with minimal intervention
• Providing lasting relief of pain and other disease symptoms
• When applicable, managing myeloma that is in remission over the
long-term
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31. Treatment Approaches
• Inactive Disease
• Active Disease
> Non-transplant Candidates
> Transplant Candidates
• Relapsed or Refractory Disease
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32. Supportive treatment including
• Erythropoietin
• Pain medication
• Bisphosphonates
• Growth factors
• Antibiotics
• Brace/corset
• Exercise
Asymptomatic myeloma or MGUS
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33. 1. Chemotherapy
2. High-dose chemotherapy with hematopoietic stem
cell transplant
3. Radiation
4. Maintenance therapy
5. Supportive care
6. Management of drug-resistant or refractory disease
7. New and emerging treatments
Treatment Of Myeloma
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34. Current frontline drugs
• Examples of current Novel agent combinations:
• Thalidomide based : TD, CTD, MPT
• Bortezomib (Velcade) based: Vdex, VMP, CVD, PAD, VRD
• Lenalidomide (Revlimid) based: LenDex, Lendex
Systemic anti-myeloma treatment
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35. Systemic anti-myeloma treatment
• Palliative treatment in wide-spread disease with eventual
fatal outcome
• Melphalan – with prednisone
- has stem cell toxicity
If stem cell transplantation is NOT planned
Melphalan/prednisone/thalidomide (MPT)
Bortezomib/melphalan/prednisone (VMP)
Thalidomide/dexamethasone(thaldex)
levalidomide/low dose dexa (Revlodex)
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36. If stem cell harvest is planned
Bortezomib/thalidomide/dexamethasone (VTD)
VCD -VELCADE/Cyclophosphamide/Dexa
VRD - VELCADE/Revlimid/Dexa
Induction Therapy Recommendations for Transplant
Candidates –
• Thal/Dex (TD)
• VELCADE/Dex (VD)
• VELCADE/Thalidomide/Dex (VTD)
• Revlimid/Low-Dose Dex (RevloDex)
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37. . Mayo Clin Proc. 2002;77:814

38. Options for relapsed/refractory disease
• Repeat initial therapy if relapse after 6mths of discontinuing
therapy
• Corticosteroids
• Thalidomide based regimens
• Bortezomib
• Salvage chemotherapy ( eg. VAD, Cyclophosphamide-VAD,
EDAP or oral cyclophosphamide
• Consider second transplant if stem cells available/ harvest
possible
• investigation regimen in clinical trial
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39. Radiation
• Myeloma is radiosensitive
• Eventually looses its susceptibility
• Relieves pain
• Can be used for control of local disease
• Total body irradiation not advised
Surgical options
• Compression of intraspinal nerves – laminectomy,
removal of myelomatous tissue and post-op irradiation
• In cases with instability  spinal fusion
• Intramedullary fixation seldom posible as soft bone
retains metal badly Medrockets.com

40. Maintenance therapy
• Alpha Interferon
• Prednisone
• Melphalan
• Velcade
• Revlimid
• Dexamethasone
Supportive therapy
• Erythropoetin
• Biphosphonates
• Antibiotics and GM-CSF
• Anti-virals esp. herpes
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41. Management of Complications
• UREMIA: rehydratation, diuretics,steroids,antibiotics if renal infection is
suspected, hemodialysis if these measures fail.
• HYPERCALCEMIA: rehydratation, steroids, bisphosphonates, diuretics.
• PARAPLEGIA: decompressive laminectomy, radiotherapy, chemotherapy.
• BONE LESIONS: if painful and localised, chemo or local radio-therapy, analgetics,
biphosphonates.
• SEVERE ANEMIA: transfusions, erytropoetin
• HYPERVISCOSITY SYNDROME: plasmapheresis, correction of hypercalcemia.
• BLEEDING: platelet concentrates, fresh frozen plasma
• INFECTIONS: antibiotic treatment

42. Newer drugs
• Pomalidomide
• Next-generation proteasome inhibitors- carfilzomib,
NPI-0052
• Doxil-pegylated liposomal doxorubicin
• Histone deacetylase (HDAC) inhibitors-vorinostat,
panobinostat
• Monoclonal antibodies-elotuzumab
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