Multiple myeloma - Etiopathogenesis, Clinical features, Advances in Management

1. MULTIPLE MYELOMA
Chairperson- Dr Chandrashekhar
Student-Dr Gurusangappa

2. MYELOMA
• Myeloma is a disease characterized by clonal
expansion of malignant plasma cells that
accumulate in the marrow, leading to anemia
and associated cytopenias,
hypogammaglobulinemia, osteolytic bone
disease, hypercalcemia, and renal dysfunction.

5. MYELOMA
• Myeloma is part of a spectrum of diseases called
plasma cell dyscrasias.(15%)
1. essential monoclonalgammopathy.(66%)
2. smoldering myeloma.(3%)
3. solitary plasmacytoma.(2%)
4. extramedullary plasmacytomas .
5. macroglobulinemia .(3%)
6. AL amyeloidosis & LCDD(10%)
7. Other rare diseases(2%)

7. NORMAL B-CELL DEVELOPMENT

9. EPIDEMIOLOGY
• second most common hematologic cancer.
• 1.4 percent of all cancers.
• 10 percent of hematologic malignancies, with
a prevalence of 83,367 people in 2011.
• median age at onset of 69 years.
• Men are affected more frequently than
women (1.6:1 ratio)

10. EPIDEMIOLOGY
• MGUS is present in 3.2 to 4.0 percent of the
general population.
• The incidence of myeloma is highest in African
Americans and Pacific Islanders;
• intermediate in Europeans and North
American whites; and
• lowest in people from developing countries
including Asia.

11. GENETIC PREDISPOSITION
• fourfold in first-degree relatives.
• CDKN2A.
• six single nucleotide polymorphisms (SNPs) at
chromosomes 2p23.3, 3p22.1, 3q26.2,
6p21.33, 7p15.3, 17p11.2, and 22q13.1.
• hyperphosphorylated paratarg-7 (pP-7) carrier
status

12. LIFE STYLE AND OCCUPATIONAL
FACTORS
• high body mass index and risk of myeloma.
• Occupational exposure to pesticides, organic
solvents (benzene, petroleum derivatives,
styrene) or chronic radiation.
• Thorotrast.
• Exposure to acute radiation.
• fresh wood, wood dust, or working in saw mill
factories

13. LIFE STYLE AND OCCUPATIONAL
FACTORS
• autoimmune diseases (especially rheumatoid
arthritis or pernicious anemia) or infections
(HIV and hepatitis C).
• Aspirin.

14. ETIOLOGY AND PATHOGENESIS
• CELL OF ORIGIN
• GENOMIC ALTERATION
• ROLE OF MARROW MICROENVIRONMENT IN
MYELOMA
• BONE METABOLISM

15. CELL OF ORIGIN
• postgerminal–center marrow plasmablasts/
plasma cells.
• always preceded by a MG phase.
• MG cells share several similarities with
myeloma, including a similar prevalence of
hyperdiploidy and of the three primary IGH
rearrangements [t(6;14), t(11;14), and
t(14;16)].

16. • chromosome 13 deletions, RAS mutations and
non–immunoglobulin (Ig)-locus associated
MYC translocations are more frequent in
myeloma.
• early stages, myeloma cells are dependent on
the growth support provided by bone marrow
stromal cells (BMSCs).

17. GENOMIC ALTERATIONS
• Abnormal Karyotype
1)hyperdiploid states
2)non hyper diloid states
• Translocations
1) t(11;14), t(4;14),
2) MAF translocations t(14;16), t(14;20)
• Copy Number Alterations

18. • Somatic Mutations and Interclonal Diversity
1) KRAS, NRAS, FAM46C, DIS3, and TP53.
• BRAF (4%), TRAF3, CYLD, RB1, PRDM1, and
ACTG1.

20. ROLE OF MARROW
MICROENVIRONMENT
• The marrow microenvironment is composed
of
1. Extracellular matrix
2. (ECM) proteins, such as fibronectin, collagen,
laminin and osteopontin;
3. cells, including hematopoietic stem cells,
BMSCs, and endothelial cells, as well as
osteoclasts and osteoblasts

22. ROLE OF MARROW
MICROENVIRONMENT
• interact with ECM proteins and accessory cells
to gain growth, survival, and drug resistance
advantages.
• CD44, very-late antigen 4 (VLA4), neuronal
adhesion molecule (NCAM), intercellular
adhesion molecule (ICAM)-1, and syndecan 1
(CD138)

23. • chemokine receptors, such as CXCR3, CCR1,
CCR2, and CCR5.
• Accessory cells (BMSCs, endothelial cells,
osteoclasts, and osteoblasts) secrete factors
including IL-6,143–146 IGF-1,147–149 vascular
endothelial growth factor (VEGF), tumor necrosis
factor-α (TNF-α), fibroblast growth factor (FGF),
stromal cell-derived factor 1α (SDF-1α),141 and
B-cell activating factor (BAFF)

24. • microvessel density (MVD).
• lymphoid and myeloid cells are part of
marrow microenvironment and can modulate
myeloma survival.

25. BONE METABOLISM
• The presence of osteolytic bone lesions, bone
pain, increased risk of pathologic fractures
and generalized bone loss (or osteoporosis) is
a well-defined feature of myeloma.
• RANKL to RANKreceptor.
• Osteoprotegerin (OPG).
• Macrophage inflammatory protein (MIP)-1α

26. BONE METABOLISM
• Osteoblast suppression is another major
player in myeloma bone disease:
• WNT signaling antagonists, including DKK1,
frizzled related protein-2 (FRP-2),and
sclerostin (SOST), interfere with osteoblast
maturation.
• Activin A, IL-3 and IL-7.

27. BONE METABOLISM
• Bisphosphonates.
• pyridinoline (PYD) and deoxypyridinoline
(DPD) crosslinks and serum levels of tartrate-
resistant acid phosphatase isoform 5b (TRACP-
5b, N-terminal crosslinking telopeptide of type
I collagen (NTX).
• bone alkaline phosphatase (bALP) and
osteocalcin (OC),

28. CLINICAL FEATURES

31. • Bone pain is the most common symptom(70)
• Persistent localized pain signifies a pathologic
fracture.
• collapse of vertebrae

32. CLINICAL AND LABORATORY
FEATURES

34. HEMATOLOGIC ABNORMALITIES
• Anaemia (80%)
• Thrombocytopenia.
• Overt bleeding.
• Acquired von Willebrand factor (VWF)
deficiency.
• asymptomatic prolonged thrombin time can
also be present.
• venous thromboembolic events

35. IMMUNOGLOBULIN ABNORMALITIES
• Protein electrophoresis of the serum (SPEP)
and/or of urine (UPEP).
• single narrow peak, migrating in the γ, or
rarely β.
• Immunofixation.
• IgA and especially IgD-unfavorable.
• total hypoglobulinemia and an increased risk
of infection (70 to 90%)

36. IMMUNOGLOBULIN ABNORMALITIES
• κ light-chain isotype is twice as common as
the λ isotype.
• free light chain (FLC) assay.

37. MARROW FINDINGS
• Plasmacytosis.
• diffuse involvement/focal involvement.
• morphologic appearance of myeloma plasma
cells
• Either kappa or lambda.
• CD138+, CD45–, CD38+, and CD19–
• CD56+, CD20+or CD117+

38. MARROW FINDINGS
• amyloid deposition.
• Microvessel density.(CD131 and CD34).
• myelodysplastic changes.
• cytogenetic studies.
• plasma cell labeling index.

40. RENAL DISEASE
• creatinine levels (>1.5 to 2.0 mg/dL) occur in
30 to 50 percent of myeloma patients at
diagnosis.
• two major causes:
1. myeloma cast nephropathy (also called light-
chain cast nephropathy or myeloma kidney) .
2. hypercalcemia

41. RENAL DISEASE
• Lambda light chains tend to be more
nephrotoxic than the κ type.
• Light chainglomerulopathy.
• type 1 (distal) renal tubular acidosis.
• nephrogenic diabetes insipidus.
• LCDD
• Renal vein thrombosis
• hyperuricemia, or type I cryoglobulinemia

42. RENAL DISEASE
• myeloma renal impairment is reversible in
approximately 50 percent of patients.
• Conversely, amyloid- and LCDD-related renal
impairment tends to be stable or progressive

43. PAIN
• Back or chest bone pain in approximately 60
percent of patients at diagnosis.
• worse with movement and at night.
• Pathologic fractures.
• Kyphosis or reduction of patient’s height.
• Localized pain.
• Radiculopthy.

48. INFECTIONS
• bacterial infections(pneumonias and
pyelonephritis)-25%
• Streptococcus pneumoniae, Staphylococcus
aureus, and Klebsiella pneumoniae, Escherichia
coli
• immune dysfunction.
• extrinsic factors
1. therapy related.
2. physical factors like comorbidities.

49. NEUROPATHY
• polyneuropathy by spinal cord or peripheral
nerve compression.
• POEMS syndrome

50. HYPERVISCOSITY
• Less than 10%.
• Hyperviscosity Syndrome
• IgM>IgA>IgG3

51. SPINAL CORD COMPRESSION

52. INITIAL EVALUATION OF THE PATIENT
WITH MYELOMA

53. INITIAL EVALUATION OF THE PATIENT
WITH MYELOMA
• complete blood count with differential white
cell count.
• Comprehensive serum metabolic panel for the
detection of hypercalcemia, renal
failure,zserum β2M, C-reactive protein, and
elevation of LDH

54. INITIAL EVALUATION OF THE PATIENT
WITH MYELOMA
• Myeloma protein studies
1. serum protein electrophoresis
2. nephelometric quantitation of
immunoglobulin levels.
3. serum-free light-chain assay.
4. 24-hour total urinary protein & urine
electrophoresis
5. Immunofixation of serum and urine

55. • Marrow aspiration and biopsy should include
genetic studies (FISH and cytogenetics) and
flow cytometry
• Bone survey and MRI; PET-CT (if available)
• Echocardiogram & EKG (if amyloidosis
suspected)

60. MGUS
• Non-IgG subtype.
• abnormal kappa/ lambda free light chain ratio
• serum M protein >15 g/L (1.5 g/dL)

61. SMOLDERING MYELOMA
• bone marrow plasmacytosis >10%.
• abnormal kappa/lambda free light chain ratio.
• serum M protein >30 g/L (3 g/dL).

62. Assessment of Myeloma Tumor Mass
(Salmon-Durie)
I. High tumor mass (stage III) (>1.2 × 1012 myeloma cells/m2)*
• One of the following abnormalities must be present:
A. Hemoglobin <8.5 g/dL, hematocrit <25%
B. Serum calcium >12 mg/dL
C. Very high serum or urine myeloma protein
production rates:
1. IgG peak >7 g/dL
2. IgA peak >5 g/dL
3. Urine light chains >12 g/24 h
D. >3 lytic bone lesions on bone survey (bone scan not
acceptable)

63. Assessment of Myeloma Tumor Mass
(Salmon-Durie
II. Low tumor mass (stage I) (<0.6 × 1012 myeloma
cells/m2)*
• All of the following must be present:
A. Hemoglobin >10.5 g/dL or hematocrit >32%
B. Serum calcium normal
C. Low serum myeloma protein production rates:
1. IgG peak <5 g/dL
2. IgA peak <3 g/dL
3. Urine light chains <4 g/24 h
D. No bone lesions or osteoporosis

64. Assessment of Myeloma Tumor Mass
(Salmon-Durie
III. Intermediate tumor mass (stage II) (0.6 to 1.2
× 1012 myeloma cells/m2)*
• All patients who do not qualify for high or low
tumor mass categories are considered to have
intermediate tumor mass
A. No renal failure (creatinine ≤2 mg/dL)
B. Renal failure (creatinine >2 mg/dL)

66. THERAPY

67. (1) systemic therapy to control the progression
of myeloma.
(2)symptomatic supportive care to prevent
serious morbidity from the complications of
the disease.

68. MANAGEMENT OF NEWLY
DIAGNOSED
MYELOMA
• Every newly diagnosed myeloma patient
should be assessed for fitness to undergo
auto-HSCT.
• High-dose chemoradiotherapy followed by
transplantation of either autologous marrow
or PBPCs
• two sequential transplants.

70. • The number of cycles of treatment, especially
with lenalidomide-containing regimens is
limited to roughly four cycles before stem cell
collection, as additional cycles may
compromise stem cell harvesting.

71. INDUCTION
• vincristine, doxorubicin (Adriamycin), and
dexamethasone (VAD).
• lenalidomide and dexamethasone.
• lenalidomide, bortezomib, and
dexamethasone (RVD).
• carfilzomib, lenalidomide, and
dexamethasone (CRD)

72. THERAPY FOR THE
TRANSPLANTATION-INELIGIBLE
PATIENT
• Oral administration of melphalan and
prednisone.
• thalidomide in combination with MP.
• Melphalan, prednisone, and lenalidomide
(MPR).
• bortezomib, melphalan, and prednisone
(VMP)
• continuous Rd as the new standard of care.

73. MAINTENANCE THERAPY
• Maintenance regimens have been proposed to
extend the duration of complete remission
following autologous SCT
• thalidomide maintenance.
• thalidomide and glucocorticoids.
• Lenalidomide.
• Bortezomib.

74. CONSOLIDATION THERAPY
• The use of a short course of consolidation
therapy after autologous SCT increases the CR
rate and relapse-free survival.
• bortezomib, thalidomide, and
dexamethasone.
• two cycles of the RVD regimen

75. CONTINUOUS THERAPY
• continuous therapy may result in improved
disease control.
• maintenance strategies using thalidomide,
lenalidomide, and bortezomib In
transplantation-eligible patients.
• continuous treatment with lenalidomide.
• development of toxicities is the biggest
challenge

76. APPROACH TO RELAPSED OR
REFRACTORY
PATIENTS

78. • Proteasome Inhibitors
bortezomib, carfilzomib, ixazomib and
oprozomib
• Immunomodulatory Drugs
thalidomide, lenalidomide, and
pomalidomide

79. • Histone Deacetylase Inhibitors
vorinostat, ACY- 1215,
• Monoclonal Antibodies
Daratumumab, Elotuzumab, Tabalumab,
• Other Treatments
Bendamustine, pegylated doxorubicin

80. ADJUNCTIVE THERAPIES
• Bone Disease.
• Hypercalcemia.
• Plasmapheresis.
• MRI and local radiation therapy and
glucocorticoids if cord compression.
• anemia
• Palliative Radiation Therapy

81. EMERGENT COMPLICATIONS OF NEW
MYELOMA THERAPY
• Venous Thromboembolism.
• Peripheral Neuropathy.
• Osteonecrosis of the Jaw

83. MINIMAL RESIDUAL DISEASE
• Allele-Specific Oligonucleotide Polymerase
Chain Reaction.
• Multiparameter Flow Cytometry.
• Fluorescent Polymerase Chain Reaction.

84. • The major causes of death are
1. progressive myeloma.
2. Renal failure.
3. sepsis
4. therapy-related myelodysplasia.
• myocardial infarction, chronic lung disease,
diabetes, or stroke

85. WALDENSTROM’S
MACROGLOBULINEMIA
• malignancy of lymphoplasmacytoid cells that
secreted IgM.
• origin.
• Waldenstrom’s macroglobulinemi(WM) and
IgM myeloma.
• MYD88 L265P somatic mutation,
• specificity for myelin-associated glycoprotein
(MAG).

86. WALDENSTROM’S
MACROGLOBULINEMIA
• does not cause bone lesions or hypercalcemia.
• Bone marrow
• shows >10%
• IgM+, CD19+, CD20+, and CD22+, rarely CD5+,
but CD10− and CD23−.
• renal disease is not common.
• Symptoms of hyperviscocity.
• adenopathy and hepatosplenomegaly

87. WALDENSTROM’S
MACROGLOBULINEMIA
• normocytic, normochromic anemia, but rouleaux
formation and a positive Coombs’ test.
• Plasmapheresis.
• Bortezomib and bendamustine.
• Rituximab, Fludarabine, cladribine
• highdose
• therapy plus autologous transplantation is an
option

88. POEMS SYNDROME
• progressive sensorimotor
polyneuropathy(~1.4%)
• hepatomegaly and lymphadenopathy(2/3) and
splenomegaly(1/3).
• amenorrhea in women, impotence and
gynecomastia in men. Type 2 diabetes,
Hypothyroidism and adrenal insufficiency.
• hyperpigmentation, hypertrichosis, skin
thickening, and digital clubbing.

89. POEMS SYNDROME
• Pathogenesis-high proinflammatory cytokines
• treated similarly to those with myeloma

90. HEAVY CHAIN DISEASES
• secrete a defective heavy chain that usually
has an intact Fc fragment and a deletion in the
Fd region
1. GAMMA HEAVY CHAIN DISEASE (FRANKLIN’S
DISEASE)
2. ALPHA HEAVY CHAIN DISEASE (SELIGMANN’S
DISEASE)
3. MU HEAVY CHAIN DISEASE

91. REFERENCES
• WINTROBE’S clinical haematology.
• WILLIAM’S haematology.
• HARRISON’S principles of internal medicine.