MULTIPLE MYELOMA AND ALL PLASMA CELL DISORDERS HARRISON BASED

1. PLASMA CELL DISORDERS
PRESENTER: DR. JITHIN GEORGE

4. • Electrophoretic analysis permits separation of
components of the serum proteins.
• The immunoglobulins move heterogeneously
in an electric field and form a broad peak in
the gamma region, which is usually increased
in the sera of patients with plasma cell
tumors.
• There is a sharp spike in this region called an
M component (M for monoclonal).

6. • The monoclonal antibody must be at least 5
g/L (0.5 g/dL) to be accurately quantitated by
this method. This corresponds to ~109 cells
producing the antibody.
• M component an excellent tumor marker to
manage therapy, yet it is not specific enough
to be used to screen asymptomatic

8. M PROTEINS

9. • In ~20% of myelomas, only light chains are
produced and, in most cases, are secreted in
the urine as Bence Jones proteins.
• IgG myelomas are more common than IgA and
IgD myelomas.

10. MULTIPLE MYELOMA

11. • a malignant proliferation of plasma cells
derived from a single clone.
• cause of myeloma is not known
• More in nuclear radiation exposure
• More in farmers, wood workers, leather
workers, and those exposed to petroleum
products.
• N-ras, K-ras, and B-raf mutations are most
common and combined occur in over 40% pts

12. • The neoplastic event in myeloma may involve
cells earlier in B-cell differentiation than the
plasma cell. Interleukin (IL) 6 may play a role
in driving myeloma cell proliferation.

13. INCIDENCE & PREVALENCE
• The median age at diagnosis is 70 years; it is
uncommon under age 40.
• Males are more commonly affected than
females, and blacks have nearly twice the
incidence of whites.

14. PATHOGENESIS
• Multiple myeloma (MM) cells bind via cell-
surface adhesion molecules to bone marrow
stromal cells (BMSCs) and extracellular matrix
(ECM), which triggers MM cell growth,
survival

15. • induction of various cytokines, including IL-6,
insulin-like growth factor type I (IGF-I),
vascular endothelial growth factor (VEGF), and
stromal cell–derived growth factor (SDF)-1α.
• Growth, drug resistance, and migration are
mediated via Ras/Raf/mitogen-activated
protein kinase, PI3K/Akt, and protein kinase C
signaling cascades, respectively

17. CLINICAL MANIFESTATIONS

19. • SUSCEPTIBILITY TO BACTERIAL INFECTIONS
• most common infections: pneumonias and
pyelonephritis.
• Streptococcus pneumoniae, Staphylococcus
aureus, and Klebsiella pneumoniae in the
lungs
• Escherichia coli and other gram-negative
organisms in the urinary tract

20. Causes for increased susceptibity for
infections

21. • Renal failure: Hypercalcemia is the most
common cause
• Glomerular deposits of amyloid,
hyperuricemia, recurrent infections, frequent
use of nonsteroidal anti-inflammatory agents,
iodinated contrast dye for imaging,
bisphosphonate use, and occasional
infiltration of the kidney by myeloma cells all
may contribute to renal dysfunction.

27. NEUROLOGICAL SYMPTOMS

29. Myeloma-related organ or tissue
impairment (end organ damage):

31. • Non-IgG subtype, abnormal kappa/ lambda
free light chain ratio, and serum M protein
>15 g/L (1.5 g/ dL) are associated with higher
incidence of progression of MGUS to
myeloma.

32. higher risk of progression from SMM
to MM
• bone marrow plasmacytosis >10%,
• abnormal kappa/lambda free light chain ratio,
• serum M protein >30 g/L (3 g/dL).

35. • Serum calcium, urea nitrogen, creatinine, and
uric acid levels may be elevated.
• Protein electrophoresis and measurement of
serum immunoglobulins and free light chains are
useful for detecting and characterizing M spikes,
supplemented by immunoelectrophoresis.
• A 24-h urine : quantitate Bence Jones protein
excretion.
• Serum alkaline phosphatase is usually normal

36. PROGNOSIS

38. TREATMENT

40. Patients with symptomatic and/or
progressive myeloma

41. • Thalidomide (200 mg daily) with
dexamethasone
• lenalidomide (25 mg/d on days 1–21 every 4
weeks), and bortezomib (1.3 mg/m2 on days
1, 4, 8, and 11 every 3 weeks),combined with
dexamethasone (40 mg once every week) :

43. • In patients who are transplant candidates,
alkylating agents such as melphalan should be
avoided because they damage stem cells.

44. • Improvement in the serum M component may
lag behind the symptomatic improvement
• Light chain excretion, with a functional half-
life of ~6 h, may fall within the first week of
treatment.
• Allogenic transplantation
• Maintenance therapy prolongs remissions
following standard dose regimens as well as
HDT

45. • Relapsed myeloma : lenalidomide and/or
bortezomib. These combination with
dexamethasone : response rate of up to 60% and
a 10–15% complete response rate in patients
with relapsed disease.
• The combination of bortezomib and liposomal
doxorubicin is active in relapsed myeloma.
• Thalidomide, if not used as initial therapy, can
achieve responses in refractory cases.
• The second-generation proteasome inhibitor
carfilzomib and immunomodulatory agent
pomalidomide
• High-dose melphalan and stem cell
transplantation

47. • Prophylactic administration of intravenous γ
globulin preparations is used in the setting of
recurrent serious infections.
• The anemia associated with myeloma may
respond to erythropoietin along with
hematinics

48. WALDENSTROMS
MACROGLOBULINEMIA
• associated with lymphadenopathy and
hepatosplenomegaly, but the major clinical
manifestation was hyperviscosity syndrome.
• originates from a post– germinal center B cell
that has undergone somatic mutations and
antigenic selection in the lymphoid follicle and
has the characteristics of an IgM-bearing
memory B cell.

49. • Familial occurance common
• MYD88 L265P somatic mutation
• molecular pathogenesis of the disease, with
involvement of Toll-like receptor (TLR) and
interleukin 1 receptor (IL-1R) signaling.
• activation of IL-1R–associated kinase (IRAK) 4
and IRAK1 followed by nuclear factor-κB (NF-
κB) activation.

50. • develop a peripheral neuropathy
• half of these patients are positive for anti-
MAG antibody. The neuropathy may precede
the appearance of the neoplasm.
• IgM in some patients with macroglobulinemia
may have specificity for myelin-associated
glycoprotein (MAG),

53. TREATMENT
• Plasmapheresis For hyperviscosity symptoms
• Median survival of affected individuals is ~50
months.
• Bortezomib and bendamustine are two agents
with significant efficacy in WM.
• Rituximab (anti-CD20) can produce responses,
alone or combined with either of these two
agents

54. • Fludarabine (25 mg/m2 per day for 5 days
every 4 weeks) and cladribine (0.1 mg/kg per
day for 7 days every 4 weeks) are also highly
effective single agents.
• With identification of the MYD88 mutation,
BTK and IRAK1/4 inhibitors are being
evaluated and show significant responses.

55. POEMS SYNDROME

58. HEAVY CHAIN DISEASE

59. • diagnosis depends on the demonstration of an
anomalous serum M component (often <20
g/L [<2 g/dL]) that reacts with anti-IgG but not
anti–light chain reagents.
• The M component is typically present in both
serum and urine. Most of the paraproteins
have been of the γ1 subclass
• Therapy is indicated when symptomatic and
involves chemotherapeutic combinations used
in lowgrade lymphoma. Rituximab has also
been reported to show efficacy.

60. ALPHA HEAVY CHAIN DISEASE
(SELIGMANN’S DISEASE)
• Mc heavy chain disease
• Closely related to meditteranean lymphoma
• infiltration of the lamina propria of the small
intestine with lymphoplasmacytoid cells that
secrete truncated alpha chains.
• Demonstrating alpha heavy chains is difficult
because the alpha chains tend to polymerize
and appear as a smear instead of a sharp peak
on electrophoretic profiles

61. • Light chains are absent from serum and urine.
• patients present with chronic diarrhea, weight
loss, and malabsorption and have extensive
mesenteric and paraaortic adenopathy.
Respiratory tract involvement occurs rarely
• Chemotherapy plus antibiotics may be more
effective than chemotherapy alone.

62. • Immunoproliferative small-intestinal disease
(IPSID) is recognized as an infectious
pathogen–associated human lymphoma that
has association with Campylobacter jejuni.
• It involves mainly the proximal small intestine
resulting in malabsorption, diarrhea, and
abdominal pain.

63. MU HEAVY CHAIN DISEASE

64. AMYLOIDOSIS

66. THANK YOU